EPA/635/R-13/302
Preliminary Materials
www.epa.gov/iris
Preliminary Materials for the Integrated Risk Information System (IRIS)
Toxicological Review of Diethyl Phthalate (DEP)
[CASRN 84-66-2]
December 2013
NOTICE
This document is comprised of preliminary materials, consisting of a literature search strategy,
evidence tables, and exposure-response arrays. This information is distributed solely for the
purpose of pre-dissemination review under applicable information quality guidelines. It has not
been formally disseminated by EPA. It does not represent and should not be construed to represent
any Agency determination or policy. It is being circulated for review of its technical accuracy and
science policy implications.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
DISCLAIMER
This document is comprised of preliminary materials for review purposes only. This
information is distributed solely for the purpose of pre-dissemination review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not represent
and should not be construed to represent any Agency determination or policy. Mention of trade
names or commercial products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy,
ii DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
CONTENTS
PREFACE v
1. DRAFT LITERATURE SEARCH STRATEGY 1-1
1.1. Literature Search and Screening Strategy for DEP 1-1
2. PRELIMINARY EVIDENCE TABLES AND EXPOSURE-RESPONSE ARRAYS 2-1
2.1. Data Extraction: Preparation of Preliminary Evidence Tables and Exposure-Response
Arrays 2-1
2.2. Liver Effects Evidence Tables and Array 2-2
2.3. Reproductive and Developmental Effects Evidence Tables and Exposure Array 2-15
2.4. Obesity Evidence Tables 2-47
2.5. Other Systemic Effects Evidence Tables 2-51
2.6.Carcinogenicity 2-73
3. EVIDENCE TABLE REFERENCE LIST 3-1
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
TABLES
Table LS-1. Summary of detailed search strategies for DEP (Pubmed, Toxline, Toxcenter,
TSCATS) 1-3
Table LS-2. Summary of Search Terms: Augmented Epidemiology Search 1-7
Table LS-3. Additional strategies utilized in literature search 1-9
Table 2-1. Evidence pertaining to hepatic effects in animals following exposure to DEP 2-2
Table 2-2. Evidence pertaining to MEP and sexual differentiation effects in humans 2-15
Table 2-3. Evidence pertaining to male reproductive effects in animals 2-24
Table 2-4. Evidence pertaining to MEP and the timing of male puberty in humans 2-31
Table 2-5. Evidence pertaining to MEP and the timing of female puberty in humans 2-32
Table 2-6. Evidence pertaining to MEP and gynecological conditions in humans 2-34
Table 2-7. Evidence pertaining to MEP and neurobehavioral and neurodevelopmental effects in
infants and children 2-36
Table 2-8. Evidence pertaining to female reproductive effects in animals 2-38
Table 2-9. Evidence pertaining to developmental effects in animals 2-43
Table 2-10. Evidence pertaining to MEP and obesity in humans 2-47
Table 2-11. Evidence pertaining to MEP and neurological effects in adults 2-51
Table 2-12. Evidence pertaining to MEP and diabetes and measures of insulin resistance in
humans 2-52
Table 2-13. Evidence pertaining to MEP and thyroid effects in humans 2-55
Table 2-14. Evidence pertaining to MEP and immune effects in humans 2-57
Table 2-15. Evidence pertaining to MEP and pulmonary function in humans 2-60
Table 2-16. Evidence pertaining to MEP and cardiovascular disease in humans 2-61
Table 2-17. Evidence pertaining to MEP and oxidative stress and inflammation in humans 2-65
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in animals 2-66
Table 2-19. Evidence pertaining carcinogenic effects in animals 2-73
FIGURES
Figure LS-1. Summary of literature search and screening process for DEP 1-6
Figure LS-2. Summary of augmented literature search and screening process for epidemiologic
studies of DEP 1-8
Figure 2-1. Exposure-response array of liver effects following oral exposure to DEP 2-14
Figure 2-2. Exposure-response array of male reproductive effects following exposure to DEP 2-30
Figure 2-3. Exposure-response array of female reproductive effects following exposure to DEP 2-42
Figure 2-4. Exposure response array of developmental effects following exposure to DEP 2-46
Figure 2-5. Exposure-response array of adrenal effects following exposure to DEP 2-71
Figure 2-6. Exposure-response array of pituitary effects following exposure to DEP 2-72
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1
2 PREFACE
3 This document presents the draft literature search strategy, preliminary evidence tables,
4 and preliminary exposure-response arrays for diethyl phthalate (henceforth referred to as DEP)
5 prepared under the auspices of EPA's Integrated Risk Information System (IRIS) Program. This
6 material is being released for public viewing and comment prior to a public meeting, providing an
7 opportunity for the IRIS Program to engage in early discussions with stakeholders and the public
8 on data that may be used to identify adverse health effects and characterize exposure-response
9 relationships.
10 The draft literature search strategy, preliminary evidence tables, and preliminary exposure-
11 response arrays are responsive to the National Research Council (NRC) 2011 report Review of the
12 Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde. The literature search
13 strategy, which describes the processes for identifying scientific literature, screening studies for
14 consideration, and selecting studies for inclusion in evidence tables, is responsive to NRC
15 recommendations regarding systematic review of the scientific literature. In addition, NRC
16 recommendations for standardized presentation of key study data are addressed in the preliminary
17 evidence tables and preliminary exposure-response arrays.
18 EPA welcomes all comments on the draft literature search strategy, preliminary evidence
19 tables, and preliminary exposure-response arrays, such as remarks on the following:
20 • the clarity and transparency of the materials;
21 • the approach for identifying pertinent studies;
22 • the selection of studies for data extraction to preliminary evidence tables and exposure-
23 response arrays;
24 • any methodological considerations that could affect the interpretation of or confidence
25 in study results; and
26 • any additional studies published or nearing publication that may provide data for the
27 evaluation of human health hazard or dose-response relationships.
28 The preliminary evidence tables and exposure-response arrays should be regarded solely as
29 representing the data on each endpoint that have been identified as a result of the draft literature
30 search strategy. They do not reflect any conclusions as to hazard identification or dose-response
31 assessment.
32 After obtaining public input and conducting additional study evaluation and data
33 integration, EPA will revise these materials to support the hazard identification and dose-response
34 assessment in a draft Toxicological Review.
35
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1. DRAFT LITERATURE SEARCH STRATEGY
1 1.1. Literature Search and Screening Strategy for DEP
2 The literature search for DEP was conducted in five online scientific databases (PubMed,
3 10/2012 and 8/2013; Web of Science, 11/2012 and 8/2013; Toxline, 11/2012; TSCATS2,10/2012;
4 and Toxcenter, 3/2012). The literature search approach, including the search strings and the
5 number of citations identified per database is presented in Table LS-1. The overall study selection
6 strategy and number of references obtained at each stage of the literature search and screening is
7 shown graphically in Figure LS-1. The computerized database searches were augmented by review
8 of online regulatory sources as well as "forward" and "backward" searches of Web of Science for
9 five primary literature sources (Table LS-3).
10 After electronically eliminating duplicates from the citations retrieved through the multiple
11 databases, 1,192 unique citations were identified. An additional 93 citations were obtained using
12 additional search strategies described in Table LS-3. The resulting 1,285 citations were screened
13 using the title, abstract, and/or full text for pertinence to examining the health effects of DEP
14 exposure. A total of 591 references were identified as not being pertinent and were excluded from
15 further consideration (see Figure LS-1 for exclusion categories). A total of 214 references were
16 identified as primary sources of health effects data and were considered for data extraction to
17 evidence tables and exposure-response arrays. A total of 444 references were considered
18 pertinent, but not as primary sources of health effects data (e.g., adsorption-distribution-
19 metabolism-excretion [ADME] studies), and were kept as additional resources for development of
20 the Toxicological Review. If a reference did not provide enough material to evaluate pertinence
21 (e.g., no abstract), it would be reserved for further possible review; 36 such studies were identified
22 for DEP. EPA welcomes comments on studies identified for possible further review that may
23 inform their utility to the development of the Toxicological Review.
24 As illustrated in Figure LS-1, studies were identified and "tagged" in HERO based on
25 information provided in the title and/or abstract; in some cases this information was supplemented
26 by further review of the full text of the corresponding document. Based on this review, studies
27 were distributed in different groups that reflect the primary content of the citation. It should be
28 noted that studies were not given multiple tags, and the inclusion of a citation in a given category
29 (or tag) does not preclude its use in one or more other categories. For the purposes of this
30 preliminary description of the literature search process, the strategy of only using one tag per
31 reference is utilized to allow the public and stakeholders to more easily distinguish between
32 citations that would be excluded from further review and those that may be utilized in the
33 development of the assessment.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1 The screening process described in LS-1 identified 69 animal studies as primary sources of
2 health effects data for diethyl phthalate. These studies evaluated a health effect in relation to DEP
3 or its primary metabolite MEP and were also considered for data extraction to evidence tables.
4 A list of references for the studies included in the evidence tables is provided. The full list of
5 identified citations and lists of citations in different exclusion categories can be found on the Health
6 and Environmental Research Online (HERO) Web site1 [http://hero.epa.gov/DEP].
7 Most epidemiologic studies relating to phthalates are not limited to examination of a single
8 phthalate, and the names of all of the phthalates examined may not appear in the abstract or
9 indexing terms. For these reasons, an augmented literature search using modified search terms
10 was done to identify additional human data pertaining to DEP. This augmented search was
11 conducted in the Web of Science, PubMed and ToxNet databases in June 2013, using keywords and
12 limits described in Table LS-2. Figure LS-2 presents the study search and screening process for the
13 augmented epidemiological literature search DEP.
14 After electronically eliminating duplicates from the citations retrieved through the
15 augmented search, each article was screened for relevance based on title, abstract, and in some
16 cases, full text This screening process identified 61 epidemiological studies as primary sources of
17 health effects data for DEP. These studies evaluated a health outcome in relation to DEP or its
18 primary metabolite (MEP) and were considered for data extraction to evidence tables. References
19 within the identified papers were scanned, adding in one additional reference.
20 The documentation and results for this supplementary search can be found on the Health
21 HERO Web site [http://hero.epa.gov/phthalates-humanstudies].
22
iHERO (Health and Environmental Research On-line) is a database of scientific studies and other references
used to develop EPA's risk assessments aimed at understanding the health and environmental effects of
pollutants and chemicals. It is developed and managed in EPA's Office of Research and Development (ORD)
by the National Center for Environmental Assessment (NCEA). The database includes more than 300,000
scientific articles from the peer-reviewed literature. New studies are added continuously to HERO.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1
2
Table LS-1. Summary of detailed search strategies for DEP (Pubmed, Toxline,
Toxcenter, TSCATS)
Database
Terms
Hits
Initial Strategy
PubMed
10/31/2012
8/31/13
((("Diethyl o-phthalate"[tw] OR "Diethyl phthalate"[tw] OR "Ethyl phthalate"[tw])
OR (DEP[tw] AND (phthalate[AII Fields] OR phthalate/l[AII Fields] OR
phthalate/2[AII Fields] OR phthalate/25[AII Fields] OR phthalate/adipate[AII Fields]
OR phthalate/aged[AII Fields] OR phthalate/cellulose[AII Fields] OR
phthalate/dialkoxyalkyl[AII Fields] OR phthalate/ethanol[AII Fields] OR
phthalate/ferrocene[AII Fields] OR phthalate/goethite[AII Fields] OR
phthalate/kg[AII Fields] OR phthalate/mg[AII Fields] OR phthalate/ml[AII Fields]
OR phthalate/naoh[AII Fields] OR phthalate/toxicity[AII Fields] OR
phthalate/water[AII Fields] OR phthalate's[AII Fields] OR phthalated[AII Fields] OR
phthalaten[AII Fields] OR phthalates[AII Fields] OR phthalates/kg/day[AII Fields]
OR phthalates/toxicity[AII Fields] OR phthalates'[AII Fields]))) NOT medline[sb]) OR
"84-66-2"[EC/RN Number]
200
49
Web of Science
11/1/2012
8/31/13
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=chronic OR TS=immun* OR TS=lymph*
OR TS=neurotox* OR TS=toxicokin* OR TS=pharmacokin* OR TS=biomarker* OR
TS=neurolog* OR TS=subchronic OR TS=pbpk OR TS=epidemiolog* OR TS=acute
OR TS=subacute OR TS=ld50)
80
47
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=lc50 OR TS=inhal* OR TS=pulmon* OR
TS=nasal OR TS=lung* OR TS=respir* OR TS=occupation* OR TS=workplace OR
TS=worker* OR TS=oral OR TS=orally OR TS=ingest* OR TS=gavage OR TS=diet OR
TS=diets OR TS=dietary OR TS=drinking OR TS=gastr* OR TS=intestin*)
109
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=gut OR TS=sensitiz* OR TS=abort* OR
TS=abnormalit* OR TS=embryo* OR TS=cleft* OR TS=fetus* OR TS=foetus* OR
TS=fetal* OR TS=foetal* OR TS=fertil* OR TS=malform* OR TS=ovum OR TS=ova
OR TS=ovary OR TS=placenta* OR TS=pregnan*)
60
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND ( TS=dermal* OR TS=dermis OR TS=skin OR
TS=epiderm* OR TS=cutaneous OR TS=carcinog* OR TS=cocarcinog* OR TS=cancer
OR TS=precancer OR TS=neoplas* OR TS=tumor* OR TS=tumour* OR
TS=oncogen* OR TS=lymphoma* OR TS=carcinom* OR TS=genetox* OR
TS=genotox* OR TS=mutagen* OR TS=nephrotox* OR TS=hepatotox* OR
TS=endocrin* OR TS=estrogen* OR TS=androgen* )
156
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=hormon* OR TS=blood OR TS=serum
OR TS=urine OR TS=bone OR TS=bones OR TS=skelet* OR TS=rat OR TS=rats OR
TS=mouse)
148
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Database
ToxLine
11/1/2012
TSCATS2, TSCA recent
notices
10/31/2012
Terms
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=mice OR TS=guinea OR TS=muridae OR
TS=rabbit* OR TS=lagomorph* OR TS=hamster* OR TS=ferret* OR TS=gerbil* OR
TS=rodent* OR TS=dog OR TS=dogs OR TS=beagle* OR TS=canine OR TS=cats OR
TS=feline OR TS=pig OR TS=pigs OR TS=swine OR TS=porcine OR TS=monkey* OR
TS=macaque* OR TS=baboon* OR TS=marmoset* OR TS=toxic* OR TS=adverse OR
TS=poisoning)
((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl ester"
OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS=prenatal OR TS=perinatal OR
TS=postnatal OR TS=reproduc* OR TS=steril* OR TS=teratogen* OR TS=sperm* OR
TS=neonat* OR TS=newborn* OR TS=development* OR TS=zygote* OR TS=child
OR TS=children OR TS=adolescen* OR TS=infant* OR TS=wean* OR TS=offspring
OR TS=age)
-omics search
2 ((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl
ester" OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS="Genomics" OR TS="Proteomics" OR
TS="Metabolic Profile" OR TS="Metabolome" OR TS="Metabolomics" OR
TS="Microarray" OR TS="Nanoarray")
11 ((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl
ester" OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS="Gene expression" OR TS="Transcript
expression" OR TS="transcriptomes" OR TS="transcriptome" OR TS="Phenotype"
OR TS="Transcription" OR TS="Trans-act*" OR TS="transact*" OR TS="trans act*"
OR TS=genetic OR TS="genetics" OR TS="genotype")
4 ((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl
ester" OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS="Genetic transcription" OR TS="Gene
transcription" OR TS="Gene Activation" OR TS="Genetic induction" OR
TS="Reverse transcription" OR TS="Transcriptional activation" OR
TS="Transcription factors" OR (TS="Biosynthesis" AND (TS=RNA OR TS=DNA)) OR
TS="mRNA")
6 ((TS=DEP AND TS=phthalat*) OR (TS="l,2-Benzenedicarboxylic acid, diethyl
ester" OR TS="Diethyl 1,2-benzenedicarboxylate" OR TS="Diethyl o-phthalate" OR
TS="Diethyl phthalate" OR TS="Di-n-ethyl phthalate" OR TS="Ethyl phthalate" OR
TS="Phthalic acid, diethyl ester")) AND (TS="messenger RNA" OR TS="transfer
RNA" OR TS="peptide biosynthesis" OR TS="protein biosynthesis" OR TS="protein
synthesis" OR TS="RT-PCR" OR TS="RTPCR" OR TS="Reverse Transcriptase
Polymerase Chain Reaction" OR TS="DNA sequence")
@OR+("diethyl phthalate"+"unimoll da"+solvanol+"placidol
e"+phthalol+"palatinol a"+neantine+"ethyl phthalate"+anozol+@term+@rn+84-
66-2)+@not+@org+pubmed+pubdart+crisp
@term+@rn+84-66-2+@AND+@org+tscats
84-66-2
84-66-2 (8E OR FYI) TSCA
Hits
174
139
2
11
4
6
584
105
8 TSCATS2
1 recent notices
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Database
Toxcenter
3/27/2012
NOTE: took all non
caplus items and caplus
with synonyms in titles
only,
sequence"Dupicates
were removed; results
were date limited to
avoid extensive overlap
with Toxline
Merged Reference Set
Terms
((84-66-2) not (patent/dt OR tscats/fs)) and (chronic OR immunotox? OR
neurotox? OR toxicokin? OR biomarker? OR neurolog? OR pharmacokin? OR
subchronic OR pbpk OR epidemiology/st,ct, it) OR acute OR subacute OR Id50# OR
Ic50# OR (toxicity OR adverse OR poisoning)/st,ct,it OR inhal? OR pulmon? OR
nasal? OR lung? OR respir? OR occupation? OR workplace? OR worker? OR oral
OR orally OR ingest? OR gavage? OR diet OR diets OR dietary OR drinking(w)water
OR (maximum and concentration? and (allowable OR permissible)) OR (abort? OR
abnormalit? OR embryo? OR cleft? OR fetus? OR foetus? OR fetal? OR foetal? OR
fertil? OR malform? OR ovum OR ova OR ovary OR placenta? OR pregnan? OR
prenatal OR perinatal? OR postnatal? OR reproduc? OR steril? OR teratogen? OR
sperm OR spermac? OR spermag? OR spermati? OR spermas? OR spermatob? OR
spermatoc? OR spermatog? OR spermatoi? OR spermatol? OR spermator? OR
spermatox? OR spermatoz? OR spermatu? OR spermi? OR spermo? OR neonat?
OR newborn OR development OR developmental? OR zygote? OR child OR
children OR adolescen? OR infant OR wean? OR offspring OR age(w)factor? OR
dermal? OR dermis OR skin OR epiderm? OR cutaneous? OR carcinog? OR
cocarcinog? OR cancer? OR precancer? OR neoplas? OR tumor? OR tumour? OR
oncogen? OR lymphoma? OR carcinom? OR genetox? OR genotox? OR mutagen?
