United Stat#s
lPSt I^hFjp*% Environmental Protection
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EPA/690/R-17/009
FINAL
09-26-2017
Provisional Peer-Reviewed Toxicity Values for
Diphenyl Ether
(CASRN 101-84-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jon B. Reid, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Elizabeth Owens, PhD
National Center for Environmental Assessment, Cincinnati, OH
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the EPA Office
of Research and Development's National Center for Environmental Assessment, Superfund
Health Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	5
HUMAN STUDIES	9
Oral Exposures	9
Inhalation Exposures	9
ANIMAL STUDIES	9
Oral Exposures	9
Inhalation Exposures	11
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	13
Genotoxicity	18
Metabolism/Toxicokinetic Studies	18
Other Routes	19
Mixture Studies and Developmental Studies as a Mixture	19
DERIVATION 01 PROVISIONAL VALUES	21
DERIVATION OF ORAL REFERENCE DOSES	21
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	22
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	22
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	22
APPENDIX A. SCREENING PROVISIONAL VALUES	23
APPENDIX B. DATA TABLES	28
APPENDIX C. REFERENCES	31
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COMMONLY USED ABBREVIATIONS AND ACRONYMS1
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
7V-acetyl-P-D-glucosaminidase
AR
androgen receptor
NCEA
National Center for Environmental
AST
aspartate aminotransferase

Assessment
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level

Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity

number

relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPN
chronic progressive nephropathy
RGDR
regional gas dose ratio
CYP450
cytochrome P450
RNA
ribonucleic acid
DAF
dosimetric adjustment factor
SAR
structure activity relationship
DEN
diethylnitrosamine
SCE
sister chromatid exchange
DMSO
dimethylsulfoxide
SD
standard deviation
DNA
deoxyribonucleic acid
SDH
sorbitol dehydrogenase
EPA
Environmental Protection Agency
SE
standard error
ER
estrogen receptor
SGOT
serum glutamic oxaloacetic
FDA
Food and Drug Administration

transaminase, also known as AST
FEVi
forced expiratory volume of 1 second
SGPT
serum glutamic pyruvic transaminase,
GD
gestation day

also known as ALT
GDH
glutamate dehydrogenase
SSD
systemic scleroderma
GGT
y-glutamyl transferase
TCA
trichloroacetic acid
GSH
glutathione
TCE
trichloroethylene
GST
glutathione-S-transferase
TWA
time-weighted average
Hb/g-A
animal blood-gas partition coefficient
UF
uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFa
interspecies uncertainty factor
HEC
human equivalent concentration
UFc
composite uncertainty factor
HED
human equivalent dose
UFd
database uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFl
LOAEL-to-NOAEL uncertainty factor
IVF
in vitro fertilization
UFS
subchronic-to-chronic uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
DIPHENYL ETHER (CASRN 101-84-8)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data
or methodologies that might impact the toxicity values or characterization of potential for
adverse human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency
(EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-
science).
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the EPA
Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical
Support Center (513-569-7300).
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INTRODUCTION
Diphenyl ether, CASRN 101-84-8, belongs to the class of compounds known as aromatic
ethers. It is used mainly as a perfume, particularly in soaps, and as a heat-transfer medium for
laminated electrical insulation (Lewis and Hawley, 2007). It can also be used as a chemical
intermediate for polyesters and surfactants and for such reactions as halogenation, acylation, and
alkylation (HSDB. 2015; Lewis and Hawley. 2007). Diphenyl ether is listed on U.S. EPA's
Toxic Substances Control Act's public inventory (U.S. EPA 2015). it is registered with Europe's
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program
(ECHA. 2017). and it was assessed under the U.S. EPA High Production Volume (HPV)
program (U.S. EPA, 2016).
Commercial production of diphenyl ether occurs by heating potassium or sodium
phenolate with bromo- or chlorobenzene under pressure. It is also manufactured as a byproduct
during phenol production by the high-pressure hydrolysis of chlorobenzene (HSDB. 2015).
The empirical formula for diphenyl ether is C12H10O. Its chemical structure is shown in
Figure 1. Table 1 summarizes the physicochemical properties of diphenyl ether. Diphenyl ether
is a white or colorless crystalline solid at room temperature (HSDB. 2015). Diphenyl ether's
vapor pressure indicates that it will exist almost entirely as a vapor in the atmosphere. The
estimated half-life of vapor-phase diphenyl ether in air by reaction with photochemically
produced hydroxyl radicals is 1.7 days. Diphenyl ether's Henry's law constant indicates that it
may volatilize from moist surfaces, but volatilization from dry soil surfaces is not expected based
on its vapor pressure. The moderate water solubility and soil adsorption coefficient indicate that
diphenyl ether will have low mobility in soil, but that it may still leach to groundwater or
undergo runoff after a rain event. Bioconcentration in aquatic organisms may also occur, based
on experimental bioconcentration factor (BCF) values (HSDB. 2015).
o
Figure 1. Diphenyl Ether Structure
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Table 1. Physicochemical Properties of Diphenyl Ether (CASRN 101-84-8)
Property (unit)
Value
Physical state
Solid3
Boiling point (°C)
258b
Melting point (°C)
26.8b
Density (g/cm3 at 20°C)
1.0753
Vapor pressure (mm Hg at 25 °C)
0.0225b
pH (unitless)
NA
pKb (unitless)
5.79°
Solubility in water (mg/L at 25 °C)
18b
Octanol-water partition coefficient (log Kow)
4.21b
Henry's law constant (atm-m3/mol at 25°C)
2.8 x 10 1 (estimated)13
Soil adsorption coefficient Koc (L/kg)
1,950°
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
9.60 x 10-I2b
Atmospheric half-life (d)
1.087 (estimated)13
Relative vapor density (air = 1)
5.86°
Molecular weight (g/mol)
170.21b
Flash point (open cup in °C)
115a
"European Chemicals Agency (ECHA. 20161.
bU.S. EPA (2012b).
"Hazardous Substance Data Bank. ToxNet. NIH (HSDB. 20151.
NA = not applicable; NIH = National Institutes of Health.
A summary of available toxicity values for diphenyl ether from EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Diphenyl Ether (CASRN 101-84-8)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
WHO (ADI)
Acceptable
No safety concern at current levels of
intake when used as a flavoring agent
WHO (2003);
WHO (2004a):
WHO (2004b)
Cal/EPA
NV
NA
Cal/EPA (2014):
Cal/EPA (2017a):
Cal/EPA (2017b)
OSHA (PEL)
1 ppm (7 mg/m3)
8-hr TWA for vapor (general industry,
construction, and shipyard employment)
OSHA (2011):
OSHA (2006a):
OSHA (2006b)
NIOSH (REL)
1 ppm (7 mg/m3)
10-hr TWA for vapor
NIOSH (2015)
NIOSH (IDLH)
100 ppm
Based on being 100 times the NIOSH
REL or OSHA PEL
NIOSH (2014)
ACGIH (TLV)
1 ppm
8-hr TWA; vapor; based on upper
respiratory tract irritation, eye irritation,
and nausea due in part to disagreeable
odor
ACGIH (2016)
ACGIH (STEL)
2 ppm
15-min TWA; vapor; based on upper
respiratory tract irritation, eye irritation,
and nausea due in part to disagreeable
odor
ACGIH (2015)
DOE (PAC)
PAC-1: 2 ppm;
PAC-2: 16 ppm;
PAC-3: 96 ppm
Based on TEELs
DOE (2016)
USAPHC (air-MEG)
1-hr critical: 600 mg/m3;
1-hr marginal: 130 mg/m3;
1-hr negligible: 13 mg/m3;
8-hr negligible: 7 mg/m3;
14-d negligible: 2.4 mg/m3;
1-yr negligible: 24 mg/m3
Vapor; based on upper respiratory tract
irritation, eye irritation, and nausea
U.S. APHC (2013)
Cancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2017)
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Table 2. Summary of Available Toxicity Values for Diphenyl Ether (CASRN 101-84-8)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Cal/EPA
NV
NA
Cal/EPA (2011):
Cal/EPA (2017a):
Cal/EPA (2017b)
ACGIH
NV
NA
ACGIH (2016)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency;
DOE = U.S. Department of Energy; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration;
USAPHC = U.S. Army Public Health Command; WHO = World Health Organization.
Parameters: ADI = acceptable daily intake; IDLH = immediately dangerous to life or health concentrations;
MEG = military exposure guideline; PAC = protective action criteria; PEL = permissible exposure level;
REL = recommended exposure level; STEL = short-term exposure level; TLV = threshold limit value.
NA = not applicable; NV = not available; TEEL = temporary emergency exposure limit; TWA = time-weighted
average.
Literature searches were conducted in January 2016 and updated in August 2017 for
studies relevant to the derivation of provisional toxicity values for diphenyl ether,
CASRN 101-84-8. Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: PubMed, TOXLINE (including TSCATS1), and Web of Science. The following
databases were searched outside of HERO for health-related values: American Conference of
Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (Cal/EPA), U.S. EPA
Integrated Risk Information System (IRIS), U.S. EPA Health Effects Assessment Summary
Tables (HEAST), U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), and
Occupational Safety and Health Administration (OSHA).
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases,
respectively, for diphenyl ether and include all potentially relevant repeated-dose, short-term-,
subchronic-, and chronic-duration studies, as well as reproductive and developmental toxicity
studies. Principal studies are identified in bold. The phrase "statistical significance," used
throughout the document, indicates ap-walue of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Diphenyl Ether (CASRN 101-84-8)
Category3
Number of Male/Female, Strain,
Species, Study Type, Study Duration,
Reported Doses
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Subchronic
10 M/10 F, S-D albino rat, diet, 13 wk; 0,
200, 1,000, 5,000 ppm
0, 11.7, 60.7,301 (M);
0, 14.5, 73.9, 335 (F)
Decreases in mean body weights and
food consumption, but magnitude of
changes not reported; data
insufficient to evaluate study authors'
attribution of decreases to palatability
of diet
NDr
NDr
Dow Chemical
Co (2003);
Johnson et al.
(1992) 1 Abstract 1
NPR
2. Inhalation (mg/m3)
Subchronic
20 or 10 M/10 F, S-D Spartan rat, whole
body, 7 hr/d, 5 d/wk for 20 exposures in
31 or 33 d; 0,4.9 ± 1.5 (males only),
10.0 ± 2.0 (males only), 20 ppm (males
and females)
HECet: 0,1.3,2.66,
5.3 (M);
0,4.3 (F)
HECsystemic:
0, 7.1,14.5, 29 (M);
0, 29 (F)
Eye and nasal irritation, decreased
relative and absolute liver weights,
increased relative brain weight,
decreased WBC counts, and
decreased Hb
NDr (HEC)
7.1 (HEC)
Dow Chemical
PR,
PS
Co (1986a):
Hefner et al.
(1975)

