1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
PUBLIC RELEASE DRAFT
December 2024
EPA Document# EPA-740-D-24-031
December 2024
United States Office of Chemical Safety and
Environmental Protection Agency Pollution Prevention
Draft Environmental Hazard Assessment for Butyl Benzyl
Phthalate (BBP)
Technical Support Document for the Draft Risk Evaluation
CASRN: 85-68-7
ff^l
o ^
o
,0,
xh3
December 2024
-------
PUBLIC RELEASE DRAFT
December 2024
28 TABLE OF CONTENTS
29 ACKNOWLEGEMENTS 5
30 SUMMARY 6
31 1 INTRODUCTION 7
32 2 APPROACH AND METHODOLOGY 8
33 3 AQUATIC SPECIES HAZARD 10
34 4 TERRESTRIAL SPECIES HAZARD 17
35 5 ENVIRONMENTAL HAZARD THRESHOLDS 19
36 5.1 Aquatic Species COCs 19
37 5.2 Terrestrial Species Hazard Values 21
38 6 WEIGHT OF THE SCIENTIFIC EVIDENCE CONCLUSIONS FOR
3 9 ENVIRONMENTAL HAZARD 23
40 6.1 Strengths, Limitations, Assumptions, and Key Sources of Uncertainty for Environmental
41 Hazard 23
42 7 ENVIRONMENTAL HAZARD ASSESSMENT CONCLUSIONS 27
43 REFERENCES 28
44 Appendix A SPECIES SENSITIVITY DISTRIBUTION 34
45 Appendix B TERRESTRIAL VERTEBRATE TOXICITY OF BBP 37
46 Appendix C RUBRIC FOR WEIGHT OF THE SCIENTIFIC EVIDENCE 38
47 C.l Confidence Levels 38
48 C.2 Types of Uncertainties 38
49
50 LIST OF TABLES
51 Table S-l Environmental Hazard Thresholds for BBP 6
52 Table 3-1. Acute Aquatic Vertebrate Toxicity of BBP 10
53 Table 3-2. Chronic Aquatic Vertebrate Toxicity of BBP 12
54 Table 3-3. Acute Aquatic Invertebrate Toxicity of BBP 13
55 Table 3-4. Chronic Aquatic Invertebrate Toxicity of BBP 14
56 Table 3-5. Aquatic Plant and Algae Toxicity of BBP 15
57 Table 4-1. Terrestrial Vertebrate Toxicity of BBP 17
58 Table 4-2. Terrestrial Invertebrate Toxicity of BBP 18
59 Table 4-3. Terrestrial Plant Toxicity of BBP 18
60 Table 5-1. Environmental Hazard Thresholds for BBP 22
61 Table 6-1. BBP Evidence Table Summarizing the Overall Confidence Derived from Hazard
62 Thresholds 26
63
64 LIST OF FIGURES
65 Figure 5-1. Species Sensitivity Distribution (SSD) of Acute Hazard Effects of BBP on Aquatic
Page 2 of 41
-------
67
68
69
70
71
72
73
74
75
76
77
78
PUBLIC RELEASE DRAFT
December 2024
line indicates the 5 percent Hazard Concentration (HC05 = 327 |ig/L) 20
LIST OF APPENDIX TABLES
TableApx A-l. SSD Model Input for BBP Acute Exposure Toxicity in Aquatic Vertebrates and
Invertebrates - Empirical Data 34
Table Apx A-2. SSD Model Input for BBP Acute Exposure Toxicity in Aquatic Vertebrates and
Invertebrates - WeblCE Data 35
Table Apx A-3. SSD'' Model Predictions for Acute BBP Exposure Toxicity to Aquatic Vertebrates.... 36
Table_Apx B-l. Terrestrial Vertebrate Toxicity of BBP 37
TableApx C-l. Considerations that Inform Evaluations of the Strength of the Evidence within an
Evidence Stream (i.e., Apical Endpoints, Mechanistic, or Field Studies) 40
Page 3 of 41
-------
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
PUBLIC RELEASE DRAFT
December 2024
ABBREVIATIONS AND ACRONYMS
AF
Assessment factor
BMD
Benchmark dose
BMDL
Benchmark dose limit
COC
Concentration(s) of concern
EC50
Effect concentration at which 50% of test organisms exhibit an effect
HC05
Hazard concentration that is protective of 95 percent of the species in the sensitivity
distribution
LC50
Concentration which is lethal to 50 percent of test organisms
LD50
Dose which is lethal to 50 percent of test organisms
LOAEL
Lowest-observable-adverse-effect4evel
LOEC
Lowest-observable-effect concentration
NAM
New approach method
NITE
National Institute of Technology and Evaluation
NOAEL
No-observed-adverse-effect level
NOEC
No-observed-effect concentration
NOEL
No-observed-effect level
OCSPP
Office of Chemical Safety and Pollution Prevention
OPPT
Office of Pollution Prevention and Toxics
PND
Postnatal day
POD
Point of departure
QSAR
Quantitative structure-activity relationship (model)
SSD
Species sensitivity distribution
TRV
Toxicity reference value
TSCA
Toxic Substances Control Act
U.S.
United States
Web-ICE
Web-based Interspecies Correlation Estimation
Page 4 of 41
-------
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
PUBLIC RELEASE DRAFT
December 2024
ACKNOWLEGEMENTS
This report was developed by the United States Environmental Protection Agency (U.S. EPA or the
Agency), Office of Chemical Safety and Pollution Prevention (OCSPP), Office of Pollution Prevention
and Toxics (OPPT).
Acknowledgements
The Assessment Team gratefully acknowledges the participation, review, and input from EPA OPPT
and OSCPP senior managers and science advisors. The Agency is also grateful for assistance from the
following EPA contractors for the preparation of this draft technical support document: General
Dynamics Information Technology, Inc. (Contract No. HHSN316201200013W); ICF, Inc. (Contract No.
68HERC23D0007); SpecPro Professional Services, LLC (Contract No. 68HERC20D0021); and SRC,
Inc. (Contract No. 68HERH19D0022 and 68HERC23D0007).
As part of an intra-agency review, this technical support document was provided to multiple EPA
Program Offices for review. Comments were submitted by EPA's Office of Research and Development
(ORD).
Docket
Supporting information can be found in the public docket, Docket ID EPA-HQ-QPPT-2018-0501.
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: Collin Beachum (Management Lead), Brandall Ingle-Carlson (Assessment Lead), Randall
Bernot (Environmental Hazard Assessment Lead), Jennifer Brennan, Christopher Green (Environmental
Hazard Discipline Leads)
Contributors: Azah Abdallah Mohamed, Rony Arauz Melendez, Sarah Au, Maggie Clark, Jone
Corrales, Daniel DePasquale, Lauren Gates, Emily Griffin, Ryan Klein, Sydney Nguyen, Brianne
Raccor, Maxwell Sail, Joe Valdez, Leora Vegosen.
Technical Support: Hillary Hollinger, S. Xiah Kragie
This report was reviewed by OPPT and OCSPP leadership.
Page 5 of 41
-------
146
147
148
149
150
151
152
153
154
155
156
157
158
PUBLIC RELEASE DRAFT
December 2024
SUMMARY
This technical document is in support of the TSCA Draft Risk Evaluation for butyl benzyl phthalate
(BBP) (U.S. EPA. 2025). BBP is a common chemical name for the chemical substance 1,2-
benzenedicarboxylic acid, 1-butyl 2-(phenylmethyl) ester (CASRN 85-68-7).
EPA considered all reasonably available information identified through the systematic review process
under the Toxic Substances Control Act (TSCA) to characterize environmental hazard endpoints for
BBP. After evaluating the reasonably available information, environmental hazard thresholds were
derived for aquatic vertebrates, aquatic invertebrates, aquatic plants and algae, and terrestrial vertebrates
(Table S-l).
Table S-l Environmental Hazard Thresholds for BBP
Receptor Group
Exposure
Duration
Hazard Threshold (COC
or HV)
Citation
Aquatic Vertebrates
Acute
197 |ig/L
From SSD; See Section 5
Chronic
1.9 |ig/L
(Battelle, 2018c)
Aquatic Invertebrates
Acute
197|ig/L
From SSD; See Section 5
Chronic
62.6 |ig/L
(Rhodes et al.. 1995)
Aquatic Plants and Algae
Chronic
21 |ig/L
(Adams et al., 1995)
Terrestrial Vertebrates
Chronic
311 mg/kg/day
(TNO. 1993)
Page 6 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
159 1 INTRODUCTION
160 Butyl benzyl phthalate is a clear, oily liquid with a total production volume in the United States between
161 10 and 50 million pounds (U.S. EPA. 2020). Butyl benzyl phthalate is manufactured (including
162 imported) in the United States. The chemical is processed as a reactant, incorporated into a formulation,
163 mixture, or reaction product, and incorporated into articles.
164
Page 7 of 41
-------
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
PUBLIC RELEASE DRAFT
December 2024
2 APPROACH AND METHODOLOGY
TSCA requires that EPA use data and/or information in a manner consistent with the best available
science and that EPA base decisions on the weight of scientific evidence. To meet the TSCA science
standards, EPA applies a systematic review process to identify data and information across taxonomic
groups for both aquatic and terrestrial organisms with a focus on apical endpoints (e.g., those affecting
survival, growth, or reproduction). The data collection, data evaluation, and data integration stages of
the systematic review process are used to develop the hazard assessment to support the integrative risk
characterization. EPA uses several considerations when weighing and weighting the scientific evidence
to determine confidence in the environmental hazard data. These considerations include the quality of
the database, consistency, strength and precision, biological gradient/dose response, and relevance. EPA
completed the review of environmental hazard data/information sources during risk evaluation using the
data quality review evaluation metrics and the rating criteria described in the 2021 Draft Systematic
Review Protocol supporting TSCA Risk Evaluations for Chemical Substances (U.S. EPA. 2021) and
Draft Risk Evaluation for Butyl Benzyl Phthalate (BBP) - Systematic Review Protocol (U.S. EPA.
2024c). Studies identified and evaluated by OPPT through 2020 were assigned an overall quality level
of high, medium, low, or uninformative. Data on toxicity of BBP are numerous and, in some instances,
vary substantially, thus EPA systematically evaluated all data for this hazard characterization, but relied
upon only high-quality and medium-quality studies for purposes of quantitative risk characterization.
References receiving an overall quality determination of low or uninformative either exceeded the BBP
limit of solubility in all treatments, showed no effects at the highest concentration tested, evaluated a
biotransformation (mechanistic) endpoint, and/or were part of a mixture.
EPA reviewed potential environmental hazards associated with BBP. EPA considered all available
studies to characterize the environmental hazards of BBP to surrogate species representing various
receptor groups, including aquatic vertebrates, aquatic invertebrates, amphibians, aquatic plants, algae,
and birds. Mechanistic (transcriptomic and metabolomic) and behavioral points of departure from one
study of an acute exposure of BBP to fathead minnows were used to inform of the potential mechanisms
that lead to the acute and chronic aquatic vertebrate hazard thresholds (Bencic et al.. 2024). Hazard
studies with mammalian wildlife exposed to BBP were not available, therefore EPA used ecologically
relevant endpoints from human health laboratory rat and mouse model organisms to establish a hazard
threshold for terrestrial mammals.
A Species Sensitivity Distribution (SSD) analysis was used to derive an acute aquatic hazard threshold.
An SSD is a model of the variation in sensitivity of species to a particular chemical stressor and is
generated by fitting a statistical distribution function to the proportion of species affected as a function
of concentration or dose. Empirical data that were included in the SSD analysis were limited to LC50
values (concentration which is lethal to 50% of test organisms) that were at or below the limit of water
solubility of 2690 |ig/L for BBP (U.S. EPA. 2024a). Specifically, predicted hazard data were generated
using EPA's Web-Based Interspecies Correlation Estimation Web-ICE (v4.0) toxicity predictions tool
(Raimondo. 2010). The species and corresponding empirical data are outlined in Section 5 and
Appendix A. EPA derived concentrations of concern (COC) for all other organism and exposure
durations using studies that report hazard effects at or below the limit of water solubility of 2690 |ig/L
g/L for BBP.
