A EPA
PUBLIC RELEASE DRAFT
December 2024
EPA Document #EPA-740-D-24-019
December 2024
United States Office of Chemical Safety and
Environmental Protection Agency Pollution Prevention
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)
CASRNs: 17-81-7 (DEHP), 84-74-2 (DBP), 85-68-7 (BBP), 84-69-5
(DIBP), 84-61-7 (DCHP), 28553-12-0 (DINP), 68515-48-0 (DINP)
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41 TABLE OF CONTENTS
42 TABLE OF CONTENTS 2
43 LIST OF TABLES 4
44 LIST OF FIGURES 4
45 LIST OF EQUATIONS 5
46 LIST OF APPENDIX TABLES 5
47 KEY ABBREVIATIONS AND ACRONYMS 6
48 ACKNOWLEDGEMENTS 7
49 SUMMARY 8
50 1 INTRODUCTION AND SCOPE 10
51 1.1 Phthalate Syndrome Mode of Action 11
52 1.2 Phthalates Included in the Cumulative Chemical Group Based on Toxicologic Similarity 12
53 1.3 Endpoints and Options Considered for Relative Potency Factor Derivation 13
54 1.4 Relevant Populations 15
55 1.5 Relevant Durations 15
56 1.6 Exposure Evaluations 16
57 1.7 Risk Cup Concept in Cumulative Risk Assessment 17
58 2 RELATIVE POTENCY FACTORS 18
59 2.1 Relative Potency Factor Approach 18
60 2.2 Benchmark Dose Modeling of Fetal Testicular Testosterone to Determine Toxic Potency 19
61 2.2.1 Results: Benchmark Dose Estimation 22
62 2.3 Selection of the Index Chemical and the Index Chemical Point of Departure 22
63 2.4 Relative Potency Factors for the Cumulative Phthalate Assessment Based on Decreased Fetal
64 Testicular Testosterone 24
65 2.5 Uncertainty Factors and the Benchmark Margin of Exposure 25
66 2.6 Applicability of Derived Relative Potency Factors (RPFs) 26
67 2.7 Weight of Scientific Evidence: Relative Potency Factors and Index Chemical Point of
68 Departure 27
69 3 SCENARIO-BASED PHTHALATE EXPOSURE AND RISK 29
70 3.1 Occupational Exposure for Workers 29
71 3.1.1 Industrial and Commercial Products Containing Multiple Phthalates 29
72 3.1.2 Multiple TSCA Phthalates at a Single Facility and/or Single Condition of Use 30
73 3.1.2.1 Parent Companies Reporting Use of Multiple Phthalates 30
74 3.1.2.2 Facilities Reporting Releases of Multiple Phthalates 30
75 3.1.2.3 Overlap in Industrial and Commercial COUs 31
76 3.1.3 Conclusions on Cumulative Occupational Phthalate Exposure 32
77 3.2 Consumer and Indoor Dust Exposure 32
78 3.2.1 Consumer Products Containing Multiple Phthalates 32
79 3.2.2 Consumer Use of Multiple Products and/or Articles in a Relevant Time Frame 33
80 3.2.3 Quantitative Cumulative Risk from Exposure to Indoor Dust 33
81 3.2.4 Conclusions on Cumulative Consumer and Indoor Dust Phthalate Exposure 37
82 3.3 General Population Exposure to Environmental Releases 37
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3.3.1 Comparison of Fate Parameters Across Phthalates 37
3.3.2 Geographic Consideration of Reported Releases of Phthalates 40
3.3.3 Conclusions on Cumulative General Population Exposure to Environmental Releases of
Phthalates 43
3.4 Non-TSCA Exposure to Diet 43
4 PHTHALATE EXPOSURE AND RISK FOR THE U.S. POPULATION USING NHANES
URINARY BIOMONITORING DATA 45
4.1 Temporal Trends in Phthalate Exposure Based on NHANES Urinary Biomonitoring Data 47
4.1.1 Trends in National Aggregate Production Volume Data 49
4.2 Aggregate Phthalate Exposure Based on NHANES Urinary Biomonitoring Data and Reverse
Dosimetry 49
4.3 Cumulative Phthalate Exposure Estimates Based on NHANES Urinary Biomonitoring 51
4.4 Cumulative Phthalate Risk Based on NHANES Urinary Biomonitoring 51
4.5 Conclusions from NHANES Analysis 52
5 CONCLUSION AND NEXT STEPS 62
5.1 Estimation of Cumulative Risk 62
5.2 Anticipated Impact of the Cumulative Analysis on Phthalates being Evaluated Under TSCA.. 65
5.2.1 Dibutyl Phthalate (DBP) 65
5.2.2 Dicyclohexyl Phthalate (DCHP) 66
5.2.3 Diisobutyl Phthalate (DIBP) 66
5.2.4 Butyl Benzyl Phthalate (BBP) 66
5.2.5 Diisononyl Phthalate (DINP) 67
5.2.6 Diethylhexyl Phthalate (DEHP) 67
REFERENCES 70
APPENDICES 80
Appendix A FETAL TESTICULAR TESTOSTERONE DATA FOR DEHP AND DBP 80
Appendix B CONSIDERATIONS FOR BENCHMARK RESPONSE (BMR) SELECTION
FOR REDUCED FETAL TESTICULAR TESTOSTERONE 84
B.l Purpose 84
B.2 Methods 84
B.3 Results 85
B.4 Weight of Scientific Evidence Conclusion 86
Appendix C NHANES URINARY BIOMONITORING 89
C.l Urinary Biomonitoring: Methods and Results 89
C.2 Urinary Biomonitoring: Temporal Trends Analysis 92
C.2.1 DEHP 92
C.2.2 DBP 93
C.2.3 BBP 94
C.2.4 DIBP 94
C.2.5 DINP 95
C.3 Reverse Dosimetry: Methods and Results 96
C.4 Statistical Analysis of Cumulative Phthalate Exposure 98
C.5 Limitations and Uncertainties of Reverse Dosimetry Approach 100
Appendix D Supporting Analyses for Occupational Exposure to Phthalates 101
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D. 1 Trends in National Aggregate Production Volume 101
D.2 Industrial and Commercial Products Containing Multiple Phthalates 103
D.3 Parent Company Overlap in Phthalate Manufacture and Processing 104
D.4 Conditions of Use Listed in Final Scopes for Individual Phthalate Risk Evaluations 109
Appendix E Calculation of Occupational Exposure Values Based on Cumulative Exposures
and Relative Potency Assumptions 112
E. 1 Occupational Exposure Value for the Index Chemical (DBP) 112
E.2 Estimating Inhalation Risk to Air Mixtures using Cumulative and Individual OEVs 113
Appendix F Supporting Analyses for Consumer Exposure to Phthalates 115
LIST OF TABLES
Table 2-1. Summary of Studies Included in EPA's Updated Meta-Analysis and BMD Modeling
Analysis 20
Table 2-2. BMD Modeling Results of Fetal Testicular Testosterone for DEHP, DBP, DIBP, BBP,
DCHP, and DINP 22
Table 2-3. Comparison of the Number of Studies Supporting Key Outcomes Associated with Phthalate
Syndrome11 23
Table 2-4. Comparison of Candidate Relative Potency Factors Based on BMDs, BMDio, and BMD40
Estimates 25
Table 3-1. Confidence in Phthalate Settled Dust Monitoring Studies 35
Table 3-2. Cumulative Phthalate Daily Intake (|ig/kg-day) Estimates from Indoor Dust Monitoring Data
36
Table 3-3. Summary of Physical Chemical Properties and Fate Parameters of DCHP, DBP, DIBP, BBP,
DEHP, and DINP 39
Table 4-1. Urinary Phthalate Metabolites Included in NHANES 46
Table 4-2. Cumulative Phthalate Daily Intake (|ig/kg-day) Estimates for Women of Reproductive Age
and Male Children from the 2017-2018 NHANES Cycle 54
Table 4-3. Cumulative Phthalate Daily Intake (|ig/kg-day) Estimates for Women of Reproductive Age
(16 to 49 years old) by Race and Socioeconomic Status from the 2017-2018 NHANES
Cycle 56
Table 5-1. Summary of Impact of Cumulative Assessment on Phthalates Being Evaluated Under TSCA
68
Table 5-2. Summary of Non-Attributable Cumulative Exposure From NHANES Being Combined for
Each Assessed Population 69
LIST OF FIGURES
Figure 1-1. Phthalate Syndrome Mode of Action Following Gestational Exposure 12
Figure 3-1. Mapping of Facilities with One of Multiple Phthalates 42
Figure 4-1. Median Phthalate Metabolite Concentrations Over Time for All NHANES Participants From
1999 Through 2018 49
Figure 4-2. Percent Contribution to Cumulative Exposure for DEHP, DBP, BBP, DIBP, and DINP for
Women of Reproductive Age (16 to 49 years) in 2017-2018 NHANES, Stratified by Race
59
Figure 4-3. Percent Contribution to Cumulative Exposure for DEHP, DBP, BBP, DIBP, and DINP for
Women of Reproductive Age (16 to 49 years) in 2017-2018 NHANES, Stratified by
Socioeconomic Status 60
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Figure 4-4. Percent Contribution to Cumulative Exposure for DEHP, DBP, BBP, DIBP, and DINP for
Male Children Ages 3 to 5, 6 to 11, and 12 to 15 years in 2017-2018 NHANES 61
LIST OF EQUATIONS
Equation 2-1. Calculating RPFs 18
Equation 2-2. Calculating index chemical equivalents 19
Equation 5-1. Scaling Phthalate Exposures by Relative Potency 63
Equation 5-2. Estimating Non-attributable Cumulative Exposure to DEHP, DBP, BBP, DIBP, and DINP
63
Equation 5-3. Calculating MOEs for Exposures of Interest for use in the RPF and Cumulative
Approaches 64
Equation 5-4. Cumulative Margin of Exposure Calculation 65
LIST OF APPENDIX TABLES
TableApx A-l. Summary of Fetal Testicular Testosterone Data for DEHP11 80
TableApx A-2. Summary of Fetal Testicular Testosterone Data for DBP 82
Table Apx B-l. Comparison of BMD/BMDL Values Across BMRs of 5%, 10%, and 40% with PODs
and LOAELs for Apical Outcomes for DEHP, DBP, DIBP, BBP, DCHP, and DINP .... 88
TableApx C-l. Limit of Detection (ng/mL) of Urinary Phthalate Metabolites by NHANES Survey Year
91
Table Apx C-2. Summary of Phthalate Metabolite Detection Frequencies in NHANES11 91
TableApx C-3. Fue Values Used for the Calculation of Daily Intake Values of DEHP, BBP, DBP,
DIBP, and DINP 97
Table Apx C-4. Statistical Analysis (t-test) of Cumulative Phthalate Exposure for Women of
Reproductive Age by Race11 98
Table Apx C-5. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
Exposure for Women of Reproductive Age by Race11 99
Table Apx C-6. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
Exposure for Women of Reproductive Age by Socioeconomic Status11 99
Table Apx C-l. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
Exposure for Women of Reproductive Age and Male Children by Age11 99
Table Apx D-l. Trends in Nationally Aggregated Production Volume (lbs) Data for DEHP, DBP, BBP,
DIBP, DCHP, and DINP 102
Table Apx D-2. Summary of Industrial and Commercial Products that Contain Multiple Phthalates.. 103
TableApx D-3. Parent Companies Reporting Use of Multiple Phthalates (DEHP, DBP, BBP, DIBP,
DINP, DCHP) to 2016 and 2020 CDR and 2017 through 2022 TRI 105
Table Apx D-4. Categories of Conditions of Use for High-Priority Phthalates and a Manufacturer-
Requested Phthalate 109
Table Apx F-l. Sample of Consumer Products Containing Phthalates^ 115
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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
CDR
Chemical Data Reporting
COU
Condition of use
CPSC
Consumer Product Safety Commission (U.S.)
CRA
Cumulative risk assessment
DBP
Dibutyl phthalate
DCHP
Dicyclohexyl phthalate
DEHP
Di(2-ethylhexyl) phthalate
DIBP
Diisobutyl phthalate
DIDP
Diisodecyl phthalate
DINP
Diisononyl phthalate
DMR
Discharge Monitoring Report
EPA
Environmental Protection Agency (U.S.)
GD
Gestation day
MNG
Multinucleated gonocyte
MOA
Mode of action
MOE
Margin of exposure
NASEM
National Academies of Sciences, Engineering, and Medicine
NEI
National Emissions Inventory
NR
Nipple/areolae retention
OCSPP
Office of Chemical Safety and Pollution Prevention
OES
Occupational exposure scenario
OEV
Occupational exposure value
OPPT
Office of Pollution Prevention and Toxics
POD
Point of departure
PESS
Potentially Exposed or Susceptible Subpopulations(s)
PV
Production volume
RPF
Relative potency factor
SACC
Science Advisory Committee on Chemicals
SD
Sprague-Dawley (rat)
TRI
Toxics Release Inventory
TSCA
Toxic Substances Control Act
UF
Uncertainty factor
U.S.
United States
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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 Research and Development (ORD).
Special acknowledgement is given for the contributions of technical experts from ORD, including Justin
Conley and Earl Gray. The Agency is also grateful for assistance from EPA contractors ERG (Contract
No. 68HERD20A0002 and GS-00F-079CA); ICF (Contract No. 68HERC23D0007); and SRC, Inc.
(Contract No. 68HERH19D0022).
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.
Authors: Anthony Luz, Maiko Arashiro, S. Xiah Kragie, Keith Jacobs, Yousuf Ahmad, Ryan Sullivan,
Aaron Murray, Collin Beachum (Branch Chief)
Contributors: Bryan Groza, Robert Landolfi, Daniel DePasquale , Maggie Clark
Technical Support: Hillary Hollinger and Mark Gibson
This report was reviewed and cleared by OPPT and OCSPP leadership.
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SUMMARY
The U.S. Environmental Protection Agency (EPA) has developed this draft technical support document
(TSD) for the cumulative risk assessment (CRA) of six toxicologically similar phthalates being
evaluated under Section 6 of the Toxic Substances Control Act (TSCA): di(2-ethylhexyl) phthalate
(DEHP), butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP),
diisobutyl phthalate (DIBP), and diisononyl phthalate (DINP). EPA previously issued a 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. 2023b) which was subsequently peer-
reviewed by the Science Advisory Committee on Chemicals (SACC) (U.S. EPA. 2023c). In the 2023
proposed approach, EPA identified a cumulative chemical group and potentially exposed or susceptible
subpopulations (PESS) [15 U.S.C. ง 2605(b)(4)], These conclusions were supported by the SACC in
their final peer-review report to EPA (U.S. EPA. 2023c) and carried forward in this draft cumulative risk
assessment TSD.
As each chemical substance was prioritized or requested individually, EPA is required to evaluate the
health and environmental risks of each individual phthalate and determine for each chemical substance
whether it presents unreasonable risk or injury to health or the environment. Analytical pieces from this
TSD are elaborated to inform EPA's individual phthalate risk determinations, pending completion of the
individual phthalate risk evaluations. Specifically, this TSD provides the following for reference in the
individual chemical substance risk evaluations and for consideration in any subsequent risk
management:
Common Hazard Assessment via RPFs. Section 2 calculates draft relative potency factors
(RPFs) for phthalate syndrome based on the shared endpoint and pooled dataset for assessing
fetal testicular testosterone health endpoint for each of the six chemical substances using DBP as
an index chemical. This provides a more robust basis for assessing the dose-response to the
shared hazard endpoint across all assessed phthalates. For all the assessed phthalates, RPFs have
been applied to convert exposures into equivalent units for summation across phthalates.
Scenario-Based Phthalate Exposure. Section 3 frames the relevant frequency and duration of
exposures and provides qualitative analysis of where co-exposures are expected with exposures
assessed within the individual TSCA risk evaluations under specific conditions of use (COUs)
for workers and consumers. Section 3 also provides a quantitative analysis of cumulative risk
from indoor dust using monitoring data and a general update to the literature regarding non-
TSCA exposures from diet.
National Cumulative Exposure and Risk. Average aggregate exposures to the assessed
phthalates for the U.S. population are presented in Section 4 using reverse dosimetry from
urinary biomonitoring in the National Health and Nutrition Examination Survey (NHANES).
This NHANES reverse dosimetry, combined with the RPFs, provides a common understanding
of non-attributable exposures and risks to the U.S. population, including the susceptible
subpopulations of women of reproductive age or male children, which can augment specific
acute scenarios described further in individual risk evaluations.
Examples for Calculating Cumulative Risk. This TSD also elaborates an example of
cumulative risk calculations for combining exposures from individual chemical substance risk
evaluations, from monitoring data, or in support of decision making using the RPFs. Most
notably, an option is elaborated for considering a cumulative occupational exposure value
(OEV). The calculated draft value is provided for public comment and transparency and may be
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328 considered during risk management efforts for some or all of the six toxicologically similar
329 phthalates under TSCA section 6(a), 15 U.S.C. ง2605.
330 This TSD concludes with an overview of how the RPFs can supplement the hazard values for each
331 individual phthalate and then be used in combination with the NHANES data for risk characterization
332 within the individual risk evaluations.
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1 INTRODUCTION AND SCOPE
The U.S. Environmental Protection Agency (EPA or the Agency) is individually evaluating the health
and environmental risks of several phthalates under section 6 of the Toxic Substances Control Act
(TSCA) as separate chemical substances. Phthalates are a group of chemicals used in many industrial
and consumer products, including building and construction materials, and polyvinyl chloride products,
to make plastics more flexible and durable. Some phthalates are used in cosmetic, as well as food
contact materials and have been measured in food. Studies investigating human exposure to phthalates
have demonstrated widespread exposure to some phthalates and that humans may become co-exposed to
multiple phthalates at the same time. Further, some phthalates have been shown to cause common
adverse effects on the developing male reproductive system, sometimes referred to as "phthalate
syndrome." TSCA requires EPA, in conducting risk evaluations pursuant to section 6 to consider the
reasonably available information, consistent with the best available science, and make decisions based
on the weight of scientific evidence [15 U.S.C. ง 2625(h), (i), (k)]. EPA recognizes that for some
chemical substances undergoing risk evaluation, the best available science may require analysis of
cumulative risk to ensure that any risks to human health are adequately characterized in support of
TSCA risk evaluations.
In 2023, EPA issued a Draft Proposed Approach for Cumulative Risk Assessment of High-Priority
Phthalates and a Manufacturer-Requested Phthalate under the Toxic Substances Control Act (draft
2023 approach) which outlined an approach for cumulative risk assessment (CRA) of six toxicologically
similar phthalates being evaluated under TSCA (U.S. EPA. 2023b). EPA's proposal was subsequently
peer-reviewed by the Science Advisory Committee on Chemicals (SACC) in May 2023 (U.S. EPA.
2023c). In this approach, EPA identified a cumulative chemical group and potentially exposed or
susceptible subpopulations (PESS) [15 U.S.C. ง 2605(b)(4)], Based on toxicological similarity and
induced effects on the developing male reproductive system consistent with a disruption of androgen
action and phthalate syndrome, EPA proposed a cumulative chemical group of di(2-ethylhexyl)
phthalate (DEHP), butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dicyclohexyl phthalate
(DCHP), diisobutyl phthalate (DIBP), and diisononyl phthalate (DINP), but not diisodecyl phthalate
(DIDP). DIDP was not included in the cumulative chemical group because it does not induce effects
consistent with phthalate syndrome. This approach emphasizes a uniform measure of hazard for
sensitive subpopulations, namely women of reproductive age and/or male infants and children; however
additional health endpoints are known for broader populations and described in the individual non-
cancer human health hazard assessments for DEHP (U.S. EPA. 2024h). DBP (U.S. EPA. 2024f). DIBP
(U.S. EPA. 20240. BBP (U.S. EPA. 2024e\ DCHP (U.S. EPA. 2024g). and DINP (U.S. EPA. 2025p\
including hepatic, kidney, and other developmental and reproductive toxicity.
While additional groups and subpopulations may be susceptible to health effects from phthalate
exposure, EPA identified groups with higher susceptibility to phthalate syndrome due to lifestage as (1)
pregnant women/women of reproductive age, and (2) male infants, male toddlers, and male children.
These conclusions were supported by the SACC in their final peer-review report to EPA (U.S. EPA.
2023c) and carried forward in this draft cumulative risk assessment technical support document.
Sections 1.1 through 1.7 further outline the scope of this draft cumulative risk assessment technical
support document.
This draft cumulative risk assessment technical support document is being released for public comment
and peer-review by the SACC during the summer of 2025, when EPA will be soliciting feedback on the
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implementation of its cumulative risk analysis approach. EPA will not solicit specific feedback on
options previously considered by the SACC during its May 2023 peer-review meeting (U.S. EPA.
2023c).
1.1 Phthalate Syndrome Mode of Action
EPA has previously described the mode of action (MOA) for phthalate syndrome in the Draft Proposed
Approach for Cumulative Risk Assessment of High-Priority Phthalates and a Manufacturer-Requested
Phthalate under the Toxic Substances Control Act (draft 2023 approach) (U.S. EPA. 2023b). as well as
in its non-cancer hazard assessments for DEHP (U.S. EPA. 2024h). DBP (U.S. EPA. 2024f). DIBP
(U.S. EPA. 20240. BBP (U.S. EPA. 2024e). DCHP (U.S. EPA. 2024g). and DINP (U.S. EPA. 2025p).
A brief description of the MOA for phthalate syndrome is provided in this section. Readers are directed
to EPA's draft 2023 approach and the non-cancer hazard assessments cited above for more detailed
MOA information.
Although the MOA underlying phthalate syndrome has not been fully established, key cellular-, organ-,
and organism-level effects are generally understood (Figure 1-1). Studies have demonstrated that
gestational exposure to certain phthalate diesters, and their subsequent hydrolysis to monoester
metabolites, which occur during a critical window of development (i.e., the masculinization
programming window) can lead to antiandrogenic effects on the developing male reproductive system
(NRC. 2008). In rats, the masculinization programming window in which androgen action drives
development of the male reproductive system occurs between days 15.5 to 18.5 of gestation, while the
mouse critical window corresponds to gestational days 14 to 16, and the human masculinization
programming window is between gestational weeks 8 to 14 (MacLeod et al.. 2010; Welsh et al.. 2008;
Carruthers and Foster. 2005).
In vivo pharmacokinetic studies with rats have demonstrated that the monoester metabolites of DEHP,
DBP, BBP, and DINP can cross the placenta and be delivered to the target tissue, the fetal testes
(Clewell et al.. 2013; Clewell et al.. 2010). In utero phthalate exposure can affect both Ley dig and
Sertoli cell function in the fetal testes. Histologic effects observed following phthalate exposure include
Ley dig cell aggregation and/or altered tissue distribution, as well as reductions in Leydig cell numbers.
Functional effects on Leydig cells have also been reported. Leydig cells are responsible for producing
hormones required for proper development of the male reproductive system, including insulin-like
growth factor 3 (INSL3), testosterone, and dihydrotestosterone (DHT) (Scott et al.. 2009). Phthalate
exposure during the critical window reduces mRNA and/or protein levels of INSL3, as well as genes
involved in steroidogenesis, sterol synthesis, and steroid and sterol transport (Figure 1-1) (Gray et al..
2021; Hannas et al.. 2012). Decreased steroidogenic mRNA expression leads to decreased fetal testicular
testosterone production, as well as reductions in DHT levels, which is produced from testosterone by 5a-
reductase in the peripheral tissues. Because DHT is required for growth and differentiation of the
perineum and for normal regression of nipple development in male rats, reduced DHT levels can lead to
phenotypic changes (i.e., nipple/areolae retention [NR] and reduced anogenital distance [AGD] in
males) indicative of reduced Leydig cell function and androgen action.
Gestational exposure to certain phthalate diesters can also affect Sertoli cell function, development, and
interactions with germ cells contributing to seminiferous tubule degeneration (Boekelheide et al.. 2009).
Immature Sertoli cells secrete Anti-Mullerian hormone and play an essential role in gonadal
development (Lucas-Herald and Mitchell. 2022). Reported Sertoli cell effects include decreased cell
numbers, changes in mRNA and/or protein levels of genes involved in Sertoli cell function, their
development and altered Sertoli-germ cell interactions. Because proper Sertoli cell function is necessary
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for germ cell proliferation and development, altered Sertoli cell function can contribute to increased
germ cell death, decreased germ cell numbers, and increased formation of multinucleated gonocytes
(MNGs) (Arzuaga et al. 2020).
At the organ level, a disruption of androgen action can lead to reduced testes and accessory sex gland
(e.g., epididymis, seminal vesicle [SV], prostate, etc.) weight; agenesis of accessory organs; delayed
preputial separation (PPS); testicular pathology (e.g., interstitial cell hyperplasia); and severe
reproductive tract malformations such as hypospadias. INSL3 is crucial for gubernacular cord
development and the initial transabdominal descent of the testes to the inguinal region (Adham et al..
2000). while androgen action is required for the inguinoscrotal phase of testicular descent. Thus,
reduced INSL3 and testosterone levels following gestational phthalate exposure can prevent
gubernaculum development and testicular descent into the scrotum. Collectively, these effects can lead
to reduced spermatogenesis, increased sperm abnormalities, and reduced fertility and reproductive
function (Gray et al.. 2021; Arzuaga et al.. 2020; Howdeshell et al.. 2017; NASEM. 2017; NRC. 2008).
Chemical Structure
and Properties
Cellular
Responses
Phthalate
exposure during
critical window of
development
Fetal Male Tissue
4- AR dependent
mRNA/protein I
synthesis
Metabolism to
monoester &
transport to fetal
testes
>=>
V
Unknown MIE
(not believed to be
AR or PPARa
mediated)
4- Testosterone
synthesis
o
Key genes involved in the AOP \
for phthalate syndrome
1
Scarbl
Chcr7
Mvd
Elo3b
StAR
Ebp
Nsdhl
Insl3
Cypllal
Fdps
RGD1564999 Lhcgr
Cypllbl
Hmgcr
Tm7sf2
Inha
Cypllb2
Hmgcsl
Cyp46al
NrObl
Cypl7al
Hsd3b
Ldlr
RhoxlO
Cyp51
Fldil
Insigl
Wnt7a
4- Gene
expression
(INSL3, lipid
metabolism,
cholesterol and
androgen synthesis
and transport)
IT
k
4' INSL3 synthesis
Fetal Leydig cell
V_
Abnormal cell
apoptosis/
proliferation
(Nipple/areolae
retention, 4- AGD,
Disrupted testis
tubules, Leydig cell
clusters, MNGs,
agenesis of
reproductive tissues)
Suppressed
gubernacular cord
development
(inguinoscrotal phase)
ฆ=>
Suppressed
gubernacular cord
development
(transabdominal
phase)
Adverse Organism
Outcomes
4- Androgen-
dependent tissue
weights, testicular
pathology (e.g.,
seminiferous tubule
atrophy),
malformations (e.g.,
hypospadias), 4^
sperm production
Impaired
fertility
0
Undescended
testes
Figure 1-1. Phthalate Syndrome Mode of Action Following Gestational Exposure
Figure adapted from (Conlev et al.. 2021; Gray et al.. 2021; Schwartz, et aL 2021; Howdeshell et al.. 2017). AR =
androgen receptor; INSL3 = insulin-like growth factor 3; MNG = multinucleated gonocyte; PPARa = peroxisome
proliferator-activated receptor alpha.
1.2 Phthalates Included in the Cumulative Chemical Group Based on
Toxicologic Similarity
In the draft 2023 approach ( T.S. EPA. 2023b). EPA evaluated the MOA for phthalate syndrome
consistent with modified Bradford Hill criteria (i.e., temporal and dose-response concordance; strength,
consistency and specificity; biological plausibility) outlined in EPA and other international guidance
documents (IPCS. 2007; U.S. EPA. 2005). Additional phthalates could be included based on this
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toxicological similarity but were not evaluated during this phase of risk evaluation under TSCA. For
example, Health Canada (ECCC/HC. 2020) recently conducted a CRA of phthalates, which included the
six high-priority and manufacturer-requested phthalates (DIBP, DCHP, DINP, BBP, DBP, DEHP) as
well as 10 phthalates not undergoing risk evaluation at EPA, including: butyl cyclohexyl phthalate
(BCHP, CASRN 84-64-0), dibenzyl phthalate (DBzP, CASRN 523-31-9), cyclohexyl isobutyl phthalate
(CHIBP, CASRN 5334-09-8), benzyl 3-isobutyryloxyl-l-isopropyl-2,2-dimethylpropyl phthalate (B84P,
CASRN 16883-83-3), benzyl isooctyl phthalate (BIOP, CASRN 27215-22-1),
bis(methylcyclohexyl)phthalate (DMCHP, CASRN 27987-25-3), benzyl octyl phthalate (B79P, CASRN
68515-40-2), diisoheptyl phthalate (DIHepP, CASRN 71888-89-6), diisooctyl phthalate (DIOP, CASRN
27554-26-3), and dihexyl ester phthalate (DnHP, CASRN 84-75-3).
Overall, EPA concluded that DEHP, BBP, DBP, DCHP, DIBP, and DINP, but not DIDP, are
toxicologically similar and can induce effects on the developing male reproductive system consistent
with a disruption of androgen action and phthalate syndrome. This conclusion was supported by the
SACC in its the final peer-review report to EPA (U.S. EPA. 2023c). Therefore, EPA is including
DEHP, BBP, DBP, DCHP, DIBP, and DINP in its draft CRA. DIDP was not included in the
cumulative chemical group because it does not induce effects on the developing male reproductive
system consistent with phthalate syndrome.
1.3 Endpoints and Options Considered for Relative Potency Factor
Derivation
To conduct its cumulative risk assessment of phthalates, EPA is using a relative potency factor (RPF)
approach. In the draft 2023 approach (U.S. EPA. 2023b). EPA outlined six potential options for deriving
RPFs that considered use of data from two gestational outcomes (i.e., altered expression of steroidogenic
genes in the fetal testis and decreased fetal rat testicular testosterone) and four postnatal outcomes (i.e.,
reduced anogenital distance (AGD), increased nipple retention, seminiferous tubule atrophy, and
hypospadias). Options 1 through 4 involve benchmark dose (BMD) modeling of fetal outcomes
associated with the MO A underlying phthalate syndrome (i.e., reduced fetal testicular testosterone
content and/or reduced testicular steroidogenic gene expression), and involve BMD modeling of data
from individual studies (Options 1 and 3) or combining data from studies of similar design prior to
BMD modeling (Options 2 and 4). Similarly, Options 5 and 6 involve BMD modeling of postnatal
outcomes (i.e., reduced AGD, increased nipple/areolae retention, seminiferous tubule atrophy,
hypospadias), and involve BMD modeling of data from individual studies (Option 5) or combining data
from studies of similar design prior to BMD modeling (Option 6). Section 4.4 of the draft 2023
approach(U.S. EPA. 2023b) provides further details regarding the six options considered by EPA for
deriving RPFs.
In its final peer-review report to EPA (U.S. EPA. 2023c). SACC did not endorse any single option to
derive RPFs, but instead concluded:
"In terms of options to calculate RPFs, the committee was in consensus that it prefers any
approach which uses as much of the data as possible assuming the dose-response aspects are
considered in the process for selecting endpoints. Option 2 and 4 that incorporate dose-
response data are preferable to not using some of the data. Option 6 is similar except it uses
postnatal outcomes instead offetal ones. In an attempt to use the greatest amount of data, the
committee suggests a combination ofprenatal and postnatal outcomes would provide the best of
both approaches. "
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Strengths, limitations, and uncertainties of the available datasets for each of the six key outcomes
considered for RPF derivation are discussed in detail in Section 4.4 of the draft 2023 approach (U.S.
EPA. 2023b) and discussed briefly below. Overall, EPA noted several factors that increased its
confidence in using the fetal testicular testosterone dataset to derive RPFs, including:
Reduced testosterone production in the fetal testis plays an early role in the phthalate syndrome
MOA.
Androgen action has a conserved role in the development of the male reproductive system across
mammalian species, including humans.
There are dose-response data available for all six of the toxicologically similar phthalates from
multiple studies that are similar in design to support RPF derivation (i.e., utilize the same
species/strain of rat, same route/method of exposure, similar exposure durations, similar timing
and method (ex vivo testosterone production via radioimmunoassay) of measurement.
In contrast, EPA noted several factors that decreased its confidence in using postnatal outcomes to
derive RPFs, including:
Anogenital distance (AGD). AGD is the measured distance between the anus to the base of the
penis, and decreased AGD is considered a biomarker of a disruption of androgen action and male
reproductive health. There is variability in how studies report decreased male AGD. Changes in
AGD are sometimes but not always normalized to body weight. Per OECD guidance (OECD.
2013). AGD should be normalized to body weight (preferably the cubic root of body weight)
since animal size can influence AGD. Further, in the case of DIBP only one dose-response study
is available, and this study only reports absolute AGD. Another source of uncertainty stems from
the DINP dataset. In contrast to DEHP, BBP, DBP, DCHP, and DIBP where consistent effects
on AGD are reported, statistically significant effects on AGD are less consistently reported for
DINP across studies that test comparable doses (i.e., DINP reduced AGD in two of six studies).
Inconsistency in the DINP dataset reduces EPA's confidence in deriving RPFs based on this
outcome.
Nipple/Areolae Retention. Across available studies, there is variability in how nipple/areolae
retention is reported. For example, sometimes this outcome is reported as mean number of
nipples/areolas per male, incidence of males with nipples, or mean percent of litters including
males with nipples. Variability in data reporting makes comparisons across studies difficult.
Additionally, although male pup nipple/areolae retention is a biomarker of disrupted androgen
action in rodents, it is not directly a human relevant effect. This uncertainty reduces EPA's
confidence in deriving RPFs based on nipple/areolae retention in male pups
Seminiferous Tubule Atrophy. Seminiferous tubule atrophy, associated with infertility, testicular
atrophy, and pain, has been reported consistently for DEHP, DBP, DIBP, BBP, and DCHP;
however, available studies reporting seminiferous tubule atrophy are of varying design and
durations. For example, seminiferous tubule atrophy has been reported in two-generation studies
of DCHP and BBP, while for DIBP seminiferous tubule atrophy has only been reported in one
study in which rats were exposed throughout gestation. Additionally, effects on seminiferous
tubular atrophy are less consistently reported in studies of DINP that test comparable doses.
Differences in study design and exposure duration across available studies and inconsistency in
the DINP dataset reduces EPA's confidence in deriving RPFs based on this outcome.
Hypospadias. Hypospadias, birth defects of abnormal urethral opening on the penis, have been
reported consistently in studies of DEHP, DBP, DIBP, BBP, and DCHP; however, significant
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increases in hypospadias have not been reported in studies of DINP. Further, available studies
reporting hypospadias are of varying design and duration. For example, hypospadias have been
reported in a single study of BBP (a two-generation reproductive study) and a single study of
DIBP (a gestational exposure study). Differences in study design and exposure duration and
inconsistency in the DINP dataset reduces EPA's confidence in deriving RPFs based on this
outcome.
Given the strengths, limitations, and uncertainties of each key outcome discussed above and in Section
4.4. of (U.S. EPA. 2023b). EPA has selected reduced fetal testicular testosterone as the basis for
deriving draft RPFs.
Consistent with the SACC's recommendation that it prefers any option for deriving RPFs that makes use
of as much of the available data as possible (U.S. EPA. 2023 c). EPA selected Option 2 for deriving
RPFs. This option involves combining fetal testicular testosterone data from studies of similar design
prior to conducting BMP modeling. EPA's BMD modeling approach of fetal testicular testosterone data to
derive RPFs is discussed further in Section 2.
1.4 Relevant Populations
Gestational exposure to DEHP, BBP, DBP, DIBP, DCHP and DINP can disrupt testicular
steroidogenesis and cause adverse effects on the developing male reproductive system consistent with
phthalate syndrome. Postnatal phthalate exposure can also cause male reproductive toxicity; however,
the perinatal and peripubertal lifestages are believed to be the most sensitive to phthalate exposure
(NRC. 2008). In the draft 2023 approach (U.S. EPA. 2023b). EPA proposed to focus its CRA for
phthalates on two groups that may be more susceptible to phthalate syndrome due to lifestage:
pregnant women/women of reproductive age, and
male infants, male toddlers, and male children.
While additional populations may experience health effects, these populations are considered the most
susceptible for phthalate syndrome. Overall, SACC agreed with EPA that these lifestages "should
certainly be considered susceptible populations given the abundant data from hazard assessment studies"
(U.S. EPA. 2023c). Therefore, EPA is focusing its CRA on pregnant women/women of
reproductive age, and male infants, male toddlers, and male children.