Subchronic
4 M, New Zealand White rabbit, whole
body, 7 hr/d, 5 d/wk for 20 exposures in
31 or 33 d; 0, 4.9 ± 1.5, 10.0 ±2.0 ppm
HECet: 0, 3.8, 7.66
Eye and nasal irritation
3.8 (HEC)
7.66 (HEC)
Dow Chemical
Co (1986a):
Hefner et al.
(1975)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for Diphenyl Ether (CASRN 101-84-8)
Category3
Number of Male/Female, Strain,
Species, Study Type, Study Duration,
Reported Doses
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
2 M, Beagle dog, whole body, 7 hr/d,
5 d/wk for 20 exposures in 31 or 33 d; 0,
4.9 ± 1.5, 10.0 ± 2.0 ppm
HECsystemic:
0,7.1, 14.5
Increased absolute kidney weight
NDr
7.1 (HEC)
Dow Chemical
Co (1986a):
Hefner et al.
(1975)
PR
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated exposure
for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure for >10% lifespan
for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021.
bDosimetry: Values are presented as ADDs (mg/kg-day) for oral noncancer effects and as HECs (mg/m3) for inhalation noncancer effects. Because the observed effect in the
inhalation studies in rats and rabbits was nasal irritation, the HECs were calculated using the equation for extrathoracic respiratory effects from a Category 1 gas (U.S. EPA.
19941: HECet = continuous concentration in mg/m3 x ratio of regional gas dose in laboratory animal species to that of humans for the extrathoracic
region = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRet. For dogs, only systemic effects were observed, and the HECs were calculated
using the equation for systemic effects from a Category 3 gas (U.S. EPA. 1994): HECsystemic = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days exposed ^ total
days observed) x blood-air partition coefficient (U.S. EPA. 1994).
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; CONC = concentration; ET = extrathoracic; F = female(s); Hb = hemoglobin; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; M = male(s); MW = molecular weight; ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level;
RGDR = regional gas dose ratio; S-D = Sprague-Dawley; WBC = white blood cell.
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Table 3B. Summary of Potentially Relevant Cancer Data for Diphenyl Ether (CASRN 101-84-8)
Category
Number of Male/Female, Strain, Species, Study
Type, Study Duration, Reported Doses
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level.
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HUMAN STUDIES
Oral Exposures
No studies examining possible associations between health effects in humans and oral
exposure to diphenyl ether were identified.
Inhalation Exposures
Data on the inhalation effects of diphenyl ether in humans are limited to qualitative
descriptions of short-term exposures of volunteers to diphenyl ether vapor. Short exposures of
<1 minute to 5 ppm (34.76 mg/m3) perfume-grade diphenyl ether vapor were reportedly "well
tolerated" (Dow Chemical Co. 1986a; Hefner et aL 1975). At 10 ppm (69.53 mg/m3), subjects
experienced distaste and upper respiratory irritation (Dow Chemical Co. 1973). No further data
on the possible associations between health effects in humans, and inhalation exposure to
diphenyl ether were identified.
ANIMAL STUDIES
Oral Exposures
Overview of Animal Oral Exposure Studies
Potentially relevant data for noncancer effects from oral exposure to diphenyl ether are
limited to short-term-duration studies using a single rabbit or dog (Dow Chemical Co. 1986b.
1936a. b, 1935) and a 13-week feeding study in rats (Dow Chemical Co. 2003; Johnson et aL
1992).
Short-Term-Duration Studies
Dow Chemical Co (1935); Dow Chemical Co (1936b); Dow Chemical Co (1936a); Dow
Chemical Co (1986b)
A rabbit received diphenyl ether at a dose of 100 mg/kg via stomach tube 5 days/week
over a period of 29 days for a total of 19 doses. The test article was suspended in 5-10% gum
acacia solution and feedings were prepared daily. The animal was monitored for clinical
observations during the dosing period. At necropsy, the animal was examined for gross
pathology. The animal survived the dosing period and no clinical signs of toxicity were
observed. The only reported change was gross pathology in one lobe of the liver.
A dog (8.93 kg body weight) was fed 2.11 g/kg body weight of diphenyl ether for
1 week. The animal survived the dosing period and no clinical signs of toxicity were observed.
No further study details were provided.
Subchronic-Duration Studies
Dow Chemical Co (2003); Johnson et al. (1992) [abstract]
Groups of Sprague-Dawley (S-D) albino rats (10/sex/group) were fed commercial-grade
diphenyl ether in the diet at target concentrations of 0, 200, 1,000, or 5,000 ppm for 13 weeks.
Additional groups of S-D rats (10/sex/group) were retained for a 4-week recovery period
following the 13-week dosing period. The test article (study author stated purity >98%) was
prepared neat in a premix and subsequent diets were prepared weekly. Periodic analysis of feed
confirmed homogeneity and test article concentration levels. Measured doses were reported as 0,
11.7, 60.7, and 301 mg/kg-day for males and 0, 14.5, 73.9, and 335 mg/kg-day for females.
Clinical observations were made daily. Feed consumption and body-weight gain were recorded
weekly. Blood samples were collected prior to necropsy for standard hematology and serum
chemistry. Urine samples were also collected prior to necropsy for urinalysis (appearance,
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volume, specific gravity, occult blood, protein, pH, ketones, urobilinogen, glucose, bilirubin, and
sediments). At necropsy, all animals were grossly examined. Organ weights for the brain,
gonads, heart, kidneys, liver, and spleen were recorded. A complete histopathological
examination was performed on all animals from the control and high-dose groups. Selected
organs and tissues (lungs, liver, kidneys, and gross lesions) from the low- and mid-dose groups
were also submitted for histopathology. This study was only available as an abstract (Johnson et
al.. 1992) and as a submission included within the Organisation for Economic Co-operation and
Development's (OECD's) International Uniform Chemical Information Database (IUCLID) data
set submitted for diphenyl ether by the Dow Chemical Company. The IUCLID submission is
limited to a qualitative presentation of analytical results that does not include quantitative data
for each endpoint evaluated. However, this study was flagged as a valid study that was
conducted under Good Laboratory Practices (GLPs) consistent with OECD Test Guideline 408.
Statistical analyses included multivariate repeated-measure analysis of variance (ANOVA) for
body weights and gains, food consumption, ratio data, and both multivariate and univariate
two-factor fixed effect ANOVA on log-transformed data for other endpoints. Additionally,
Dunnett's test for multiple comparisons was used for comparisons of combined data of sexes.
Dow Chemical Co (2003) only reported results qualitatively; no data were provided in
the available study report. No clinical signs of toxicity or mortality were observed. The study
authors reported a significant decrease in mean weekly body weight and food consumption in
high-dose animals during the entire dosing period, and in mid-dose females during most of the
study (specific time points not reported). The magnitude of the observed changes was not
reported. Food consumption, body-weight gains, and food conversion ratios were reported by
the study authors to be significantly increased during >1 week of the recovery period. On this
basis, the study authors attributed the decreases in body weight and food consumption, observed
during the dosing period, to unpalatability of the test diet. Specific significant changes observed
based on hematology, clinical chemistry, or urinalysis were not described in detail within the
IUCLID submission. However, the study authors noted that the few statistically significant
differences in these parameters were not dose related, were within range of historical laboratory
values, or occurred only in the recovery animals. No significant changes in absolute organ
weights were reported. Dow Chemical Co (2003) indicated that some statistically significant
differences were observed in relative organ weights in high-dose rats and mid-dose females, but
did not provide additional information. The study authors attributed changes in relative organ
weights to the significant decreases in body weights seen at termination and not direct target
organ toxicity. No significant pathological changes were reported.
No-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level
(LOAEL) values cannot be assigned for this study based on the available description in the
IUCLID submission. Decreases in food consumption and body weight were reported in
high-dose males, and mid- and high-dose females, but no data on the magnitude of the observed
changes were provided. The study authors suggested palatability of the diet to be the cause of
the observed changes, rather than a toxic effect, but this conclusion cannot be independently
evaluated without the associated data.
Chronic-Duration Studies
No studies examining the chronic or carcinogenic effects in animals from oral exposure
to diphenyl ether were identified.