Environmental Hazard from Previous Assessments
Environment Canada previously assessed environmental hazard effects of BBP (EC. 2000). Through a
survey of acute exposure (48-hour and 96-hour durations) studies of organism mortality that estimated
concentrations which are lethal to 50% of test organisms (LC50s), aquatic acute hazard was determined
Page 8 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
213 to be 510 |ig/L for the shiner perch (Cymcitogcister aggregata). Aquatic chronic exposure hazards and
214 algal exposure hazards were not identified (EC. 2000). The European Union (EU) Risk Assessment
215 Report (ECJRC. 2007) reports the lowest acute aquatic hazard value as 510 |ig/L BBP for C. aggregata
216 (ECJRC. 2007). The EU assessment also reports the lowest chronic NOEC (No-observed-effect
217 concentration) values as 140 |ig/L BBP to fish (30-day exposure to Pimephalespromelas), 75 |ig/L BBP
218 to an invertebrate (28-day exposure to Americamysis bahia), and 200 |ig/L BBP to a diatom (72-hour
219 exposure to Naviculapelliculosa) (ECJRC. 2007). Neither assessment reports hazard threshold data on
220 the effects of BBP to terrestrial organisms.
221
Page 9 of 41
-------
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
PUBLIC RELEASE DRAFT
December 2024
3 AQUATIC SPECIES HAZARD
EPA reviewed 51 studies for BBP toxicity to aquatic organisms. Some studies may have included
multiple endpoints, species, and test durations. Four of these studies received an overall quality
determination of low, uninformative, or did not meet systematic review criteria. The data from these low
or uninformative studies were not used to derive hazard thresholds because they either exceeded the
BBP limit of solubility in all treatments, showed no effects at the highest concentration tested, evaluated
a biotransformation (mechanistic) endpoint, and/or were part of a mixture. Forty-seven studies received
an overall quality determination high or medium quality, were used to derive hazard thresholds, and are
detailed in the subsections below. Studies that demonstrated no acute or chronic adverse effects at the
highest concentration tested (unbounded NOECs), or where hazard values exceeded the limit of
solubility for DBP in water as determined by EPA at 2690 |ig/L, (U.S. EPA, 2024, 11799672) are
included in Table 3-1, Table 3-2, Table 3-3, Table 3-4, and Table 3-5, but were excluded from
consideration for the development of hazard thresholds (Section 5). Additionally, predicted hazard data
for 18 species were generated using EPA's Web-ICE (v4.0) tool (Raimondo, 2010). including
predictions for 14 fish, and four invertebrate species. No toxicity studies using spiked sediment for
benthic exposures were identified for BBP. Thus, all hazard data to benthic invertebrates were
represented by water exposures.
Acute Aquatic Vertebrates
EPA reviewed seven high/medium quality studies for acute toxicity in aquatic vertebrates (Table 3-1).
Of these studies, six contained acceptable endpoints that identified definitive hazard values below the
BBP limit of water solubility (2690 |ig/L). For the fathead minnow (Pimephales promelas), bluegill
{Lepomis macrochirus), rainbow trout (Oncorynchus mykiss), and shiner perch (Cymatogaster
aggregcita) the 96-hour mortality LC50s ranged from 510 to 2100 |ig/L BBP (Adams et al.. 1995;
Ozretich et al.. 1983; EG&G Bionomics. 1979a. c, d). These values were combined with acute hazard
effects values of BBP to aquatic invertebrates to derive an SSD and subsequent acute exposure threshold
(Appendix A).
Table 3-1. Acute Aquatic Vertebrate Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Fathead minnow
{Pimephales
promelas)
1500 |ig/L a
96-hour LC50
Mortality
(Adams et al., 1995)
(High)
2100 |ig/L a
96-hour LC50
Mortality
(EG&G Bionomics,
1979d)(High)
Bluegill
{Lepomis
macrochirus)
1700 |ig/L a
96-hour LC50
Mortality
(EG&G Bionomics,
1979c) (Medium)
Sheepshead
minnow
{Cyprinodon
variegatus)
3000 |ig/L b
96-hour NOEC
Mortality
(EG&G Bionomics,
1979a) (Medium)
Page 10 of 41
-------
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
PUBLIC RELEASE DRAFT
December 2024
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Rainbow trout
(Oncorynchus
mykiss)
820 |ig/L a
96-hour LC50
Mortality
(Ozretich et al.,
1983)(High)
3300 |ig/L b
96-hour LC50
Mortality
(EG&G Bionomics,
1979d)(High)
Shiner perch
(Cymatogaster
aggregcita)
510 |ig/L a
96-hour LC50
Mortality
(Ozretich et al.,
1983) (Medium)
11 Value used as input for SSD derivation of acute aquatic hazard threshold.
h Hazard value is greater than the BBP limit of solubility (2690 ng/L).
TSCA section 4(h)(1)(B) requires EPA to encourage and facilitate the use of scientifically valid test
methods and strategies that reduce or replace the use of vertebrate animals while providing information
of equivalent or better scientific quality and relevance that will support regulatory decisions. In line with
EPA's New Approach Methods Work Plan, EPA OPPT and ORD have been collaborating on
developing new methods for use in TSCA risk evaluations. Specifically, a project was conducted to
generate omics-based PODs and compared them to traditional endpoints using fathead minnow as the
model organism for three of the phthalates undergoing a TSCA risk evaluation, including BBP (Bencic
et al.. 2024). In this study, points of departure (PODs) were derived for transcriptomic change (tPOD; 60
|ig/L), metabolomic change (mPOD; 120 |ig/L), and behavioral change (bPOD 90 |ig/L) resulting from
24-hour duration of aquatic BBP exposure to fathead minnows. Additionally, a 24-hour mortality
NOEC/LOEC of 1000 /2000 |ig/L was identified. In 2000 |ig/L BBP exposures, 38 percent mortality
was observed. These results suggest that fathead minnow larvae exhibited changes in gene expression,
metabolite levels, and swimming behavior at sublethal concentrations of BBP. While hazard thresholds
are usually calculated with in vivo data measuring an apical endpoint (e.g., mortality, reproduction,
growth), these mechanistic (transcriptomic and metabolomic) and behavior points of departure represent
potential information that may be used for reducing the time needed for toxicity testing in vivo and
provide an alternate method to characterize hazard as well as provide important evidence for
mechanisms of action. At this time, EPA has not used the omics-based PODs in the BBP draft risk
evaluation. There are uncertainties with respect to the extent to which these sub-organismal and
individual-level effects (e.g., behavior) at short exposure durations are comparable to ecologically
relevant outcomes, such as survival and reproduction, in wild fish populations.
Chronic Aquatic Vertebrates
EPA reviewed eight high or medium quality studies for chronic toxicity in aquatic vertebrates (Table
3-2). Of these studies, four contained acceptable chronic endpoints that identified definitive hazard
values below the BBP limit of water solubility (2690 |ig/L), for four fish species. One study found
effects of BBP on amphibian growth (Battelle, 2018a). Another study of dietary BBP exposure to the
fish, Sander lucioperca, found slightly reduced growth and female skewed sex ratios after five weeks of
high doses (360 g/kg bw/day) of BBP amended diets (Jarmolowicz et al.. 2014). However, feeding
treatments were not replicated and diet concentrations were not verified analytically.
Chronic water exposure studies include a 21-day reproduction test of BBP exposure to zebrafish (Danio
rerio), which found 3% lower fecundity, 2% lower fertilization success, 100% increase in plasma
vitellogenin, and reduced gonad weight in males in treatments with 33 |ig/L BBP (Lowest-observable-
Page 11 of 41
-------
287
288
289
290
291
292
293
294
295
296
297
298
299
PUBLIC RELEASE DRAFT
December 2024
effect concentration, LOEC) (Battelle, 2018c). No effects were observed at 11 pg/L BBP (NOEC).
In a separate study, fewer (10% less) eggs per Japanese medaka (Oryzias latipes) female were found
after five weeks of exposure to 95 pg/L BBP, but no effects on fertilization rates, growth, gonad weight,
or plasma vitellogenin were found in the same study (Battelle, 2018b). Other chronic exposure studies
resulted in no growth or reproductive effects of BBP to rainbow trout (Oncorhynchus mykiss) (Rhodes et
al.. 1995) or fathead minnow {Pimephalespromelas) (ABC Laboratories. 2008) (Table 3-2). Fish
behaviors may also be altered due to chronic BBP exposure, as Mummichog (Fundulus heteroclitus)
shoaled with smaller fish when exposed for 28-days to 100 pg/L BBP compared to control fish that
shoaled with larger fish (Kaplan et al.. 2013).
Table 3-2. Chronic Aquatic Vertebrate Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
African clawed
frog (Xenopus
laevis)
No hazard effects;
Greater growth in
all BBP exposures
21-day
LOEC
Growth
(Battelle, 2018a)
(High)
Zebrafish
(Danio rerio)
11/33 ng/L°
21-day
NOEC/LOEC
Reproduction
(Battelle, 2018c)
(High)
Rainbow trout
(Oncorhynchus
mykiss)
>200 pg/L
No effects
observed
21-day
Mortality and
Growth
(Rhodes et al.. 1995)
(High)
Japanese
medaka
{Oryzias
latipes)
35/95 pg/L b
5-week
NOEC/LOEC
Growth
(10% reduction in
egg production)
(Battelle. 2018b)
(Medium)
Fathead
minnow
(Pimephales
promelas)
>65 pg/L
164-day
NOEC
Growth and
Reproduction
(ABC Laboratories,
2008)(High)
> 82 pg/L
6-week
Reproduction
(ABC Laboratories,
2008)(High)
Mummichog
(Fimduhis
heteroclitus)
100 pg/L
28-day
LOEC
Behavior
(Kaplan et al., 2013)
(High)
European
pikeperch
{Sander
lucioperca)
180.0/360.0 g/kg
bw/day
NOEC/LOEC
5-week diet
exposure
Reproduction and
Growth
(Jarmolowicz et al.,
2014) (Medium)
a 3% lower fecundity; 2% lower fertilization success; 100% increase in plasma vitellogenin; reduced gonad
weight in males.
h 10% fewer eggs per female; no effects on fertilization rates, growth, gonad weight, or plasma vitellogenin.
Bolded number indicates the values used to derive the chronic exposure Concentration of Concern (COC).
Page 12 of 41
-------
300
301
302
303
304
305
306
307
308
309
310
311
312
PUBLIC RELEASE DRAFT
December 2024
Acute Aquatic Invertebrates
EPA reviewed 17 high or medium quality studies for acute toxicity in aquatic invertebrates (Table 3-3).
Fifty percent mortality effects (LC50s) or short-term effects (EC50s) of acute exposures of BBP to
aquatic invertebrates ranged from 0.46 mg/L to concentrations of BBP above the limit of water
solubility (i.e., >2690 |ig/L). Of these studies, seven contained acceptable endpoints that identified
definitive hazard values below the BBP limit of water solubility (2690 |ig/L). These values were
combined with acute hazard effects values of BBP to aquatic invertebrates to derive an SSD and
subsequent acute exposure threshold (Appendix A). For midge (Chironomus teutons), amphipod
(Hyalella azteca), mayfly, (Hexagenia sp.) opossum shrimp (Americamysis bahia), Taiwan abalone
(Haliotis diversicolor), and Virginia oyster (Crassostrea virginica), acute BBP water exposure resulted
in LC50 values ranging from 460 |ig/L to 2650 |ig/L BBP.
Table 3-3. Acute Aquatic Invertebrate Toxicity of BBP
Test Organism
Hazard
Values
Duration
Endpoint
Citation
(Study Quality)
Midge
(Chironomus tentans)
1640 |ig/L a
48-hour
LC50 (no
sediment)
Mortality
(Monsanto, 1982)
(Medium)
3600 |ig/L b
48-hour LC50
Mortality
(SRI International
1984) (Medium)
Amphipod
(Hyalella azteca)
460 |ig/L a
10-day
LC50 (no
sediment)
Mortality
(Call etal.. 2001a)
(High)
Mayfly
(Hexagenia sp.)
1100 |ig/L a
96-hour LC50
Mortality
(ABC Laboratories,
1986c) (High)
Opossum shrimp
(Americamysis bahia)
1100 |ig/L a
96-hour LC50
Mortality
(Springborn
Bionomics, 1988)
(High)
900 |ig/L a
96-hour LC50
Mortality
(EG&G Bionomics,
1979b)(High)
Moina macrocopa
(Water Flea)
3690 |ig/L b
48-hour LC50
Immobilization
(Wang et al 2011)
(High)
Crayfish
(Procambarus sp.)
