United States
Environmental Protection
1=1 m m Agency
EPA/690/R-15/007F
Final
9-29-2015
Provisional Peer-Reviewed Toxicity Values for
Diethylene Glycol Monomethyl Ether
(CASRN 111-77-3)
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
Jeff Swartout
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWER
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 contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
li
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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) 4
HUMAN STUDIES 9
Oral Exposure 9
Inhalation Exposure 9
ANIMAL STUDIES 9
Oral Exposures 9
Inhalation Exposures 16
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 17
Acute and Short-Term Tests (Oral, Inhalation, and Dermal) 17
Sub chronic-Duration and Developmental Studies by Dermal and Subcutaneous Exposure 18
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 18
Metabolism/Toxicokinetic Studies 18
Mode-of-Action/Mechanistic Studies 22
DERIVATION 01 PROVISIONAL VALUES 22
DERIVATION OF ORAL REFERENCE DOSES 23
Derivation of the Subchronic Provisional RfD (Subchronic p-RfD) 23
Derivation of the Chronic Provisional RfD (Chronic p-RfD) 28
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 29
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 29
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 30
Derivation of Provisional Oral Slope Factor (p-OSF) 30
Derivation of Provisional Inhalation Unit Risk (p-IUR) 30
APPENDIX A. SCREENING PROVISIONAL VALUES 31
APPENDIX B. DATA TABLES 32
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 50
APPENDIX D. REFERENCES 60
in
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
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
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere
Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD
Number
QSAR
quantitative structure-activity
CBI
covalent binding index
relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day
known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase
known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database 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
iv
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
DIETHYLENE GLYCOL MONOMETHYL ETHER (CASRN 111-77-3)
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 a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by 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 derived values. It is not intended to
be a comprehensive treatise on a given chemical or its toxicological nature.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of a 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 this toxicity assessment.
Other U.S. Environmental Protection Agency (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 contents and appropriate use of this PPRTV assessment should
be directed to the U.S. EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
1 Diethylene Glycol Monomethyl Ether
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INTRODUCTION
Diethylene glycol monomethyl ether (DGME), also known by the International Union of
Pure and Applied Chemistry (IUPAC) name of 2-(2-methoxyethoxy)ethanol, CASRN 111-77-3,
is a solvent used in paints, printing inks, nitrocellulose resins, waxes, and dyes. DGME is also
used as a deicer and added to hydrocarbon fuels, including jet and diesel fuel, and as an
antimicrobial agent (HSDB, 2014). The use of DGME as an inert ingredient in pesticides is
regulated under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); specifically,
this compound is restricted for use as a deactivator or stabilizer for formulations used before
crops emerge from soil (40 CFR 180.920; U.S. EPA 2012b). DGME is approved by the U.S.
Food and Drug Administration (FDA) as an indirect food additive when used as a component of
adhesives for food packaging (21 CFR 175.105; FDA 2014). DGME is regulated under section
8(d) of the Toxic Substances Control Act (TSCA) (40 CFR 716.120; U.S. EPA 2013). requiring
all handlers of this material to submit copies and lists of unpublished health and safety studies to
EPA. DGME is a liquid at room temperature with a relatively low vapor pressure and is
expected to precipitate as a liquid if it is released into the air and will remain as a liquid if
released into water (HSDB, 2014). The empirical formula for DGME is C5H12O3 (see Figure 1).
The physicochemical properties for DGME are provided below in Table 1.
Figure 1. DGME Structure
Table 1. Physicochemical Properties of DGME (CASRN 111-77-3)3
Property (unit)
Value
Boiling point (°C)
193
Melting point (°C)
<-84
Density (g/cm3)
1.035
Vapor pressure (lmnHg at 25°C)
0.25
pH (unitless)
ND
Solubility in water (g/L at 25°C)
l,000b
Relative vapor density (air = 1)
4.14
Molecular weight (g/mol)
120.15
aHSDB (2014).
bC1iemTDn1i]S (2015V
ND = no data.
A summary of available health-related values for DGME from EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for DGME (CASRN 111-77-3)
Source/Parameter3
Value (applicability)
Reference
Noncancer
ACGIH
NV
ACGIH (2015)
ATSDR
NV
ATSDR (2015)
Cal/EPA
NV
Cal/EPA (2015a): Cal/EPA (2015b): Cal/EPA
(2014)
NIOSH
NV
NIOSH (2015)
OSHA
NV
OSHA (2011); OSHA (2006)
IRIS
NV
U.S. EPA (2015)
DWSHA
NV
U.S. EPA (2012a)
HEAST
NV
U.S. EPA (2011a)
CARA (HEEP)
NV
U.S. EPA (1994)
WHO
NV
WHO (2015)
Cancer
IRIS
NV
U.S. EPA (2015)
HEAST
NV
U.S. EPA (2011a)
IARC
NV
IARC (2015)
NTP
NV
NTP (2014)
DWSHA
NV
U.S. EPA (2012a)
Cal/EPA
NV
Cal/EPA (2015a): Cal/EPA (2015b): Cal/EPA
(2011)
ACGIH
NV
ACGIH (2015)
"Sources: ACGIH = American Conference of Governmental Industrial Hygenists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities Database; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profiles;
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; WHO = World Health Organization.
NV = not available.
Literature searches were originally conducted on sources published from 1900 through
March 2015, for studies relevant to the derivation of provisional toxicity values for DGME
(CASRN 111-77-3). 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: ACGIH, ATSDR, Cal/EPA,
U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA Office of Water, U.S. EPA
TSCATS2/TSCATS8e, NIOSH, NTP, and OSHA.
3 Diethylene Glycol Monomethyl Ether
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3 A and 3B provide an overview of the relevant databases for DGME and include
all potentially relevant, repeated, short-term-, subchronic-, and chronic-duration 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 DGME (CASRN 111-77-3)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL1
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
Short-term
6 M/0 F, F344 rat,
gavage, 2 d
0, 100, 200, 400, 800
ADD: 0, 100, 200,
400, 800
No suppression of
TNP-LPS or TNP-SRBC
immune response
800
NDr
NDr
Smialowicz et
al. (1992)
PR
0 M/5 F, Wistar rat,
gavage, lid
0, 125, 250, 500,
1,000, 2,000, 3,000,
4,000
ADD: 0, 125, 250,
500, 1,000, 2,000,
3,000, 4,000
Decreases in relative
thymus and pituitary
weights, hematocrit and
total protein
2,000
1,074
3,000
Yamano et al.
(1993)
PR
4-8 M/0 F, Wistar rat,
gavage, 5 d
0, 2,000
Decreased lymphocyte
population in thymus
NDr
NDr
2,000
Kawamoto et
al. (1990a)
PR
4-8 M/0 F, Wistar rat,
gavage, 20 d
0, 500, 1,000, 2,000
Decreased relative thymus
weight
500
NDr
1,000
Kawamoto et
al. (1990a)
PR
50 M/0 F, S-D rat,
gavage, up to 20 d;
(5 animals euthanized
every 2 d for
histopathological
evaluation of testes)
0, 5.1 mmol/kg-d
ADD: 0,610
No treatment-related
effects on testicular
weight or histopathology
(no other endpoints
examined)
610
NDr
NDr
Clieever et al.
PR
(1988)
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Table 3A. Summary of Potentially Relevant Noncancer Data for DGME (CASRN 111-77-3)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL1
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Subchronic
10 M/0 F, albino
CD rat, gavage, 5 d/wk,
6 wk
0, 900, 1,800, 3,600
ADD: 0, 643, 1,286,
2,571
Decreased absolute and
relative testicular weights,
testicular atrophy,
proteinaceous casts in the
kidney and increased
BUN
1,286
NDr
2,571
Eastman
Kodak (19921
NPR
Developmental
0 M/50 F, pregnant
CD-I mouse, gavage,
GDs 7-14
0, 4,000
ADD: 0, 4,000
Maternal: decreased
survival and body weight
Fetal: decreased number
of viable litters, decreased
number and survival of
live pups, decreased litter
weight
NDr
NDr
Maternal: 4,000
[PEL]
Fetal: 4,000
[PEL]
Bioassav Svs
(1983a1
NPR
Developmental
(dose
range-finding
study)
0 M/9 F, pregnant
S-D rat, gavage,
GDs 7-16
0, 1,000, 1,495, 2,235,
3,345, 5,175
ADD: 0, 1,000, 1,495,
2,235,3,345,5,175
Maternal: reduced body
weight
Fetal: decreased body
weight, reduced cranial
ossification
Maternal: 2,235
Fetal: NDr
NDr
380
Maternal: 3,345
Fetal: 1,000
Hardin et al.
(19861
PR
Developmental
0 M/25 F, pregnant
S-D rat, gavage,
GDs 7-16
0, 720, 2,165
ADD: 0, 720,2,165
Maternal: No
treatment-related
adverse effects
Fetal: increased rib
malformations and renal
pelvis dilation, decreased
skeletal ossification
Maternal:
2,165
Fetal: NDr
NDr
50
Maternal: NDr
Fetal: 720
Hardin et al.