OR genetic(w)toxic? OR nephrotox? OR hepatotox? OR endocrin? OR estrogen? OR
androgen? OR hormon?) AND ("1,2-Benzenedicarboxylic acid, 1,2-diethyl ester"/ti
OR "1,2-Benzenedicarboxylic acid, diethyl ester"/ti OR Anozol/ti OR "Diethyl 1,2-
benzenedicarboxylate"/ti OR "Diethyl o-phenylenediacetate"/ti OR "Diethyl o-
phthalate"/ti OR "Diethyl phthalate"/ti OR "Di-n-ethyl phthalate"/ti OR "DPX-
F5384"/ti OR "Estol 1550"/ti OR "Ethyl phthalate"/ti OR Neantine/ti OR "o-
Benzenedicarboxylic acid diethyl ester"/ti OR "o-Bis(ethoxycarbonyl)benzene"/ti
OR "Palatinol A"/ti OR "Phthalic acid, diethyl ester"/ti OR Phthalol/ti OR "Placido
E"/ti OR Solvanol/ti OR (DEP/ti AND (phthalate/ti OR phthalates/ti))
-omics search
("Computational biology" OR "Bio-Informatics" OR Bioinformatics OR ("Molecular
Biology" AND Computational) OR Informatics OR ("Information Science" AND
Medical))
Genomics OR Proteomics OR "Metabolic Profile" OR "Metabolome" OR
"Metabolomics" OR "Microarray" OR "Nanoarray"
"Gene expression" OR "Transcript expression" OR transcriptomes OR
transcriptome OR Phenotype OR Transcription OR Trans-act? OR
transact? OR trans()act? OR genetic OR genetics OR genotype
"Systems biology" OR ("Biological systems" AND (monit? OR data OR analysis))
(Genetic transcription OR "Gene transcription" OR "Gene Activation" OR "Genetic
induction" OR "Reverse transcription" OR "Transcriptional activation" OR
"Transcription factors" OR (Biosynthesis AND (RNA OR DNA)))
mRNA OR "messenger RNA" OR "transfer RNA" OR "peptide biosynthesis" OR
"protein biosynthesis" OR "protein synthesis" OR RT-PCR OR RTPCR OR "Reverse
Transcriptase Polymerase Chain Reaction" OR "DNA
(duplicates eliminated through electronic screen)
Hits
2,526
65
1,192
1
2
3
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Database Searches
PubMed
n=196
Toxline
n=6S8
WOS
n=332
TSCATS
n=110
Toxcenter
n=43
Search update; PubMed n= 49; WOSn=47
Additional Search Strategies
(see Table 1 -2 for methods and results)
n=93
n=l,192 (after duplicates removed electronically)
Combined Dataset
n=i,285
Manual Screening for Pertinence
(Title/Abstract/Full Text)
Excluded/Not Pertinent (591)
2
17
49
151
144
13
69
134
12
Abstract only
Foreign Language
R e views/book chapters
M e asu r e m e nt m e th o d s
Not chemical specific
Use in sample prep or assay
Manufacture/use
Chemical treatment/disposal/ remediation
Miscellaneous
Kept for Possible Further Review (36)
32 No abstract
4 Inadequate reporting in abstract
Kept as Additional Resource (444)
32 Regulator,1 documents
36 Re'.'ievuS and editorials
97 Ecosystem effects
17 Risk assessments
131 Exposure levels
29 Chemical/physical properties
67 Fate and transport
12 Mixtures only
23 Toxicokinetics
Primary Sources of Health Effects
Data (214)
75 Human health effects studies
69 Animal toxicology studies
70 Mechanistic and genotoxicity studies
2
3
4
Figure LS-1. Summary of literature search and screening process for DEP
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table LS-2. Summary of Search Terms: Augmented Epidemiology Search
Database,
Search Date
PubMed
6/6/2013
No date
restriction
Web of Science
6/6/2013
No date
restriction
ToxNet
6/6/2013
No date
restriction
Merged
Reference Set
Terms
(phthalate OR phthalates OR phthalic acid) AND
(human OR case-control OR pregnancy OR cohort
OR workers OR children OR survey)
(TS="phthalic acid" OR TS="phthalate" OR
TS="phthalates") AND (TS="humans" OR
TS="human" OR TS="case-control" OR
TS="pregnancy" OR TS="cohort" OR
TS="workers" OR TS="child" OR TS="children"
ORTS="survey")
(phthalate OR phthalates OR phthalic acid) AND
(human OR case-control OR pregnancy OR
cohort OR workers OR children OR survey)
Merged dataset, with duplicates eliminated
through electronic screen
Hits
Imported: 2,505
After duplicates deleted:
2,482
Imported: 1,840
After duplicates deleted:
1,836
Imported: 2,505
After duplicates deleted:
2,427
4,130
This document is a draft for review purposes only and does not constitute Agency policy,
1-7 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Pubmed
n=2482
Database Searches
(see Table LS-3 for keywords and limits)
Web of Science
n=1836
v i
Toxline
(incl. TSCATS)
N=2426
From Other Sources
(n=l)
Combined Dataset from Database Searches
(After duplicates removed electronically)
n=4128
Manual Screening For Pertinence
(Title/Abstract/Full Text)
Excluded (not pertinent, n=2110)
848 Miscellaneous
606 Exposure or PK Studies
637 Animal & Ecological Studies
19 Duplicates (identified by title, abstract,
or full text)
Kept for Possible Further Review
900 No Abstract
Additional Resource (but not
primary source of human health
effects data)
580 Reviews, Reports
67 Study proposals, pilot studies
300 In vitro, mechanisms; measures in
stored blood
29 Background Materials
Included: Primary Sources of Human
Health Effects Data (total, 145)*
61 di-ethyl phthalate (DEP) studies
* Includes 8 non-English language studies.
Studies could examine more than 1 phthalate
2
3
Figure LS-2. Summary of augmented literature search and screening process
for epidemiologic studies of DEP.
This document is a draft for review purposes only and does not constitute Agency policy,
1-8 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table LS-3. Additional strategies utilized in literature search
System Used
Selected Key Reference(s) or Sources
Date
Additional References
Identified
Manual search of
citations from
regulatory documents
NICNAS (National Industrial Chemicals Notification
and Assessment Scheme). (2008). Existing chemical
hazard assessment report. Diethyl phthalate.
National Industrial Chemicals Notification and
Assessment
Scheme. http://www.nicnas.gov.au/lndustry/Existing
_Chemicals/Phthalate_Hazard_Assessments/DEP%20
hazard%20assessment%2030-4-07.pdf.
ATSDR (Agency for Toxic Substances and Disease
Registry). (1995). Toxicological profile for diethyl
phthalate. Atlanta, GA: U.S. Department of Health
and Human Services, Public Health Service.
WHO (World Health Organization). (2003). Concise
International Chemical Assessment Document 52:
Diethyl phthalate. Geneva.
http://www.who.int/ipcs/publications/cicad/en/cica
d52.pdf.
5/2013
10 citations added
5/2013
5/2013
4 citations added
2 citations added
Web of Science,
forward search
Jones, HB; Garside, DA; Liu, R; et al. (1993) The
influence of phthalate esters on Leydig cell structure
and function in vitro and in vivo. Exp Mol Pathol
58:179-193.
Shiraishi, K; Miyata, K; Houshuyama, S. (2006)
Subacute oral toxicity study of diethylphthalate
based on the draft protocol for "Enhanced OECD Test
Guideline no. 407". Arch Toxicol. 80: 10-16.
Field, EA; Price, CJ; Sleet, RB; et al. (1993)
Developmental toxicity evaluation of diethyl and
dimethyl phthalate in rats. Teratology, Jul; 48 (1): 33-
44.
Swan SH. (2008). Environmental phthalate exposure
in relation to reproductive outcomes and other
health endpoints in humans. Environmental Research
108(2): 177-184.
Pereira, C; Mapuskar, K; Rao, CV. (2007) Chronic
toxicity of diethyl phthalate—A three generation
lactational and gestational exposure study on male
Wistar rats. Envir Toxicol and Pharma 23:319-327.
6/2013
6/2013
6/2013
6/2013
6/2013
4 citations added
0 citations added
2 citations added
10 citations added
0 citations added
Web of Science,
backward search
Jones, HB; Garside, DA; Liu, R; et al. (1993) The
influence of phthalate esters on Leydig cell structure
and function in vitro and in vivo. Exp Mol Pathol
58:179-193.
Shiraishi, K; Miyata, K; Houshuyama, S. (2006)
Subacute oral toxicity study of diethylphthalate
based on the draft protocol for "Enhanced OECD Test
Guideline no. 407". Arch Toxicol. 80: 10-16.
6/2013
6/2013
1 citations added
0 citations added
This document is a draft for review purposes only and does not constitute Agency policy,
1-9 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
System Used
References obtained
during the
assessment process
Background Check
Selected Key Reference(s) or Sources
Field, EA; Price, CJ; Sleet, RB; et al. (1993)
Developmental toxicity evaluation of diethyl and
dimethyl phthalate in rats. Teratology, Jul; 48 (1): 33-
44.
Swan SH. (2008). Environmental phthalate exposure
in relation to reproductive outcomes and other
health endpoints in humans. Environmental Research
108(2): 177-184.
Pereira, C; Mapuskar, K; Rao, CV. (2007) Chronic
toxicity of diethyl phthalate-A three generation
lactational and gestational exposure study on male
Wistar rats. EnvirToxicol and Pharma 23:319-327.
DEP references in previous assessment or previously
added to the HERO project page
Searched a combination of CASRNs and synonyms on
the following databases:
ATSDR
(http://www.atsdr.cdc.gov/substances/index.asp)
CalEPA (Office of Environmental Health Hazard
Assessment) (http://www.oehha.ca.gov/risk.html)
eChemPorta!4
(http://www.echemportal.orR/echemportal/participa
nt/paRe.action?pagelD=9)
EPA Acute Exposure Guideline Levels
(http://www.epa.Rov/oppt/aeRl/pubs/chemlist.htm)
EPA- IRISTrack/New Assessments and ReviewsS
(http://cfpub.epa.Rov/ncea/iristrac/)
EPANSCEP
(http://www.epa.Rov/ncepihom/)
EPA RfD/RfC and CRAVE meeting notes
EPA Science Inventory
(http://cfpub.epa.gov/si/)
Federal Docket
(www.reRulations.Rov)
Health Canada First Priority List Assessments
(http://www.hc-sc.RC.ca/ewh-
semt/pubs/contaminants/psll-lspl/index-enR.php)
Health Canada Second Priority List Assessments
(http://www.hc-sc.RC.ca/ewh-
semt/pubs/contaminants/ps!2-lsp2/index-enR.php)
IARC
(http://monoRraphs.iarc.fr/htdiR/search.html)
IPCS INCHEM
(http://www.inchem.org/)
HER (TERA database)
(http://iter.ctcnet.net/publicurl/pub search list.cfm)
NAS via NAP
(http://www.nap.edu/)
Date
6/2013
6/2013
6/2013
10/2012
Additional References
Identified
2 citations added
6 citations added
4 citations added
47 citations added
1 citations added
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
System Used
Selected Key Reference(s) or Sources
NCI
(http://www.cancer.gov)
NCTR
(http://www.fda.gov/AboutFDA/CentersOffices/OC/
OfficeofScientificandMedicalPrograms/NCTR/default.
htm)
NIEHS
(http://www.niehs.nih.gov/)
NIOSHTIC2
(http://www2a.cdc.gov/nioshtic-2/)
NTP - RoC, status, results, and management reports
(http://NTPsearch.niehs.nih.gov/querv.html)
WHO assessments - CICADS, EHC
(http://www.who.int/ipcs/assessment/en/)
Date
Additional References
Identified
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1
2. PRELIMINARY EVIDENCE TABLES AND
EXPOSURE-RESPONSE ARRAYS
2 2.1. Data Extraction: Preparation of Preliminary Evidence Tables and
3 Exposure-Response Arrays
4 The 214 references identified as primary sources of health effects data for DEP in Fig LS-1
5 were considered for data extraction to evidence tables and exposure-response arrays. References
6 were first collated with respect to exposure route, exposure duration, and type of endpoint, to
7 identify those most pertinent for evaluating the human health effects from chronic exposure to DEP.
8 Of the 214 studies, 70 studies which included endpoints related to possible mechanisms of toxicity
9 were not extracted into evidence tables or exposure-response arrays. Studies investigating the
10 effects of acute exposures were not included in the evidence tables and exposure-response arrays.
11 In an effort to focus the hazard identification on observed effects of DEP exposure, evidence tables
12 and exposure-response arrays were not developed for studies that did not report effects for the
13 endpoints evaluated and corresponding effects were not observed across the database of DEP
14 studies. The remaining 2 3 animal studies were included in the evidence tables. Human health
15 effects are represented in the non-date limited augmented epidemiological search and were
16 evaluated for relevance to DEP. The 61 studies identified as relevant to DEP are included in the
17 evidence tables.
18 The tables are arranged in the order from the health effect with the most data to the health
19 effect with the least data. For each included endpoint, all studies reporting data on that endpoint
20 are included regardless of the reported level or statistical significance of the response. Within each
21 endpoint, the studies are presented beginning with short term and subchronic exposure durations
22 followed by those with chronic exposures. The information in the preliminary evidence tables is
23 displayed graphically in preliminary exposure-response arrays. In these preliminary arrays, a
24 significant effect (indicated by a filled data point) is based on statistical significance as determined
25 by the study authors, unless specified, without consideration of biological significance.
26 In total data from 84 references were summarized in preliminary evidence tables. Studies were not
27 excluded based on study quality considerations, so as to allow for public input on methodological
28 considerations that could affect the interpretation of, or confidence in, each study's results. A
29 reference list for the studies included in the evidence tables is presented in Section 2.7. The
30 complete list of references considered in preparation of these materials can be found on the HERO
31 Web site at [http://hero.epa.gov/DEP] and [http://hero.epa.gov/phthalates-humanstudies] .
32
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1 2.2. Liver Effects Evidence Tables and Array
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Results
Liver weight
(Moody and Reddv. 1978)
Rat (F344); 4 exposed males, 14
control males
0, 2.0% (0, 1753 mg/kg-day)
Diet
21 days
(Kwacketal., 2009)
Rat (Sprague Dawley); 6
males/group
0, 500 mg/kg-day DEP
and 0, 250 mg/kg-day MEP
Gavage in corn oil
28 days
(Shiraishietal., 2006)
Rat (Sprague-Dawley);
10/sex/group
0, 40, 200, 1,000 mg/kg-day
Gavage in corn oil
28 days
(Mapuskaretal., 2007)
Mouse (Swiss); 5 females/group
0, 0 (oil control), 10, 25, 50 mg/kg
(0, 0 (oil control), 1.25, 3.125, 6.25
mg/kg-day)
Diet (DEP dissolved in corn oil)
90 days
(Brown et al.. 1978)
Rat (Sprague Dawley); 5/sex/group
0, 1, 5%
Diet
42 days, and
15/sex/group
0, 0.2, 1, 5% in diet (M: 0, 150, 770,
3160 mg/kg-day; F: 0, 150, 750,
3710 mg/kg-day)
112 days
Relative liver weight (percent change compared to control)
0 1753
16%*
Relative liver weight (percent change compared to control)
0 500 (DEP) 0 250 (MEP)
13% - 6%
Relative liver weight (percent change compared to control)
0 40 200 1000
Males - -2% -3% -2%
Females - -4% -1% 3%
No significant changes in absolute or relative liver weight compared to
controls were observed (Quantitative data not reported by study authors)
Relative liver weight (percent change compared to control)
Males 0 150 770 3160
42 day - N/A 15%* 33%
112 day - -3% 3% 33%*
Females 0 150 750 3710
42 day - N/A 9% 33%*
112 day - 6%* 8%* 31%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Fuji! etal., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation;
liver weights measured in 21-
24/sex/group (FO and Fl parental,
Fl and F2 weanlings)
0, 600, 3,000, 15,000 ppm (0, 40,
197, 1016 mg/kg-day in FO males;
0, 51, 255, 1297 mg/kg-day in FO
females; 0, 46, 222, 1150 mg/kg-
day in Fl males; 0, 56, 267, 1375
mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental
males (14 weeks of dosing during
premating and mating) and ~133
days for FO and Fl parental
females (10 weeks premating, 3
weeks mating, 3 weeks gestation,
3 weeks lactation)
(Sonde et al.. 2000)
Rat (Sprague Dawley); 6
males/group
0, 50 ppm (0, 13.7 mg/kg-day)
Drinking water
120 days
(NIP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20 breeding
pairs/treatment group
Fl: 20 breeding
pairs/group/generation
FO: 0, 0.25, 1.25, 2.5 %
(0,340,1770, 3640 mg/kg-day)
Fl: 0, 2.5% (0, 3640 mg/kg-day)a
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days segregation
(126 days total)
Fl: in utero and via lactation, and
then in the diet through a 7 day
mating period at 74±10 days old
(females allowed to deliver litters)
Results
Absolute liver weight (percent change compared to control)
Males
FO parental
Fl parental
Fl weanling
F2 weanling
Females
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222 1016/1150
-5% -1% -2%
2% 5% 14%*
-5% -2% -4%
0% 3% 8%
0 51/56 255/267 1297/1375
0% 0% 11*%
5% 4% 11*%
-8% -6% -12*%
1% 4% 8%
Relative liver weight (percent change compared to control)
Males
FO parental
Fl parental
Fl weanling
F2 weanling
Females
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222 1016/1150
-3% -1% 7*%
2% 2% 11*%
-5*% -1% 11*%
0% 3% 16*%
0 51/56 255/267 1297/1375
-1% 2% 10*%
4% 2% 10*%
-5% -3% 9*%
0% 2% 16*%
No change in absolute or relative liver weight compared to controls
(Quantitative data not reported by study authors)
Absolute liver weight in Fl parental mice (percent change compared to
control)
Males
Females (n=19)
0 3640
3%
15%*
Relative liver weight in Fl parental mice (percent change compared to
control)
Males
Females (n=19)
0 3640
18*%
28%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Pereira and Rao. 2006)
Rat (Wistar); 6 females/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
150 days
(Pereira et al., 2006)
Rat (Wistar); 6 males/group
0, 10, 25, 50 mg/kg diet (0, 0.57,
1.425, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
(Sinkarand Rao. 2007)
Rat (Wistar); 8/sex/group
0, 50 ppm (0, 2.5 mg/kg-day)
Drinking water
180 days
(Pereira and Rao. 2007)
Rat (Wistar); 6 breeding
pairs/group; liver weights
measured in 6 pups/sex/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
100 days (premating) + 10 days
(mating) and through gestation
and weaning of the PND 21 male
and female pups
(150 days total for parental
animals)
Results
Relative liver weight (percent change compared to control)
0 2.85
* 8%
Relative liver weight3 (percent change compared to control)
0 0.57 1.425 2.85
21%* -9 -13
Study authors did not report a change in absolute or relative liver weight
compared to controls (quantitative data not provided)
Absolute liver weight at PND 21 (percent change compared to control)
0 2.85
Males - -16%*
Females - -56%*
Relative liver weight at PND 21 (percent change compared to control)
0 2.85
Males - 31%*
Females - -42%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Pereira et al.. 2007a)
Rat (Wistar);
Multigenerational study design:
6 breeding
pairs/group/generation;
liver weights measured in 6 adult
males/group/generation
FO: 0, 50 mg/kg diet (0, 2.85
mg/kg-day)
Fl: 0, 25 mg/kg diet (0, 1.425
mg/kg-day)
F2: 0, 10 mg/kg diet (0, 0.57
mg/kg-day)
Diet (DEP dissolved in corn oil)
FO: Adult exposure [150 days: 100
days (premating) + 10 days
(mating) and through gestation
and weaning]
Fl, F2: Developmental exposure
[GDO - PND21] and Adult exposure
[150 days (see FO protocol) starting
PND 35-40]
(NIP. 1995)
Mouse (BgCsFi); 10/sex/group
0, 12.5, 25, 50, 100 nl/day (5
days/week) (0, 14, 28, 56, 112
mg/day)
Dermal (neat)
28 days, and
60/sex/group
0, 7.5, 15, 30 nL/day (5 days/week)
(0, 8.4, 16.8, 33.6 mg/day)
Dermal (mixed with acetone)
104-105 weeks (liver weights
recorded at 15-month interim
sacrifice only [9-10/sex/group])
Rat (F344/N); 10/sex/group
0, 37.5, 75, 150, 300 nl/day (5
days/week) (0, 42, 84, 168, 336
mg/day)
Dermal (neat)
28 days, and
60/sex/group
0, 100, 300 nl/day (5 days/week)
(0, 112, 336 mg/day)
Results
Relative liver weight3 (percent change compared to control)
Males
FO
0 2.85
-9%
Fl
0 1.425
34%*
F2
0 0.57
50%*
Absolute liver weight [28 day study] (percent change compared to control)
Mouse
Males
Females
Rats
Males
Females
0 14 28 56 112
4% 1% 2% 2%
9% 15%* 9% 14%*
0 42 84 168 336
-1% 0% 0% 4%
2% 6% 6% 2%
Relative liver weight [28 day study] (percent change compared to control)
Mouse
IWIalpc
IVICMCO
Females
Rats
Males
Females
0 14 28 56 112
7% 4% 3% 3%
£- /O *-T /O J /O J /O
7% 9%* 6% 10%*
0 42 84 168 336
2% 3% 6% 11%*
4% 5% 8%* 7%*
Absolute liver weight at 15 months [104 week study] (percent change
compared to control)
Mouse
Males
Females
Rat
Males
Females
0 8.4 16.8 33.6
-2% 1% 0%
-8% -4% -5%
0 112 336
2% -1%
1% 2%
Relative liver weight at 15 months [104 week study] (percent change
compared to control)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Dermal (neat)
104 weeks (liver weights recorded
at 15-month interim sacrifice only
[9-10/sex/group])
Results
Mouse 0 8.4
Males - 3%
Females - -1%
16.8 33.6
-1% 5%
0% 4%
Rat 0 112 336
Males - 9% 7%
Females - 5% 4%
Serum clinical chemistry; liver function
(Kwacketal., 2009)
Rat (Sprague Dawley); 6
males/group
0, 500 mg/kg-day DEP
and
0, 250 mg/kg-day MEP
Gavage in corn oil
28 days
(Mapuskaretal., 2007)
Mouse (Swiss); 5 females/group
0, 0 (oil control), 10, 25, 50 mg/kg
(0, 0 (oil control), 1.25, 3.125, 6.25
mg/kg-day)
Diet (DEP dissolved in corn oil)
90 days
(Sonde et al.. 2000)
Rat (Sprague Dawley); 6
males/group
0, 50 ppm (0, 13.7 mg/kg-day)
Drinking water
120 days
(percent change compared to control)
GOT (ALT)
GPT (AST)
ALP
Glucose
Total bilirubin
Cholesterol
Serum
0 500 (DEP)
-0.1%
21%
20%
14%
40%
-13%
(percent change compared to control)
ALT3 Serum
AST3 Serum
ACP3 Serum
LDH3 Serum
Choi- Serum
Esterol3 Liver
Tri- Serum
glycerides3 Liver
Glycogen3 Liver
0 1.25
382%*
231%*
44%*
12%
-13%*
126%*
47%*
1229%*
29%*
Serum
0 250 (MEP)
14%
58%
6%
15%
30%
-11%
3.125 6.25
1131%* 921%*
523%* 681%*
66%* 91%*
304%* 396%*
-53%* -55%*
68%* 74%*
65%* 153%*
1371%* 1771%*
56%* 87%*
(percent change compared to control)
Serum
0 13.7
ALT3 - 349%*
AST3 - 323%*
ALP3 - 245%*
ACP3 - 75%*
SDH3 - -10%
Cholesterol3 - 2600%*
Triglycerides3 - -81%*
Glycogen3 N/A N/A
Liver
0 13.7
-28%*
-30%*
-18%
61%*
100%*
11873%*
119%*
364%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Pereira and Rao. 2006)
Rat (Wistar); 6 females/group
0, 0 (oil control), 50 mg/kg diet (0,
0 (oil control), 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
(Pereira et al., 2006)
Rat (Wistar); 6 males/group
0, 10, 25, 50 mg/kg diet (0, 0.57,
1.425, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
Results
(percent change compared to control)
ALT3
AST3
ALP3
ACP3
LDH3
SDH3
Glucose3
Glycogen3
Cholesterol3
Triglycerides3
Serum
0 2.85
286%*
569%*
-53%*
254%*
225%*
21%
1033%*
N/A N/A
356%*
250%*
Liver
0 2.85
119%*
389%*
-75%*
206%*
182%*
45%
N/A N/A
29%
782%*
41%
(percent change compared to control)
A, -ra Serum
A 1 X
HLI .