>2400 |ig/L
96-hour LC50
Mortality
(ABC Laboratories,
1986b) (high)
(Polychaete worm)
(Nereis virens)
> 3000 |ig/L b
96-hour LC50
Mortality
(Springborn
Bionomics, 1986b)
(High)
Taiwan abalone
(Haliotis diversicolor)
2650 |ig/L a
96-hour EC50
Growth
(Liu et al., 2009)
(High)
Virginia oyster
(Crassostrea virginica)
1300 |ig/L a
96-hour EC50
Growth
(ABC Laboratories,
1986a) (High)
Hydra
(Hydra littoralis)
>1920 |ig/L
96-hour LC50
Mortality
(ABC Laboratories,
1986a) (High)
Pink shrimp
(Penaeus duorarum)
>3400 |ig/L
96-hour LC50
Mortality
(Soringborn
Bionomics, 1986a)
(High)
Midge
(Paratanytarsus
>3600 |ig/L
48-hour LC50
Mortality
(SRI International,
1984) (Medium)
Page 13 of 41
-------
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
PUBLIC RELEASE DRAFT
December 2024
Test Organism
Hazard
Values
Duration
Endpoint
Citation
(Study Quality)
dissimilis)
Midge
(Paratanytarsus
parthenogenetica)
7200 |ig/L b
48-hour LC50
Mortality
(Monsanto, 1983 a)
(High)
Waterflea
(Daphnia magna)
>1400 |ig/L
48-hour LC50
Immobilization
(SDringborn
Bionomics, 1984)
(Medium)
>960 |ig/L
48-hour LC50
Immobilization
(Adams et al., 1995)
(High)
a Value used as input for SSD derivation of acute aquatic hazard threshold.
h Hazard value is greater than the BBP limit of solubility (2690 ng/L).
Chronic Aquatic Invertebrates
EPA reviewed six high or medium quality studies for chronic toxicity in aquatic invertebrates (Table
3-4). All six studies contained acceptable chronic endpoints that identified definitive hazard values
below the BBP limit of water solubility (2690 |ig/L). Chronic effects of BBP on aquatic invertebrates
ranged from reduced opossum shrimp (Americamysis bahia) reproduction after 28-days at 170 |ig/L
BBP (Springborn Bionomics, 1986c) to growth reduction in midges (Chironomus tentcms) after 10-days
at 1420 |ig/L BBP (Call etal.. 2001bV
In a 21-day study of Daphnia magna, 80% mortality and 70% fewer offspring per female occurred when
exposed to 1400 |ig/L BBP compared to no-BBP control treatments (Rhodes et al.. 1995). Daphnia
magna exposed to BBP in a 21-day static renewal bioassay produced 50% fewer offspring at 220 |ig/L
BBP (LOEC) but were not affected at 350 |ig/L BBP (NOEC) (Monsanto. 1983b). In a study that lasted
42-days, 35% fewer/), magna survived in 760 |ig/L BBP compared to control treatments (EG&G
Bionomics. 1979e).
Rotifer (Brachionus calyciflorus) population growth rates were also reduced in chronic BBP exposures
(Cruciani et al.. 2015; Zhao et al.. 2009). In a 96-hour exposure experiment, B. calyciflorus population
growth rates were reduced by 25% at 2000 |ig/L (Cruciani et al.. 2015). In another study with a 144-
hour chronic exposure duration, B. calyciflorus population growth rates were reduced by 15% at 500
|ig/L BBP (Zhao et al.. 2009). In a 28-day exposure experiment, Americamysis bahia reproductive
success (offspring/female/day) was reduced by 50% when exposed to 170 |ig/L BBP (Springborn
Bionomics. 1986c). In a 10-day water exposure experiment, the oligochaete worm (Lumbricuius
variegatus) survival was reduced by 50% when exposed to 1230 |ig/L BBP (Call et al.. 2001b). In a 10-
day water exposure experiment, the midge (Chironomus tentcms) dry weight was reduced by 50% when
exposed to 1420 |ig/L BBP (Call et al.. 2001b).
Table 3-4. Chronic Aquatic Invertebrate Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Rotifer
(Brachionus
calyciflorus)
1000/2000 |ig/L
NOEC/LOEC
96-hour
Population growth
rate
(Cruciani et al.,
2015) (Medium)
50/500 |ig/L
NOEC/LOEC
144-hour
Population growth
rate
(Zhao et al., 2009)
(Medium)
Waterflea
280/1400 jig/L
21-day
Mortality
(Rhodes et al., 1995)
Page 14 of 41
-------
341
342
343
344
345
346
347
348
349
350
351
352
PUBLIC RELEASE DRAFT
December 2024
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
(Daphnia magna)
NOEC/LOEC
(High)
4800 |ig/L
160-hour EC50
Immobilization
(Monsanto, 1983 c)
(Medium)
220/350 |ig/L
NOEC/LOEC
21-day
Reproduction
(Monsanto, 1983b)
(Medium)
260/760 |ig/L
NOEC/LOEC
Two generation
(42-day)
Mortality
(EG&G Bionomics,
1979e) (High)
Opossum shrimp
(Americamysis bahia)
75/170 |ig/L
(NOEC/LOEC)
28-day
Reproduction
(Springborn
Bionomics, 1986c)
(High)
Oligochaete worm
(Lumbriculus
variegatus)
1230 |ig/L
10-day
(no sediment)
Mortality
(Call et al.. 2001b)
(High)
Midge
(Chironomus tentans)
1420 |ig/L
10-day EC50
(no sediment)
Growth
(Call et al.. 2001b)
(High)
Bolded number indicates the values used to derive the chronic exposure Concentration of Concern (COC).
Aquatic Plants and Algae
EPA reviewed nine high or medium quality studies for toxicity in aquatic plants and algae (Table 3-5).
Eight of these studies found population level hazard effects (96-h EC50) that ranged from 210 |ig/L
(green algae Raphidocelis subcapitata) to 600 |ig/L (diatoms Naviculapelliculosa and Skeletonema
costatum) and were less than the BBP limit of water solubility (2690 |ig/L) (Adams et al.. 1995; EG&G
Bionomics. 1978). A study of the cyanobacterium, Microcystis aeruginosa, did not find effects of BBP
on population growth rate (EG&G Bionomics. 1978). Cyanobacterium are bacteria and not algae or
plants, but EPA includes this study to illustrate the differential types of effects of BBP on different taxa
(U.S. EPA. 2021Y
Table 3-5. Aquatic Plant and Algae Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Raphidocelis
subcapitata
(Green Algae)
210 jig/L
96-hour EC50
Population
(Adams et al., 1995)
(High)
400 |ig/L
96-hour EC50
Population
(EG&G Bionomics,
1978) (Medium)
Navicula pelliculosa
(Diatom)
600 |ig/L
96-hour EC50
Population
(EG&G Bionomics,
1978) (Medium)
410 |ig/L
72-hour E50
Population
(Carolina Ecotox,
1995a) (High)
Skeletonema costatum
(Diatom)
600 |ig/L
96-hour EC50
Population
(EG&G Bionomics,
1978) (Medium)
Dunaliella tertiolecta
(Green Algae)
1000 |ig/L
96-hour EC50
Population
(EG&G Bionomics,
1978) (Medium)
Microcystis
aeruginosa (Blue-
Green Algae)"
>1000000 |ig/L
96-hour EC50
Population
(EG&G Bionomics,
1978) (Medium)
Scenedesmus
330 |ig/L
72-hour EC50
Population
(Carolina Ecotox,
Page 15 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
subspicatus (Green
algae)
1995b)(High)
Chlorella vulgaris
(Green Algae)
>2880 |ig/L
72-hour EC50
Population
(Carolina Ecotox, 1997)
(High)
11 Cyanobacterial species, not algae.
Bolded number indicates the values used to derive the algal Concentration of Concern (COC).
353
Page 16 of 41
-------
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
PUBLIC RELEASE DRAFT
December 2024
4 TERRESTRIAL SPECIES HAZARD
EPA assigned an overall quality level of high or medium to five acceptable studies containing hazard
data for seven different taxa. These studies contained relevant toxicity data for the Norway rat (Rattus
norvegicus), the chicken (Gallus gallus), the nematode (Caenorhabditis elegans), and four plant species
(Ipomoea aquatica, Trifolium repens, Sinapis alba, Brassica rapa).
Terrestrial Vertebrates
No reasonably available information was identified for exposures of BBP to wild mammalian
populations. In lieu of wild mammal studies, EPA reviewed nine studies on BBP hazard to laboratory
rodents that were designed to determine human health hazards of BBP that also contained ecologically
relevant reproductive endpoints (Table Apx B-l). Thus, EPA used data from laboratory rodent studies
as surrogates for the potential BBP hazards to wild mammal populations. EPA's decision to focus on
ecologically relevant (population level) reproductive endpoints in the rat and mouse data set for BBP for
consideration of a hazard threshold in terrestrial mammals is due to the sensitivity of these taxa to BBP
in eliciting phthalate syndrome (U.S. EPA, 2024b). Of the nine rat and mouse studies containing
ecologically relevant reproductive endpoints, EPA selected the study with the most sensitive LOAEL
(lowest observed adverse effect level) for evaluating data quality and for deriving the hazard threshold
for terrestrial mammals. The most sensitive reproductive endpoint was from a study that involved the
Sprague-Dawley strain of Norway rat (Rattus norvegicus) (TNO. 1993). with a 136-day LOAEL of 446
mg/kg-bw/day BBP and NOAEL (no observed adverse effect level) of 217 mg/kg-bw/day for reduced
pup weight. This study was assigned an overall quality determination of high. This study found
significantly decreased pup weights (males, females, and combined) on postnatal day (PND) 21 in the
second litter only (no effect in first litter) at 446 mg/kg-bw/day. Males were exposed for 10 weeks pre-
mating, during mating and until sacrifice on day 161. Exposure to F0 females was for 2 weeks pre-
mating, during mating (up to 3 weeks), gestation (~3 weeks) and lactation (~3 weeks) of litter FOa, for 7-
13 days after weaning (1-2 weeks), and during mating (up to 3 weeks), gestation (~3 weeks) and
lactation (~3 weeks) of litter FOb. The female premating mean dose was used for the NOAEL and
LOAEL because it is the lowest mean dose value for females across premating, gestation, and lactation.
One study of BBP effects on chicken (Gallus gallus) hens administered 5 g/kg bw/day BBP to birds on
days 1 to 3 and again on days 21 to 23 of a 42-day experiment (University of Arizona. 1978). Hens fed
this regime of BBP laid >90% fewer eggs over the course of 42 days compared to control hens. This
study exposed hens to BBP at only one dose; therefore, EC50s were not derived. Also, oral doses were
administered directly but by unknown methods and BBP doses were not analytically verified.
Table 4-1. Terresi
trial Vertebrate Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Norway rat
(Rattus
norvegicus)
217 mg/kg bw/d
NOAEL and 446 mg/kg
bw/d LOAEL
311 mg/kg bw/d
geometric mean of
NOAEL and LOAEL
136 days
Reduced pup
weight during
lactation;
increased pup
mortality at PND
2-4
(TNO. 1993)
(High)
Chicken (Gallus
gallus)
5 g/kg bw/d
BBP added to
diet on days 1 to
3 and days 21 to
23 of 42 day
Reproduction;
>90% fewer eggs
produced in one
treatment dose
(Universitv of
Arizona, 1978)
(Medium)
Page 17 of 41
-------
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
PUBLIC RELEASE DRAFT
December 2024
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
experiment
Terrestrial Invertebrates
EPA reviewed one medium quality study for BBP toxicity in a terrestrial invertebrate (Table 4-2). The
study exposed the soil nematode Caenorhabditis elegcms to water solutions of BBP. No nematode
mortality after 24-hours occurred up to and including 100,000 |ig/L BBP (Kwon et al.. 2011). Also, the
exposure concentration of 100,000 |ig/L is well above the limit of water solubility for BBP (2690 |ig/L
(U.S. EPA. 2024b)). indicating that these experimental conditions are unlikely to occur in ecosystems.