(1986)
PR, PS
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Table 3A. Summary of Potentially Relevant Noncancer Data for DGME (CASRN 111-77-3)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL1
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Developmental
(dose
range-finding
study)
0 M/4-6 F, pregnant
Wistar rat, gavage,
GDs 7-17
0, 125, 250, 500,
1,000, 2,000, 3,000,
4,000
ADD: 0, 125, 250,
500, 1,000, 2,000,
3,000, 4,000
Maternal: decreased
weight gain
Fetal: decreased body
weight
Maternal: 1,000
Fetal: 500
NDr
NDr
Maternal: 2,000
Fetal: 1,000
Yamano et al.
(1993)
PR
Reproductive/
Developmental
0 M/22 F, pregnant
Wistar rat, gavage,
GDs 7-17
0, 200, 600, 1,800
ADD: 0, 200, 600,
1,800
Maternal: decreased body
and thymus weight
Fetal: decreased male and
female fetal body weight
Maternal: 600
Fetal: NDr
NDr
NDr
Maternal: 1,800
Fetal: 200
Yamano et al.
(1993)
PR
2. Inhalation (mg/m3)a
Subchronic
10 M/10 F, F344 rat,
6 h/d, 5 d/wk, 13 wk
0,31, 102, 216 ppm
HEC: 0, 26, 88, 190
No treatment-related
effects observed at any
concentration
190
NDr
NDr
Miller et al.
(1985)
PR
"Dosimetry: values are presented as adjusted daily dose (ADD) in mg/kg-day for oral noncancer effects and a human equivalent concentration (HEC) (in mg/m3) for
inhalation noncancer effects. Values from animal developmental studies are not adjusted.
HECexresp for Category 3 gas = (ppm x molecular weight ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x ratio of animal:human blood-gas partition
coefficients.
bNotes: PS = principal study; PR = peer reviewed; NPR = not peer reviewed.
ADD = adjusted daily dose; BUN = blood urea nitrogen; FEL = frank effect level; GD = gestation day; HEC = human equivalent concentration; ND = no data;
NDr = not determined; S-D = Sprague-Dawley
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Table 3B. Summary of Potentially Relevant Cancer Data for DGME (CASRN 111-77-3)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL1
Reference
(comments)
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
ND = no data
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HUMAN STUDIES
Oral Exposure
No studies have been identified.
Inhalation Exposure
No studies have been identified.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to DGME were evaluated in short-term-duration
studies (Yamano et al.. 1993; Kawamoto et ai. 1990a. b), a 6-week study (Eastman Kodak.
1992), three developmental toxicity studies (Yamano et al, 1993; Hardin et al.. 1986; Bioassav
Svs. 1983b). and one acute immunotoxicity study (Smiatowicz et al.. 1992).
Short-Term-Duration Studies
Smialowicz et al. (1992)
Smiatowicz et al. (1992) treated groups of six 8-10-week-old male F344 rats with
DGME by gavage (in distilled water) for 2 consecutive days following immunization with
trinitrophenyl-lipopolysaccharide (TNP-LPS). The doses for DGME were 0, 100, 200, 400 and
800 mg/kg-day. The antibody response was determined 3 days later by the primary
plaque-forming cell (PFC) response using previously established methods (Smialowicz et al,
1987). Hemagglutination titers to TNP-haptinated sheep red blood cells (SRBC) were also
determined subsequent to treatment.
DGME showed no significant suppression of the antibody response as measured by the
PFC assay; SRBC hemagglutination titers were unaffected. Decreased cellularity of the spleen
was observed in 400-mg/kg group only, but it was not dose related and was not considered by the
study authors to be a treatment-related effect. A no-observed-adverse-effect level (NOAEL) of
800 mg/kg-day for acute immunotoxicity is identified for this study; A
lowest-observed-adverse-effect level (LOAEL) is not established.
Yamano et al. (1993)
3-month-old female virgin Wistar rats (5/group) were exposed to doses of 0, 125, 250,
500, 1,000, 2,000, 3,000, or 4,000 mg/kg-day DGME (>99.0% purity) for 11 consecutive days
via gavage in water. During the exposure period, body weight, food consumption, and clinical
signs of toxicity were monitored daily. Urine was collected for urinalysis on Day 10 within
30 minutes after dosing (commercial reagent strips were used, but the specific tests were not
reported). On Day 12, blood was collected for hematology (red blood cell [RBC] count,
hemoglobin [Hb], hematocrit [Hct], white blood cell [WBC] count) and clinical chemistry
(aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP],
blood urea nitrogen [BUN], total cholesterol, total protein, and glucose). The rats were
sacrificed, and weights were recorded for the liver, kidney, heart, spleen, stomach, brain, adrenal
gland, thymus, ovary, and pituitary gland. Gross pathology and histopathology evaluation were
not performed.
No clinical signs of toxicity were reported. Body-weight gain and food consumption
were significantly decreased throughout the exposure period in the 4,000-mg/kg-day group,
compared with controls (data presented graphically). Food consumption and body-weight gain
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were also decreased relative to controls throughout exposure at 3,000 mg/kg-day, although the
decrease in body-weight gain was only statistically significant on Days 2 and 8 at this dose.
Urinary pH trended towards acidic in a dose-related fashion from 125 mg/kg-day to
4,000 mg/kg-day (statistics not presented by the study authors). Hematological changes included
statistically significant decreases in RBC counts (~9%), WBC counts (-37%), Hb (-13%), and
hematocrit (-12%) at 4,000 mg/kg-day, compared with controls (see Table B-l). Hematocrit
was also statistically significantly decreased by 8% at 3,000 mg/kg-day (see Table B-l). Clinical
chemistry findings included statistically significant increases in BUN (+26%) and triglycerides
(+89%>) at 4,000 mg/kg-day, compared with controls; no clear dose-related pattern was observed
in these measures at lower doses (see Table B-2). Statistically significant decreases were
observed in total serum protein levels at 3,000 and 4,000 mg/kg-day (-8 and —10%, respectively)
(see Table B-2). Relative thymus weights were decreased dose-dependently by 25, 57, and 69%
at 2,000, 3,000, and 4,000 mg/kg-day, respectively, compared with control, but this effect was
statistically significant (p < 0.01) at 4,000 mg/kg-day only. Similarly, relative pituitary weights
were decreased by 20 (not statistically significant), 24 (p < 0.05), and 25% (p < 0.05) at 2,000,
3,000, and 4,000 mg/kg-day, respectively, compared with control. In addition, relative kidney
weight was statistically significantly increased (p < 0.01) by 12% at 4,000 mg/kg-day only
(see Table B-3). Absolute organ weights were not reported.
A NOAEL of 2,000 mg/kg-day and a LOAEL of 3,000 mg/kg-day are identified in
female virgin rats for statistically significant decreases in pituitary weights, hematocrit and total
protein, compared with controls.
Kawamoto et al. (1990a); Kawamoto et al. (1990b)
Male Wistar rats were administered DGME (>98% pure) daily via gavage in water at 0,
500, 1,000, and 2,000 mg/kg-day DGME daily for 20 days (4-8/group) or 0 and
2,000 mg/kg-day for 1, 2, or 5 days (4/group) (Kawamoto et al.. 1990a. b). Body weight was
measured every 5 days in the 20-day study. Organ weights (liver, kidney, spleen, thymus, heart,
lung, testis) were measured at 1, 2, 5, and 20 days of exposure (2,000 mg/kg-day only), but only
relative organ weights were reported, and only for the control and high-dose groups. Thymus
and testes weights were measured in all dose groups following 20 days of exposure; relative
organ weights, only, were reported graphically. Histopathology was evaluated in the thymus of
rats given 2,000 mg/kg-day DGME for 5 days. Histopathology was not evaluated in the 20-day
study.
Statistically significant reductions in body-weight gain were observed in rats given
2,000 mg/kg-day beginning at 10 days of exposure (-8, -8, and —10% compared with controls at
10, 15, and 20 days of exposure, respectively). Exposure to 2,000 mg/kg-day DGME for 5 or
20 days resulted in a decrease in the relative weights of the liver (-9 to —10%), spleen (—26%),
thymus (-27 to -40%), and testis (-16 to —19%), compared with controls (see Table B-4).
Relative testis weight was similar to controls at 500 and 1,000 mg/kg-day. Relative thymus
weight was decreased dose dependently by 15, 27, and 40% at 500, 1,000, and 2,000 mg/kg-day,
respectively1, but statistical significance was not reached until 1,000 mg/kg-day. Absolute organ
weights were not reported. Histopathological evaluation of the thymus of rats treated with
2,000 mg/kg-day DGME for 5 days revealed a reduction in lymphocytes in the thymus cortex. A
Relative thymus and testis organ weights for 500 and 1,000 mg/kg-day were reported only in graphical form by the
study authors.