Liver
a Serum
AST
Liver
a Serum
ACP
Liver
. ™..a Serum
LDH
Liver
Glycogen3 Liver
Choi- Serum
Esterol3 Liver
Tri- Serum
Glycerides3 Liver
0 0.57 1.425 2.85
1783%* 1483%* 1592%*
254%* 192%* 250%*
498%* 591%* 779%*
333%* 475%* 676%*
310%* 117%* 90%*
100%* 19% 55%
53%* 30%* 38%*
106%* 67%* 83%*
40%* 115%* 191%*
-19% -90%* -94%*
-3% 37%* 176%*
141%* 114%* 136%*
275%* 226%* 234%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Sinkarand Rao. 2007)
Rat (Wistar); 8/sex/group
0, 50 ppm (0, 2.5 mg/kg-day)
Drinking water
180 days
(Pereira and Rao. 2007)
Rat (Wistar); 6 breeding
pairs/group; liver function was
measured in 6 pups/sex/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
100 days (premating) + 10 days
(mating) and through gestation
and weaning of the PND 21 male
and female pups (150 days total
for parental animals)
Results
(percent change compared to control)
Males
ALT3
AST3
ALP3
ACP3
LDH3
SDH3
Gluta-
thione3
Females
ALT3
AST3
ALP3
ACP3
LDH3
SDH3
Gluta-
thione3
Serum
0 2.5
N/A N/A
-5%
4%
-21%*
-50%*
-50%
N/A N/A
Serum
0 2.5
N/A N/A
4%
0%
0%
-21%*
-8%
N/A N/A
Liver
0 2.5
7%
N/A N/A
0%
30%*
50%
0%
-8%
Liver
0 2.5
0%
N/A N/A
-29%*
0%
0%
-34%*
-17%
(percent change compared to control)
Males
ALP3
ACP3
LDH3
Females
ALP3
ACP3
LDH3
Serum
0 2.85
1300%*
379%*
226%*
Serum
0 2.85
1244%*
463%*
303%*
Liver
0 2.85
-64%*
321%*
72%*
Liver
0 2.85
-25%
382%*
142%*
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
(Pereira et al.. 2007a)
Rat (Wistar);
Multigenerational study design:
6 breeding
pairs/group/generation;
liver function assessed in 6 adult
males/group/generation
0, 50 mg/kg diet (0, 2.85 mg/kg-
day) (FO rats)
0, 25 mg/kg diet (0, 1.425 mg/kg-
day) (Fl rats)
0, 10 mg/kg diet (0, 0.57 mg/kg-
day) (F2 rats)
Diet (DEP dissolved in corn oil)
FO: Adult exposure [150 days: 100
days (premating) + 10 days
(mating) and through gestation
and weaning]
Fl, F2: Developmental exposure
[GDO - PND21] and Adult exposure
[150 days (see FO protocol) starting
PND 35-40]
(NIP. 1995)
Rat (F344/N); 10/sex/group
0, 100, 300 nl (5 days/week) (0,
112, 336 mg/day)
Dermal
104-105 weeks (clinical chemistry
reported from 15-month interim
sacrifice only [9-10/sex/group])
Results
(percent change compared to control)
Serum
ALT3
Liver
Serum
AST3
Liver
Serum
Tri-
Glycerides3
Liver
Chol-
,a Serum
esterol
FO Males
0 2.85
213%*
62%*
790%*
421%*
233%*
25%*
116%*
Fl Males
0 1.425
1602%*
78%*
1673%*
541%*
380%*
119%*
-21%*
F2 Males
0 0.57
1444%*
104%*
1600%*
597%*
443%*
169%*
-94*%
(percent change compared to control)
Males 0 112 336
Urea nitrogen - 5% 3%
Creatinine - 7% -5%
ALP - -3% 7%
SDH - 0% 0%
Females 0 112 336
Urea nitrogen - 2% 0%
Creatinine - 2% -7%
ALP - 11% 16%*
SDH - -10% -10%
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Hepatic cytochrome (CYP) P450s
(Fuji! etal., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation;
heptatic CYPs evaluated in 6 FO
males/group
0, 600, 3000, 15,000 ppm (0, 40,
197, 1016 mg/kg-day)
Diet
~98 days (FO parental males; 14
weeks of dosing during premating
and mating)
Liver lipid peroxidation0
(Sonde et al.. 2000)
Rat (Sprague Dawley); 6
males/group
0, 50 ppm (0, 13.7 mg/kg-day)
Drinking water
120 days
(Pereira and Rao. 2006)
Rat (Wistar)1 6 females/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
150 days
(Pereira et al.. 2006)
Rat (Wistar); 6 males/group
0, 10, 25, 50 mg/kg diet (0, 0.57,
1.425, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
Liver antioxidant systems
(Pereira and Rao, 2006)
Rat (Wistar); 6 females/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
150 days
Results
(percent change compared to control)
0 40 197 1016
CYP1A1 - 0% 0% 0%
CYP1A2 - 11% -3% -48%
CYP2B1 - 25% -15% 13%
CYP3A4 - 12% -40% 65%*
CYP4A1 - 9% -16% 358%*
(percent change compared to control)
0 13.7
600%*
(percent change compared to control)
0 2.85
3380%*
(percent change compared to control)
0 0.57 1.425 2.85
725%* 233%* 475%*
(percent change compared to control)
Liver
0 2.85
Glutathione3 - -17%*
Glutathione reductase3 - -81%*
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Results
(Pereira et al.. 2006)
Rat (Wistar); 6 males/group
0,10, 25, 50 mg/kg diet (0, 0.57,
1.425, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
(percent change compared to control)
Glutathione
Liver
0.57 1.425
-62%* 12%
2.85
-36%*
(Pereira et al., 2007a)
Rat (Wistar);
Multigenerational study design:
6 breeding
pairs/group/generation;
liver antioxidants measured in 6
adult males/group/generation
0, 50 mg/kg diet (0, 2.85 mg/kg-
day) (FO rats)
0, 25 mg/kg diet (0,1.425 mg/kg-
day) (Fl rats)
0,10 mg/kg diet (0, 0.57 mg/kg-
day) (F2 rats)
Diet (DEP dissolved in corn oil)
FO: Adult exposure [150 days: 100
days (premating) + 10 days
(mating) and through gestation
and weaning]
Fl, F2: Developmental exposure
[GDO - PND21] and Adult exposure
[150 days (see FO protocol) starting
PND 35-40]
(percent change compared to control)
Glutathione3
Glutathione
reductase3
Liver
FO Males
0 2.85
-16%*
-66%*
Fl Males
0 1.425
-60%*
-93%*
F2 Males
0 0.57
-79%*
-97%*
Histopathological effects
(Shiraishietal.. 2006)
Rat (Sprague-Dawley);
10/sex/group
0, 40, 200,1,000 mg/kg-day DEP
Gavage in corn oil
28 days
No remarkable observations were noted.
(Brown et al.. 1978)
Rat (Sprague Dawley); 5/sex/group
0,1, 5% (M: 0, 770, 3160 mg/kg-
day; F: 0, 750, 3710 mg/kg-day)
Diet
42 days, and
15/sex/group
0, 0.2,1, 5% in diet (M: 0,150,
770, 3160 mg/kg-day; F: 0,150,
750, 3710 mg/kg-day)
112 days
No remarkable observations were noted.
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Results
(NIP. 1995)
Mouse (B^F!); 60/sex/group
7.5,15, 30 nL/day (5 days/week)
(0, 8.4,16.8, 33.6 mg/day)
Dermal (mixed with acetone)
104-105 weeks (50/sex/group)
Interim sacrifice at 15 months
(10/sex/group)
Incidence of basophilic focus in the liver
Males
Females
0
0/50
8.4
1/50
16.8
9/50*
33.6
3/50
0
2/50
8.4
3/51
16.8
6/50
33.6
2/50
(Fuiiietal., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation
0, 600, 3000,15,000 ppm in the
diet (0, 40,197,1016 mg/kg-day in
FO males; 0, 51, 255,1297 mg/kg-
day in FO females; 0,46, 222,1150
mg/kg-day in Fl males; 0, 56, 267,
1375 mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental
males (14 weeks of dosing during
premating and mating) and ~133
days for FO and Fl parental
females (10 weeks premating, 3
weeks mating, 3 weeks gestation,
3 weeks lactation)
No remarkable observations were noted in the animals that were examined
(i.e. control and high dose FO and Fl parental males and females).
(Mapuskaretal., 2007)
Mouse (Swiss); 5 females/group
0, 10, 25, 50 mg/kg (0, 1.25, 3.125,
6.25 mg/kg-day)
Diet (DEP dissolved in corn oil)
90 days
Intracellular vacuolations, proliferation of peroxisomesand mitochondria.
(Quantitative data not reported by study authors).
(Sinkarand Rao, 2007)
Rat (Wistar); 8/sex/group
0, 50 ppm (0, 2.5 mg/kg-day)
Drinking water
180 days
Vacuolations in hepatocytes, loss of hepatic architecture, degenerative
changes in the centrilobular and periportal areas, and necrotic changes.
(Quantitative data not reported by study authors.)
(Pereira and Rao. 2006)
Rat (Wistar); 6 females/group
0, 50 mg/kg diet (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
150 days
Loss of hepatic architecture, granular deposits in hepatocytes and
vacuolation in the centrilobular and periportal areas.
(Quantitative data not reported by study authors.)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-1. Evidence pertaining to hepatic effects in animals following
exposure to DEP
Reference and Study Design
Results
(Pereira et al.. 2006)
Rat (Wistar); 6 males/group
0,10, 25, 50 mg/kg diet (0, 0.57,
1.425, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
150 days
Rats in the 0.57 mg/kg-day group, but not the 1.425 or 2.85 mg/kg-day
group, showed severe intra- and intercellular vacuolations, loss of hepatic
architecture, fatty degeneration in the centrilobular and periportal areas,
and increased number of peroxisomes. Rats in the .425 or 2.85 mg/kg-day
groups showed granular deposits in the hepatocytes and mild vacuolations
in the centrilobular and periportal areas. All groups showed increased
mitochondrial proliferation in a dose-dependent manner.
(Quantitative data not reported by study authors.)
(Pereira and Rao. 2007)
Rat (Wistar); 6 breeding
pairs/group; livers examined
microscopically in 6 pups/sex/litter
0, 50 mg diet/kg (0, 2.85 mg/kg-
day)
Diet (DEP dissolved in corn oil)
100 days (premating) + 10 days
(mating) and through gestation
and weaning of the PND 21 male
and female pups (150 days total
for parental animals)
Mild vacuolations in the livers of PND 21 pups.
(Quantitative data not reported by study authors/
*Statistically significant (p<0.05) based on analysis of data by study authors.
Percent change compared to control = treated value - control value x 100
control value
aValues were digitally extracted from graphically presented data
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
J.UUUU :
1000 --
-^ 100 --
-a a
M
< 10 -
M :
E-
-
01 -i
(/I J. -
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i
— td 1
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signifcantly
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t ALT, AST
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150-daystudy; F2 rats
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Figure 2-1. Exposure-response array of liver effects following oral exposure to DEP
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
2.3. Reproductive and Developmental Effects Evidence Tables and
Exposure Array
Table 2-2. Evidence pertaining to MEP and sexual differentiation effects in
humans
Reference and Study Design
Results
Anogenital distance (AGO)
(Suzuki et al.) (Japan)
Birth cohort study; 111 male infants (time period not given)
Outcome: AGO measured 1-3 d after birth (AGD1 to
anterior genitalia, mean 45.8 mm, 14.8 mm/kg; AGD2 to
posterior genitalia, mean 20.3 mm, 6.6 mm/kg)
Exposure: Maternal urine sample, mean 29 wks gestation
MEP in urine (ng/mL):
Median 75th percentile
Unadjusted 7.8 32
SG-adjusted 11 44
Analysis: Linear regression considering gestational week,
birth order, maternal age, maternal smoking during
pregnancy, maternal environmental tobacco smoke
exposure, maternal urinary daidzein (soy isoflavone) and
equol (a urinary metabolite of daidzein) concentrations and
environmental tobacco smoke (smoking status of husbands
of non-smoking women) as potential confounders
Association between MEP and AGO measures
reported as not statistically significant (quantitative
results not reported)
(Swan. 2008) (United States; Minnesota, Missouri,
California)
Multicenter birth cohort study, 2000-2002; 106 boys, mean
age 12.8 mo (Oto36 mo)
Outcome: AGO (to posterior genitalia) measured atO-
36 mo (mean 70.4 mm, 7.1 mm/kg)
Exposure: Maternal urine sample, 3rd trimester
MEP in urine (ng/mL):
Median 75th percentile
Unadjusted 128 437
Analysis: Regression analysis using mixed model adjusting
for age and weight percentile
Related references: (Swan et al.. 2005) (exposure data)
Percent change in AGO per interquartile increase
in MEP concentration(p-value):
MEP
-4.0 (0.005)
The association between MEP and AGO was similar
in magnitude or slightly smaller than seen between
the DEHP metabolites and AGO (percent change per
DEHP metabolite -3.9 to -4.5), and slightly larger
than seen between MBP, MiBP, or MMP and AGO
(percent change -3.2 to -3.6).
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to MEP and sexual differentiation effects in
humans
Reference and Study Design
Results
Cryptorchidism or testicular position
(Swan. 2008) (United States; Minnesota, Missouri,
California)
Multicenter birth cohort study, 2000-2002; 106 boys, mean
age 12.8 mo (Oto36 mo)
Outcome: Incomplete testicular descent assessed at clinical
exam (10% prevalence)
Exposure: Maternal urine sample, 3rd trimester
MEP in urine (ng/mL):
Median 75th percentile
Unadjusted 128 437
Analysis: Logistic regression, adjusting for age and weight
percentile
Related references: (Swan et al.. 2005) (exposure data)
MEP reported as not associated with testicular
position (quantitative results not reported)
(Main et al.. 2006) (Denmark, Finland)
Case-control study within two birth cohorts; n = 130 boys
born 1997-2001; 62 3-mo-old boys with cryptorchidism,
68 controls
Outcome: Cryptorchidism, at birth and/or 3 mo
Exposure: Breast milk samples collected 1-3 mo of age
MEP in breast milk (u.g/L), all samples:
Median (range)
Denmark 0.93 (0.07-33.6)
Finland 0.97 (0.25-41.4)
Analysis: Mann-Whitney U test for comparison of MEP
concentrations in boys with and without cryptorchidism
Median MEP in breast milk (u.g/L)
Controls Cases
0.976 0.898
(p > 0.40)
Infant hormone levels
(Lin et al.. 2011) (Taiwan)
Birth cohort study; 155 newborn infants (81 boys, 74 girls),
born 2000-2001
Outcome: Cord blood hormone levels
Exposure: Maternal urine sample 3rd trimester
MEP in urine:
Median 75th perc. 95th perc.
Unadjusted (ng/mL) 35 61 241
Cr-adjusted (u.g/g Cr) 56 106 346
Analysis: Pearson correlation analysis and linear regression
adjusted for maternal age, BMI, smoking habit, gestational
age, parity, and use of contraceptive drugs as potential
confounders.
Pearson correlation coefficient (r) and regression
coefficient (P), log-MEP (u.g/g Cr) and cord blood
hormone level
Boys
Free testosterone (ng/dL)
Estradiol (pg/mL)
Free testosterone:
estradiol ratio
Girls
Free testosterone (ng/dL)
Estradiol (pg/mL)
-0.10
0.02
-0.13
-0.24*
0.01
NR
-0.02
-0.17
0.02
NR
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to MEP and sexual differentiation effects in
humans
Reference and Study Design
Results
Free testosterone:
estradiol ratio
-0.29*
-0.02
NR = not reported
*p < 0.01; all other p-values > 0.10
The correlation between MEP and free testosterone
in girls was smaller than the correlation between
this outcome and the summed DEHP metabolites
(r = -0.38); the DEHP association remained in the
adjusted regression analysis.
(Main et al., 2006) (Denmark, Finland)
Case-control study within two birth cohorts; n = 130 boys
born 1997-2001; 62 3-mo-old boys with cryptorchidism,
68 controls (includes 5 preterm cases, 3 preterm controls)
Outcome: Serum steroidal and gonadotropin hormone
levels in infants, samples collected when breast milk samples
delivered to hospital
Exposure: Breast milk samples collected 1-3 mo of age.
MEP in breast milk (u.g/L), all samples:
Median (range)
Denmark 0.93 (0.07-33.6)
Finland 0.97 (0.25-41.4)
Analysis: Cases and controls combined for analysis of
association between metabolite concentration and hormone
analysis using partial Spearman correlation coefficients
adjusted for country of birth; hormone ratios evaluated
using regression analysis, considering gestational age,
weight for gestational age, parity, smoking, diabetes, and
country of origin as potential covariates
Spearman correlation coefficient (p-value), MEP
(u.g/L) and serum hormone level (n = 96 boys)
SHBG (nmol/L)
Free testosterone (nmol/L)
Testosterone (nmol/L)
LH (IU/L)
FSH (IU/L)
0.323 (0.002)
-0.191(0.068)
-0.010 (0.93)
0.185 (0.075)
0.050 (0.63)
Adjusted regression coefficient (95% Cl), log-MEP
and log-hormone level (adjusted for country of
origin)
SHBG (nmol/L)
Free testosterone (nmol/L)
LH: free testosterone ratio
1.15(1.03,1.28)
0.86 (0.69, 1.06)
1.26 (0.99, 1.60)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to MEP and sexual differentiation effects in
humans
Reference and Study Design
Results
Gender-related play
(Swan et al.. 2010) (United States)
(United States; Minnesota, Missouri, California, Iowa)
Multicenter birth cohort study, 2000-2002 and 2002-2005
(Iowa); n = 145, ages 4-7 years; second follow-up study of
birth cohort
Outcome: Gender-specific play based on Pre-School
Activities Inventory (24 items completed by parent or
caregiver; sub-scores of male-oriented items and female-
oriented items and a composite score consisting of male
summation minus female summation scores)
Exposure: Maternal urine sample, 3rd trimester
MEP in urine (ng/mL). Distribution not reported for this
analysis; EPA assumed similar distribution as seen in Swan et
a I., 2005
MEP in urine (ng/mL):
Median 75th percentile
Unadjusted 128 437
Analysis: Regression analysis using Generalized Linear
Models, considering creatinine, sex and age of child,
maternal age, parental education, number of same and
opposite sex siblings, ethnicity, clinic location, and parental
attitude as potential covariates
Related references: (Swan et al.. 2005) (exposure data)
log-MEP reported as not associated with masculine
or composite activity score (quantitative results not
reported)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to male reproductive effects in humans
Reference and Study Design
Results
Reproductive hormones
(Joensen et al., 2012)(Denmark)
881 men from the general population, assessed at
military conscript exam*, median age 19.1 yrs (5th,
95th percentiles: 18.4, 22.0 yrs), 2007-2009
Outcome: Serum steroidal and gonadotropin
hormones
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine (ng/mL):
Median 95th percentile
Unadjusted 78 1,936
Analysis: Linear regression considering age, BMI,
smoking, alcohol consumption, time of blood
sampling, assay type, ethnicity, BMI squared, in
utero exposure to tobacco smoke, previous or
current diseases, recent fever, and recent use of
medication as potential covariates.