1.5 Relevant Durations
As described in the non-cancer human health hazard assessment for DINP (U.S. EPA. 2025p) and draft
non-cancer human health hazard assessments for DEHP (U.S. EPA. 2024h). DBP (U.S. EPA. 2024f).
BBP (U.S. EPA. 2024e\ DIBP (U.S. EPA. 20240. and DCHP (U.S. EPA. 2024g). there is evidence that
effects on the developing male reproductive system consistent with a disruption of androgen action can
result from a single exposure during the critical window of development (i.e., gestation day (GD) 14 to
18). Therefore, EPA considers effects on fetal testicular testosterone relevant as an acute effect
associated with higher, acute exposures. Notably, SACC agreed with EPA's decision to consider effects
on the developing male reproductive system consistent with a disruption of androgen action to be
relevant for setting a point of departure (POD) for acute durations during the July 2024 peer-review
meeting of the DINP human health hazard assessment (U.S. EPA. 2024q). In addition, phthalates have
relatively rapid elimination kinetics with half-lives on the order of several hours before being quickly
excreted from the body (ATSDR. 2022; EC/HC. 2015). Thus, unlike chemical substances with more
bioaccumulative potential, historical exposures are not as relevant as concurrent or recent exposures
particularly in relation to critical windows of development. Taken together, EPA is focusing the
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application of its phthalate CRA on acute exposure durations which are expected to represent the
highest relevant exposures for the common health effect for susceptible populations. Notably, protecting
for acute exposure durations will be protective of longer duration exposures, since acute exposures are
higher than longer duration exposures.
1.6 Exposure Evaluations
In the draft 2023 approach (U.S. EPA. 2023b). EPA proposed both a reverse-dosimetry method for
estimating cumulative non-attributable phthalate exposure from NHANES urinary biomonitoring and
the development of scenarios for combining exposures from multiple sources in conjunction with the
individual phthalate risk evaluations (U.S. EPA. 2023b). The proposed scenario-based approach
included estimating and combining reasonable combinations of exposure attributable to TSCA COUs, to
non-TSCA sources (e.g., diet, food packaging cosmetics, etc.), and any other non-attributable exposures
to determine cumulative risk.
Overall, the SACC endorsed the use of reverse dosimetry for estimating exposure using biomonitoring,
over the use of modeling, where monitoring represents exposed sub-populations. However, the SACC
noted that highly exposed subpopulations, including workers with occupational exposures, would not
likely be represented by a national survey. Nonetheless, NHANES data do provide total exposure,
including non-attributable and non-TSCA exposures, which could be aggregated with any scenario-
specific estimates.
Exposures and risks for each individual phthalate under its conditions of use (COUs) continue to be
evaluated in individual risk evaluations in accordance with TSCA.1 EPA assesses exposure for
consumers, workers, and general population exposed to environmental releases for each individual
phthalate. Within these exposed populations, there are PESS with increased susceptibility to the
developmental and reproductive effects associated with phthalate syndrome, including pregnant
women/women of reproductive age, male infants, male toddlers, and male children. The 2023 proposal
laid out a multi-step approach and conceptual model which suggested the results of the individual
phthalate risk evaluations could be combined into a single cumulative risk assessment.
These individual assessments represent a mix of deterministic and probabilistic methods as well as
differing tiers of analyses (i.e. screening through more refined approaches). In its review, the SACC
specifically expressed "concern" about mixing these estimates in an approach that combines estimates
from these individual assessments (U.S. EPA. 2023c). In addition, credible exposure scenario-based
approaches would need to be informed by site specific data and "laborious" to construct (if even
possible) with reasonably available data.
Therefore, EPA is using NHANES data to supplement, not substitute, evaluations for exposure
scenarios for TSCA COUs to provide non-attributable, total exposure for addition to the relevant
scenarios presented in the individual risk evaluations. Section 5.1 provides this quantitative approach
to be tabulated in each individual relevant risk evaluation for evaluating cumulative risk resulting from
aggregate exposure to a single phthalate from an exposure scenario or COU plus non-attributable
cumulative risk from NHANES.
1 Conditions of use (COUs) are defined as "the circumstances, as determined by the Administrator, under which a chemical
substance is intended, known, or reasonably foreseen to be manufactured, processed, distributed in commerce, used, or
disposed of." (15 U.S.C. 2602(4))
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Finally, the SACC recommended more discussion and analyses related to exposure, specifically related
to emphasis on the importance of indoor dust exposures, updates to estimates of phthalates in diet given
the highly diverse U.S. population, and specific emphasis on potential risk to arctic communities from
exposures to environmental releases (U.S. EPA. 2023c). The SACC also recommended that EPA
provide the physical-chemical and fate parameters for consideration across the group. These
recommendations are addressed in Section 3 in a qualitative or semi-quantitative manner.
1.7 Risk Cup Concept in Cumulative Risk Assessment
The analogy of a "risk cup" is used throughout this document to describe cumulative exposure estimates.
The "risk cup" term is used to help conceptualize the contribution of various phthalate exposure routes
and pathways to overall cumulative risk estimates and serves primarily as a communication tool. The
"risk cup" concept describes exposure estimates where the full cup represents the total exposure that
leads to risk (cumulative margin of exposure (MOE)) and each chemical substance contributes a specific
amount of exposure that adds a finite amount of risk to the cup.
To estimate non-cancer cumulative risks from exposure to phthalates, EPA is using a cumulative MOE
approach. As discussed further in Section 5.1, the cumulative MOE is a ratio of the index chemical POD
to the cumulative exposure estimate expressed in index chemical equivalent units. The MOE is then
compared to the benchmark MOE (i.e., the total uncertainty factor associated with the assessment) to
characterize risk. The MOE estimate is interpreted as a human health risk of concern if the MOE
estimate is less than the benchmark MOE (i.e., the total UF). On the other hand, if the MOE estimate is
equal to or exceeds the benchmark MOE, the risk is not considered to be of concern and mitigation is
not needed. Typically, the larger the MOE, the more unlikely it is that a non-cancer adverse effect
occurs relative to the benchmark. When determining whether a chemical substance presents
unreasonable risk to human health or the environment, calculated risk estimates are not "bright-line"
indicators of unreasonable risk, and EPA has the discretion to consider other risk-related factors in
addition to risks identified in the risk characterization.
A full risk cup indicates that the cumulative MOE has dropped below the benchmark MOE of 30,
whereas cumulative MOEs above the benchmark indicate that only a percentage of the risk cup is full.
For example, a cumulative MOE of 120 would indicate that the risk cup is 25 percent full, since the
benchmark MOE is 30.
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2 RELATIVE POTENCY FACTORS
This section describes the approach used by EPA to derive draft relative potency factors (RPFs) for the
six phthalates (i.e., DEHP, DBP, BBP, DIBP, DCHP, DINP) that EPA is including in its draft CRA.
These RPFs are used to scale each phthalate exposure by potency and to calculate risk in common units
of index chemical (DBP) equivalents for cumulative assessment.
The remainder of this hazard chapter is organized as follows:
Section 2.1- Describes the general principles of the RPF approach.
Section 2.2 - Describes the benchmark dose (BMD) modeling approach used by EPA for
deriving draft RPFs.
Section 2.3 - Describes selection of the index chemical used as a point of reference to
standardize the potency of each phthalate,
Section 2.4 - Describes the draft RPFs derived by EPA for each phthalate included in the CRA.
Section 2.5 - Describes the uncertainty factors selected by EPA for use as the benchmark margin
of exposure (benchmark MOE).
Section 2.6 - Describes the applicability of the draft RPFs.
Section 2.7 - Describes EPA's weight of scientific evidence conclusions.
2.1 Relative Potency Factor Approach
As described in the draft 2023 approach (U.S. EPA. 2023b). EPA proposed to use a RPF approach to
characterize risk from cumulative exposure to phthalates under TSCA. Overall, SACC was "generally
supportive of the approach," but noted several uncertainties (U.S. EPA. 2023 c). which are addressed by
EPA in Section 2.4. Consistent with its initial proposal (U.S. EPA. 2023b). EPA is using a RPF
approach for its draft CRA of phthalates under TSCA.
For the RPF approach, chemical substances being evaluated require data that support toxicologic
similarity (e.g., components of a mixture share a known or suspected common mode of action or share a
common apical endpoint/effect) and have dose-response data for the effect of concern over similar
exposure ranges (U.S. EPA. 2023a. 2000. 1986). RPF values account for potency differences among
chemicals in a mixture and scale the dose of one chemical to an equitoxic dose of another chemical (i.e.,
the index chemical). The chemical selected as the index chemical is often among the best characterized
toxicologically and considered to be representative of the type of toxicity elicited by other components
of the mixture. Implementing an RPF approach requires a quantitative dose response assessment for the
index chemical and pertinent data that allow the potency of the mixture components to be meaningfully
compared to that of the index chemical. In the RPF approach, RPFs are calculated as the ratio of the
potency of the individual component to that of the index chemical using either (1) the response at a fixed
dose; or (2) the dose at a fixed response (Equation 2-1).
Equation 2-1. Calculating RPFs
= mEjuc
1 BMDR_i
where:
BMD = benchmark dose (mg/kg/day)
R = magnitude of response (i.e., benchmark response)
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i = ith chemical
IC = index chemical
After scaling the chemical component doses to the potency of the index chemical, the scaled doses are
summed and expressed as index chemical equivalents for the mixture (Equation 2-2).
Equation 2-2. Calculating index chemical equivalents
Index Chemical EquivalentsMIX = ฃf=i dj x RPFt
where:
Index chemical equivalents = dose of the mixture in index chemical equivalents (mg/kg-day)
di = dose of the ilh chemical in the mixture (mg/kg-day)
RPFi = relative potency factor of the ilh chemical in the mixture (unitless)
Non-cancer risk associated with exposure to the mixture can then be assessed by calculating a MOE,
which in this case is the ratio of the index chemical's non-cancer benchmark dose lower confidence limit
(BMDL) to an estimate of mixture exposure expressed in terms of index chemical equivalents. The
MOE is then compared to the benchmark MOE (i.e., the total uncertainty factor associated with the
assessment) to characterize risk.
2.2 Benchmark Dose Modeling of Fetal Testicular Testosterone to
Determine Toxic Potency
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 BMD modeling (NASEM. 2017). Meta-
analysis is a statistical procedure that can be used to summarize outcomes from a number of studies and
can be used to 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
and provide a more robust dataset across the chemicals for modeling dose-response of a common
endpoint.
To derive RPFs for DEHP, DBP, BBP, DIBP, DCHP, and DINP based on reduced fetal testicular
testosterone, EPA used the same meta-analysis and BMD modeling approach used by NASEM (2017).
with several notable updates. First, EPA identified new fetal testicular testosterone data that was not
included in the 2017 NASEM analysis. This new data was included in EPA's updated meta-analysis and
BMD analysis. Table 2-1 provides a summary of studies included in the updated analysis. EPA's
updated analysis also utilized the most up-to-date version of the Metafor meta-analysis package for R
(https://wviechtb.github.io/metafor/index.html) available at the time of the updated analysis (i.e.,
Version 4.6.0). However, EPA also conducted the updated analysis using the same version of Metafor
originally used by NASEM (2017) (i.e., Version 2.0.0) so that results could be compared. As part of its
updated analysis, EPA also evaluated benchmark responses (BMRs) of 5, 10, and 40 percent based on
biological and statistical considerations (comparatively, NASEM evaluated BMRs of 5 and 40%).
Results of EPA's updated meta-analysis and BMD analysis are provided in Section 0. Readers are
directed to EPA's Draft Meta-Analysis and Benchmark Dose Modeling of Fetal Testicular Testosterone
for Di(2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), Butyl Benzyl Phthalate (BBP),
DiisobutylPhthalate (DIBP), andDicyclohexylPhthalate (DCHP) (U.S. EPA. 2024d) and Non-Cancer
Human Health Hazard Assessment for Diisononyl Phthalate (U.S. EPA. 2025p) for a more thorough
discussion of the methodology and results of EPA's updated analysis.
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751 Table 2-1. Summary of Studies Included in EPA's Updated Meta-Analysis and BMP Modeling Analysis
Reference
Study Details
Phthalate
Strain/
Species
Exposure
Route
(Method)
Exposure
Window
Measured Outcome (Timing of
Measure)
TSCA Study
Quality Rating
DEHP
DBP
DIBP
BBP
DCHP
DINP
(Martino-Andrade et
aL 2008)
Wistar rat
Oral
(gavage)
GD 13-21
Fetal testis testosterone content
(GD 21)
Medium
confidence
X17
X17
(Furr et al.. 2014)
SD rat
Oral
(gavage)
GD 14-18
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 18)
High confidence
X17
X17
X17
xb
Xb
(Howdeshell et al..
2008)
SD rat
Oral
(gavage)
GD 8-18
Ex vivo fetal testicular
testosterone production (2-hour
incubation) (GD 18)
High confidence
X17
X17
X17
X17
(Grav et al.. 2021)
SD rat
Oral
(gavage)
GD 14-18
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 18)
High (DEHP,
DBP, BBP,
DCHP) or
Medium (DIBP)
confidence
xb
xb
xb
xb
xb
(Hannas et al.. 2011)
SD rat
Oral
(gavage)
GD 14-18
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 18)
Medium
confidence
xa
xa
xa
Wistar rat
Oral
(gavage)
GD 14-18
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 18)
Medium
confidence
xa
(Kuhl et al.. 2007)
SD rat
Oral
(gavage)
GD 18
Fetal testis testosterone content
(GD 19)
Low confidence
xa
(Struve et al.. 2009)
SD rat
Oral
(gavage)
GD 12-19
Fetal testis testosterone content
(GD 19; 4 or 24 hours post-
exposure)
Medium
confidence
xa
(Johnson et al..
2011)
SD rat
Oral
(gavage)
GD 12-20
Fetal testis testosterone content
(GD 20)
Medium
confidence
xa
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Reference
Study Details
Phthalate
Strain/
Species
Exposure
Route
(Method)
Exposure
Window
Measured Outcome (Timing of
Measure)
TSCA Study
Quality Rating
DEHP
DBP
DIBP
BBP
DCHP
DINP
(Johnson et al..
2007)
SD rat
Oral
(gavage)
GD 19
Fetal testis testosterone content
(GD 19)
Medium
confidence
X17
(Lin et al.. 2008)
Long-
Evans rat
Oral
(gavage)
GD 2-20
Fetal testis testosterone content
(GD 21)
Medium
confidence
X17
(Cultv et al.. 2008)
SD rat
Oral
(gavage)
GD 14-20
Ex vivo fetal testicular
testosterone production (24-hour
incubation) (GD 21)
Medium
confidence
X17
(Saillenfait et al..
2013)
SD rat
Oral
(gavage)
GD 12-19
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 19)
High confidence
X17
(Bobere et al.. 2011)
Wistar rat
Oral
(gavage)
GD 7-21
Ex vivo fetal testicular
testosterone production (GD 21)
& fetal testis testosterone
content (GD 21)
Medium
confidence
X17
(Grav et al.. 2024)
SD rat
Oral
(gavage)
GD 14-18
Ex vivo fetal testicular
testosterone production (3-hour
incubation) (GD 18)
Medium
confidence
xb
11 Data included in NASEM (2017) analysis.
h Cells highlighted in gray indicate data not included in the 2017 NASEM analysis. However, this data was included in EPA's updated analysis.
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2.2.1 Results: Benchmark Dose Estimation
Table 2-2 summarizes BMD modeling results of fetal testicular testosterone for DEHP, DBP, DIBP,
BBP, DCHP, and DINP from EPA's updated meta-analysis using Metafor Version 4.6.0. Readers are
directed to EPA's Draft Meta-Analysis and Benchmark Dose Modeling of Fetal Testicular Testosterone
for Di(2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), Butyl Benzyl Phthalate (BBP),
DiisobutylPhthalate (DIBP), andDicyclohexylPhthalate (DCHP) (U.S. EPA. 2024d) and Non-Cancer
Human Health Hazard Assessment for Diisononyl Phthalate (U.S. EPA. 2025p) for more detailed
reporting and discussion of results.
Table 2-2. BMD Modeling Results of Fetal Testicular Testosterone for DEHP, DBP, DIBP, BBP,
DCHP, and DINP
Phthalate
Model Providing
Best Fit"
BMD5 Estimates
(mg/kg-day)
[95% Confidence
Interval]
BMD10 Estimates
(mg/kg-day)
[95% Confidence
Interval]
BMD40 Estimates
(mg/kg-day)
[95% Confidence
Interval]
DBP
Linear Quadradic
14 [9, 27]
29 [20, 54]
149 [101, 247]
DEHP
Linear Quadradic
17 [11, 31]
35 [24, 63]
178 [122, 284]
DIBP
Linear Quadradic
_b
55 [NA, 266]*
279 [136, 517]
BBP
Linear Quadradic
_b
_b
284 [150, 481]
DCHP
Linear Quadradic
8.4 [6.0, 14]
17 [12, 29]
90 [63, 151]
DINP
Linear Quadradic
74 [47, 158]
152 [97, 278]
699 [539, 858]
11 Based on lowest Akaike information criterion (AIC) and visual inspection.
b BMD and/or BMDL estimate could not be derived.
2.3 Selection of the Index Chemical and the Index Chemical Point of
Departure
As described in EPA mixture and cumulative risk assessment guidance documents (2023a. 2016. 2002a.
2000. 1986). for the RPF approach to be applied one chemical must be selected as the index chemical.
The index chemical is used as the point of reference for standardizing the common toxicity of the other
chemicals being evaluated as part of the cumulative chemical group. Once the index chemical is
selected, RPFs are calculated (i.e., the ratio of the toxic potency of one chemical to that of the index
chemical). RPFs are used to convert exposures of all chemicals in the cumulative chemical group into
exposure equivalents of the index chemical. Given that the RPF method portrays risk as exposure in
terms of index chemical equivalents, it is preferred that the index chemical: 1) have the highest quality
toxicological database of chemicals in the cumulative chemical group; 2) have high quality dose-
response data; 3) be considered the most representative of the type of toxicity caused by other chemicals
in the cumulative chemical group; and 4) be well characterized for the proposed mode of action (2023a.
2016. 2002a. 2000. 1986).
Table 2-3 provides a high-level comparison of the number of studies available for each phthalate that
examined each outcome considered for RPF derivation. Of the six phthalates included in the cumulative
chemical group (i.e., DEHP, DBP, BBP, DIBP, DCHP, and DINP), EPA considered DEHP and DBP
as candidates for the index chemical because both phthalates have high quality toxicological databases
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demonstrating effects on the developing male reproductive system consistent with a disruption of
androgen action and phthalate syndrome, demonstrate toxicity representative of all phthalates in the
cumulative chemical group, and are well characterized for the MOA associated with phthalate
syndrome. Compared to DEHP and DBP, other phthalates included in the cumulative chemical group
(i.e., BBP, DIBP, DCHP, DINP) have considerably smaller databases and fewer dose-response data
(Table 2-3), and were not considered candidates for the index chemical.
Table 2-3. Comparison of the Number of Studies Supporting Key Outcomes Associated with
Phthalate Syndrome"
Key Outcome
# of Studies Per Phthalate by Species
DEHP
DBP
BBP
DIBP
DCHP
DINP
[ Steroidogenic gene and
Ins 13 expression in fetal
testis
7
(all rat)
9
(rat [8]; mouse [1])
2
(all rat)
6
(rat [5];
mouse [1])
2
(all rat)
5
(all rat)
[ Fetal testicular
testosterone
15
(rat [13];
mouse [2])
17
(rat [16]; mouse
[1])
5
(all rat)
6
(rat [5];
mouse [1])
3
(all rat)
9
(all rat)
[ Anogenital distance
(AGD)
19
(rat [16];
mouse [3])
18
(all rat)
5
(all rat)
4
(rat [3];
mouse [1])
5
(all rat)
6
(all rat)
t Nipple retention (NR)
12
(all rat)
8
(all rat)
2
(all rat)
1
(all rat)
2
(all rat)
3
(all rat)
t Hypospadias
10
(rat [9];
mouse [1])
11
(rat [9]; rabbit [1];
marmoset [1])
3
(all rat)
1
(all rat)
1
(all rat)
3
(all rat)
| Seminiferous tubule
atrophy
3
(all rat)
8
(all rat)
3
(all rat)
1
(all rat)
2
(all rat)
5
(all rat)
t Multinucleated
gonocytes (MNGs)
7
(all rat)
11
(rat [9]; mouse [1];
marmoset [1])
1
(all rat)
1
(all rat)
2
(all rat)
4
(all rat)
11 Data from Section 3.1.3.1 through Section 3.1.3.7 of EPA" s draft proposed approach for CRA of phthalates
under TSCA (U.S. EPA. 2023b).
The toxicological databases for DEHP and DBP are characterized elsewhere in EPA's draft non-cancer
human health hazard assessments of DEHP (U.S. EPA. 2024h) and DBP (U.S. EPA. 2024f). as well as
in the 2023 draft approach (U.S. EPA. 2023b). and are briefly summarized herein. Briefly, numerous
studies of experimental rodent models are available that demonstrate that gestational exposure to DEHP
and DBP during the critical window of development (i.e., GD 15.5 to 18.5 in rats) can reduce
steroidogenic gene and Insl3 mRNA expression in the fetal testis and reduced fetal testis testosterone
content and/or ex vivo fetal testis testosterone production. Consistent with a disruption of androgen
action, studies have demonstrated that DEHP and DBP can reduce male offspring anogenital distance,
increase nipple/areolae retention, and cause severe reproductive tract malformations such as hypospadias
and cryptorchidism, as well as cause numerous other effects consistent with phthalate syndrome (e.g.,
reduce weight of androgen sensitive tissues such as the prostate and testis; increase incidence of
testicular pathology such as seminiferous tubule atrophy; increase incidence of multinucleated
gonocytes; cause various sperm effects; and decrease male fertility).
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Because RPFs are being derived using fetal testicular testosterone data, EPA next compared the quantity
and quality of available dose-response data for this outcome for DBP and DEHP. As can be seen from
Table 2-1, EPA included fetal testicular testosterone data from 8 studies of DBP and 8 studies of DEHP
in its updated meta-analysis and BMD analysis. As can be seen from TableApx A-l, most of the
available fetal testicular testosterone data for DEHP are from studies of rats dosed with 100 mg/kg-day
DEHP or higher. One study of DEHP provides testosterone data at a dose of 50 mg/kg-day (Saillenfait et
al.. 20131 while one other study of DEHP provides testosterone data at a dose of 10 mg/kg-day (Lin et
al.. 2008). Comparatively, more dose-response data is available for the low-end range of the dose-
response curve for DBP. As can be seen from Table Apx A-2, this includes two studies of DBP that
provide testosterone data at 1 mg/kg-day DBP (Furr et al.. 2014; Johnson et al.. 2007). two studies that
provide testosterone data at 10 mg/kg-day DBP (Furr et al.. 2014; Johnson et al.. 2007). two studies that
provide testosterone data at 33 mg/kg-day DBP (Furr et al.. 2014; Howdeshell et al.. 2008). and two
studies that provide testosterone data at 50 mg/kg-day DBP (Furr et al.. 2014; Howdeshell et al.. 2008).
As can be seen from Table 2-2, the BMD5/BMDL5 estimates for DEHP and DBP based on decreased
fetal testicular testosterone are 17/11 mg/kg-day and 14/9 mg/kg-day, respectively, while the
BMD10/BMDL10 estimates for DEHP and DBP are 35/24 mg/kg-day and 29/20 mg/kg-day, respectively
(Table 2-2).
Overall, DBP has more dose-response data than DEHP in the low-end range of the dose-response curve
where the BMD and BMDL estimates at the 5 and 10 percent response level are derived. Therefore,
EPA has preliminarily selected DBP as the index chemical.
As with any risk assessment that relies on BMD analysis, the point of departure (POD) is the lower
confidence limit used to mark the beginning of extrapolation to determine risk associated with human
exposures. For the index chemical, DBP, EPA calculated BMDL5, BMDL10 and BMDL40 values of 9,
20, and 101 mg/kg-day for reduced fetal testicular testosterone (Table 2-2). EPA selected the 95 percent
lower confidence limit for the BMD5 (i.e., 14 mg/kg-day), the BMDL5 (i.e., 9 mg/kg-day DBP). EPA
selected the BMDL5 as the POD because as discussed further in Appendix B, EPA does not consider
BMRs of 10 or 40 percent health protective for all phthalates included in the cumulative chemical group.
Using allometric body weight scaling to the three-quarters power (U.S. EPA. 2011b). EPA
extrapolated an HEP of 2.1 mg/kg-day from the BMDLs of 9 mg/kg-day to use as the index
chemical POD for the draft CRA of phthalates.
2.4 Relative Potency Factors for the Cumulative Phthalate Assessment
Based on Decreased Fetal Testicular Testosterone
As described in EPA mixture and cumulative risk assessment guidance documents (2023a. 2016. 2002a.
2000. 1986). RPFs are calculated using Equation 2-1 by taking the ratio of the toxic potency of one
chemical to that of the index chemical. As described in Section 2.3, EPA has preliminarily selected DBP
as the index chemical and is using BMD5, BMD10, and BMD40 estimates from the best-fitting linear
quadratic model derived using Metafor Version 4.6.0 (Table 2-2) to calculate RPFs based on decreased
fetal testicular testosterone.
Table 2-4 shows calculated RPFs using BMD5, BMD10, and BMD40 estimates. As can be seen from
Table 2-4, RPFs calculated using BMD5, BMD10, and BMD40 estimates for DEHP, DCHP, and DINP
were nearly identical for each phthalate. RPFs ranged from 0.82 to 0.84 for DEHP, 1.66 to 1.71 for
DCHP, and 0.19 to 0.21 for DINP. For DIBP, an RPF of 0.53 was calculated using both BMD10 and
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BMD40 estimates; however, no RPF could be calculated using a BMD5 because a BMD could not be
estimated for DIBP at the 5 percent response level. For BBP, an RPF of 0.52 was calculated using the
BMD40 estimate. RPFs could not be estimated for BBP at the 5 or 10 percent response levels because
BMD5 and BMD10 values could not be estimated for BBP.
As discussed by the National Resource Council in 2008 (NRC. 2008). there may be challenges
associated with the RPF approach because phthalates may have differing shape and slope dose-response
curves leading to variability in RPFs across different BMRs. This concern was echoed by the SACC
during their peer-review of EPA's Draft Proposed Approach for Cumulative Risk Assessment (CRA) of
High-Priority Phthalates and a Manufacturer-Requested Phthalate under the Toxic Substances Control
Act (U.S. EPA. 2023c). However, EPA's current analysis demonstrates that for reduced fetal testicular
testosterone, RPFs do not vary across a range of BMRs (i.e., BMRs of 5, 10, and 40%), which provides
confidence in the overall approach.
For input into the draft CRA of phthalates under TSCA, EPA is using RPFs calculated using
BMD40 estimates shown in Table 2-4. There is some uncertainty in the applicability of the selected
RPFs for DIBP and BBP at the low response levels (i.e., 5 to 10 percent changes), since RPFs could not
be estimated for BBP at the 5 or 10 percent response levels or for DIBP at the 5 percent response level.
However, the lack of variability in calculated RPFs for DEHP, DCHP, and DINP across response levels,
and the fact that the RPF for DIBP was identical at the 10 and 40 percent response levels, increases
EPA's confidence in the selected RPFs for BBP and DIBP.
Table 2-4. Comparison of Candidate Relative Potency Factors Based on BMDs, BMD10, and
BMD40 Estimates
Phthalate
RPF
(Based on
BMDs)
RPF
(Based on
BMD10)
RPF
(Based on BMD40)
(Selected RPFs)
DBP
(Index Chemical)
1
1
1
DEHP
0.82
0.83
0.84
DIBP
a
0.53
0.53
BBP
a
a
0.52
DCHP
1.67
1.71
1.66
DINP
0.19
0.19
0.21
11 RPF could not be estimated because BMD5 or BMD10 could not be estimated.
2.5 Uncertainty Factors and the Benchmark Margin of Exposure
Consistent with Agency guidance (U.S. EPA. 2022. 2002b). EPA selected an intraspecies uncertainty
factor (UFh) of 10, which accounts for variation in susceptibility across the human population and the
possibility that the available data might not be representative of individuals who are most susceptible to
the effect.
As described in Section 2.3, EPA used allometric body weight scaling to the three-quarters power to
derive an HED of 2.1 mg/kg-day DBP from the BMDL5 of 9 mg/kg-day for reduced fetal testicular
testosterone, which accounts for species differences in toxicokinetics. Consistent with EPA Guidance
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(U.S. EPA. 201 lb), the interspecies uncertainty factor (UFa), was reduced from 10 to 3 to account for
remaining uncertainty associated with interspecies differences in toxicodynamics.
EPA considered reducing the UFa further to a value of 1 based on apparent differences in
toxicodynamics between rats and humans. As discussed in Section 3.1.4 of the 2023 draft approach
(U.S. EPA. 2023b). several explant (Lambrot et al.. 2009; Hallmark et al.. 2007) and xenograft studies
(van Den Driesche et al.. 2015; Spade et al.. 2014; Heger et al.. 2012; Mitchell et al.. 2012) using human
donor fetal testis tissue have been conducted to investigate the antiandrogenicity of mono-2-ethylhexyl
phthalate (MEHP; a monoester metabolite of DEHP), DBP, and monobutyl phthalate (MBP; a
monoester metabolite of DBP) in a human model. Generally, results from human explant and xenograft
studies suggest that human fetal testes are less sensitive to the antiandrogenic effects of phthalates,
although effects on Sertoli cells and increased MNGs have been observed in available studies of donor
fetal testis tissue. As discussed in EPA's 2023 draft approach (U.S. EPA. 2023b). the available human
explant and xenograft studies have limitations and uncertainties, which preclude definitive conclusions
related to species differences in sensitivity. For example, key limitations and uncertainties of the human
explant and xenograft studies include: small sample size; human testis tissue was collected from donors
of variable age and by variable non-standardized methods; and most of the testis tissue was taken from
fetuses older than 14 weeks, which is outside of the critical window of development (i.e., gestational
weeks 8 to 14 in humans). Therefore, EPA did not reduce the UFa from a value of 3 to 1.
Overall, a total uncertainty factor of 30 was selected for use as the benchmark margin of exposure
for the cumulative risk analysis (based on an interspecies uncertainty factor [UFaI of 3 and an
intraspecies uncertainty factor [UFhI of 10).
2.6 Applicability of Derived Relative Potency Factors (RPFs)
Exposure Route
EPA derived RPFs using data from gestational exposure studies in which pregnant rats were orally
dosed with DEHP, DBP, BBP, DIBP, DCHP, or DINP. Because RPFs were derived from oral exposure
studies, they are most directly applicable for the oral exposure route. As described in the non-cancer
human health hazard assessment for DINP (U.S. EPA. 2025p) and draft non-cancer human health hazard
assessments for DEHP (U.S. EPA. 2024h). DBP (U.S. EPA. 2024f). BBP (U.S. EPA. 2024e). DIBP
(U.S. EPA. 2024i). and DCHP (U.S. EPA. 2024g). there are no dermal or inhalation exposure studies
available that have evaluated fetal testicular testosterone in rats following gestational exposure during
the critical window of development. Therefore, EPA could not derive route-specific RPFs. For the draft
phthalate CRA, EPA is using the oral RPFs to scale inhalation and dermal phthalate exposures. This
requires an inherent assumption of similar potency across exposure routes, which is a source of
uncertainty. However, EPA cannot predict whether use of oral RPFs for the inhalation and dermal
exposure routes will lead to an under- or overestimation of risk.
Population
Because the draft RPFs are based on reduced fetal testicular testosterone, EPA considers the draft RPFs
most directly applicable to pregnant women, women of reproductive age, and male infants. Use of the
draft RPFs for other lifestages (e.g., adult males) may be conservative.
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2.7 Weight of Scientific Evidence: Relative Potency Factors and Index
Chemical Point of Departure
EPA has preliminary selected an HED of 2.1 mg/kg-day (BMDLs of 9 mg/kg-day) as the index chemical
(i.e., DBP) POD. This POD is based on a meta-analysis and BMD modeling of decreased fetal testicular
testosterone from eight studies of rats exposed to DBP during gestation. EPA has also derived draft
RPFs of 1 for DBP (index chemical), 0.84 for DEHP, 0.53 for DffiP, 0.52 for BBP, 1.66 for DCHP, and
0.21 for DINP, respectively, based on a uniform measure {i.e., reduced fetal testicular testosterone).
Overall, EPA has robust overall confidence in the proposed index chemical (DBP) POD and the
draft RPFs based on the following weight of the scientific evidence considerations:
EPA has previously considered the weight of scientific evidence and concluded that oral
exposure to DEHP, DBP, BBP, DIBP, DCHP, and DINP can induce effects on the developing
male reproductive system consistent with a disruption of androgen action (see EPA's 2023 draft
approach (U.S. EPA. 2023b)). Notably, EPA's conclusion was supported by the SACC (U.S.
EPA. 2023 cY
EPA selected DBP as the index chemical because it has a high quality toxicological database
demonstrating effects on the developing male reproductive system consistent with a disruption of
androgen action and phthalate syndrome; demonstrates toxicity representative of all phthalates in
the cumulative chemical group; is well characterized for the MOA associated with phthalate
syndrome; and has the most fetal testicular testosterone dose-response data in the low-end range
of the dose-response curve where the BMD and BMDL estimates at the 5 and 10 percent
response level are derived.
As discussed in the Draft Non-cancer Raman Health Hazard Assessment for Dibutyl Phthalate
(DBP) (U.S. EPA. 2024f). EPA has also preliminarily selected the HED of 2.1 mg/kg-day
(BMDLs of 9 mg/kg-day) for calculation of risk from exposures to DBP in the individual
chemical risk evaluation. EPA has robust overall confidence in the proposed POD selected for
DBP. Overall, the same weight of evidence considerations apply to the POD selected for the
individual DBP risk evaluation and the draft CRA. Readers are directed to thq Draft Non-cancer
Human Health Hazard Assessment for Dibutyl Phthalate (DBP) (U.S. EPA. 2024f) for a
complete discussion of the weight of evidence supporting the selected POD.
In the MOA for phthalate syndrome, which has been described by EPA elsewhere (U.S. EPA.
2023b). 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 and 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.
EPA derived draft RPFs using a meta-analysis and BMD modeling approach, which integrates
fetal testicular testosterone data from 14 medium- and high-quality studies for DEHP, DBP,
BBP, DIBP, DCHP, and DINP (Table 2-1). Notably, the statistical significance of the meta-
analysis results were robust to leaving out individual studies as part of a sensitivity analysis (see
updated meta-analysis technical support document (U.S. EPA. 2024d)).
EPA derived candidate RPFs using BMD5, BMD10, and BMD40 estimates (Table 2-2) to allow
for a comparison of RPFs at the three evaluated BMR levels of 5, 10, and 40 percent. RPFs
calculated using BMD5, BMD10, and BMD40 estimates for DEHP, DCHP, and DINP were nearly
identical for each phthalate (Table 2-4). RPFs ranged from 0.82 to 0.84 for DEHP, 1.66 to 1.71
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for DCHP, and 0.19 to 0.21 for DINP. For DIBP, an RPF of 0.53 was calculated using both
BMDio and BMD40 estimates; however, no RPF could be calculated using a BMD5 because a
BMD could not be estimated for DIBP at the 5 percent response level. For BBP, an RPF of 0.52
was calculated using the BMD40 estimate. RPFs could not be estimated for BBP at the 5 or 10
percent response levels because BMD5 and BMD10 values could not be estimated for BBP. There
is some uncertainty in the applicability of the selected RPFs based on BMD40 estimates for DIBP
and BBP at the low response levels (i.e., 5 to 10 percent changes), since RPFs could not be
estimated for BBP at the 5 or 10 percent response levels or for DIBP at the 5 percent response
level. However, the lack of variability in calculated RPFs for DEHP, DCHP, and DINP across
response levels, and the fact that the RPF for DIBP was identical at the 10 and 40 percent
response levels, increases EPA's confidence in the selected RPFs for BBP and DIBP.
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3 SCENARIO-BASED PHTHALATE EXPOSURE AND RISK
This section provides a qualitative analysis of co-exposures expected for consumers, workers, and
general population exposed to environmental releases for each individual phthalate under their COUs.