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LOAEL of 1,000 mg/kg-day and a NOAEL of 500 mg/kg-day in the 20-day study is identified in
male rats based on a statistically significant decrease in relative thymus weight, compared with
controls.
(he ever et al. (1988)
Cheever et al. (1988) conducted a study of the metabolism and testicular toxicity of
diethylene glycol dimethyl ether (DGdME), its principal metabolite (2-methoxyethoxy)acetic
acid, and the immediate metabolic precursor 2-(2-methoxyethoxy)acetic acid (i.e., DGME).
Each compound (purity 97% to 99.5%) was administered by gavage in distilled water to groups
of 50 male Sprague-Dawley (S-D) rats (190-240 g) at doses of 0 or 5.1 mmol/kg-day
(610 mg/kg-day) for up to 20 days. The exposure level of 5.1 mmol/kg-day was equivalent to a
dose found previously to produce testicular atrophy for DGdME. Five rats from each group were
euthanized every 2 days for evaluation of testicular histopathology. Testicular toxicity was not
observed in rats treated with DGME or (2-methoxyethoxy)acetic acid at any time point. The
study authors concluded that the testicular toxicity previously observed for DGdME was
probably due to a minor metabolite, methoxyacetic acid, which is not a metabolite of DGME. A
NOAEL for testicular toxicity of 610 mg/kg-day was established in this study; a LOAEL was not
identified.
Subchronic-Duration Studies
Eastman Kodak (1992)
In a study that was not peer reviewed, groups of male Albino CD rats (10/group) were
exposed to undiluted doses of 0, 900, 1,800, or 3,600 mg/kg DGME (>99.5% purity) via gavage
(undiluted) 5 days/week for 6 weeks (adjusted daily doses [ADD] of 0, 643, 1,286, and
2,571 mg/kg-day). Body weights were recorded on Days 0, 3, 6, 13, 20, 27, 34, and 41. All
doses were recalculated weekly to adjust for changes in body weights. Control rats were given
gavage doses of distilled water equal to the largest volume given a treated animal. Animals were
observed 5 days/week for clinical signs of toxicity and mortality. Blood was collected just prior
to sacrifice for hematology (Hb, hematocrit, RBC counts, red cell indices, total and relative white
cell counts) and clinical chemistry (AST, ALT, ALP, lactate dehydrogenase [LDH], BUN,
creatinine, and glucose). At sacrifice, animals were examined for gross pathology, and the
following tissues were collected and fixed for histology: lung, heart, thymus, kidneys, liver,
spleen, brain, salivary glands, stomach, cecum, colon, duodenum, jejunum, ileum, pancreas,
esophagus, adrenal glands, pituitary, thyroid, parathyroid, trachea, mesenteric lymph nodes,
testes (control, mid- and high-dose groups only), epididymides (control and high-dose only),
prostate, seminal vesicles, coagulating gland, bone marrow, tongue, nasal cavities, and eyes.
Prior to fixation, the liver, kidneys, heart, testes, brain, and spleen were weighed. Thymus
weights were not reported.
No mortality was observed in rats treated with DGME. One animal in the high-dose
group had bloody urine, blood around the nares, and an unkempt coat. No clinical signs of
toxicity were observed in animals from the low- and mid-dose groups. Terminal body weights
were significantly reduced at 1,286 and 2,571 mg/kg-day by 6 and 11%, respectively, compared
with controls. In the 2,571-mg/kg-day group, body weights were significantly reduced (p < 0.05)
on Days 3, 27, and 34 by 7, 8, and 11%, respectively, compared with controls (see Table B-5).
These changes were accompanied by significant reductions (p < 0.05) in food consumption
throughout the exposure period in rats exposed to 2,571 mg/kg-day (see Table B-5). No
significant changes in hematological parameters were observed. The only exposure-related
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clinical chemistry finding was a significant 23% increase (p < 0.05) in BUN in the
2,571-mg/kg-day group, compared with controls (see Table B-6).
Absolute and relative testes weights were reduced in the high-dose group (27 and 16%,
respectively) (see Table B-7). Absolute liver weight was not affected by DGME treatment,
although relative liver weight was significantly increased by 11% at 2,571 mg/kg-day (p < 0.05).
Similarly, absolute heart weight was unaffected, while relative heart weight was increased
(p < 0.05) in the mid- and high-dose groups by 13 and 15%, respectively. No statistically
significant change was observed in absolute kidney weight. Relative kidney weight was altered
in the mid- and high-dose groups; however, these changes were not dose related (+5, -14, and
+17%) at 643, 1,286, and 2,571 mg/kg-day, respectively). Absolute brain and spleen weights
were significantly reduced (p < 0.05) at the highest administered dose, while relative brain and
spleen weights did not differ from controls (see Table B-7). The reported increases in relative
organ weights at the highest dose are likely due to the reduction in body weight at the exposure
level. However, the decreased relative testes weights in the high-dose group cannot be attributed
to a reduction in body weight.
No gross pathology changes were noted in this study. Histopathological changes were
found in the testes, epididymides, and kidneys of rats in the high-dose group. No
histopathological lesions were reported for the thymus. In the testes, an increase in the incidence
of seminiferous tubule atrophy was observed at 2,571 mg/kg-day, compared with controls
(see Table B-8). In the epididymides at this dose, there were low incidences of degenerated
spermatozoa and hypospermia. In the kidney, hyaline droplet degeneration was seen in all
control and treated animals (except one high-dose rat), but there was no indication that this was
treatment related (severity was not reported). This lesion may be related to a2u-g accumulation,
which is common in male rats, but is not considered relevant to human toxicity (U.S. EPA.
1991a). However, the criteria for establishing alpha 2u-globulin (a2u-g) accumulation, as the
etiologic agent for the male rat kidney effects reported in this study have not been met (a2u-g
specific antibody staining not performed, sequence of events not observed (U.S. EPA. 1991a).
Also in the kidney, there was an increase in the incidence of proteinaceous casts in high-dose
rats. Although casts are sometimes seen in association with a2u-g accumulation, they were not
observed in control rats or rats from the low- or mid-dose groups in this study, and are therefore
considered to be potentially treatment related. A lowest-observed-adverse-effect level adjusted
daily dose (LOAELadd) of 2,571 mg/kg-day and a no-observed-adverse-effect level adjusted
daily dose (NOAELadd) of 1,286 mg/kg-day are identified for decreased absolute and relative
testicular weight, testicular atrophy, proteinaceous casts in the kidney, and increased BUN.
Developmental Studies
Bioassay Sys (1983a)
In a non-peer-reviewed study, groups of 50 timed-pregnant CD-I mice were exposed to 0
or 4,000 mg/kg-day DGME (purity not specified) via gavage in water on Gestation Days
(GDs) 7-14. All dams were weighed on GD 7. Females confirmed as pregnant were weighed
on GD 14, and dams producing viable litters were weighed on Postnatal Day (PND) 3. Dams
were allowed to deliver naturally. The following developmental indices were measured: number
of animals producing litters, number of animals with totally resorbed litters, and number of live
and dead pups within 12 hours of parturition and on PND 3. Litters were weighed on PNDs 0
(within 12 hours of parturition), 1, and 3. Mated females that failed to deliver a litter by GD 23
were sacrificed and necropsied, and the status of pregnancy was assessed. All uteri not
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obviously gravid were treated with sodium sulfide to assess the prior existence of pregnancy. All
animals that died during the exposure period were necropsied to determine cause of death.
Reproductive postimplantation survival index was calculated as the number of mice producing
viable litters divided by the number of mice that were pregnant. For comparisons between
treated and untreated groups, the following adjusted values were calculated: mean percent of
dead pups/litter, mean percent of litter weight change from PNDs 1-3, and mean percent of pup
viability/litter from PNDs 1-3.
Five females from the exposed group died during the exposure period, and none were
attributed to gavage error (further necropsy details were not reported). No control animals died.
Pregnancies were confirmed in 32/50 and 36/50 females from the control and exposed groups,
respectively (see Table B-9). Exposure to 4,000 mg/kg-day resulted in only 14% of confirmed
pregnant rats delivering viable litters. The other dams had stillborn litters (25%) or totally
resorbed litters (50%). In contrast, 97% of confirmed-pregnant controls delivered viable litters;
the other 3% were totally resorbed (see Table B-9). Maternal body weight and body-weight gain
on GD 18 were significantly decreased in the exposed group by 19 and 48%, respectively,
compared with controls (see Table B-9). Maternal body weight remained significantly decreased
by 17%) on PND 3 in exposed dams that produced viable litters, compared with controls
(see Table B-9). In viable litters, significant exposure-related decreases were observed in the
number of live pups per litter (68% decrease), pup survival from PNDs 1-3 (87% decrease),
litter weight on PNDs 1 and 3 (71 and 88% decrease, respectively), and litter weight gain from
PNDs 1-3 (200%) decrease) (see Table B-10). A maternal LOAEL (frank effect level [FEL]) of
4,000 mg/kg-day was identified in mice for decreased survival and decreased maternal body
weight. A fetal LOAEL and FEL of 4,000 mg/kg-day was identified for decreased number of
viable litters, decreased number and survival of live pups, and decreased litter weight, compared
with controls. Because only a single dose level was tested, maternal or fetal NOAELs were not
identified.