Table 4-2. Terrestrial Invertebrate Toxicity of BBP
Test Organism
Hazard Values
Duration
Endpoint
Citation
(Study Quality)
Nematode
{Caenorhabditis
elegans)
>100,000 |ig/L
NOEC
24-hour
Mortality
(Kwon et al.,
2011) (Medium)
Terrestrial Plants
EPA reviewed four high or medium quality studies for BBP toxicity in terrestrial plants (Table 4-3). A
study of Ipomoea aquatica (Swamp Morning glory) found a 50% reduction in plant biomass after 21-
day s of hydroponic water exposure to 100,000 |ig/L BBP (LOEC), but plant biomass was not affected
when exposed to 50,000 |ig/L BBP (Chen et al.. 2011). The exposure concentration of 100,000 |ig/L is
well above the limit of water solubility for BBP (2690 |ig/L (U.S. EPA. 2024b)). indicating that these
experimental conditions are unlikely to occur in ecosystems. One study exposed three plant species to
BBP vapor over 21-days. No BBP vapor-phase concentration affected plant growth to Trifolium repens
(Dutch Clover), Sinapis alba (White Mustard), Brassica rapa (Bird Rape) (Gorsuch et al.. 2008).
Table 4-3. Terrestrial Plant Toxicity of BBP
Test Organism
Hazard
Values
Duration
Endpoint
Citation
(Study Quality)
Ipomoea aquatica
(Swamp morning
glory)
50,000 |ig/L
NOEC and
100,000 |ig/L
LOEC
28-day
Growth
(Chen et al., 2011) (Hish)
Trifolium repens
(Dutch clover)
>5.7 |ig/m3
NOEL
21-day
Vapor-phase
toxicity
(Gorsuch et al., 2008)
(High)
Sinapis alba (White
mustard)
>5.7 |ig/m3
NOEL
21-day
Vapor-phase
toxicity
(Gorsuch et al., 2008)
(High)
Brassica rapa (Bird
rape,)
>5.7 |ig/m3
NOEL
21-day
Vapor-phase
toxicity
(Gorsuch et al., 2008)
(High)
Page 18 of 41
-------
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
PUBLIC RELEASE DRAFT
December 2024
5 ENVIRONMENTAL HAZARD THRESHOLDS
EPA calculates hazard thresholds to identify potential concerns to aquatic and terrestrial species. After
weighing the scientific evidence, EPA selects the appropriate toxicity value from the integrated data to
use for hazard thresholds. Table 5-1 summarizes the concentrations of concern (COCs) identified for
BBP. See Section 6 for more details about how EPA weighed the scientific evidence.
In aquatic species, EPA uses probabilistic approaches (e.g., SSD) when data from at least eight species
(Raimondo. 2010) are available and deterministic approaches (e.g., deriving a geometric mean of several
comparable values) when limited data are available. For BBP, an SSD was derived for acute aquatic
exposure hazards and a deterministic approach was used to assess chronic hazard in aquatic and
terrestrial taxa. For the deterministic approaches, COCs are calculated by dividing a hazard value by an
assessment factor (AF) according to EPA methods (U.S. EPA. 2016. 2013. 2012).
Equation 5-1
COC = toxicity value '¦ AF
For terrestrial species, EPA estimates hazard by calculating a toxicity reference value (TRV) or by
assigning the hazard threshold as the most sensitive and ecologically relevant reproductive endpoint in
the case of mammals, birds, and terrestrial plants.
5.1 Aquatic Species COCs
Acute Aquatic Concentration of Concern
For aquatic species, EPA uses probabilistic approaches (e.g., SSD) when data from at least eight species
(Raimondo. 2010) data are available. An SSD is a model of the variation in sensitivity of species to a
particular chemical stressor and is generated by fitting a statistical distribution function to the proportion
of species affected as a function of concentration or dose. It can be used to visualize which species are
most sensitive to a toxic chemical exposure, and to predict the concentration of a toxic chemical that is
hazardous to a percentage of test species. This hazardous concentration (HC) is represented as an HCp,
where p is the percent of species below the threshold. EPA used an HC05 (a hazardous concentration
threshold for 5% of species) to estimate a concentration that is protective of 95% of species. This HC05
can then be used to derive a COC, and the lower bound of the 95th percent confidence interval (CI) of
the HC05 can be used to account for uncertainty instead of dividing by an AF. EPA has more confidence
in the probabilistic approach compared to the deterministic approach when enough data are available
because an HC05 is representative of a larger proportion of species in the environment.
The aquatic acute COC for BBP was derived from an SSD that contained LC50s for five fish species
and six invertebrate species identified in systematic review, bolstered by an additional 18 predicted
LC50 values from the Web-ICE v4.0 toxicity value estimation tool. Web-ICE is a tool developed by
U.S. EPA's Office of Research and Development that estimates the acute toxicity of a chemical to a
species, genus, or family from the known toxicity of the chemical to a surrogate species. It was used to
obtain estimated acute toxicity values for BBP in species that were not represented in the empirical data
set. (Figure 5-1). SSDs were derived using EPA's SSD Toolbox (vl.l) (Etterson. 2020) and plotted
using R Statistical Software (v4.4.1) (R Core Team. 2019) using the ssdtools R package (vl.0.6) and the
ggplot2 R package (v3.5.1; Appendix A). All studies included in the SSD were rated high or medium
quality. The Maximum Likelihood method and a Weibull distribution model were used. The Weibull
distribution was based on an examination of Akaike's Information Criterion corrected for sample size
Page 19 of 41
-------
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
PUBLIC RELEASE DRAFT
December 2024
(aicc) for goodness of fit ( kirnham and Anderson. 2002). visual examination of Q-Q plots, and
evaluation of the line of best fit near the low-end of the SSD. The HC05 for this distribution was 327
|ig/L BBP with a 95% confidence interval of 197 ug/L to 552 |ig/L. After taking the lower 95th percent
confidence interval of this HC05 as an alternative to the use of assessment factors, the acute aquatic
COC for vertebrates and invertebrates was 197 jig/L BBP (Figure 5-1).
Species Sensitivity for BBP
100%
80° o
T3
a 60%'
to
<
in
11
o
-------
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
PUBLIC RELEASE DRAFT
December 2024
to 626 |ig/L (626 |ig/L) and applied an AF of 10, resulting in a COC = 62.6 jig/L BBP.
Aquatic Algae Concentration of Concern
Of the eight studies that investigated the effects of BBP on algae, EPA derived a COC based on the
lowest and most protective EC50 value which was 210 |ig/L for BBP hazard effects on the green algae
Raphidocelis subcapitata. EPA calculated a COC by applying an AF of 10, resulting in a COC = 21
ji«/L BBP.
5.2 Terrestrial Species Hazard Values
Terrestrial Mamnuil Hazard Threshold
Nine laboratory rat and mouse studies were assessed with the most sensitive and ecologically relevant
reproductive endpoint value chosen to represent the terrestrial mammalian hazard threshold. Phthalates
were filtered to identify those with reproductive effects as the most sensitive endpoints. The terrestrial
mammalian hazard threshold was derived from the most sensitive among acceptable-quality studies
involving the Sprague-Dawley strain of Norway rat (Rattus norvegicus) (TNO. 1993). with a 136-day
LOAEL of 446 mg/kg-bw/day BBP and NOAEL of 217 mg/kg-bw/day for reduced pup weight. EPA
calculated a geometric mean of the NOAEL and LOAEL from this study to equal the hazard threshold
of 311 mg/kg-bw/day BBP.
Avian Hazard Threshold
One study of BBP effects on chicken (Gallus gallus) hens administered 5 g/kg bw/day BBP to birds on
days 1 to 3 and again on days 21 to 23 of a 42-day experiment (University of Arizona. 1978). Hens fed
this regime of BBP laid >90% fewer eggs over the course of 42 days compared to control hens. This
study exposed BBP to hens at only one dose; therefore, EC50s via a dose-response experimental design
could not be derived. Also, oral doses were administered directly but by unknown methods. The
methods do not describe if or how BBP was added to food rations or any methods for analytically
verifying BBP doses. No other evidence of BBP toxicity to birds was reasonably available to consider
for a hazard threshold. EPA did not derive an avian hazard threshold due to these uncertainties in
experimental design and analysis from the one available study.
Terrestrial Invertebrate Hazard Threshold
EPA reviewed one medium quality study for BBP toxicity in a terrestrial invertebrate (Table 4-2). The
study exposed the soil nematode Ccienorhcibditis elegcms to water solutions of BBP. No nematode
mortality after 24 hours occurred up to and including 100,000 |ig/L BBP (Kwon et al.. 2011). No other
evidence of BBP toxicity to terrestrial invertebrates was reasonably available to consider for a hazard
threshold. Thus, EPA did not derive a terrestrial invertebrate hazard threshold.
Terrestrial Plants Hazard Threshold
EPA reviewed four high or medium quality studies for BBP toxicity in terrestrial plants (Table 4-3). A
study of Ipomoea aquatica (Swamp Morning glory) found a 50% reduction in plant biomass after 21
days of hydroponic exposure to 100,000 |ig/L BBP (LOEC), but plant biomass was not affected when
exposed to 50000 |ig/L BBP (Chen et al.. 2011). This study exposed plants to water well above the BBP
limit of water solubility (2690 |ig/L) in a hydroponic scenario. Other available studies exposed plants to
BBP fumigant and found no hazard effects up to and including the highest concentrations of exposure.
No other evidence of BBP toxicity to terrestrial plants in soil was reasonably available to consider for a
hazard threshold. Thus, EPA did not derive a terrestrial plant hazard threshold.
Page 21 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
534
535 Table 5-1. Environmental Hazard Thresholds for BBP
Receptor Group
Exposure
Duration
Hazard Threshold (COC
or HV)
Citation
Aquatic Vertebrates
Acute
197 |ig/L
From SSD
Chronic
1.9 |ig/L
(Battelle, 2018c)
Aquatic Invertebrates
Acute
197 |ig/L
From SSD
Chronic
62.6 |ig/L
(Rhodes et al.. 1995)
Aquatic Plants and Algae
Chronic
21 |ig/L
(Adams et al., 1995)
Terrestrial Vertebrates
Chronic
311 mg/kg/day
(TNO. 1993)
536
Page 22 of 41
-------
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
PUBLIC RELEASE DRAFT
December 2024
6 WEIGHT OF THE SCIENTIFIC EVIDENCE CONCLUSIONS FOR
ENVIRONMENTAL HAZARD
EPA uses several considerations when weighing and weighting the scientific evidence to determine
confidence in the environmental hazard data. These considerations include the quality of the database,
consistency, strength and precision, biological gradient/dose response, and relevance. This approach is
described in the Draft Systematic Review Protocol Supporting TSCA Risk Evaluations for Chemical
Substances (U.S. EPA. 2021). Table 6-1 summarizes how these considerations were determined for each
environmental hazard threshold. Criteria for assessing confidence is described in Appendix C Evidence
Integration.
EPA determined that BBP poses hazards from acute and chronic exposures to aquatic vertebrates, acute
and chronic exposures to aquatic invertebrates, chronic exposure to algae, and chronic dietary exposure
to terrestrial mammals. EPA has robust confidence in the weight of evidence in these findings.
6.1 Strengths, Limitations, Assumptions, and Key Sources of Uncertainty
for Environmental Hazard
The weight of evidence suggests that BBP poses acute hazard effects to vertebrate and invertebrate
animals at 197 jug/L BBP. EPA has robust confidence in this hazard threshold because the quality of the
database of studies included 11 high or medium quality studies that consistently resulted in LC50s
between 460 |ig/L (Lake Superior Research Institute. 1997) up to 2650 |ig/L BBP (Liu et al.. 2009).
These studies all were conducted with reasonable dose-response designs and results, which enabled
precise LC50 calculations (Table 3-1 and Table 3-3). These hazard effects were documented across a
range of species that live in freshwater and marine environments in the water column as well as in or
near the benthos/sediment. Additional consideration of acute (24-hour) larval fish transcriptomics,
metabolomics, and behavior data revealed within-organism effects occurring in the same order of
magnitude (ranging from 60 |ig/L to 120 |ig/L BBP), consistent with the hypothesis that hazard occurs
at similar exposures. EPA used a probabilistic technique (SSD) to derive a COC that is protective of
95% of the aquatic animals in a community by incorporating hazard values across species and habitats.