Per TSCA, each evaluation must assess risks to human health and the environment under the chemical
substance's COUs and determine whether the chemical substance presents unreasonable risk.2
3.1 Occupational Exposure for Workers
Occupational exposures to a combination of phthalates may occur in a variety of industrial and
commercial settings. For instance, businesses may manufacture, import, process, or dispose of multiple
phthalates within the same facility, which may lead to worker exposure to multiple phthalates. Also,
some products used by workers may contain more than one phthalate, or workers may use multiple
phthalate-containing products throughout a workday. Due to the workplace and task-specific nature of
cumulative exposure scenarios that may exist in phthalate-containing workplaces, it was not possible to
provide a full quantitative assessment of cumulative risk for workers who may be exposed to multiple
phthalates. However, EPA was able to characterize the various businesses that use multiple phthalates
and the products that contain multiple phthalates, and has developed one option for deriving an
occupational exposure value (OEV) based on relative potency considerations. In addition to individual
chemical OEVs, this cumulative option is intended to summarize the occupational exposure scenario and
sensitive health endpoint into a single value. Similar to the individual OEVs, the calculated draft
cumulative OEV may be used to support risk management efforts for these evaluated phthalates under
TSCA section 6(a), 15 U.S.C. 6155 ง2605.
This section provides an overview of the industrial and commercial products identified by EPA that
contain multiple phthalates (Section 3.1.1), and the parent companies that report use of multiple
phthalates and facilities that report release of multiple phthalates (Section 3.1.2). Section 3.1.3 provides
a summary of EPA's preliminary conclusions, while Appendix E summarizes one option being
considered by EPA for deriving an OEV based on relative potency considerations.
3.1.1 Industrial and Commercial Products Containing Multiple Phthalates
One way workers may be occupationally exposed to multiple phthalates being evaluated under TSCA
(i.e., DEHP, DBP, BBP, DIBP, DCHP, DINP) is through use of an industrial or commercial product that
contains multiple phthalates. To assess the potential for co-exposure to multiple phthalates through the
use of industrial and commercial products containing multiple phthalates, EPA reviewed product safety
data sheets (SDSs) for products included in the occupational exposure assessments for DEHP (U.S.
EPA. 20250. DBP (U.S. EPA. 2025k\ BBP (U.S. EPA. 20250. DIBP (U.S. EPA. 2025ml DCHP (U.S.
EPA. 2024c\ and DINP (U.S. EPA. 2025oY
Overall, only 15 industrial and commercial products were identified that contained multiple phthalates
(TableApx D-2). The majority of products identified that contain multiple phthalates are laboratory
chemicals (13 out of 15 identified products with multiple phthalates are laboratory chemicals), with the
exception of one clay polymer product and one adhesive. Further, the laboratory chemical formulations
shown in Table Apx D-2 have low phthalate concentrations (generally less than 1 percent by weight
fraction). The clay polymer product also has low phthalate concentrations (less than 2.5 percent by
weight fraction) and solid physical form, and the material is commonly used in fashioning commercial
2 Conditions of use (COUs) are defined as "the circumstances, as determined by the Administrator, under which a chemical
substance is intended, known, or reasonably foreseen to be manufactured, processed, distributed in commerce, used, or
disposed of." (15 U.S.C. 2602(4))
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pens, while the adhesive product also has low concentrations of two phthalates (i.e., 1-5% DBP and 1-
5% DCHP).
Given the small number of industrial and commercial products identified that contain multiple
phthalates and given the low concentrations of phthalates in the identified products (TableApx D-2),
EPA does not expect these products to be a significant source of phthalate exposures contributing
to cumulative risk under most occupational and commercial exposure scenarios.
3.1.2 Multiple TSCA Phthalates at a Single Facility and/or Single Condition of Use
EPA acknowledges that there is potential for workers to be exposed to multiple phthalates being
evaluated under TSCA at a single facility. This may occur if a single facility works with multiple
phthalates. To provide an overview of potential phthalate co-exposures that may occur in the workplace,
EPA relied on programmatic data from the Chemical Data Reporting (CDR) rule, Toxics Release
Inventory (TRI), Discharge Monitoring Report (DMR), and the National Emissions Inventory (NEI).
These databases provide manufacture, processing, and release data reported by businesses across the
U.S.
3.1.2.1 Parent Companies Reporting Use of Multiple Phthalates
To better understand the landscape of parent companies that work with multiple phthalates, EPA first
reviewed 2016 and 2020 CDR data and 2017 through 2022 TRI data to identify parent companies that
report use of multiple phthalates. One limitation of this initial analysis is that only DEHP and DBP are
reportable under TRI (DINP is reportable to TRI as of January 2024). Data from CDR provides
manufacture and processing information from parent companies, including overall production volume
and number of facilities, and all phthalates considered in this cumulative assessment are reported to
CDR.
Table Apx D-3 characterizes the various parent companies from CDR and TRI that report use of
multiple phthalates. As can be seen from Table Apx D-3, EPA identified 56 domestic parent companies
that report use of multiple phthalates being evaluated under TSCA. Though these data provide a broad
overview of the various businesses involved in the phthalate industry, the CDR data provide information
about the parent company only and are not granular enough to determine if multiple phthalates are being
processed within a singular facility. Therefore, there is uncertainty associated with assigning co-
exposures based on parent company reporting data from CDR.
3.1.2.2 Facilities Reporting Releases of Multiple Phthalates
Data from TRI, DMR, and NEI provide release information for businesses that meet reporting
thresholds. TRI provides data for releases to air, water, and land, while DMR provides data for releases
to water, and NEI provides data for releases to air. However, since release reporting for some phthalates
is not currently required by programmatic reporting standards (i.e., for DIBP, DINP, and DCHP), TRI
and NEI data are limited to businesses that release DEHP and DBP, while DMR data are limited to
businesses that release DEHP, DBP, and BBP. Identified facilities from TRI (2017 to 2022), DMR
(2017 to 2023), and NEI (2017 and 2020) that reported use of multiple phthalates considered in this
cumulative assessment are provided in the Draft Summary of Facility Release Data for Di(l-ethylhexyl)
Phthalate (DEHP), Dibutyl Phthalate (DBP), and Butyl Benzyl Phthalate (BBP) (U.S. EPA. 2024p).
Overall, EPA identified 1,922 unique facilities that report releases of DEHP, DBP, or BBP to TRI,
DMR, and NEI (U.S. EPA. 2024p). Of the identified facilities, 1,461 report environmental releases of a
single phthalate, including 973, 483, and 5 facilities that report releases of DEHP, DBP, and BBP,
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respectively. Overall, 461 facilities were identified that reported releases of multiple phthalates,
including the following combinations:
419 facilities report releases of DBP and DEHP;
15 facilities report releases of DEHP and BBP;
4 facilities report releases of DBP and BBP; and
23 facilities report releases of DBP, DEHP, and BBP
This analysis indicates that there are approximately 461 facilities where workers may become co-
exposed to multiple phthalates while working. It is important to note that TRI, DMR, and NEI often
provide information from the release facility rather than the parent company, and this reduces
uncertainty when assigning potential co-exposure for a particular chemical in a facility.
There are some limitations and uncertainties associated with the current analysis. First, it is important to
re-iterate that because DIBP, DINP, and DCHP are not reportable to TRI, DMR, or NEI, specific
facilities working with these phthalates were not identified by EPA and therefore the number of facilities
identified by EPA as working with one or multiple phthalates is an underestimate. Another uncertainty
with the current analysis is that facilities that work with multiple phthalates may run campaigns in which
each phthalate is only used for part of the year. Further, these campaigns may not overlap and therefore
workers may not actually be co-exposed to multiple phthalates at all of the facilities identified by EPA.
For example, Exxon runs continuous half-year operations dedicated to the manufacture of DINP and
DIDP, which are staggered campaigns (ExxonMobil 2022). This makes it difficult to determine if
workers are actually co-exposed to multiple phthalates in the workplace, without conducting a facility-
by-facility analysis, which is outside the scope of this cumulative assessment.
3.1.2.3 Overlap in Industrial and Commercial COUs
EPA acknowledges that there is overlap in industrial and commercial COUs, and that overlap in COUs
may lead to worker co-exposure to multiple phthalates at facilities where multiple phthalates are
handled. As part of the 2023 draft proposal (U.S. EPA. 2023b). COU tables from final scope documents
were compared for DEHP, DBP, BBP, DCHP, DIBP, and DINP, demonstrating COU overlap
(TableApx D-4).
As part of its cumulative approach, EPA considered combining phthalate exposures for COUs with
overlap for multiple phthalates. For example, exposures for phthalates with the industrial use of
adhesives and sealants COU could be combined to estimate occupational cumulative exposure and risk.
However, this approach would require several assumptions that would likely lead to unrealistic
cumulative exposure estimates that are not reflective of the complexity and wide range of cumulative
exposure scenarios that may exist in phthalate-containing workplaces. For example, this approach would
require the assumption that most facilities with industrial use of adhesives and sealants are working with
multiple phthalates and that these facilities are working with multiple phthalates concurrently and not
running staggered campaigns with each individual phthalate. As discussed in Section 3.1.2.2, not all
facilities work with multiple phthalates. In fact, the majority of facilities may work with only one
phthalate (e.g., 1,461 of the 1,922 facilities identified in Section 3.1.2.2 report use of a single phthalate).
Given the complexity and wide range of cumulative exposure scenarios that may exist in phthalate-
containing workplaces, EPA considers there to be too much uncertainty associated with combining
phthalate exposures across COUs that apply to multiple phthalates.
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3.1.3 Conclusions on Cumulative Occupational Phthalate Exposure
As discussed above in Sections 3.1.1 and 3.1.2, workers may be occupationally exposed to multiple
phthalates through use of an industrial or commercial product containing multiple phthalates or through
working at a facility that handles multiple phthalates. However, EPA identified a limited number of
industrial and commercial products that contained multiple phthalates, and the products that were
identified contained low concentrations of phthalates (Section 3.1.1). This indicates that industrial and
commercial products containing multiple phthalates are not anticipated to be a major source of
cumulative phthalate exposure for most workers.
As discussed in Section 3.1.2, EPA identified approximately 461 facilities that report working with
multiple phthalates. However, these facilities report working with varying combinations of phthalates
(e.g., DEHP and DBP, DEHP and BBP, DBP and BBP, or DEHP, DBP, and BBP), and may run
campaigns in which each phthalate is only used for part of the year. These campaigns may not overlap
and therefore there is uncertainty as to whether workers are actually co-exposed to multiple phthalates at
all of the facilities identified by EPA. For example, Exxon runs continuous half-year operations
dedicated to the manufacture of DINP and DIDP, which are staggered campaigns (ExxonMobil 2022).
Due to the wide range of cumulative exposure scenarios that may exist in phthalate-containing
workplaces, it was not possible to provide a robust quantitative assessment of cumulative risk for
workers who may be exposed to multiple phthalates. Instead, EPA has developed an option for deriving
an OEV that accounts for cumulative exposure and differences in relative potency based on air
monitoring methods (Appendix E.l).
3.2 Consumer and Indoor Dust Exposure
Consumers may become co-exposed to multiple TSCA phthalates through a variety of potential
exposure scenarios. Relevant consumer exposure scenarios that may lead to co-exposure to multiple
TSCA phthalates include:
Consumer use of a product that contains multiple phthalates, thus the consumer is directly
exposed simultaneously;
Consumer use of multiple products and/or articles with multiple phthalates in a relevant time
frame (e.g., same day); or
Products and/or articles containing multiple phthalates contaminate indoor dust which is then
inhaled or ingested.
This section provides a qualitative overview of consumer use scenarios could plausibly lead to co-
exposure to multiple phthalates (Sections 3.2.1 and 3.2.2) and a quantitative assessment of cumulative
exposure to indoor dust using available monitoring data (Section 3.2.3).
3.2.1 Consumer Products Containing Multiple Phthalates.
Most products previously identified by EPA only contain a single phthalate (See Table Apx F-l from
2023 CRA proposal (U.S. EPA. 2023b)). EPA identified a product (PSI PolyClay Canes and PSI
PolyClay Bricks) that contains multiple phthalates (DEHP, BBP, DBP, and DINP), with each phthalate
below 2.5 percent. EPA compared the source and manufacturer information for the consumer products
and articles included in the consumer exposure assessments for DEHP (U.S. EPA. 2025e). DBP (U.S.
EPA. 2025c). BBP (U.S. EPA. 2025b). DIBP (U.S. EPA. 2025d\ DCHP (U.S. EPA. 2024a). and DINP
(U.S. EPA. 2025a). This comparison identified one additional trade name, 3M Economy Vinyl
Electrical Tape 1400, 1400C, as containing DEHP and DINP. A few other generic product and article
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categories contained multiple phthalates (e.g., Car Mats (BBP, DBP, DEHP, DIBP, DINP); synthetic
leather (DBP, DEHP, DIBP, DINP); adult toy (BBP, DBP, DEHP, DINP); garden hose and cutting
board (DBP, DEHP, DIBP, DINP); footwear (BBP, DBP, DIBP); shower curtain, children toys
compliant, football, wallpaper (DBP, DEHP, DIBP); children's toys (BBP, DBP, DINP); packaging
(BBP, DBP, DEHP); work gloves, pet chew toys, 3M electrical vinyl tape (DEHP, DINP)); however,
EPA is unable to confirm whether multiple phthalates are used concurrently in each of these items, or if
the phthalates are used interchangeably.
3.2.2 Consumer Use of Multiple Products and/or Articles in a Relevant Time Frame
Co-exposures to multiple phthalates across products and/or articles are dependent on evidence of co-use
and/or co-location. In the context of TSCA, co-uses typically refer to scenarios from which an individual
(e.g., consumer) may be exposed to two or more COUs such as when a spray and powdered cleaner are
used concurrently to clean a bathtub. Due to the numerous consumer products and articles found in the
domestic environment that contain phthalates, it is likely that a consumer may be simultaneously
exposed to phthalates from two or more different consumer products or articles. However, for co-
exposure to occur, exposure would need to occur in a narrow timeframe (i.e., same day) due to the fast
elimination kinetics of phthalates.
As described in EPA's 2023 draft approach (U.S. EPA. 2023b). there is limited information on the co-
use and/or co-location of consumer products to serve as evidence for co-exposure to different chemicals
present in multiple consumer products. Some studies have investigated co-use patterns for personal care
products (Safford et al.. 2015; Biesterbos et al.. 2013). Thus far, only one co-use study by Han et al. has
been identified, which considered multiple TSCA-relevant consumer products in its analysis, including
laundry detergents, fabric softeners, air fresheners, dishwashing detergents, and all-purpose cleaners.
However, the authors found no strong correlation of co-use between any pair of household and personal
care products (Han et al.. 2020).
Another approach to determine co-use of products has been to use purchase data or presence of certain
consumer products in the home to extrapolate combined exposure and risk (Stanfield et al.. 2021;
Tornero-Velez et al.. 2021). However, the presence of consumer products in the home is insufficient to
conclude resultant daily exposure for consumers. This further emphasizes the importance of co-use data
that help to describe consumer use patterns (e.g., which combinations of products are used, how often,
how much, etc.) for products currently on the market. Currently, available co-use studies indicate that
there is lack of evidence of co-use specifically for the TSCA COUs shown in Table Apx D-4. This may
in part be because many of the TSCA COUs associated with the phthalates are not necessarily common
household products regularly studied for concurrent use.
At this time, EPA did not estimate co-exposure of phthalates from multiple consumer products and
articles, as there is limited quantitative information on the co-occurrence of exposures to phthalate-
containing consumer products and articles within the same day.
3.2.3 Quantitative Cumulative Risk from Exposure to Indoor Dust
As emphasized by the SACC in their review of the draft 2023 approach document, indoor dust is a key
pathway for phthalate exposure and represents a sink for mixtures of phthalates from multiple sources,
summarized succinctly from their report as follows (U.S. EPA. 2023c):
"Dust is a very relevant exposure pathway that may vary by community and can reflect
many sources - for example outdoor dust and soil can be tracked inside, take home
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occupation exposures, building materials, furniture and products in the home can all
contribute to household dust levels and human exposures to mixtures with phthalates.
Household dust exposures will also vary by age, as younger children have faster
metabolisms, greater relative surface area, more exposure to the floor, and increased
hand to month behavior, making them likely to ingest more. "
To estimate cumulative risk from phthalate exposure from indoor dust, EPA relied on monitoring data of
settled dust for six phthalates (i.e., BBP, DBP, DCHP, DEHP, DIBP and DINP). Using the monitoring
studies on settled dust gathered via systematic review, EPA estimated average daily doses for:
Geometric mean dust ingestion and mean phthalate concentration;
Geometric mean dust ingestion and 95th percentile phthalate concentration;
High end dust ingestion and mean phthalate concentration; and
High end dust ingestion and 95th percentile phthalate concentration.
Settled dust monitoring concentrations were estimated from various monitoring studies across the US
(Table 3-1) (Hammel et al.. 2019; Bi et al.. 2018; Bi et al.. 2015; Dodson et al.. 2015; Shin et al.. 2014;
Guo and Kantian. 2011; Wilson et al.. 2003; Rudel et al.. 2001; Wilson et al.. 2001). These studies were
selected as they contained original settled dust data, were conducted in the U.S., and reported high
quality sampling and analytical methods and measured dust in homes, offices, or other indoor
environments representative of the U.S. general population. Studies with unclear sampling descriptions
(e.g., unclear number of samples collected, unclear whether suspended dust or settled dust), were
excluded from the analysis.
Using monitoring studies listed in Table 3-1, EPA calculated cumulative risk for various age groups (0-
1 month, 1-3 months, 3-6 months, 6-12 months, 1-2 years, 2-3 years, 3-6 years, 6-11 years, 11-16
years, 16-21 years, 21-30 years, 30-40 years, 40-50 years, 50-60 years, 60-70 years and over 80 years)
using the RPF approach described above in Section 2.
Table 3-2 provides the cumulative phthalate intake estimate for ages 3 to 6 years, and 16 to 50 years
from the indoor dust monitoring data. When comparing these dust intake estimates to cumulative risk
estimates for NHANES in Table 4-3, the percent contribution of NHANES to the risk cup is always
greater than ingestion of settled dust. This is anticipated as NHANES urinary biomonitoring provides an
estimate of aggregate exposure (i.e., exposure via all routes and pathways, including dust ingestion) to
each phthalate rather than just through ingestion of phthalates in settled dust.
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1235 Table 3-1. Confidence in Phthalate Settled Dust Monitoring Studies
Phthalate
Statistic
Nซ
Ingestion
(^g/g)
Studies
Study
Confidence
BBP
Mean
388
46
(Hammel et al.. 2019; Bi et al.. 2018; Bi et al.. 2015; Guo
and Kannan. 2011; Wilson et al.. 2001)
Robust
95th
234
151
(Hammel et al.. 2019; Dodson et al.. 2015)
DBP
Mean
329
38.8
(Hammel et al.. 2019; Bi et al.. 2018; Bi et al.. 2015;
Dodson et al.. 2015; Guo and Kannan. 2011; Rudel et al..
2001; Wilson etal..2001)
Robust
95th
234
64.8
(Hammel et al.. 2019; Dodson et al.. 2015)
DCHP
Mean
3
1.9
(Rudel et al.. 2001)
Slight
95th
49
7.4
(Dodson et al.. 2015)
DEHP
Mean
346
174
(Hammel et al.. 2019; Bi et al.. 2018; Bi et al.. 2015;
Rudel et al.. 2001)
Robust
95th
234
479
(Hammel et al.. 2019; Dodson et al.. 2015)
DIBP
Mean
43
16
(Bietal.. 2015)
Moderate
95th
188
33.9
(Hammel et al.. 2019)
DINP
Mean
188
78.8
(Hammel et al.. 2019)
Moderate
95th
188
787.6
(Hammel et al., 2019)
" EPA did not calculate central tendencies or 95th percentiles for individual studies, rather gathered the central tendencies and
95th percentiles that were reported in the individual studies. This is why the 'n' and number of studies vary between means and
95th percentile estimates as some studies only reported central tendencies while others only reported 95th percentile values.
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Table 3
ป-2. Cumu
ative Pht
lalate Daily
ntake (iig/kg-day)
Estimates from Indoor Dust Monitorin
2 Data
Age
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
Mean*
Aggregate
Daily Intake
(jig/kg-day)
High-End*
RPF
Aggregate Daily Intake
in DBP Equivalents
(jig/kg-day)
Mean
Cumulative Daily
Intake in DBP
Equivalents (ju.g/kg-
day)
Cumulative
MOE
(POD = 2,100
jig/kg-day)
% Contribution to
Risk Cup
(Benchmark = 30)"
3-6
50
BBP
0.10
0.66
0.52
0.05
0.34
6,095
0.5%
years
age
DBP
0.08
0.47
1
0.08
DCHP
0.00
0.00
1.66
0.00
DEHP
0.23
1.45
0.84
0.19
DIBP
0.01
0.07
0.53
0.01
DINP
0.06
0.40
0.21
0.01
95
BBP
0.07
0.43
0.52
0.23
2.39
880
3.4%
DBP
0.03
0.17
1
0.17
DCHP
0.00
0.01
1.66
0.01
DEHP
0.20
1.26
0.84
1.06
DIBP
0.03
0.16
0.53
0.09
DINP
0.64
3.98
0.21
0.84
16-50
50
BBP
0.01
0.08
0.52
0.00
0.02
97,684
0.0%
years
DBP
0.00
0.06
1
0.00
age"
DCHP
0.00
0.00
1.66
0.00
DEHP
0.01
0.18
0.84
0.01
DIBP
0.00
0.01
0.53
0.00
DINP
0.00
0.05
0.21
0.00
95
BBP
0.00
0.06
0.52
0.03
0.31
6,830
0.4%
DBP
0.00
0.02
1
0.02
DCHP
0.00
0.00
1.66
0.00
DEHP
0.01
0.16
0.84
0.13
DIBP
0.00
0.02
0.53
0.01
DINP
0.04
0.51
0.21
0.11
" Cumulative estimates from the 16-21 years age range were used to represent 16-50 years of age as all of these age groups (16-21 years, 21-30 years, 30-40 years and 40-50
years) had the same % contribution to the risk cup (0.0% and 0.4% for the 50th and 95th percentiles). 16-21 years of age had the lowest MOEs of these age groups (16-21
years, 21-30 years, 30^-0 years and 40-50 years).
ABolded values are carried forward to calculate cumulative Daily Intake (DBP Equivalents, (rg/kg-day).
1238
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3.2.4 Conclusions on Cumulative Consumer and Indoor Dust Phthalate Exposure
For co-exposure to occur, exposure would need to occur in a narrow timeframe (i.e., same day) due to
the fast elimination kinetics of phthalates. This could occur from use of a single product containing
multiple phthalates but, as discussed above in Sections 3.2.1, EPA has not identified much evidence of
multiple phthalates being used in a single consumer product to suggest that this is a substantial pathway
of co-exposure to multiple phthalates for consumers.
Due to the numerous consumer products and articles found in the domestic environment that contain
phthalates, it is highly plausible that a consumer may be simultaneously exposed to phthalates from two
or more different consumer products or articles. EPA identified limited quantitative information on the
co-occurrence or co-use of phthalate-containing consumer products and articles within the same day to
facilitate a robust and specific cumulative scenario based on specific COUs.
However, as discussed in Section 3.2.3, occurrence of TSCA phthalates in house dust is widespread.
EPA has estimated cumulative exposure and risk from exposure to phthalates from ingestion of house
dust. The highest cumulative phthalate exposure from ingestion of house dust was for children (3-5
years of age) using high-end dust ingestion assumptions and 95th percentile phthalate concentrations in
house dust. When comparing these dust intake estimates to cumulative risk estimates for NHANES in
Table 4-3, the percent contribution of NHANES to the risk cup is always much greater than ingestion of
settled dust. This is anticipated as NHANES urinary biomonitoring provides an estimate of aggregate
exposure (i.e., exposure via all routes and pathways, including dust ingestion) to each phthalate rather
than just through ingestion of phthalates in settled dust.
Therefore, at this time, EPA did not estimate co-exposure of phthalates from the direct use of multiple
consumer products (Section 3.2.2) beyond the estimation of non-attributable exposure described further
in Section 4.
3.3 General Population Exposure to Environmental Releases
General population exposures to environmental releases occur when phthalates are released into the
environment and the environmental media is then a pathway for exposure. As described in the draft
approach, the general population may be exposed to multiple phthalates either from single facilities
releasing more than one phthalate or from being in close proximity to co-located facilities. This section
provides a brief overview of the chemical properties across the phthalates of interest in Section 3.3.1 and
considers the geographic distribution of facilities with phthalate releases in Section 3.3.2.
3.3.1 Comparison of Fate Parameters Across Phthalates
Phthalate releases from facilities are expected to occur to air, water, and land. Based on the fate
parameters of the various phthalates, once released into the environment, phthalates are expected to
primarily partition to sediment and biosolids. However, despite phthalates being expected primarily in
sediments and biosolid, exposure to the general population would be mostly likely to occur primarily
through drinking water and fish ingestion based on the individual phthalate risk evaluation exposure
assessments. The physical chemical properties and fate parameters govern environmental fate and
transport and are detailed in the draft technical support documents for each chemical substance: DEHP
(U.S. EPA. 2024m\ BBP (U.S. EPA. 2024H. DBP (U.S. EPA. 2024k). DffiP (U.S. EPA. 2024n). DCHP
(U.S. EPA. 20241). DINP (U.S. EPA. 2025q). These properties and parameters for the cumulative
chemical group are summarized below in Table 3-3 and in this section.
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The magnitude of the partitioning coefficients identified for these phthalates suggest that they may exist
in surface water in both aqueous form and in suspension, and sorbed to organic carbon fractions in soil,
sediment, and air in the environment. The lower Henry's Law constants of these phthalates indicate that
they are not expected to volatilize from surface water. DEHP, BBP, DBP, DIBP, DCHP, and DINP have
very low to slight solubility in water. DEHP and DIDP have very low water solubility (0.003 mg/L for
DEHP; 0.00061 mg/L for DINP; 0.00017 mg/L for DIDP), while BBP, DBP, DIBP, and DCHP are
slightly soluble in water (2.3 mg/L for BBP; 11.2 mg/L for DBP; 6.2 mg/L for DIBP; 0.03 - 1.48 mg/L
for DCHP). Sorption to organics present in sediment and suspended and dissolved solids present in
water is expected to be a dominant process given the range of identified log Koc values across DEHP,
DBP, BBP, DIBP, DCHP, and DINP (Table 3-3). BBP's solubility and range of log Koc values for
phthalates in the cumulative chemical group (Table 3-3) suggests that they are unlikely to exhibit
mobility in soils, which is also supported by fugacity modeling results. In general, amongst phthalates in
the cumulative chemical group, as molecular weight decreases, water solubility and vapor pressure
increase, while tendency to partition to organic carbon (sorption to soils and sediments) and
environmental half-lives also decrease.
Phthalates in the cumulative chemical group in surface water are subject to two primary competing
processes: biodegradation and adsorption to organic matter in suspended solids and sediments.
Phthalates in the cumulative chemical group in the freely dissolved phase are expected to show low
persistence, with rapid biodegradation under aerobic conditions. The fraction of phthalates in the
cumulative chemical group adsorbed to particulates increases with water salinity due to a salting out
effect, as indicated by greater log Koc values measured in saltwater as compared to those measured with
freshwater. Monitoring data in the U.S. generally show low detection frequencies in surface water.
Sampling of U.S. surface water sediments yielded a wide range of concentrations; however all of these
phthalates were generally found in low concentrations where they were detected and often with low
detection frequencies. Phthalates in the cumulative chemical group are expected to be removed in
conventional drinking water treatment processes by means of aggregation to floccules and subsequent
settling and filtration processes, as well as by oxidation by chlorination byproducts in post-treatment and
transmission of finished drinking water.
The vapor pressures of the phthalates in the cumulative chemical group indicate that they will
preferentially adsorb to particulates in the atmosphere, with adsorbed fractions being resistant to
photolysis. This is consistent with measured and estimated octanokair partition coefficients (Table
3-3). Phthalates in the cumulative chemical group that do occur in the atmosphere will likely degrade via
OH-mediated indirect photolysis with a half-life of hours to days based on an estimated OH reaction
rate constants, and assuming a 12-hour day with 1.5xlO6 OH/cm3 (U.S. EPA. 2017). Phthalates in the
cumulative chemical group are generally consistently detected at low concentrations in ambient air;
however, given their atmospheric half-lives, they are not expected to be persistent in air or undergo long
range transport.
Phthalates in the cumulative chemical group present low bioconcentration potential in fish, are unlikely
to biomagnify, and will exhibit trophic dilution in aquatic species. Biomagnification or bioaccumulation
of terrestrial and avian species is also not likely.
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1327
DIBP, BBP, DEHP, and DINP
Property
DEHP
(U.S. EPA 2024m)
BBP
(U.S. EPA. 2024i)
DBP
(U.S. EPA. 2024k)
DIBP
(U.S. EPA. 2024n)
DCHP
(U.S. EPA. 20241)
DINP
(U.S. EPA. 2025a)
Molecular formula
C24 H38 O4
C19H20O4
C16H22O4
C16H22O4
C20H26O4
C26H42O4
Molecular Weight
(g/mol)
390.56
312.37
278.35
278.35
330.43
418.62
Physical state of the
chemical
Colorless, oily liquid
Clear oil, liquid
Colorless to faint
yellow, oily liquid
Colorless, clear,
viscous liquid
White, granular
solid
Clear Liquid
Melting Point (ฐC)
-55
-35
-35
-64
66
-48
Boiling Point (ฐC)
384
370
340
296.5
225
>400
Density (g/cm3)
0.981
1.119
1.0459 to 1.0465
1.049
1.383
0.97578
Vapor Pressure (mmHg)
142xl0"7
8.25 xlO"6
2.01X10"5
4.76 xlO"5
8.69xl0"7
5.40xl0-?
Water Solubility (ng/L)
3,000
2,690,000
11,200,000
6,200,000
30000 - 1,480,000
610
Log Kow
7.6
4.73
4.5
4.34
4.82
8.8
Log Kqa (estimated
using EPI Suite)
10.76
9.2
8.63
9.47
10.23
11.9
Log Koc
3.75-5.48
2.09-2.91
3.16-4.19
2.5-3.14
3.46-4.12
5.5-5.7
Henry's Law Constant
(atm-m3/mol)
1.71xl0"5
7.61xl0"7
1.81xl0"6
1.83xl0"7
9.446xl0"8
9.14 xlO5
Flash Point (ฐC)
206
199
157.22
185
207
213
Autoflammability (ฐC)
390
-
402.778
432
No data
400
Viscosity (cP)
57.94
55
20.3
41
Not applicable
(solid)
77.6
Overall Enviromnental
Persistance
Low
Low
Low
Low
Low
Low
Bioaccumulation Factor
(Log BAF A-G)
3.02
1.60
2.20
1.41
2.14
1.14
Bioconcentration Factor
(Log BCF A-G)
2.09
2.88
2.20
1.41
2.13
0.39
1328
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3.3.2 Geographic Consideration of Reported Releases of Phthalates
In the draft 2023 approach (U.S. EPA. 2023b). EPA recognized that the general population, those
impacted by facility release of phthalates, could be exposed to multiple phthalates from single facilities
that release more than one phthalate or be exposed to multiple phthalates due to living in close proximity
to co4ocated facilities. Given the chemical properties described in Section 3.3.1 and the chemical-
specific Fate TSDs, the major pathway for any environmental exposure would be sediments and
biosolids from continuous or recent concurrent releases. Therefore, EPA analyzed the co4ocation of all
the known phthalate-releasing facilities within common watersheds.
As described above in Section 3.1.2.2, EPA identified DMR, NEI, and TRI data for DEHP, DBP, and
BBP, but not for DCHP, DINP, and DIBP. These EPA databases provide information on facilities
releasing phthalates to various environmental media and provide latitude and longitude data for
releasing facilities. Using the release information, EPA identified 1,461 facilities that report use of a
single phthalate, while 461 report use of multiple phthalates (i.e., any combination of DEHP, DBP, or
BBP). Using the available location data, EPA mapped the reporting facilities in Figure 3-1 to look for
geographic patterns or hotspots. Individual facilities are broadly dispersed around the United States. Of
note, no releasing facilities are reported in Alaska, an area of note in the SACC review of the draft 2023
approach (U.S. EPA. 2023c).
EPA also analyzed the locations of the identified facilities by watershed or hydrologic units. A
hydrologic unit represents the area of the landscape that drains to a portion of the stream network and is
identified by a unique Hydrologic Unit Code (HUC). EPA searched for the HUC12 watershed level,
which represents an average size of 36 square miles (The RPS Methodology: Comparing Watersheds.
Evaluating Options | US EPA), for each the identified facilities. These are listed in in the Draft Summary
of Facility Release Data for Di (2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), and Butyl
Benzyl Phthalate (BBP) (U.S. EPA. 2024p). In the following HUC 12 watersheds, four or more releasing
facilities are identified
120401040703
180300090701
120401040706
120402040100
101900030304
040601020303
180701050401
180701060701
170900120202
180701030202
030501010804
030501010701
180702030804
180701060502
180400030205
180701060102
180703041202
071401010403
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in Harris County, TX (11 facilities)
in Fresno County, CA (9 facilities)
in Harris County, TX (8 facilities)
in Harris County and Brazoria County, TX (8 facilities)
in Denver County, CO (6 facilities)
in Wexford County, MI (6 facilities)
in Los Angeles County, CA (5 facilities)
in Los Angeles County, CA (5 facilities)
in Multnomah County, OR (5 facilities)
in Ventura County, CA (5 facilities)
in Burke and Catawba Counties, NC (5 facilities)
in Caldwell County, NC (5 facilities)
in San Bernardino and Riverside Counties, CA (4 facilities)
in Los Angeles County, CA (4 facilities)
in San Joaquin County, CA (4 facilities)
in Los Angeles County, CA (4 facilities)
in San Diego County, CA (4 facilities)
in St. Clair County, IL and St. Louis County, MO (4 facilities)
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020301040205 in Hudson County, NJ and Kings County, NY (4 facilities)
020402010407 in Burlington County, NJ and Bucks County, PA (4 facilities)
020200041108 in Schenectady County, NY (4 facilities)
Even where co4ocated facilities within watersheds have been identified, there is difficulty in estimating
the cumulative exposures in those locations. First, the programmatic data from DMR, NEI, and TRI are
reported per facility for a single reporting year. Although information such as the highest release is
reported, there is no information on the timing of release of phthalates into the environment, making it
difficult to identify any areas that are impacted by multiple phthalates concurrently.
Additionally, although EPA identified 461 facilities reporting the use of multiple phthalates, the
reporting data does not state whether the multiple phthalates are used concurrently within the facility
and released simultaneously to the environment. Often, use or production of multiple chemicals such as
the phthalates occur in campaigns, where a single phthalate is used for a determined period of time
before the facility uses another phthalate for another period of time. In these instances, phthalates would
not be released from the facility concurrently and, therefore, may not pose a cumulative exposure to
surrounding communities based on the fate parameters of the phthalates. EPA recognizes that the lack of
data on the timing of the releases makes it difficult to quantify cumulative exposure from facilities
reporting use of multiple phthalates.
In general, EPA recognizes that there may be discrete locations impacted by the release of multiple
phthalates either through single facilities releasing multiple phthalates or multiple facilities within the
same watershed or releasing to the same wastewater facility. Releases would need to be continuous to
lead to ongoing exposure given the relatively low persistence in the environment. In the risk evaluations
for the individual phthalates, the general population exposures from pathways such as drinking water,
recreational swimming, ambient air, incidental soil ingestion, and fish ingestion for each phthalate are
estimated and found to be much lower than exposures for consumer and occupational populations, even
when quantified using a screening-level assessment using conservative (e.g., low tier, high risk)
assumptions.
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1404
1405
Figure 3-1. Mapping of Facilities with One of Multiple Phtlialates
0 200 400
Kilometers
I Kilometers
Tribal Lands
Tribal Lands
States
I ] States
Facilities Reporting
Phthalate Releases
O BBP
O DBP
O DEHP
o Multiple
2,000
I Kilometers
0 250 500 1,000 1,500 2,000
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3.3.3 Conclusions on Cumulative General Population Exposure to Environmental
Releases of Phthalates
The general population may be exposed to the environmental releases of multiple phthalates from a
facility that releases multiple phthalates or from facilities in proximity releasing into the same
watershed. As discussed above in Section 3.3.1 and in the individual chemical technical support
documents, phthalates are expected to partition primarily to sediments and biosolids with human
exposure most likely to occur through drinking water and fish ingestion. However, the phthalates have
relatively low persistence, low bioaccumulation potential, and low long-range transport so they are
unlikely to build up in the environment, including artic environments. Localized, site specific co-
exposures are possible but overall exposures are expected to be marginal compared to total exposure.