Hardin et al. (1986); range-finding study
In a dose-range-finding study, groups of time-mated pregnant S-D rats (9/group) were
exposed to 0, 1,000, 1,495, 2,235, 3,345, or 5,175 mg/kg-day DGME (purity not specified) on
GDs 7-16 via gavage in distilled water. Dams were weighed daily on GDs 6-16 and before
sacrifice on GD 21. Food consumption was determined for GDs 7-12, 12-17, and 17-21. At
sacrifice, uteri were removed and weighed, and fetuses were counted, weighed, and examined for
gross external defects. Fetuses were fixed in alcohol or Bouin's fluid for visceral and skeletal
examination. Adjusted maternal body-weight gain was calculated by subtracting gravid uterine
weight from weight gain between GDs 6 and 21.
Two females exposed to 5,175 mg/kg-day died during exposure; no other deaths occurred
(see Table B-l 1). Maternal body weight was significantly decreased by 11% at 5,175 mg/kg-day
on GD 16 and by 17 and 29% at 3,345 and 5,175 mg/kg-day, respectively, on GD 21 compared
with controls (see Table B-l 1). Adjusted maternal body-weight gain from GDs 6-21 was
significantly decreased by 30% at 5,175 mg/kg-day (see Table B-l 1). Body weight effects were
accompanied by significant decreases in food consumption between GD 7 and 12 at 3,345 and
5,175 mg/kg-day (see Table B-l 1). No viable litters were produced from dams exposed to
5,175 mg/kg-day. The numbers of viable litters and live fetuses/litter in dams exposed to
3,345 mg/kg-day were significantly reduced by 67 and 73%, respectively, compared with
controls (see Table B-l 1). A dose-related trend in the reduction of live fetal body weight
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beginning at 1,000 mg/kg-day was evident (see Table B-l 1). Male fetal body weight was
decreased by 5% to 43% over the dose range, becoming statistically significant only at the
second highest dose (3,345 mg/kg-day). Female fetal body weight was decreased by 8% to 37%
over the dose range, becoming statistically significant only at the second highest dose
(3,345 mg/kg-day). However, the 5% to 8% reduction in fetal body weight at 1,000 mg/kg-day
is considered to be real and biologically significant. Skeletal examination showed significant
increases in malformations at 2,235 mg/kg-day and decreased ossification at >1,495 mg/kg-day
(see Table B-12). Cardiac malformations and variations were significantly increased at
2,235 mg/kg-day (see Table B-12). No exposure-related effects were observed at
1,000 mg/kg-day. A maternal LOAEL of 3,345 mg/kg-day and NOAEL of 2,235 mg/kg-day are
identified for reduced maternal body weight. A fetal LOAEL of 1,000 mg/kg-day is identified
for decreased fetal body weight; a NOAEL is not established. The occurrence of fetal effects at
doses that did not produce maternal effects indicates that the developing organism is a sensitive
target of toxicity for DGME.
Hardin et al. (1987); main study
Hardin et al. (1986) is selected as the principal study for derivation of the
subchronic p-RfD value. Based on the results of the dose-range finding study, additional
groups of time-mated pregnant S-D rats (25/group) were exposed to doses of 0, 720, or
2,165 mg/kg-day DGME on GDs 7-16 via gavage in distilled water. Body weights, food
consumption, and fetal endpoints were assessed as described above for the dose-range finding
study. There were no exposure-related effects on survival or number of viable litters. Maternal
body weight at GD 21 was statistically significantly decreased in dams exposed to
2,165 mg/kg-day; however, maternal body weights from all exposed groups were within 10% of
that from controls throughout the study (see Table B-13) and not considered to be biologically
significant. In rats given 2,165 mg/kg-day, the number of live fetuses/litter was significantly
decreased by 35%, and male and female fetal body weights were significantly decreased by
24 and 27%, respectively (see Table B-13). There was a significant exposure-related trend for
increased gross malformations (see Table B-13). Skeletal examination showed a significant
increase in total malformations (primarily rib malformations) and reduced cranial and
appendicular skeleton ossification at both doses (see Table B-14). Additional effects that were
seen in the high-dose group only included sternebrae, vertebrae, and rib variations (primarily
reduced ossification) (see Table B-14). Visceral examination showed an increase in the
incidence of dilated renal pelvis at both doses. Cardiovascular malformations were also
observed in the high-dose group (see Table B-l5). A maternal NOAEL of 2,165 mg/kg-day is
identified, and no maternal LOAEL is identified. A fetal LOAEL of 720 mg/kg-day is identified
for increased rib malformations and renal pelvis dilation and decreased skeletal ossification,
compared with controls. No fetal NOAEL is identified.
Yamano et al. (1993); range-finding study
In a dose-range-finding study, groups of pregnant Wistar rats (4-6/group) were exposed
to doses of 0, 125, 250, 500, 1,000, 2,000, 3,000, or 4,000 mg/kg-day DGME (>99.0% purity) on
GDs 7-17 via gavage in water. Body weight, food consumption, and clinical signs of toxicity
were monitored daily. Dams were sacrificed on GD 20. The position and number of live and
dead fetuses, number of resorptions, and number of corpora lutea were recorded. Live fetuses
were weighed, sexed, and examined for external malformations.
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Body-weight gain was significantly decreased in dams exposed to >2,000 mg/kg-day
(40-80% of control and about >40 g less at the end of treatment based on visual inspection of
data reported graphically). Based on a reference body weight of 156 g for Wistar female rat
(U.S. EPA. 1988). this change in absolute body weight at the end of treatment would be more
than 10% compared to the control group. Food consumption was also significantly decreased in
dams exposed to doses >3,000 mg/kg-day (10—40% of control based on visual inspection of data
reported graphically). No exposure-related changes were observed in the number of implants or
the number of corpora lutea; however, all embryos were resorbed at doses of 3,000 and
4,000 mg/kg-day. In rats given 2,000 mg/kg-day, the incidence of dead or resorbed fetuses was
increased (+44% early stage, +21% late stage), the number of live fetuses was decreased (—65%),
and the weights of male and female fetuses were decreased by 31 and 27%, respectively
(see Table B-16). At 1,000 mg/kg-day, the weights of male and female fetuses were also
decreased by 13 and 17%, respectively (see Table B-16); although not statistically significant,
these reductions are considered to be real and biologically significant. External malformations
(omphalocele2, anasarca3, and anury4) were observed in one fetus at 1,000 mg/kg-day and three
fetuses (two litters) at 2,000 mg/kg-day. External anomalies (dorsum subcutaneous hematomas)
were observed in five fetuses (three litters) at 2,000 mg/kg-day (see Table B-16). A maternal
LOAEL of 2,000 mg/kg-day and a NOAEL of 1,000 mg/kg-day were identified for decreased
maternal weight gain, compared with controls. A fetal LOAEL of 1,000 mg/kg-day and NOAEL
of 500 mg/kg-day were identified for decreased male and female fetal body weight, compared
with controls.
Yamano et al. (1993); main study
Based on the results of the dose-range-finding study, additional groups of Wistar rats
(22/group) were exposed to 0, 200, 600, or 1,800 mg/kg-day DGME (>99.0% purity) on
GDs 7-17 via gavage in water. Body weight, food consumption, and clinical signs of toxicity
were monitored throughout gestation. On GD 20, 14 dams/group were sacrificed. Maternal
thymus weight was measured, and uteri and fetuses were examined as in the dose-range-finding
study (described above). Additionally, one-half of the live fetuses in each litter were preserved
in Bouin's fixative for visceral examination and the other half were preserved in alcohol for
skeletal examination. The remaining eight dams/dose were allowed to deliver naturally. The
gestation length, litter size, and number and sex of live and dead pups were noted. Pups were
examined for external anomalies. On PND 4, litters were culled to eight pups/litter
(approximately four/sex). During the lactation period (PNDs 0-21), the pups were examined for
growth and external differentiation (detachment of ears, hair growth, teeth appearance, and
opening of eyelids) (the timing and frequency of postnatal observations was not reported). Body
weights were recorded on PNDs 7, 14, and 21. On PND 21, pups were sacrificed and x-rayed for
skeletal observations. Dams were also sacrificed on PND 21, and the number of implants was
recorded.
All dams survived and produced live fetuses. In dams sacrificed on GD 20, food
consumption, and thymus weight were significantly decreased at 1,800 mg/kg-day
(see Table B-17). Although maternal terminal body weights were also significantly decreased at
this dose level, these changes remained within 10% of controls. Also at this dose, the percent of
protrusion of abdominal contents through an opening at the navel,
generalized edema with accumulation of serum in the connective tissue.