Limitations of SSDs include its reliance on model species that may not exist or interact in the same
ecological community and are weighted equally. Another assumption that may limit the scope of SSD
inference is whether the number of species used is adequate. The shape of the data distribution that is
fitted to the effects data can be subjective and dependent on the three or four lowest values (Newman et
al.. 2000). Notwithstanding the limitations of SSD analyses, this method is widely used and accepted in
risk assessments. Thus, EPA has robust confidence in the quality, consistency, strength and precision,
and relevance of the studies used in determining the acute aquatic COC (197 jug/L BBP).
The weight of evidence suggests that BBP poses chronic hazard effects to vertebrate animals at 1.9 jug/L
BBP. EPA has robust confidence in the hazard threshold for four reasons. First, the reasonably available
database of studies used for this determination includes eight high or medium quality studies to
determine growth or reproduction effects using standard methods. Second, these studies were conducted
on a range of different species including zebrafish (Danio rerio), fathead minnow (Pimephales
promelas), and Japanese medaka (Oryzias latipes) (Table 3-2). Third, these studies found consistent
effects within the same order of magnitude of BBP concentrations. Finally, all of these studies were
conducted with reasonable dose-response designs and results, which enabled precise estimations of
effect concentrations. Thus, EPA has robust confidence in the quality, consistency, strength and
precision, and relevance of the studies used in determining the chronic aquatic COC for vertebrates (1.9
ji«/L BBP).
Page 23 of 41
-------
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
PUBLIC RELEASE DRAFT
December 2024
The weight of evidence suggests that BBP poses chronic hazard effects to invertebrate animals at 62.6
ji«/L BBP. EPA has robust confidence in the hazard threshold for four reasons. First, the reasonably
available database of studies used for this determination includes six high or medium quality studies to
determine growth or reproduction effects using standard methods. Second, these studies were conducted
on a range of different species including rotifers (Brachionus calyciflorus), water fleas {Daphnia
magna), opossum shrimps (Americamysis bahia), oligochaete worms (Lumbricuius variegatus), and
midges (Chironomus tentans), representing three different phyla (Table 3-4). Third, these studies found
consistent effects within the same order of magnitude of BBP concentrations. Finally, all of these studies
were conducted with reasonable dose-response designs and results, which enabled precise estimations of
effect concentrations. Thus, EPA has robust confidence in the quality, consistency, strength and
precision, and relevance of the studies used in determining the chronic aquatic COC for invertebrates
(62.6 jig/L BBP)
The weight of evidence suggests that BBP poses chronic hazard effects to algae at 21 jug/L BBP. EPA
has robust confidence in the hazard threshold for four reasons. First, the reasonably available database of
studies used for this determination includes eight high or medium quality studies to determine
population growth effects of BBP using standard methods. Second, these studies were conducted on a
range of different species including green algae (Raphidocelis subcapitata, Dunaliella tertiolecta,
Scenedesmus subspicatus, and Chlorella vulgaris) and diatoms (Naviculapellicidosa and Skeletonema
costatum) representing two different phyla (Table 3-5). Third, these studies found consistent effects
within the same order of magnitude of BBP concentrations. Finally, all of these studies were conducted
with reasonable dose-response designs and results, which enabled precise estimations of effect
concentrations. Thus, EPA has robust confidence in the quality, consistency, strength and precision, and
relevance of the studies used in determining the chronic aquatic COC for algae (21 jug/L BBP).
No studies on terrestrial wildlife involving mammals were identified. In lieu of terrestrial wildlife
studies, nine references for rat studies as human health model organisms were used to determine a
lowest and most conservative BBP concentration that affected apical endpoints (survival, reproduction,
growth) in rodents and that could serve as an indication of hazard effects in wild mammal populations.
The weight of evidence suggests that BBP poses chronic dietary exposure hazard effects to terrestrial
mammals at 311 mg/kg bw/day BBP. EPA has robust confidence in this hazard threshold for three
reasons (Table 6-1). First, the reasonably available database of studies used for this determination
include nine high or medium quality studies to determine reproductive effects of BBP using standard
methods. The terrestrial mammalian hazard threshold was derived from the most sensitive among
acceptable-quality studies involving the Sprague-Dawley rat (Rattus norvegicus) (TNO. 1993). with a
136-day LOAEL of 446 mg/kg-bw/day BBP and NOAEL of 217 mg/kg-bw/day for reduced pup weight.
Second, these nine studies found consistent effects within the same order of magnitude of BBP doses.
Finally, all of the studies were conducted with reasonable dose-response designs and results, which
enabled precise estimation of effect concentrations. However, ecologically relevant population level
effects were not observed in ecologically relevant species. Considerable uncertainties surround whether
or how these effects on individual growth and reproductive development translate into effects on wild
mammal fitness and population parameters. Because of these uncertainties of extrapolations to wildlife
mammal species, EPA has moderate confidence that the hazards are representative of the range of wild
mammal species. Therefore, EPA has robust confidence in the quality, consistency, and strength and
precision, of the studies used in determining the hazard threshold for terrestrial mammals (311 mg/kg
bw/day BBP), but moderate confidence in their relevance to wild mammal populations.
EPA has less confidence in the use of one avian study (University of Arizona. 1978). one terrestrial
Page 24 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
632 invertebrate study (Kwon et al.. 2011). and one terrestrial plant study (Chen et al.. 2011) to derive
633 hazard thresholds for these groups for many reasons. First, as only one study is available for each taxa,
634 consistency across studies is unknown. Second, each study has at least one limitation in study design or
635 analysis that limits the precision, biological gradient/dose response, and/or relevance of their results. For
636 example, the study of C. elegans worms and the study of plant Ipomoeci aquatica (Swamp Morning
637 glory) exposed organisms to concentrations (100000 |ig/L in both cases) well above the limit of
638 solubility of BBP (2690 |ig/L). The study of BBP effects on chicken egg production had limited
639 descriptions of the methods and of dose administration and analytical verification (University of
640 Arizona. 1978). Therefore, EPA has slight confidence in the quality, consistency, strength and precision,
641 and relevance of these studies and did not derive hazard thresholds for these organisms.
Page 25 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
Table 6-1. BBP Evidence Table Summarizing the Overall Confidence Derived from Hazard Thresholds
Types of Evidence
Quality of
the Database
. ^ Strength and
Consistency L
Precision
Biological
Gradient/Dose-
Response
Relevance
Hazard
Confidence
Aquatic
Acute aquatic assessment
+++
+++
+++
+++
+++
Robust
Chronic aquatic assessment
+++
+++
+++
+++
+++
Robust
Algal assessment
+++
+++
+++
+++
+++
Robust
Terrestrial
Chronic mammalian assessment
+++
+++
+++
+++
++
Robust
Chronic avian assessment
+
+
++
Slight
Terrestrial invertebrate assessment
+
+
++
Slight
Terrestrial plant assessment
+
+
++
Slight
3 Relevance includes biological, physical/chemical, and environmental relevance.
+++ Robust confidence suggests thorough understanding of the scientific evidence and uncertainties. The supporting weight of scientific evidence
outweighs the uncertainties to the point where it is unlikely that the uncertainties could have a significant effect on the hazard estimate.
++ Moderate confidence suggests some understanding of the scientific evidence and uncertainties. The supporting scientific evidence weighed against
the uncertainties is reasonably adequate to characterize hazard estimates.
+ Slight confidence is assigned when the weight of scientific evidence may not be adequate to characterize the scenario, and when the assessor is
making the best scientific assessment possible in the absence of complete information. There are additional uncertainties that may need to be considered.
-------
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
PUBLIC RELEASE DRAFT
December 2024
7 ENVIRONMENTAL HAZARD ASSESSMENT CONCLUSIONS
EPA considered the quality, consistency, strength and precision, biological gradient/dose response, and
relevance of the reasonably available data to weigh the scientific evidence in determining the
environmental hazards of BBP. EPA determined that BBP poses acute and chronic exposure hazards to
aquatic vertebrates, acute and chronic exposure hazards to aquatic invertebrates, chronic exposure
hazards to algae, and chronic dietary exposure hazards to terrestrial mammals. BBP hazards include:
Aquatic species
LC50 values from 11 acute duration exposures of BBP to aquatic fish and invertebrates were
used to develop an SSD. The lower 95% confidence value of the HC05 was used as the COC at
197 |ig/L BBP.
The most sensitive aquatic vertebrate for which a clear population4evel fitness endpoint could be
obtained was for the zebrafish (Danio rerio). This 21-day reproduction test of BBP exposure to
IX rerio found 3% lower fecundity, 2% lower fertilization success, 100% increase in plasma
vitellogenin, and reduced gonad weight in males in treatments with 33 |ig/L BBP (LOEC). No
effects were observed at 11 |ig/L BBP (NOEC). Based on the presence of a clear dose-response
relationship and a population-level fitness endpoint, the 21-day ChV for reduction in
reproduction was selected to derive the chronic COC for aquatic vertebrates as 1.9 |ig/L BBP.
A 21-day study of Daphnia magna found 80% mortality and 70% fewer offspring per female due
to BBP chronic exposure, leading to a COC of 62.6 |ig/L BBP for chronic invertebrate hazard.
EPA derived a COC for chronic algal BBP exposure from the EC50 value of 210 |ig/L to the
green algae Raphidocelis sabcapitata resulting in a COC of 21 |ig/L BBP.
Terrestrial Species
The terrestrial mammalian hazard threshold was derived from the most sensitive among
acceptable-quality studies involving the Sprague-Dawley rat (Rattus norvegicus) with a 136-day
dietary exposure hazard threshold of 311 mg/kg-bw/day BBP.
No evidence of BBP toxicity to terrestrial invertebrates was reasonably available to consider for
a hazard threshold. Thus, EPA did not derive a terrestrial invertebrate hazard threshold.
No evidence of BBP toxicity to terrestrial plants in soil was reasonably available to consider for
a hazard threshold. Thus, EPA did not derive a terrestrial plant hazard threshold.
-------
707
708
709
710
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
PUBLIC RELEASE DRAFT
December 2024
REFERENCES
ABC Laboratories. (1986a). Final report of the flow-through acute toxicity of butyl benzyl phthalate to
hydra littoralis [TSCA Submission], (EPA/OTS Doc #40-8626215). St. Louis, MO: Monsanto.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0510534.xhtml
ABC Laboratories. (1986b). Flow-through acute toxicity report - 96 hr flow-through toxicity study of
benzyl butyl phthalate to the freshwater crayfish, procambarus sp (final report) w-attach and
letter 072888. (EPA/OTS Doc #40-8626254). St. Louis, MO: Monsanto Company.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0522398.xhtml
ABC Laboratories. (1986c). Flow-through Acute Toxicity Study of Benzyl Butyl Phthalate to the
Mayfly, Hexagenia Sp. with Attached Protocol and Cover Letter dated 092586 [TSCA
Submission], (EPA/OTS Doc #40-8626257). Monsanto Co.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0522401.xhtml
ABC Laboratories. (2008). Determination of the effect of butyl benzyl phthalate (BBP) on the
development, growth and reproduction of the fathead minnow (Pimephales promelas). (ABC
Study No. 50003). Brussels, Belgium: CEFIC - European Council for Plasticisers &
Intermediates.
Adams. WJ: Biddinger. GR; Robillard. KA; Gorsuch. JW. (1995). A summary of the acute toxicity of 14
phthalate esters to representative aquatic organisms. Environ Toxicol Chem 14: 1569-1574.
http://dx.doi.org/10.1002/etc.562014Q916
Battelle. (2018a). 21-d Amphibian Metamorphosis Assay (AMA) of benzyl butyl phthalate with African
clawed frog, Xenopus laevis. (BATTO1-00387). Washington, DC: U.S. Environmental
Protection Agency.
Battelle. (2018b). Fish short-term reproduction assay of benzyl butyl phthalate with Japanese medaka.
(BATTO 1-00406). Washington, DC: U.S. Environmental Protection Agency.
Battelle. (2018c). Fish short-term reproduction assay of benzyl butyl phthalate with zebrafish.
(BATTO 1-00407). Washington, DC: U.S. Environmental Protection Agency.