Therefore, at this time, EPA did not estimate co-exposure of phthalates from multiple releasing facilities
or facilities releasing multiple phthalates. Given the reliance on screening methods for estimating
general population exposure to environmental releases, EPA discourages the aggregation of modelled
screening estimates without more refined exposure models or monitoring data.
3.4 Non-TSCA Exposure to Diet
Non-TSC A exposures to a combination of phthalates may occur through diet which includes the
consumption of phthalates from food packaging. Using a scenario-based approach, U.S. Consumer
Product Safety Commission (CPSC) found the majority of women's exposure to DEHP, DINP, and
DIBP was from diet (DCHP was not included in their analysis). Their estimates were in general
agreement (within an order of magnitude) with two other studies estimating phthalate exposure using
scenario-based exposure assessment methods with differences attributable to differing approaches for
dietary exposure estimation (Clark et al.. 2011; Wormuth et al.. 2006). U.S. CPSC (2014) estimated
dietary exposure using two datasets of phthalate residues in food items (Bradley et al.. 2013; Page and
Lacroix. 1995). Additional studies were used for food categorization and consumption estimates,
including the U.S. EPA National Center for Environmental Assessment's analysis of food intake and
diet composition (Clark et al.. 2011; U.S. EPA. 2007; Wormuth et al.. 2006).
Health Canada concluded that the main sources of exposure to the general Canadian population for
medium-chain phthalates were food, indoor air, dust, and breast milk (ECCC/HC. 2020). For their
estimation of dietary intake of DIBP, BBP, DBP, and DEHP, Health Canada used the 2013 Canadian
Total Diet Study (ECCC/HC. 2020). For other phthalates, they used the 2013 through 2014 and 2014
through 2015 Food Safety Action Plan (Canadian Food Inspection Agency) and/or a dietary exposure
study from the United States (Schecter et al.. 2013). A United Kingdom total diet study (Bradley et al..
2013) was used to fill in data gaps. The phthalate concentrations were matched to 2004 Canadian
Community Health Survey on nutrition (Statistics Canada. 2004) consumption values for each
individual food.
In the draft 2023 approach (U.S. EPA. 2023b). EPA proposed using a scenario-based exposure
assessment to determine non-attributable and non-TSCA source exposure levels to all phthalates and to
reconstruct an aggregated daily exposure profile for receptors varied by age (women of reproductive
age, male infants, toddlers, and children). The approach proposed was to use similar methods to Health
Canada (ECCC/HC. 2020) and U.S. CPSC (2014). which determined that diet comprised a large portion
of total daily intake for populations of interest. In its review of the approach, SACC recommended
reviewing literature related to estimates of exposure from diet given the highly diverse U.S. population
(U.S. EPA. 2023 c). EPA conducted a literature search to investigate if there were any large-scale
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phthalate dietary assessments that would influence a national scale dietary assessment or warrant an
update to the previously conducted analyses. However, EPA has concluded that there is limited updated
information to substantially change the daily intake estimates previously constructed by the other
agencies using scenario-based methods, including for sensitive subpopulations.
Health Canada (ECCC/HC. 2020) and U.S. CPSC (2014) had both estimated total phthalate daily intake
values using reverse dosimetry with human urinary biomonitoring data and scenario-based exposure
assessment approaches. Health Canada and U.S. CPSC found that both the reverse dosimetry and
scenario-based approaches resulted in daily intake values that were generally similar in magnitude.
However, this depended on the recency and quality of data available for use, particularly for data on
major exposure pathways like diet. Rather than construct new national estimates of dietary intake, EPA
is similarly using reverse dosimetry with national human urinary biomonitoring data, described further
in Section 4, which provides total intake for total population and subpopulations by demographic
category.
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4 PHTHALATE EXPOSURE AND RISK FOR THE U.S.
POPULATION USING NHANES URINARY BIOMONITORING
DATA
The U.S. Center for Disease Control's (CDC) National Health and Nutrition Examination Survey
(NHANES) is an ongoing exposure assessment of the U.S. population's exposure to environmental
chemicals using biomonitoring. The NHANES biomonitoring dataset is a national, statistical
representation of the general, non-institutionalized, civilian U.S. population. As described in the Draft
Proposed Approach for Cumulative Risk Assessment of High-Priority Phthalates and a Manufacturer-
Requested Phthalate under the Toxic Substances Control Act (draft 2023 approach) (U.S. EPA. 2023b).
a reverse dosimetry approach for exposure and risk analysis relies on CDC's NHANES urinary
biomonitoring dataset and a single compartment toxicokinetic model to estimate total exposure to
individual phthalates for the U.S. civilian population. However, exposures measured via NHANES
cannot be attributed to specific sources. Given the short half4ives of phthalates, neither can NHANES
capture acute, low frequency exposures. Instead, as concluded by the SACC review of the draft 2023
approach, NHANES provides a "snapshot" or estimate of total, non-attributable phthalate exposure for
the U.S. population and relevant subpopulations (U.S. EPA. 2023 c). These estimates of total non-
attributable exposure can supplement assessments of scenario-specific acute risk in individual risk
evaluations.
As can be seen from Table 4-1, monoester metabolites of BBP, DBP, DEHP, DIBP, and DINP in human
urine are regularly measured as part of the NHANES biomonitoring program and are generally
detectable in human urine at a high frequency, including during the most recent NHANES survey period
(i.e., 2017 to 2018). For DEHP, four urinary metabolites are regularly monitored as part of NHANES,
including mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate
(MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-ethyl-5-oxohexyl)
phthalate (MEOHP). For DBP and DIBP, two urinary metabolites of each phthalate are regularly
monitored, including mono-n-butyl phthalate (MnBP) and mono-3-hydroxybutyl phthalate (MHBP) for
DBP and mono-2-methyl-2-hydroxypropyl phthalate (MHiBP) and mono-isobutyl phthalate (MIBP) for
DIBP. For DINP, three urinary metabolites are regularly monitored (i.e., mono-isononyl phthalate
[MINP], mono-oxoisononyl phthalate [MONP], and mono-(carboxyoctyl) phthalate [MCOP]), while
one metabolite is regularly monitored for BBP (i.e., mono-benzyl phthalate [MBzP]). One urinary
metabolite of DCHP (i.e., monocyclohexyl phthalate [MCHP]) was included in NHANES from 1999
through 2010, but was excluded from NHANES after 2010 due to low detection levels and a low
frequency of detection in human urine (detected in less than 10 percent of samples in 2009 to 2010
NHANES survey) (CDC. 2013a). Further details regarding the limit of detection, frequency of detection,
additional methodological and results for each phthalate can be found in Appendix C, as well as in the
environmental media and general population exposure assessments for DEHP (U.S. EPA. 2025h). DBP
(U.S. EPA. 2025a). BBP (U.S. EPA. 2025f). DIBP (U.S. EPA. 20250. DINP (U.S. EPA. 2025n\ and
DCHP (U.S. EPA. 2024bY
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Table 4-1. Urinary Phthalate Metabolites Included in NHANES
Associated
NHANES
% Samples Below the
LOD in 2017-20186
NHANES (All
Participants, N=2,762)
Phthalate
NHANES Urinary Metabolite "
Parent
Compound
Reporting
Yearsb
Mono-2-ethylhexyl phthalate (MEHP)
DEHP
1999-2018
43.77%
Mono-(2-ethyl-5 -hydroxyhexyl) phthalate
(MEHHP)
DEHP
2001-2018
0.98%
DEHP
Mono-(2-ethyl-5 -oxohexyl) phthalate
(MEOHP)
DEHP
2001-2018
0.83%
Mono-(2-ethyl-5 -carboxypentyl) phthalate
(MECPP)
DEHP
2003-2018
0.18%
DBP
Mono-3-hydroxybutyl phthalate (MHBP)
DBP
2013-2018'#
24.91%
Mono-n-butyl phthalate (MnBP)
DBP, BBP
1999-2018
0.69%
BBP
Mono-benzyl phthalate (MBzP)
BBP
1999-2018
3.8%
Mono-isobutyl phthalate (MIBP)
DIBP
2001-2018
4.89%
DIBP
Mono-2-methyl-2-hydroxypropyl Phthalate
(MHiBP)
DIBP
2013-2018'#
2.17%
DCHP
Mono-cyclohexyl phthalate (MCHP)
DCHP
1999-2010
_C
Mono-isononyl phthalate (MiNP)
DINP
1999-2018
12.57%
DINP
Mono-oxoisononyl phthalate (MONP)
DINP
2015-2018
12.85%
Mono-(carboxyoctyl) phthalate (MCOP)
DINP
2005-2018
0.51%
LOD = limit of detection
"NHANES reports uncorrected and creatinine corrected urine concentrations for each metabolite.
b 2017-2018 is the most recently available NHANES dataset.
c In the 2009 to 2010 survey year (last survey in which MCHP was monitored), MCHP was above the LOD in 4.3 percent
of samples for all adults 16 years and older, and 7.9 percent of samples for all children 3 to less than 16 years of age (see
Appendix C for further details).
''MHBP and MHiBP were measured in the 2013 to 2018 NHANES cycles; however, the data for the 2013 to 2014
NHANES cycle was determined to be inaccurate due to procedural error and only released as surplus data, which is not
readily Diibliclv available (httr>s://wwwn.cdc.eov/Nchs/Nhanes/2013-2014/SSPHTE H.htm). As a result, the dresent
analysis only includes urinary MHBP data from the 2015 to 2018 NHANES cycles.
EPA analyzed NHANES urinary biomonitoring data from 1999 through 2018 for metabolites of DEHP,
DBP, BBP DIBP, DINP, and DCHP for several subpopulations reported within NHANES to determine
median and 95th percentile exposure estimates for each urinary metabolite measured in NHANES. EPA
also analyzed the available urinary biomonitoring data to understand temporal trends in phthalate
exposure for the civilian U.S. population (discussed further in Section 4.1). These analyses were
performed for the following populations reported within NHANES, including:
Male and female children aged 3 to less than 6 years, 6 to 11 years, and 11 to less than 16 years;
Male and female adults 16 years of age and older; and
Women of reproductive age (16 to 49 years of age).
Using reverse dosimetry, EPA also estimated non-attributable daily intake values for DEHP, DBP, BBP,
DIBP, and DINP using the most recent NHANES urinary biomonitoring data from 2017 to 2018.
Reverse dosimetry involves estimating aggregate exposure (expressed as a daily intake value) for each
individual phthalate from human urinary biomonitoring data for metabolites unique to each parent
phthalate (discussed further in Section 4.2). Reverse dosimetry approaches that incorporate basic
pharmacokinetic information are available for phthalates (Koch et al.. 2007; Koch et al.. 2003; David.
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2000) and have been used in previous human health cumulative risk assessments conducted by U.S.
CPSC (2014) and Health Canada (ECCC/HC. 2020). Consistent with EPA's decision to focus its draft
phthalate CRA on women of reproductive age (16 to 49 years) and male infants, male toddlers, and male
children as susceptible subpopulations (Section 1.4) (U.S. EPA. 2023b) EPA used NHANES urinary
biomonitoring and reverse dosimetry to estimate daily intake values for:
Women of reproductive age (16 to 49 years of age);
Male children 3 to less than 6 years of age (used as a proxy for male infants and toddlers);
Male children 6 to 11 years of age; and
Male children 12 to less than 16 years of age.
Daily intake values were calculated for women of reproductive age, because this population most
closely aligns with the selected hazard (i.e., reduced fetal testicular testosterone content) and generally
too few pregnant women are sampled as part of NHANES to support a statistical analysis in survey
years after 2005 to 2006 (CDC. 2013b; NCHS. 2012). and other national datasets are not available.
Daily intake values were calculated for male children because testosterone plays an important role in
male sexual development during fetal and postnatal lifestages. Since NHANES does not include urinary
biomonitoring for infants or toddlers, and other national datasets are not available, EPA used
biomonitoring data from male children 3 to less than 6 years of age as a proxy for male infants (<1 year)
and toddlers (1-2 years).
For women of reproductive age, daily intake values were also calculated based on race as reported in
NHANES (i.e., white non-Hispanic, black non-Hispanic, Mexican-American, other) and socioeconomic
status (i.e., above or below the poverty line, unknown income) to better understand if these factors
influence phthalate exposure and cumulative risk for the U.S. population. A similar analysis by race was
not done for male children because the NHANES sample size is smaller for this population.
EPA provides a summary of temporal trends observed for each phthalate metabolite in Section 4.1.
Sections 4.2 and 4.3 provide estimates of aggregate and cumulative phthalate daily intake values,
respectively, for women of reproductive age and male children reported within NHANES. Section 4.4.
provides cumulative risk estimates for women of reproductive age and male children within the U.S.
population based on daily intake estimates from NHANES. Section 4.5 summarizes EPA weight of
scientific evidence conclusions.
4.1 Temporal Trends in Phthalate Exposure Based on NHANES Urinary
Biomonitoring Data
EPA evaluated NHANES urinary biomonitoring data from 1999 to 2018 for DEHP, DBP, BBP, DIBP,
and DINP to determine any trends in phthalate exposure within the U.S. civilian population over the past
two decades. This temporal trends analysis was conducted for the following populations:
All NHANES participants;
All adults (16 years and older);
Female adults (16 years and older);
Male adults (16 years and older);
Children 3 to less than 6 years, 6 to less than 11 years, and 11 to less than 16 years (not stratified
by sex);
Male children less than 16 years of age; and
Female children less than 16 years of age.
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Results for this temporal trends analysis are summarized below and in more detail in Appendix C.2. For
convenience, median phthalate urinary metabolite concentrations for the NHANES 'All Participants'
group from 1999 through 2018 are provided in Figure 4-1. Overall, several notable trends in phthalate
exposure for the U.S. population were observed, including:
Overall 50th and 95th percentile urinary metabolites of DEHP (MEHP, MEHPP, MEOHP,
MEOCP), DBP (MnBP), and BBP (MBzP) have statistically significantly decreased over time
(1999-2018) for all populations, indicating declining exposure for these phthalates in the U.S.
population (see Appendices C.2.1 - C.2.3 for further details).
For DIBP, 50th and 95th percentile urinary MTBP concentrations statistically significantly
increased over time (1999-2018) for all lifestages, while 50th and 95th percentile MHiBP urinary
concentrations statistically significantly decreased over time (2015-2018) for most life stages
(see Appendix C.2.4 for further details). However, urinary MHiBP data is only available from
two NHANES survey periods and it is unclear if this trend in declining exposure will persist as
additional NHANES data becomes available.
For DINP, urinary concentrations of MCOP and MINP statistically significantly increased from
2005 through 2014 for all NHANES participants. After 2014, urinary concentrations of MCOP
and MINP statistically significantly decreased for all NHANES participants (see Appendix C.2.5
for further details).
EPA did not conduct a temporal trends analysis for DCHP. The DCHP urinary metabolite, MCHP, was
monitored as part of NHANES from 1999 through 2010, but was not included in subsequent survey
years because of the low detection levels and low frequency of detection of MCHP in urine. For
example, in the 2009 to 2010 NHANES survey, MCHP was detectable in only 4.3 percent of samples
for all adults 16 years and older, and 7.9 percent of samples for all children 3 to less than 16 years of
age. These results indicate low exposure to DCHP for the U.S. civilian population (Appendix C.l).
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30-
I 20
10-
Metabolite
MzBP (BBP)
MHBP (DBP)
MnBP(DBP)
MCHP (DCHP)
MECPP (DEHP)
MEHP(DEHP)
MEHHP (DEHP)
* MEOHP (DEHP)
ฃ MiBP(DIBP)
0 MHiBP (DIBP)
ฎ MCOP(DINP)
ffl MiNP (DINP)
ซ MONP(DINP)
J? f j? V' J? j? 'jt J?
NHANES Cycle
Figure 4-1. Median Plithalate Metabolite Concentrations Over Time for All NHANES
Participants From 1999 Through 2018
4.1^ Trends in National Aggregate Production Volume Data
EPA also considered whether temporal trends in national aggregate production volume data mirror those
observed in NHANES urinary biomonitoring data. To do this, EPA extracted national aggregate
production volume (PV) data for DEHP, DBP, DIBP, BBP, DCHP, and DINP from the 2016 and 2020
Chemical Data Reporting (CDR) (Appendix D. l). In CDR, national aggregate PV data is reported as a
range to protect PV data claimed as confidential business information (CBI). Given the large ranges in
reported PV data for each phthalate, EPA was unable to conclude whether or not there are any trends in
PV for any phthalate over this time period.
4.2 Aggregate Phthalate Exposure Based on NHANES Urinary
Biomonitoring Data and Reverse Dosimetry
Using DEHP, DBP, BBP, DIBP, and DINP urinary metabolite concentrations measured in the most
recently available NHANES survey from 2017 to 2018, EPA estimated the daily intake of each phthalate
through reverse dosimetry. NHANES provides an estimate of aggregate exposure for each individual
phthalate. EPA defines aggregate exposure as the "combined exposures to an individual from a single
chemical substance across multiple routes and across multiple pathways" (40 CFR ง 702.33). Reverse
dosimetry approaches that incorporate basic pharmacokinetic information are available for phthalates
(Koch et al.. 2007; Koch et al... 2003; David, 2000) and have been used in previous phthalate risk
assessments conducted by U.S. CPSC (2014) and Health Canada (SCCC/HC. 2020) to estimate daily
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intake values for exposure assessment. For phthalates, reverse dosimetry can be used to estimate a daily
intake value for a parent phthalate diester based on phthalate monoester metabolites measured in human
urine. Further details regarding the reverse dosimetry method used by EPA to estimate daily intake
values, as well as a discussion of limitations and uncertainties associated with the reverse dosimetry
method, are provided in Appendices C.3 and C.5, respectively.
Table 4-2 shows the 50th and 95th percentile aggregate daily intake values for DBP, DEHP, BBP, DIBP,
and DINP for women of reproductive age (16 to 49 years) and male children (ages 3 to 5, 6 to 11, and 12
to 15 years), while Table 4-3 shows the aggregate 50th and 95th percentile daily intake values for women
of reproductive age stratified by race and socioeconomic status. For women of reproductive age (Table
4-2), aggregate daily intake values were highest for DEHP and DINP, with 50th and 95th percentile
aggregate daily intake values of 0.53 and 1.48 |ig/kg-day, respectively, for DEHP and 0.7 and 5.6 |ig/kg-
day, respectively, for DINP. Comparatively, aggregate daily intake values for women of reproductive
age were lower for DBP (50th and 95th percentile daily intake values: 0.21 and 0.61 |ig/kg-day,
respectively), BBP (50th and 95th percentile daily intake values: 0.08 and 0.42 |ig/kg-day, respectively),
and DIBP (50th and 95th percentile daily intake values: 0.2 and 0.57 |ig/kg-day, respectively) (Table
4-2).
As can be seen from Table 4-2, for male children, aggregate exposure to each individual phthalate was
generally the highest for male children 3 to 5 years old, and declined with age such that male children 11
to 15 years old generally had the lowest aggregate exposure estimates. Similar to women of reproductive
age, aggregate daily intake values were highest for DEHP and DINP for all age groups for male
children, followed by DBP, DIBP, and BBP (Table 4-2). Aggregate daily intake values ranged from 0.66
to 2.11 |ig/kg-day and 2.51 to 6.44 |ig/kg-day at the 50th and 95th percentiles, respectively, for DEHP
(depending on age group), and ranged from 0.6 to 1.4 |ig/kg-day and 3.4 to 4.8 |ig/kg-day at the 50th and
95th percentiles, respectively, for DINP (depending on age group) (Table 4-2). Comparatively, aggregate
daily intake values for male children were lower for DBP (ranging from 0.33 to 0.56 |ig/kg-day and 0.62
to 2.02 |ig/kg-day day at the 50th and 95th percentiles, respectively, depending on age group); BBP
(ranging from 0.14 to 0.22 |ig/kg-day and 0.64 to 2.46 |ig/kg-day day at the 50th and 95th percentiles,
respectively, depending on age group); and DIBP (ranging from 0.21 to 0.57 |ig/kg-day and 0.59 to 2.12
|ig/kg-day day at the 50th and 95th percentiles, respectively, depending on age group) (Table 4-2).
A public commentor on the draft risk evaluations for DIDP and DINP (EPA-HQ-OPPT-2024-0073-
0081) indicated that EPA may be overestimating phthalate daily intake values using reverse dosimetry
compared to a more recent Bayesian approach developed by scientists in EPA's Office of Research and
Development (Stanfield et al.. 2024). EPA considered the Bayesian approach for estimating phthalate
daily intake values reported by Stanfield et al. However, an important limitation of the Bayesian
approach published by Stanfield et al. is that it does not incorporate phthalate-specific information, such
as fractional urinary excretion values, which will lead to an underestimation of daily intake values for
phthalates. For example, Stanfield et al. report a median daily intake value of 0.41 |ig/kg-day DEHP for
all NHANES participants in the 2015 to 2016 NHANES cycle using the Bayesian approach (see Table
S8 of Stanfield et al.), while EPA estimated a daily intake of 1.07 |ig/kg-day for the same population in
the 2017 to 2018 NHANES cycle {Note: an exact comparison was not possible because Stanfield et al.
did not evaluate 2017-2018 NHANES data, while EPA only estimated daily intake values for 2017-2018
data). For DEHP, the sum fractional urinary excretion of urinary metabolites (MEHP, MEHHP,
MEOHP, MECPP) is 0.453, and normalizing the Bayesian daily intake estimates for fractional urinary
excretion provides a very similar daily intake estimate as that obtained using the reverse dosimetry
approach (i.e., 0.41 |ig/kg-day ^ 0.453 = 0.91 |ig/kg-day). Therefore, EPA expects that if the Bayesian
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approach were to account for fractional urinary excretion values, daily intake estimates using the
Bayesian approach would be similar to the reverse dosimetry daily intake estimates.
4.3 Cumulative Phthalate Exposure Estimates Based on NHANES Urinary
Biomonitoring
In contrast to aggregate exposure, which refers to exposure to a single chemical substance, cumulative
exposure refers to aggregate exposure to multiple chemical substances. To estimate cumulative phthalate
exposure, EPA scaled the individual aggregate phthalate daily intake estimates for each population by
relative potency using the RPFs shown in Table 2-4. Phthalate daily intake values, expressed in terms of
index chemical equivalents (i.e., DBP equivalents in |ig/kg-day), were then summed to estimate
cumulative phthalate daily intake values for each population. Table 4-2 shows the 50th and 95th
percentile cumulative daily intake values for DBP, DEHP, BBP, DIBP, and DINP for women of
reproductive age (16 to 49 years old) and male children (ages 3 to 5, 6 to 11, and 12 to 15), while Table
4-3 shows 50th and 95th percentile cumulative daily intake values for women of reproductive age
stratified by race and socioeconomic status.
For women of reproductive age, 50th and 95th percentile cumulative daily intake estimates were 0.95 and
3.55 |ig DBP-equivalents/kg-day (Table 4-2). When stratified by race and socioeconomic status, there
was some evidence for higher cumulative exposure for black non-Hispanic women of reproductive age
at the 95th percentile. For this population 50th and 95th percentile cumulative daily intake estimates were
0.67 and 5.16 |ig DBP-equivalents/kg-day (Table 4-3). However, differences in cumulative exposure
between races and socioeconomic status for women of reproductive age at the 50th or 95th percentiles
were statistically non-significant (Appendix C.4). As can be seen from Figure 4-2 and Figure 4-3, DEHP
was the largest contributor to 50th percentile cumulative exposure estimates (contributing 36 to 52%,
depending on race and socioeconomic status), followed by DBP (15 to 28%), DINP (12 to 22%), DIBP
(7 to 12%), and BBP (3 to 5%). For 95th percentile cumulative exposure estimates, DEHP (contributing
28 to 70%, depending on race and socioeconomic status) and DINP (14 to 47%) were the largest
contributors to cumulative exposure, followed by DBP (9 to 25%), DIBP (4 to 12%), and BBP (3 to
8%).
For male children ages 3 to 5 year, 6 to 11 years, and 12 to 15 years, 50th and 95th percentile cumulative
daily intake estimates decreased with age, with the highest cumulative exposure being estimated for
male children ages 3 to 5 years (50th and 95th percentile: 3.04 and 10.8 |ig DBP-equivalents/kg-day),
followed by 6 to 11 year olds (50th and 95th percentile: 1.89 and 7.35 |ig DBP-equivalents/kg-day), and
then 12 to 15 year olds (50th and 95th percentile: 1.19 and 4.36 |ig DBP-equivalents/kg-day) (Table 4-2).
However, the differences between age groups were not statistically significantly different at either the
50th or 95th percentiles (Appendix C.4). As can be seen from Figure 4-4, DEHP was the largest
contributor to both 50th and 95th percentile cumulative exposure for all age groups (contributing 48 to
58% depending on age group), followed by DBP (14 to 23%), DINP (9 to 23%), DIBP (7 to 12%), and
BBP (4 to 12%).
4.4 Cumulative Phthalate Risk Based on NHANES Urinary Biomonitoring
To calculate cumulative risk based on phthalate exposure for the U.S. civilian population from
NHANES, cumulative margins of exposure (MOEs) were calculated for each population by dividing the
index chemical POD (i.e., 2,100 |ig/kg-day for DBP) by the cumulative daily intake estimate (in DBP
equivalents) for each population. As can be seen from Table 4-2 and Table 4-3, for women of
reproductive age, cumulative MOEs ranged from 407 for black non-Hispanic women of reproductive
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age at the 95th percentile to 3,151 for black non-Hispanic women of reproductive age at the 50th
percentile. These MOEs are above the benchmark of 30, therefore representing less risk than the
benchmark. Specifically, in terms of a risk cup, these MOEs indicate that the risk cup is 1.0 to 7.4
percent full at a benchmark MOE of 30. Of note, the 95th percentile for black non-Hispanic women
represents a value at which approximately one million individuals would be expected to have higher
exposures, assuming a subpopulation size near 20 million. These results indicate that cumulative
exposure to DEHP, DBP, DIBP, BBP, and DINP, based on the most recent NHANES survey data
(2017 to 2018), does not currently pose a risk to most women of reproductive age within the U.S.
civilian population.
As can be seen from Table 4-2, cumulative MOEs ranged from 194 for male children 3 to 5 years of age
at the 95th percentile to 1,758 for male children 12 to 15 years of age at the 50th percentile. These MOEs
indicate that the risk cup is 1.7 to 15.5 percent full at a benchmark MOE of 30. These results indicate
that cumulative exposure to DEHP, DBP, DIBP, BBP, and DINP, based on the most recent
NHANES survey data (2017 to 2018), does not currently pose a risk to most male children within
the U.S. civilian population.
4.5 Conclusions from NHANES Analysis
Herein, EPA used NHANES urinary biomonitoring data for DEHP, BBP, DBP, DIBP, and DINP to
evaluate temporal trends in phthalate exposure for the U.S. population, to estimate aggregate and
cumulative phthalate exposure via reverse dosimetry, and to estimate cumulative risk exposure to
DEHP, BBP, DBP, DIBP, and DINP for all populations, including women of reproductive age and male
children. Based on this analysis, EPA preliminarily concludes the following:
Temporal trends analysis of NHANES urinary biomonitoring data from 1999 to 2018 indicates
declining exposure to DEHP, DBP, and BBP for the U.S. population. In contrast, exposure to
DIBP for the U.S. population has increased from 1999 to 2018, while exposure to DINP has
fluctuated (i.e., increased from 2005 to 2014, then declined back to approximately 2005 levels in
2018) (Section 4.1).
Aggregate phthalate exposure for all subpopulations in the U.S. was highest for DEHP and DINP
based on the most recent NHANES survey data (2017 to 2018) (Section 4.2).
DEHP was the largest contributor to cumulative phthalate exposure for all subpopulations in the
U.S., followed by DINP or DBP, and then BBP and DIBP (Section 4.3).
Based on the most recent NHANES survey data (2017 to 2018), cumulative exposure to non-
attributable sources of DEHP, DBP, DIBP, BBP, and DINP does not currently pose a risk to
most of the U.S. population, including most women of reproductive age or male children within
the U.S. population (Section 4.4). Cumulative MOEs for all populations were above the
benchmark of 30 and ranged from 194 to 636 based on 95th percentile exposure estimates.
However, these data do not account for acute or low-frequency exposures assessed in the
individual chemical risk evaluations, such as those that may occur as a result of use of certain
consumer products or occupational exposures.
Ultimately the NHANES reverse dosimetry combined with the relative potency factors provides a
common understanding of regular exposures and risks to the U.S. population, including the susceptible
subpopulations of women of reproductive age or male children. However, as national biomonitoring
data does not oversample highly exposed subpopulations, this conclusion cannot be extrapolated to
low-frequency, high-exposure scenarios. Therefore, NHANES reverse dosimetry provides a basis for
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1752 estimating total exposure that can augment specific acute scenarios in individual risk evaluations, as
1753 described further in Section 5.
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1754 Table 4-2. Cumulative Phthalate Daily Intake (jig/kg-day) Estimates for Women of Reproductive Age and Male Children from the
1755 2017-2018 NHANES Cycle ^
Population
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
RPF
Aggregate
Daily Intake
in DBP
Equivalents
(jig/kg-day)
%
Contribution
to Cumulative
Exposure
Cumulative Daily
Intake
(DBP Equivalents,
jig/kg-day)
Cumulative
MOE (POD =
2,100 jig/kg-
day)
% Contribution
to Risk Cup
(Benchmark =
30)fl
Females
50
DBP
0.21
1
0.210
22.1
0.950
2,211
1.4%
(16-49 years
old; n =
1,620)
DEHP
0.53
0.84
0.445
46.9
BBP
0.08
0.52
0.042
4.38
DIBP
0.2
0.53
0.106
11.2
DINP
0.7
0.21
0.147
15.5
95
DBP
0.61
1
0.610
17.2
3.55
592
5.1%
DEHP
1.48
0.84
1.24
35.0
BBP
0.42
0.52
0.218
6.15
DIBP
0.57
0.53
0.302
8.51
DINP
5.6
0.21
1.18
33.1
Males
50
DBP
0.56
1
0.560
18.4
3.04
690
4.3%
(3-5 years
old; n = 267)
DEHP
2.11
0.84
1.77
58.2
BBP
0.22
0.52
0.114
3.76
DIBP
0.57
0.53
0.302
9.93
DINP
1.4
0.21
0.294
9.66
95
DBP
2.02
1
2.02
18.6
10.8
194
15.5%
DEHP
6.44
0.84
5.41
49.9
BBP
2.46
0.52
1.28
11.8
DIBP
2.12
0.53
1.12
10.4
DINP
4.8
0.21
1.01
9.30
Males
50
DBP
0.38
1
0.380
20.1
1.89
1,111
2.7%
(6-11 years
old; n =553)
DEHP
1.24
0.84
1.04
55.1
BBP
0.16
0.52
0.083
4.40
DIBP
0.33
0.53
0.175
9.26
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Population
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
RPF
Aggregate
Daily Intake
in DBP
Equivalents
(jig/kg-day)
%
Contribution
to Cumulative
Exposure
Cumulative Daily
Intake
(DBP Equivalents,
jig/kg-day)
Cumulative
MOE (POD =
2,100 jig/kg-
day)
% Contribution
to Risk Cup
(Benchmark =
30)fl
DINP
1
0.21
0.210
11.1
95
DBP
1.41
1
1.41
19.2
7.35
286
10.5%
DEHP
4.68
0.84
3.93
53.5
BBP
0.84
0.52
0.437
5.94
DIBP
1.62
0.53
0.859
11.7
DINP
3.4
0.21
0.714
9.71
Males
50
DBP
0.33
1
0.330
27.6
1.19
1,758
1.7%
(12-15 years
old; n =308)
DEHP
0.66
0.84
0.554
46.4
BBP
0.14
0.52
0.073
6.09
DIBP
0.21
0.53
0.111
9.32
DINP
0.6
0.21
0.126
10.5
95
DBP
0.62
1
0.620
14.2
4.36
482
6.2%
DEHP
2.51
0.84
2.11
48.3
BBP
0.64
0.52
0.333
7.63
DIBP
0.59
0.53
0.313
7.17
DINP
4.7
0.21
0.987
22.6
11A cumulative exposure of 70 |Jg DBP equivalents/kg-day would result in a cumulative MOE of 30 (i.e., 2,100 |Jg DBP-equivalents/kd-day ^ 70 |Jg
DBP equivalents/kg-day = 30), which is equivalent to the benchmark of 30, indicating that the exposure is at the threshold for risk. Therefore, to
estimate the percent contribution to the risk cup, the cumulative exposure expressed in DBP equivalents is divided by 70 |Jg DBP equivalents/kg-day to
estimate percent contribution to the risk cup.
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Table 4-3. Cumulative Phthalate Daily Intake (jig/kg-day) Estimates for Women of Reproductive Age (16 to 49 years old) by Race
Race/
Socioeconomic
Status (SES)
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
RPF
Aggregate
Daily Intake
in DBP
Equivalents
(jig/kg-day)
%
Contribution to
Cumulative
Exposure
Cumulative Daily
Intake
(DBP Equivalents,
jig/kg-day)
Cumulative
MOE (POD =
2,100 jig/kg-
day)
% Contribution
to Risk Cup
(Benchmark =
30)fl
Race: White
50
DBP
0.22
1
0.22
21.6
1.02
2,058
1.5%
Non-Hispanic
(n = 494 )
DEHP
0.59
0.84
0.50
48.6
BBP
0.10
0.52
0.05
5.1
DIBP
0.20
0.53
0.11
10.4
DINP
0.70
0.21
0.15
14.4
95
DBP
0.58
1
0.58
17.6
3.30
636
4.7%
DEHP
1.44
0.84
1.21
36.6
BBP
0.29
0.52
0.15
4.6
DIBP
0.55
0.53
0.29
Oฉ
00
DINP
5.10
0.21
1.07
32.4
Race: Black
50
DBP
0.10
1
0.10
15.0
0.667
3,151
1.0%
Non-Hispanic
(n = 371)
DEHP
0.38
0.84
0.32
47.9
BBP
0.04
0.52
0.02
3.1
DIBP
0.15
0.53
0.08
11.9
DINP
0.70
0.21
0.15
22.1
95
DBP
0.48
1
0.48
9.3
5.16
407
7.4%
DEHP
4.28
0.84
3.60
69.7
BBP
0.30
0.52
0.16
3.0
DIBP
0.40
0.53
0.21
4.1
DINP
3.40
0.21
0.71
13.8
Race: Mexican
50
DBP
0.19
1
0.19
22.4
0.849
2,474
1.2%
American
(n = 259 )
DEHP
0.49
0.84
0.41
48.5
BBP
0.06
0.52
0.03
3.7
DIBP
0.17
0.53
0.09
10.6
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Race/
Socioeconomic
Status (SES)
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
RPF
Aggregate
Daily Intake
in DBP
Equivalents
(jig/kg-day)
%
Contribution to
Cumulative
Exposure
Cumulative Daily
Intake
(DBP Equivalents,
jig/kg-day)
Cumulative
MOE (POD =
2,100 jig/kg-
day)
% Contribution
to Risk Cup
(Benchmark =
30)fl
DINP
0.60
0.21
0.13
14.8
95
DBP
0.42
1
0.42
11.6
3.61
582
5.2%
DEHP
1.24
0.84
1.04
28.9
BBP
0.39
0.52
0.20
5.6
DIBP
0.46
0.53
0.24
6.8
DINP
8.10
0.21
1.70
47.1
Race: Other
50
DBP
0.26
1
0.26
25.3
1.03
2041
1.5%
(n = 496)
DEHP
0.64
0.84
0.54
52.2
BBP
0.07
0.52
0.04
3.5
DIBP
0.15
0.46
0.07
6.7
DINP
0.60
0.21
0.13
12.2
95
DBP
0.84
1
0.84
20.7
4.06
517
5.8%
DEHP
1.37
0.84
1.15
28.3
BBP
0.41
0.52
0.21
5.2
DIBP
0.46
0.53
0.24
6.0
DINP
7.70
0.21
1.62
39.8
SES: Below
50
DBP
0.21
1
0.21
22.0
0.955
2,199
1.4%
Poverty Level
(n = 1,056 )
DEHP
0.53
0.84
0.45
46.6
BBP
0.09
0.52
0.05
4.9
DIBP
0.20
0.53
0.11
11.1
DINP
0.70
0.21
0.15
15.4
95
DBP
0.82
1
0.82
18.2
4.50
467
6.4%
DEHP
1.75
0.84
1.47
32.7
BBP
0.34
0.52
0.18
3.9
DIBP
0.51
0.53
0.27
6.0
DINP
8.40
0.21
1.76
39.2
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Race/
Socioeconomic
Status (SES)
Percentile
Phthalate
Aggregate
Daily Intake
(jig/kg-day)
RPF
Aggregate
Daily Intake
in DBP
Equivalents
(jig/kg-day)
%
Contribution to
Cumulative
Exposure
Cumulative Daily
Intake
(DBP Equivalents,
jig/kg-day)
Cumulative
MOE (POD =
2,100 jig/kg-
day)
% Contribution
to Risk Cup
(Benchmark =
30)fl
SES: At or
50
DBP
0.20
1.00
0.20
27.9
0.718
2,924
1.0%
Above Poverty
Level
(n = 354)
DEHP
0.31
0.84
0.26
36.3
BBP
0.06
0.52
0.03
4.3
DIBP
0.15
0.53
0.08
11.1
DINP
0.70
0.21
0.15
20.5
95
DBP
0.48
1.00
0.48
16.3
2.94
713
4.2%
DEHP
1.07
0.84
0.90
30.5
BBP
0.45
0.52
0.23
7.9
DIBP
0.65
0.53
0.34
11.7
DINP
4.70
0.21
0.99
33.5
SES: Unknown
50
DBP
0.26
1.00
0.26
23.2
1.12
1,870
1.6%
(n =210)
DEHP
0.67
0.84
0.56
50.1
BBP
0.06
0.52
0.03
2.8
DIBP
0.23
0.53
0.12
10.9
DINP
0.70
0.21
0.15
13.1
95
DBP
0.60
1.00
0.60
25.5
2.35
893
3.4%
DEHP
0.86
0.84
0.72
30.7
BBP
0.21
0.52
0.11
4.6
DIBP
0.35
0.53
0.19
7.9
DINP
3.50
0.21
0.74
31.2
11A cumulative exposure of 70 |Jg DBP equivalents/kg-day would result in a cumulative MOE of 30 (i.e., 2,100 |Jg DBP-equivalents/kd-day ^ 70 |Jg DBP
equivalents/kg-day = 30), which is equivalent to the benchmark of 30, indicating that the exposure is at the threshold for risk. Therefore, to estimate the
percent contribution to the risk cup, the cumulative exposure expressed in DBP equivalents is divided by 70 |Jg DBP equivalents/kg-day to estimate
percent contribution to the risk cup.