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Reproductive/Developmental Studies
No studies examining the reproductive or developmental effects in animals from oral
exposure to diphenyl ether were identified.
Inhalation Exposures
Overview of Animal Inhalation Exposure Studies
Potentially relevant data for noncancer effects from inhalation exposure to diphenyl ether
come from a single study that used rats, rabbits, and dogs (Dow Chemical Co. 1986a; Hefner et
al.. 1975).
Subchronic-Duration Studies
Dow Chemical Co (1986a); Hefner et al. (1975)
Groups of male Spartan S-D rats (n = 20), male New Zealand White rabbits (n = 4), and
male Beagle dogs (n = 2) were exposed to diphenyl ether vapor (perfume-grade, purity 99.85%
containing 0.01-0.04% diphenyl) at target concentrations of 0, 5, or 10 ppm for 7 hours/day,
5 days/week for a total of 20 exposures over 31-33 days. The animals were exposed
whole-body using exposure chambers. Measured chamber concentrations were 4.9 ±1.5 and
10.0 ± 2.0 ppm (34 and 69.5 mg/m3, respectively2). Additional groups of 10 male and 10 female
Spartan S-D rats were exposed to diphenyl ether vapor at target concentrations of 0 or 20 ppm
(140 mg/m3) for 7 hours/day, 5 days/week for a total of 20 exposures in 27 days. Only the
nominal concentration was determined for the 20 ppm (140 mg/m3) exposure chamber. The
converted mg/m3 value for this high-exposure group was based on nominal concentration, but
was not verified by analytical sampling of the chamber air. It should be noted that the exposure
methodology for the two experiments in rats was considerably different. For the first
experiment, the exposure chamber for the animals was 1,000 liters, and nitrogen gas was used as
the carrier for diphenyl ether. For the additional exposure group with the higher concentration,
the exposure chamber was 160 liters and filtered room air was used as the carrier. Food and
water were provided ad libitum to all animals between exposures. Clinical observations were
made on all animals during exposures and periodically between exposures. Body weights were
recorded at regular intervals. Blood samples were collected from all rats exposed to diphenyl
ether at 140 mg/m3 after 1, 4, and 19 days of exposure. Blood samples were also collected at the
end of the exposure period from 10 rats per dose group, and all of the rabbits and dogs.
Hematologic and biochemical evaluations on blood samples included red, white, and differential
cell counts, hemoglobin (Hb) concentrations, packed cell volume, blood urea nitrogen (BUN),
serum alanine aminotransferase (ALT), and alkaline phosphatase (ALP). At necropsy, all
animals were grossly examined. Organ weights for the brain, heart, liver, kidney, and testes
were obtained for all animals exposed to 0, 34, or 69.5 mg/m3 diphenyl ether vapor and from
10 rats (5/sex) exposed to 0 or 140 mg/m3 diphenyl ether vapor. The spleen and thymus from
10 rats (5/sex) exposed to 0 or 140 mg/m3 diphenyl ether vapor, and the adrenal glands from all
of the dogs included in the study were also weighed. All major organs and tissues as well as any
other grossly visible pathologic lesions were examined histologically. Statistical analyses
employed ANOVA and Dunnett's test.
Rats exposed to >69.5 mg/m3 diphenyl ether experienced eye and nasal irritation
(incidence, severity, or statistical significance is not reported). Body- and organ-weight changes
Concentrations converted to mg/m3 by ppm x (MW 24.45). For example,
4.9 ppm x 170 g/mol 24.45 L/mol = 34 mg/m3.
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are shown in Table B-l. Mean terminal body weight among male rats exposed to 140 mg/m3
was statistically significantly lower than concurrent controls (-7%), but was not biologically
significant (<10%) and was similar to the other treated groups, which did not differ from their
control group. Similarly, relative brain weight among male rats exposed to 140 mg/m3 was
statistically significantly elevated over concurrent controls (9%), but was identical to the value
for the controls for the low- and mid-exposure groups. Conversely, mean absolute and relative
liver weights among male rats exposed to 34 and 69.5 mg/m3 were statistically and biologically
significantly decreased compared to their concurrent control (-12% or more based on absolute
weights; -8% or more based on relative weights), but liver weights among rats exposed to the
high-exposure level of 140 mg/m3 were comparable to their concurrent control. Body weight
and organ weights were not different compared to controls in female rats exposed to 140 mg/m3
diphenyl ether vapor (see Table B-l). Hb levels were significantly decreased in male rats at
69.5 mg/m3 (see Table B-2). White blood cell (WBC) counts were also decreased in male rats at
>34 mg/m3 (see Table B-2). No significant changes in biochemical parameters or pathology
were observed among exposed rats (data not shown). For rats, a LOAEL of 34 mg/m3 is
identified based on reduced absolute and relative liver weights, and decreased WBC counts; all
in male rats. Because 34 mg/m3 is the lowest concentration, a NOAEL cannot be identified.
Exposure concentrations of 0, 34, and 69.5 mg/m3 are converted to human equivalent
concentrations (HECs) of 0, 7.1, and 14.5 mg/m3, using the procedures described in U.S. EPA
(1994) for systemic effects for a Category 3 gas in rats.3
Rabbits exposed to 69.5 mg/m3 diphenyl ether vapor experienced mild eye and nasal
irritation (incidence and severity data not reported). Because no numerical information was
provided, statistical significance cannot be determined. No significant exposure-related changes
in body weights, organ weights, or hematology were observed among exposed rabbits (body-,
liver-, kidney-, and brain-weight data are shown in Table B-l; all other data not shown). Serum
chemistry revealed significant decreases in BUN values among rabbits exposed to >34 mg/m3
compared to controls (see Table B-2). The study authors indicated that the BUN levels among
exposed rabbits were within the normal range of variation observed for control rabbits at their
laboratory (15-27 mg/100 mL). Both control and exposed rabbits demonstrated lesions in the
respiratory tract (incidence data not reported). The study authors noted that these lesions were
associated with an inflammatory response to some type of respiratory infection. Additionally,
the abdominal viscera of some rabbits contained granulomatous foci as a result of infestation
with tapeworm larvae. No treatment-related pathological changes among exposed rabbits were
reported. For rabbits, a LOAEL of 69.5 mg/m3 is identified for eye and nasal irritation, with a
corresponding NOAEL of 34 mg/m3. Exposure concentrations of 0, 34, and 69.5 mg/m3 are
converted to HECs of 0, 3.8, and 7.66 mg/m3, respectively, using the procedures described in
U.S. EPA (1994) for extrathoracic respiratory effects of a Category 1 gas in rabbits.4
Dogs exposed to diphenyl ether vapor exhibited no clinical signs of toxicity or irritation.
Changes observed in the terminal body weights and serum chemistry (BUN) of dogs exposed to
diphenyl ether did not demonstrate a clear concentration-response; body weight (see Table B-l)
and BUN (see Table B-2) decreased in dogs exposed to 34 mg/m3 but not 69.5 mg/m3.
Biologically significant absolute kidney-weight increases were observed in male dogs with a
3HECsystemic = Concentration x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood-gas partition
coefficient.
4HECet = Concentration x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x RGDRet.
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19.6% increase at 34 mg/m3 and 35.3% at 69.5 mg/m3 (see Table B-l). Both control and
exposed dogs demonstrated lesions in their lungs (incidence data not reported). The study
authors noted that these lesions were characteristic of a focal minimal inflammatory reaction and
were accompanied by the presence of nematode parasites. No treatment-related pathological
changes among exposed dogs were reported. Based on increased absolute kidney weight in male
dogs, a LOAEL of 34 mg/m3 is identified. Because 34 mg/m3 is the lowest concentration tested,
a NOAEL cannot be identified. Exposure concentrations of 0, 34, and 69.5 mg/m3 are converted
to HECs of 0, 7.1, and 14.5 mg/m3, using the procedures described in U.S. EPA (1994) for
systemic effects for a Category 3 gas in dogs.5
Chronic-Duration Studies
No studies examining the chronic or carcinogenic effects in animals from inhalation
exposure to diphenyl ether were identified.
Reproductive/Developmental Studies
No studies examining the reproductive or developmental effects in animals from
inhalation exposure to diphenyl ether were identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4A provides an overview of genotoxicity studies of diphenyl ether, and Table 4B
provides an overview of acute studies of diphenyl ether.
5HECsystemic = Concentration x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood-gas partition
coefficient.
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Table 4A. Summary of Diphenyl Ether (CASRN 101-84-8) Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
Reference
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella
typhimurium TA98,
TA100, TA1535, and
TA1537
0, 3.3, 10, 33.3, 100,
333.3 ng/plate