Bencic. DC: Flick. RW: Bell. ME: Henderson. WM; Huang. W: Purucker. ST: Glinski. DA: Blackwell.
BR: Christen. CH; Stacy. EH: Biales. AD. (2024). A multiomics study following acute exposures
to phthalates in larval fathead minnows (Pimephales promelas) - The potential application of
omics data in risk evaluations under TSCA (internal use only). (EPA/600/X-24/098). Cincinnati,
OH: U.S. Environmental Protection Agency.
Burnham. KP; Anderson. DR. (2002). Model selection and multimodel inference: a practical
information-theoretic approach (2nd ed.). New York: Springer.
http://www.springer.com/statistics/statistical+theory+and+methods/book/978-0-387-95364-9
Call. DJ: Cox. DA: Geiger. PL: Genisot. KI; Markee. TP: Brooke. LT; Polkinghorne. CN: Vandeventer.
FA: Gorsuch. JW: Robillard. KA: Parkerton. TF; Reilev. MC: Anklev. GT; Mount. DR. (2001a).
An assessment of the toxicity of phthalate esters to freshwater benthos. 2. Sediment exposures.
Environ Toxicol Chem 20: 1805-1815. http://dx.doi.org/10.1002/etc.562020Q826
Call. DJ: Markee. TP: Geiger. PL: Brooke. LT: Vandeventer. FA: Cox. DA: Genisot. KI; Robillard.
KA; Gorsuch. JW; Parkerton. TF; Reilev. MC; Anklev. GT; Mount. DR. (2001b). An assessment
of the toxicity of phthalate esters to freshwater benthos. 1. Aqueous exposures. Environ Toxicol
Chem 20: 1798-1804. http://dx.doi.org/10.1002/etc.562020Q825
Carolina Ecotox. (1995a). [Redacted] The toxicity of butyl benzyl phthalate (Santicizer 160) to Navicula
pelliculosa. (14-01-1). St. Louis, MO: Monsanto Company.
Carolina Ecotox. (1995b). The toxicity of butyl benzyl phthalate (Santicizer 160) to Scenedesmus
subspicatus. (14-01-2). St. Louis, MO: Monsanto Company.
Carolina Ecotox. (1997). Effect of butyl benzyl phthalate (Santicizer 160) on the growth and
reproduction of Chlorella vulgaris. (14-06-1). St. Louis, MO: Monsanto Company.
Page 28 of 41
-------
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
PUBLIC RELEASE DRAFT
December 2024
Chen. WC; Huang. HC; Wang. YS; Yen. JH. (2011). Effect of benzyl butyl phthalate on physiology and
proteome characterization of water celery (Ipomoea aquatica Forsk.). Ecotoxicol Environ Saf 74:
1325-1330. http://dx.doi.org/10.1016/i.ecoenv.2011.03.009
Chen. X: Xu. S: Tan. T: Lee. ST: Cheng. SH: Lee. FWF: Xu. SJL; Ho. KC. (2014). Toxicity and
estrogenic endocrine disrupting activity of phthalates and their mixtures. Int J Environ Res
Public Health 11: 3156-3168. http://dx.doi.org/10.3390/iierphl 10303156
Cruciani. V: Iovine. C: Thome. JP; Joaquim-Justo. C. (2015). Impact of three phthalate esters on the
sexual reproduction of the Monogonont rotifer, Brachionus calyciflorus. Ecotoxicology 25: 192-
200. http://dx.doi.org/10.1007/slQ646-015-1579-5
EC. (2000). Butylbenzylphthalate. (En 40-215/44E). Gatineau, Canada: Minister of Public Works and
Government Services, http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psl2-
1 sp2/butvlb enzylphthal ate/index-eng. php
ECJRC. (2007). European Union Risk Assessment Report: Benzyl butyl phthalate (CAS No: 85-68-7,
EINECS: 201-622-7). (EUR 22773 EN). Luxembourg: European Commission.
https://echa.europa.eu/documents/10162/bad5c928-93a5-4592-a4f6-e02c5e89c299
EG&G Bionomics. (1978). Initial submission: acute toxicity of benzyl butyl phthalate to freshwater and
marine algae with cover letter dated 08/14/92 [TSCA Submission], (EPA/OTS Doc #88-
920008595). St. Louis, MO: Monsanto Co.
EG&G Bionomics. (1979a). Acute toxicity of S-160 to sheepshead minnows (Cyprinodon variegatus).
(BP-79-4-39). St. Louis, MO: Monsanto Company.
EG&G Bionomics. (1979b). Acute toxicity study with santicizer 160 in mysid shrimp (Mysidopsis
bahia) with cover letter dated 100692 and attachment [TSCA Submission], (EPA/OTS Doc #86-
930000013). St. Louis: Monsanto Company.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0544350.xhtml
EG&G Bionomics. (1979c). [Sanitized] Acute toxicity of S-160 to Bluegill (Lepomis macrochirus).
(BW-79-3-408). St. Louis, MO: Monsanto Company.
EG&G Bionomics. (1979d). [Sanitized] Acute toxicity of S-160 to Fathead minnow (Pimephales
promalas). (BW-79-3-409). St. Louis, MO: Monsanto Company.
EG&G Bionomics. (1979e). [Sanitized] The chronic toxicity of Santicizer 160 (BN-78-1384327-1) to
the water flea (Daphnia magna). (BW-79-2-404). St. Louis, MO.
EG&G Bionomics. (1983). Acute toxicity of fourteen phthalate esters to rainbow trout (Salmo gairdneri)
under flow-through conditions (final report) report no BW-83-3-1373 [TSCA Submission],
(Bionomics Report No. BW-83-3-1373. OTS0508403. 42005 B4-5. 40-8326144.
TSCATS/206776). Washington, DC: Chemical Manufacturers Association.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS05084Q3.xhtml
EG&G Bionomics. (1984). Acute toxicity of twelve phthalate esters to mysid shrimp (Mysidopsis bahia)
[TSCA Submission], (EPA/OTS Doc #40-8426078). Washington, DC: Chemical Manufacturers
Association. https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0508405.xhtml
Ema. M; Itami. T; Kawasaki. H. (1992). Teratogenic evaluation of butyl benzyl phthalate in rats by
gastric intubation. Toxicol Lett 61: 1-7. http://dx.doi.org/10.1016/0378-4274(92)90057-0
Ema. M; Miyawaki. E. (2002). Effects on development of the reproductive system in male offspring of
rats given butyl benzyl phthalate during late pregnancy. Reprod Toxicol 16: 71-76.
http ://dx.doi .org/10.1016/S0890-623 8(01 )00200-3
EnviroSystem. (1991). Early life-stage toxicity of di-n-butyl phthalate (DnBP) to the rainbow trout
(Oncorhynchus mykiss) under flow-through conditions [TSCA Submission], (9102-CMA.
OTS0533141. 42005 L5-5. 40-9126399). Washington, DC: Chemical Manufacturers
Association. https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTSQ533141.xhtml
Etterson. M. (2020). Species Sensitivity Distribution (SSD) Toolbox. Duluth, MN: U.S. Environmental
Protection Agency. Retrieved from https://www.epa.gov/sciencematters/species-sensitivitv-
Page 29 of 41
-------
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
PUBLIC RELEASE DRAFT
December 2024
distribution-toolbox-new-tool-identifv-and-protect-vulnerable
Gorsuch. JW; Staples. CA; Brown. D; Enste-Diefenbach. R. (2008). Vapor-phase toxicity of butylbenzyl
phthalate to three plant species: white mustard, Chinese cabbage, and white clover. Bull Environ
Contam Toxicol 81: 220-224. http://dx.doi.org/10.1007/sQ0128-008-9449-v
Hazelton Labs. (1985). Twenty-six week subchronic study and modified mating trial in F344 rats: Butyl
benzyl phthalate. Final report. (Project No. 12307-02-03). National Toxicology Program.
Jarmolowicz. S: Demska-Zakes. K; Zakes. Z. (2014). Impact of butyl benzyl phthalate on development
of the reproductive system of European pikeperch, Sander lucioperca (L.). Acta Vet Hung 62:
397-407. http://dx.doi.org/10.1556/AVet.2014.008
Kaplan. LAE; Nabel. M; Van Cleef-Toedt. K; Proffitt. AR; Pylypiw. HM. Jr. (2013). Impact of benzyl
butyl phthalate on shoaling behavior in Fundulus heteroclitus (mummichog) populations. Mar
Environ Res 86: 70-75. http://dx.doi.Org/10.1016/i.marenvres.2013.02.014
Kwon. HC: Roh. JY; Lim. D; Choi. J: Kwon. JH. (2011). Maintaining the constant exposure condition
for an acute caenorhabditis elegans mortality test using passive dosing. Environmental Health
and Toxicology 26: e2011015. http://dx.doi.org/10.5620/eht.2011.26.e2011015
Lake Superior Research Institute. (1997). Sediment toxicity testing program for phthalate esters.
(Unpublished Report PE-88.0-SED-WIS). Arlington, VA: Chemical Manufacturers Association.
Linden. E; Bengtsson. BE: Svanberg. O; Sundstrom. G. (1979). The acute toxicity of 78 chemicals and
pesticide formulations against two brackish water organisms, the bleak (Alburnus alburnus) and
the harpacticoid Nitocra spinipes. Chemosphere 8: 843-851. http://dx.doi.org/10.1016/0Q45-
6535(79)90015-8
Liu. Y; Guan. Y; Yang. Z; Cai. Z; Mizuno. T; Tsuno. H; Zhu. W: Zhang. X. (2009). Toxicity of seven
phthalate esters to embryonic development of the abalone Haliotis diversicolor supertexta.
Ecotoxicology 18: 293-303. http://dx.doi.org/10.1007/sl0646-008-Q283-0
Monsanto. (1982). Acute toxicity of santicizer 160 to Chironomus tentans [TSCA Submission], (ES-82-
SS-79. 43-000-760.27-4382444. OTS0206416. 878213591. TSCATS/020550). Monsanto Co.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0206416.xhtml
Monsanto. (1983a). Acute toxicity of santicizer 160 to the midge paratanytarsus parthenogenetica with
cover letter [TSCA Submission], (EPA/OTS Doc #878213576).
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/QTS0206416.xhtml
Monsanto. (1983b). Chronic toxicity of santicizer 160 to daphnia magna: 21-day chronic renewal study
[TSCA Submission], (EPA/OTS Doc #878213583).
Monsanto. (1983c). Santicizer 160 (S-160) natural water die-away toxicity test with Daphnia magna
[TSCA Submission], (EPA/OTS Doc #878213611).
Newman. MC: Ownbv. PR: Mezin. LCA; Powell. DC: Christensen. TRL; Lerberg. SB: Anderson. BA.
(2000). Applying species-sensitivity distributions in ecological risk assessment: Assumptions of
distribution type and sufficient numbers of species. Environ Toxicol Chem 19: 508-515.
Nikonorow. M; Mazur. H; Piekacz. H. (1973). Effect of orally administered plasticizers and polyvinyl
chloride stabilizers in the rat. Toxicol Appl Pharmacol 26: 253-259.
http://dx.doi.org/10.1016/0041-008X(73)90259-7
NTP. (1990). Final report on the developmental toxicity of butyl benzyl phthalate (CAS no. 85-68-7) in
CD-I-Swiss mice [NTP], (NTP Report #90-114). Research Triangle Park, NC: National
Toxicology Program, National Institute of Environmental Health Sciences.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/PB91129999.xhtml
Ozretich. RJ; Randall. RC: Boese. BL; Schroeder. WP; Smith. JR. (1983). Acute toxicity of butylbenzyl
phthalate to Shiner perch (Cymatogaster aggregata). Arch Environ Contam Toxicol 12: 655-660.
http://dx.doi.org/10.1007/bf0106Q747
Piersma. AH: Verhoef. A: Dortant. PM. (1995). Evaluation of the OECD 421 reproductive toxicity
screening test protocol using butyl benzyl phthalate. Toxicology 99: 191-197.
Page 30 of 41
-------
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
897
898
899
900
901
PUBLIC RELEASE DRAFT
December 2024
http://dx.doi.org/10.1016/0300-483X(95K)3029-F
R Core Team. (2019). R: A language and environment for statistical computing. Vienna, Austria: R
Foundation for Statistical Computing. https://www.R-proiect.org/
Raimondo. S. .. D...N. Vivian. andM.G. Barron. (2010). Web-Based Interspecies Correlation Estimation
(Web-ICE) for Acute Toxicity: User Manual Version 3.1. (600R10004). Raimondo, S., D.N.