1759
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All Females AH Females White Non-Hispanic White Non-Hispanic Black Non-Hispanic Black Non-Hispanic
SO"1 Percentile 95"1 Percentile 50"1 Percentile 95tb Percentile 50"1 Percentile 95"1 Percentile
1760
1761
1762
Mexican American
50"' Percentile
Mexican American
95H1 Percentile
Race: Other
50"' Percentile
Race: Other
95th perCentile
I DBP
IDEHP
I BBP
I DIBP
IDINP
Figure 4-2. Percent Contribution to Cumulative Exposure for DEHP, DBP, BBP, DIBP, and DINP for Women of Reproductive Age
(16 to 49 years) in 2017-2018 NHANES, Stratified by Race
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All Females
50th Percentile
All Females
95"' Percentile
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1765
At or Above The
Poverty Line
50"' Percentile
At or Above The
Poverty Line
50th Percentile
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Below The Poverty Line
50th Percentile
Unknown SES
50,b Percentile
Below The Poverty Line
95th Percentile
Unknown SES
95"' Percentile
DBP
IDEHP
I BBP
I DIBP
I DINP
Figure 4-3. Percent Contribution to Cumulative Exposure for DEHP, DBP, BBP, DIBP, and DINP for Women of Reproductive Age
(16 to 49 years) in 2017-2018 NHANES, Stratified by Socioeconomic Status
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50th Percentile
Males (3-5 Years Old)
95tb Percentile
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Males (6-11 Years Old)
5Qtb percentile
Males (6-11 Years Old)
95th Percentile
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1768
Males (12-15 Years Old)
50th Percentile
Males (12-15 Years Old)
95"' Percentile
DBP
IDEHP
I BBP
I DIBP
I DINP
Figure 4-4. Percent Contribution to Cumulative Exposure for DE.H.P, DBP, BBP, DIBP, and DINP for Male Children Ages 3 to 5, 6 to
11, and 12 to 15 years in 2017-2018 NHANES
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5 CONCLUSION AND NEXT STEPS
EPA's draft 2023 approach (U.S. EPA. 2023b) laid out a multi-step method and conceptual model for
assessing cumulative risk, with the final two steps in EPA's draft conceptual model as follows:
Estimate cumulative exposure by combining exposures from TSCA COUs (scaled by relative
potency and expressed in index chemical (DBP) equivalents), the relevant non-attributable
cumulative exposures, and the non-TSCA cumulative exposures to estimate cumulative exposure
in a reasonable manner for consumers and workers.
Estimate cumulative risk for each specific exposure scenario by calculating a cumulative MOE
that can in turn be compared to the benchmark MOE.
As described in Section 1.6, the SACC specifically expressed concern about combining estimates from
individual assessments that represent a mix of deterministic and probabilistic methods as well as
differing tiers of analyses (i.e. screening through more refined approaches) (U.S. EPA. 2023b). In
Section 3.1, EPA explored the potential for co-exposures in occupational settings but concluded it would
not be feasible to provide a robust quantitative assessment due to the wide range of plausible exposure
scenarios and instead calculated an option for deriving an OEV based on cumulative exposure and
relative potency assumptions (Appendix E). EPA calculated the anticipated contribution to the risk cup
from monitored concentrations of phthalates in dust, a key pathway for consumer exposure, in Section
3.2 and found the contribution to be a fraction of total exposure.
Therefore, EPA has authored this technical support document to support a cumulative risk analysis for
each chemical substance by adding non-attributable cumulative phthalate exposure (from NHANES) to
the relevant exposure scenarios for individual TSCA COUs. These risk estimates are estimated using the
draft RPFs for phthalate syndrome based on the shared endpoint and pooled dataset for assessing fetal
testicular testosterone health endpoint, as laid out in Section 2.
Section 5.1 describes how to apply this quantitative approach for evaluating cumulative risk resulting
from aggregate exposure to a single phthalate from an exposure scenario or COU plus non-attributable
cumulative risk from NHANES. This quantitative approach will be used in each of the individual
relevant phthalate risk evaluations. Section 5.2 discusses the anticipated impact that this cumulative
approach will have for each of the phthalates being evaluated under TSCA.
5.1 Estimation of Cumulative Risk
As described above, EPA is focusing its exposure assessment for the cumulative risk analysis on
evaluation of exposures through individual TSCA consumer and occupational COUs for each phthalate
and non-attributable cumulative exposure to DEHP, DBP, BBP, DIBP, and DINP using NHANES
urinary biomonitoring data and reverse dosimetry. To estimate cumulative risk, EPA first scaled each
individual phthalate exposure by relative potency using the RPFs presented in Table 2-4 to express
phthalate exposure in terms of index chemical (DBP) equivalents. Exposures from individual consumer
or worker COUs/OES (occupational exposure scenario) were then combined to estimate cumulative risk.
Cumulative risk was estimated using the four-step process outlined below, along with one empirical
example of how EPA calculated cumulative risk for one occupational OES for DCHP (i.e., Application
of Paints and Coatings (Solids)).
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Step 1: Convert Exposure Estimates for the Individual Phthalate from Each Individual Consumer
and Occupational CPU to Index Chemical Equivalents
In this step, acute duration exposure estimates for an individual phthalate from each consumer and
occupational COU/OES are scaled by relative potency and expressed in terms of index chemical (DBP)
equivalents using Equation 5-1. This step is repeated for all individual exposure estimates for each route
of exposure being assessed for each COU (i.e., inhalation, dermal, and aggregate exposures for
occupational COUs; inhalation, ingestion, dermal, and aggregate exposure for consumer COUs).
Equation 5-1. Scaling Phthalate Exposures by Relative Potency
Phthalate Exposure (in DBP equivalents) = ADRoute xx RPFPhthaiate
Where:
Phthalate exposure is the acute exposure for a given route of exposure for an individual phthalate
from a single occupational or consumer COU expressed in terms of |ig/kg index chemical (DBP)
equivalents.
ADRoute l is the acute dose in |ig/kg from a given route of exposure from a single occupational or
consumer COU/OES.
RPFphthaiate is the relative potency factor (unitless) for each respective phthalate (Table 2-4).
Example: 50th percentile inhalation and dermal DCHP exposures for female workers of reproductive age
are 38.7 and 2.07 |ig/kg for the Application of Paints and Coatings (Solids) OES (U.S. EPA. 2024o).
Using Equation 5-1, inhalation, dermal, and aggregate DCHP exposures for this OES can be scaled by
relative potency to 64.24, 3.44, and 67.68 |ig/kg DBP equivalents, respectively.
DCHPInhalation_cou = 64.24 M-g/kg DBP equivalents = 38.7 \ig/kgDCHP x 1.66
DCHPDermal_cou = 3.44 [ig/kgDBP equivalents = 2.07 |ig/kg DCHP x 1.66
DCHPAggregate_cou = 67.68 |ig/kg DBP equivalents
= (2.07 |ig/kg DCHP + 38.7 |ig/kg DCHP) x 1.66
Step 2: Estimate Non-attributable Cumulative Exposure to DEHP, DBP, BBP, DIBP, and DINP
Using NHANES Urinary Biomonitoring Data and Reverse Dosimetry (see Section 4 for further
details)
Non-attributable exposure for a national population to DEHP, DBP, BBP, DIBP, and DINP was
estimated using Equation 5-2, where individual phthalate daily intake values estimated from NHANES
biomonitoring data and reverse dosimetry were scaled by relative potency, expressed in terms of index
chemical (DBP) equivalents, and summed to estimate non-attributable cumulative exposure in terms of
DBP equivalents. Equation 5-2 was used to calculate the cumulative exposure estimates provided in
Table 4-2 and Table 4-3.
Equation 5-2. Estimating Non-attributable Cumulative Exposure to DEHP, DBP, BBP, DIBP, and
DINP
Cumulative Exposure (Non attributable)
= (DIdehp x RPFdehp) + (DIdbp x RPFdbp) + (DIBBP x RPFbbp)
+ (DIDIBp x RPFdibp) + (DIdinp x RPFdinp)
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Where:
Cumulative exposure (non-attributable) is expressed in index chemical (DBP) equivalents
(lig/kg-day).
DI is the daily intake value (|ig/kg-day) for each phthalate that was calculated using NHANES
urinary biomonitoring data and reverse dosimetry (DI values for each phthalate for each assessed
population are provided in Table 4-2 and Table 4-3).
RPF is the relative potency factor (unitless) for each phthalate from Table 2-4.
Example: The 95th percentile cumulative exposure estimate of 5.16 |ig/kg-day DBP equivalents for
black, non-Hispanic women of reproductive age (Table 4-3) is calculated using Equation 5-2 as follows:
5.16 |ig/kg DBP equivalents
= (4.28 |ig/kg DEHP x 0.84) + (0.48 |ig/kg DBP x 1) + (0.30 |ig/kg BBP x 0.52)
+ (0.40 [ig/kg DIBP x 0.53) + (3.40 \ig/kgDINP x 0.21)
Step 3: Calculate MOEs for Each Exposure to the Individual Phthalate and for the Non-
attributable Cumulative Exposure
Next, MOEs are calculated for each exposure of interest that is included in the cumulative scenario
using Equation 5-3. For example, this step involves calculating MOEs for inhalation and dermal
phthalate exposures expressed in index chemical equivalents for each individual COU/OES in step 1 and
an MOE for non-attributable cumulative phthalate exposure from step 2 above.
Equation 5-3. Calculating MOEs for Exposures of Interest for use in the RPF and Cumulative
Approaches
Index Chemical (DBP) POD
MO Ei =
Exposurex in DBP Equivalents
Where:
MOEi (unitless) is the MOE calculated for each exposure of interest included in the cumulative
scenario.
Index chemical (DBP) POD is the POD selected for the index chemical, DBP. The index
chemical POD is 2,100 |ig/kg (Section 2.3).
Exposurei is the exposure estimate in DBP equivalents for the pathway of interest (i.e., from step
1 or 2 above).
Example: Using Equation 5-3, the MOEs for inhalation and dermal DCHP exposure estimates for the
Application of Paints and Coatings (Solids) OES in DBP equivalents from step 1 and the MOE for the
non-attributable cumulative exposure estimate in DBP equivalents from step 2, are 33, 610, and 407,
respectively.
2,100 [xg/kg
MOEcumuiative Non-attribUtable ~ 407
5.16 \ig/kg
2,100 \ig/kg
MOEcou_Inhalation = 32.7 = 642[ig/kg
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2,100 ug/kg
MOEcou_Dermai = 610 =
cou Dermal 3.44\ig/kg
Step 4: Calculate the Cumulative MOE
For the cumulative MOE approach, MOEs for each exposure of interest in the cumulative scenario are
first calculated (Step 3). The cumulative MOE for the cumulative scenario can then be calculated using
Equation 5-4. Equation 5-4 shows the addition of MOEs for the inhalation and dermal exposures routes
from an individual COU, as well as the MOE for non-attributable cumulative exposure to phthalates
from NHANES urinary biomonitoring and reverse dosimetry. Additional MOEs can be added to the
equation as necessary (e.g., for the ingestion route for consumer scenarios).
Equation 5-4. Cumulative Margin of Exposure Calculation
1
Cumulative MOE = jjj
MOEcou-jnhdidtign MOEcou_Dermai MOilcujnujative-Non-attrt&uta&ie
Example: The cumulative MOE for the Application of Paints and Coatings (Solids) OES is 28.9 and is
calculated by summing the MOEs for each exposure of interest from step 3 as follows:
1
Cumulative MOE = 28.9 = j
327 + 610 + 407
5.2 Anticipated Impact of the Cumulative Analysis on Phthalates being
Evaluated Under TSCA
The cumulative analysis approach outlined in Section 5.1 is being used by EPA to supplement the
individual phthalate risk evaluations. The cumulative analysis approach will have varying impacts on
each of the individual phthalate risk evaluations and will be influenced by three key factors. This
includes: (1) scaling individual phthalate acute exposure estimates for each COU/OES by relative
potency; (2) calculation of the cumulative MOE using the index chemical POD; and (3) addition of non-
attributable cumulative exposure from NHANES. The overall effect of these three factors for each
phthalate being evaluated under TSCA is summarized in Table 5-1 and is discussed further in Section
5.2.1 through Section 5.2.6.
5.2.1 Dibutyl Phthalate (DBP)
Application of the cumulative analysis outlined in Section 5.1 will have a small overall effect for DBP.
Cumulative risk estimates will be approximately l.lx more sensitive than in the individual DBP risk
evaluation (Table 5-1). This preliminary conclusion is based on the following considerations:
Scaling by Relative Potency. DBP is the index chemical and the RPF for DBP is 1 (Table 2-4).
Scaling by relative potency will have no effect on scaled exposure estimates.
Index Chemical POD. EPA selected the same POD of 2.1 mg/kg-day based on the BMDLs for
reduced fetal testicular testosterone as the acute POD for the individual DBP risk evaluation
(U.S. EPA. 2024e) and as the index chemical POD for use in the CRA (Section 2.3), so this also
will have no effect.
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Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2). This is the only factor
that will contribute to the slightly more sensitive cumulative risk estimates for DBP.
5.2.2 Dicyclohexyl Phthalate (DCHP)
Application of the cumulative analysis outlined in Section 5.1 will lead to risk estimates that are
approximately 2x to 2.2x more sensitive (Table 5-1). This preliminary conclusion is based on the
following considerations:
Scaling by Relative Potency. The RPF for DCHP is 1.66 (Table 2-4). This means acute DCHP
exposures when multiplied by the RPF and expressed in terms of index chemical (DBP)
equivalents will increase by 66 percent, which will be the primary factor contributing to the more
sensitive risk estimates.
Index Chemical POD. The POD for the index chemical (DBP) used to calculate cumulative risk
is 2.1 mg/kg (Section 2.3), while the acute POD for DCHP used to calculate MOEs in the
individual DCHP risk evaluation is 2.4 mg/kg (U.S. EPA. 2024g). The index chemical (DBP)
POD is 12.5 percent lower (i.e., more sensitive) than the individual DCHP POD, which will
contribute to the more sensitive risk estimates.
Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2) and will contribute to
the more sensitive risk estimates.
5.2.3 Diisobutyl Phthalate (DIBP)
Application of the cumulative analysis outlined in Section 5.1 will lead to risk estimates that are
approximately 1.5x to 1.7x more sensitive (Table 5-1). This preliminary conclusion is based on the
following considerations:
Scaling by Relative Potency. The RPF for DIBP is 0.53 (Table 2-4). This means acute DIBP
exposures when multiplied by the RPF and expressed in terms of index chemical (DBP)
equivalents will decrease by a factor of approximately 2.
Index Chemical POD. The POD for the index chemical (DBP) used to calculate cumulative risk
is 2.1 mg/kg (Section 2.3), while the acute POD for DIBP used to calculate MOEs in the
individual DIBP risk evaluation is 5.7 mg/kg (U.S. EPA. 2024i). The index chemical (DBP)
POD is 2.7 times lower (i.e., more sensitive) than the DIBP POD, which will contribute to lower
cumulative MOEs.
Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2) and will contribute to
the more sensitive risk estimates.
5.2.4 Butyl Benzyl Phthalate (BBP)
Application of the cumulative analysis outlined in Section 5.1 will lead to risk estimates that are
approximately 3.2x to 3.5x more sensitive (Table 5-1). This preliminary conclusion is based on the
following considerations:
Scaling by Relative Potency. The RPF for BBP is 0.52 (Table 2-4). This means acute BBP
exposures when multiplied by the RPF and expressed in terms of index chemical (DBP)
equivalents will decrease by a factor of approximately 2.
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Index Chemical POD. The POD for the index chemical (DBP) used to calculate cumulative risk
is 2.1 mg/kg (Section 2.3), while the acute POD for BBP used to calculate MOEs in the
individual BBP risk evaluation is 12 mg/kg. The index chemical (DBP) POD is 5.7 times lower
(i.e., more sensitive) than the BBP POD, which will contribute to lower cumulative MOEs.
Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2) and will contribute to
the more sensitive risk estimates.
5.2.5 Diisononyl Phthalate (DINP)
Application of the cumulative analysis outlined in Section 5.1 will lead to risk estimates that are
approximately 1.3x to 1.4x more sensitive (Table 5-1). This preliminary conclusion is based on the
following considerations:
Scaling by Relative Potency. The RPF for DINP is 0.21 (Table 2-4). This means acute DINP
exposures when multiplied by the RPF and expressed in terms of index chemical (DBP)
equivalents will decrease by a factor of approximately 5.
Index Chemical POD. The POD for the index chemical (DBP) used to calculate cumulative risk
is 2.1 mg/kg (Section 2.3), while the acute POD for DINP used to calculate MOEs in the
individual DINP risk evaluation is 12 mg/kg. The index chemical (DBP) POD is 5.7 times lower
(i.e., more sensitive) than the DINP POD, which will contribute to lower cumulative MOEs.
Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2) and will contribute to
the more sensitive risk estimates.
5.2.6 Diethylhexyl Phthalate (DEHP)
Application of the cumulative analysis outlined in Section 5.1 will lead to risk estimates that are less
sensitive than in the individual DEHP risk evaluation (Table 5-1). This is because DEHP is data-rich and
the POD used for the individual chemical assessment based on male reproductive tract malformations is
more sensitive than the index chemical POD, which washes out the addition of the non-attributable
cumulative exposure. This preliminary conclusion is based on the following considerations:
Scaling by Relative Potency. The RPF for DEHP is 0.84 (Table 2-4). This means acute DEHP
exposures when multiplied by the RPF and expressed in terms of index chemical (DBP)
equivalents will decrease by 16 percent.
Index Chemical POD. The POD for the index chemical (DBP) used to calculate cumulative risk
is 2.1 mg/kg (Section 2.3), while the acute POD for DEHP used to calculate MOEs in the
individual DEHP risk evaluation is 1.1 mg/kg. The index chemical (DBP) POD is 1.9 times
higher (i.e., less sensitive) than the DEHP POD, which will contribute to less sensitive
cumulative MOEs.
Addition of Non-Attributable Cumulative Exposure. This will add 6.2 to 15.5 percent to the risk
cup, depending on the population and lifestage being assessed (Table 5-2) and will contribute to
the more sensitive risk estimates.
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2021 Table 5-1. Summary of Impact of Cumulative Assessment on Phthalates Being Evaluated Under TSCA
Phthalate
Individual Phthalate Assessment
Cumulative Analysis
Conclusions
Acute POD
(mg/kg-day)
POD Type and Effect
Benchmark
MOE
RPF
Index
Chemical POD
(mg/kg-day)
Cumulative
Benchmark
MOE
DBP (index
chemical)
2.1
BMDLs (| fetal testicular
testosterone)
30
1
2.1
30
Risk estimates will be ~l.lx more sensitive
DEHP
1.1
NOAEL (Phthalate
syndrome-related effects)
30
0.84
Individual chemical assessment will be more sensitive
based on slightly different endpoint
BBP
12
NOAEL (Phthalate
syndrome-related effects)
30
0.52
Risk estimates will be ~3.2x to 3.5x more sensitive
DIBP
5.7
BMDLs (| fetal testicular
testosterone)
30
0.53
Risk estimates will be ~1.5x to 1.7x more sensitive
DCHP
2.4
NOAEL (Phthalate
syndrome-related effects)
30
1.66
Risk estimates will be ~2x to 2.2x more sensitive
DINP
12
BMDLs (| fetal testicular
testosterone)
30
0.21
Risk estimates will be ~1.3x to 1.4x more sensitive
2022
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2023 Table 5-2. Summary of Non-Attributable Cumulative Exposure From NHANES Being Combined
2024 for Each Assessed Population
Population
Lifestage
Non-Attributable
Cumulative Exposure
from NHANES (DBP
Equivalents, |Jg/kg-day)
NHANES
Population
%
Contribution
to Risk Cup
Worker
Women of reproductive
age (16-49 years)
5.16
Black, non-
Hispanic women of
reproductive age
(16-49 years)
7.4%
Consumer
Adult (S21 years)
Teenager (16-20 years)
Young Teen (11-15
years)
4.36
Males (12-15
years)
6.2%
Child (6-10 years)
7.35
Males (6-11 years)
10.5%
Preschooler (3-5 years)
Toddler (1-2 years)
Infant (<1 year)
10.8
Males (3-5 years)
15.5%
2025
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REFERENCES
Adham. IM; Emmen, JM; Engel. W. (2000). The role of the testicular factor INSL3 in establishing the
gonadal position [Review], Mol Cell Endocrinol 160: 11-16.
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/10328887
Allen. BC: Kavlock. RJ; Kimmel. CA; Faustman. EM. (1994a). Dose-response assessment for
developmental toxicity II: Comparison of generic benchmark dose estimates with no observed
adverse effect levels. Fundam Appl Toxicol 23: 487-495.
http://dx.doi.org/10.1006/faat.1994.1133
Allen. BC: Kavlock. RJ: Kimmel CA: Faustman. EM. (1994b). Dose-response assessment for
developmental toxicity III: statistical models. Fundam Appl Toxicol 23: 496-509.
http://dx.doi.org/10.1006/faat.1994.1134
Anderson. WA; Castle. L; Hird. S: Jeffery. J: Scotter. MJ. (2011). A twenty-volunteer study using
deuterium labelling to determine the kinetics and fractional excretion of primary and secondary
urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate. Food Chem Toxicol
49: 2022-2029. http://dx.doi.Org/10.1016/i.fct.2011.05.013
Anderson. WAC: Castle. L; Scotter. MJ: Massev. RC: Springall. C. (2001). A biomarker approach to
measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 18: 1068-
1074. http://dx.doi.org/10.1080/0265203011005Q113
Arzuaga. X: Walker. T; Yost. EE: Radke. EG: Hotchkiss. AK. (2020). Use of the Adverse Outcome
Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl
phthalate (DBP)-induced male reproductive toxicity. Reprod Toxicol 96: 445-458.
ATSDR. (2022). Toxicological profile for di(2-ethylhexyl)phthalate (DEHP) [ATSDR Tox Profile],
(CS274127-A). Atlanta, GA. https://www.atsdr.cdc.gov/ToxProfiles/tp9.pdf
Aylward. LL; Hays. SM; Zidek. A. (2016). Variation in urinary spot sample, 24 h samples, and longer-
term average urinary concentrations of short-lived environmental chemicals: implications for
exposure assessment and reverse dosimetry. J Expo Sci Environ Epidemiol 27: 582-590.
http://dx.doi.org/10.1038/ies.2016.54
Bi. C: Maestre. JP; Li. H; Zhang. G: Givehchi. R; Mahdavi. A: Kinney. KA; Siegel. J: Horner. SD; Xu.
Y. (2018). Phthalates and organophosphates in settled dust and HVAC filter dust of U.S. low-
income homes: Association with season, building characteristics, and childhood asthma. Environ
Int 121: 916-930. http://dx.doi.Org/10.1016/i.envint.2018.09.013
Bi. X: Yuan. S: Pan. X: Winstead. C: Wang. Q. (2015). Comparison, association, and risk assessment of
phthalates in floor dust at different indoor environments in Delaware, USA. J Environ Sci Health
A Tox Hazard Subst Environ Eng 50: 1428-1439.
http://dx.doi.org/10.1080/10934529.2Q15.1074482
Biesterbos. JW: Dudzina. T; Delmaar. CJ: Bakker. MI: Russel. FG: von Goetz. N: Scheepers. PT;
Roeleveld. N. (2013). Usage patterns of personal care products: important factors for exposure
assessment. Food Chem Toxicol 55: 8-17. http://dx.doi.Org/10.1016/i.fct.2012.ll.014
Boberg. J: Christiansen. S: Axelstad. M: Kledal. TS: Vinggaard. AM: Dalgaard. M: Nellemann. C: Hass.
U. (2011). Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally
exposed rats. Reprod Toxicol 31: 200-209. http://dx.doi.org/10.1016/i.reprotox.2010.11.001
Boekelheide. K: Klevmenova. E: Liu. K: Swanson. C: Gaido. KW. (2009). Dose-dependent effects on
cell proliferation, seminiferous tubules, and male germ cells in the fetal rat testis following
exposure to di(n-butyl) phthalate. Microsc Res Tech 72: 629-638.
http://dx.doi.org/10.1002/iemt.20684
Bradley. EL: Burden. RA: Bentaveb. K: Driffield. M: Harmer. N: Mortimer. DN: Speck. PR: Ticha. J:
Castle. L. (2013). Exposure to phthalic acid, phthalate diesters and phthalate monoesters from
Page 70 of 117
-------
2073
2074
2075
2076
2077
2078
2079
2080
2081
2082
2083
2084
2085
2086
2087
2088
2089
2090
2091
2092
2093
2094
2095
2096
2097
2098
2099
2100
2101
2102
2103
2104
2105
2106
2107
2108
2109
2110
2111
2112
2113
2114
2115
2116
2117
2118
2119
2120
PUBLIC RELEASE DRAFT
December 2024
foodstuffs: UK total diet study results. Food Addit Contam Part A Chem Anal Control Expo Risk
Assess 30: 735-742. http://dx.doi.org/10.1080/19440049.2Q13.781684
Carruthers. CM: Foster. PMD. (2005). Critical window of male reproductive tract development in rats
following gestational exposure to di-n-butyl phthalate. Birth Defects Res B Dev Reprod Toxicol
74: 277-285. http://dx.doi.org/10.1002/bdrb.2005Q
CDC. (2013a). Fourth national report on human exposure to environmental chemicals, updated tables,
September 2013. (CS244702-A). Atlanta, GA.
http://www.cdc.gov/exposurereport/pdf/FourthReport UpdatedTables Sep2013.pdf
CDC. (2013b). National Health and Nutrition Examination Survey: Sample design, 2007-2010. In Vital
and Health Statistics: Series 2, Number 160. Atlanta, GA: U.S. Department of Health and
Human Services.
Chi. C: Xia. M; Zhou. C: Wang. X: Weng. M; Shen. X. (2017). Determination of 15 phthalate esters in
air by gas-phase and particle-phase simultaneous sampling. J Environ Sci 55: 137-145.
http://dx.doi.Org/10.1016/i.ies.2016.01.036
Clark. KE; David. RM; Guinn. R; Kramarz. KW: Lampi. MA: Staples. CA. (2011). Modeling human
exposure to phthalate esters: A comparison of indirect and biomonitoring estimation methods.
Hum Ecol Risk Assess 17: 923-965. http://dx.doi.org/10.1080/10807Q39.2011.588157
Clewell. RA; Campbell. JL; Ross. SM; Gaido. KW: Clewell Hi. Ill: Andersen. ME. (2010). Assessing
the relevance of in vitro measures of phthalate inhibition of steroidogenesis for in vivo response.
Toxicol In Vitro 24: 327-334. http://dx.doi.Org/10.1016/i.tiv.2009.08.003
Clewell. RA: Sochaski. M; Edwards. K; Creasy. DM: Willson. G: Andersen. ME. (2013). Disposition of
diiosononyl phthalate and its effects on sexual development of the male fetus following repeated
dosing in pregnant rats. Reprod Toxicol 35: 56-69.
http://dx.doi.Org/10.1016/i.reprotox.2012.07.001
Conlev. JM; Lambright. CS: Evans. N: Cardon. M; Medlock-Kakalev. E; Wilson. VS: Gray. LE. (2021).
A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect
levels (NOAELs) produces reproductive tract malformations in the male rat. Environ Int 156:
106615. http://dx.doi.org/10.1016/i.envint.2021.106615
Cultv. M; Thuillier. R; Li. W: Wang. Y; Martinez-Arguelles. D; Benjamin. C: Triantafilou. K; Zirkin. B;
Papadopoulos. V. (2008). In utero exposure to di-(2-ethylhexyl) phthalate exerts both short-term
and long-lasting suppressive effects on testosterone production in the rat. Biol Reprod 78: 1018-
1028. http://dx.doi.org/10.1095/biolreprod.107.065649
David. RM. (2000). Exposure to phthalate esters [Letter], Environ Health Perspect 108: A440.
http://dx.doi.org/10.1289/ehp.108-a440a
Dodson. RE: Camann. DE; Morello-Frosch. R; Brodv. JG: Rudel. RA. (2015). Semivolatile organic
compounds in homes: strategies for efficient and systematic exposure measurement based on
empirical and theoretical factors. Environ Sci Technol 49: 113-122.
http://dx.doi.org/10.1021/es502988r
EC/HC. (2015). State of the science report: Phthalate substance grouping: Medium-chain phthalate
esters: Chemical Abstracts Service Registry Numbers: 84-61-7; 84-64-0; 84-69-5; 523-31-9;
5334-09-8; 16883-83-3; 27215-22-1; 27987-25-3; 68515-40-2; 71888-89-6. Gatineau, Quebec:
Environment Canada, Health Canada. https://www.ec.gc.ca/ese-ees/4D845198-761D-428B-
A519-7548 !B25B3E5/SoS Phthalates%20%28Medium-chain%29 EN.pdf
ECCC/HC. (2020). Screening assessment - Phthalate substance grouping. (Enl4-393/2019E-PDF).
Environment and Climate Change Canada, Health Canada.
https://www.canada.ca/en/environment-climate-change/services/evaluating-existing-
substances/screening-assessment-phthalate-substance-grouping.html
ExxonMobil. (2022). EM BRCP DINP/DIDP facility - virtual tour (sanitized). Houston, TX.
Page 71 of 117
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2131
2132
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2158
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2160
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PUBLIC RELEASE DRAFT
December 2024
Faustman. EM; Allen. BC; Kavlock. RJ; Kimmel. CA. (1994). Dose-response assessment for
developmental toxicity: I characterization of data base and determination of no observed adverse
effect levels. Fundam Appl Toxicol 23: 478-486. http://dx.doi.Org/10.1006/faat.1994.l 132
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
predict disruption of sexual differentiation. Toxicol Sci 140: 403-424.
http://dx.doi. org/10.1093/toxsci/kfu081
Gray. LE: Furr. J: Tatum-Gibbs. KR; Lambright. C: Sampson. Ft; Hannas. BR: Wilson. VS: Hotchkiss.
A; Foster. PM. (2016). Establishing the Biological Relevance of Dipentyl Phthalate Reductions
in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels. Toxicol Sci
149: 178-191. http://dx.doi.org/10.1093/toxsci/kfv224
Gray. LE; Lambright. CS; Conlev. JM; Evans. N; Furr. JR; Hannas. BR; Wilson. VS; Sampson. H;
Foster. PMD. (2021). Genomic and Hormonal Biomarkers of Phthalate-Induced Male Rat
Reproductive Developmental Toxicity Part II: A Targeted RT-qPCR Array Approach That
Defines a Unique Adverse Outcome Pathway. Toxicol Sci 182: 195-214.
http://dx.doi.org/10.1093/toxsci/kfab053
Gray. LE; Lambright. CS; Evans. N; Ford. J; Conlev. JM. (2024). Using targeted fetal rat testis genomic
and endocrine alterations to predict the effects of a phthalate mixture on the male reproductive
tract. CurrRes Toxicol 7: 100180. http://dx.doi.org/10.1016/i.crtox.2024.100180
Guo. Y; Kannan. K. (2011). Comparative assessment of human exposure to phthalate esters from house
dust in China and the United States. Environ Sci Technol 45: 3788-3794.
http://dx.doi.org/10.1021/es20021Q6
Hallmark. N; Walker. M; McKinnell. C; Mahood. IK; Scott. H; Bavne. R; Coutts. S; Anderson. RA;
Greig. I; Morris. K; Sharpe. RM. (2007). Effects of monobutyl and di(n-butyl) phthalate in vitro
on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: Comparison
with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ
Health Perspect 115: 390-396. http://dx.doi.org/10.1289/ehp.9490
Hammel. SC; Levasseur. JL; Hoffman. K; Phillips. AL; Lorenzo. AM; Calafat. AM; Webster. TF;
Stapleton. HM. (2019). Children's exposure to phthalates and non-phthalate plasticizers in the
home: The TESIE study. Environ Int 132: 105061.
http://dx.doi.Org/10.1016/i.envint.2019.105061
Han. Eu; Choi. K; Sim. S; Choi. J; Uhm. Y; Kim. S; Lim. E; Lee. Y. (2020). Patterns of household and
personal care product use by the Korean population: implications for aggregate human exposure
and health risk. Environ Sci Eur. http://dx.doi.Org/10.l 186/sl2302-020-00417-3
Hannas. BR; Lambright. CS; Furr. J; Evans. N; Foster. PMD; Gray. EL; Wilson. VS. (2012). Genomic
biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted RT-PCR
array approach for defining relative potency. Toxicol Sci 125: 544-557.
http ://dx. doi. org/10.1093/toxsci/kfr315
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
Heger. NE; Hall. SJ; Sandrof. MA; McDonnell. EV; Henslev. JB; McDowell. EN; Martin. KA; Gaido.
KW; Johnson. KJ; Boekelheide. K. (2012). Human fetal testis xenografts are resistant to
phthalate-induced endocrine disruption. Environ Health Perspect 120: 1137-1143.
http://dx.doi.org/10.1289/ehp.1104711
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PUBLIC RELEASE DRAFT
December 2024
Hines. C; Hopf. N; Deddens. J; Silva. M; Calafat A. (2011). Estimated daily intake of phthalates in
occupationally exposed groups. J Expo Sci Environ Epidemiol 21: 133-141.
http://dx.doi.org/10.1038/ies.2009.62
Howdeshell. KL; Hotchkiss. AK; Gray. LE. (2017). Cumulative effects of antiandrogenic chemical
mixtures and their relevance to human health risk assessment [Review], Int J Hyg Environ
Health 220: 179-188. http://dx.doi.Org/10.1016/i.iiheh.2016.ll.007
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
IPCS. (2007). Harmonization project document no. 4: Part 1: IPCS framework for analysing the
relevance of a cancer mode of action for humans and case-studies: Part 2: IPCS framework for
analysing the relevance of a non-cancer mode of action for humans. Geneva, Switzerland: World
Health Organization.
http://www.who.int/ipcs/methods/harmonization/areas/cancer mode.pdf?ua=l
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.
http://dx.doi.org/10.1095/biolreprod.107.06295Q
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
pathways. Toxicol Sci 120: 460-474. http://dx.doi.org/10.1093/toxsci/kfr020
Koch. HM; Becker. K: Wittassek. M: Seiwert. M: Angerer. J: Kolossa-Gehring. M. (2007). Di-n-
butylphthalate and butylbenzylphthalate - urinary metabolite levels and estimated daily intakes:
Pilot study for the German Environmental Survey on children. J Expo Sci Environ Epidemiol 17:
378-387. http://dx.doi.org/10.1038/si.ies.7500526
Koch. HM: Drexler. H: Angerer. J. (2003). An estimation of the daily intake of di(2-
ethylhexyl)phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ
Health 206: 77-83. http://dx.doi.org/10.1078/1438-4639-002Q5
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
Lambrot. R: Muczynski. V: Lecureuil. C: Angenard. G: Coffigny. H: Pairault. C: Moison. D: Frydman.