As reported by Ravnborg et al., 2011.
Results for individual phthalate metabolites (including MEP)
reported as "few significant associations" with free
testosterone, estradiol, SHBG, LH, inhibin-B, or FSH
(quantitative results not reported); analyses adjusted for age,
BMI, smoking, alcohol consumption, and time of blood
sampling (and assay type for inhibin-B only).
(Meeker et al.. 2009)(United States; Boston)
425 male partners seen in sub-fertility clinic from
2000-2004; mean age 36 yrs;
Outcome: Serum steroidal and gonadotropin
hormones
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine (ng/mL):
Median 75th percentile
SG-adjusted 153 518
Analysis: Linear regression using untransformed
(testosterone, estradiol) or natural logarithm
transformed (free androgen index, FSH, LH)
hormone levels; considering age, BMI, smoking
status, race, previous infertility example, prior
ability to impregnate partner, and season and time
of sample collection as potential confounders.
Related references: (Duty et al.. 2005)
Regression coefficient (95% Cl) for change in hormone with
interquartile range (IQR) increase in adjusted MEP
concentration (adjusted for age, BMI, smoking, season and
time of sample collection)
Untransformed hormone level (0.0 = no effect)
Testosterone (ng/dL) 8.87 (-7.18, 24.9)
Estradiol (pg/mL) 0.71 (-0.97, 2.40)
Ln-transformed hormone level (1.0 = no effect)
Free androgen index 1.04 (0.99,1.09)
FSH (IU/L) 0.98 (0.91, 1.06)
LH (IU/L) 0.98 (0.91, 1.04)
(Jonsson et al., 2005) (Sweden)
234 men ages 18-21 yrs from the general
population, assessed at military conscript exam
Outcome: Serum steroidal and gonadotropin
hormones
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine:
Mean difference (95% Cl), highest compared with lowest
quartile of MEP (nmol/mmol Cr)
Testosterone (nM)
Free testosterone (T/SHBG)
Estradiol (pM)
FSH (IU/L)
LH (IU/L)
-0.3 (-2.3, 1.8)
0.06 (-0.05, 0.2)
1.8 (-4.2, 7.7)
0.5 (-0.5, 0.6)
0.7 (0.1,1.2)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to male reproductive effects in humans
Reference and Study Design
Results
Median 75 percentile
Unadjusted (ng/mL) 240 870
Adjusted (nmol/mmol Cr) 83 310
Analysis: Mean difference between high and low
quartiles
MEP quartiles: low <9.95 and high >308 nmol/mmol Cr.
Positive difference indicates lower value in highest exposure
quartile
Sperm parameters
(Joensen et al.. 2012) (Denmark)
881 men from the general population, assessed at
military conscript exam*, median age 19.1 yrs (5th,
95th percentiles: 18.4, 22.0 yrs), 2007-2009
Outcome: Semen analysis
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine (ng/mL):
Median 95th percentile
Unadjusted 78 1,936
Analysis: Linear regression, considering age, BMI,
smoking, alcohol consumption, ethnicity, BMI
squared, in utero exposure to tobacco smoke,
previous or current diseases, recent fever, recent
use of medication, abstinence time, and time from
ejaculation to analysis as potential covariates.
Results for individual phthalate metabolites (including MEP)
reported as "few significant associations" with sperm volume,
count, or percentage progressively motile sperm (quantitative
results not reported; analyses adjusted for abstinence time
[volume, concentration, and count] or time from ejaculation to
analysis [progressively motile], percent of morphologically
normal sperm was left unadjusted).
(Liu et al.) (China)
97 male partners seen in sub-fertility clinic 2009-
2010; mean age 32 yrs
Outcome: Semen analysis; results dichotomized
above and below WHO reference values; n = 43
with normal semen parameters
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine:
Median 66th percentile
Unadjusted (ng/mL) 12.6 21.3
Cr-adjusted (u.g/g Cr) 15.2 28.5
Analysis: Logistic regression, adjusting for age, BMI,
abstinence time, smoking, alcohol use, and
education
OR (95% Cl) by tertile of MEP (adjusted for age, BMI,
abstinence time, smoking, alcohol use)
MEP
Tertile
1 (low)
2
3 (high)
(trend p)
Sperm
concentration
<20xl06/mL
(n = H)
1.0 (referent)
1.4 (0.2, 8.8)
1.5(0.2,9.6)
(0.66)
Sperm motility
<50% motile
(n = 34)
1.0 (referent)
0.7 (0.2, 1.9)
0.4 (0.1, 1.2)
(0.10)
Semen volume
<2mL
(n = 15)
1.0 (referent)
0.2(0.1,1.2)
0.8 (0.2, 3.0)
(0.78)
This document is a draft for review purposes only and does not constitute Agency policy,
2-20 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to male reproductive effects in humans
Reference and Study Design
Results
(Pant et al.. 2008) (India)
300 male partners (n = 100 fertile, 200 infertile)
seen in obstetrics and gynecology department from
both urban and rural areas; mean age 29 yrs; time
period not reported
Outcome: Semen analysis
Exposure: Semen sample
DEP in semen (u.g/mL), mean ± SE:
Fertile Infertile
Rural areas 0.64 ±0.24 1.13 ±0.11
Urban areas 0.74 ± 0.04 3.11 ± 0.26
Analysis: Pearson correlation analysis
Pearson correlation coefficient between semen DEP and sperm
parameter:
-0.19*
0.03
-0.02
0.07
Sperm concentration (x 10 /mL)
Sperm motility (%)
Morphology (percent abnormal)
DNA fragmentation index
(chromatin integrity)
*p < 0.05; all other p-values > 0.05
The correlation between DEP and sperm concentration was
similar to or slightly smaller that the correlation between this
outcome and DBP (r=-0.20) or DEHP (r = -0.25).
(Mauser etal., 2007) (United States; Boston)
n = 379 male partners seen in sub-fertility clinic
2000-2004; mean age 36 yrs
Outcome: Sperm DNA damage assessed by neutral
comet assay
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine (ng/mL):
Median 75th perc. 95th perc.
SG-adjusted 154 513 2,030
Analysis: Linear regression, considering age,
abstinence time, smoking status, and race as
potential covariates
Related reference: (Dutyetal.. 2003b)
Regression coefficient (95% Cl) for DNA damage associated
with interquartile range increase in In-MEP (adjusted for age
and smoking status)
Comet extent
(u.m)
Tail distribution
(u.m)
%DNAtail
6.06 (0.941, 12.3) 2.72 (0.46, 5.00) -0.26 (-2.52, 2.02)
(Mauseretal.. 2006) (United States; Boston)
n = 443 male partners seen in sub-fertility clinic
2000-2004; mean age 36 yrs
Outcome: Semen analysis; results dichotomized
above and below WHO reference values
Exposure: Urine sample, collected at same time as
serum sample for hormone analysis
MEP in urine (ng/mL):
Median 75th perc. 95th perc.
SG-adjusted 158 535 2,214
Analysis: Logistic regression, considering age, race,
BMI, abstinence time, and smoking as potential
covariates
Related references: (Duty et al., 2004); (Duty etal.,
2003a); (Mauser et al., 2005)
OR (95% Cl) by quartile of MEP (ng/mL) (adjusted for age,
abstinence time, and smoking; comparison group = 210 men
without deficiencies on any of these three parameters)
MEP
quartile
1 (low)
2
3
4 (high)
(trend p)
Sperm
concentration
<20xl06/mL
1.0 (referent)
1.5 (0.7, 3.6)
1.0 (0.4,2.5 )
1.2 (0.5, 3.0)
(0.94)
Sperm motility
< 50% motile
1.0 (referent)
1.1 (0.6,1.9)
0.8 (0.5, 1.5)
1.0 (0.6, 1.8)
(0.84)
Sperm
morphology
< 4% normal
1.0 (referent)
0.8 (0.4, 1.6)
0.7 (0.3, 1.3)
0.5(0.3,1.1)
(0.07)
OR (95% Cl) for sperm motion parameters by quartile of MEP
(ng/mL) (adjusted for age, smoking and abstinence time)
MEP
Curvilinear
This document is a draft for review purposes only and does not constitute Agency policy,
2-21 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to male reproductive effects in humans
Reference and Study Design
(Zhang etal., 2006) (China)
52 men seen in Shanghai Institute of Planned
Parenthood Research in 2002; mean age 32 yrs
Outcome: Semen analysis
Exposure: Semen samples
Mean (range)
DEP (mg/L) 0.47 (0.13-1.32)
Analysis: Spearman correlation analysis
Results
(ng/mL) Straight line velocity
quartile velocity (u.m/s) (urn/s) Linearity (%)
1 (low) 1.0 (referent) 1.0 (referent) 1.0 (referent)
2 0.02 -0.28 0.34
(-2.66, 2.70) (-4.82, 4.25) (-1.55, 2.23)
3 0.81 -0.47 1.67
(-1.92,3.55) (-5.09,4.16) (-0.25,3.60)
4 (high) 2.11 4.48 -0.31
(-0.61,4.83) (-0.13,9.08) (-2.23,1.61)
(trend p) 0.10 0.07 0.93
MEP quartile cut points: 8.7-58.7, 59.6-157.6, 157.9-534.3,
535.0-11,371 ng/mL
No interaction with polychlorinated biphenyls (PCBs)
Spearman correlation coefficient (p-value), semen DEP (mg/L)
and sperm parameter:
Sperm density (x 106/mL) -0.25 (0.15)
Sperm liability (%) -0.13 (0.45)
Sperm rate of malformations (%) 0.19 (0.28)
This document is a draft for review purposes only and does not constitute Agency policy,
2-22 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-2. Evidence pertaining to male reproductive effects in humans
Reference and Study Design
Results
(Jonsson et al.. 2005)(Sweden)
234 men ages 18-21 yrs from the general
population, assessed at military conscript exam
Outcome: Semen analysis
Exposure: Urine sample (collected at same time as
semen sample)
MEP in urine: Median 75th percentile
Unadjusted (ng/mL) 240 870
Adjusted (nmol/mmol Cr) 83 310
Analysis: Mean difference between high and low
quartiles
Mean difference (95% Cl), highest (>308 nmol/mmol Cr)
compared with lowest (<9.95 nmol/mmol Cr) quartile MEP
(Positive difference indicates lower value in highest exposure
quartile)
Sperm concentration (x 106/mL) 5.0 (-15, 25)
Sperm motility (%) -0.4 (-6.4, 5.6)
Sperm damage (chromatin integrity) 0.8 (-2.8, 4.4)
Infertility
(Tranfo et al.. 2012) (Italy)
Case-control study; n = 56 infertile couples from
assisted reproduction center, n = 56 fertile couples
(parents of one or more children, living in same
area); mean age 39-40 yrs in both groups; time
period not reported
Outcome: Primary or secondary infertility as
assessed by WHO criteria (cause attributed to males
in 8/56 couples)
Exposure: Urine sample
MEP in urine, fertile couples:
Median 95th percentile
Cr-adjusted (u.g/g Cr) 52 651
Analysis: Mann-Whitney test for comparison of
MEP concentrations by group
MEP concentration in urine (u.g/g Cr) in fertile and infertile
couples
Fertile Infertile p-value
Median
95th
percentile
52
651
199
2507
<0.001
Sex-stratified comparison was also significant for men and for
women (p < 0.001, quantitative results not reported).
The case-control difference in MEP was the largest of the 4
phthalate metabolites examined; differences were also seen
with MnBP, and to a lesser extent with MBzP and the
summation of MEHP+ MEHHP.
(Pant et al.. 2008) (India)
Case-control study; n = 100 fertile, 200 infertile men
visiting obstetrics and gynecology department from
both urban and rural areas; mean age 29 yrs; time
period not reported
Outcome: Infertility based on female partners who
had not conceived after 1-yr unprotected
intercourse and who had no diagnosed fertility
disorder
Exposure: Semen sample
DEP in semen (u.g/mL), mean ± SE:
Fertile Infertile
Rural areas 0.64 ±0.24 1.13 ±0.11
Urban areas 0.74 ± 0.04 3.11 ± 0.26
Analysis: Two-way ANOVA for difference in DEP
concentrations between fertile and infertile with
rural/urban as additional variable
DEP concentration in semen (u.g/mL), mean ± SE, in fertile and
infertile men
Rural:
Fertile (n = 40)
0.64 ±0.24
Urban:
Fertile (n = 60)
0.74 ± 0.04
*p<0.05
Infertile (n = 88)
1.13 ±0.11
Infertile (n = 112)
3.11 ±0.26*
The case-control difference in DEP was similar or smaller than
the difference seen with DBP, DEHP, or DMP.
This document is a draft for review purposes only and does not constitute Agency policy,
2-23 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
Results
Serum Hormone levels
(Fuji! et al.. 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation;
reproductive hormones
measured in 6 FO males/group
0, 600, 3000,15,000 ppm (0, 40,
197,1016 mg/kg-day)
Diet
~98 days (FO parental males; 14
weeks dosing during premating
and mating)
(percent change compared to control)
Testosterone
Progesterone
0
40
-28%
36%
197
-80%*
125%
1016
-50%*
16%
(Pereira et al.. 2008a)
Rat (Wistar); 6 males/group
0, 0 (oil control), 10, 25, 50
mg/kg (0, 0 (oil control), 0.57,
1.425, 2.85 mg/kg-day
Diet (DEP dissolved in corn oil)
150 days
(percent change compared to oil control)
Testosterone
Androstenedione
0
0.57
-35%*
-28%*
1.425
-43%*
-43%*
2.85
-62%*
-32%*
Anogenital distance (AGO)
(Fuiiietal., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation;
AGO measured in 22-24
litters/group/generation
0, 600, 3,000, 15,000 ppm (0,
40,197,1016 mg/kg-day in FO
males; 0, 51, 255,1297 mg/kg-
day in FO females; 0,46, 222,
1150 mg/kg-day in Fl males; 0,
56, 267,1375 mg/kg-day in Fl
females)
Diet
~98 days for FO and Fl parental
males (14 weeks of dosing
during premating and mating)
and ~133 days for FO and Fl
parental females (10 weeks
premating, 3 weeks mating, 3
weeks gestation, 3 weeks
lactation)
(percent change compared to control)
Males
Fl males at PNDO
FlmalesatPND4
F2 males at PNDO
F2 males at PND4
40/46
1%
-4%
-1%
-2%
197/222 1016/1150
4%
-2%
0%
-1%
-3%
-2%
1%
0%
This document is a draft for review purposes only and does not constitute Agency policy,
2-24 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
Results
Reproductive organ weight
(Kwacketal.. 2009)
Rat (Sprague Dawley); 6
males/group
0, 500 mg/kg-day DEP
and
0, 250 mg/kg-day MEP
Gavage in corn oil
28 days
(Shiraishietal., 2006)
Rat (Sprague-Dawley);
10/sex/group
0, 40, 200, 1,000 mg/kg-day
Gavage in corn oil
28 days
(Brown et al.. 1978)
Rat (Sprague Dawley);
5/sex/group
0, 1, 5% (M: 0,770, 3160 mg/kg-
day; F: 0, 750, 3710 mg/kg-day)
Diet 42 days, and
15/sex/group
0, 0.2, 1,5% (M: 0,150, 770,
3160 mg/kg-day; F: 0, 150, 750,
3710 mg/kg-day)
Diet
112 days
(Pereira et al., 2008a)
Rat (Wistar); 6 males/group
0, 0 (oil control), 10, 25, 50
mg/kg diet (0, 0 (oil control),
0.57, 1.425, 2.85 mg/kg-day
Diet (DEP dissolved in corn oil)
150 days
(Pereira et al.. 2007b)
Rat (Wistar); 6/sex/group
0, 50 (FO) (0, 2.85 mg/kg-day)
0, 25 (Fl) (0, 1.425 mg/kg-day)
Diet
150 days/generation ]
Relative weights (percent change compared to control)
Testis weight (paired)
Epididymis weight (left)
0 500 (DEP) 0 250 (MEP)
0 -9% 0 -7%
0 4% 0 -3%
Relative weights (percent change compared to controls)
0
testes
epididymes
40 200 1000
6% 6% 11%
9% 9% 9%
Relative gonad weight (percent change compared to control)
Males 0
42 day study
112 day study
150 770 3160
N/A 9% 43%*
-3% 0% 29%*
Absolute testis weight (percent change compared to control)
0 0.57 1.425 2.85
-18%* -23%* -28%*
Absolute epididymis weight (percent change compared to oil control)
0 0.57 1.425 2.85
-22%* -35%* -43%*
Absolute testis weight (percent change compared to control)
FO parental males
0 2
Fl adult males
85 0 1.425
5% - -8%
This document is a draft for review purposes only and does not constitute Agency policy,
2-25 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
(Fuiii et al., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation;
reproductive organs weighed in
21-24 males/group (FO and Fl
parental, Fl and F2 weanlings)
0, 600, 3,000, 15,000 ppm (0,
40, 197, 1016 mg/kg-day in FO
males; 0, 51, 255, 1297 mg/kg-
day in FO females; 0, 46, 222,
1150 mg/kg-day in Fl males; 0,
56, 267, 1375 mg/kg-day in Fl
females)
Diet
~98 days for FO and Fl parental
males (14 weeks dosing during
premating and mating) and
~133 days for FO and Fl
parental females (10 weeks
premating, 3 weeks mating, 3
weeks gestation, 3 weeks
lactation)
Results
Absolute testis weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
-3% 1%
-1% -1%
7% 0%
0% 0%
1016/1150
3%
-2%
-11%
-6%
Relative testis weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
0% 0%
-2% -3%
6% 0%
0% 2%
1016/1150
0%
-3%
2%
4%
Absolute epididymis weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
-5% -1%
0% 3%
-3% -2%
0% 1%
1016/1150
-5%*
1%
-9%
-6%
Relative epididymis weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
0% 0%
0% 5%
-3% -1%
-1% 0%
1016/1150
0%
0%
5%
-1%
Absolute prostate weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
3% 13%
3% 4%
0% 0%
0% 0%
1016/1150
8%
-5%
-20%*
-12%
Relative prostate weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
5% 12%
5% 2%
2% 2%
0% 0%
1016/1150
12%
-6%
-6%
-6%
Absolute seminal vesicle weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 40/46 197/222
0% 3%
-4% 1%
0% 0%
-5% -5%
1016/1150
-2%
-5%
0%
-10%
Relative seminal vesicles (percent change compared to control)
FO parental
Fl parental
Fl weanling
0 40/46 197/222
0% 3%
-3% 0%
4% 4%
1016/1150
3%
-6%
17%
This document is a draft for review purposes only and does not constitute Agency policy,
2-26 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
(NIP. 1995)
Mouse (BgCsFi); 10/sex/group
0, 12.5, 25, 50, 100 u.l/day (5
days/week) (0, 14, 28, 56, 112
mg/day)
Dermal (neat)
28 days, and
Rat (F344/N); 10/sex/group
0, 37.5, 75, 150, 300 nl (5
days/week) (0, 42, 84, 168, 336
mg/day)
Dermal (neat)
28 days
(NIP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20
breeding pairs/treatment group
Fl: 20 breeding
pairs/group/generation
FO: 0, 0.25, 1.25, 2.5 % (0, 438,
875, 1750, 4375 mg/kg-d)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days
segregation (126 days total)
Fl: in utero + lactation, and
then in the diet through a 7 day
mating period at 74±10 days old
(Fl females were allowed to
deliver litters)
Results
F2 weanling - -9% -4% -4%
Absolute testis (right) weight (percent change compared to control)
0 14 28 56 112
Mouse - -3% -3% 0% -2%
0 42 84 168 336
Rat - -3% -2% -2% -2%
Relative testis (right) weight (percent change compared to control)
0 14 28 56 112
Mouse - -5% -1% -1% -1%
0 42 84 168 336
Rat - 0% 3% 3% 5%
Absolute weights in Fl parental males (percent change compared to control)
Testis
Epididymis
Prostate
Seminal vesicles
0 3640
-8%
.9*
32%*
-11%
Relative weights in Fl parental males (percent change compared to control)
Testis
Epididymis
Prostate
Seminal vesicles
0 3640
1%
1%
32%*
-4%
Testicular lipid peroxidation
(Pereira et al.. 2008a)
Rat (Wistar); 6 males/group
0, 0 (oil control), 10, 25, 50
mg/kg (0, 0 (oil control), 0.57,
1.425, 2.85 mg/kg-day
Diet (DEP dissolved in oil)
150 days
(percent change compared to control)
0 0.57 1.425 2.85
Testisb- 130%* 215%* 285%*
This document is a draft for review purposes only and does not constitute Agency policy,
2-27 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
Results
Effects on sperm
(Kwacketal.. 2009)
Rat (Sprague Dawley); 6
males/group
0, 500 mg/kg-day DEP
and
0, 250 mg/kg-day MEP
Gavage in corn oil
28 days
(Shiraishietal., 2006)
Rat (Sprague-Dawley);
10/sex/group
0, 40, 200, 1,000 mg/kg-day
DEP
Gavage in corn oil
28 days
(Fuiii et al., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding pairs/group/
generation; sperm parameters
assessed in 23-24 parental
males/group/generation
0, 600, 3,000, 15,000 ppm
(0, 40, 197, 1016 mg/kg-day in
FO males; 0, 46, 222, 1150
mg/kg-day in Fl males)
Diet
~98 days for FO and Fl parental
males (14 weeks dosing during
premating and mating) and
~133 days for FO and Fl
parental females (10 weeks
premating, 3 weeks mating, 3
weeks gestation, 3 weeks
lactation)
Sperm parameters (percent change compared to control)
No. of sperm (x 106/g
right cauda
epididymis)
Motility (%)
0 500 (DEP)
-16%
-25%
0 250 (MEP)
-41%*
-56%*
Dose-related effects on sperm (morphology, count) were not observed.