Preincubation assay; cytotoxicity was observed at
333.3 ng/plate (~S9).
Haworth et al.
(1983)
Mutation
S. typhimurium TA98,
TA100, TA1535, and
TA1537
3 |imol/platc


Spot test.
Florin et al. (1980)
Mutation
S. typhimurium TA97,
TA98, TA100,
TA1535, and
TA1537? (five tester
strains not specified)
Not specified


Nonmutagenic up to cytotoxic dose.
Bronzetti et al.
(1981) 1abstract 1
Mutation
S. typhimurium TA98,
TA100, TA1535, and
TA1537
0, 1,3, 10, 30,
100 ng/plate without
S9 activation; 0, 3, 10,
30, 100, 300 ng/plate
with S9 activation


Plate incorporation assay; cytotoxicity was observed at
300 and 100 |ig/platc. with and without S9 activation,
respectively.
Test substance: Therminol® VP-1 (diphenyl
ether 73.5%, biphenyl 26.5%).
Monsanto (1990a)
Mutation
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538,
and/or TA1978
0, 5 (1:9),
10 (conc.) |iL/platc
(±S9); 10 |iL/platc
(+S9)


NA
Westinghouse
Electric
Corporation (1977)

Mutation
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538,
TA2636, and TA1532
0, 0.1-500 ng/plate


Plate incorporation or preincubation assay;
cytotoxicity was observed at 50-100 ng/plate,
depending on strain (not specified).
Similar results were obtained in an experiment with
Dowtherm A® (diphenyl ether -74%, biphenyl -26%)
using the same protocol.
Paeano et al. (1983)

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Table 4A. Summary of Diphenyl Ether (CASRN 101-84-8) Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
Reference
Genotoxicity studies in nonmammalian eukaryotic organisms
Gene conversion
Saccharomyces
cerevisiae diploid D7
strain
Up to 103 M (-S9)


A nonsignificant increase in trp conversion and ilv+
reversion was reported.
Moderate cytotoxicity was observed with direct
exposure and enhanced when diphenyl ether was
dissolved inDMSO (concentration was not specified).
Paeano et al. (1983)

Genotoxicity studies in mammalian cells in vitro
CAs
CHO cells
0, 10, 50, 100,
150 ng/mL (-S9);
0, 5, 30, 50 ng/mL
(+S9)


Cytotoxicity was observed at 150 |ig/mL (-S9).
Monsanto (1989b)
UDS
Primary rat
hepatocytes
Preliminary assay: 0,
0.1,0.5, 1,5, 10, 50,
100, 250, 500,
1,000 ng/mL;
Repeat assay: 0, 1, 5,
10, 50, 100, 250,
1,000 ng/mL


Cytotoxicity was observed >100 ng/mL; precipitate
was noted at >250 |ig/mL.
Test substance: Therminol® VP-1 (diphenyl
ether 73.5%, biphenyl 26.5%).
Monsanto (1987a)
UDS
Primary rat
hepatocytes
Preliminary assay: 0,
0.05,0.1,0.5, 1.0,5.0,
10, 50, 100, 250,
500 ng/mL;
Repeat assay: 1, 5, 10,
50, 100, 250 ng/mL


Cytotoxicity was observed at >200 |ig/mL.
SRI International
(1987)
Genotoxicity studies in nonmammalian cells in vivo
Mitotic effects;
Induction of
larval
malformations
Paracentrotus lividus
embryos;
100 embryos were
scored
0, 3 x 10-5, 6 x 10-5,
9 x 10-5 M
+
+
Lethality was observed at 9 x 10 " M; observations
included an increase in percentage of embryos at
interphase, and percentage of mitotic abnormalities
and a decrease in mitoses/embryo.
Paeano et al. (1983)

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Table 4A. Summary of Diphenyl Ether (CASRN 101-84-8) Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
Reference
Sperm
inactivation
assay
Sphaerechinus
granulans sperm; 2-,
5-, 10-, 30-, or
60-min exposure;
1% DMSO (control)
0, 10~5 M
+
+
Fertilization rates were -9.5, -31, -84, -89, and -50%
(2, 5, 10, 30, and 60 min, respectively) compared to
vehicle control.
Paeano et al. (1983)

Induction of
developmental
abnormalities
S. granulans sperm,
zygotes
0, 105 M
+
+
After exposure, observations made on eggs following
fertilization included early cytolysis and abnormal
cleavage (5 hr); cytolysis and pathologic survivors
(24 hr); cytolysis (48 hr). Observations made on
sperm included undifferentiated or filled blastulae
(24 hr); and loss of motility and cytolysis (48 hr).
Paeano et al. (1983)

Genotoxicity studies in mammalian cells in vivo
Bone marrow
micronucleus
assay
CD-I mice
(15/sex/dose); single
injection (i.p.); corn
oil vehicle; sacrifice
24, 48, and 72 hr after
exposure
0, 100, 500,
1,000 mg/kgbody
weight


No significant increase in micronucleated PCEs was
observed in any group; however, a significant decrease
in the PCE:total erythrocyte ratio was noted in mice at
1,000 mg/kg (48-hr sacrifice). Mortalities included
one male and three females in the high-dose group.
Test substance: Therminol® VP-1 (diphenyl
ether 73.5%, biphenyl 26.5%).
Monsanto (1990b)