R: Habert. R: Rouiller-Fabre. V. (2009). Phthalates impair germ cell development in the human
fetal testis in vitro without change in testosterone production. Environ Health Perspect 117: 32-
37. http://dx.doi.org/10.1289/ehp. 11146
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
Lucas-Herald. AK: Mitchell. RT. (2022). Testicular Sertoli cell hormones in differences in sex
development [Review], Front Endocrinol (Lausanne) 13: 919670.
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/10706127
Page 73 of 117
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2250
2251
2252
2253
2254
2255
2256
2257
2258
2259
2260
PUBLIC RELEASE DRAFT
December 2024
MacLeod. DJ; Sharpe. RM; Welsh. M; Fisken. M; Scott. HM; Hutchison. GR; Drake. AJ; van Den
Driesche. S. (2010). Androgen action in the masculinization programming window and
development of male reproductive organs. Int J Androl 33: 279-287.
http://dx.doi.org/10.1111/i. 1365-2605.2009.01005.X
Mage. DT; Allen. RH; Kodali. A. (2008). Creatinine corrections for estimating children's and adult's
pesticide intake doses in equilibrium with urinary pesticide and creatinine concentrations. J Expo
Sci Environ Epidemiol 18: 360-368. http://dx.doi.org/10.1038/si.ies.7500614
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
Mitchell. RT; Childs. AJ: Anderson. RA; van Den Driesche. S: Saunders. PTK; McKinnell. C: Wallace.
WHB; Kelnar. CJH; Sharpe. RM. (2012). Do phthalates affect steroidogenesis by the human
fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. J Clin Endocrinol
Metab 97: E341-E348. http://dx.doi.org/10.1210/ic.2011-2411
NASEM. (2017). Application of systematic review methods in an overall strategy for evaluating low-
dose toxicity from endocrine active chemicals. In Consensus Study Report. Washington, D.C.:
The National Academies Press, http://dx.doi.org/10.17226/24758
NCHS. (2012). The National Health and Nutrition Examination Survey: Sample design, 1999-2006.
(Vital and Health Statistics: Series 2, No. 155). Hyattsville, MD: National Center for Health
Statistics, http://www.cdc.gov/nchs/data/series/sr 02/sr02 155.pdf
NCHS. (2021). National Health and Nutrition Examination Survey - 2017-2018 Data Documentation,
Codebook, and Frequencies: Phthalates and Plasticizers Metabolites - Urine (PHTHTE J)
[Website], https://wwwn.cdc.gov/Nchs/Nhanes/2017-2018/PHTHTE J.htm
NRC. (2008). Phthalates and cumulative risk assessment: The task ahead. Washington, DC: National
Academies Press, http://dx.doi.org/10.17226/12528
OECD. (2013). Guidance document supporting OECD test guideline 443 on the extended one
generation reproductive toxicity test. In Series on Testing and Assessment. (No. 151 /
ENV/JM/MONO(2013)10). Paris, France: OECD Environment, Health and Safety Publications.
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/3449546
Page. BP: Lacroix. GM. (1995). The occurrence of phthalate ester and di-2-ethylhexyl adipate
plasticizers in Canadian packaging and food sampled in 1985-1989: A survey. Food Addit
Contam 12: 129-151. http://dx.doi.org/10.1080/026520395Q9374287
Rudel. RA: Brodv. JG: Spengler. JD; Vallarino. J: Geno. PW: Sun. G: Yau. A. (2001). Identification of
selected hormonally active agents and animal mammary carcinogens in commercial and
residential air and dust samples. J Air Waste Manag Assoc 51: 499-513.
http://dx.doi.org/10.1080/10473289.2Q01.10464292
Safford. B; Api. AM: Barratt. C: Comiskev. D; Daly. EJ; Ellis. G: McNamara. C: O'Mahony. C:
Robison. S: Smith. B; Thomas. R; Tozer. S. (2015). Use of an aggregate exposure model to
estimate consumer exposure to fragrance ingredients in personal care and cosmetic products.
Regul Toxicol Pharmacol 72: 673-682. http://dx.doi.Org/10.1016/i.yrtph.2015.05.017
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
Schecter. A: Lorber. M; Guo. Y; Wu. O; Yun. SH; Kannan. K; Hommel. M; Imran. N: Hynan. LS:
Cheng. D; Colacino. JA; Birnbaum. LS. (2013). Phthalate concentrations and dietary exposure
Page 74 of 117
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2266
2267
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2269
2270
2271
2272
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2299
2300
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December 2024
from food purchased in New York State. Environ Health Perspect 121: 473-494.
http://dx.doi.org/10.1289/ehp.1206367
Schwartz. CL; Christiansen. S: Hass. U; Ram hoi. L; Axelstad. M; Lobl. NM; Svingen. T. (2021). On the
use and interpretation of areola/nipple retention as a biomarker for anti-androgenic effects in rat
toxicity studies [Review], Front Toxicol 3: 730752.
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/10492323
Scott. HM: Mason. JI; Sharpe. RM. (2009). Steroidogenesis in the fetal testis and its susceptibility to
disruption by exogenous compounds [Review], Endocr Rev 30: 883-925.
http://dx.doi.org/10.1210/er.2009-0Q16
Shin. HM: Bennett. DH: Barkoski. J: Ye. X: Calafat. AM: Tancredi. D; Hertz-Picciotto. I (2019).
Variability of urinary concentrations of phthalate metabolites during pregnancy in first morning
voids and pooled samples. Environ Int 122: 222-230.
http://dx.doi.Org/10.1016/i.envint.2018.l 1.012
Shin. HM: McKone. TE; Nishioka. MG: Fallin. MP: Croen. LA: Hertz-Picciotto. I: Newschaffer. CJ:
Bennett. DH. (2014). Determining source strength of semivolatile organic compounds using
measured concentrations in indoor dust. Indoor Air 24: 260-271.
http://dx.doi.org/10. Ill 1/ina. 12070
Spade. DJ: Hall. SJ: Saffarini. C: Huse. SM; McDonnell. EV; Boekelheide. K. (2014). Differential
response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal
testis xenograft bioassay. Toxicol Sci 138: 148-160. http://dx.doi.org/10.1093/toxsci/kft266
Stanfield. Z; Addington. CK; Dionisio. KL; Lyons. D; Tornero-Velez. R; Phillips. KA; Buckley. TJ;
Isaacs. KK. (2021). Mining of Consumer Product Ingredient and Purchasing Data to Identify
Potential Chemical Coexposures. Environ Health Perspect 129: 67006.
http://dx.doi.org/10.1289/EHP8610
Stanfield. Z; Setzer. RW: Hull. V: Savre. RR; Isaacs. KK: Wambaugh. JF. (2024). Characterizing
chemical exposure trends from NHANES urinary biomonitoring data. Environ Health Perspect
132: 17009. http://dx.doi.org/10.1289/EHP12188
Statistics Canada. (2004). Canadian Community Health Survey - Nutrition (CCHS). Detailed
information for 2004 (cycle 2.2) [Website],
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/7273228
Struve. MF; Gaido. KW; Henslev. JB; Lehmann. KP; Ross. SM; Sochaski. MA; Willson. GA; Donnan.
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
Tornero-Velez. R; Isaacs. K; Dionisio. K; Prince. S: Laws. H; Nye. M; Price. PS: Buckley. TJ. (2021).
Data Mining Approaches for Assessing Chemical Coexposures Using Consumer Product
Purchase Data. Risk Anal 41: 1716-1735. http://dx.doi.Org/10.l 111/risa. 13650
U.S. CPSC. (2014). Chronic Hazard Advisory Panel on Phthalates and Phthalate Alternatives (with
appendices). Bethesda, MD: U.S. Consumer Product Safety Commission, Directorate for Health
Sciences. https://www.cpsc.gov/s3fs-public/CHAP-REPORT-With-Appendices.pdf
U.S. CPSC. (2015). Estimated phthalate exposure and risk to pregnant women and women of
reproductive age as assessed using four NHANES biomonitoring data sets (2005/2006,
2007/2008, 2009/2010, 2011/2012). Rockville, Maryland: U.S. Consumer Product Safety
Commission, Directorate for Hazard Identification and Reduction.
https://web.archive.org/web/20190321120312/https://www.cpsc.gov/s3fs-public/NHANES-
Biomonitoring-analvsis-for-Commission.pdf
U.S. EPA. (1986). Guidelines for the health risk assessment of chemical mixtures. Fed Reg 51: 34014-
34025.
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2345
2346
2347
2348
2349
2350
2351
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PUBLIC RELEASE DRAFT
December 2024
U.S. EPA. (2000). Supplementary guidance for conducting health risk assessment of chemical mixtures
(pp. 1-209). (EPA/630/R-00/002). Washington, DC: U.S. Environmental Protection Agency,
Risk Assessment Forum, http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=20533
U.S. EPA. (2002a). Guidance on cumulative risk assessment of pesticide chemicals that have a common
mechanism of toxicity [EPA Report], Washington, D.C.
U.S. EPA. (2002b). A review of the reference dose and reference concentration processes.
(EPA630P02002F). Washington, DC. https://www.epa.gov/sites/production/files/2014-
12/documents/rfd-final.pdf
U.S. EPA. (2005). Guidelines for carcinogen risk assessment [EPA Report], (EPA630P03001F).
Washington, DC. https://www.epa.gov/sites/production/files/2Q13-
09/documents/cancer guidelines final 3-25-05.pdf
U.S. EPA. (2007). Analysis of total food intake and composition of individual's diet based on the
USDA's 1994-1996, 1998 continuing survey of food intakes by individuals (CSFII) [EPA
Report], (EPA/600/R-05/062F). Washington, DC.
https://heronet.epa.gov/heronet/index.cfm/reference/download/reference id/1065008
U.S. EPA. (201 la). Exposure factors handbook: 2011 edition [EPA Report], (EPA/600/R-090/052F).
Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development,
National Center for Environmental Assessment.
https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockev=P 100F2QS.txt
U.S. EPA. (2011b). Recommended use of body weight 3/4 as the default method in derivation of the
oral reference dose. (EPA100R110001). Washington, DC.
https://www.epa.gov/sites/production/files/2013-Q9/documents/recommended-use-of-bw34.pdf
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. (2016). Pesticide cumulative risk assessment: Framework for screening analysis.
Washington, DC: Office of Pesticide Programs, https://www.epa.gov/pesticide-science-and-
assessing-pesticide-risks/pesticide-cumulative-risk-assessment-framework
U.S. EPA. (2017). Estimation Programs Interface Suite v.4.11. Washington, DC: U.S. Environmental
Protection Agency, Office of Pollution Prevention Toxics. Retrieved from
https://www.epa.gov/tsca-screening-tools/download-epi-suitetm-estimation-program-interface-
v411
U.S. EPA. (2020a). Use report for butyl benzyl phthalate (BBP) - 1,2-Benzenedicarboxylic acid, 1- butyl
2(phenylmethyl) ester (CAS RN 85-68-7). (EPA-HQ-OPPT-2018-0501-0035). Washington, DC:
U.S. Environmental Protection Agency. https://www.regulations.gov/document/EPA-HQ-OPPT-
2018-0501-0035
U.S. EPA. (2020b). Use report for di-ethylhexyl phthalate (CAS RN 117-81-7). (EPA-HQ-OPPT-2018-
0433-0024). Washington, DC: U.S. Environmental Protection Agency.
https://www.regulations.gov/document/EPA-HQ-OPPT-2018-0433-0024
U.S. EPA. (2020c). Use report for di-isobutyl phthalate (CAS RN 84-69-5). (EPA-HQ-OPPT-2018-
0434-0029). Washington, DC: U.S. Environmental Protection Agency.
https://www.regulations.gov/document/EPA-HQ-OPPT-2018-0434-0029
U.S. EPA. (2020d). Use report for dibutyl phthalate (DBP) - (1,2-Benzenedicarboxylic acid, 1,2- dibutyl
ester) (CAS RN 84-74-2). (EPA-HQ-OPPT-2018-0503-0023). Washington, DC: U.S.
Environmental Protection Agency. https://www.regulations.gov/document/EPA-HQ-OPPT-
2018-0503-0023
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U.S. EPA. (2020e). Use report for dicyclohexyl phthalate (CAS RN 84-61-7). (EPA-HQ-OPPT-2018-
0504-0030). Washington, DC: U.S. Environmental Protection Agency.
https://www.regulations.gov/document/EPA-HQ-OPPT-2018-0504-003Q
U.S. EPA. (2021). Final use report for di-isononyl phthalate (DINP) - (1,2-benzene-dicarboxylic acid,
1,2-diisononyl ester, and 1,2-benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich)
(CASRN 28553-12-0 and 68515-48-0). (EPA-HQ-OPPT-2018-0436-0035). Washington, DC:
U.S. Environmental Protection Agency. https://www.regulations.gov/document/EPA-HQ-OPPT-
2018-0436-0035
U.S. EPA. (2022). ORD staff handbook for developing IRIS assessments [EPA Report], (EPA 600/R-
22/268). Washington, DC: U.S. Environmental Protection Agency, Office of Research and
Development, Center for Public Health and Environmental Assessment.
https://cfpub.epa.gov/ncea/iris drafts/recordisplav.cfm?deid=356370
U.S. EPA. (2023a). Advances in dose addition for chemical mixtures: A white paper. (EPA/100/R-
23/001). Washington, DC. https://assessments.epa.gov/risk/document/&deid=359745
U.S. EPA. (2023b). 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. (2023c). Science Advisory Committee on Chemicals meeting minutes and final report, No.
2023-01 - A set of scientific issues being considered by the Environmental Protection Agency
regarding: Draft Proposed Principles of Cumulative Risk Assessment (CRA) under the Toxic
Substances Control Act and a Draft Proposed Approach for CRA of High-Priority Phthalates and
a Manufacturer-Requested Phthalate. (EPA-HQ-OPPT-2022-0918). Washington, DC: U.S.
Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention.
https://www.regulations.gov/document/EPA-HO-OPPT-2022-0918-0Q67
U.S. EPA. (2024a). Draft Consumer and Indoor Dust Exposure Assessment for Dicyclohexyl Phthalate
(DCHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024b). Draft Environmental Media and General Population and Environmental Exposure
for Dicyclohexyl Phthalate (DCHP). Washington, DC: Office of Pollution Prevention and
Toxics.
U.S. EPA. (2024c). Draft Environmental Release and Occupational Exposure Assessment for
Dicyclohexyl Phthalate (DCHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024d). 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).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024e). Draft Non-cancer Human Health Hazard Assessment for Butyl benzyl phthalate
(BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024f). Draft Non-cancer Human Health Hazard Assessment for Dibutyl Phthalate (DBP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024g). Draft Non-Cancer Human Health Hazard Assessment for Dicyclohexyl Phthalate
(DCHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024h). Draft Non-cancer Human Health Hazard Assessment for Diethylhexyl Phthalate
(DEHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024i). Draft Non-cancer Human Health Hazard Assessment for Diisobutyl phthalate
(DIBP). Washington, DC: Office of Pollution Prevention and Toxics.
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U.S. EPA. (2024i). Draft Physical Chemistry Assessment for Butyl benzyl phthalate (BBP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024k). Draft Physical Chemistry Assessment for Dibutyl Phthalate (DBP). Washington,
DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (20241). Draft Physical Chemistry Assessment for Dicyclohexyl Phthalate (DCHP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024m). Draft Physical Chemistry Assessment for Diethylhexyl Phthalate (DEHP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024n). Draft Physical Chemistry Assessment for Diisobutyl phthalate (DIBP). Washington,
DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024o). Draft Risk Calculator for Occupational Exposures for Dicyclohexyl Phthalate
(DCHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024p). Draft Summary of Facility Release Data for Di(2-ethylhexyl) Phthalate (DEHP),
Dibutyl Phthalate (DBP), and Butyl Benzyl Phthalate (BBP). Washington, DC: Office of
Pollution Prevention and Toxics.
U.S. EPA. (2024q). Science Advisory Committee on Chemicals Meeting Minutes and Final Report No.
2024-2, Docket ID: EPA-HQ-OPPT-2024-0073: For the Draft Risk Evaluation for Di-isodecyl
Phthalate (DIDP) and Draft Hazard Assessments for Di-isononyl Phthalate (DINP). Washington,
DC: U.S. Environmental Protection Agency, Science Advisory Committee on Chemicals.
U.S. EPA. (2025a). Consumer and Indoor Exposure Assessment for Diisononyl Phthalate (DINP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025b). Draft Consumer and Indoor Dust Exposure Assessment for Butyl benzyl phthalate
(BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025c). Draft Consumer and Indoor Dust Exposure Assessment for Dibutyl Phthalate
(DBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025d). Draft Consumer and Indoor Dust Exposure Assessment for Diisobutyl phthalate
(DIBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025e). Draft Consumer and Indoor Exposure Assessment for Diethylhexyl Phthalate
(DEHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025f). Draft Environmental Media and General Population and Environment Exposure for
Butyl benzyl phthalate (BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025g). Draft Environmental Media and General Population and Environmental Exposure
for Dibutyl Phthalate (DBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025h). Draft Environmental Media and General Population and Environmental Exposure
for Diethylhexyl Phthalate (DEHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025i). Draft Environmental Media and General Population and Environmental Exposure for
Diisobutyl phthalate (DIBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025i). Draft Environmental Release and Occupational Exposure Assessment for Butyl
benzyl phthalate (BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025k). Draft Environmental Release and Occupational Exposure Assessment for Dibutyl
Phthalate (DBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (20251). Draft Environmental Release and Occupational Exposure Assessment for
Diethylhexyl Phthalate (DEHP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025m). Draft Environmental Release and Occupational Exposure Assessment for
Diisobutyl phthalate (DIBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025n). Environmental Media and General Population Screening for Diisononyl Phthalate
(DINP). Washington, DC: Office of Pollution Prevention and Toxics.
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U.S. EPA. (2025o). Environmental Release and Occupational Exposure Assessment for Diisononyl
Phthalate (DINP) Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025p). Non-Cancer Human Health Hazard Assessment for Diisononyl Phthalate (DINP)
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025q). Physical Chemistry Assessment for Diisononyl Phthalate (DINP). Washington, DC:
Office of Pollution Prevention and Toxics.
van Den Driesche. S: McKinnell. C: Calarrao. A: Kennedy. L; Hutchison. GR; Hrabalkova. L; Jobling.
MS: Macpherson. S: Anderson. RA; Sharpe. RM; Mitchell. RT. (2015). Comparative effects of
di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis
xenografts. Environ Health Perspect 123: 223-230. http://dx.doi.org/10.1289/ehp. 1408248
Welsh. M; Saunders. PTK; Fisken. M; Scott. HM; Hutchison. GR: Smith. LB: Sharpe. RM. (2008).
Identification in rats of a programming window for reproductive tract masculinization, disruption
of which leads to hypospadias and cryptorchidism. J Clin Invest 118: 1479-1490.
http: //dx. doi. or g/10.1172/i ci34241
Wilson. NK; Chuang. JC: Lyu. C. (2001). Levels of persistent organic pollutants in several child day
care centers. J Expo Anal Environ Epidemiol 11: 449-458.
http://dx.doi.org/10.1038/si.iea.750019Q
Wilson. NK: Chuang. JC: Lyu. C: Menton. R; Morgan. MK. (2003). Aggregate exposures of nine
preschool children to persistent organic pollutants at day care and at home. J Expo Anal Environ
Epidemiol 13: 187-202. http://dx.doi.org/10.1038/si.iea.750027Q
Wormuth. M; Scheringer. M; Vollenweider. M; Hungerbuhler. K. (2006). What are the sources of
exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 26: 803-824.
http://dx.doi.org/10.1111/i. 1539-6924.2006.00770.X
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2473 APPENDICES
2474
2475 Appendix A FETAL TESTICULAR TESTOSTERONE DATA FOR DEHP AND DBP
2476
2477 Table Apx A-l. Summary of Fetal Testicular Testosterone Data for DEHP"
Brief Study Description, Measured Outcome
Dose (mg/kg-day)
(Reference)
0
10
50
100
117
150
234
300
469
500
600
625
750
875
900
938
Long-Evans rats gavaged with 0, 10, 100, 750
mg/kg-day DEHP on GD 2-20. Fetal testis
testosterone content on GD 21 (Lin et al.. 2008)
100%
(n=6)
157%*
(n=6)
-
78%
(n=6)
-
-
-
-
-
-
-
-
33%*
(n=9)
-
-
-
Pregnant Wistar rats gavaged with 0, 150 mg/kg-
day DEHP on GD 13-21. Fetal testis testosterone
content on GD 21 (Martino-Andrade et al.. 2008)
100%
(n=7)
-
-
-
-
71%*
(n=7)
-
-
-
-
-
-
-
-
-
-
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
Droduction (3-hour incubation) on GD 18 (Hannas
etal.. 2011)
100%
100%
50%*
36%*
24%*
14%*
18%*
(n=6)
(n=3)
(n=3)
(n=6)
(n=4)
(n=4)
(n=3)
Pregnant SD 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
Droduction (3-hour incubation) on GD 18 (Hannas
etal.. 2011)
100%
107%
61%*
40%*
21%*
29%*
48%*
(n=6)
(n=3)
(n=3)
(n=6)
(n=4)
(n=4)
(n=4)
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 (Cultv et al.. 2008)
100%
(n=3)
-
-
-
41%*
(n=3)
-
37%*
(n=3)
-
23%*
(n=3)
-
-
-
-
-
-
8.5%
(n=3)
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
Droduction (3-hour incubation) on GD 18 (Furr et
al.. 2014)
100%
(n=3)
-
-
37%*
(n=2)
-
-
-
18%*
(n=3)
-
-
7.1%*
(n=3)
-
-
-
6.0%*
(n=2)
-
Pregnant SD rats (2-3 dams/group) gavaged with 0,
100, 300, 600, 900 mg/kg-day DEHP on GD 14-18
(Block 32). Ex vivo fetal testicular testosterone
Droduction (3-hour incubation) on GD 18 (Furr et
al.. 2014)
100%
(n=2)
-
-
79%*
(n=3)
-
-
-
35%*
(n=3)
-
-
15%*
(n=3)
-
-
-
12%*
(n=2)
-
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Brief Study Description, Measured Outcome
(Reference)
Dose (mg/kg-day)
0
10
50
100
117
150
234
300
469
500
600
625
750
875
900
938
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 (Howdeshell et al..
2008)
100%
(n=4)
-
-
82%
(n=4)
-
-
-
58%*
(n=4)
-
-
41%*
(n=4)
-
-
-
22%*
(n=4)
-
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 (Saillenfait et al.. 2013)
100%
(n=16)
-
72%*
(n=8)
-
-
-
-
-
-
-
-
16%*
(n=8)
-
-
-
-
Pregnant SD rats (2-3 dams/group) gavaged with 0,
100, 300, 600, 900 mg/kg-day DEHP on GD 14-18
(Block 76). Ex vivo fetal testicular testosterone
Droduction (3-hour incubation) on GD 18 (Gray et
al.. 2021)
100%
(n=3)
-
-
104%
(n=3)
-
-
-
75%
(n=2)
-
-
30%
(n=3)
-
-
-
20%
(n=3)
-
Pregnant SD rats (3 dams/group) gavaged with 0,
100, 300, 600, 900 mg/kg-day DEHP on GD 14-18
(Block 77). Ex vivo fetal testicular testosterone
Droduction (3-hour incubation) on GD 18 (Gray et
al.. 2021)
100%
(n=3)
-
-
99%
(n=3)
-
-
-
67%
(n=3)
-
-
25%
(n=3)
-
-
-
25%
(n=3)
-
" Asterisk (*) indicates a statistically significant effect compared to the concurrent control as calculated by original study authors. Percent testosterone values indicate the
percent testosterone or testosterone production compared to the concurrent control as calculated by EPA.
2478
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2479 Table Apx A-2. Summary of Fetal Testicular Testosterone Data for DBP
Brief Study Description, Measured Outcome (Reference)
Dose (mg/kg-day)
0
1
10
33
50
100
112
300
500
581
600
900
Pregnant Wistar rats gavaged with 0, 100, 500 mg/kg-day DBP on GD 13-
21. Fetal testis testosterone content on GD 21 (Martino-Andrade et al..
2008)
100%
(n=7)
-
-
-
-
71%
(n=8)
-
-
37%*
(n=7)
-
-
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 (Furr et al.. 2014)
100%
(n=3)
-
-
32%
(n=3)
86%
(n=2)
65%*
(n=3)
-
23%*
(n=3)
-
-
-
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 (Furr et al.. 2014)
100%
(n=3)
88%
(n=3)
80%
(n=4)
-
-
64%*
(n=4)
-
-
-
-
-
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 (Furr et al.. 2014)
100%
(n=3)
160%
(n=4)
119%
(n=4)
-
-
75%
(n=3)
-
-
-
-
-
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 (Howdeshell et al.. 2008)
100%
(n=3)
-
-
94%
(n=4)
78%
(n=4)
84%
(n=4)
-
66%*
(n=4)
-
33%*
(n=4)
-
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. (Kuhl et al..
2007)
100%
(n=10)
-
-
-
-
71%
(n=10)
-
-
33%*
(n=10)
-
-
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) (Strove et al.. 2009)
100%
(n=9)
-
-
-
-
-
56%
(n=7)
-
-
3.7%*
(n=7)
-
-
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 (24 hour
post-exposure) (Strove et al.. 2009)
100%
(n=9)
-
-
-
-
-
29%*
(n=7)
-
-
7.1%*
(n=7)
-
-
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 (Johnson et al.. 2011)
100%
(n=5)
-
-
-
-
77%
(n=6)
-
-
-
-
-
-
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..
2011)
100%
(n=6)
-
-
-
-
-
-
-
15%*
(n=5)
-
-
-
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 (Johnson et al..
2007)
100%
(n=5)
109%
(n=5)
67%
(n=5)
-
-
84%
(n=5)
-
-
-
-
-
-
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Brief Study Description, Measured Outcome (Reference)
Dose (mg/kg-day)
0
1
10
33
50
100
112
300
500
581
600
900
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 (Grav et al.. 2021)
100%
(n=3)
-
-
-
-
-
-
62%
(n=4)
-
-
25%
(n=4)
16%
(n=4)
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 (Grav et al.. 2021)
100%
(n=4)
-
-
-
-
-
-
47%
(n=3)
-
-
22%
(n=4)
13%
(n=4)
" Asterisk (*) indicates a statistically significant effect compared to the concurrent control as calculated by original study authors. Percent testosterone values indicate the
percent testosterone or testosterone production compared to the concurrent control as calculated by EPA.
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Appendix B CONSIDERATIONS FOR BENCHMARK RESPONSE
(BMR) SELECTION FOR REDUCED FETAL
TESTICULAR TESTOSTERONE
B.l Purpose
EPA has conducted an updated meta-analysis and benchmark dose modeling (BMD) analysis of
decreased fetal rat testicular testosterone (U.S. EPA. 2024d). During the July 2024 Science Advisory
Committee on Chemicals (SACC) peer-review meeting of the draft risk evaluation of diisodecyl
phthalate (DIDP) and draft human health hazard assessments for diisononyl phthalate (DINP), the
SACC recommended that EPA should clearly state its rationale for selection of benchmark response
(BMR) levels evaluated for decreases in fetal testicular testosterone (U.S. EPA. 2024q). This appendix
describes EPA's rationale for evaluating BMRs of 5, 10, and 40 percent for decreases in fetal testicular
testosterone.
B.2 Methods
As described in EPA's Benchmark Dose Technical Guidance (U.S. EPA. 2012). "Selecting a BMR(s)
involves making judgments about the statistical and biological characteristics of the dataset and about
the applications for which the resulting BMDs/BMDLs will be used." For the updated meta-analysis and
BMD modeling analysis of fetal rat testicular testosterone, EPA evaluated BMR values of 5, 10, and 40
percent based on both statistical and biological considerations (U.S. EPA. 2024d).
In 2017, NASEM (2017) modeled BMRs of 5 and 40 percent for decreases in fetal testicular
testosterone. NASEM did not provide explicit justification for selection of a BMR of 5 percent.
However, justification for the BMR of 5 can be found elsewhere. As discussed in EPA's Benchmark
Dose Technical Guidance (U.S. EPA. 2012). a BMR of 5 percent is supported in most developmental
and reproductive studies. Comparative analyses of a large database of developmental toxicity studies
demonstrated that developmental NOAELs are approximately equal to the BMDLs (Allen et al.. 1994a.
b; Faustman et al.. 1994).
EPA also evaluated a BMR of 10 percent as part of the updated BMD analysis. BMD modeling of fetal
testosterone conducted by NASEM (2017) indicated that BMDs estimates are below the lowest dose
with empirical testosterone data for several of the phthalates (e.g., DIBP, BBP). 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.
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% fGrav et al.. 2016; Howdeshell et al.. 2015)."
Further description of methods and results for the updated meta-analysis and BMD modeling analysis
that evaluated BMRs of 5, 10, and 40 percent for decreased fetal testicular testosterone are provided in
EPA's Draft Meta-Analysis and Benchmark Dose Modeling of Fetal Testicular Testosterone for Di(2-
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ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), Butyl Benzyl Phthalate (BBP), Diisobutyl
Phthalate (DIBP), andDicyclohexylPhthalate (DCHP) (U.S. EPA. 2024cT).
B.3 Results
BMD estimates, as well as 95 percent upper and lower confidence limits, for decreased fetal testicular
testosterone for the evaluated BMRs of 5, 10, and 40 percent are shown in TableApx B-l. BMDs
estimates ranged from 8.4 to 74 mg/kg-day for DEHP, DBP, DCHP, and DINP; however, a BMDs
estimate could not be derived for BBP or DIBP. Similarly, BMDio estimates ranged from 17 to 152 for
DEHP, DBP, DCHP, DIBP and DINP; however, a BMDio estimate could not be derived for BBP.
BMD40 estimates were derived for all phthalates (i.e., DEHP, DBP, DCHP, DIBP, BBP, DINP) and
ranged from 90 to 699 mg/kg-day.
In the mode of action (MOA) for phthalate syndrome, which is described elsewhere (U.S. EPA. 2023b)
and in Section 1.1 of this document, 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 reproductive tract malformations. Decreased fetal testicular testosterone should occur at
lower or equal doses than downstream apical outcomes associated with a disruption of androgen action.
Because the lower 95 percent confidence limit on the BMD, or BMDL, is used for deriving a point of
departure (POD), EPA compared BMDL estimates at the 5, 10, and 40 percent response levels for each
phthalate (DEHP, DBP, DCHP, DIBP, BBP, DINP) to the lowest identified apical outcomes associated
with phthalate syndrome to determine which response level is protective of downstream apical
outcomes.
Table Apx B-l provides a comparison of BMD and BMDL estimates for decreased fetal testicular
testosterone at BMRs of 5, 10, and 40 percent, the lowest LOAEL(s) for apical outcomes associated
with phthalate syndrome, and the POD selected for each phthalate for use in risk characterization. As
can be seen from Table Apx B-l, BMDL40 values for DEHP, DBP, DIBP, BBP, DCHP, and DINP are
all well above the PODs selected for use in risk characterization for each phthalate by 3x (for BBP) to
25 .4x (for DEHP). Further, BMDL40 values for DEHP, DBP, DIBP, BBP, and DCHP, but not DINP, are
above the lowest LOAELs identified for apical outcomes on the developing male reproductive system.
These results clearly demonstrate that a BMR of 40 percent is not appropriate for use in human health
risk assessment.
As can be seen from Table Apx B-l, BMDL10 values for DBP (BMDL10, POD, LOAEL = 20, 9, 30
mg/kg-day, respectively) and DCHP (BMDL10, POD, LOAEL = 12, 10, 20 mg/kg-day, respectively) are
slightly higher than the PODs selected for use in risk characterization and slightly less than the lowest
LOAELs identified based on apical outcomes associated with the developing male reproductive system.
This indicates that a BMR of 10% may be protective of apical outcomes evaluated in available studies
for both DBP and DCHP. BMDL10 values could not be derived for DIBP or BBP (Table Apx B-l).
Therefore, no comparisons to the POD or lowest LOAEL for apical outcomes could be made for either
of these phthalates at the 10 percent response level.
For DEHP, the BMDL10 is greater than the POD selected for use in risk characterization by 5x (BMDL10
and POD = 24 and 24.8 mg/kg-day, respectively) and is greater than the lowest LOAEL identified for
apical outcomes on the developing male reproductive system by 2.4x (BMDL10 and LOAEL = 24 and 10
mg/kg-day, respectively). This indicates that a BMR of 10 percent for decreased fetal testicular
testosterone is not health protective for DEHP. For DEHP, the BMDL5 (11 mg/kg-day) is similar to the
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selected POD (NOAEL of 4.8 mg/kg-day) and the lowest LOAEL identified for apical outcomes on the
developing male reproductive system (10 mg/kg-day).
B.4 Weight of Scientific Evidence Conclusion
As discussed elsewhere (U.S. EPA. 2023b). DEHP, DBP, BBP, DIBP, DCHP, and DINP are
toxicologically similar and induce effects on the developing male reproductive system consistent with a
disruption of androgen action. Because these phthalates are toxicologically similar, it is more
appropriate to select a single BMR for decreased fetal testicular testosterone to provide a consistent
basis for dose response analysis and for deriving PODs relevant to the single chemical assessments and
CRA. EPA has reached the preliminary conclusion that a BMR of 5 percent is the most appropriate and
health protective response level for evaluating decreased fetal testicular testosterone when sufficient
dose-response data are available to support modeling of fetal testicular testosterone in the low-end range
of the dose-response curve. This conclusion is supported by the following weight of scientific evidence
considerations.
For DEHP, the BMDLio estimate is greater than the POD selected for use in risk characterization
by 5x and is greater than the lowest LOAEL identified for apical outcomes on the developing
male reproductive system by 2.4x. This indicates that a BMR of 10 percent is not protective for
DEHP.
The BMDL5 estimate for DEHP is similar to the selected POD and lowest LOAEL for apical
outcomes on the developing male reproductive system.
BMDLio estimates for DBP (BMDLio, POD, LOAEL = 20, 9, 30 mg/kg-day, respectively) and
DCHP (BMDLio, POD, LOAEL = 12, 10, 20 mg/kg-day, respectively) are slightly higher than
the PODs selected for use in risk characterization and slightly less than the lowest LOAELs
identified based on apical outcomes associated with the developing male reproductive system.
This indicates that a BMR of 10 percent may be protective of apical outcomes evaluated in
available studies for both DBP and DCHP. However, this may be a reflection of the larger
database of studies and wider range of endpoints evaluated for DEHP, compared to DBP and
DCHP.
NASEM (2017) 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% fGrav et al.. 2016; Howdeshell et al.. 2015/"
However, publications supporting a 40 percent response level are relatively narrow in scope and
assessed the link between reduced fetal testicular testosterone in SD rats on GD 18 and later life
reproductive tract malformations in F1 males. More specifically, Howdeshell et al. (2015) found
reproductive tract malformations in 17 to 100 percent of F1 males when fetal testosterone on GD
18 was reduced by approximately 25 to 72 percent, while Gray et al. (2016) found dose-related
reproductive alterations in F1 males treated with dipentyl phthalate (a phthalate not currently
being evaluated under TSCA) when fetal testosterone was reduced by about 45 percent on GD
18. Although NASEM modeled a BMR of 40 percent based on biological considerations, there is
no scientific consensus on the biologically significant response level and no other authoritative
or regulatory agencies have endorsed the 40 percent response level as biologically significant for
reductions in fetal testosterone.
BMDL40 values for DEHP, DBP, DIBP, BBP, DCHP, and DINP are above the PODs selected for
use in risk characterization for each phthalate by 3x to 25.4x (Table Apx B-l). BMDL40 values
for DEHP, DBP, DIBP, BBP, and DCHP, but not DINP, are above the lowest LOAELs
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2614 identified for apical outcomes on the developing male reproductive system. These results clearly
2615 demonstrate that a BMR of 40 percent is not health protective.