Vivian, and M.G. Barron. http://nepis.epa.gov/exe/ZvPURL.cgi?Dockev=P10068ND.txt
Rhodes. JE; Adams. WJ: Biddinger. GR; Robillard. KA; Gorsuch. JW. (1995). Chronic toxicity of 14
phthalate esters to Daphnia magna and rainbow trout (Oncorhynchus mykiss). Environ Toxicol
Chem 14: 1967-1976. http://dx.doi.org/10.1002/etc.5620141119
RTI International. (1989). Developmental toxicity evaluation of butyl benzyl phthalate (CAS No. 85-68-
7) administered in feed to CD rats on gestational days 6 to 15 (pp. 500). (NTP-89-246). Research
Triangle Park, NC: National Toxicology Program.
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchQuery=PB90115346
Springborn Bionomics. (1984). Acute toxicity of fourteen phthalate esters to Daphnia magna (final
report) [TSCA Submission], (Report No. BW-84-4-1567. OTS0508408. 42005 B4-10. 40-
8426150. TSCATS/206781). Washington, DC: Chemical Manufacturers Association.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS05084Q8.xhtml
Springborn Bionomics. (1986a). Acute toxicity of butylbenzyl phthalate to pink shrimp (Penaeus
duorarum) under flow-through conditions [TSCA Submission], (EPA/OTS Doc #40-8626236).
Monsanto Co.
Springborn Bionomics. (1986b). Acute toxicity of butylbenzyl phthalate to polychaetes
(Nereis/Neanthes virens) under flow-through conditions [Bionomics Report #BW-86-7-2094]
[TSCA Submission], In Four acute toxicity studies, one chronic toxicity study and an uptake on
an elimination study with 14C-benzyl butyl phthalate with attachments and cover letter dated
091586. (252.1085.6114.522. BW-86-7-2094. OTS0522399. 40-8626256. 42005 B5-7.
TSCA/406078). Monsanto Co.
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchQuery=OTS0522399
Springborn Bionomics. (1986c). Chronic toxicity of butylbenzyl phthalate to mysid shrimp (Mysidopsis
bahia) [Bionomics Report #BW-86-7-2074] [TSCA Submission], In Four acute toxicity studies,
one chronic toxicity study and an uptake on an elimination study with 14C-benzyl butyl
phthalate with attachments and cover letter dated 091586. (252-1085-6113-530. BW-86-7-2074.
OTS0522399. 40-8626256. 42005 B5-7. TSCA/406078). St. Louis, MO: Monsanto Co.
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchOuerv=OTSQ522399
Springborn Bionomics. (1986d). Six acute and chronic toxicity reports regarding butylbenzyl phthalate.
(40-8626222). St. Louis, MO: Monsanto Chemical Co.
Springborn Bionomics. (1988). Acute toxicity of benzyl butyl phthalate to mysid shrimp (Mysidopsis
bahia) under flow-through conditions with cover letter dated 011888 [TSCA Submission],
(252.0687.6118.510/SLS# 87-10-2525. OTS0522497. 40-8826335. 42005 I2B-2.
TSCATS/406178). Monsanto Company.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0522497.xhtml
SRI International. (1984). Acute toxicity studies on S-160 using two midge species as the test organisms
[TSCA Submission], (EPA/OTS Doc #878213936). St. Louis, MO: Monsanto.
Streufort. JM. (1978). Some effects of two phthalic acid esters on the life cycle of the midge
(Chironomus plumosus) [TSCA Submission], (OTS0000013-0. FYI-AX-1178-0013.
TSC ATS/029296). Washington, DC: Manufacturing Chemists Association.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0000013Q.xhtml
TNO. (1993). Dietary one-generation reproduction study with butyl benzyl phthalate in rats with cover
letter dated 040793 [TSCA Submission], (EPA/OTS Doc #86-930000189). St. Louis, MO:
Monsanto Co.
Page 31 of 41
-------
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
PUBLIC RELEASE DRAFT
December 2024
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchOuerv=OTSQ538169
TNO. (1998). [Redacted] Oral developmental reproduction study with butyl benzyl phthalate in Wistar
rats. (V98.408 final). European Council for Plasticizers and Intermediates.
U.S. EPA. (1998). Guidelines for ecological risk assessment [EPA Report], (EPA/630/R-95/002F).
Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum.
https://www.epa.gov/risk/guidelines-ecological-risk-assessment
U.S. EPA. (2005). Guidelines for carcinogen risk assessment [EPA Report], (EPA630P03001F).
Washington, DC. https://www.epa.gov/sites/production/files/2013-
09/documents/cancer guidelines final 3-25-05.pdf
U.S. EPA. (2012). Sustainable futures: P2 framework manual [EPA Report], (EPA/748/B-12/001).
Washington DC. http://www.epa.gov/sustainable-futures/sustainable-futures-p2-framework-
manual
U.S. EPA. (2013). Interpretive assistance document for assessment of discrete organic chemicals.
Sustainable futures summary assessment [EPA Report], Washington, DC.
http://www.epa.gov/sites/production/files/2015-05/documents/05-iad discretes iune2013.pdf
U.S. EPA. (2016). Weight of evidence in ecological assessment [EPA Report], (EPA/100/R-16/001).
Washington, DC: Office of the Science Advisor.
https://nepis.epa. gov/Exe/ZvPURL.cgi?Dockev=P100SFXR.txt
U.S. EPA. (2020). Final scope of the risk evaluation for butyl benzyl phthalate (1,2-benzenedicarboxylic
acid, 1-butyl 2-(phenylmethyl) ester); CASRN 85-68-7 [EPA Report], (EPA-740-R-20-015).
Washington, DC: Office of Chemical Safety and Pollution Prevention.
https://www.epa.gov/sites/default/files/2020-09/documents/casrn 85-68-
7 butyl benzyl phthalate finalscope.pdf
U.S. EPA. (2021). Draft systematic review protocol supporting TSCA risk evaluations for chemical
substances, Version 1.0: A generic TSCA systematic review protocol with chemical-specific
methodologies. (EPA Document #EPA-D-20-031). Washington, DC: Office of Chemical Safety
and Pollution Prevention. https://www.regulations.gov/document/EPA-HQ-OPPT-2021-0414-
0005
U.S. EPA. (2024a). Draft Physical Chemistry and Fate and Transport Assessment for Butyl Benzyl
Phthalate (BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024b). Draft Physical Chemistry Assessment for Butyl benzyl phthalate (BBP).
Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024c). Draft Systematic Protocol for Butyl Benzyl Phthalate (BBP). Washington, DC:
Office of Pollution Prevention and Toxics.
U.S. EPA. (2025). Draft Risk Evaluation for Butyl Benzyl Phthalate (BBP). Washington, DC: Office of
Pollution Prevention and Toxics.
University of Arizona. (1978). Initial submission: Evaluation of butyl benzyl phthalate with laying hens
with cover letter dated 080792 [TSCA Submission], (EPA/OTS Doc #88-920007247). St. Louis,
MO: Monsanto Co.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0545565.xhtml
Wang. JX; Xi. YL; Flu. K; Liu. XB. (2011). Effect of butyl benzyl phthalate on life table-demography of
two successive generations of cladoceran Moina macrocopa Straus. J Environ Biol 32: 17-22.
Wolf. C: Lambright. C: Mann. P; Price. M; Cooper. RL; Ostbv. J: Gray. LE. Jr. (1999). Administration
of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-
DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169,
and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of
reproductive malformations in the male rat. Toxicol Ind Health 15: 94-118.
http://dx.doi.org/10.1177/0748233799015001Q9
Zhao. LL; Xi. YL: Huang. L; Zha. CW. (2009). Effects of three phthalate esters on the life-table
Page 32 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
951 demography of freshwater rotifer Brachionus calyciflorus Pallas. Aquatic Ecology 43: 395-402.
952 http://dx.doi.org/10.1007/slQ452-008-9179-6
953
954
Page 33 of 41
-------
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977
978
979
980
981
982
983
984
985
PUBLIC RELEASE DRAFT
December 2024
Appendix A SPECIES SENSITIVITY DISTRIBUTION
An SSD was derived using only acute duration exposure studies that calculated LC50s. The SSD
Toolbox is a resource that can fit SSDs to environmental hazard data (Etterson. 2020). It runs on Matlab
2018b (9.5) for Windows 64 bit. For this draft BBP risk evaluation, EPA created one SSD with the SSD
Toolbox Version 1.1 to evaluate acute aquatic vertebrate and invertebrate toxicity. The use of this
probabilistic approach increases confidence in the hazard threshold identification as it is a more data-
driven way of accounting for uncertainty. For the acute SSD, acute exposure hazard data for aquatic
vertebrates and invertebrates were curated to prioritize study quality and to assure comparability
between toxicity values. For example, the empirical data set included only LC50s for high and medium
quality acute duration assays that measured mortality for aquatic vertebrates and invertebrates.
TableApx A-l shows the empirical data and TableApx A-2 shows the modelled data from Web-ice
that were used in the SSD.
With this data set, the SSD Toolbox was used to apply a variety of algorithms to fit and visualize SSDs
with different distributions. An HC05 was calculated for each. The SSD Toolbox's output contained
several methods for choosing an appropriate distribution and fitting method, including goodness-of-fit,
standard error, and sample-size corrected Akaike Information Criterion (AICc, (Burnham and Anderson,
2002)). Most p-values for goodness-of-fit were less than 0.05, showing no evidence of lack of fit. The
distribution and model with the lowest AICc value, and therefore the best fit for the data was the
Weibull Distribution (Table_Apx A-3). Because numerical methods may lack statistical power for small
sample sizes, a visual inspection of the data were also used to assess goodness-of-fit. For the Q-Q plot,
the horizontal axis gives the empirical quantiles while the vertical axis gives the predicted quantiles
(from the fitted distribution). The Q-Q plot demonstrates a good model fit with the data points in close
proximity to the line across the data distribution. Q-Q plots were visually used to assess the goodness-
of-fit for the distributions with the Weibull distribution demonstrating the best fit near the low end of the
distribution, which is the region from which the HC05 is derived. The results for this model (Figure
5-1) predicted 5 percent of the species (HC05) to have their LC50s exceeded at 377 |ig/L (154 to 531
|ig/L 95% CI).
Table Apx A-l. SSD Model Input for BBP Acute Exposure Toxicity in Aquatic Vertebrates and
Invertebrates - Empirical Data
Species
Description
Acute Toxicity Value LC50
(Hg/L)
Citation(s)
Hycdella ctztecct
Aquatic
invertebrate
460
(Lake Superior Research
Institute. 1997; Adams et al..
1995: EG&G Bionomics. 1984)
Cymatogaster aggregate!
Aquatic
vertebrate
510
(Chen et al.. 2014; Ozretich et
al.. 1983)
Oncorhvnchiis mykiss
Aquatic
vertebrate
820
(Ozretich et al.. 1983)
Americamvsis bahia
Aquatic
invertebrate
1100
(EG&G Bionomics. 1979b)
900
(Snrinaborn Bionomics. 1988)
Hexagenia sp.