a+ = positive; - = negative.
CA = chromosomal aberration; CHO = Chinese hamster ovary; DMSO = dimethylsulfoxide; DNA = deoxyribonucleic acid; i.p. = intraperitoneal; PCE = polychromatic
erythrocyte; UDS = unscheduled DNA synthesis.
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute studies
Acute oral study
Three rats (strain not specified)
exposed orally to diphenyl ether at
doses ranging from 50-1,600 mg/kg.
Animals appeared moderate to quite
weak; rough coats, slight ataxia.
Approximate LD50 for diphenyl ether is
400-1,600 mg/kg.
Eastman Kodak
(1979)
Acute oral study
S-D albino rats (5/group) given a
single oral dose of diphenyl ether of
2,000, 2,510, or 3,160 mg/kg. Rats
were observed for 14 d.
Mortality: 0/5 at low dose; 3/5 at mid
dose; 5/5 at high dose. Animals died
within 1-2 d. Rats exhibited reduced
appetite and activity (1-3 d in survivors),
increased weakness.
Oral LD50 for diphenyl ether was
2,450 mg/kg (95% confidence limits of
2,200-2,720 mg/kg).
Monsanto (1977)
Acute inhalation study
S-D rats (6/sex) exposed to
Therminol® VP-1 aerosol at
concentrations ranging from
1,000-5,300 mg/m3 for 4 hr. Rats
were observed for 14 d and sacrificed
for necropsy.
Test substance: Therminol® VP-1
(diphenyl ether 73.5%,
biphenyl 26.5%).
11/12 rats exposed to 5,300 mg/m3 died.
Clinical signs during exposure included
salivation, hypoactivity, and active
animals. Following exposure, the rats
exhibited labored breathing, red
encrustation around the nose and eyes,
salivation, and hypoactivity. The
animals also showed decreases in body
weights. No macroscopic abnormalities
were observed.
Inhalation LC50 for Therminol® VP-1 was
4,450 mg/m3 for males, and 2,660 mg/m3
for combined males and females.
Insufficient data to calculate an LC50 for
females.
Monsanto (1986)
LC50 = median lethal concentration; LD50 = median lethal dose; S-D = Sprague-Dawley.
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Genotoxicity
Diphenyl ether was negative in tests for mutagenicity in bacteria (Monsanto. 1990a;
Haworth et al.. 1983; Pagano et aL 1983; Bronzetti et al.. 1981; Florin et al.. 1980;
Westingfaouse Electric Corporation. 1977) and gene conversion, and mitotic recombination in
yeast (Pagano et al. 1983). Assays for chromosomal aberrations (CAs) in Chinese hamster
ovary (CHO) cells and unscheduled deoxyribonucleic acid (DNA) synthesis in primary rat
hepatocytes were also negative (Monsanto. 1989b. 1987a; SRI International. 1987). In vivo,
diphenyl ether was negative for the induction of micronuclei (MN) in bone marrow cells
collected from CD-I mice receiving a single intraperitoneal (i.p.) injection of diphenyl ether
(Monsanto. 1990a). but did induce developmental and mitotic abnormalities in sea urchin
embryos and gametes (Pagano et al.. 1983). The study authors suggested a possible health
concern to humans, and urged mutagenicity and carcinogenicity testing in mammals, but
admittedly, the possible hazard is only "suggested."
Metabolism/Toxicokinetic Studies
No studies on the toxicokinetics of diphenyl ether in humans were available.
Toxicokinetic studies in animals show that diphenyl ether is readily absorbed and distributed to
various rat tissues, with highest levels found in the liver and kidneys, and is rapidly excreted in
urine and feces.
A pi and Ford (2003) applied I4C-di phenyl ether to the clipped skin of S-D rats using a
semi-occlusive dressing for 6 hours. Diphenyl ether was diluted in diethyl phthalate to
administer a total application volume of 2 mL/kg and concentrations of 0.5, 5, and 50%
(approximately 10, 100, and 1,000 mg/kg). At 72 hours post application, approximately 0.2% of
the administered doses were retained in the body, with low levels measured in the liver, kidney,
and gastrointestinal (GI) tract (0.01-0.05, 0.01-0.05, and 0.24-0.35%), respectively). Diphenyl
ether was also found in the cage and air (0.19-2.8%>). The study authors suggested that this
indicated that the 14C-label volatilized from the skin and/or was expired from the animals.
Diphenyl ether was primarily eliminated in the urine (15.84-18.65%)), with smaller amounts also
found in the feces (1.18-3.79%).
Following a single i.p. injection of 5 mg/kg 14C-diphenyl ether to 12 male S-D rats. Law
and Chakrabarti (1983) measured radioactivity irreversibly bound to tissue proteins in the livers
and kidneys of treated rats 2 hours postinjection, and in the lungs after 4 hours. Additional
similar investigations by Law et al. (1983) found radioactivity in all organs and tissues within
1 hour (peaked between 1 and 4 hours; remained at 8 hours postadministration). The highest
levels of diphenyl ether were detected in the liver, lung, kidney, and spleen.
Following intragastric administration of 10 mg/kg 14C-diphenyl ether to male S-D rats,
Law et al. (1983) observed maximum concentration of unchanged diphenyl ether in the blood
within 15 hours. The study authors described the blood concentration time curve as a
one-compartment open pharmacokinetic model. More than 90%> of the administered dose was
excreted within 3 days; roughly 80%> of the administered dose was detected in the urine, and
about 10%o in the feces. Mass spectral data of the urinary extract showed that the treated rats
metabolized diphenyl ether to its 2-hydroxy-, 4-hydroxy-, 4,4'-dihydroxy-,
4-methoxy-monohydroxy-, and 4-methoxy-dihydroxy- derivatives. Similarly, Poon et al. (1986)
measured these same metabolites in the urine of guinea pigs following i.p. administration with
diphenyl ether.
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Other Routes
Api and Ford (2003) applied diphenyl ether (purity >99%) to the skin of S-D rats
(12/sex/dose) using a semi-occlusive dressing at 0, 100, 300, or 1,000 mg/kg-day, 6 hours/day
for 13 weeks. Animals were monitored during the study for clinical signs, skin irritation, and
changes in body weights and/or food consumption. Prior to necropsy, blood samples and urine
were collected and submitted for analysis. At necropsy, selected organs were examined and
weighed. Major tissues were collected from the control and high-dose animals, and submitted
for histopathology; kidneys from all dose groups were submitted for histopathology. Slight skin
reactions at the site of application were observed among treated rats with incidence exhibiting a
dose-response. High-dose males exhibited a slight reduction in body weight. Absolute and
relative liver weights were significantly higher in male rats at 300 mg/kg-day compared to
controls, but only relative liver weights were significantly higher than controls at
1,000 mg/kg-day. Relative brain and kidney weights were also higher among high-dose male
rats compared to controls. In female rats, relative liver weights were increased over controls at
>300 mg/kg-day, and absolute liver weight was increased at 1,000 mg/kg-day. No
histopathological lesions were seen in any organ examined.
Mixture Studies and Developmental Studies as a Mixture
Biodynamics (1989); Monsanto (1989a); Biodynamics (1987); Monsanto (1987b)
Biodynamics, Inc. conducted oral developmental toxicity studies in rats using eutectic
mixture of biphenyl and diphenyl ether known as Therminol® VP-1 Heat Transfer Fluid
(73.5% diphenyl ether; 26.5% biphenyl). In these studies, groups of mated S-D CD rats received
daily doses of Therminol® VP-1 via gavage in corn oil on Gestation Days (GDs) 6-15. Animals
had free access to food and water. Survival and clinical signs were monitored twice daily. Body
weights were measured on GDs 0, 6, 10, 12, 15, and 20. Food consumption was recorded on
GDs 0-6, 6-10, 10-15, and 15-20. Dams were sacrificed on GD 20 and subjected to a complete
gross necropsy. The intact uterus (ovaries attached) was removed from all animals, weighed,
and examined for numbers of live and dead fetuses, resorptions, and implantation sites. Ovaries
were examined for the presence and number of corpora lutea. All fetuses were removed,
weighed, sexed, and subjected to gross examination for external malformations. Data were not
evaluated statistically by the study authors. Monsanto (1987b) reported the findings of the initial
range-finding study among rats (5/group) dosed with Therminol® VP-1 at 0, 100, 200, 400, 800,
or 1,500 mg/kg-day, and Biodynamics (1989)/Biodynamics (1987) reported the findings of the
definitive developmental study among rats (24/group) dosed with Therminol® VP-1 at 0, 50, 200,
or 500 mg/kg-day.
Maternal toxicity in rats, based on decreases in maternal body weights and weight gains,
as well as food consumption, were observed in these developmental studies at doses of
Therminol® VP-1 >100 mg/kg-day (Biodynamics. 1989. 1987; Monsanto. 1987b). Additionally,