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TableApx B-l. Comparison of BMD/BMDL Values Across BMRs of 5%, 10%, and 40% with PODs and LOAELs for Apical
Outcomes for DEHP, DBP, DIBP, BBP, DCHP, and DINP
Phthalate
POD (mg/kg-day) Selected for
use in Risk Characterization
(Effect)
Lowest LOAEL(s)
(mg/kg-day) for Apical
Effects on the Male
Reproductive System
BMDs
Estimate "
(mg/kg-day)
[95% CI]
BMDio
Estimate "
(mg/kg-day)
[95% CI]
BMD40
Estimate "
(mg/kg-day)
[95% CI]
Reference For
Further Details on
the Selected POD
and Lowest
Identified LOAEL,
DEHP
NOAEL = 4.8
(| male RTM in F1 and F2 males)
10 to 15
(NR, | AGD, RTMs)
17 [11, 31]
35 [24, 63]
178 [122, 284]
(U.S. EPA. 2024h)
DBP
BMDLs = 9
Q fetal testicular testosterone)
30
(t Testicular Pathology)
14 [9, 27]
29 [20, 54]
149 [101, 247]
(U.S. EPA. 2024f)
DIBP
BMDLs = 24
Q fetal testicular testosterone)
125
(t Testicular Pathology)
_b
55 [NA,
266]*
279 [136, 517]
(U.S. EPA. 2024i)
BBP
NOAEL = 50
(phthalate syndrome-related
effects)
100
(1 AGD)
_b
_b
284 [150, 481]
(U.S. EPA. 2024e)
DCHP
NOAEL = 10
(phthalate syndrome-related
effects)
20
(t Testicular Pathology)
8.4 [6.0, 14]
17 [12, 29]
90 [63, 151]
(U.S. EPA. 2024a)
DINP
BMDLs = 49
Q fetal testicular testosterone)
600
(I sperm motility)
74 [47, 158]
152 [97, 278]
699 [539, 858]
(U.S. EPA. 2025d)
Abbreviations: AGD = anogenital distance; BMD = benchmark dose; BMDL = lower 95% confidence limit on BMD; CI = 95% confidence interval;
LOAEL = lowest observable-adverse-effect level; NOAEL = no observable-adverse-effect level; POD = point of departure; RTM = reproductive tract
malformations
11 The linear-quadratic model provided the best fit (based on lowest AIC) for DEHP, DBP, DIBP, BBP, DCHP, and DINP.
b BMD and/or BMDL estimate could not be derived.
2618
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Appendix C NHANES URINARY BIOMONITORING
C.l Urinary Biomonitoring: Methods and Results
EPA analyzed urinary biomonitoring data from the U.S. Centers for Disease Control and Prevention
(CDC) National Health and Nutrition Evaluation Surveys (NHANES), which reports urinary
concentrations for 15 phthalate metabolites specific to individual phthalate diesters.
DEHP. Four urinary metabolites of DEHP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHP), mono(2-
ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and
mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) have been reported in the NHANES data. MEHP has
been reported in NHANES beginning with the 1999 cycle and measured in 26,740 members of the
general public, including 7,331 children under age 16 and 19,409 adults aged 16 and over. MEHHP was
added starting in the 2001 to 2002 NHANES cycle and has been measured in 24,199 participants,
including 6,617 children and 17,852 adults. MEOHP was added starting in the 2001 to 2002 NHANES
cycle and has been measured in 24,199 participants, including 6,617 children and 17,582 adults. MECPP
was added starting in the 2003 to 2004 NHANES cycles and has been measured in 21,417 participants,
including 5,839 children and 15,578 adults. Metabolites of DEHP were quantified in urinary samples
from a one-third subsample of all participants aged 6 and older. Beginning with the 2005-2006 cycle of
NHANES, all participants between 3-5 years were eligible for DEHP metabolite urinary analysis.
Urinary DEHP metabolite concentrations were quantified using high performance liquid
chromatography-electrospray ionization-tandem mass spectrometry. Limits of detection (LOD) for each
cycle on NHANES are provided in TableApx C-l. Values below the LOD were replaced by the lower
limit of detection divided by the square root of two (NCHS. 2021). As can be seen from Table Apx C-2,
MEHHP, MEOHP, and MECPP were above the LOD in the urine of more than 99 percent of all
NHANES participants (n=2,762) in the most recent survey (2017 to 2018), while MEHP was above the
LOD in approximately 46 percent of samples.
DBP. Two urinary metabolites of DBP, mono-n-butyl phthalate (MnBP) and mono-3-hydroxybutyl
phthalate (MHBP), have been reported in the NHANES data. MnBP has been reported in NHANES
beginning with the 1999 cycle and was measured in 26,740 members of the general public, including
7,331 children under age 16 and 19,409 adults aged 16 and over. Although MHBP was measured in the
2013 to 2018 NHANES cycles, the data for the 2013 to 2014 NHANES cycle was determined to be
inaccurate due to procedural error and only released as surplus data, which is not readily publicly
available (https://wwwn.cdc.gov/Nchs/Nhanes/2013-2014/SSPHTE H.htm). As a result, the present
analysis only includes urinary MHBP data from the 2015 to 2018 NHANES cycles. The present analysis
of MHBP includes data from the 2015 to 2018 NHANES cycles and has been measured in 5,737
participants, including 1,961 children under age 16 and 3,776 adults aged 16 and older. Urinary MnBP
and MHBP concentrations were quantified using high performance liquid chromatography-electrospray
ionization-tandem mass spectrometry. Limits of detection (LOD) for each cycle on NHANES are
provided in TableApx C-l. Values below the LOD were replaced by the lower limit of detection
divided by the square root of two (NCHS. 2021). As can be seen from Table_Apx C-2, MnBP was
above the LOD in the urine of more than 99 percent of all NHANES participants (n=2762) in the most
recent survey (2017 to 2018), while MHBP was above the LOD in approximately 75 percent of samples.
BBP. One urinary metabolite of BBP, mono-benzyl phthalate (MBzP), has been reported in the
NHANES dataset. MBzP has been reported in NHANES beginning with the 1999 cycle and measured in
26,740 members of the general public, including 7,331 children aged 15 and under and 19,409 adults
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aged 16 and over. Urinary MBzP concentrations were quantified using high performance liquid
chromatography-electrospray ionization-tandem mass spectrometry. Limits of detection (LOD) for each
cycle on NHANES are provided in TableApx C-l. Values below the LOD were replaced by the lower
limit of detection divided by the square root of two (NCHS. 2021). As can be seen from Table Apx C-2,
MBzP was above the LOD in the urine of 96.2 percent of all NHANES participants (n=2762) in the
most recent survey (2017 to 2018).
DIBP. Two urinary metabolites of DIBP, mono-2-methyl-2-hydroxypropyl phthalate (MHiBP) and
mono-isobutyl phthalate (MIBP), have been reported in the NHANES dataset. MIBP has been reported
starting in the 2001 to 2002 NHANES cycle and has been measured in 24,199 participants, including
6,617 children and 17,582 adults. Although MHiBP was measured in the 2013 to 2018 NHANES cycles,
the data for the 2013 to 2014 NHANES cycle was determined to be inaccurate due to procedural error
and only released as surplus data, which is not readily publicly available
(https://wwwn.cdc.gov/Nchs/Nhanes/2013-2014/SSPHTE H.htm). As a result, the present analysis only
includes urinary MHiBP data from the 2015 to 2018 NHANES cycles. From 2015 to 2018, MHiBP and
has been measured in 5,737 members of the general public, including 1,961 children aged 15 and under
and 3,776 adults aged 16 and over. Urinary MIBP and MHiBP concentrations were quantified using
high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Limits of
detection (LOD) for each cycle of NHANES are provided in TableApx C-l. Values below the LOD
were replaced by the lower limit of detection divided by the square root of two (NCHS. 2021). As can
be seen from Table Apx C-2, MHiBP was above the LOD in the urine of approximately 98 percent of
all NHANES participants (n=2,762) in the most recent survey (2017 to 2018), while MIBP was above
the LOD in approximately 95 percent of samples.
DINP. Three metabolites of DINP, mono-isononyl phthalate (MINP), mono-oxoisononyl phthalate
(MONP), and mono-(carboxyoctyl) phthalate (MCOP) have been reported in the NHANES dataset.
MINP has been reported in NHANES beginning with the 1999 cycle and measured in 26,740 members
of the general public, including 7,331 children aged 15 and under and 19,409 adults aged 16 and over.
MCOP was added starting in the 2005 to 2006 NHANES cycle and has been measured in 18,812
participants, including 5,123 children and 13,689 adults. Most recently (in 2017 to 2018), NHANES
began reporting concentrations of MONP, which has been measured in 2,762 participants, including 866
children and 1,896 adults. Urinary MINP, MONP, and MCOP concentrations were quantified using high
performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Limits of
detection (LOD) for each cycle on NHANES are provided in Table Apx C-l. Values below the LOD
were replaced by the lower limit of detection divided by the square root of two (NCHS. 2021). As can
be seen from Table Apx C-2, MCOP was above the LOD in the urine of greater than 99 percent of all
NHANES participants (n=2,762) in the most recent survey (2017 to 2018), while MINP and MONP
were above the LOD in approximately 87 percent of samples.
DCHP. One metabolite of DCHP, mono-cyclohexyl phthalate (MCHP), has been reported in the
NHANES dataset. MCHP has been reported in NHANES beginning with the 1999 cycle and measured
in 15,829 members of the general public, including 4,130 children age 15 and under and 11,699 adults
age 16 and over. However, MCHP was excluded from the NHANES survey due to low detection levels
and a low frequency of detection in human urine after the 2009 to 2010 survey cycle (CDC.
2013a).Urinary MCHP concentrations were quantified using high performance liquid chromatography-
electrospray ionization-tandem mass spectrometry. Limits of detection (LOD) for each cycle on
NHANES are provided in Table Apx C-l. Values below the LOD were replaced by the lower limit of
detection divided by the square root of two (NCHS. 2021). In the 1999 to 2000 NHANES survey,
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2713 MCHP was above the LOD in 100 percent of urine samples; however, the percent of samples with
2714 levels of MCHP above the LOD dropped precipitously in subsequent survey years. In the 2009 to 2010
2715 survey year (last survey in which MCHP was monitored), MCHP was above the LOD in 4.3 percent of
2716 samples for all adults aged 16 years and older, and 7.9 percent of samples for all children 3 to less than
2717 16 years of age (see Appendix B of the Draft Environmental Media, General Population, and
2718 Environmental Exposure for Dicyclohexyl Phthalate (DCHP) (U.S. EPA. 2024b)).
2719
2720 TableApx C-l. Limit of Detection (ng/mL) of Urinary Phthalate Metabolites by NHANES Survey
2721 Year
Phthalate
Urinary
Metabolite
NHANES Survey Year
1999-
2000
2001-
2002
2003-
2004
2005-
2006
2007-
2008
2009-
2010
2011-
2012
2013-
2014
2015-
2016
2017-
2018
DEHP
MEHP
0.86
0.86
0.9
1.2
1.2
0.5
0.5
0.8
0.8
0.8
MEHHP
-
-
0.32
0.7
0.7
0.2
0.2
0.4
0.4
0.4
MECPP
-
-
0.25
0.6
0.6
0.2
0.2
0.4
0.4
0.4
MEOHP
-
-
0.45
0.7
0.7
0.2
0.2
0.2
0.2
0.2
DBP
MnBP
0.94
0.94
0.4
0.6
0.6
0.4
0.2
0.4
0.4
0.4
MHBP
-
-
-
-
-
-
-
-
0.4
0.4
BBP
MBzP
0.47
0.47
0.11
0.3
0.3
0.216
0.3
0.3
0.3
0.3
DIBP
MiBP
-
0.94
0.26
0.3
0.3
0.2
0.2
0.8
0.8
0.8
MHiBP
-
-
-
-
-
-
-
-
0.4
0.4
DCHP
MCHP
0.93
0.93
0.2
0.3
0.3
0.402
-
-
-
-
DINP
MiNP
0.79
0.79
1.54
1.23
1.23
0.77
0.5
0.9
0.9
0.9
MCOP
-
-
-
0.7
0.7
0.2
0.2
0.3
0.3
0.3
MONP
-
-
-
-
-
-
-
-
-
0.4
2722
2723 Table Apx C-2. Summary of Phthalate Metabolite Detection Frequencies in NHANES"
Parent
Phthalate
Urinary Metabolite
Percentage Below the Limit of Detection
2017-2018 NHANES
(All Participants;
N=2762)
2017-2018 NHANES
(Women Aged 16-49;
N=470)
2017-2018 NHANES
(Children Aged 6-17;
N=866)
BBP
Mono-benzyl phthalate (MBzP)
3.8%
6.25%
0.81%
DBP
Mono-n-butyl phthalate (MnBP)
0.69%
0.81%
0.58%
Mono-3-hydroxybutyl phthalate
(MHBP) '
24.91%
27.82%
15.82%
DEHP
Mono-2-ethylhexyl phthalate
(MEHP)
43.77%
41.13%
36.84%
Mono-(2-ethyl-5-hydroxyhexyl)
phthalate (MEHHP)
0.98%
1.21%
0.12%
Mono-(2-ethyl-5-oxohexyl)
phthalate (MEOHP)
0.83%
1.21%
0.12%
Mono-(2-ethyl-5-carboxypentyl)
phthalate (MECPP)
0.18%
-
-
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Parent
Phthalate
Urinary Metabolite
Percentage Below the Limit of Detection
2017-2018 NHANES
(All Participants;
N=2762)
2017-2018 NHANES
(Women Aged 16-49;
N=470)
2017-2018 NHANES
(Children Aged 6-17;
N=866)
DIBP
Mono-isobutyl phthalate (MiBP)
4.89%
7.46%
1.5%
Mono-2-methyl-2-
hydroxypropyl Phthalate
(MHiBP)
2.17%
2.34%
1.03%
DINP
Mono-isononyl phthalate
(MiNP)
12.57%
14.37%
18.01%
Mono-(carboxyoctyl) phthalate
(MCOP)
0.51%
0.40%
0.11%
Mono-oxoisononyl phthalate
(MONP)
12.85%
11.06%
7.62%
- Indicates that the metabolite was not included as part of the analysis.
ฐ Collection of DCHP was discontinued after the 2009-2010 NHANES cycle and is not included in this table.
C.2 Urinary Biomonitoring: Temporal Trends Analysis
C.2.1 DEHP
Temporal trends in urinary MEHP, MEHHP, MEOHP, and MEOCP, which are metabolites of DEHP,
are summarized below and discussed in detail in Section 10.2 of EPA's Draft Environmental Media and
General Population and Environmental Exposure for Diethylhexyl Phthalate (DEHP) (U.S. EPA.
2025h). Overall, 50th and 95th percentile urinary MEHP, MEHPP, MEOHP and MEOCP
concentrations have significantly decreased over time (1999-2018) for all lifestages.
For MEHP (NHANES reporting years: 1999-2018). the following trends were observed:
Overall, median and 95th percentile MEHP urinary concentrations have decreased over time
(1999-2018) for all lifestages.
Median and 95th percentile urinary MEHP concentrations decreased significantly among all
children under age 16, as well as among children aged 3 to less than 6 years, 6 to less than 11
years, and 11 to less than 16 years from 1999 to 2018. There were also significant decreases in
median and 95th percentile urinary MEHP concentrations for all male children and all female
children under age 16 from 1999 to 2018.
Median and 95th percentile urinary MEHP concentrations decreased significantly among all
adults, female adults, and male adults 16 years and older from 1999 to 2018. Among women of
reproductive age, there were statistically significant decreases in 50th and 95th percentile MEHP
urinary concentrations from 1999 to 2018.
For MEHHP and MEOHP (NHANES reporting years for both metabolites: 2001-2018). the following
trends were observed:
Overall, median and 95th percentile MEHHP and MEOHP concentrations have decreased over
time (2001-2018) for all lifestages.
Statistically significant decreases in 50th and 95th percentile urinary MEHHP and MEOHP
concentrations were observed among all children under age 16, as well as among children aged 3
to less than 6 years, 6 to less than 11 years, and 11 to less than 16 years from 1999 to 2018.
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Median and 95th percentile urinary MEHHP and MEOHP concentrations also decreased
significantly for all male and all female children, and female children under age 16, from 1999 to
2018.
Median and 95th percentile MEHHP and MEOHP urinary concentrations decreased significantly
among all adults, as well as among adult males, and among adult females 16 years and older
from 2001 to 2018. Among women of reproductive age, there were statistically significant
decreases in 50th and 95th percentile MEHHP and MEOHP urinary concentrations from 2001 to
2018.
For MECPP (NHANES reporting years: 2003-2018). the following trends were observed:
Overall, median and 95th percentile MECPP concentrations have decreased over time (2003-
2018) for all lifestages.
Statistically significant decreases in 50th and 95th percentile urinary MECPP concentrations were
observed among all children under age 16, as well as among children aged 3 to less than 6 years,
6 to less than 11 years, and 11 to less than 16 years from 2003 to 2018. Median and 95th
percentile urinary MECPP concentrations also decreased significantly for all male and all female
children and female children under age 16 from 1999 to 2018.
Median and 95th percentile MECPP urinary concentrations decreased significantly among all
adults, as well as among adult males, and among adult females 16 years and older from 2003 to
2018. Among women of reproductive age, there were statistically significant decreases in 50th
and 95th percentile MECPP urinary concentrations from 2003 to 2018.
C.2.2 DBP
Temporal trends in urinary MnBP and MHBP, which are metabolites of DBP, are summarized below
and discussed in detail in Section 10.2 of EPA's Draft Environmental Media and General Population
and Environmental Exposure for Dibutyl Phthalate (DBP) (U.S. EPA. 2025g). Overall, 50th and 95th
percentile urinary MnBP concentrations have decreased over time (1999-2018) for all life stages.
For urinary MHBP, consistent temporal trends across populations are less apparent; however, MHBP
has only been measured in NHANES from 2015 to 2018. This shorter sampling period may account for
some of the observed variability and inconsistency.
For MnBP (NHANES reporting years: 1999-2018). the following trends were observed:
Overall, 50th and 95th MnBP urinary concentrations have decreased over time (1999-2018) for
all life stages.
From 1999 to 2018, 50th and 95th percentile urinary MnBP concentrations significantly decreased
over time for all children under 16 years of age, as well as for children aged 3 to less than 6
years, 6 to less than 11 years, and 11 to less than 16 years; all adults, all female adults, and all
male adults 16 years and older; and women of reproductive age (16 to 49 years of age).
For MHBP (NHANES reporting years: 2015-2018). the following trends were observed:
While 95th percentile MHBP concentrations tended to decrease over time for children and adults,
they increased over time among women of reproductive age. Meanwhile, 50th percentile MHBP
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concentrations tended to increase over time among children under 16, decrease for adults, and
have no significant changes for women of reproductive age.
From 2015 to 2018, 50th percentile MHBP concentrations increased over time among all children
under 16, and among adolescents aged 11 to less than 16 years old. However, 95th percentile
MHBP concentrations decreased over time among all children under 16, male children under 16,
children aged 6 to less than 11 years, and adolescents aged 11 to less than 16 years.
Additionally, 50th percentile MHBP concentrations decreased over time among all adults and for
adult females. During this period, 95th percentile MHBP concentrations also decreased among all
adults, adult males, and adult females. Among women of reproductive age, 95th percentile
MHBP concentrations increased significantly, though no significant changes were observed at
the 50th percentile.
C.2.3 BBP
Temporal trends in urinary MBzP, a metabolite of BBP, are summarized below and discussed in detail
in Section 10.2 of EPA's Draft Environmental Media and General Population and Environment
Exposure for Butyl benzyl phthalate (BBP) (U.S. EPA. 2025f). Overall, 50th and 95th percentile
urinary MBzP concentrations significantly decreased over time (1999-2018) for all lifestages.
For MBzP (NHANES reporting years: 1999-2018). the following trends were observed:
Overall, MBzP urinary concentrations have decreased over time across all life stages between
1999 and 2018.
From 1999 to 2018, 50th and 95th percentile MBzP concentrations decreased significantly for all
children under 16 over time, as well as for male children and female children. This significant
trend held for all age groups: 3 to less than 6 years, 6 to less than 11, and 11 to less than 16 years.
The 50th and 95th percentile MBzP urinary concentrations also decreased significantly amongst
all adults, adult males, and adult females ages 16 years and older.
From 1999 to 2018, both 50th and 95th percentile MBzP urinary concentrations decreased
amongst women of reproductive age (16 to 49 years of age) over time.
C.2.4 DIBP
Temporal trends in urinary MIBP and MHiBP, which are metabolites of DIBP, are summarized below
and in more detail in Section 10.2 of EPA's Draft Environmental Media and General Population and
Environmental Exposure for Diisobutyl phthalate (DIBP) (U.S. EPA. 2025i). Overall, 50th and 95th
percentile urinary MIBP concentrations significantly increased over time (1999-2018) for all
lifestages, while 50th and 95th percentile MHiBP urinary concentrations decreased over time
(2015-2018) for most life stages.
For MIBP (NHANES reporting years: 2001-2018). the following trends were observed:
Overall, median and 95th percentile MIBP urinary concentrations significantly increased over
time for all life stages from 2001 to 2018.
From 2001 to 2018, median and 95th percentile urinary MIBP concentrations significantly
increased among all children 3 to less than 16 years, as well as for children 6 to less than 11
years and children 11 to less than 16 years. MIBP concentrations also significantly increased
among toddlers 3 to less than 6 years at the 95th percentile. Similarly, median and 95th percentile
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MIBP concentrations significantly increased among all adults, adult males, and adult females,
females ages 16 years and older, as well as for women of reproductive age (16 to 49 years).
For MHiBP (NHANES reporting years: 2015-2018). the following trends were observed:
Overall, median and 95th percentile MHiBP urinary concentrations decreased over time for most
life stages.
From 2015 to 2018, median MHiBP urinary concentrations decreased among all children 3 to
less than 16 years, as well as for the children 6 to less than 11 years. However, median MHiBP
urinary concentrations increased among adolescents 11 to less than 16 years. During this time,
95th percentile MHiBP urinary concentrations decreased significantly over time among all
children 3 to less than 16 years, male children, female children, and among the following age
groups: toddlers 3 to less than 6 years, children 6 to less than 11 years, and adolescents 11 to less
than 16 years.
Significant decreases in median MHiBP urinary concentrations were observed among all adults
aged 16 and older, adult females, adult males, and women of reproductive age (16 to 49 years).
Additionally, 95th percentile MHiBP urinary concentrations decreased significantly among all
adults aged 16 and older, as well as for male adults, and women of reproductive age (16 to 49
years).
C.2.5 DINP
Temporal trends in urinary MINP and MCOP, which are metabolites of DINP, are summarized below
and in more detail in Section 10.2 of EPA's Draft Environmental Media and General Population
Screening for Diisononyl Phthalate (DINP) (U.S. EPA. 2025n). ForMONP, no temporal trends analysis
was conducted because MONP has only been measured in the most recent NHANES survey (2017 to
2018).
For MINP (NHANES reporting years: 1999-2018). the following trends were observed:
Among all NHANES participants, the direction of the trend of MiNP concentrations changed
over time. MiNP significantly increased (p<0.001 for both 50th and 95th percentile exposures)
between 1999 and 2014, but decreased between 2015 and 2018; the decrease was statistically
significant at the 95th percentile (p=0.007), but not at the 50th percentile.
Overall, urinary concentrations of MINP have generally decreased over time for most lifestages.
Among all children under 16, significant changes were observed in 50th and 95th percentile MINP
concentrations (50th percentile, p < 0.001; 95th percentile, p < 0.001), as well as a significant
increase in 95th percentile concentrations among male children under 16 (p < 0.001), and a
significant decrease among female children under 16 (p < 0.001). Within age groups, MINP
concentrations significantly decreased among children aged 3 to less than 6 years of age (95th
percentile, p < 0.001) and significantly increased among adolescents 11 to less than 16 years of
age (50th percentile, p < 0.001; 95th percentile, p < 0.001); no significant changes in 50th or 95th
percentile MINP concentrations over time were observed among children aged 6 to less than 11.
MINP concentrations significantly decreased among all adults (50th percentile, p < 0.001; 95th
percentile, p < 0.001), adult males (95th percentile, p < 0.001), and adult females (50th percentile,
p < 0.001). A significant increase in MINP concentrations were observed among adult females
(50th percentile, p < 0.001; 95th percentile, p < 0.001) and in 50th percentile concentrations among
women of reproductive age (p = 0.03).
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For MCOP (NHANES reporting years: 2005-2018). the following trends were observed:
Among all NHANES participants, the direction of the trend of MiNP concentrations changed
over time. Between 2005 and 2014, MCOP concentrations significantly increased among all
NHANES participants (50th percentile, p<0.001). After 2014, MCOP concentrations significantly
decreased at both the 50th and 95th percentile for all participants (p<0.001 for both analyses).
Overall, median MCOP concentrations have decreased over time for all lifestages, while 95th
percentile concentrations increased over time for all lifestages.
There was a significant decrease in 50th percentile urinary MCOP concentrations among all
children under 16 (p < 0.001), as well as among children aged 6 to less than 11 years (p < 0.001).
Increases in 95th percentile urinary MCOP concentrations were observed among all children
under 16 (p < 0.001), all male children under 16 (p < 0.001), and all female children under 16 (p
< 0.001). Additionally, a significant increase in 95th percentile concentrations over time was
observed among toddlers aged 3 to less than 6, and a significant decrease in MCOP
concentrations was observed among children aged 6 to less than 11 years old (p < 0.001). At
both the 50th and 95th percentile, significant differences in urinary MCOP concentrations were
observed between male and female children under 16 over time (50th percentile, p < 0.001; 95th
percentile, p < 0.001).
Among adults, 50th percentile MCOP concentrations significantly decreased over time for all
adults, but significantly increased over time for adults at the 95th percentile of exposure.
Significant decreases in MCOP were also observed among adult males (50th percentile, p <
0.001) and adult females (50th percentile, p < 0.001; 95th percentile, p = 0.005) but not for
women of reproductive age. Additionally, a significant difference in 95th percentile MCOP
concentrations were observed between adult men and women (p < 0.001), but no difference was
observed for 50th percentile MCOP concentrations.
C.3 Reverse Dosimetry: Methods and Results
Using urinary metabolite concentrations for DEHP, DBP, BBP, DIBP, and DINP measured in the most
recently available NHANES sampling cycle (2017 to 2018), EPA estimated phthalate daily intake
through reverse dosimetry. Reverse dosimetry approaches that incorporate basic pharmacokinetic
information are available for phthalates (Koch et al.. 2007; Koch et al.. 2003; David. 2000) and have
been used in previous phthalate risk assessments conducted by U.S. CPSC (2014) and Health Canada
(ECCC/HC. 2020) to estimate daily intake values for exposure assessment. For phthalates, reverse
dosimetry can be used to estimate a daily intake (DI) value for a parent phthalate diester based on
phthalate monoester metabolites measured in human urine using EquationApx C-l (Koch et al.. 2007).
EquationApx C-l. Calculating the Daily Intake Value from Urinary Biomonitoring Data
(UE5uTn x CE)
Phthalate DI = -^ x MWParent
Where:
Phthalate DI = Daily intake (|ig/kgbw/day) value for the parent phthalate diester
UEsum = The sum molar concentration of urinary metabolites associated with the parent phthalate
diester (in units of |imole per gram creatinine).
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CE = The creatinine excretion rate normalized by body weight (in units of mg creatinine per kg
bodyweight per day). CE can be estimated from the urinary creatinine values reported in
biomonitoring studies (i.e., NHANES) using the equations of Mage et al. (2008) based on age,
gender, height, and race, as was done by Health Canada (ECCC/HC, 2020) and U.S. CPSC
(2014).
FueSum = The summed molar fraction of urinary metabolites. The molar fraction describes the
molar ratio between the amount of metabolite excreted in urine and the amount of parent
compound taken up. Fue values used for daily intake value calculations are shown in TableApx
C-3.
MWparent = The molecular weight of the parent phthalate diester (in units of g/mole).
Daily intake values were calculated for each participant from NHANES. A creatinine excretion rate for
each participant was calculated using equations provided by Mage et al. (2008). The applied equation is
dependent on the participant's age, height, race, and sex to accommodate variances in urinary excretion
rates. Creatinine excretion rate equations were only reported for people who are non-Hispanic Black and
non-Hispanic White, so the creatinine excretion rate for participants of other races were calculated using
the equation for non-Hispanic White adults or children, in accordance with the approach used by U.S.
CPSC (2015).
Table Apx C-3. Fue Values Used for the Calculation of Daily Intake Values of DEHP, BBP, DBP,
DIBP, and DINP
Parent
Phthalate
Study Population
Metabolite(s)
Fuet?
Fue
Sum
Reference
DEHP
N = 10 men (20-42 years of
age) and 10 women (18-77
years of age)
MEHP
0.062
0.452
(Anderson et al.. 2011)
MEHHP
0.149
MEOHP
0.109
MECPP
0.132
BBP
N = 14 volunteers (gender
and age not provided)
MBzP
0.73
0.73
(Anderson et al., 2001)
DBP
N = 13 volunteers (gender
and age not provided)
MBP
0.69
0.69
(Anderson et al.. 2001)
DIBP
N = 13 volunteers (gender
and age not provided)
MiBP
0.69
0.69
(Anderson et al., 2001)
DINP
N = 10 men (20-42 years of
age) and 10 women (18-77
years of age)
MINP
0.030
0.192
(Anderson et al., 2011)
MONP
0.063
MCOP
0.099
11 Fue values are presented on a molar basis and were estimated by study authors based on metabolite excretion
over a 24-hour period (DINP, DBP, DIBP).
h Fue value of 0.69 based on excretion of DBP urinary metabolite MnBP
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2940 C.4 Statistical Analysis of Cumulative Phthalate Exposure
2941 TableApx C-4. Statistical Analysis (t-test) of Cumulative Phthalate Exposure for Women of
2942 Reproductive Age by Race"
Variable
Method
Variances
tValue
DF
Probt
Race \h
Race 2b
50th Percentile
Pooled
Equal
-0.7049
8
0.5009
white
black
50th percentile
Pooled
Equal
-0.2509
8
0.8082
white
mexic
50th percentile
Pooled
Equal
0.5053
8
0.6270
white
other
50th percentile
Pooled
Equal
-0.4905
8
0.6369
black
mexic
50th percentile
Pooled
Equal
-1.0495
8
0.3246
black
other
50th percentile
Pooled
Equal
-0.7143
8
0.4954
mexic
other
50th percentile
Pooled
Equal
0.5780
8
0.5792
white
black
50th percentile
Pooled
Equal
-0.4230
8
0.6834
white
mexic
50th percentile
Pooled
Equal
1.0271
8
0.3344
white
other
50th percentile
Pooled
Equal
0.8771
8
0.4060
black
mexic
50th percentile
Pooled
Equal
-0.6560
8
0.5302
black
other
50th percentile
Pooled
Equal
-1.1843
8
0.2703
mexic
other
50th percentile
Pooled
Equal
-0.7049
8
0.5009
white
black
50th percentile
Pooled
Equal
-0.2509
8
0.8082
white
mexic
50th percentile
Pooled
Equal
0.5053
8
0.6270
white
other
50th percentile
Pooled
Equal
-0.4905
8
0.6369
black
mexic
50th percentile
Pooled
Equal
-1.0495
8
0.3246
black
other
50th percentile
Pooled
Equal
-0.7143
8
0.4954
mexic
other
95th percentile
Pooled
Equal
0.5780
8
0.5792
white
black
95th percentile
Pooled
Equal
-0.4230
8
0.6834
white
mexic
95th percentile
Pooled
Equal
1.0271
8
0.3344
white
other
95th percentile
Pooled
Equal
0.8771
8
0.4060
black
mexic
95th percentile
Pooled
Equal
-0.6560
8
0.5302
black
other
95th percentile
Pooled
Equal
-1.1843
8
0.2703
mexic
other
95th percentile
Pooled
Equal
-0.7049
8
0.5009
white
black
95th percentile
Pooled
Equal
-0.2509
8
0.8082
white
mexic
95th percentile
Pooled
Equal
0.5053
8
0.6270
white
other
95th percentile
Pooled
Equal
-0.4905
8
0.6369
black
mexic
95th percentile
Pooled
Equal
-1.0495
8
0.3246
black
other
95th percentile
Pooled
Equal
-0.7143
8
0.4954
mexic
other
95th percentile
Pooled
Equal
0.5780
8
0.5792
white
black
95th percentile
Pooled
Equal
-0.4230
8
0.6834
white
mexic
95th percentile
Pooled
Equal
1.0271
8
0.3344
white
other
95th percentile
Pooled
Equal
0.8771
8
0.4060
black
mexic
95th percentile
Pooled
Equal
-0.6560
8
0.5302
black
other
95th percentile
Pooled
Equal
-1.1843
8
0.2703
mexic
other
" Independent t-test with pooled variance (assuming equal variance in exposures among both racial
groups) to assess differences in mean phthalate exposure between different racial groups.
h Racial groups include White non-Hispanic, Black non-Hispanic, Mexican American, and Other.
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2943
2944 TableApx C-5. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
2945 Exposure for Women of Reproductive Age by Race"
Dependent
Source
DF
SS
MS
F Value
ProbF
50th percentile
Model
3
0.053263348
0.017754449
0.491687573
0.693011899
Error
16
0.577747344
0.036109209
Corrected
Total
19
0.631010692
95th percentile
Model
3
7.932713778
2.644237926
0.850142129
0.486666284
Error
16
49.76556906
3.110348067
Corrected
Total
19
57.69828284
Abbreviations: DF = Degrees of freedom; MS = mean squares; SS = sum-of-squares;
11 ANOVA to determine whether there are significant differences in phthalate exposure among racial groups
among women of reproductive age. Post-hoc tests were performed to examine differences in exposure between
races. No differences were observed and output was not generated.
2946
2947 Table Apx C-6. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
2948 Exposure for Women of Reproductive Age by Socioeconomic Status"
Dependent
Source
DF
SS
MS
F Value
ProbF
50th percentile
Model
2
0.058905
0.029453
0.299768
0.74638
Error
12
1.179014
0.098251
Corrected
Total
14
1.237919
95th percentile
Model
2
6.019748
3.009874
0.085482
0.918624
Error
12
422.5295
35.21079
Corrected
Total
14
428.5493
Abbreviations: DF = Degrees of freedom; MS = mean squares; SS = sum-of-squares;
11 ANOVA to determine whether there are significant differences in phthalate exposure among socioeconomic
status groups among women of reproductive age. Post-hoc tests were performed to examine differences in
exposure between socioeconomic status. No differences were observed and output was not generated.
2949
2950 Table Apx C-7. Statistical Analysis (ANOVA with Tukey Post-Hoc Test) of Cumulative Phthalate
2951 Exposure for Women of Reproductive Age and Male Children by Age"
Dependent
Source
DF
SS
MS
F Value
ProbF
50th percentile
Model
3
0.527705678
0.175901893
1.061407322
0.393002372
Error
16
2.651602472
0.165725155
Corrected
Total
19
3.17930815
95th percentile
Model
3
6.568006156
2.189335385
1.403496422
0.278192271
Error
16
24.95864302
1.559915189
Corrected
Total
19
31.52664917
Abbreviations: DF = Degrees of freedom; MS = mean squares; SS = sum-of-squares;
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Dependent
Source
DF
SS
MS
F Value
ProbF
11ANOVA to determine whether t
(women aged 16-49, boys age 3-i
examine differences in exposure 1
lere are significant differences in phthalate exposure among age groups
, boys age 6-11, and boys age 12-15). Post-hoc tests were performed to
jetween races. No differences were observed and output was not generated.
C.5 Limitations and Uncertainties of Reverse Dosimetry Approach
Controlled human exposure studies have been conducted and provide estimates of the urinary molar
excretion factor (i.e., the Fue) to support use of a reverse dosimetry approach. These studies most
frequently involve oral administration of an isotope4abelled (e.g., deuterium or carbon-13) phthalate
diester to a healthy human volunteer and then urinary excretion of monoester metabolites is monitored
over 24 to 48 hours. Fue values estimated from these studies have been used by both U.S. CPSC (2014)
and Health Canada (ECCC/HC. 2020) to estimate phthalate daily intake values using urinary
biomonitoring data.