Aquatic
invertebrate
1100
(Adams et al.. 1995;
EnviroSvstem. 1991; ABC
Laboratories. 1986c; EG&G
Bionomics. 1983)
Page 34 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
Species
Description
Acute Toxicity Value LC50
(Hg/L)
Citation(s)
Crcissostreci virginica
Aquatic
invertebrate
1300
(ABC Laboratories. 1986a;
Linden etal.. 1979)
Chironomns tentans
Aquatic
invertebrate
1640
(Monsanto. 1982)
Lepomis macrochirns
Aquatic
vertebrate
1700
(EG&G Bionomics. 1979c;
Streufort. 1978)
Pimephcdes promelas
Aquatic
vertebrate
1500
(Adams et al.. 1995)
2100
(EG&G Bionomics. 1979d)
Haliotis diversicolor
Aquatic
invertebrate
2650
(Liu et al.. 2009)
986
987 TableApx A-2. SSD Model Input for BBP Acute Exposure Toxicity in Aquatic Vertebrates and
988 Invertebrates - WeblCE Data
Species
Description
Acute Toxicity Value LC50
(^g/L)
Caecidotea brevicauda
Invertebrate
447
Gammarus pseudolimnaeus
Invertebrate
480
Ceriodaphnia dubia
Invertebrate
523
Salve linus namaycush
Fish
637
Oncorhynchus clarkii
Fish
702
Perca flavescens
Fish
715
Oncorhynchus kisutch
Fish
766
Salmo trutta
Fish
851
Salmo solar
Fish
937
Oncorhynchus tshawytscha
Fish
965
Micropterus salmoides
Fish
1022
Poecilia reticulata
Fish
1306
Cyprinus carpio
Fish
1902
Cyprinodon variegatus
Fish
1915
Ictalurus punctatus
Fish
1916
Daphnia magna
Invertebrate
1919
Carassius auratus
Fish
2315
Page 35 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
989
990 Table Apx A-3. SSD" Model Predictions for Acute BBP Exposure Toxicity to Aquatic Vertebrates
Distribution6
HC05 (jig/L)
p- value
Weibull
327
0.93
Normal
475
0.70
Logistic
467
0.66
Gumbel
487
0.38
Burr
464
0.63
11 The SSD was generated using SSD Toolbox vl.l.
h The model with the lowest AICc value, and therefore the best model fit, is bolded in this table.
991
992
Page 36 of 41
-------
993
994
995
996
997
998
999
1000
1001
1002
PUBLIC RELEASE DRAFT
December 2024
Appendix B TERRESTRIAL VERTEBRATE TOXICITY OF BBP
In lieu of wild mammal studies, EPA considered nine studies on BBP to laboratory rodents that were
designed to determine human health hazards of BBP that also contained ecologically relevant
reproductive endpoints (TableApx B-l). Of the studies containing ecologically relevant reproductive
endpoints to rat and mouse, EPA selected the study with the most sensitive LOAEL (lowest observed
adverse effect level) for evaluating data quality and for deriving the hazard threshold for terrestrial
mammals (Table Apx B-l).
Table Apx B-l. Terrestrial Vertebrate Toxicity of
BBP
Test Organism
(Species)
Hazard Values
Duration
Endpoint
Citation
Rat (Rattus
norvegicus)
250/500 mg/kg-
bw/day
GD 15 - 17
Reproduction
(Ema and Mivawaki.
2002)
500/750 mg/kg-
bw/day
GD 5 - 17
(Ema et al.. 1992)
247/821 mg/kg-
bw/day
Two
generation
(SDrineborn Bionomics.
1986d; Nikonorow et al..
1973)
500/1000 mg/kg-
bw/day
29 days
(Wolf et al.. 1999;
Piersma et al.. 1995)
419/1641 mg/kg-
bw/day
GD 6 - 15
(RTI International. 1989)
254/2270 mg/kg-
bw/day
10 weeks
(Hazelton Labs. 1985)
0.115/0.321
mg/kg-bw/day
9 weeks
drinking water
(TNO. 1998)
Mice
247/821 mg/kg-
bw/day
Two
generation
(NTP. 1990)
910/2330 mg/kg-
bw/day
GD 6 - 15
Page 37 of 41
-------
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1047
PUBLIC RELEASE DRAFT
December 2024
Appendix C RUBRIC FOR WEIGHT OF THE SCIENTIFIC
EVIDENCE
The weight of the scientific evidence fundamentally means that the evidence is weighed (i.e., ranked)
and weighted (i.e., a piece or set of evidence or uncertainty may have more importance or influence in
the result than another). Based on the weight of the scientific evidence and uncertainties, a confidence
statement was developed that qualitatively ranks (i.e., robust, moderate, slight, or indeterminate) the
confidence in the hazard threshold. The qualitative confidence levels are described below.
The evidence considerations and criteria detailed within U.S. EPA (2021) guides the application of
strength-of-evidence judgments for environmental hazard effect within a given evidence stream and
were adapted from Table 7-10 of the 2021 Draft Systematic Review Protocol (U.S. EPA. 2021).
EPA used the strength-of-evidence and uncertainties from U.S. EPA (2021) for the hazard assessment to
qualitatively rank the overall confidence rating for environmental hazard (Table Apx C-l). Confidence
levels of robust (+ + +), moderate (+ +), slight (+), or indeterminant are assigned for each evidence
property that corresponds to the evidence considerations (U.S. EPA. 2021). The rank of the Quality of
the Database consideration is based on the systematic review overall quality determination (High,
Medium, or Low) for studies used to calculate the hazard threshold, and whether there are data gaps in
the toxicity data set. Another consideration in the Quality of the Database is the risk of bias (i.e., how
representative is the study to ecologically relevant endpoints). Additionally, because of the importance
of the studies used for deriving hazard thresholds, the Quality of the Database consideration may have
greater weight than the other individual considerations. The high, medium, and low systematic review
overall quality determinations ranks correspond to the evidence table ranks of robust (+ + +), moderate
(+ +), or slight (+), respectively. The evidence considerations are weighted based on professional
judgment to obtain the overall confidence for each hazard threshold. In other words, the weights of each
evidence property relative to the other properties are dependent on the specifics of the weight of the
scientific evidence and uncertainties that are described in the narrative and may or may not be equal.
Therefore, the overall score is not necessarily a mean or defaulted to the lowest score. The confidence
levels and uncertainty type examples are described below.
C.l Confidence Levels
Robust (+ + +) confidence suggests thorough understanding of the scientific evidence and
uncertainties. The supporting weight of the scientific evidence outweighs the uncertainties to the
point where it is unlikely that the uncertainties could have a significant effect on the exposure or
hazard estimate.
Moderate (+ +) confidence suggests some understanding of the scientific evidence and
uncertainties. The supporting scientific evidence weighed against the uncertainties is reasonably
adequate to characterize exposure or hazard estimates.
Slight (+) confidence is assigned when the weight of the scientific evidence may not be adequate
to characterize the scenario, and when the assessor is making the best scientific assessment
possible in the absence of complete information. There are additional uncertainties that may need
to be considered.
C.2 Types of Uncertainties
The following uncertainties may be relevant to one or more of the weight of the scientific evidence
considerations listed above and will be integrated into that property's rank in the evidence table:
Scenario Uncertainty: Uncertainty regarding missing or incomplete information needed to fully
Page 38 of 41
-------
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
PUBLIC RELEASE DRAFT
December 2024
define the exposure and dose.
o The sources of scenario uncertainty include descriptive errors, aggregation errors, errors
in professional judgment, and incomplete analysis.
Parameter Uncertainty: Uncertainty regarding some parameter.
o Sources of parameter uncertainty include measurement errors, sampling errors,
variability, and use of generic or surrogate data.
Model Uncertainty: Uncertainty regarding gaps in scientific theory required to make predictions
on the basis of causal inferences.
o Modeling assumptions may be simplified representations of reality.
Table 6-1 summarizes the weight of the scientific evidence and uncertainties, while increasing
transparency on how EPA arrived at the overall confidence level for each exposure hazard threshold.
Symbols are used to provide a visual overview of the confidence in the body of evidence, while de-
emphasizing an individual ranking that may give the impression that ranks are cumulative (e.g., ranks of
different categories may have different weights).
Page 39 of 41
-------
PUBLIC RELEASE DRAFT
December 2024
TableApx C-l. Considerations that Inform Evaluations of the Strength of the Evidence within an Evidence Stream Apical
Endpoints, Mechanistic, or Field Studies)
Consideration
Increased Evidence Strength (of the Apical
Endpoints, Mechanistic, or Field Studies
Evidence)
Decreased Evidence Strength (of the Apical Endpoints, Mechanistic, or
Field Studies Evidence)
The evidence considerations and criteria laid out here guide the application of strength-of-evidence judgments for an outcome or environmental hazard effect
within a given evidence stream. Evidence integration or synthesis results that do not warrant an increase or decrease in evidence strength for a given
consideration are considered "neutral" and are not described in this table (and, in general, are captured in the assessment-specific evidence profile tables).
Quality of the database'1
(risk of bias)
A large evidence base of high- or medium-quality
studies increases strength.
Strength increases if relevant species are
represented in a database.
An evidence base of mostly /ow-quality studies decreases strength.
Strength also decreases if the database has data gaps for relevant species,
i.e., a trophic level that is not represented.
Decisions to increase strength for other considerations in this table should
generally not be made if there are serious concerns for risk of bias; in other
words, all the other considerations in this table are dependent upon the
quality of the database.
Consistency
Similarity of findings for a given outcome (e.g., of a
similar magnitude, direction) across independent
studies or experiments increases strength,
particularly when consistency is observed across
species, life stage, sex, wildlife populations, and
across or within aquatic and terrestrial exposure
pathways.
Unexplained inconsistency (i.e., conflicting evidence; see U.S. EPA (2005)
decreases strength.)
Strength should not be decreased if discrepant findings can be reasonably
explained by study confidence conclusions; variation in population or
species, sex, or life stage; frequency of exposure (e.g., intermittent or
continuous); exposure levels (low or high); or exposure duration.
Strength (effect magnitude)
and precision
Evidence of a large magnitude effect (considered
either within or across studies) can increase strength.
Effects of a concerning rarity or severity can also
increase strength, even if they are of a small
magnitude.
Precise results from individual studies or across the
set of studies increases strength, noting that
biological significance is prioritized over statistical
significance.
Use of probabilistic model (e.g., Web-ICE, SSD)
may increase strength.
Strength may be decreased if effect sizes that are small in magnitude are
concluded not to be biologically significant, or if there are only a few
studies with imprecise results.
Biological gradient/dose-
response
Evidence of dose-response increases strength.
Dose-response may be demonstrated across studies
or within studies and it can be dose- or duration-
dependent.
A lack of dose-response when expected based on biological
understanding and having a wide range of doses/exposures evaluated in the
evidence base can decrease strength.
-------
PUBLIC RELEASE DRAFT
December 2024
Consideration
Increased Evidence Strength (of the Apical
Endpoints, Mechanistic, or Field Studies
Evidence)
Decreased Evidence Strength (of the Apical Endpoints, Mechanistic, or
Field Studies Evidence)
Dose response may not be a monotonic dose-
response (monotonicity should not necessarily be
expected, e.g., different outcomes may be expected
at low vs. high doses due to activation of different
mechanistic pathways or induction of systemic
toxicity at very high doses).
Decreases in a response after cessation of exposure
(e.g., return to baseline fecundity) also may increase
strength by increasing certainty in a relationship
between exposure and outcome (this particularly
applicable to field studies).
In experimental studies, strength may be decreased when effects resolve
under certain experimental conditions (e.g., rapid reversibility after
removal of exposure).
However, many reversible effects are of high concern. Deciding between
these situations is informed by factors such as the toxicokinetics of the
chemical and the conditions of exposure, see (U.S. EPA, 1998). cndooint
severity, judgments regarding the potential for delayed or secondary
effects, as well as the exposure context focus of the assessment (e.g.,
addressing intermittent or short-term exposures).
In rare cases, and typically only in toxicology studies, the magnitude of
effects at a given exposure level might decrease with longer exposures
(e.g., due to tolerance or acclimation).
Like the discussion of reversibility above, a decision about whether this
decreases evidence strength depends on the exposure context focus of the
assessment and other factors.
If the data are not adequate to evaluate a dose-response pattern, then
strength is neither increased nor decreased.
Biological relevance
Effects observed in different populations or
representative species suggesting that the effect is
likely relevant to the population or representative
species of interest (e.g., correspondence among the
taxa, life stages, and processes measured or observed
and the assessment endpoint).
An effect observed only in a specific population or species without a clear
analogy to the population or representative species of interest decreases
strength.
Physical/chemical relevance
Correspondence between the substance tested and
the substance constituting the stressor of concern.
The substance tested is an analog of the chemical of interest or a mixture of
chemicals which include other chemicals besides the chemical of interest.
Environmental relevance
Correspondence between test conditions and
conditions in the region of concern.
The test is conducted using conditions that would not occur in the
environment.
" Database refers to the entire data set of studies integrated in the environmental hazard assessment and used to inform the strength of the evidence. In this context,
database does not refer to a computer database that stores aggregations of data records such as the ECOTOX Knowledgebase.
Page 41 of 41
------- |