4absence of tail.
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dead or resorbed fetuses was significantly increased, and the number of live fetuses per litter was
significantly decreased (-41%), compared with controls. Male and female fetal body weights
were decreased in a dose-related pattern beginning at 200 mg/kg-day. Fetal body weight for
males was reduced by 12%, 21%, and 36% and for females by 10%, 19%, and 35% at 200, 600,
and 1,800 mg/kg-day, respectively, compared with controls (see Table B-17). Although the
reduced fetal body weights were not statistically significant below the 600 mg/kg-day exposure,
a clear dose-related trend beginning at 200 mg/kg-day is evident. The 10% and 12% decreases
in females and males, respectively, are considered to be biologically significant. External
malformations and anomalies, visceral malformations and variations, and skeletal malformations
and variations were significantly increased in fetuses at 1,800 mg/kg-day, compared with
controls (see Tables B-18, B-19, and B-20, respectively). External malformations or anomalies
included anasarca, omphalocele, anury, and dorsum subcutaneous hematoma (see Table B-18).
Visceral malformations and variations included right aortic arch, ventricular septal defect,
thymic remnant in the neck, and dilated renal pelvis (see Table B-19). Skeletal malformations
and variations included agenesis of sacrococcygeal vertebrae, splitting of vertebral bodies, and
delayed ossification (see Table B-20). Significant increases in visceral variations (thymic
remnant in the neck) and skeletal variations (decreased ossification) were also observed at
600 mg/kg-day, compared with controls (see Tables B-19 and B-20, respectively).
In dams allowed to give birth and sacrificed on PND 21, gestation length was
significantly increased by ~2 days in dams at 1,800 mg/kg-day, compared with controls
(see Table B-21). In the 1,800-mg/kg-day group, the number of live pups/litter was significantly
decreased by 63% (see Table B-21), and postnatal survival between PND 0 and 4 was only 5.4%
(see Table B-21); survival at PND 4 was reduced to 62.4% at 600 mg/kg-day. However, normal
growth and development was observed in pups surviving past PND 4 in all dose groups. No
exposure-related changes were observed in the percentage of fetuses with external malformation
or anomalies (see Table B-21), and no skeletal observations were reported. A maternal LOAEL
of 1,800 mg/kg-day and a NOAEL of 600 mg/kg-day are identified in pregnant rats for decreased
thymus weight, compared with controls. A developmental LOAEL of 200 mg/kg-day is
identified for decreased male and female fetal body weight; a NOAEL is not established.
Inhalation Exposures
Subchronic-Duration Studies
Miller et al. (1985)
Male and female Fischer 344 rats (10/sex/group) were exposed to DGME
(purity >99.5%)) as a preheated (60°C) vapor to time-weighted average (TWA)-measured
concentrations of 0, 31, 102, or 216 ppm (26, 88, and 190 mg/m3)5 by whole-body exposure for
6 hours/day, 5 days/week for 13 weeks. The study authors considered the highest exposure level
(190 mg/m3) to be the maximum attainable concentration due to the relatively low vapor pressure
of DGME (it was also >60% of the theoretical maximum vapor concentration for DGME at 25°C
and 1 atm pressure). Animals were monitored daily (postexposure) for mortality and clinical
signs of toxicity. Body weights were recorded prior to the first exposure, weekly thereafter, and
at terminal sacrifice. Hematological parameters were measured after 12 weeks of exposure,
including packed cell volume (PCV), Hb concentration, erythrocyte, platelet, and total and
differential leukocyte counts, and erythrocyte indices (mean corpuscular volume [MCV], mean
corpuscular hemoglobin [MCH], and mean corpuscular hemoglobin concentration [MCHC]).
5ppm x (molecular weight [120.15] 24.45) x (hours exposed [6] 24 hours) x (days exposed [5] 7 days)
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Clinical chemistry analyses were performed after 13 weeks of exposure (BUN, ALT, AST, ALP,
glucose, total protein, albumin, and globulin). Urinalysis parameters (including bilirubin,
glucose, ketones, blood, pH, protein, urobilinogen, and specific gravity) were examined after
12 weeks of exposure. Rats were sacrificed after 13 weeks of exposure and subjected to gross
pathology (48 tissues). Selected organs (liver, kidneys, heart, thymus, and testes) were weighed.
Complete histopathological examinations were performed for rats in the control and
high-exposure groups only.
No treatment-related mortality or clinical signs of toxicity were observed. The death of
one female rat in the 88-mg/m3 group was attributed to injuries incurred during handling. The
body weights of treated male rats did not vary significantly from controls. Female rats exposed
at 88 mg/m3, but not 190 mg/m3, showed a statistically significant reduction in body weight
relative to controls from 4 weeks of exposure until study termination; however, the body weights
of rats in this group remained within 10% of controls throughout the study. This effect was not
considered to be treatment related by the study authors. No significant effects on hematology,
clinical chemistry, or urinalysis parameters were observed in treated rats (limited data shown).
No significant effects on absolute or relative organ weights were reported (data were shown for
control and high-exposure groups only). No histopathological effects in treated rats were noted
(data for gross and microscopic pathology were not shown). A NOAEL of 190 mg/m3 is
established in this study; no LOAEL is determined.
Carcinogenic Studies
No studies could be located regarding the carcinogenic effects of oral or inhalation
exposure to DGME in humans or animals.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Acute and Short-Term Tests (Oral, Inhalation, and Dermal)
The acute toxicity of DGME is low. Oral LD50 values ranged from about
4,068-14,430 mg/kg in rats and from 7,128-8,188 mg/kg in mice (dose conversion based on a
density for DGME of 1,017 g/mL) (Eastman Kodak. 1992; Cook. 1984; Olin Corporation. 1977;
Dow Chemical Co. 1947). No toxic effects were reported in rats exposed to DGME via
inhalation at a nominal concentration of 200,000 mg/m3 (200 mg/L) for 1 hour (Olin
Corporation, 1977). However, this nominal concentration is several orders of magnitude greater
than the maximum attainable concentration of 190 mg/m3 reported by Miller et al. (1985).
Actual measured concentrations were not available for this study, but are likely to have been
much lower than nominal; no details were provided regarding the method used to generate the
chamber air concentrations (Olin Corporation. 1977). No toxicity was reported in rats exposed
to a substantially saturated vapor of DGME for 6 hours (concentration not given) (Cook. 1984).
Dermal toxicity studies in rabbits reported no toxic effects at the highest tested dose
(2,000 mg/kg) (Olin Corporation. 1977) or identified LD50 values in the range of
9,133-9,404 mg/kg (Eastman Kodak, 1992; Cook, 1984). Primary irritation studies showed no
or only slight evidence of skin irritation in rabbits (Eastman Kodak. 1992; Cook. 1984; Olin
Corporation. 1977; Dow Chemical Co. 1954) or guinea pigs (Eastman Kodak. 1992); slight and
generally transient eye irritation has been noted in rabbits exposed to undiluted DGME (Cook.
1984; Olin Corporation. 1977; Dow Chemical Co. 1954).
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Subchronic-Duration and Developmental Studies by Dermal and Subcutaneous Exposure
Kara man. et al. (2002) presented a case study of a 5-year-old boy with multisystemic
anomalies of the cardiovascular and skeletal systems (ventricular septal defect, a unilateral 12th
costal rib, scoliosis of the thoracolumbar spine, LI hemivertebra), as well as a retrocaval ureter,
which is a rare congenital anomaly resulting from abnormal development of the inferior vena
cava. The boy's mother worked in the thread-dying section of a weaving company in Turkey for
the previous 7 years. Dermal contact with DGME was suspected, but not confirmed. Exposure
levels were not estimated in this study.
DGME was shown to induce maternal and developmental toxicity in New Zealand white
rabbits by dermal administration during gestation (Scortichini et al.. 1986; John et al.. 1984; John
et al. 1983; Ouellette et al. 1983) (see Table 4). Decreased maternal weight gain and an
increase in the percent of resorptions was observed at dermal doses >750 mg/kg-day.
Developmental effects were observed at dermal doses as low as 250 mg/kg-day (delayed
ossification of the skull and cervical spurs) (Scortichini et al, 1986; John et al.. 1984). No
maternal or developmental toxicity was observed in Wistar rats injected subcutaneously with
DGME on GDs 6-20 at doses up to 1,000 mg/kg-day (Doe. 1984) (see Table 4).
Male guinea pigs administered DGME to the skin daily for 13 weeks also showed
evidence of systemic toxicity, including decreased spleen weight at 200 mg/kg-day and changes
in liver histopathology at 40 mg/kg-day (Hobson et al.. 1986) (see Table 4).
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
DGME is used as a deicing agent in jet propulsion fuel-8 (JP-8). Comet assay
measurements were performed to evaluate genotoxicity in leukocytes from U.S. Air Force
personnel exposed to JP-8 (Krieg et al.. 2012). Postshift urinary concentrations of DGME were
correlated with the number of leukocytes with highly damaged DNA (measured postshift);
however, this association was not statistically significant for creatinine-adjusted urinary
concentrations.