(Quantitative data not reported by study authors)
Sperm parameters (percent change compared to control)
FO parental males
No. of sperm (x 10s)
Pertestis
Per gram testis
Per cauda
epididymis
Per gram cauda
Epididymis
Motility (%)
Abnormal sperm (%)
Tailless sperm (%)
Fl parental males
No. of sperm (x 10s)
Pertestis
Per gram testis
Per cauda
epididymis
Per gram cauda
Epididymis
Motility (%)
Abnormal sperm rate
Tailless sperm rate (%)
0 40
-8%
-9%
-8%
-4%
-4%
a633%
a733%
0 46
-2%
0%
-5%
-4%
-2%
38%
29%
197 1016
-7% -6%
-7% -2%
2% -3%
0% 3%
1% 1%
73%* -5%
85%* -7%
222 1150
-1% -4%
2% -2%
-5% -2%
-5% -2%
-3% -1%
118%* 153%*
116%* 141%*
This document is a draft for review purposes only and does not constitute Agency policy,
2-28 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-3. Evidence pertaining to male reproductive effects in animals
Reference and Study Design
Results
(NTP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20
breeding pairs/treatment group
Fl: 20 breeding
pairs/group/generation
FO: 0, 0.25,1.25, 2.5 % (0, 438,
875, 1750, 4375 mg/kg-d)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days
segregation (126 days total)
Fl: in utero + lactation, and
then in the diet through a 7 day
mating period at 74±10 days old
(Fl females were allowed to
deliver litters)
Sperm parameters (percent change compared to control)
Fl parental males
No. of sperm (x 103/mg
caudal tissue)
Motility (%)
Abnormal sperm (%)
Tailless sperm (%)
3640
-30%*
-4%
65%
0%
*Statistically significant (p<0.05) based on analysis of data by study authors.
a Large standard deviation reported
Percent change compared to control = treated value - control value x 100
control value
bValues used to derive these results were digitally extracted from bar graphs within the publication.
This document is a draft for review purposes only and does not constitute Agency policy,
2-29 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
10000
1000
n
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M
100
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o
Q
10
• statistically
significant
change
D not statistically
significanly
changed
0.1
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o
ro ro
I I
00
o
O
(N
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03 O3
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testosterone
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01
o
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« I
" gonads
o
o
Q.
^ O
in
O
ID
(N
prostate
x|/ testis,
epididymis
u Q.
CD 3
:= Q.
1" 5
x|/ testis,
epididymis,
prostate
LO Q
9 z
-
iJ Q.
CD 3
:= Q.
x|/ seminal
vesicles
Male reproductive organ weight changes
01 M
g E
(N .^
» >~
_: T3
x|/ count,
motility
o
o
LO
o
tab-
normal
>-
O3
-a
ii
(N
x|/ count,
tab-
normal
Sperm effects
Figure 2-2. Exposure-response array of male reproductive effects following exposure to DEP
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-4. Evidence pertaining to MEP and the timing of male puberty
VinmQTic
in
humans
Reference and Study Design
Results
(Mieritz et al., 2012) (Denmark)
Nested case-control study in cohort of 555 boys, 6-19 yrs
old, participating in the COPENHAGEN Puberty Study, 2006-
2008; 38 boys with pubertal gynecomastia and 190 age-
matched controls.
Outcome: Anthropometry, pubertal stage (pubic hair and
genital development), presence of gynecomastia, and
serum testosterone
Exposure: Urine sample, collected at clinical evaluation
MEP in urine (ng/mL):
Median 95th percentile
Groups 36.24 263.9
(boys without gynecomastia, all ages)
Analysis: Two-tailed Mann-Whitney U-test for
comparisons between groups; linear regression with age
adjustment for association with serum testosterone; probit
analysis with phthalate concentrations divided in quartiles
for analysis of puberty timing.
MEP concentration (ng/mL) by group
Median
95th percentile
Group 1
(n = 38)
38.70
314.3
Group 2
(n = 189)
37.95
359.9
Group 3
(n = 517)
36.24
263.9
Group 1 = boys with palpable gynecomastia
Group 2 = boys without palpable gynecomastia
(age-matched)
Group 3 = boys without palpable gynecomastia (all
ages)
No association between MEP concentration and
timing of puberty or serum testosterone level
(quantitative results not reported).
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-5. Evidence pertaining to MEP and the timing of female puberty in
humans
Reference and Study Design
Results
Central precocious puberty and premature thelarche
(Frederiksen et al.. 2012) (Denmark)
Case-control study, n = 24 girls with precocious puberty (n =
13 with central precocious puberty, n = 6 with early normal
puberty, n = 5 with premature thelarche) recruited from
outpatient clinic 2008-2009 and n = 184* age-matched
controls from COPENHAGEN Puberty Study cohort,
recruited from high schools 2006-2008
Outcome: Precocious puberty, early normal puberty, or
premature thelarche, defined based on clinical standards
Exposure: Urine sample (child's), collected at clinical
evaluation
MEP in urine (ng/mL), controls:
Median (range)
Unadjusted 38(4.8-1,649)
Analysis: MEP concentrations in cases and controls
compared with Mann-Whitney U test
'study reports number of controls inconsistently; text
reports 164 controls, while Table 4 reports 184.
Median (range) MEP (ng/mL) in cases and controls:
Controls
38 (4.8-1,649)
Precocious
puberty
30(12-371)
(p-value)
(>0.05)
(Lomenicket al., 2010) (United States, Ohio and Kentucky)
Case-control study; n = 28 girls with central precocious
puberty, n = 28 age- and race-matched controls; recruited
from pediatric endocrinology clinic 2005-2008; mean age
7 yrs
Outcome: Central precocious puberty defined based on
clinical standards (appearance of physical characteristics of
puberty before 8 yrs of age, with laboratory confirmation of
central origin of breast development); no cases had
received medical treatment prior to urine sample collection
Exposure: Urine sample (child's), collected at clinical
evaluation
MEP in urine of controls
MeaniSE
Unadjusted (ng/mL) 253 ± 58
Cr-adjusted (u.g/g Cr) 244 ± 51
Analysis: MEP concentrations in cases and controls
compared with Wilcoxon rank-sum test
Mean ± SE MEP in cases and controls:
Central
precocious
Controls puberty (p-value)
Unadjusted 253 ± 58 139 ± 24 (0.40)
(ng/mL)
Cr-adjusted 244 ± 51 165 ± 26 (0.38)
Cr)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-5. Evidence pertaining to MEP and the timing of female puberty in
humans
Reference and Study Design
Results
Pubertal development (general population)
(Frederiksen et al.. 2012) (Denmark)
725 healthy girls ages 5.6-19.1 yrs from COPENHAGEN
Puberty Study cohort, recruited from high schools during
2006-2008
Outcome: Stage of breast or pubic hair development;
Serum steroid and gonadotropin hormones
Exposure: Urine sample (child's), collected at time of
pubertal stage assessment
MEP in urine (ng/mL), all 725 participants:
Median 95th percentile
Unadjusted 39 262
Analysis: Probit analysis, results verified using Pool-
Adjacent-Violators algorithm.
Mean age (95% Cl) (yrs) at entry into breast stage 2
or pubic hair stage 2, by quartile of MEP:
Pubic hair stage 2
(n not reported)
MEP Breast stage 2
quartile (n = 394)
1 (low) 9.94 (9.47,10.42) 10.95 (10.66, 11.25)
2 10.08 (9.59, 10.57) 11.22 (10.91,11.53)
3 9.89 (9.40,10.37) 11.20 (10.91,11.50)
4 (high) 9.83 (9.30,10.37) 11.13 (10.82,11.46)
Levels of FSH, LH, estradiol, testosterone were
similar across MEP exposure groups (quantitative
results not reported)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-6. Evidence pertaining to MEP and gynecological conditions in
humans
Reference and Study Design
Results
Endomethosis and leiomyomas
(Buck Louis et al.. 2013) (California and Utah, United States)
Matched cohort study ; n = 473 women undergoing
laparoscopy or laparotomy and 127 population age- and
residence-matched referents, aged 18-44 yrs (2007-2009)
Outcome: Endometriosis confirmed by surgery (operative
cohort) or MRI (population cohort)
Exposure: Urine sample
MEP in urine (ng/mL), Cr-adjusted :
Geometric mean (95% Cl)
Operative cohort-Endometriosis 107.2 (88.73,129.4)
Operative cohort-Controls 109.6 (93.64,128.3)
Population cohort-Endometriosis 152.0 (59.11, 390.8)
Population cohort-Controls 138.2 (107.1,178.4)
Analysis: Student's t-test or Wilcoxon test for continuous
data; logistic regression, adjusting for age, BMI, and
creatinine; sensitivity analyses conducted restricting cohort
to endometriosis stages 3 and 4 diagnoses or visually and
histologically confirmed endometriosis, and referent group
consisting of women with postoperative diagnosis of normal
pelvis
Confirmed cases of endometriosis matched to women
without endometriosis within each cohort: operative
cohort, 190 cases, 283 controls; population cohort: 14
cases, 127 controls.
OR (95% Cl) for endometriosis per unit increase in
In-MEP, by cohort (adjusted for age, BMI, and
creatinine)
Operative cohort
Population cohort
1.01 (0.82,1.24)
1.07 (0.56, 2.04)
Adjusted OR (95% Cl) for endometriosis per unit
increase in In-MEP in operative cohort (sensitivity
analysis):
Endometriosis stage 3 and 4
(n = 339)
1.04 (0.75, 1.43)
Visual/histological confirmed 1.04 (0.78,1.39)
endometriosis (n = 473)
Comparison with women with 1.05 (0.81,1.35)
postoperative diagnosis
normal pelvis (n = 320)
Note: Concentrations were log transformed and
rescaled by their SDs for analysis.
(Huang etal., 2010) (Taiwan)
Case-control study, n = 28 endometriosis cases, n = 36
leiomyoma cases, n = 16 adenomyosis cases, and n = 29
controls; mean ages ~38, 41, and 36 yrs, respectively;
recruited from laparotomy patients in medical center, 2005-
2007
Outcome: Clinical diagnosis of endometriosis, leiomyoma,
or adenomyosis confirmed by pathology
Exposure: Urine sample
MEP in urine) Median (range)
Unadjusted (ng/mL) Cr-adjusted(u.g/g Cr)
Control 37.2 (10.6-396.2)
Endometriosis 31.6 (13.4-712.9)
Leiomyoma 28.5 (6.7-705.9)
Adenomyosis 33.8 (9.7-96.8)
OR (95% Cl) for case status by MEP above compared
with below the median (for endometriosis, adjusted
for GSTM1 polymorphism and BMI; for leiomyomas
and adenomyosis, adjusted for GSTM1
polymorphism and age)
Endometriosis Leiomyomas Adenomyosis
0.66
(0.21, 2.09)
1.32
(0.44, 3.96)
1.08
(0.26,4.57)
71.4 (5.6-373.3)
58.0 (13.4-422.3)
103.7 (11.2-519.0)
53.4 (13.4-147.7)
Analysis: Logistic regression, considering age, BMI, and
GSTM1 polymorphism as covariates.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-6. Evidence pertaining to MEP and gynecological conditions in
humans
Reference and Study Design
Results
(Weuve et al.. 2010) (United States, NHANES)
Case-control study of 1,227 female participants in the 1999-
2004 NHANES, ages 20-54 yrs; n = 87 endometriosis cases,
n = 151 leiomyomata cases, and n = 1,020 controls; mean
age ~36 yrs
Outcome: Self-reported diagnosis of endometriosis or
leiomyomata; median time since diagnosis, 9 yrs
Exposure: Urine sample, collected at time of survey
MEP in urine (ng/mg Cr):
Geometric mean (SE)
207 (27.5)
210(21.9)
220(14.1)
Analysis: Logistic regression, adjusting for variables shown
in results column
Endometriosis cases
Leiomyomata cases
Controls
OR (95% Cl) for gynecological condition by quartile of
MEP (ng/mg Cr) (adjusted for age, race/ethnicity, age
at menarche, current pregnancy status and current
breast-feeding status)
MEP Quartile Endometriosis Leiomyomata
1 (low) 1.0 (referent) 1.0 (referent)
2 0.89 (0.44, 1.82) 0.72 (0.35,1.46)
3 1.13(0.56,2.27) 1.29(0.74,2.25)
4 (high) 1.12(0.53,2.35) 0.85(0.47,1.54)
(trend p) (0.6) (0.9)
(Itoh et al.. 2009) (Japan)
Case-control study, n = 57 endometriosis patients, n = 80
controls; all seeking evaluation for infertility
Outcome: Clinical diagnosis of endometriosis (American
Fertility Society stages II-IV) by laparoscopy; controls were
stages 0-1
Exposure: Urine sample
Unadjusted MEP in urine (u.g/L):
Median 75th percentile
Controls 21.4 53.2
Cases 39.6 74.9
Cr-adjusted MEP in urine (u.g/g Cr):
Median 75th percentile
Controls 11.2 24.7
Cases 18.9 37.7
Analysis: Logistic regression, adjusting for menstrual
regularity and average menstrual cycle length; Jonkheere
Terpstra trend test for concentration by stage.
OR for endometriosis by MEP (u.g/g Cr) above
compared with below the median (adjusted for
menstrual regularity and average menstrual cycle
length)
OR (95% Cl) = 1.72 (0.81, 3.68)
Median MEP in urine by stage of endometriosis:
Endometriosis
stage
0
I
IV
(trend p)
Unadjusted
(Mg/U
20.3
28.5
49.1
44.9
31.2
(0.09)
Cr-adjusted
Cr)
10.5
16.1
19.1
17.6
16.1
(0.23)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-7. Evidence pertaining to MEP and neurobehavioral and
neurodevelopmental effects in infants and children
Reference and Study Design
Results
Attention and executive function in pre-school and school-aged children
(Engel, 2010) (United States, New York City)
Birth cohort study, n = 177 children from original
birth cohort studied by Engel et al. (2009), 54%
boys, three follow-up exams at ages 4.5-5.5, 6-
6.5, 7-9 yrs
Outcome: Behavior assessed by maternal
reporting on Behavior Rating Inventory of
Executive Function (BRIEF) and Behavior
Assessment System for Children—Parent Rating
Scales (BASC-PRS)
Exposure: Maternal urine sample, 25-40 wks
gestation*
Median 75th percentile
MEP(u.g/L)* 386 1,025
Sum LMW (U.M/L) 1.88 4.59
(sum of MBP, MEP, MiBP, and MMP)
Analysis: Generalized linear regression model,
adjusting for variables shown in results column.
Other (no-specified) variables were considered).
MEP concentrations not reported in (Engel et al.,
2010); values reported here are from an earlier
analysis of this cohort described in (Engel et al.,
2009)
Regression coefficient for change in behavioral score per unit
increase in In-phthalate level (u.M/L) in boys (adjusted for
race, educational level and marital status of the primary
caretaker, and urinary creatinine)
MEP
Low molecular
weight phthalate
sum
Clinical scales (higher score = more problem behaviors)
Aggression
Anxiety
Attention problems
Atypicality
Conduct problems
Depression
Hyperactivity
Somatization
Withdrawal
Adaptive scales (lower score = more problem behaviors
Adaptability -0.97* -1.08*
Leadership -0.84 -0.88
Social skills -0.97 -1.04
Composite scales (higher score = more problem behaviors)
Externalizing problems 1.33* 1.75*
0.91
0.79
1.28*
0.74
1.85*
0.97*
0.83
0.11
0.44
1.24*
0.78
1.29*
0.95
2.40*
1.18*
1.03
0.36
0.46
Internalizing problems
Adaptive skills
Behavioral Symptoms
Index
0.80
-0.79
1.32*
0.99
-0.98
1.55*
BRIEF Scores (higher score = worse executive functioning)
0.89 1.13
Behavioral regulation
index
Metacognition index
Global executive
composite score
0.89
1.02
1.05
1.23*
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-7. Evidence pertaining to MEP and neurobehavioral and
neurodevelopmental effects in infants and children
Reference and Study Design
Results
*p < 0.05
Study authors reported there were few significant
associations between phthalate concentration and behavior
among girls (quantitative results not reported)
Social function in pre-school and school-aged children
(Miodovniketal., 2011) (United States, New York
City)
Birth cohort study, n = 137, ages 7-9 yrs, Mt Sinai
Children's Environmental Health study (enrolled
1998-2002)
Outcome: Social functioning based on maternal
reporting on Social Responsiveness Scale (SRS)
(5 domains)
Exposure: maternal urine sample, 25-40 wks
gestation
Phthalates in urine (u.g/L):
Median 75th percentile
372 964
MEP
419
1,015
Low molecular weight
phthalate metabolites
Low molecular weight phthalate metabolites
include MMP, MEP, MiBP, and MBP. See Engel et
al. (2008) for data pertaining to individual
metabolite levels in the Mt. Sinai Children's
Environmental Health cohort.