Use of reverse dosimetry and urinary biomonitoring data to estimate daily intake of phthalates is
consistent with approaches employed by both U.S. CPSC (2014) and Health Canada (ECCC/HC. 2020).
However, there are challenges and sources of uncertainty associated with the use of reverse dosimetry
approaches. U.S. CPSC considered several sources of uncertainty associated with use of human urinary
biomonitoring data to estimate daily intake values and conducted a semi-quantitative evaluation of
uncertainties to determine the overall effect on daily intake estimates (see Section 4.1.3 of (U.S. CPSC.
2014)). Identified sources of uncertainty include: (1) analytical variability in urinary metabolite
measurements; (2) human variability in phthalate metabolism and its effect on metabolite conversion
factors (i.e., the Fue); (3) temporal variability in urinary phthalate metabolite levels; (4) variability in
urinary phthalate metabolite levels due to fasting prior to sample collection; (5) variability due to fast
elimination kinetics and spot samples; and (6) creatinine correction models for estimating daily intake
values.
In addition to some of the limitations and uncertainties discussed above and outlined by U.S. CPSC
(2014). the short half-lives of phthalates can be a challenge when using a reverse dosimetry approach.
Phthalates have elimination half-lives on the order of several hours and are quickly excreted from the
body in urine and to some extent feces (ATSDR. 2022; EC/HC. 2015). Therefore, spot urine samples, as
collected through NHANES and many other biomonitoring studies, are representative of relatively
recent exposures. Spot urine samples were used by Health Canada (ECCC/HC. 2020) and U.S. CPSC
(2014) to estimate daily intake values. However, due to the short half-lives of phthalates, a single spot
sample may not be representative of average urinary concentrations that are collected over a longer term
or calculated using pooled samples (Shin et al.. 2019; Aylward et al.. 2016). Multiple spot samples
provide a better characterization of exposure, with multiple 24-hour samples potentially leading to better
characterization, but are less feasible to collect for large studies (Shin et al.. 2019). Due to rapid
elimination kinetics, U.S. CPSC concluded that spot urine samples collected at a short time (2 to 4
hours) since last exposure may overestimate human exposure, while samples collected at a longer time
(greater than 14 hours) since last exposure may underestimate exposure (see Section 4.1.3 of (U.S.
CPSC. 2014) for further discussion).
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3000
3001
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Appendix D Supporting Analyses for Occupational Exposure to
Phthalates
1). 1 Trends in National Aggregate Production Volume
EPA also considered whether trends in national aggregate production volume data may mirror temporal
trends noted in NHANES urinary biomonitoring data. To do this, EPA extracted national aggregate
production volume (PV) data for DEHP, DBP, DIBP, BBP, DCHP, and DINP from the 2016 and 2020
Chemical Data Reporting (CDR), which is shown in Table Apx D-l. In CDR, national aggregate PV
data is reported as a range to protect PV data claimed as confidential business information (CBI). Given
the large ranges in reported PV data for each phthalate, it is difficult to definitively conclude whether or
not there are any trends in PV for any phthalate. Based on available CDR data, there is no evidence of a
trend in national aggregate PV for DEHP (PV ranged from 10,000,000 lbs to less than 50,000,000 lbs in
2012 through 2019), DBP (PV ranged 1,000,000 lbs to less than 10,000,000 lbs in 2012 through 2019),
or DCHP (PV ranged from 500,000 lbs to less than 1,000,000 lbs in 2012 through 2019). For BBP, there
is some limited evidence of a decline in PV, which was reported as 10,000,000 to less than 50,000,000
lbs from 2012 to 2015 and declined to 10,000,000 to less than 20,000,000 lbs from 2016 through 2019.
For DIBP, there is some limited evidence of a decline in PV, with PV reported as ranging from
1,000,000 to less than 20,000,000 lbs in 2012 and declining to less than 1,000,000 lbs in 2013 through
2019. For DINP (CASRN 28553-12-0), there is some limited evidence of a decline in PV with PV
reported as 100,000,000 to less than 250,000,000 lbs in 2012 through 2018 and declining to 50,000,000
to less than 100,000,000 lbs in 2019. In contrast, there is some limited evidence of an increase in PV for
DINP (CASRN 68515-48-0), with PV reported as 100,000,000 to less than 250,000,000 lbs in 2012
through 2015 and 100,000,000 to less than 1,000,000,000 lbs in 2016 through 2019.
Overall given the large ranges in reported PV. it is difficult to conclude whether or not there are any
trends in PV data for any phthalate.
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3014 Table Apx D-l. Trends in Nationa
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ly Aggregated Production Volume (lbs) Data for DEHP, DBP, BBP, DIBP, DCHP, and DINP
Phthalate
CASRN
2019
2018
2017
2016
2015
2014
2013
2012
DEHP
117-81-7
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
DBP
84-74-2
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
1,000,000 -
<10,000,000
BBP
85-68-7
1,000,000 -
<20,000,000
1,000,000 -
<20,000,000
1,000,000 -
<20,000,000
1,000,000 -
<20,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
10,000,000 -
<50,000,000
DIBP
84-69-5
407,303
403,833
384,591
440,833
<1,000,000
<1,000,000
<1,000,000
1,000,000 -
<20,000,000
DCHP
84-61-7
500,000 -
<1,000,000
<1,000,000
500,000 -
<1,000,000
500,000 -
<1,000,000
500,000 -
<1,000,000
500,000 -
<1,000,000
500,000 -
<1,000,000
500,000 -
<1,000,000
DINP
28553-12-0
50,000,000 -
<100,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
68515-48-0
100,000,000 -
<1,000,000,000
100,000,000 -
<1,000,000,000
100,000,000 -
<1,000,000,000
100,000,000 -
<1,000,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
100,000,000 -
<250,000,000
3015
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3016 D.2 Industrial and Commercial Products Containing Multiple Phthalates
3017
Table Apx D-2. Summary of Industrial ant
Commercial Products that Contain Multip
e Phthalates
Manufacturer
Product
Physical
State
Source
Use
I) 111P
DBP
BBP
DIBP
DINP
DCHP
Restek
Corporation
33227 / EPA Method 8061A
Phthalate Esters Mixture
No data
available
Restek Corporation
(2019)
Laboratory
chemical
0.10%
0.10%
0.10%
0.10%
0.10%
Phenova
BN Extractables - Skinner List
Liquid
Phenova (2017a)
Laboratory
chemical
0.20%
0.20%
0.20%
Phenova
Custom 8061 Phthalates Mix
Liquid
Phenova (2017)
Laboratory
chemical
0.10%
0.10%
0.10%
0.10%
Phenova
Custom 8270 Cal Mix 1
Liquid
Phenova (2018a)
Laboratory
chemical
0.10%
0.10%
0.10%
Phenova
Custom 8270 Cal Standard
Liquid
Phenova (2017c)
Laboratory
chemical
0.20%
0.20%
0.20%
Phenova
Custom 8270 Plus Cal Mix
Liquid
Phenova (2017d)
Laboratory
chemical
0.10%
0.10%
0.10%
Phenova
Custom Low ICAL Mix
Liquid
Phenova (2017e)
Laboratory
chemical
0.10%
0.10%
0.10%
Phenova
Custom SS 8270 Cal Mix 1
Liquid
Phenova (2018b)
Laboratory
chemical
0.10%
0.10%
0.10%
Phenova
EPA 525.2 Semivolatile Mix
Liquid
Phenova (2018c)
Laboratory
chemical
0.10%
0.10%
0.10%
Lord
Corporation
Fusor 108B, 109B Metal
Bonding ADH PT B
Paste
LORD Corporation
(2017)
Adhesive
(acrylic)
1-5%
1-5%
SPEX CertiPrep
LLC
Phthalate Standard
Liquid
SPEX CertiPrep LLC
(2017b)
Laboratory
chemical
0.10%
0.10%
0.10%
0.10%
SPEX CertiPrep
LLC
Phthalates in Polyvinyl
chloride)
Solid
SPEX CertiPrep LLC
(2017c)
Laboratory
chemical
0.30%
0.30%
0.30%
3.00%
SPEX CertiPrep
LLC
Phthalates in Polyethylene
Standard
Solid
SPEX CertiPrep LLC
(2017c)
Laboratory
chemical
0.30%
0.30%
0.30%
3.00%
SPEX CertiPrep
LLC
Phthalates in Polyethylene
Standard w/BPA
Solid
SPEX CertiPrep LLC
(2017d)
Laboratory
chemical
0.10%
0.10%
0.10%
0.10%
Penn State
Industries
PSI PolyClay Canes and PSI
PolyClay Bricks
Solid
Penn State Industries
(2016)
Polymer clay
bricks, canes
<2.5%
<2.5%
<2.5%
<2.5%
3019
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3020 D.3 Parent Company Overlap in Phthalate Manufacture and Processing
3021 Data from CDR provide manufacture and processing information from parent companies, including
3022 overall production volume and number of facilities, and all phthalates considered in this cumulative
3023 assessment are reported to CDR. Though these data provide a broad overview of the various businesses
3024 involved in the phthalate industry, the CDR data provide information about the parent company only and
3025 are not granular enough to determine if multiple phthalates are being processed within a singular facility.
3026 Therefore, there is uncertainty associated with assigning co-exposures based on parent company
3027 reporting data from CDR. Table Apx D-3 characterizes the various parent companies from 2016 and
3028 2020 CDR that report use of multiple phthalates considered in this cumulative assessment, as well as
3029 parent companies reporting use of DEHP and DBP under the 2017 to 2022 TRI.
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December 2024
3030 TableApx D-3. Parent Companies Reporting Use of Multiple Phthalates (DEHP, DBP, BBP, DIBP, DINP, DCHP) to 2016 and 2020
3031 CDR and 2017 through 2022 TRI ^
CDR or
TRI Year
Use Category
Domestic Parent
Company Name
Address
City
State
Postal
Code
Reported in
TRI
Reported in CDR
DEHP
DBP
DBP
DEHP
DINP
DCHP
BBP
DBP
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
ALAC International Inc
350 Fifth Avenue
New York
NY
10118
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Allchem Industries
Holding Corp
6010 NW First
Place
Gainesville
FL
32607
X
X
2017-2022
TRI
Processing
American Polymers
Corp
n/a "
n/a "
n/a "
n/a "
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
BASF Corporation
100 Park Avenue
Florham Park
MI
7932
X
X
2016 CDR:
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBI4
CBF
CBF
CBF
CBI4
X
X
X
2016 CDR
Industrial Processing and Use;
Consumer and Commercial Use
CBF (reporting site
name is Air Prod &
Chem Hamilton Blvd
Fac)
CBF
CBF
CBF
CBF
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is Exxon Mobil
BR Chemical Plant)
CBF
CBF
CBF
CBF
X
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is Greenchem)
CBF
CBF
CBF
CBF
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is M. Argueso &
Co., Inc.)
CBF
CBF
CBF
CBF
X
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is Mak
Chemicals)
CBF
CBF
CBF
CBF
X
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is Tremco
Incorporated)
CBF
CBF
CBF
CBF
X
X
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
CBF (reporting site
name is Tricon
International, Ltd)
CBF
CBF
CBF
CBF
X
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
ChemSpec, Ltd.
1559 Corporate
Woods Parkway
Uniontown
OH
44685
X
X
2017-2022
TRI
Waste Handling
Clean Harbors Inc
n/a "
n/a "
n/a "
n/a "
X
X
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CDRor
TRIYear
Use Category
Domestic Parent
Company Name
Address
City
State
Postal
Code
Reported in
TRI
Reported in CDR
DEHP
DBP
DBP
DEHP
DINP
DCHP
BBP
DBP
2020-2022
TRI
Processing
Danfoss Power
Solutions (US) Co
n/a "
n/a "
n/a "
n/a "
X
X
2017 TRI
Processing
DOW Inc
n/a "
n/a "
n/a "
n/a "
X
X
xrf
2017-2019
TRI
Processing
EATON Corp
n/a "
n/a "
n/a "
n/a "
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Formosa Plastics
Corporation, U.S.A.
9 Peach Tree Hill
Rd.
Livingston
N.T
7039
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
FRP Services & Co.
(America) INC
25 West 45th
Street
New York
NY
10036
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
G..T. Chemical Co., Inc.
40 Veronic Ave.
Somerset
N.T
8873
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
GEON Performance
Solutions LLC
25777 Detroit
Road, Suite 202
Westlake
OH
44145
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Greenchem Industries
LLC
222 Clematis St.
West Palm
Beach
FL
33401
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
HI G Capital LLC
7500 East
Pleasant Valley
Road
Independence
OH
44131
X
X
2016 CDR;
2020 CDR;
2017-2018
TRI
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Hallstar Co
120 S. Riverside
Drive
Chicago
IL
60606
X
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Harwick Standard
Distribution
Corporation
60 S. Seiberling
St.
Akron
OH
44305
X
X
2017-2021
TRI
Processing
Henkel of America Inc
n/a "
n/a "
n/a "
n/a "
X
X
xrf
2017-2022
TRI
Waste Handling
Heritage-WTI LLC
n/a "
n/a "
n/a "
n/a "
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
ICC Industries Inc.
460 Park Ave
New York
NY
10022
X
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
ICC Industries Inc.
725 Fifth Avenue
New York
NY
10022
X
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Industrial Chemicals
Inc.
2042 Montreat
Dr.
Birmingham
AL
35216
X
X
X
2016 CDR;
2020 CDR;
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Lanxess Corporation
Ill RIDC Park
West Dr.
Pittsburgh
PA
15275
X
X
X
X
X
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December 2024
CDRor
TRIYear
Use Category
Domestic Parent
Company Name
Address
City
State
Postal
Code
Reported in
TRI
Reported in CDR
DEHP
DBP
DBP
DEHP
DINP
DCHP
BBP
DBP
2017-2022
TRI
2017-2022
TRI
Waste Handling
Lehigh Hanson
n/a "
n/a "
n/a "
n/a "
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
M.A. Global Resources
Inc
1028 Branch
Line Lane
Apex
NC
27502
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
MC International, LLC
2 Ne 40th St
Miami
FL
33137
X
X
X
2016 CDR;
2017-2022
TRI
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Mexichem SAB DE CV
170 Pioneer
Drive
Leominster
MA
01453
X
X
X
X
2017-2022
TRI
Processing
Parker Hannifin Corp
n/a "
n/a "
n/a "
n/a "
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
POLYONE
CORPORATION
33587 Walker Rd
Avon Lake
OH
44012
X
X
2017-2022
TRI
Waste Handling
RC Lonestar Inc
n/a "
n/a "
n/a "
n/a "
X
X
2017-2022
TRI
Waste Handling
RI Technologies Inc
n/a "
n/a "
n/a "
n/a "
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Royce International
3400 Tamiami
Trail, Suite 300
Sarasota
FL
34239
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Shrieve Chemical
Company
1755 Woodstead
Court
The
Woodlands
TX
77380
X
X
2020 CDR;
2018-2022
TRI
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Sika Corporation
201 Polito
Avenue
Lyndhurst
N.T
7071
X
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Silver Fern Chemical
2226 Queen
Anne Avenue N.
Seattle
WA
98109
X
X
2016 CDR;
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Soyventis North
America LLC
100 Town Square
PI.
Jersey City
N.T
07310
X
X
2018-2022
TRI
Processing
Superior Industrial
Solutions Inc
n/a "
n/a "
n/a "
n/a "
X
X
2020 CDR;
2016 CDR
(under
different
address);
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Teknor Apex Co
505 Central Ave
Pawtucket
RI
02861
X
X
X
Page 107 of 117
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CDRor
TRIYear
Use Category
Domestic Parent
Company Name
Address
City
State
Postal
Code
Reported in
TRI
Reported in CDR
DEHP
DBP
DBP
DEHP
DINP
DCHP
BBP
DBP
2017-2022
TRI
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
The Chemical
Company
44 Southwest
Avenue
Jamestown
RI
2835
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Tribute Energy, Inc.
2100W. Loop
South
Houston
TX
77027
X
X
2020 CDR;
2016 CDR
(under
different
address);
2017-2022
TRI
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Univar Solutions Inc.
3075 Highland
Pkwy., Ste. 200
Downers
Grove
IL
60515-
5560
X
X
X
X
X
2017-2020
TRI
Waste Handling
US Ecology Inc
n/a "
n/a "
n/a "
n/a "
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Valtris
7500 East
Pleasant Valley
Independence
OH
44131
X
X
2017 TRI
Waste Handling
Veolia Environmental
Services North America
LLC
n/a "
n/a "
n/a "
n/a "
X
X
2017-2022
TRI
Processing
W R Grace & Co
n/a "
n/a "
n/a "
n/a "
X
X
2017-2019
TRI
Waste Handling
Waste Management Inc
n/a "
n/a "
n/a "
n/a "
X
X
2016 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Wego Chemical Group
239 Great Neck
Road
Great Neck
NY
11021
X
X
2020 CDR
Manufacture; Industrial Processing and
Use; Consumer and Commercial Use
Wilbur-Ellis Company
LLC
345 California
Street
San Francisco
CA
94104
X
X
" 'n/a' = not applicable, parent company address not provided in TRI.
4 Because all information is claimed as CBI, it is possible that this row represents multiple parent companies that reported some combination of the flagged phthalates.
c Because parent company information is claimed as CBI, it is possible that there are fewer parent companies than rows with CBI parent companies but non-CBI reporting site names.
d In TRI, these companies reported releases of DBP and/or DEHP and used a different parent company name than in CDR. In CDR, these sites only reported for DINP. As well, the physical
reporting sites themselves have different addresses. Therefore, there is uncertainty in whether the same parent company applies to both the TRI and CDR reports.
3032
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3033
3034
3035
3036
3037
D.4 Conditions of Use Listed in Final Scopes for Individual Phthalate Risk
Evaluations
TableApx D-4. Categories of Conditions of Use for High-Priority Phthalates and a
Manufacturer-Requested Phthalate
Use
Conditions of Use
DBP
BBP
DEHP
DCHP
DIBP
DINP
Adhesive and sealants
X
X
X
X
Automotive care products
X
X
Building/construction materials not
covered elsewhere
X
X
X
Castings
X
Chemical intermediate
X
Fabric, textile, and leather products
not covered elsewhere
X
X
Finishing agent
X
Floor coverings
X
X
Fuels and related products
X
Industrial
Hydraulic fluid
X
Hydraulic fracturing
X
Ink, toner, and colorant products
X
X
X
Laboratory chemicals
X
X
Paints and coatings
X
X
X
Plastic and rubber products not
covered elsewhere
X
X
X
Plasticizer
X
Solvent
X
Transportation equipment
manufacturing
X
Adhesives and sealants
X
X
X
X
X
X
Air care products
X
X
Arts, crafts and hobby materials
X
X
Automotive care products
X
X
X
Commercial
Batteries
X
Building/construction materials not
covered elsewhere
X
X
X
X
Castings
X
Chemical intermediate
X
Chemiluminescent light stick
X
Page 109 of 117
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December 2024
Use
Conditions of Use
DBP
BBP
DEHP
DCHP
DIBP
DINP
Cleaning and furnishing care
products
X
X
Dyes and pigments
X
Electrical and electronic products
X
X
Explosive materials
X
Fabric, textile, and leather products
not covered elsewhere
X
X
X
Floor coverings
X
X
X
X
Foam seating and bedding products
X
Furniture and furnishings not
covered elsewhere
X
X
X
Hydraulic fluid
X
Ink, toner, and colorant products
X
X
X
X
Commercial
Inspection penetrant kit
X
Laboratory chemical
X
X
X
X
X
Lawn and garden care products
X
Lubricants
X
Paints and coatings
X
X
X
X
X
X
Personal care products
X
Pigment
X
Plastic and rubber products
X
Plastic and rubber products not
covered elsewhere
X
X
X
X
X
X
Solvent
X
Toys, playground, and sporting
equipment
X
X
Adhesives and sealants
X
X
X
X
X
X
Air care products
X
X
Arts, crafts and hobby materials
X
X
X
X
X
Automotive Care products
X
X
X
Consumer
Batteries
X
Building/construction materials not
covered elsewhere
X
X
X
Chemiluminescent light stick
X
Cleaning and furnishing care
products
X
X
X
Dyes and pigments
X
Page 110 of 117
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December 2024
Use
Conditions of Use
DBP
BBP
DEHP
DCHP
DIBP
DINP
Electrical and electronic products
X
X
Fabric, textile, and leather products
not covered elsewhere
X
X
X
X
X
Floor coverings
X
X
X
X
Foam seating and bedding products
X
Furniture and furnishings not
covered elsewhere
X
X
X
Ink, toner, and colorant products
X
X
X
X
Lawn and garden care products
X
Paints and coatings
X
X
X
X
X
X
Paper products
X
Plastic and rubber products
X
Plastic and rubber products not
covered elsewhere
X
X
X
X
X
X
Reference material and/or
laboratory reagent
X
Toys, playground, and sporting
equipment
X
X
X
X
X
"Table taken from EPA's Draft Proposed Approach for Cumulative Risk Assessment ofHigh-Priority Phthalates and a
Manufacturer-Reauested Phthalate under the Toxic Substances Control Act (U. S. EPA, 2023b). COU overlap based on
COU tables presented in the final scoping documents for DEHP, DBP, BBP, DIBP, DCHP, and DINP.
3038
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3039
3040
3041
3042
3043
3044
3045
3046
3047
3048
3049
3050
3051
3052
3053
3054
3055
3056
3057
3058
3059
3060
3061
3062
3063
3064
3065
3066
3067
3068
3069
3070
3071
3072
3073
3074
3075
3076
3077
3078
3079
3080
3081
3082
3083
PUBLIC RELEASE DRAFT
December 2024
Appendix E Calculation of Occupational Exposure Values Based on
Cumulative Exposures and Relative Potency Assumptions
EPA typically derives an occupational exposure value (OEV) to represent the exposure concentration
below which exposed workers and occupational non-users are not expected to exhibit any appreciable
risk of adverse toxicological outcomes. For exposures to individual chemicals, this can be easily
calculated based on the POD for the most sensitive human health effect supported by the weight of
scientific evidence, expressed relative to benchmarks and standard occupational scenario assumptions.
A singular value cannot be applied across the board for application to cumulative risk analysis of all
phthalates, given that neither the identity nor relative ratio of the phthalates present in a given exposure
scenario can be generalized. Therefore, EPA derived an inhalation OEV for the index chemical, which
can then incorporate RPFs to determine whether cumulative exposures result in risk relative to
benchmark based on measurement of phthalates in air (Appendix E.2).
Similar to OEVs for individual chemicals, the index chemical OEV may be used to support risk
management efforts for phthalates under TSCA section 6(a), 15 U.S.C. 2605. TSCA requires risk
evaluations to be conducted without consideration of cost and other non-risk factors, and thus this most
sensitive OEV represents a risk-only number. If risk management is implemented following the final
risk evaluation for any phthalates covered by the cumulative risk analysis TSD, EPA may consider cost
and other non-risk factors, such as technological feasibility, the availability of alternatives, and the
potential for critical or essential uses. Any existing chemical exposure limit (ECEL) used for
occupational safety risk management purposes could differ from the OEVs used in these example
calculations based on additional consideration of exposures and non-risk factors consistent with TSCA
section 6(c).
The index chemical OEV represents the exposure concentration below which exposed workers and
occupational non-users are not expected to exhibit any appreciable risk for reduced fetal testicular
testosterone, the basis of RPFs across the phthalates. This OEV accounts for PESS. This value is
expressed relative to benchmarks and standard occupational scenario assumptions of 8 hours per day, 5
days per week exposures for a total of 250 days exposure per year, and a 40-year working life.
E.l Occupational Exposure Value for the Index Chemical (DBP)
This section presents the calculations used to estimate a draft OEV for the index chemical, DBP, using
inputs derived in this analysis. For DBP, the index chemical HED used for cumulative risk assessment
and application of RPFs is 2.1 mg/kg-day, for reduced fetal testicular testosterone (Section 2.3). Based
on average adult body weight of 80 kg and default resting breathing rate of 14.7 m3/day (0.6125 m3/hour
for 24 hours) (U.S. EPA. 2011a). the inhalation HEC based on route-to-route extrapolation is 11.4
mg/m3.
Draft Occupational Exposure Value for DBP
The draft OEV was calculated as the concentration at which the MOE would equal the benchmark MOE
for occupational exposures using EquationApx E-l. The OEV was derived based on acute exposures,
the most sensitive exposure scenario relevant to reduced fetal testicular testosterone.
Equation Apx E-l.
Page 112 of 117
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3084
3085
3086
3087
3088
3089
3090
3091
3092
3093
3094
3095
3096
3097
3098
3099
3100
3101
3102
3103
3104
3105
3106
3107
3108
3109
3110
3111
3112
3113
3114
3115
3116
3117
3118
3119
PUBLIC RELEASE DRAFT
December 2024
OEVi
HEC
acute
AT,
index
Benchmark MOEacute
24/i
HECacute
~ED
IR
resting
IR,
workers
OEVindex (pprri) =
11.4 mg/m3 0.6125^
30 * ~W * TTTtf" = 056 mg/m
d 1-Zbir
EV * Molar Volume 0.56 mg/m3 * 24.45 ^-7
m^ &/ mol
MW
278
9
mol
= 0.049 ppm
The parameters used in the above equations are described below.
Where:
A TnECacute
Benchmark MOEacute
OKI index
ED
HECacute
IR
Molar Volume
MW
Averaging time for the POD/HEC used for evaluating non-cancer,
acute occupational risk, based on study conditions and/or any HEC
adjustments (24hrs/day)
Acute non-cancer benchmark margin of exposure, based on the total
uncertainty factor of 30
Draft occupational exposure value based on reduced fetal testicular
testosterone
Exposure duration (8 hrs/day)
Human equivalent concentration for acute, intermediate, or chronic
occupational exposure scenarios
Inhalation rate (default is 1.25 m3/hr for workers and 0.6125 m3/hr for
the general population at rest)
24.45 L/mol, the volume of a mole of gas at 1 atm and 25 ฐC
Molecular weight ofDBP (278.0 g/mole)
E.2 Estimating Inhalation Risk to Air Mixtures using Cumulative and
Individual QEVs
As stated above, the index chemical OEV alone cannot be used to summarize risk thresholds for
cumulative exposures covering any mixture of phthalates. In EPA's proposed approach, adapted from
the OSHA Technical Manual (OTM) - Section II: Chapter 1 | Occupational Safety and Health
Administration, concentrations of the individual phthalates are compared to their respective OEV, and
the ratios are summed together to determine if the cumulative concentration is greater than 1 (indicating
potential risk). This is presented in the equation below:
Ci C2 Cn
E m = + + +
Ll L2 Ln
Where:
Em is the minimum equivalent exposure for the mixture (Em should be less than or equal to 1 for
compliance);
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3120
3121
3122
3123
3124
3125
3126
3127
3128
3129
3130
3131
3132
3133
3134
3135
3136
3137
3138
3139
3140
3141
3142
3143
3144
3145
3146
3147
3148
3149
3150
3151
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PUBLIC RELEASE DRAFT
December 2024
Cn is the measured concentration of a particular substance;
Ln is the corresponding occupational exposure value for a particular substance in the same units
as the concentration.
The OSHA method has a few complications however when applied to the phthalates. First, the health
endpoint and POD from the DBP dataset that is the basis of the RPF for comparison across phthalates is
not always the most sensitive POD for each phthalate. Therefore, risks must be evaluated both for the
individual phthalate OEV and also the cumulative hazard index based on RPFs. The equation above
would therefore be applied to the RPF-adjusted OEVs (derived from the OEVindex of 0.049 ppm and
represented by Li, L2 etc. in the above equation). Risk for the most sensitive endpoint would then also
be considered independently for each individual phthalate. Individual OEVs for each phthalate are
derived based on the most sensitive human health effect relative to benchmarks from their respective
risk evaluation and human health hazard assessment.
Another major limitation is that only two phthalates (DEHP and DBP) currently have fully validated air
monitoring methods, including OSHA Method 104 for DEHP and DBP and NIOSH Method 5020,
which is fully validated for DBP and partially validated for DEHP. Although air monitoring methods for
DIBP, BBP, and DCHP have been reported in the peer-reviewed literature (Chi et al.. 2017). this
approach is therefore currently limited in its application to workplaces only for DEHP and DBP, until
validated methods are available for BBP, DIBP, DCHP, and DINP. Additionally, an OEV based only on
workplace air concentrations will not be inclusive of non-attributable national (non-occupational)
exposure. As a possible alternative approach, urinary biomonitoring of phthalate metabolites in workers
is available for all phthalate species and could be inclusive of both occupational and non-workplace
exposures to phthalates (depending on whether a baseline/background comparison was implemented).
Urinary biomonitoring and reverse dosimetry methods have been previously applied by NIOSH for
measuring phthalate intake among workers (Hines et al.. 2011).
Urinary biomonitoring is clearly limited in that it does not allow real-time workplace monitoring and
could only be implemented either based on a regular schedule or some triggering event/air concentration
limit. Baseline measurements would also be required to establish internal dose based on non-attributable
national exposures. Despite these limitations this approach could be valuable for being able to measure
all phthalate species and being inclusive of aggregate exposures, including non-attributable, non-
occupational exposures. EPA will explore the possibility of developing a method for applying the RPF
approach to urinary biomonitoring in addition to other alternative approaches. Draft methods may be
shared alongside future phthalate risk evaluations. EPA welcomes feedback for these and any other
potential alternative approaches.
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3156 Appendix F Supporting Analyses for Consumer Exposure to
3157 Phthalates
3158
3159 Table Apx F-l. Sample of Consumer Products Containing Phthalates^
Phthalate
Product "bc
Manufacturer d
Sakrete Blacktop Repair Tube
Sakrete of North America
Concrete Patching Compound
Quikrete Companies
Mortar Repair Sealant
Quikrete Companies
DAP Roof & Flashing Sealant, Polyurethane
DAP Products, Inc.
Pre-Mixed Stucco Patch
Quikrete Companies
Hercules Plumber's Caulk - White/Linen
HCC Holdings Inc.
Wilsonart Color Matched Caulk
Wilsonart LLC
Acrylic Caulk
Momentive Performance Materials -
Daytona
Silicone Fortified Window & Door Sealant
Henry Company
Air Bloc 33
Henry Company
PSI PolyClay Canes and PSI PolyClay
Bricks e
Penn State Industries
Double Bubble Urethane High Peel Strength
D50 Part A (04022)
Royal Adhesives & Sealants
Dymonic FC Anodized Aluminum
Tremco Canadian Sealants [Canada]
GE7000
Momentive Performance Materials
Hydrogel SX
Prime Resins Inc.
Permatite Acrylic Sealant
Permatite / Division of DSI
Protecto Sealant 25XL
Protecto Wrap Company
BBP
Spectrem 3 Aluminum Stone - 30 CTG
Tremco Canadian Sealants [Canada]
Spectrem 4
Tremco U.S Sealants
STP 17925 Power Steering Fluid & Stop
Leak
Armored AutoGroup Inc.
126VR Disc Brake Quiet 0.25 Fl. Oz Pouch
ITW Permatex
Steri-Crete SL Component A
Dudick, Inc.
Stonclad UT Resin Polyol
Stonhard, Division of StonCor Group,
Inc.
ENSURE Sterilization Emulator
SciCan Ltd. [Canada]
Phthalates in Poly(vinyl chloride)
SPEX CertiPrep, LLC
Elmer's Model + Hobby Cement
Elmers Products, Inc.
Accent MBRU 6pk Silver Metallic 2oz
Rust-Oleum Corporation
Champion Sprayon Acrylic Matte Finish
Chase Products Co.
6840 Ultra Black
BJB Enterprises, Inc.
Handstamp - Blue
Identity Group
Repair and Refinishing Spray
Multi-Tech Products Corp.
Armacell WB Finish
Mon-Eco Industries, Inc.
Black Tire Paint Concentrate
Akron Paint and Varnish (dba APV
Engineered Coatings)
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Phthalate
Product abc
Manufacturer d
IC 1-gl 2pk Gray Shop Coat Primer
Rust-Oleum Corporation
BBP
Klean-Strip Mask & Peel Paint Booth
Coating
W. M. Barr
Lacquer Touch-up Paint - Clear Topcoat
Ford Motor Company
SK Clear-Seal Satin Sealer 5 Gal
Rust-Oleum Corporation
3M Bondo Glazing & Spot Putty
3M Company
SureFlex Multi-Purpose Adhesive, SH-360
Barristo Enterprises, Inc. dba
SureHold
Lanco Seal
Lanco Mfg. Corp.
PSI PolyClay Canes and PSI PolyClay
Bricks e
Penn State Industries
Hydrostop Premiumcoat Finish Coat
GAF
Hydrostop Premiumcoat Foundation Coat
GAF
DBP
Hydrostop Trafficcoat Deck Coating
GAF
Pro 1-GL 2PK Flat Aluminum Primer
Rust-Oleum Corporation
DURALAQ-WB WATERBORNE WHITE
ACRYLIC FINISH DULL RUBBED
Benjamin Moore & Co.
Hydrostop Premiumcoat Foundation Coat
Summer
GAF
Bondo Gray Filler Primer
3M Company
Pettit XL Vivid 1861 Black
Kop-Coat, Inc. / Pettit Marine Paint
Accurate Solo 1000, Accurate LT-30,
Accurate LT-32, Accurate 2015, Accurate
2495, Accurate 4064, Accurate 4350
Western Powders, Inc.
Cartridge 9 mm FX Marking, Toxfree primer
General Dynamics - Ordnance and
Tactical Systems - Canada Inc.
[Canada]
Rimfire Blank Round - Circuit Breaker
Olin Corporation - Winchester
Division, Inc.
Wizard 31 Epoxy Ball Plug Hardener
Brunswick Bowling Products, LLC
765-1553 BALKAMP VINYL REPAIR KIT
Permatex, Inc.
Chocolate
Wellington Fragrance
PSI PolyClay Canes and PSI PolyClay
Bricksฎ
Penn State Industries
DUPLI-C OLOR BED ARMOR
Dupli-Color Products Company
DEHP
DUPLI-COLOR High Performance Textured
Metallic Coating Charcoal
Dupli-Color Products Company
264 BLACK TRUCK BED LNR 6UC
The Valspar Corporation
RED GLAZING PUTTY 1# TUBE
The Valspar Corporation
Prime WPC/Prime Essentials/Prime SPC
Carlton Hardwood Flooring
Lenox MetalMax
Lenox Tools
6.17 OZ 100040 FH FRESH SCENT PET
TW 12PK
Fresh House
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Phthalate
Product abc
Manufacturer d
KRYLON Fusion All-In-One Textured
Galaxy
Krylon Products Group
Self-cath pediatric 30 pack
Coloplast Corp.
3M Economy Vinyl Electrical Tape 1400,
1400C
3M
Pronto Putty
The Valspar Corporation
Red Glazing Putty 1# Tube
Quest Automotive Products
BD Loop Goop
Royal Adhesives and Sealants Canada
Ltd.
SCOFIELDฎ CureSeal 350
Sika Corporation
DC HP
Duco Cement (bottle and tube)l
ITW Consumer - Devcon/Versachem
Fusor 108B, 109B Metal Bonding ADHPT
B
LORD Corporation
DIBP
DIBP
Blue Label Washable PVA Adhesive
Colorlord Ltd.
BETAKRIL TEXTURE
Betek Boya ve Kimya Sanayi A.S
[Turkeyl
Centerfire Pistol & Revolver and Rifle
Cartridges
Companhia Brasileira de Cartuchos
(CBC)
Art Board
Ningbo Zhonghua Paper Co. Ltd.
Glitter Boards
DJECO
Painting - Oh, It's Magic
DJECO
11 This table includes a sample of products listed in the Use Reports for each DBP, BBP, DIBP, DEHP, DCHP
(U.S. EPA. 2021. 2020a. b. c. d. e).
h This table may represent updated information with products listed that are not identified in the published
Use Reports.
c This is not a comprehensive list of products containing each phthalate nor does the presence of a product on
this list indicate its availability in the United States for consumer purchase
d Some manufacturers may appear over-represented in this table. This may mean that they are more likely to
disclose product ingredients online than other manufacturers, but this does not imply anything about use of
the chemical compared to other manufacturers in this sector.
' The SDS for PSI PolyClay Canes and PSI PolyClay Bricks, which lists the product as containing multiple
phthalates is available here: https://www.pennstateind.com/MSDS/POLYCLAY MSDS.pdf.
'Table from Draft Proposed Approach for Cumulative Risk Assessment ofHigh-Priority Phthalates and a
Manufacturer-Requested Phthalate under the Toxic Substances Control Act (U.S. EPA, 2023b).
3160
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