DGME was found to be negative for mutagenicity with and without metabolic activation
in Salmonella typhimurium reverse mutation tests using strains TA1535, TA100, TA1537, and
TA98 (BASF. 1989).
Metabolism/Toxicokinetic Studies
In a study (Cheever et al.. 1988) of the metabolism and testicular toxicity of di ethylene
glycol dimethyl ether (DGdME) summarized previously in this document,
(2-methoxyethoxy)acetic acid was found to be a major urinary metabolite, accounting for about
70% of the administered dose. A second urinary metabolite, methoxyacetic acid, was a minor
metabolite, accounting for only 6% of the administered dose. The study authors stated that
DGME is the immediate metabolic precursor to (2-methoxyethoxy)acetic acid and that
methoxyacetic acid is not a metabolite of DGME. (2-Methoxyethoxy)acetic acid was not found
to be a testicular toxicant and the study authors attributed all the testicular toxicity of DGdME to
methoxyacetic acid.
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Table 4. Other Studies
Test
Materials and Methods
Results
References
Other route animal studies
Dermal subchronic
Male guinea pigs (6/treatment group and 7 controls) were
dermally exposed to DGME at 0, 40, 200, and
1,000 mg/kg-d, 6 h/d, 5 d/wk, for 13 wk. Gauze patches
containing DGME (neat) were applied to the shaved
backs and held in place with an occlusive bandage to
minimize oral exposure and volatilization. At study
termination, hematology (RBC, total and differential
WBC counts; Hb, hematocrit, MCV, MCH, and MCHC),
clinical chemistry (ALT, AST, AP, creatine kinase, gGT,
and LDH activities, BUN, calcium, cholesterol,
creatinine, glucose, and total protein), and urinalysis
(specific gravity, pH, and activities of AP, ALT, gGT)
parameters were evaluated. Animals were subjected to
gross and histopathological examinations (23 tissues).
No treatment-related effects on survival or body weight
were observed. Decreased absolute and relative spleen
weight (14-22%) was observed in guinea pigs exposed to
200 and 1,000 mg/kg-d. A significant increase in urinary
calcium excretion was noted in all treatment groups. A 3%
decrease in MCHC was observed at 1,000 mg/kg-d. Serum
LDH was increased 2.5-fold at the highest dose. No
changes in gross pathology were observed.
Histopathological changes were observed in the liver
(mild, periportal hepatocellular fatty change: 0/6, 2/6, 6/6,
and 6/6 at 0, 40, 200, and 1,000 mg/kg-d, respectively).
Hobsonet al. (1986)
Dermal developmental
Pregnant New Zealand white rabbits (6/group) were
administered 0 or 1,000 mg/kg-d DGME dermally on
GDs 6-18. DGME was applied under an occlusive
bandage to minimize oral exposure and volatilization.
Dosing occurred daily, and bandages were replaced as
needed. Animals were monitored daily for clinical signs
of toxicity; body weights were also recorded daily (group
means on GDs 6, 9, 12, 15, and 19 only). Animals were
sacrificed on GD 19. Maternal liver weights were
measured and all rabbits were subjected to gross
pathology. Numbers of corpora lutea, live and resorbed
fetuses, and resorption sites (nonpregnant animals) were
recorded.
No treatment-related mortality was observed. Decreased
maternal body weight gain was observed in treated rabbits
at GDs 6-8. Decreased ingesta at necropsy suggested poor
nutritional state of treated does. Dermal treatment
produced an 8-fold increase in the number of
resorptions/litter.
Ouellette et al. (1983)
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Table 4. Other Studies
Test
Materials and Methods
Results
References
Dermal developmental
Pregnant New Zealand white rabbits (25/group) were
treated dermally with 0, 50, 250, or 750 mg/kg-d DGME
(99.2% pure) on GDs 6-18. DGME was applied under an
occlusive bandage to minimize oral exposure and
volatilization. Dosing occurred daily, and bandages were
replaced as needed. Body weights were statistically
analyzed on GDs 6, 9, 12, 15, 19, and 29. Animals were
sacrificed on GD 29; hematology parameters (RBC,
WBC, and platelet counts, Hb, PCV, MCV, MCH, and
MCHC) were evaluated (GD 29); liver weights were
recorded. Reproductive endpoints included numbers of
resorptions, dead and live fetuses, and resorption sites.
Fetuses were weighed, sexed, and examined for external
(all animals), and visceral (50% of fetuses) or skeletal
(50% of fetuses) malformations.
Maternal effects were seen at 750 mg/kg-d only, including
decreased weight gain and 7% reductions in RBC count
and PCV. A 22% increase in the percent of implantations
resorbed was also observed in the high-dose group.
Significant developmental effects occurring at
250 mg/kg-d included delayed ossification of the skull
(9/21, 6/22, 19/23, and 16/18 litters at 0, 50, 250, and
750 mg/kg-d, respectively) and cervical spurs (0/21, 3/22,
8/23, and 6/18 litters at 0, 50, 250, and 750 mg/kg-d,
respectively). Other developmental effects seen in the
high-dose group only included mild forelimb flexure,
slight-to-moderate dilation of the renal pelvis, retrocaval
ureter, and delayed ossification of the sternebrae.
Scortichini et al. (1986);
John et al. (1984)
Dermal developmental
Pregnant New Zealand white rabbits (10/group) were
treated dermally with undiluted DGME at doses of 0, 100,
300, and 1,000 mg/kg-d on GDs 6-18. DGME was
applied under an occlusive bandage to minimize oral
exposure and volatilization. Dosing occurred daily and
bandages were replaced as needed. Animals were
observed daily for signs of toxicity. Body weights were
statistically analyzed on GDs 6, 9, 12, 15, and 19.
Animals were sacrificed on GD 19. Gross observations of
uterine contents (numbers of resorptions, dead and live
fetuses, and resorption sites), skin, and internal organs
were performed.
3 rabbits from the high-dose group died or were sacrificed
moribund. In the 7 surviving animals given
1,000 mg/kg-d, 5 showed decreased ingesta in the digestive
tract, and three showed a decreased amount of fat in the
abdominal cavity. Maternal body-weight gain was also
significantly decreased at 1,000 mg/kg-d (GDs 6-18). A
significantly higher percent of resorbed implantations
occurred at 1,000 mg/kg-d (GD 19).
John et al. (1983)
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Table 4. Other Studies
Test
Materials and Methods
Results
References
Subcutaneous injection
developmental
Pregnant Wistar-derived rats (15/group) were injected
subcutaneously with DGME on GDs 6-20 at 0, 250, 500,
or 1,000 nL/kg (~0, 254, 509, and 1,017 mg/kg-d).
Animals were observed daily for clinical signs of toxicity.
Body weights were recorded on GDs 1 and 6-20.
Maternal animals were allowed to deliver; numbers of
live and dead fetuses were recorded. Offspring were
weighed on PNDs 1 and 4. Animals that failed to produce
a litter were sacrificed on GD 24.
No maternal or developmental toxicity was observed.
Doe (1984)
Studies of mode of action/mechanism/therapeutic action
Developmental toxicity
in vitro
Chick embryonic limb bud cells were exposed to DGME
at concentrations of 0.001-100 |iL/mL (8.53 x 10 6 to
0.853M) for 5 d. Effects on cartilage development
(chondrogenesis) and cell proliferation were evaluated by
staining with alcian green (proteoglycans) and crystal
violet, respectively.
After treatment at 100 |iL/mL. proteoglycan abundance
and cell proliferation were significantly decreased. The
effect on proteoglycans was not concentration-related, and
the effect on cell proliferation was significant only at the
highest tested concentration.
Scofield et al. (2006)
Liver toxicity in vitro
Primary rat hepatocytes were exposed to DGME at 0,
0.001, 0.01, 0.1, 1, and 10 mM for up to 24 h. Toxicity
was evaluated by measuring LDH release (cell membrane
integrity), tetrazolium dye (MTT) reduction activity (cell
viability/mitochondrial function), gSH level (oxidative
damage), and rate of protein synthesis (cellular function).
At the highest tested dose (10 mM), DGME exhibited no
significant effects on LDH leakage, protein synthesis rates,
or gSH levels. DGME induced a small but significant
dose-related decrease in MTT dye reduction at >0.1 mM.
Geiss and Frazier
(2001)
Neurotoxicity in vitro
Xenopus oocytes expressing glutamate receptors were
exposed to a receptor agonist (kainite [KA] or
N-methyl-D-aspartate [NMDA]) and 100 |imol/L DGME
for 30 s.
DGME did not significantly affect KA- or NMD A-induced
membrane currents.
MusshofF et al. (1999)
ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; gGT = y-glutamyl transferase;
Hb = hemoglobin; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean
corpuscular volume; RBC = red blood cell; WBC = white blood cell
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Absorption studies indicate that diethylene glycol ethers penetrate the human skin at a
slower rate than their corresponding monoethylene glycol counterparts (Dugard et al.. 1984).