Analysis: Generalized linear regression model,,
considering maternal age, IQ, marital status,
education, and urinary creatinine, and child's sex,
race, and age as potential covariates
Regression coefficient (95% Cl) for change in social
functioning score per unit increase in In-MEP (u.g/L) (adjusted
for child race, sex, caretaker marital status, urinary
creatinine)
Total SRS
Cognition
Communication
Mannerisms
Motivation
Awareness
1.38 (0.23, 2.53)
1.28(0.10,2.47)
1.67 (0.44, 2.90)
0.77 (-0.46, 2.00)
0.77 (-0.28,1.83)
1.10 (0.06, 2.14)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-8. Evidence pertaining to female reproductive effects in animals
Reference and Study Design
Results
Fertility and birth outcomes
(Fuji! et al.. 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding
pairs/group/generation
0, 600, 3,000, 15,000 ppm (0, 40,
197, 1016 mg/kg-day in FO males;
0, 51, 255, 1297 mg/kg-day in FO
females; 0, 46, 222, 1150 mg/kg-
day in Fl males; 0, 56, 267, 1375
mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental
males (14 weeks of dosing during
premating and mating) and ~133
days for FO and Fl parental
females (10 weeks premating, 3
weeks mating, 3 weeks gestation,
3 weeks lactation)
(Hardin et al.. 1987)
Mouse (CD-I); 50 dams/group
0, 4500 mg/kg-day
Gavage in corn oil
GD 6-GD 13
(Howdeshell et al.. 2008)
Rat (Sprague Dawley); 3-5 dams/
treatment group and 9 control
dams
0 (vehicle control), 100, 300, 600,
900 mg/kg-day
Gavage in corn oil
GD 8-GD 18
No. of implantations (percent change compared to control)
FO parental
females
Fl parental
females
0
51/56 255/267 1297/1375
2% 1% 1%
0% 4% 3%
Fertility Index (percent change compared to control)
FO parental
females
Fl parental
females
0
51/56 255/267 1297/1375
0% 4% 0%
0% 0% 0%
Gestation length (days) (percent change compared to control)
FO parental
females
Fl parental
females
0
51/56 255/267 1297/1375
0% 0% -1%
0% 0% -1%*
No. of pups delivered (percent change compared to control)
FO parental
females
Fl parental
females
0
51/56 255/267 1297/1375
-1% 1% 1%
4% 7% 2%
(percent change compared to control)
No. of live pups/litter
Birth weight
Surviving pups
Percent survival
0 4500
0%
-6%
0 4500
99.4 95.7
(percent change compared to control)
No. of implantations
No. of live fetuses
Total resorptions
Fetal mortality (%)
0 100 300 600 900
5% 3% 4% 13%
7% 5% -6% 16%
-100% -100% 325%* -100%
2.9 0 11.1* 0
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-8. Evidence pertaining to female reproductive effects in animals
Reference and Study Design
(NTP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20 breeding
pairs/treatment group
Fl: 20 breeding
pairs/group/generation
FO: 0, 0.25, 1.25, 2.5 %
(0,340,1770, 3640 mg/kg-day)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days
segregation (126 days total)
Fl: in utero + lactation, and then
in the diet through a 7 day mating
period at 74±10 days old (Fl
females were allowed to deliver
litters)
(NTP. 1988)
Rat (Sprague Dawley); 31-32
dams/group; reproductive
endpoints reported for dams with
litters (27-32 litters/group)
0, 0.25, 2.5, 5% (0, 198, 1909,
3214 mg/kg-day)
Diet
GD 6 to GDIS
(Singh et al.. 1972)
Rat (Sprague Dawley); 5
dams/group
0 (untreated), 0.506, 1.012, 1.686
mL/kg (0, 627, 1133, 1888 mg/kg)
Intraperitoneal injections
GD5, 10, and 15 (termination on
GD20)
Note: Statistical analysis was not
conducted by study authors for
this endpoint
Results
(percent change compared to control)
FO females
No. of live pups/litter
Live pup weight
Fl females
No. of live pups/litter
Fertility index (%)
Live pup weight
0 340 1770 3640
23%* 14% 3%
-2% -2% 1%
0 3640
-14%*
95 95
-3%
(percent change compared to control)
Corpora lutea
per dam
Implantation
sites per litter
Resorptions
per litter
Percent
resorptions
per litter
Live fetuses
per litter
No. of
corpora lutea
No. of
resorptions
No. of live
fetuses
0 198 1909 3214
4% -2% 1%
4% -1% 2%
5% 13% -11%
3.8 3.9 4.1 3.1
4% -2% 3%
0 627 1133 1888
60 65 59 57
0 28 0 2
59 35 57 54
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-8. Evidence pertaining to female reproductive effects in animals
Reference and Study Design
Results
Anogenital distance
(Fuji! et al.. 2005)
Rat (Sprague Dawley),
Multigenerational study design:
24 breeding
pairs/group/generation;
AGO measured in 21-24
litters/group/generation
0, 600, 3,000, 15,000 ppm (0, 40,
197, 1016 mg/kg-day in FO males;
0, 51, 255, 1297 mg/kg-day in FO
females; 0, 46, 222, 1150 mg/kg-
day in Fl males; 0, 56, 267, 1375
mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental
males (14 weeks dosing during
premating and mating) and ~133
days for FO and Fl parental
females (10 weeks premating, 3
weeks mating, 3 weeks gestation,
3 weeks lactation)
(percent change compared to control)
Females
Fl pups at PNDO
Fl pups at PND4
F2 pups at PNDO
F2 pups at PND4
0 51/56 255/267 1297/1375
-5% -5% 1%
-3% -2% -1%
-2% 0% -1%
-1% -1% -2%
Reproductive organ weights
(Fuiiietal., 2005)
Rat (Sprague Dawley),
Multigenerational study design:
24 breeding
pairs/group/generation;
reproductive organs weighed in
21-24 females/group (FO and Fl
parental, Fl and F2 weanlings)
0, 600, 3,000, 15,000 ppm (0, 40,
197, 1016 mg/kg-day in FO males;
0, 51, 255, 1297 mg/kg-day in FO
females; 0, 46, 222, 1150 mg/kg-
day in Fl males; 0, 56, 267, 1375
mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental
males (14 weeks dosing during
premating and mating) and ~133
days for FO and Fl parental
females (10 weeks premating, 3
weeks mating, 3 weeks gestation,
3 weeks lactation)
Absolute ovary weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 51/56 255/267 1297/1375
-4% -10% -5%
1% 2% 4%
4% -8% -4%
0% 0% -4%
Relative ovary weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 51/56 255/267 1297/1375
-5% -8% -5%
0% 0% 2%
7% -3% 17%
-3% -3% 0%
Absolute uterus weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 51/56 255/267 1297/1375
2% 4% -4%
4% 7% -1%
3% 7% -22%*
-11% -17% -27%*
Relative uterus weight (percent change compared to control)
FO parental
Fl parental
Fl weanling
F2 weanling
0 51/56 255/267 1297/1375
0% 6% -3%
4% 4% 0%
5% 9% -5%
-12% -17% -20%*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-8. Evidence pertaining to female reproductive effects in animals
Reference and Study Design
(Pereira et al., 2007b)
Rat (Wistar); 6/sex/group
0, 50 (FO) (0, 2.85 mg/kg-day)
0, 25 (Fl) (0, 1.425 mg/kg-day)
Diet
150 days/generation
(NIP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20 breeding
pairs/treatment group
Fl: 20 breeding pairs/group
FO: 0, 0.25, 1.25, 2.5 %
(0,340,1770, 3640 mg/kg-day)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days
segregation (126 days total)
Fl: in utero + lactation, and then
in the diet through a 7 day mating
period at 74±10 days old (Fl
females were allowed to deliver
litters)
(Shiraishietal., 2006)
Rat (Sprague-Dawley);
10/sex/group
0, 40, 200, 1,000 mg/kg-day
Gavage in corn oil
28 days
Results
Absolute ovary weight (percent compared to control)
FO parental females Fl adult females
0 2.85 0 1.425
40%* - 23%*
Ovary weight in Fl parental females (percent change compared to control)
Absolute
Relative
0 3640
-3%
3%
Uterus weight in Fl parental females (percent change compared to control)
Absolute
Relative
0 3640
-4%
-4%
Relative weights (percent change compared to control)
0 40 200 1000
Ovary - 0% 3% 8%
Uterus - -6% -6% 6%
*Statistically significant (p<0.05) based on analysis of data by study authors.
Percent change compared to control = treated value - control value x 100
control value
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
10,000
1,000 :
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rats; Pereira etal,, 2007b;Fujii etal., 2005
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0
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<
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r+
mice; NTP, 1984
rati;Shiraishi elal., 200G
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Figure 2-3. Exposure-response array of female reproductive effects following exposure to DEP
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-9. Evidence pertaining to developmental effects in animals
Reference and Study Design
Results
Skeletal variations
(NTP. 1988)
Rat (Sprague Dawley); 31-32
dams/group; 27-32 litters/group
0, 0.25, 2.5, 5% (0, 198, 1909, 3214
mg/kg-day)
Diet
GD 6 to GDIS
(Singh et al.. 1972)
Rat (Sprague Dawley); 5 dams/group
0 (untreated), 0.506, 1.012, 1.686 mL/kg
(0, 627, 1133, 1888 mg/kg)
Intraperitoneal
injections on GD5, 10, and 15
(termination on GD 20)
Note: Statistical analysis was not
conducted by study authors for this
endpoint
External
malformations
per litter
Visceral
malformations
per litter
Skeletal
malformations
per litter
Fetuses
malformed per
litter
0 198 1909 3214
0 0.03 0 0.06
0.11 0 0 0.13
0 0.07 0.07 0
0.11 0.07 0.07 0.19
Percent litters
with extra rib
(male and
female
fetuses)
No. of skeletal
abnormalities
0 198 1909 3214
-44 39 47 74*
0 627 1133 1888
0 5 8 13
Fetal body weight
(Singh et al.. 1972)
Rat (Sprague Dawley); 5 time-mated
females/group
0 (untreated), 0.506, 1.012, 1.686 mL/kg
(0, 627, 1133, 1888 mg/kg)
Intraperitoneal injections
GD 5, 10, and 15 (termination on GD 20)
Fetal (GD20) body weight (percent change compared to control)
fMale,and 0 627 1133 1888
female
fetuses
(aV6ruage - -46%* -41%* -41%*
weight per
group)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-9. Evidence pertaining to developmental effects in animals
Reference and Study Design
(NTP. 1988)
Rat (Sprague Dawley); 31-32 females
(dams)/group; 27-32 litters/group
0, 0.25, 2.5, 5% (0, 198, 1909, 3214
mg/kg-day)
Diet
GD 6 to GDIS
Results
Fetal body weight (percent change compared to control)
0 198 1909 3214
Male and
female
fetuses - 6% 7% 4%
(average
weight/litter)
Postnatal growth
(Fuji! etal., 2005)
Rat (Sprague Dawley);
Multigenerational study design:
24 breeding pairs/group/generation; pup
weight assessed in 21-24 litters/group
0, 600, 3,000, 15,000 ppm (0, 40, 197,
1016 mg/kg-day in FO males; 0, 51, 255,
1297 mg/kg-day in FO females; 0, 46,
222, 1150 mg/kg-day in Fl males; 0, 56,
267, 1375 mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental males
(14 weeks of dosing during premating
and mating) and ~133 days for FO and Fl
parental females (10 weeks premating, 3
weeks mating, 3 weeks gestation, 3
weeks lactation)
(Pereira and Rao. 2007)
Rat (Wistar); 6 breeding pairs/group;
body weight measured in 6
pups/sex/group
0, 50 mg/kg (0, 2.85 mg/kg-day)
Diet (DEP dissolved in corn oil)
100 days (premating) + 10 days (mating)
and through gestation and weaning of
the PND 21 male and female pups
(150 days total for parental animals)
Weanling body weight (litter average) (percent change compared to
control)
Males
Fl pup
F2 pup
Females
Fl pup
F2 pup
0 40/46 197/222 1016/1150
-4% -7% -18%*
-2% -4% -19%*
0 51/56 255/267 1297/1375
1% 0% -12%*
1% 0% -12%*
Weanling body weight (percent change compared to control)
0 2.85
Males - -35%*
Females - -24%*
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-9. Evidence pertaining to developmental effects in animals
Reference and Study Design
(NTP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20 breeding
pairs/treatment group
Fl: 20 breeding pairs/group
FO: 0, 0.25, 1.25, 2.5 %
(0,340,1770, 3640 mg/kg-day)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days segregation (126
days total)
Fl: in utero + lactation, and then in the
diet through a 7 day mating period at
74±10 days old (Fl females were allowed
to deliver litters)
Note: Statistical analysis was not
conducted by study authors for this
endpoint
Results
Weanling body weight (percent change compared to control)
Males
Females
0
.
-
3640
-25%
-23%
*Statistically significant (p<0.05) based on analysis of data by study authors.
Percent change compared to control = treated value - control value x 100
control value
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1,000
TO
7
BO
O
0
100
10
• statistically significantly changed
D not statistically significantly changed
• changed but statistics not conducted
DOC
[ ] [] [
n |
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•
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1 1
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r- 1 9
rh
u
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rats; NTP, 1998b
skeletal abnormalities
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ai
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Postnatal Growth
Figure 2-4. Exposure response array of developmental effects following exposure to DEP
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
2.4. Obesity Evidence Tables
Table 2-10. Evidence pertaining to MEP and obesity in humans
Reference and Study Design
Results
(Trasande et al., 2013) (United States,
NHANES)
n = 2,884 participants in the 2003-2008
NHANES, 6-19 yrs old
Outcome: BMI z-score, obesity (BMI z-
score >95th percentile), and overweight
(BMI z-score >85th percentile) (measured)
Exposure: Urine sample, collected at
same time BMI measurement
ZLMW phthalates in urine (u.M):
Geometric mean
Not obese 0.701
Obese 0.855
ZLMW phthalates = sum of MEP, MBP,
andMIBP
Analysis: Logistic regression for
overweight and obese classification;
linear regression of BMI z-score as
continuous variable; adjusted for
variables shown in results column
Full sample results, no association with In-LMW phthalates: OR or
regression coefficient (95% Cl) per one unit increase in ZLMW
phthalates (nM) (Model 2 results shown, adjusted for urinary
creatinine, sex, poverty-income ratio, parental education, serum
cotinine, age, and race/ethnicity, caloric intake and television
watching)
Overweight OR (95% Cl)
Obese OR (95% Cl)
BMI z-score p (95% Cl)
1.01(0.90,1.13)
1.02 (0.90, 1.17)
0.03 (-0.03, 0.09)
Interaction by ethnicity seen, with associations seen between In-LMW
phthalates and each of the obesity measures in blacks, but not in
whites or Hispanics. The patterns seen with ZLMW phthalates were
also seen in analyses for MEP. Using same adjustment factors as
above, the associations with In-MEP are:
ZLMW phthalates
Hispanic White Black
Overweight
OR (95%
CD
Obese
OR (95%
CD
0.88
(0.72,1.08)
0.97
(0.83,1.14)
0.97
(0.78,1.22)
0.94
(0.69,1.29)
1.21
(1.05,1.39)
1.22
(1.07,1.39)
MEP
Black
1.18
(1.04, 1.34)
1.19
(1.05, 1.35)
BMI z-score -0.04 0.02 0.09 0.08
P(95%CI) (-0.15,0.06) (-0.08,0.12) (0.003,0.18) (0.01,0.16)
(Wang et al.. 2013) (China)
259 primary and middle school students,
8-15 yrs old, stratified sample from 6
schools, selected based on sex and BMI
Outcome: BMI, waist circumference
(measured)
Exposure: First morning urine sample,
collected at same time BMI measurement
MEP in urine (ng/mL):
Geometric mean (SE)
15.3(1.1)
Analysis: Linear regression, sampling
weights applied to adjust for sampling
strategy; see results for covariates
considered.
Regression coefficient (95% Cl) for change in BMI or waist circumferenc
per unit increase in SG-adjusted In-MEP (adjusted for age and sex in
Model 1; plus sum of DEHP, MCHP, sum of DBP and MMP in Model 2)
BMI
Waist
circumference
Model 1
P (95% Cl)
0.025 (0.009, 0.040)
0.020 (0.008, 0.032)
Model 2
P (95% Cl)
0.022 (0.005, 0.0040)
0.020 (0.006, 0.033)
The magnitude of the effect of MEP was similar to that for £DBP (BMI:
0.035, WC: 0.023) metabolites, and for MiBP (BMI: 0.027, WC: 0.022)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-10. Evidence pertaining to MEP and obesity in humans
Reference and Study Design
Results
(Lind et al.. 2012a) (Sweden)
Prospective cohort study, n = 1,016
(507 men, 509 women), age 70 yrs at
enrollment, Prospective Investigation of
Vasculature in Uppsala Seniors study,
2001-2003.
Outcome: BMI, waist circumference
measured at enrollment; dual energy
X-ray absorptiometry (DXA) (n = 890
participated) and MRI of abdominal
region (n = 287 randomly selected) 2 yrs
later
Exposure: Serum sample (fasting),
collected at baseline
MEP in serum (ng/mL):
Median 75th percentile
Women 11.6 16.8
Men 11.6 18.5
Analysis: Linear regression, adjusted for
variables shown in results column
Related reference: (Olsen et al.,
2012)reports cross-sectional analysis of
BMI from this study population, see Table
14
Regression coefficient (95% Cl) for change in body metric per unit
increase in In-MEP (ng/mL) (adjusted for serum cholesterol and
triglycerides, education, exercise, and smoking)
Outcome
2
Males
(95% Cl)
Females
P (95% Cl)
BMI (kg/m") 0.31 (-0.097, 0.72) 0.008 (-0.67, 0.69)
Waist circumference (cm) 0.73 (-0.45,1.9) -0.80 (-2.4, 0.81)
DXA total fat (kg) 269 (-776,1315)
MRI visceral adipose tissue 16 (0.49, 32)
(cm2)
-469 (-1,877, 938)
3.6 (-11,19)
(Teitelbaumetal., 2012) (United States,
New York City)
Prospective cohort study, n = 387
Hispanic and black children (80 boys, 307
girls), 6 to 8 yrs at cohort enrollment,
Growing Up Healthy Study, 2004-2008
Outcome: BMI and waist circumference
measured lyr after enrollment. Normal
weight = BMI <85th percentile (n=2284);
overweight = BMI >85th percentile
(n=578)
Exposure: Urine sample, collected at
enrollment Cr-adjusted phthalates in
urine (u.g/g Cr), median:
MEP ZLowMWP
Boys 152 253.2
Girls 177.7 294
Low molecular weight phthalate
metabolites included MEP, MBP, and
MiBP.
Analysis: Linear regression, considering
Full sample results, regression coefficient (95% Cl) for change for
change in body metric per unit change in In-MEP (u.g/g Cr) (adjusted
for creatinine, age, sex, sedentary hours, metabolic equivalent hours,
Hispanic ethnicity, caloric intake, season, parental education level)
BMI (kg/m2)
Waist circumference (cm)
0.19 (-0.17, 0.55)
0.51 (-0.45, 1.46)
Among girls, mean measurement by quartile of MEP (u.g/g Cr),
stratified by weight group (adjusted for same variables as above)
MEP
quartile BMI (kg/m
1 (low)
2
3
4 (high)
(trend p)
16.3
16.4
16.1
15.9
(0.41)
Normal weight
Waist
circumference
(cm)
59.9
60.1
59.3
58.7
(0.37)
BMI (kg/m
21.3
21.7
23.8
23.5
(<0.0001)
Overweight
Waist
circumfere
nee (cm)
73.4
73.5
79.2
78.8
(<0.0001)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-10. Evidence pertaining to MEP and obesity in humans
Reference and Study Design
sex, age at baseline, sedentary hours,
metabolic equivalent hours, caloric
intake, race, ethnicity, season of urine
collection, family income, and parent
education as potential covariates.
Restricted to children with creatinine >10
mg/dL
(Hatch et al., 2008)(United States,
NHANES)
4,369 (2,251 males, 2,118 females)
participants in the 1999-2002 NHANES,
ages 6-80 yrs; separate analyses by sex-
age group (ages 6-11, 12-19, 20-59, 60-
80)
Outcome: BMI, waist circumference
(measured)
Exposure: Urine sample, collected at
time of obesity measurement
MEP in urine (u.g/g Cr):
Range of geometric means in different
age-sex groups = 94-226
Unadjusted geometric means not
reported
Analysis: Linear regression, adjusting for
variables shown in results column
Results
Interaction between BMI percentile and MEP was significant (p < 0.05)
in analyses of both BMI and waist circumference in girls.
Regression coefficient for change in body metric perquartile increase
in unadjusted MEP (ug/L), by age (age, creatinine, height,
race/ethnicity, socioeconomic status, fat intake, dairy intake, fruit and
vegetable intake, physical activity, TV/video and computer use,
smoking status, and for women, menopausal status, parity)
MEP 6-11 yrs 12-19 yrs 20-59 yrs 60-80 yrs
Quartile p p p p
Waist circumference, males
1 (low) 1.0 (referent) 1.0 (referent) 1.0 (referent) 1.0
(referent)
2 -0.75 -1.00 0.85 0.11
3 1.42 -0.30 1.25 1.55
4 (high) -0.67 -1.20 2.19 1.68
(trend p) (0.99) (0.64) (0.11) (0.21)
Waist circumference, females
1 (low) 1.0 (referent) 1.0 (referent) 1.0 (referent) 1.0
(referent)
2 0.74 2.31 0.07 -0.62
3 0.99 2.7 0.46 -1.62
4 (high) 1.05 4.11 2.07 -0.22
(trend p) (0.61) (0.02) (0.1) (0.82)
BMI, males
1 (low) 1.0 (referent) 1.0 (referent) 1.0 (referent) 1.0
(referent)
2 -0.29 -0.05 0.36 0.18
3 0.97 0.02 0.47 0.76
4 (high) -0.02 -0.13 0.82 1.05
(trend p) (0.65) (0.89) (0.11) (0.03)
BMI, females
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-10. Evidence pertaining to MEP and obesity in humans
Reference and Study Design
Results
1 (low) 1.0 (referent) 1.0 (referent) 1.0 (referent)
2
3
4 (high)
(trend p)
0.35
0.54
0.30
(0.66)
0.84
1.16
1.74
(0.03)
-0.03
0.10
0.92
(0.14)
1.0
(referent)
-0.03
-0.79
-0.21
(0.64)
(Stahlhut et al.. 2007) (United States,
NHANES)
1,451 male participants in the 1999-2002
NHANES; ages >18 yrs; excluded if taking
insulin, oral hypoglycemic agents, or sex
hormone agonists/antagonists, analyses
only)
Outcome: Waist circumference
(measured)
Exposure: Urine sample, collected at
time of obesity measurement
MEP in urine (u.g/g Cr):
Median
Cr-adjusted 188.1
Analysis: Linear regression, adjusting for
variables shown in results column
Adjusted regression coefficient per unit increase in In-MEP (adjusted
for age, age-squared, race/ethnicity, fat intake, calorie intake, physical
activity level, smoking exposure based on cotinine, urinary creatinine,
glomerular filtration rate, serum ALT, and GGT)
P ± SE (p-value)
Waist circumference 0.66 ±0.31
(n = 1,292) (0.041)
Association with MEP was similar to or smaller than seen for MBP
(adjusted Model 2 Beta = 0.79) or MBzP (adjusted Model 2 Beta = 1.09)
Increase in waist circumference began in 3rd quartile of exposure (data
shown graphically).