dams exhibited increased incidence of excessive salivation, staining of the skin/fur in the
ano-genital area, and alopecia at >200 mg/kg-day. No embryotoxic or fetotoxic effects were
seen below 800 mg/kg-day. Embryotoxicity, characterized by significantly increased
frequencies of uterine resorptions and significantly decreased numbers of viable fetuses per litter,
was observed at 800 mg/kg-day in conjunction with maternal toxicity. Fetotoxic effects,
characterized by a higher female:male sex ratio and significantly lower fetal weights, were noted
in the single litter recovered from the surviving dam receiving Therminol® VP-1 at
1,500 mg/kg-day.
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The same researchers also conducted a subchronic-duration inhalation study in S-D rats
using the Therminol® VP-1 Heat Transfer Fluid (Monsanto. 1989a). In this study, groups of rats
(25/sex) were exposed whole-body to Therminol® VP-1 aerosol at target concentrations of 0, 10,
50, or 125 mg/m3 for 6 hours/day, 5 days/week for 7 or 14 weeks. Rats were monitored for
clinical signs and body-weight changes. Ten rats per group were sacrificed at 7 weeks, and
sampled for hematology and serum biochemical analysis only. The remaining animals
(15/group) were sacrificed at 14 weeks and subjected to gross examination. Adrenals, brain,
heart, kidneys, liver, spleen, and testes were weighed and a complete histopathological
examination was conducted. Measured concentrations in the exposure chambers were 0, 10, 51,
or 130 mg/m3. Animals in all exposure groups exhibited clinical signs, including focal loss of
hair and red/pink discharge around the nose. Additionally, mid- and high-exposure animals
exhibited salivation, red discharge around the eye, and lacrimation. Significant reductions in
body weights were observed in the high-exposure animals from Weeks 2-6. Changes in
hematology parameters did not demonstrate a clear exposure-response. Relative liver weights in
males, and relative liver, brain, and spleen weights in females were significantly lower than
controls among high-exposure rats. No microscopic changes were observed.
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer references values,
respectively.
Table 5. Summary of Noncancer Reference Values for Diphenyl Ether (CASRN 101-84-8)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
(HEC)
UFc
Principal Study
Subchronic p-RfD
(mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
NDr
Screening
Subchronic p-RfC
(mg/m3)
Rat/M
Eye and nasal
irritation
4 x 1(T3
NOAEL
(HEC)
1.3
300
Dow Chemical Co (1986a):
Hefner et al. (1975)
Screening Chronic
p-RfC (mg/m3)
Rat/M
Eye and nasal
irritation
4 x 1(T4
NOAEL
(HEC)
1.3
3,000
Dow Chemical Co (1986a):
Hefner et al. (1975)
HEC = human equivalent concentration; M = male(s); NDr = not determined;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; p-RfD = provisional reference dose; UFC = composite uncertainty factor.
Table 6. Summary of Cancer Reference Values for Diphenyl Ether (CASRN 101-84-8)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)-1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
Information on the oral toxicity of diphenyl ether is available from a 13-week feeding
study in rats (Dow Chemical Co. 2003; Johnson et aL 1992). and short-term-duration studies in
rabbits and dogs using a single test subject per experiment. The available information is not
sufficient for use in deriving subchronic or chronic provisional reference doses (p-RfDs). A
description of the study is available only as an abstract (Johnson et aL 1992) and a summary
submission within the IUCLID data set (Dow Chemical Co. 2003). The available study
description does not include any data. Decreases in food consumption and body weight were
reported in high-dose males, and mid- and high-dose females, but no data on the magnitude of
the observed changes were provided. The study authors suggested palatability of the diet as the
cause of the observed changes, rather than a toxic effect, but this conclusion cannot be
independently evaluated without the associated data. NOAEL and LOAEL values could not be
assigned for this study based on the available description in the IUCLID submission. As a result
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of the uncertainties in the available data for diphenyl ether, subchronic and chronic p-RfDs are
not derived.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The database of potentially relevant studies for deriving subchronic and chronic
inhalation reference values for diphenyl ether is limited to a single study that used rats, rabbits,
and dogs (Dow Chemical Co. 1986a; Hefner et aL 1975). This study was peer-reviewed with
adequate numbers of exposure groups and investigated numerous endpoints. However, the
critical effect (i.e., eye and nasal irritation in rats; see Appendix A for a detailed discussion for
the selection of the critical effect) is based solely on qualitative statements made by the study
authors (Dow Chemical Co. 1986a; Hefner et aL 1975). Due to the uncertainty in this critical
effect given the complete lack of quantitative data, it is not sufficiently reliable to use in deriving
subchronic or chronic provisional reference concentrations (p-RfCs) for diphenyl ether.
However, the available inhalation study (Dow Chemical Co. 1986a; Hefner et aL 1975) is
suitable for the derivation of "screening-level" values for subchronic and chronic inhalation
exposure to diphenyl ether (see Appendix A).
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 7 identifies the cancer WOE descriptor for diphenyl ether.
Table 7. Cancer WOE Descriptor for Diphenyl Ether
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are no human data to support this.
"Likely to Be Carcinogenic to
Humans "
NS
NA
There are no suitable animal studies to
support this.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no suitable animal studies to
support this.
"Inadequate Information to
Assess Carcinogenic Potential"
Selected
Both
This descriptor is selected due to the
lack of any information on the
carcinogenicity of diphenyl ether.
"Not Likely to Be Carcinogenic
to Humans "
NS
NA
There are no suitable animal studies to
support this.
NA = not applicable; NS = not selected; WOE = weight of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The lack of data on the carcinogenicity of diphenyl ether precludes derivation of
quantitative estimates for either oral (provisional oral slope factor [p-OSF]) or inhalation
(provisional inhalation unit risk [p-IUR]) exposure.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional toxicity values for diphenyl ether. However,
information is available for this chemical, which although insufficient to support derivation of a
provisional toxicity value under current guidelines, may be of limited use to risk assessors. In
such cases, the Superfund Health Risk Technical Support Center summarizes available
information in an appendix and develops a "screening value." Appendices receive the same
level of internal and external scientific peer review as the main documents to ensure their
appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of screening values should be directed to the Superfund Health Risk Technical Support Center.
DERIVATION OF A SUBCHRONIC PROVISIONAL REFERENCE
CONCENTRATION
The database of potentially relevant studies for deriving subchronic and chronic
inhalation reference values for diphenyl ether is limited to a single study that used rats, rabbits,
and dogs (Dow Chemical Co, 1986a; Hefner et aL 1975). The study is a whole-body inhalation
toxicity study that exposed rats (20 males), rabbits (4 males), and dogs (2 males) to diphenyl
ether 7 hours/day, 5 days/week for 31-33 days with chamber concentrations of 0, 34, and
69.5 mg/m3. An additional group of 10 male and 10 female rats were exposed to 140 mg/m3
under modified experimental conditions (e.g., smaller volume in exposure chamber, different
carrier gas for diphenyl ether exposure, etc.) (Dow Chemical Co. 1986a; Hefner et aL 1975).
This study was peer reviewed with adequate numbers of exposure groups and investigated
numerous endpoints.
Both male rats and rabbits, but not dogs, exhibited eye and nasal irritation following
exposure to chamber concentrations of 69.5 and 140 mg/m3 diphenyl ether. After the
no-observed-adverse-effect levels (NOAELs) of 34 mg/m3 for both rats and rabbits were
converted to human equivalent concentrations (HECs), rats were more sensitive than rabbits to
eye and nasal irritation (male rat HECet =1.3 mg/m3, rabbit HECet = 3.8 mg/m3).6 Other
possible effects in rats include statistically significantly decreased absolute and relative liver