Penetration of DGME through the epidermis in vitro is relatively slow (0.21 mg/cm2-hour), and
does not significantly impair barrier function (Dugard et al.. 1984). The flux and permeability of
DGME from JP-8 was measured in static diffusion cells using excised rat skin (McDougal et al..
2000; McDougal et al.. 1999). DGME was measured as a minor component of JP-8 (0.08%)
with a flux and permeability coefficient of 0.052 mg/cm2-hour and 0.81 cm/hour, respectively
(from JP-8 vehicle). Significant dermal absorption is suggested, however, by
subchronic-duration and developmental studies of dermal toxicity in rabbits (see Table 4). Liver
toxicity was observed in guinea pigs following dermal exposure to doses 200 mg/kg-day, or
greater, for 13 weeks (Hobson et al. 1986). Developmental effects were observed at dermal
doses as low as 250 mg/kg-day (delayed ossification of the skull and cervical spurs) (Scortichini
et al.. 1986; John et al.. 1984).
Rats administered DGME orally or via i.p. injection showed induction of xenobiotic
metabolism (including increased microsomal protein content and induction of CYP450
mixed-function oxidase activity), without significant induction of the ethanol-inducible CYP450
isoform (P4502E1), or increased gGT, cytochrome b5 or NADPH-cytochrome c reductase in
hepatic microsomes (Ballow. 1992; Kawamoto et al.. 1991. 1990b). DGME is a poor substrate
for alcohol dehydrogenase (P450J) in vitro (Calhoun. 1982).
Mode-of-Action/Mechanistic Studies
In vitro mechanistic studies are described in Table 4. Scotleld et al. (2006) demonstrated
DGME-induced inhibition of cell proliferation in chick limb bud cells. DGME altered
mitochondrial function in primary rat hepatocytes, but did not affect membrane integrity, gSH
levels, or protein synthesis (Geiss and Tra/ier. 2001). DGME did not impair receptor-meditated
ion currents in Xenopus oocytes (Musshoff et al.. 1999).
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer references values,
respectively.
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Table 5. Summary of Noncancer Reference Values for DGME (CASRN 111-77-3)
Toxicity
Type (units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
PODhed/hec
UFc
Principal
Study
Subchronic
p-RfD
Rat/females
(pregnant)
Thymic remnants,
dilation of renal pelvis
and reduced
ossification in fetal rats
4 x 10"2 mg/kg-d
BMDLos
12
300
Yamano et
al. (1993)
Hardin et
al. (1986)
Chronic
p-RfD
Rat/females
(pregnant)
Thymic remnants,
dilation of renal pelvis
and reduced ossification
in fetal rats
4 x 10"2 mg/kg-d
BMDL05
12
300
Yamano et
al. (1993)
Hardin et
al. (1986)
Subchronic
p-RfC
NDr
Chronic
p-RfC
NDr
NDr = not determined
Table 6. Summary of Cancer Reference Values for DGME (CASRN 111-77-3)
Toxicity Type
Species/Sex Tumor Type Cancer Value Principal Study
Provisional oral slope factor (p-OSF) (mg/kg-d) 1
NDr
Provisional inhalation unit risk (p-IUR) (mg/m3) 1
NDr
NDr = not determined
DERIVATION OF ORAL REFERENCE DOSES
Derivation of the Subchronic Provisional RfD (Subchronic p-RfD)
There are four short-term-duration studies, one 6-week sub chronic-duration study, and
three developmental toxicity studies available for consideration for the derivation of the
subchronic provisional reference dose (p-RfD). The candidate points of departure (PODs) from
these studies are listed in Table 7. Two of the short-term-duration studies (both peer reviewed)
evaluated only immunotoxicity (Smialowicz et aL 1992) and testicular toxicity (Cheever et aL
1988); no treatment-related effects were reported in these studies. Two short-term-duration
(peer-reviewed) studies (Yamano et aL 1993; Kawamoto et aL 1990a) both reported decreased
thymus weights in adult rats after treatment with DGME for 11 and 20 days, respectively. The
one subchronic-duration study (Eastman Kodak. 1992) was conducted comprehensively for
systemic toxicity, reporting decreased body weight, testicular atrophy, and kidney effects at the
highest dose (2,571 mg/kg-day), but was not peer reviewed. Hardin et al. (1986) conducted two
developmental toxicity studies using pregnant S-D rats. The first one was a range-finding study
with only 9 dams that found fetal effects at a maternal dose of 1,000 mg/kg-day and maternal
effects at 3,345 mg/kg-day, establishing DGME as a developmental toxicant. The second, more
comprehensive Hardin et al. (1986) study used 25 dams and found similar effects as the
range-finding study, also with developmental effects occurring at a lower dose (720 mg/kg-day)
than the maternal NOAEL of 2,165 mg/kg-day; a developmental NOAEL was not established.
The comprehensive developmental Yamano et al. (1993) study also found developmental effects
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at lower doses than those for maternal effects and failed to establish a developmental NOAEL,
with a developmental LOAEL of 200 mg/kg-day. Yamano et al. (1993) also conducted a smaller
range-finding study, reporting a developmental NOAEL and LOAEL of 500 and
1,000 mg/kg-day, respectively. The Bioassav Svs (1983a) developmental toxicity study in mice
tested only one high dose (4,000 mg/kg-day), which was an FEL for maternal and fetal mortality.
Table 7. PODs Considered for the Subchronic p-RfD for DGME
Endpoint
Animal PODa
(mg/kg-d)
PODHEDb
(mg/kg-d)
Hardin et al. (1986): pregnant S-D rat, GDs 7-16, savage
Renal pelvis dilation, fetal
BMDLo5c = 50
12
Reduced cranial ossification, fetal
BMDL05 ~ 53
13
Total rib malformations, fetal
BMDLo5= 131
31
Reduced ossification of appendicular skeleton, fetal
BMDL05 = 187
45
Decreased fetal body weight (F)d
BMDLrdos6 = 380
91
Decreased fetal body weight (M)d
BMDLrdos = 480
115
Yamano et al. (1993): pregnant Wistar rat, GDs 7-17: savage
Decreased number of ossification centers; sacral and caudal
vertebrae, fetal
BMDLi sd — 142
34
Thymic remnant in the neck, fetal
BMDL05 ~ 55
13
Incidence of dilated renal pelvis, fetal
BMDL05 = 90
22
Decreased number of sternebrae ossified, fetal
BMDLi sd = 318
76
Decreased fetal body weight (M)
BMDLrdos — 195
47
Decreased fetal body weight (F)
BMDLrdos = 196
47
Decreased number of ossification centers; thoracic vertebrae, fetal
BMDLi sd = 161
39
Kawamoto et al. (1990a): Wistar rat, 20-d savage
Decreased relative thymus weight
NOAEL = 500
120
Yamano et al. (1993): Wistar rat, 11-d savase
Decreased relative thymus weight
BMDLi sd — 1,074
258
Eastman Kodak (1992): CD rat, 6-w savase
Decreased body and organ weights; testicular atrophy;
proteinaceous casts in the kidney, increased BUN
NOAEL = 1,286
309
Bioassav Svs (1983a): presnant CD-I mouse, GDs 7-14, savase
Decreased maternal and fetal survival
FEL = 4,000
560
aBMD modeling results are described in more detail in Appendix C.
' HED calculated by multiplying animal POD by a DAF of 0.24 for rats or 0.14 for mice (U.S. EPA. 2011b').
°BMR = 5% incidence.
drange-finding study.
°BMR = 5% relative deviation.
BMDL = benchmark dose lower confidence limit; FEL = frank effect level; NOAEL = no-observed-adverse-effect
level
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Thus, the two studies of Hardin et al. (1986) and Yamano et al. (1993) establish DGME
as a developmental toxicant, finding similar fetal effects at similar maternal exposures. In the
Hardin et al. (1986) developmental toxicity study in rats, the most sensitive endpoints (i.e., those
at the LOAEL of 720 mg/kg-day) include increased rib malformations, decreased ossification
(including reduced cranial and appendicular skeleton ossification), and renal pelvis dilation6 in
fetuses. In the Yamano et al. (1993) study, sensitive developmental endpoints included
decreased male and female fetal body weights (at 200 mg/kg-day), decreased ossification (sacral
and caudal vertebrae, thoracic vertebrae and sternebrae), and increased incidence of thymic
remnant in the neck (at 600 mg/kg-day). These results are supported by the finding of similar
developmental effects (dilation of the renal pelvis, retrocaval ureter, and delayed ossification of
the sternebrae) in fetuses of pregnant rabbits treated derm ally with DGME (Scortichini et al..