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
2.5. Other Systemic Effects Evidence Tables
Table 2-11. Evidence pertaining to MEP and neurological effects in adults
Reference and Study Design
Results
(Shiue, 2013a) (United States, NHANES)
2,287 participants aged >50 yrs in the 2003-
2004 NHANES
Outcome: Self-reported status, in the last year:
• vision (n=136 "poor", comparison = "fair,"
"good," and "excellent")
• hearing (n=261 "lots of trouble" or "deaf",
comparison = "good" and "little trouble")
• balance function (n=748 positive response to
"dizziness, difficulty with balance, or
difficulty with falling")
• ear ringing (n=754 positive response to
"ringing, roaring, or buzzing" in ear)
Exposure: Urine sample, collected at time of
survey; measured concentrations were not
reported.
Analysis: Logistic regression, adjusting for age,
sex, ethnicity, and urinary creatinine. Referent
group not defined.
OR (95% Cl) for poor status, per unit increase in In-MEP
(adjusted for age, sex, ethnicity, and urinary creatinine)
Vision
Hearing
Balance
Ears ringing/roaring/buzzing
0.92 (0.70,1.21)
1.14(0.95,1.37)
0.94 (0.83, 1.06)
0.99 (0.88, 1.12)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-12. Evidence pertaining to MEP and diabetes and measures of insulin
resistance in humans
Reference and Study Design
Results
(James-Todd et al.. 2012) (United States,
NHANES)
Case-control study of 2,350 female participants
in the 2001-2008 NHANES, ages 20-79 yrs;
n=215 cases, 2135 controls. Cross-sectional
analysis of insulin resistance measures among
women without history of diabetes.
Outcome: Positive response to, "Other than
during pregnancy, have you ever been told by
a doctor or health professional that you have
diabetes or sugar diabetes?"; among women
without history of diabetes, fasting blood
glucose (FBG) (n=985), homeostasis model
assessment-estimated insulin resistance
(HOMA) (n=971), glycosolated hemoglobin Ale
(n=2092)
Exposure: Urine sample, collected at time of
survey
MEP in urine (units not reported):
Geometric mean (95% Cl)
Unadjusted 164.8 (150.5,180.3)
Analysis: Logistic regression, adjusting for
urinary creatinine, fasting time, age,
race/ethnicity, education, poverty status,
behavioral factors
OR (95% Cl) for diabetes by quartile of MEP (adjusted for urinary
creatinine, age, race/ethnicity, education, poverty status, fasting
time, total caloric intake, total fat intake, smoking status, and
physical activity; little change with additional adjustment for BMI
and waist circumference)
MEP
Quartile
1 (low) 1.0 (referent)
2 0.95 (0.60-1.51)
3 1.09 (0.61-1.96)
4 (high) 0.89 (0.47-1.67)
Among women without diabetes, OR (95% Cl)] for glucose and
insulin parameters by quartile of MEP (Model 1 adjusted for
urine creatinine, age, race/ethnicity, education level, poverty
status, fasting time, total caloric intake, total fat intake, smoking
status, and physical activity; Model 2 also adjusted for BMI and
waist circumference)
MEP
Quartile Model 1
Fasting glucose (mg/dL)
1 (low)
2
3
4 (high)
Ln(HOMA)
1 (low)
2
3
4 (high)
Ale (%)
1 (low)
2
3
4 (high)
1.0 (referent)
0.95 (-0.94, 2.85)
1.18 (-0.91, 3.27)
-0.03 (-2.16, 2.09)
1.0 (referent)
0.06 (-0.10. 0.14)
0.07(-0.08, 0.23)
0.10 (-0.07, 0.26)
1.0 (referent)
0.01 (-0.04,0.06)
-0.02 (-0.07, 0.03)
-0.03 (-0.08, 0.02)
Model 2
1.0 (referent)
1.10 (-0.83, 3.04)
0.38 (-1.91, 2.67)
-0.61 (-2.99, 1.78)
1.0 (referent)
0.03 (-0.09, 0.14)
0.01(-0.11, 0.14)
-0.04 (-0.17, 0.09)
1.0 (referent)
-0.02 (-0.07, 0.02)
-0.03 (-0.07, 0.02)
-0.05 (-0.10, 0.00)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-12. Evidence pertaining to MEP and diabetes and measures of insulin
resistance in humans
Reference and Study Design
Results
(Lind et al.. 2012b)(Sweden)
n = 1,003 (501 men, 502 women), age 70 yrs at
enrollment; cross-sectional analysis within the
Prospective Investigation of Vasculature in
Uppsala Seniors study, 2001-2003.
Outcome: Diabetes (n=88; history of diabetes
or fasting glucose >7.0 mmol/L, mean duration
8.9 years); ratio of fasting proinsulin to insulin;
HOMA
Exposure: Serum sample (fasting), collected at
time of clinical assessment
MEP in serum (ng/mL):
Median 75th percentile
Women 11.6 16.8
Men 11.6 18.5
Analysis: Logistic regression for diabetes
classification; linear regression for continuous
outcomes (proinsulin/insulin and HOMA-IR);
adjusting for variables shown in results column
Related reference: (Olsen et al.. 2012)
presents blood glucose data for this study
population; the regression coefficient per unit
increase in serum In-MEP was 0.007 (-0.01,
0.03) (see Table 14)
Diabetes analysis: OR(95% Cl) per unit increase in serum In-MEP
(adjusted for sex, serum cholesterol and triglycerides, BMI,
smoking, exercise and education)
1.28 (0.97,1.7)
Diabetes analysis: OR (95% Cl) by quintile of In-MEP P (adjusted
for sex, serum cholesterol and triglycerides, BMI, smoking,
exercise and education)
MEP
Quintile
1
2
3
4
5 (high)
(trend p)
1.0 (referent)
2.25(1.06,4.79)
2.87(1.37,6.03)
2.44(1.14,5.21)
2.27(1.08,4.81)
(0.061)
Regression coefficient (95% Cl) for insulin measures per unit
increase in serum In-MEP (adjusted for sex, serum cholesterol and
triglycerides, BMI, smoking, exercise and education)
Proinsulin/insulin -0.05 (-0.097, -0.002)
HOMA 0.069(0.023,0.116)
The magnitude of the association between proinsulin/insulin and
MEP was similar to that for two of the other metabolites studied,
but in the opposite direction of MEHP and MiBP (0.046 and 0.06,
respectively), and much greater compared to MMP (-0.005). The
magnitude of the association between HOMA-IR and MEP was
greater than that for the other metabolites studied (range: -0.012
to 0.47). The magnitude of the association between prevalent
diabetes and MEP was greater than that for MEHP or MiBP, and
similar to that for MMP in the highest quintile.
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-12. Evidence pertaining to MEP and diabetes and measures of insulin
resistance in humans
Reference and Study Design
Results
(Svensson et al.. 2011) (Mexico)
n=221 women; average age 54 years; healthy
controls from a case-control study of breast
cancer
Outcome: Self-reported diabetes
Exposure: First morning urine samples
MEP in urine (u.g/g creatinine):
Geometric Mean (SD)
No diabetes 108.0 (3.4)
Diabetes 101.3(2.7)
Analysis: Logistic regression, adjusting for
creatinine and education (age and waist-height
ratio not found to be potential confounders).
OR(95% Cl) per unit increase in In-MEP
1.02 (0.74, 1.39)
(Stahlhut et al.. 2007) (United States, NHANES)
1,451 male participants in the 1999-2002
NHANES; ages>18yrs; excluded if taking
insulin, oral hypoglycemic agents, or sex
hormone agonists/antagonists, or if not fasting
before specimen collection
Outcome: Homeostatic model assessment
(HOMA)
Exposure: Urine sample, collected at time of
survey
MEP in urine (u.g/g Cr):
Median
Cr-adjusted 188.1
Analysis: Linear regression, considering
variables shown in results column
Regression coefficient per unit increase in In-MEP (Model 1
adjusted for age, age-squared, race/ethnicity, fat intake, calorie
intake, physical activity level, smoking exposure based on cotinine,
and urinary creatinine; Model 2 also adjusted for glomerular
filtration rate, serum ALT, and GGT)
Outcome
HOMA (In)
(n = 622)
Model 1
± SE (p-value)
0.056 ± 0.020
(0.008)
Model 2
± SE (p-value)
0.044 ± 0.021
(0.045)
Increases in HOMA began in 3r quartile of exposure (data shown
graphically).
Association with MEP was similar to or smaller than seen for MBP
(adjusted Model 2 Beta = 0.043) or MBzP (adjusted Model 2 Beta
= 0.061)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-13. Evidence pertaining to MEP and thyroid effects in humans
Reference and Study Design
Results
Thyroid hormones and thyroid stimulating hormone
(Boas et al.. 2010)(Denmark)
758 children, who were participants in
longitudinal cohort study, examined 2006-
2007 at ages 4-9 yrs
Outcome: Serum thyroid hormone levels
(non-fasting sample)
Exposure: Urine sample (child's), collected
same day as serum samples
Unadjusted MEP in urine (u.g/L):
Median 75th percentile
Boys 21 39
Girls 21 44
Cr-adjusted MEP in urine (u.g/g Cr):
Median 75th percentile
Boys 31 52
Girls 36 65
Analysis: Linear regression, adjusting for sex
and age
Regression coefficient (p-value) for change in hormone level with
unit change in In-MEP (adjusted for sex and age) (0.0 = no effect)
T3
Free T3
T4
Free T4
TSH
IGF-1
IGFBP-3
Unadjusted MEP
-0.06 (0.015)
-0.13(0.013)
-1.49 (0.29)
-0.01 (0.93)
0.02 (0.30)
-0.01 (0.21)
0.00 (0.88)
Cr-adjusted MEP
-0.02 (0.61)
0.00 (0.99)
-1.18 (0.54)
-0.07 (0.71)
0.06 (0.005)
-0.01 (0.56)
0.02 (0.11)
Similar patterns seen in analyses stratified by gender.
Units for hormone analyses were not reported in the publication.
(Huang et al.. 2007) (Taiwan)
76 pregnant women undergoing
amniocentesis due to age >35 yrs or abnormal
a-fetoprotein or p-hCG test, 2005-2006
Outcome: Serum thyroid hormone levels
collected during 2nd trimester
Exposure: Urine sample, collected same day
as serum samples
MEP in urine:
75th 95th
Median percentile
Unadjusted (ng/mL) 28 52 2,346
Cr-adjusted (ug/g Cr) 68 205 4,414
Analysis: Spearman correlation analysis;
linear regression, adjusting for variables
shown in results column
Spearman correlation coefficient between hormone level and MEP
T3 (ng/dL)
T4(ug/dL)
Free T4 (ng/dL)
TSH (uJU/mL)
Unadjusted MEP
(ng/mL)
-0.019
-0.039
0.017
-0.082
Cr-adjusted MEP (u.g/g
Cr)
-0.008
-0.021
0.041
-0.107
Adjusted regression coefficient (p-value) for change in ln-T4 with
change in In-MEP (adjusted for age, BMI, gestational age, and
other phthalate metabolites - MBP, MEHP, MBzP, MMP):
T4 (nmole/L)
FreeT4(pmole/L)
0.013 (0.40)
0.026 (0.12)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-13. Evidence pertaining to MEP and thyroid effects in humans
Reference and Study Design
Results
(Meeker etal.. 2007) (United States, Boston)
408 male partners seen in subfertility clinic
during 2000-2004, mean ± SD age 36 ± 5.3 yrs
Outcome: Serum thyroid hormone levels
Exposure: Urine sample, collected same day
as serum samples
MEP in urine (ng/mL): 75th 95th
Median percentile percentile
SG-adjusted 158 535 2,343
Analysis: Linear regression, considering age,
BMI, smoking status, race, previous
examination for infertility, prior impregnation
of partner, timing of blood and urine samples,
and time of day as potential covariates
Regression coefficient (95% Cl) for change in hormone level per
IQR change in SG-adjusted MEP (ng/mL, after back-transformation
from InMEP) (adjusted for age, BMI, current smoking, and time of
blood sample)
Untransformed hormone levels (0.0 = no effect)
Total T3 (ng/mL) 0.018 (-0.009, 0.044)
Free T4 (ng/dL) 0.011(-0.048, 0.026)
Ln-transformed hormone levels (1.0 = no effect)
TSH (uJU/mL) 0.94 (0.85,1.03)
Adjusted for
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-14. Evidence pertaining to MEP and immune effects in humans
Reference and Study Design
Results
Asthma and hypersensitivity conditions
(Bertelsen et al.) (Norway)
623 children aged 10 yrs participating in the
Environment and Childhood Asthma study;
children with current asthma over-sampled
(2001-2004)
Outcome: Current asthma (parental report
of history of asthma plus >1 of the
following: dyspnea, chest tightness and/or
wheezing in previous 12 mo; use of asthma
medications in previous 12 mo; positive
exercise challenge test)
Exposure: First morning urine sample,
collected at study examination
MEP in urine (u.g/L): 75th 95th
Median percentile percentile
Unadjusted 56.7 94.4 360.2
SG-adjusted 56.3 101.1 320.2
Analysis: Logistic regression, adjusting for
urine specific gravity, sex, parental asthma,
and household income
OR (95% Cl) for current asthma by quartile of MEP (u.g/L) (adjusted
for urine specific gravity, sex, parental asthma, and household
income)
1: <32.6 (ref) 1.0 (referent)
2: >32.6-56.7 0.97 (0.55, 1.7)
3: >56.7-94.4 0.85 (0.47, 1.6)
4: >94.4 0.99 (0.55, 1.8)
Increase in odds of current asthma per Iog10 IQR MEP = 0.98 (0.39,
2.5)
(Just et al.. 2012) (United States, New York)
244 children (ages 4.9-9.1 yr) in Columbia
Center for Children's Environmental Health
birth cohort, 2006-2010
Outcome: Measured fractional exhaled
nitric oxide (feNO) (1-3 measures per child),
measured seroatopy (specific IgE to dust
mite, cockroach, or mouse allergens, > 0.35
lU/ml), wheeze within past year or in
subsequent year (based on parent report at
feNO study visit and at the next study visit),
with additional information to model
wheezing phenotype
Exposure: urine sample (child's), collected
at time of feNO measurement
MEP in urine (ng/mL):
Geometric mean (95% Cl)
Unadjusted 111 (96,129)
Analysis: Generalized estimating equation
regression models adjusted for variables
shown in results column
Adjusted percent difference in feNO per unit increase in In-MEP
(ng/mL) (adjusted for specific gravity, age, sex, race/ethnicity, time
of day of feNO collection, and ambient NO; similar results with
additional adjustment for seroatopy and MnBP, MBzP, and MEHHP)
% Difference (95% Cl) p-value
6.5 (1.0, 12.4) 0.021
No association between urinary concentration of MEP and incident
seroatopy or reported wheeze (quantitative results not reported).
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-14. Evidence pertaining to MEP and immune effects in humans
Reference and Study Design
Results
(Kanazawa et al.. 2010) (Sapporo, Japan)
Cross-sectional study, n = 134 residents
(41 dwellings), including 33 reporting at
least one symptom and 101 with no
reported symptoms
Outcome: Self-reported "sick house
syndrome" symptoms (fatigue; feeling
heavy-headed; headache; nausea/dizziness;
difficulty concentrating; itching, burning or
irritation of the eyes; irritated, stuffy, or
runny nose; hoarse, dry throat; cough; dry
or flushed facial skin; scaling/itching of the
scalp or ears; and dry, itching or red-
skinned hands)
Exposure: Air and dust samples in
dwellings
DEP in room air (ng/m3):
Median Range
Total cone 60.7 22.3-203
DEP in dust (mg/kg):
Median Range
Multi-surface 0.35 0.3 in all statistical tests
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-14. Evidence pertaining to MEP and immune effects in humans
Reference and Study Design
Results
(Bornehag et al.. 2004) (Sweden)
Nested case-control study; n = 198 cases,
202 controls; ages 2-7 yrs (follow-up of
Dampness in Buildings and Health cohort,
n = 10,852), 2001-2002.
Outcome: Eczema, wheezing, or rhinitis
(Cases report at least two incidents of
eczema, or wheezing or rhinitis without a
cold, in the preceding year, and at follow-
up 1.5 yrs later).
Exposure: Surface dust samples from
children's bedrooms,
DEP in dust (mg/g)
Median
All homes 0.000
Analysis: Mann-Whitney U-test for
comparing concentrations in all homes;
t-test for comparing log-transformed
concentrations in homes with
concentrations above detection limit
Concentration in dust (mg/g dust)
Median, all
homes
(n = 346)
Controls 0.000
Cases (all) 0.000
p>0.2 in both tests
Geometric mean (95% Cl),
homes with phthalate >
detection limit (n = 175)
0.058 (0.035, 0.097)
0.102(0.049,0.211)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-15. Evidence pertaining to MEP and pulmonary function in humans
Reference and Study Design
Results
(Hoppin et al.. 2004) (United States, NHANES)
240 participants in NHANES III (1988-1994); ages 20-60
yrs, only African-American and white participants;
excluded if missing information on phthalate levels,
pulmonary function, medical or smoking history
Outcome: FVC, FEV1, PEF, MMEF
Exposure: Urine sample, collected at time of pulmonary
function testing
Mean (SD)
323 (6.4)
307 (4.9)
MEP in urine (ng/mL):
Men
Women
MEP in urine (u.g/g Cr):
Men
Women
240 (5.4)
321 (4.2)
Analysis: Linear regression, stratified by sex and
adjusted for variables shown in results column.
Regression coefficient for change in pulmonary function
measure per interquartile range increase in MEP (608.8
ng/g creatinine) (adjusted for age, age squared, height,
BMI, smoking, race)
B(SE)
Men Women
FVC -121 (58)* 37 (50)
FEV1 -102 (47)* 67 (43)
PEF -250 (167) 86 (124)
MMEF -106(116) 162(95)
*p<0.05
Results among non-smokers only showed no significant
associations for either men or women
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-16. Evidence pertaining to MEP and cardiovascular disease in humans
Reference and Study Design
Results
(Trasande et al., 2013) (United States,
NHANES)
2,447 participants in the 2003-2008 NHANES,
8-19 yrs old
Outcome: Systolic blood pressure (SBP) and
diastolic blood pressure (DBP) z-score (based
on CDC norms, sex and age); prehypertension
(BP>90th percentile for age/height/sex); fasting
serum triglycerides (n=906; high = > 100
mg/dL); nonfasting high density cholesterol
(HDL; n=2555; low = < 40 mg/dL))
Exposure: Urine sample, collected at time of
BMI measurement
ZLMW phthalates in urine (nM):
Geometric mean
BP<90th percentile 0.817
BP>90th percentile 1.002
ZLow MWP = sum of MEP, MBP, and MIBP
Analysis: Logistic regression for pre-
hypertension (BP>90th percentile)
classification; linear regression for SBP and DBP
z-score and triglycerides and HDL as continuous
variable; all models adjusted for variables
shown in results column.
Change in z-score (95% Cl) per unit increase in In-phthalates
(adjusted for sex, caloric intake, television watching,
poverty:income, parental education, serum cotinine, urinary
creatinine, BMI, race/ethnicity, age)
ZLMW phthalates
SBP 0.03 (-0.02, 0.07)
DBP 0.02 (-0.04, 0.07)
Triglycerides -0.22 (-4.40,0.07)
MEP
0.02 (-0.02, 0.06)
0.02 (-0.03, 0.06)
not reported
HDL
0.13 (-0.60, 0.85)
not reported
OR (95% Cl) for BP>90th percentile per unit increase in In-
phthalates
ZLMW phthalates MEP
BP>90th percentile 1.19(0.96,1.47) 1.20(1.01,1.43)
High triglycerides 0.85 (0.71,1.01) not reported
Low HDL 1.00(0.87,1.15) not reported
Interactions with covariates examined in supplemental analyses;
none of these stratified analyses showed a statistically significant
association between ZLow MWP and SBP.
The OR for BP>90th percentile associated with MEP was larger in
magnitude than that for other phthalate metabolites studied (ORs
ranged from 0.80 to 1.12)
(Shiue. 2013b) (United States, NHANES)
Case-control study of 11,010 participants in
2001-2002 NHANES (204 cases, 10,826
controls) and 10,122 participants in 2003-2004
NHANES (212 cases, 9910 controls). Not age-
matched; mean age 67 years for cases, 28
years for controls.