weights in male rats at >7.1 mg/m3 (HECsystemic). These liver-weight changes are of uncertain
toxicological significance in consideration of the inconsistent dose-response relationship, the
absence of histological changes, and because no clinical chemistry abnormalities (i.e., serum
glutamic pyruvic transaminase [SGPT]) were observed to support that the liver is indeed a target
organ for diphenyl ether-induced toxicity. In addition, no benchmark response (BMR) level has
been established for the decrease in liver weight in adult animals. Hematological effects were
observed in male rats including significantly decreased hemoglobin (Hb) at 14.5 mg/m3
(HECsystemic) and significantly decreased white blood cell (WBC) counts at >7.1 mg/m3
(HECsystemic). The biological relevance of decreased WBC counts in male rats is unclear
6Human equivalent concentration extrathoracic (HECet) = Concentration x (hours per day exposed ^ 24) x (days per
week exposed ^ 7) x RGDRet.
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because the study authors did not perform immune function tests to verify that a toxic functional
change was associated with this effect (Dow Chemical Co. 1986a; Hefner et aL 1975).
Other possible effects observed in the study was a biologically significant kidney-weight
increase in male dogs with a 19.6% increase at 7.1 mg/m3 (HECsystemic) and 35.3% at
14.5 mg/m3 (HECsystemic) (see Table B-l) (Dow Chemical Co. 1986a; Hefner et aL 1975).
Although not statistically significant, the weight change in the dog kidney is exposure related
and of large magnitude. However, the dog study (Dow Chemical Co. 1986a; Hefner et aL 1975)
uses a small number of animals (two male Beagles/exposure group). Related to pathology,
specifically for the kidney, the study authors report that all major organs and tissues were
examined grossly and histologically, and concluded that no discernible, attributable lesions were
revealed. There is no clinical evidence examined or reported by the study authors for renal
effects. Blood urea nitrogen (BUN) was reduced, rather than increased, as would be expected for
possible kidney effects in rabbits and dogs (statistically significant at the low and high exposure
in rabbits, and the low exposure, but not at the high exposure, in dogs; see Table B-2).
Therefore, there is a lack of evidence to support that the kidney is indeed a target organ for
diphenyl ether-induced toxicity.
Based on the available inhalation data for diphenyl ether, there is sufficient support for
the selection of eye and nasal irritation in male rats as the critical effect. For example, red
discharge around the eye and lacrimation at the mid and high concentration (51 and 130 mg/m3,
respectively) were observed in the subchronic-duration rat inhalation study of aerosolized
Therminol® VP-1 mixture containing 73.5% diphenyl ether and 26.5% biphenyl (Monsanto.
1989a). Animals in all exposure groups of aerosolized Therminol® VP-1 mixture also exhibited
red/pink discharge around the nose. Furthermore, eye and nasal irritation was also observed in
both sexes of rats, and male rabbits exposed to diphenyl ether (Dow Chemical Co. 1986a; Hefner
et aL 1975). This endpoint also represents an effect relevant to human health following diphenyl
ether inhalation exposure because human subjects experienced upper respiratory irritation at
69.53 mg/m3 following prolonged exposures (duration not provided) (Dow Chemical Co. 1973).
Therefore, nasal and eye irritation in male rats is selected as the critical point of departure (POD)
based on a weight-of-evidence (WOE) approach.
No numerical data was provided for the eye and nasal irritation reported in Dow
Chemical Co (1986a); Hefner et al. (1975); only qualitative statements were provided in the text
summary of the paper. The lack of numerical data precludes applying benchmark dose (BMD)
methodology and, therefore, requires reliance on the rat NOAEL value. The following
dosimetric adjustments are made for male rats with a NOAEL for respiratory effects in the
extrathoracic (ET) region:
Exposure concentration adjustment for continuous exposure:
CONCadj = CONCchamber x (MW ^ 24.45) x (hours exposed ^ 24) x
(days exposed ^ 7 days per week)
= 4.9 ppm x (170 -h 24.45) x (7 hours ^ 24 hours) x (5 days ^ 7 days)
= 7.1 mg/m3
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HEC conversion for respiratory effects:
CONCresp (HEC) = CONCadj x RGDRet
where
where
RGDRet - (Ve/SAet)^] ^ (VE/SAEi)[human]
VE[rat] = Rat minute volume determined according to the following7:
ln(VE) = bo + bi x ln(BW)
SAET[rat] = Rat default surface area of the ET region (15 cm2)
[see Table 4-4 in U.S. EPA (1994)1.
VE[human] = Human minute volume of 13.8 L (U.S. EPA, 1994).
SAet[human] = Human default surface area of the ET region (200 cm2)
(U.S. EPA, 1994).
= 0.184
RGDRet = (0.190 L/min - 15 cm2) - (13.8 L/min - 200 cm2)
CONCresp (HEC)
CONCadj x RGDRet
= 7.1 mg/m3 x 0.184
= 1.3 mg/m3
Approach for Deriving the Screening Subchronic p-RfC
The NOAEL (HEC) of 1.3 mg/m3 for eye and nasal irritation in rats from the subchronic
inhalation study (Dow Chemical Co. 1986a: Hefner et aL 1975) is selected as the POD for
deriving a screening subchronic provisional reference concentration (p-RfC) for diphenyl ether.
The p-RfC for diphenyl ether, based on the NOAEL (HEC) of 1.3 mg/m3 for inducing eye and
nasal irritation in rats, is derived as follows:
Screening Subchronic p-RfC
CONCresp (HEC) - UFC
1.3-300
4 x lO-3 mg/m3
Table A-l summarizes the uncertainty factors for the screening subchronic p-RfC for
diphenyl ether.
7Rat minute volume determined according to the following: ln(VE) = bo + bi x ln(BW) where: bo and bi
(bo = -0.578, bi = 0.821), which are provided for the rat in Tables 4-6 (U.S. EPA. 19941 and default BW are
provided (male = 0.267 kg for S-D rats) (U.S. EPA. 19881. ln(VE)[maie] = -0.578 + 0.821 x ln(0.267) = -1.66.
VE[maie] = 0.190 L/min.
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Table A-l. Uncertainty Factors for the Screening Subchronic p-RfC for Diphenyl Ether
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for residual uncertainty, including toxicodynamic
differences, between rats and humans following diphenyl ether inhalation. The toxicokinetic
uncertainty has been accounted for by calculating an HEC by applying an RGDR in extrapolating
from animals to humans according to the procedures in the RfC methodology (U.S. EPA. 1994).
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database.
Repeated-exposure inhalation toxicity data for diphenyl ether alone are limited to the 31-33-d
inhalation studv in rats, rabbits, and does (Dow Chemical Co. 1986a: Hefner et al.. 1975). In a
mixture study, 73.5% diphenyl ether and 26.5% biphenyl (Therminol® VP-1 Heat Transfer Fluid)
was tested for subchronic inhalation toxicity (as an aerosol) and oral developmental toxicity in rats.
The mixture was found to produce embryo- and fetotoxic effects at maternally toxic oral doses
(Biodvnamics. 1989; Monsanto. 1989a: Biodvnamics. 1987; Monsanto. 1987b). It is unknown to
what extent the finding can be attributed to diphenyl ether or how results might be affected by route
of exposure, but it suggests the possibility that diphenyl ether may affect development. Tests for
the developmental or reproductive toxicity of diphenyl ether itself, however, were not located by
any route of exposure.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of diphenyl ether in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because a 31 to 33-d (subchronic-duration) study is selected as the principal
study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; RfC = reference concentration; RGDR = regional gas dose ratio; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
DERIVATION OF A SCREENING CHRONIC PROVISIONAL REFERENCE
CONCENTRATION
There are no chronic-duration studies of humans or animals exposed via inhalation to
diphenyl ether. A screening chronic p-RfC is derived using the same CONCresp (HEC) for nasal
and eye irritation in male rats that was selected as the POD for derivation of the screening
subchronic p-RfC with an additional uncertainty factor of 10 (total of 3,000) to adjust for chronic
exposure as shown in Table A-2.
Screening Chronic p-RfC = CONCresp (HEC) - UFc
= 1.3-3,000
= 4 x i(H m «/m3
Table A-2 summarizes the uncertainty factors for the screening chronic p-RfC for
diphenyl ether.
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Table A-2. Uncertainty Factors for the Screening Chronic p-RfC for Diphenyl Ether
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for residual uncertainty, including toxicodynamic
differences, between rats and humans following diphenyl ether inhalation. The toxicokinetic
uncertainty has been accounted for by calculation of an HEC through application of a RGDR in
extrapolating from animals to humans according to the procedures in the RfC methodology (U.S.
EPA. 1994).
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database.
Repeated-exposure inhalation toxicity data for diphenyl ether alone are limited to the 31-33-d
inhalation studv in rats, rabbits, and does (Dow Chemical Co. 1986a: Hefner et al.. 1975). In a
mixture study, 73.5% diphenyl ether and 26.5% biphenyl (Therminol® VP-1 Heat Transfer Fluid)
was tested for subchronic inhalation toxicity (as an aerosol) and oral developmental toxicity in rats.
The mixture was found to produce embryo- and fetotoxic effects at maternally toxic oral doses
(Biodvnaraics. 1989; Monsanto. 1989a: Biodvnamics. 1987; Monsanto. 1987b). It is unknown to
what extent the finding can be attributed to diphenyl ether or how results might be affected by route
of exposure, but it suggests the possibility that diphenyl ether may affect development. Tests for
the developmental or reproductive toxicity of diphenyl ether itself, however, were not located by
any route of exposure.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of diphenyl ether in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because a 31-33-d (subchronic-duration) study is selected as the principal
study.
UFC
3,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; RfC = reference concentration; RGDR = regional gas dose ratio; UC = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
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APPENDIX B. DATA TABLES
Table B-l. Mean Body and Organ Weights of Animals Exposed via Inhalation to
Diphenyl Ether Vapor for 7 Hours/Day, 5 Days/Week for a Total of 20 Exposures"
Parameterb
Exposure Group, mg/m3 (HECsystemic)0
0(0)
34 (7.1)
69.5 (14.5)
0(0)
140 (29)
Rats (male)
Mean body weight (g)
400 ± 27.9
378.2 ±24.6
(-5.5%)
385.4 ± 18.5
(-3.7%)
409.0 ±9.8
380.0 ± 18.3*
(-7.1%)
Absolute liver weight (g)
12.1 ± 1.4
10.4 ± 1.1*
(-14%)
10.7 ± 1.1*
(-12%)
11.4 ±0.8
11.1 ± 1.0
(-2.6%)
Relative liver weight (g/100 g)
3.04 ±0.35
2.74 ±0.20*
(-10%)
2.80 ±0.21*
(-7.9%)
2.79 ±0.18
2.92 ±0.15
(+4.7%)
Absolute kidney weight (g)
2.9 ±0.3
2.8 ±0.3
(-3.5%)
2.7 ±0.2
(-6.9%)
3.1 ±0.1
2.8 ±0.2
(-10%)
Relative kidney weight (g/100 g)
0.73 ±0.08
0.73 ±0.05
(0%)
0.71 ±0.04
(-2.8%)
0.76 ±0.02
0.75 ±0.03
(+2.8)
Absolute brain weight (g)
1.9 ±0.1
1.8 ±0.1
(-5.3%)
1.8 ±0.1
(-5.3%)
1.8 ±0.1
1.8 ±0.0
(0%)
Relative brain weight (g/100 g)
0.47 ±0.03
0.49 ±0.03
(+4.3%)
0.47 ±0.03
(0%)
0.43 ±0.01
0.47 ±0.02*
(+9.3%)
Rats (female)
Mean body weight (mg)
Not tested
Not tested
Not tested
244.7 ± 12.3
246.3 ± 12.1
(+0.7%)
Absolute liver weight (mg)
Not tested
Not tested
Not tested
6.5 ±0.4
6.6 ±0.4
(+1.5%)
Relative liver weight (g/100 g)
Not tested
Not tested
Not tested
2.64 ±0.19
2.65 ±0.10
(+0.4%)
Absolute kidney weight (mg)
Not tested
Not tested
Not tested
1.8 ±0.1
1.8 ±0.1
(0%)
Relative kidney weight (g/100 g)
Not tested
Not tested
Not tested
0.74 ±0.04
0.71 ±0.05
(-4.1%)
Absolute brain weight (g)
Not tested
Not tested
Not tested
1.7 ±0.0
1.7 ±0.1
(0%)
Relative brain weight (g/100 g)
Not tested
Not tested
Not tested
0.68 ±0.03
0.68 ±0.03
(0%)
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Table B-l. Mean Body and Organ Weights of Animals Exposed via Inhalation to
Diphenyl Ether Vapor for 7 Hours/Day, 5 Days/Week for a Total of 20 Exposures"
Parameterb
Exposure Group, mg/m3 (HECsystemic)0
0(0)
34 (7.1)
69.5 (14.5)
0(0)
140 (29)
Rabbits (male)
Mean body weight (kg)
2.91 ±0.15
2.57 ±0.07
(+12%)
2.81 ±0.32
(-3.4%)
Not tested
Not tested
Absolute liver weight (g)
84.1 ± 17.2
69.4 ±7.9
(-17%)
85.6 ± 16.0
(+1.8%)
Not tested
Not tested
Relative liver weight (g/100 g)
2.91 ±0.66
2.70 ±0.27
(-7.2%)
3.04 ±0.33
(+4.5%)
Not tested
Not tested
Absolute kidney weight (g)
15.1 ± 1.1
13.4 ± 1.7
(-11%)
13.7 ±2.5
(-9.3%)
Not tested
Not tested
Relative kidney weight (g/100 g)
0.52 ±0.05
0.52 ±0.06
(0%)
0.49 ±0.03
(-3.4%)
Not tested
Not tested
Absolute brain weight (g)
8.7 ±0.4
8.6 ±0.4
(—1.1%_
9.1 ± 0.5
(+4.6%)
Not tested
Not tested
Relative brain weight (g/100 g)
0.31 ±0.02
0.34 ±0.02
(+9.7%)
0.33 ±0.02
(+6.5%)
Not tested
Not tested
Dogs (male)
Mean body weight (kg)
12.25 ± 1.49
10.85 ±0.64*
(-11%)
12.95 ± 1.91
(+5.7%)
Not tested
Not tested
Absolute liver weight (g)
308.0 ±23.7
288.9 ±2.8
(-6.2%)
328.7 ±37.2
(+6.7%)
Not tested
Not tested
Relative liver weight (g/100 g)
2.52 ± 0.11
2.67 ±0.12
(+6.0%)
2.55 ±0.09
(+1.2%)
Not tested
Not tested
Absolute kidney weight (g)
51.5 ±2.6
61.6 ±3.0
(+20%)
69.7 ± 11.0
(+35%)
Not tested
Not tested
Relative kidney weight (g/100 g)
0.42 ±0.03
0.65 ±0.14
(+55%)
0.48 ±0.04
(+14%)
Not tested
Not tested
Absolute brain weight (g)
90.8 ± 1.6
81.7 ±4.7
(-10%)
83.1 ±0.9
(-8.5%)
Not tested
Not tested
Relative brain weight (g/100 g)
0.75 ±0.78
0.75 ±0.00
(0%)
0.71 ±0.65
(-5.3%)
Not tested
Not tested
"Dow Chemical Co (1986a): Hefner et al. (1975).
bMean± SD (percent change from respective control).
°HECsystemic = Concentration x (hours per day exposed + 24) x (days per week exposed + 7) x blood-gas partition
coefficient.
* Significantly different from respective control (p < 0.05).
HEC = human equivalent concentration; SD = standard deviation.
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Table B-2. Selected Hematological or Serum Chemistry Effects on Animals Exposed via
Inhalation to Diphenyl Ether Vapor for 7 Hours/Day, 5 Days/Week
for a Total of 20 Exposures3
Endpointb
Exposure Group, mg/m3 (HECsystemic)0
0(0)
34 (7.1)
69.5 (14.5)
0(0)
140 (29)
Number of animals
20
20
20
10
10
Hemoglobin (g/100 mL)
in male rats
17.2 ±0.8
16.7 ± 0.4 (-3%)
16.2 ± 0.6* (-6%)
16.8 ±0.7
17 ± 1.0 (+1%)
White blood cell count
(x 103/mm3) in male rats
20.3 ±2.7
12.6 ±3.4* (-38%)
11.5 ± 1.7* (-43%)
15.1 ± 1.9
18.7 ±3.7 (+24%)
BUN in male rabbits
21.3 ±0.5
15.0 ± 1.4*
16.5 ± 1.0*
Not dosed
Not dosed
BUN in male rats
22.2 ±4.8
21.9 ±2.5
24.1 ±4.1
Not measured
Not measured
BUN in male dogs
16.0 ±0.7
12.0 ±0.0*
15.0 ± 1.4
Not dosed
Not dosed
aDow Chemical Co (1986a): Hefner et at (1975).
bMean± SD (percent change from respective control).
°HECsystemic = Concentration x (hours per day exposed + 24) x (days per week exposed + 7) x blood-gas partition
coefficient.
* Significantly different from respective control (p < 0.05) by ANOVA and Dunnett's test, as reported by the study
authors.
ANOVA = analysis of variance; BUN = blood urea nitrogen; HEC = human equivalent concentration; POD = point
of departure; SD = standard deviation.
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APPENDIX C. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2015). Phenyl ether.
2015 TLVs and BEIs. Based on the documentation of the threshold limit values for
chemical substances and physical agents and biological exposure indices [TLV/BEI],
Cincinnati, OH. http://www.acgih.ore/forms/store/ProductFormPublic/20154lvs-and-beis
ACGIH (American Conference of Governmental Industrial Hygienists). (2016). 2016 TLVs and
BEIs: Based on documentation of the threshold limit values for chemical substances and
physical agents and biological exposure indices. Cincinnati, OH.
https://www.acgih.org/forms/store/ProductFormPublic/2016-tlvs-and-beis
A pi. AM: Ford, RA. (2003). Evaluation of the dermal subchronic toxicity of di phenyl ether in
the rat. Food Chem Toxicol 41: 259-264.
AT SDR (Agency for Toxic Substances and Disease Registry). (2017). Minimal risk levels
(MRLs). lune 2017. Atlanta, GA: Agency for Toxic Substances and Disease Registry
(ATSDR). Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp
Biodynamics (Biodynamics Corp). (1987). Developmental toxicity study in rats with
THERMINOL VP-1 heat transfer fluid with cover letter dated 011388.
(TSCATS/305170, OTS0514002, Doc I.D. 86-880000112). St. Louis, MO: Monsanto
Chemical Co.
Biodynamics (Biodynamics Corp). (1989). Chemical listing subject to submission and a
developmental toxicity study in rats with therminol VP-1 heat transfer fluid (final report)
with attachments and cover letter dated 060889. (TSCATS/403890). St Louis, MO:
Monsanto.
Bron/.etti. G; Esposito. A; Pagano. G: Ouinto. I. (1981). A comparative study on the toxicity and
mutagenicity of biphenyl (BP) and diphenyl ether (DPE) in sea urchin, S. typhimurium
and S. cerevisiae. Mutat Res Environ Mutagen Relat Subj 85: 233.
http://dx.doi.org/10.1016/0165-1161(81)90076-5
Cal/EPA (California Environmental Protection Agency). (201 1). Hot spots unit risk and cancer
potency values. Appendix A. Sacramento, CA: Office of Environmental Health Hazard
Assessment.
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