Outcome: Self-reported stroke (definition not
described), time since diagnosis not reported
Exposure: Urine sample, collected at time of
survey
MEP in urine of controls
Mean ± SD
2001-2002 444.12 ± 1,226.73
2003-2004 466.82 ± 1,325.59
Analysis: Student's t-test comparing urinary
concentrations; logistic regression, adjusting
for creatinine, age, sex, smoking, hypertension,
cholesterol, BMI, prior cardiovascular disease,
binge drinking
MEP concentrations (units not reported) in cases and controls
Time period Cases (mean ±SD) Controls (mean ±SD) p-value
2001-2002 506.46 ± 1,233.80 444.12 ± 1,226.73 0.745
2003-2004 321.20 ±559.95 466.82 ± 1,325.59 0.438
OR (95% Cl) for stroke and urinary MEP concentrations (units not
reported) (adjusted for creatinine, age, and sex; little difference in
results seen with additional adjustment for smoking,
hypertension, high cholesterol, BMI, prior cardiovascular disease,
and binge drinking)
Time period OR (95% Cl)
2001-2002 1.00003 (0.99979-1.00027)
2003-2004 0.9998 (0.9993-1.0003)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-16. Evidence pertaining to MEP and cardiovascular disease in humans
Reference and Study Design
Results
(Olsenetal., 2012) (Sweden)
1,016 (507 men, 509 women), age 70 yrs at
enrollment, cross-sectional analysis within the
Prospective Investigation of Vasculature in
Uppsala Seniors study, 2001-2003.
Outcome: BMI and blood pressure measured
at study visit; fasting serum sample for LDL and
HDL cholesterol, triglycerides, and glucose;
Framingham risk score
Exposure: Serum sample, collected at time of
examination; results not shown
Analysis: Linear regression, adjusted for the
variables shown in results column.
Regression coefficient for change in outcome per unit increase in
In-MEP (adjusted for sex, smoking, diabetes (except for glucose)
and the other variables in the table; model for Framingham Risk
Score only adjusted for sex)
(P [SE])
0.062 (-0.01, 0.14)
-0.007 (-0.03, 0.04)
-0.002 (-0.03, 0..04)
0.197 (-0.17, 0.56)
-2.35 (-4.31, -0.40)
-1.79 (-2.56, -0.82)
0.007 (-0.01, 0.03)
0.02 (-0.27, 0.32)
LDL
HDL
Triglycerides
BMI
SBP
DBP
Glucose
Framingham Risk Score
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-16. Evidence pertaining to MEP and cardiovascular disease in humans
Reference and Study Design
(Lind and Lind, 2011) (Sweden)
n=l,016 (507 men, 509 women), age 70 yrs at
enrollment, cross-sectional analysis within the
Prospective Investigation of Vasculature in
Uppsala Seniors study, 2001-2003
Outcome: Carotid artery intima media
thickness (IMT); grey scale media of the intima
media complex (IM-GSM); plaque in carotid
artery;
Exposure: Serum sample (fasting), collected at
time of clinical assessment
MEP in serum (ng/mL):
Median 75th percentile
11.6 17.5
Analysis: Linear regression for continuous
outcomes (IMT, IM-GSM) and ordinal logistic
regression for number of carotid arteries with
plaques (0, 1, 2), adjusted for variables shown
in results column
Results
Median IMT by quintile of MEP (adjusted for sex, BMI, fasting
blood glucose, SBP, DBP, HDL and LDL cholesterol, triglycerides,
smoking, antihypertensive treatment, statin use)
MEP
Quintile IMT IM-GSM
Median IMT (p-value) Median (p-value)
1 M~GSM
1 (low) 0.87 (referent) 72 Referent
2 0.87 (0.44) 74 (0.80)
3 0.89 (0.30) 74 (0.69)
4 0.86 (0.63) 75 (0.26)
5 (high) 0.87 (0.82) 85 (0.0001)
Regression coefficient (P [p-value]) per unit increase in serum MEP
(adjusted for sex, BMI, fasting blood glucose, SBP, DBP, HDL and
LDL cholesterol, triglycerides, smoking, antihypertensive
treatment, statin use)
IMT 4.5 (0.0001)
IM-GSM -0.0032 (0.88)
OR for presence of plaques and median value of plaque GSM by
quintile of MEP (adjusted for sex, BMI, fasting blood glucose, SBP,
DBP, HDL and LDL cholesterol, triglycerides, smoking,
antihypertensive treatment, statin use)
MEP Plaque
Quintile prevalence Plaque GSM
OR (p-value) Median (p-value)
1 (low) 1.0 (referent) 68 (referent)
2 1.24 (0.16) 67 (0.74)
3 1.07 (0.86) 70 (0.91)
4 1.35 (0.13) 65 (0.92)
5 (high) 1.54 (0.018) 72 (0.13)
Odds ratio or regression coefficient per unit increase in serum
MEP
Plaque prevalence OR (95% Cl) 1.17(0.99,1.39)
Plaque GSM P [p-value 3.0(0.19)
The regression models did not show evidence of interaction by
gender (interaction term p-values ranged from 0.18 to 0.85).
The magnitude of the ORs for plaque prevalence for MEP were
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-16. Evidence pertaining to MEP and cardiovascular disease in humans
Reference and Study Design
Results
generally greater than those for the other phthalate metabolites
evaluated (ORs for quintile 5 ranged from 0.64 (MiBP) to 1.15
(MMP).
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-17. Evidence pertaining to MEP and oxidative stress and inflammation
in humans
Reference and Study Design
Results
(Ferguson et al.. 2012) (United States, NHANES)
10,026 participants in 1999-2006 NHANES, ages >6 yrs
Outcome: Serum markers of oxidative stress
(bilirubin) and inflammation (alkaline phosphatase,
ferritin, absolute neutrophil count, and fibrinogen)
Exposure Urine samples, collected same day as serum
samples (data reported in Ferguson et al., 2011)
MEP in urine (ug/g Cr):
75th 95th
Median percentile percentile
Cr-adjusted 145 383 1,879
Analysis: Linear regression, adjusting for variables
shown in results column.
Regression coefficient for percent change in serum
marker level per IQR increase in MEP (adjusted for age,
sex, race and ethnicity, serum cotinine, poverty index
ratio, BMI, and urinary creatinine)
Serum marker
Bilirubin (mg/dL)
(n = 7,175)
Alkaline phosphatase (U/L)
(n = 7,176)
Ferritin, adjusted
(n = 5,299)
Neutrophil count
(1,000 cells/ul)
(n = 8,331)
P (95% Cl)
1.06 (-0.30, 2.42)
-3.33 (-5.05, -1.84)
-5.99 (-9.31,-2.75)
-0.83 (-1.72, 0.06)
Authors reported no statistically significant association
between phthalate metabolites and fibrinogen
(quantitative results not reported)
(Ferguson et al.. 2011) (United States, NHANES)
10,026 participants in 1999-2006 NHANES, ages >6 yrs
Outcome: Serum markers of oxidative stress
(gamma glutamyltransferase; GGT) and
inflammation (C-reactive protein; CRP)
Exposure Urine samples, collected same day as serum
samples
MEP in urine (u.g/g Cr):
75th 95th
Median percentile percentile
Cr-adjusted 145 383 1,879
Analysis: Linear regression, considering age, sex, race
and ethnicity, poverty index ratio BMI, serum cotinine,
alcohol use, education, and urinary creatinine as
covariates
Regression coefficient for change in In-transformed
serum marker level per unit increase in In-MEP (adjusted
for age, sex, race and ethnicity, serum cotinine, poverty
index ratio, BMI, and urinary creatinine)
Serum marker
GGT (U/L)
(n = 7,181)
CRP (mg/dL)
(n = 8,342)
P (95% Cl)
0.008
(-0.002, 0.018)
-0.020
(-0.040, 0.0003)
p-value
(0.11)
(0.05)
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in
animals
Reference and Study Design
Results
Adrenal gland weight
(Brown et al.. 1978)
Rat (Sprague Dawley); 5/sex/group
0, 1, 5% (0, 750, 3710 mg/kg-day) in
females; 0, 770, 3160 mg/kg-day in males)
Diet
42 days, and
15/sex/group
0, 0.2, 1, 5 % (0, 150, 770, 3160 mg/kg-day
in males; 0, 150, 750, 3710 mg/kg-day in
females)
Diet
112 days.
(Fuiiietal., 2005)
Rat (Sprague Dawley),
Multigenerational study design:
24 breeding pairs/group/generation;
adrenal weight measured in 21-
24/sex/group/generation
0, 600, 3,000, 15,000 ppm (0, 40, 197,
1016 mg/kg-day in FO males; 0, 51, 255,
1297 mg/kg-day in FO females; 0, 46, 222,
1150 mg/kg-day in Fl males; 0, 56, 267,
1375 mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental males (14
weeks dosing during premating and
mating) and ~133 days for FO and Fl
parental females (10 weeks premating, 3
weeks mating, 3 weeks gestation, 3 weeks
lactation)
Relative adrenal gland weight (percent change compared to control)
Males
42 day
112 day
Females
42 day
112 day
0 150
N/A
-5%
0 150
N/A
-3%
Absolute adrenal gland weight (percent
control)
Males
FO
Fl
Fl pup
F2 pup
Females
FO
Fl
Flpup
F2 pup
0 40/46
-5%
-2%
0
0%
0 51/56
3%
3%
0
-4%
770
-14%
-3%
750
5%
3%
change
197/222
-9%
-7%
-8%
0%
255/267
1%
-1%
-12%*
-4%
3160
8%
17%*
3710
8%
12%
compared to
1016/1150
12%*
-7%*
-12%*
-12%*
1297/1375
-4%
-1%
-19%*
-17%*
Relative adrenal gland weight (percent change compared to control)
Males
FO
Fl
Flpup
F2 pup
Females
FO
Fl
Flpup
F2 pup
0 40/46
-2%
0%
0%
-3%
0 51/56
1%
1%
3%
-3%
197/222
-8%
-7%
-6%
-3%
255/267
2%
-4%
-6%
-3%
1016/1150
-8%
-8%*
0%
-7%
1297/1375
-7%
-3%
0%
-7%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in
animals
Reference and Study Design
(Gray et al., 2000)
Rat (Sprague Dawley); 19 female controls
and 5 female DEP-treated; adrenal
weights were assessed in 17 control litters
(n=45 males) and 3 DEP-treated litters
(n=12 males)
0, 750 mg/kg-day
Gavage
GD14-PND3
Note: The litter was the statistical unit of
comparison. Body weight was analyzed as
a covariate.
(Kwacketal., 2009)
Rat (Sprague Dawley); 6 males/group
0, 500 mg/kg-day DEP
0, 250 mg/kg-day MEP
Gavage in corn oil
28 days
(Shiraishietal., 2006)
Rat (Sprague-Dawley); 10/sex/group
0, 40, 200, 1,000 mg/kg-day DEP
Gavage in corn oil
28 days
Results
Absolute adrenal gland weight (percent change compared to
compared to control)
Male offspring at 3-5
months of age
0
750
-13%
Relative adrenal gland weight (percent change compared to control)
Males
0 500 (DEP)
-25%
0 250 (MEP)
0%
Relative adrenal gland weight (percent change compared to control)
0 40 200
Males - -7% -7%
Females - 0 2%
1000
3%
14%*
Hormonal changes
(Shiraishietal., 2006)
Rat (Sprague-Dawley); 10/sex/group
0, 40, 200, 1,000 mg/kg-day DEP
Gavage in corn oil
28 days
estradiol serum concentration (percent change compared to control)
0 40 200
Males - -14% -22%
Females - 19% 23%
1000
-54%*
34%
Dose-dependent changes in T3, T4, and TSH were not observed.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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-------
Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in
animals
Reference and Study Design
Results
Adrenal gland histopathology
(Pereira et al.. 2008 b)
Rat (Wistar);
Multigenerational study design:
6 breeding pairs/group/generation;
adrenal glands assessed in 6
adults/group/ generation
FO: 0, 50 mg/kg diet (0, 2.85 mg/kg-day)
(FO rats)
Fl: 0, 25 mg/kg diet (0, 1.425 mg/kg-day)
(Fl rats)
F2: 0, 10 mg/kg diet (0, 0.57 mg/kg-day)
(F2 rats)
Diet
FO: Adult exposure [150 days: 100 days
premating + mating, gestation, and
weaning]
Fl, F2: Developmental exposure [GDO-
PND21] and Adult exposure [150 days (see
FO protocol) starting PND 35-40]
(Shiraishietal., 2006)
Rat (Sprague-Dawley); 10/sex/group
0, 40, 200, 1,000 mg/kg-day DEP
Gavage in corn oil
28 days
Vacuolations and degeneration of the zona fasciculata region of the
adrenal cortex.
Severity in males: FO>F1=F2
Severity in females: FO=F1
-------
Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in
animals
Reference and Study Design
(Fuji! etal., 2005)
Rat (Sprague Dawley),
Multigenerational study design:
24 breeding pairs/group/generation;
adrenal weight measured in 21-
24/sex/group/generation
0, 600, 3,000, 15,000 ppm (0, 40, 197,
1016 mg/kg-day in FO males; 0, 51, 255,
1297 mg/kg-day in FO females; 0, 46, 222,
1150 mg/kg-day in Fl males; 0, 56, 267,
1375 mg/kg-day in Fl females)
Diet
~98 days for FO and Fl parental males (14
weeks dosing during premating and
mating) and ~133 days for FO and Fl
parental females (10 weeks premating, 3
weeks mating, 3 weeks gestation, 3 weeks
lactation)
(NIP. 1984)
Mouse (CD-I);
Continuous breeding protocol
FO: 40 control and 18-20 breeding
pairs/treatment group
Fl: 20 breeding pairs/group/generation
FO: 0, 0.25, 1.25, 2.5 %
(0,340,1770, 3640 mg/kg-day)
Fl: 0, 2.5% (0, 3640 mg/kg-day)
Diet
FO: 7 days premating + 98 days
cohabitation + 21 days segregation (126
days total)
Fl: in utero + lactation, and then in the
diet through a 7 day mating period at
74±10 days old (Fl females were allowed
to deliver litters)
Results
Absolute pituitary gland weight (percent change compared to
control)
Males
FO
Fl
Flpup
F2 pup
Females
FO
Fl
Flpup
F2 pup
0 40/46 197/222 1016/1150
5% 6% -5%
-1% -1% -4%
0% 3% -3%
3% 3% -3%
0 51/56 255/267 1297/1375
-4 -6 -7
0% 3% -4%
3% 9% -9%
-6% -6% -6%
Relative pituitary gland weight (percent change compared to
control)
Males
FO
Fl
Fl pup
F2 pup
Females
FO
Fl
Flpup
F2 pup
0 40/46 197/222 1016/1150
8% 6 0
-1% -2% -5%
2.5% 5% 15%*
3% 3% 3%
0 51/56 255/267 1297/1375
-5% -5% -7%
-2% 0% -5%
5% 11% 14%
-9% -9% 0%
Absolute pituitary gland weight in Fl parental mice (percent change
compared to control)
Males
Females
0 3640
-5%
-17%*
Relative pituitary gland weight in Fl parental mice (percent change
compared to control)
Males
Females
0 3640
-5%
-12%*
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-69 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
Table 2-18. Evidence pertaining to adrenal and pituitary gland effects in
animals
Reference and Study Design
(Shiraishietal., 2006)
Rat (Sprague-Dawley); 10/sex/group
0, 40, 200, 1,000 mg/kg-day DEP
Gavage in corn oil
28 days
Results
Dose-related changes in pituitary weight were not observed.
*Statistically significant (p<0.05) based on analysis of data by study authors.
Percent change compared to control = treated value - control value x 100
control value
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-70 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
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Figure 2-6. Exposure-response array of pituitary effects following exposure to DEP
772/s document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
2.6. Carcinogenicity
Table 2-19. Evidence pertaining carcinogenic effects in animals
Reference and Study Design
Results
Breast cancer
(Lopez-Carrillo et al.. 2010) (Mexico)
Case-control study, n = 223
hospitalized women, 221 population
controls matched by age and
residency, >18 yrs of age, >1 yr in study
area, 2007-2008; mean age 53 years.
Participation rates: 94.8% of cases and
99.5% of controls.
Outcome: Histologically-confirmed
breast cancer
Exposure: Urine sample (for cases,
urine collected on average 2 mo after
diagnosis, but before treatment)
MEP in urine (u.g/g Cr):
Geometric mean (95% Cl)
Cases 170 (142, 203)
Controls 107 (91,125)
Analysis: Logistic regression,
considering variables shown in results
column
OR (95% Cl) for breast cancer, by tertile of MEP (adjusted for current
age, age at menarche, parity, menopausal status, and other phthalate
metabolites)
MEP tertile
(Hg/g Cr)
1 (9.4-56.2)
2 (56.2-181.4)
3 (181.4-18,986)
(trend p)
Full sample Pre-menopause
1.0
(referent)
1.42
(0.85-2.38)
2.20
(1.33-3.63)
(0.003)
1.0
(referent)
1.84
(0.73, 4.6)
4.13
(1.6, 10.7)
(0.060)
Post-
menopause
1.0
(referent)
1.32
(0.69, 2.53)
1.84
(0.99, 3.42)
(0.060)
The association with MEP was larger in magnitude than the association
seen with any other phthalate metabolite; MBzP and MCPP were
inversely associated with breast cancer risk.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1
2 3. EVIDENCE TABLE REFERENCE LIST
3
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
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28 atherosclerosis in the elderly. Atherosclerosis 218: 207-213.
29 http://dx.doi.0rg/10.1016/j.atherosclerosis.2011.05.001
30 Lind. PM: Roos. V: Ronn. M: Tohansson. L: Ahlstrom. H: Kullberg. 1: Lind. L. (2012a). Serum
31 concentrations of phthalate metabolites are related to abdominal fat distribution two years
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35 with prevalent diabetes in the elderly. Diabetes Care 35: 1519-1524.
36 http://dx.doi.org/10.2337/dcll-2396
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40 Lomenick. JP: Calafat. AM: Melguizo Castro. MS: Mier. R: Stenger. P: Foster. MB: Wintergerst. KA.
41 (2010). Phthalate exposure and precocious puberty in females. J Pediatr 156: 221-225.
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44 Needham. LL: Ruiz-Ramos. R: Cebrian. ME. (2010). Exposure to phthalates and breast
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1 reproductive hormones in infants three months of age. Environ Health Perspect 114: 270-
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3 Mapuskar. K: Pereira. C: Rao. CV. (2007). Dose-dependent sub-chronic toxicity of diethyl phthalate
4 in female Swiss mice. Pestic Biochem Physiol 87: 156-163.
5 http://dx.doi.0rg/10.1016/j.pestbp.2006.07.005
6 Meeker. ID: Calafat. AM: Hauser. R. (2007). Di(2-ethylhexyl) phthalate metabolites may alter
7 thyroid hormone levels in men. Environ Health Perspect 115: 1029-1034.
8 http://dx.doi.org/10.1289/ehp.9852
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10 associated with decreased steroid hormone levels in adult men. J Androl 30: 287-297.
11 http://dx.doi.org/10.2164/iandrol.108.006403
12 Mieritz, MG: Frederiksen, H: S0rensen, K: Aksglaede, L: Mouritsen, A: Hagen, CP: Skakkebaek, NE:
13 Andersson. AM: Tuul. A. (2012). Urinary phthalate excretion in 555 healthy Danish boys with
14 and without pubertal gynaecomastia. Int J Androl 35: 227-235.
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50 http://dx.doi.0rg/10.1016/i.pestbp.2007.07.008
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1 Pereira, C: Mapuskar, K: Rao, CV. (2008b). A three-generation toxicity study of diethyl phthalate on
2 histology of adrenal and thyroid glands of rats. Toxicology International 15: 63-67.
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9 Shiraishi. K: Miyata. K: Houshuyama. S: Imatanaka. N: Umano. T: Minobe. Y: Yamasaki. K. (2006).
10 Subacute oral toxicity study of diethylphthalate based on the draft protocol for
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Preliminary Materials for the IRIS Toxicological Review ofDiethyl Phthalate
1 Tranfo, G: Caporossi, L: Paci, E: Aragona, C: Romanzi, D: De Carolis, C: De Rosa, M: Capanna, S:
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7 sample. Environ Health Perspect 121: 501-506. http://dx.doi.org/10.1289/ehp.1205526
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9 associated with body mass index and waist circumference in Chinese school children. PLoS
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12 phthalates with endometriosis and uterine leiomyomata: findings from NHANES, 1999-
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15 a cross-sectional study. Biomed Environ Sci 19: 205-209.
16
17
This document is a preliminary draft for review purposes only and does not constitute Agency policy.
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