1986; John. 1984). Taken together, these findings indicate a concern for the negative impact of
DGME on skeletal development, kidney, and urinary tract development, and postnatal immune
system development. The thymus appears to be a particularly sensitive target organ, as reduced
thymus weight and reduced thymic lymphocytes were reported in adult animals at somewhat
higher doses (Yamano et al.. 1993; Kawamoto et al.. 1990a). Maternal effects were only seen at
higher doses in these studies, indicating that DGME is a developmental toxicant. In particular,
the fetal thymic remnants suggest a concern for early postnatal development of T cell-mediated
immune response mechanisms. The only immunoxicity study is for adult rats and shows no
impact of DGME on adult immune function (Smialowicz et al.. 1992). There are no early
life-stage immunotoxicity studies; the lack of such studies is considered a significant deficiency
in the toxicity database for DGME, which is reflected in the selection of the database uncertainty
factor for both the subchronic and chronic p-RfDs (see Tables 8 and 10, respectively).
Data sets for sensitive developmental endpoints in Hardin et al. (1986) and Yamano et al.
(1993) were considered to derive potential PODs via benchmark dose (BMD) modeling
(see Table 7 and Appendices C). Total skeletal malformations from Hardin et al. (1986) were
not modeled because the specific endpoints within each of these categories are not considered to
be independent. A number of less sensitive endpoints for adult animals were also BMD
modeled, with resulting benchmark dose lower confidence limits (BMDLs) also shown in
Table 7. All dichotomous models in the EPA BMD software (BMDS Version 2.5) were fit to
each of the dichotomous endpoints observed from the Hardin et al. (1986) and Yamano et al.
(1993) studies. Similarly, all BMDS continuous models were fit to the continuous endpoints in
the Yamano et al. (1993) study. Nested dichotomous models could not be used because
individual animal data were not available. Appendix C presents the modeling results for the
three endpoints yielding the lowest BMDLs: (1) number of litters with reduced cranial
ossification, (2) number of litters with dilated renal pelvis (see Tables C-l and C-2) (Hardin et
al.. 1986). and (3) incidence of thymic remnants (see Tables C-3) (Yamano et al.. 1993).
BMDLs for other endpoints were much higher.
In EPA's Recommended Use of Body Weight3/4 as the Default Method in Derivation of
the Oral Reference Dose (U.S. EPA, 201 lb), the Agency endorses a hierarchy of approaches to
derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
6 According to John (1984). dilation of the fetal renal pelvis is indicative of delayed fetal development.
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human equivalent oral exposures, EPA endorses body weight scaling to the 3/4 power
(i.e., BW3/4) to extrapolate toxicologically equivalent doses of orally administered agents from
all laboratory animals to humans for the purpose of deriving an RfD under certain exposure
conditions. More specifically, the use of BW3/4 scaling for deriving an RfD is recommended
when the observed effects are associated with the parent compound or a stable metabolite, but
not for portal-of-entry effects. A validated human physiologically based toxicokinetic model for
DGME is not available for use in extrapolating doses from animals to humans. Therefore,
scaling by BW3/4 is relevant for deriving human equivalent doses (HEDs) for these effects.
Following U.S. EPA (2011b) guidance, all PODs are converted to HEDs by application
of dosimetric adjustment factors (DAFs) as follows:
DAF = (BWa1/4 - BWh1/4)
Using a BWa of 0.25 kg for rats and 0.025 kg for mice, and a BW of 70 kg for humans,
the resulting DAFs are 0.24 and 0.14 for rats and mice, respectively (U.S. EPA. 1988). Each
POD candidate is multiplied by the appropriate species-specific DAF to obtain PODheds, which
are shown in Table 7.
The lowest PODhed in Table 7 is 12 mg/kg-day for fetal renal pelvis dilation reported by
Hardin et al. (1986). Two other PODheds, virtually the same at 13 mg/kg-day, were for reduced
cranial ossification (Hardin et al.. 1986) and increased incidence of thymic remnants (Yamano et
al.. 1993) developmental endpoints, and should be considered as co-critical effects.
The subchronic p-RfD for DGME, based on a BMDLos[hed] (for dichotomous
developmental endpoints) of 12 mg/kg-day, is derived as follows:
Table 8 summarizes the uncertainty factors (UFs) for the subchronic p-RfD for DGME.
where:
DAF
BWa
BWh
dosimetric adjustment factor
animal body weight
human body weight
Subchronic p-RfD = BMDLo5[hed] ^ UFc
= 12 mg/kg-day -^300
= 4 x 10"2 mg/kg-day
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Table 8. Uncertainty Factors for the Subchronic p-RfD for DGME (CASRN 111-77-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for residual uncertainty in potential toxicokinetic and
toxicodynamic differences between laboratory animals and humans. Interspecies toxicokinetic
variability has been accounted for bv application of a DAF (U.S. EPA. 1988s).
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of DGME in humans.
UFd
10
A UFd of 10 is applied because, although the database contains two acceptable developmental
studies. Hardin et al. (1986) and Yamano et al. (1993). there is no multieeneration reproduction
study. In addition, given the concern for developmental immunotoxicity, the lack of an early
life-stage immunotoxicity study is a significant weakness.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
NA
Not applicable for subchronic p-RfD derivation
UFC
300
Composite UF = UFA x UFH x UFD x UFL
NA = not applicable
The confidence in the subchronic p-RfD for DGME is medium as described in Table 9.
Table 9. Confidence Descriptors for the Subchronic p-RfD for
DGME (CASRN 111-77-3)
Confidence Categories
Designation
Discussion
Confidence in study
H
Confidence in the co-t>rincit>al studies (Yamano et al.. 1993; Hardin et
al.. 1986') is hishbecause in each case, preliminary studies were
conducted to determine appropriate doses and comprehensive
developmental endpoints were examined. Each of the co-principal
studies identified sensitive effects at similar dose levels (600 and
720 me/ke-dl (Yamano et al.. 1993; Hardin et al.. 1986s) (respectively).
and Yamano et al. (1993) also identified a NOAEL. Dose-resDon.se data
are available for both studies. Both studies were well reported.
Confidence in database
L
There is low confidence in the database. Although no peer-reviewed
subchronic-duration oral study is available, a 6-wk gavage study in rats
(Eastman Kodak. 1992s) provided a comprehensive evaluation of
systemic toxicity endpoints. Two peer-reviewed, adequately reported
developmental toxicity studies with dose-response data in rats are
available (Yamano et al.. 1993; Hardin et al.. 1986s). There are no
reproductive toxicity studies of DGME. In addition, the lack of
information on early life-stage immunotoxicity is a significant weakness.
Confidence in
subchronic p-RfD
L
The overall confidence in the subchronic p-RfD is low because the
deficiencies in the database, particularly the lack of a full-length
peer-reviewed subchronic-duration systemic-toxicity study, outweigh the
strength of the principal studies.
H = high; L = low.
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Derivation of the Chronic Provisional RfD (Chronic p-RfD)
There are no chronic-duration studies for DGME. The most sensitive endpoints for
less-than-chronic-duration exposure are the developmental effects found in two studies (Yamano
et ai. 1993; Hardin et al.. 1986) with PODheds of 12 mg/kg-day (BMDLos), which are the basis
for the subchronic p-RfD. However, for the chronic p-RfD, susceptibility to effects arising from
longer term-duration exposure must be considered. One concern for long-term-duration
exposure is the finding of reduced thymus weight in the two short-term-duration studies
(Yamano et al.. 1993; Kawamoto et al.. 1990a) with a PODhed of 120 mg/kg-day for the
Kawamoto et al. (1990a) study. Note that with the application of a 10-fold UFs, the extrapolated
sensitivity of this endpoint would be the same as the developmental effects. However, in the
longer 6-week study, which assessed thymus weight and histopathology, no effects on the
thymus were reported. In addition, the lack of effects of DGME on antibody response in adult
rats at doses up to 800 mg/kg-day (Smialowicz et al.. 1992) suggests that adult immunotoxicity
may not be an issue. The NOAEL for other systemic effects after a 6-week exposure is
309 mg/kg-day (Eastman Kodak. 1992). which would not constitute a more sensitive POD than
the developmental PODhed forming the basis for the subchronic p-RfD.
Therefore, the PODhed (BMDLos[hed]) of 12 mg/kg-day for developmental effects in
fetal rats is used as the POD for the chronic p-RfD. The chronic p-RfD is derived as follows:
Chronic p-RfD = BMDLos[hed] ^ UFc
= 12 mg/kg-day -^300
= 4 x 10"2 mg/kg-day
Table 10 summarizes the UFs for the chronic p-RfD for DGME.
Table 10. Uncertainty Factors for the Chronic p-RfD for DGME (CASRN 111-77-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for residual uncertainty in potential toxicokinetic and
toxicodynamic differences between laboratory animals and humans. Interspecies toxicokinetic
variability has been accounted for bv application of a DAF (U.S. EPA. 1988").
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of DGME in humans.
UFd
10
A UFd of 10 is applied because the database contains a subchronic study and two acceptable
developmental studies (Yamano et al.. 1993; Hardin et al.. 1986). however, there are no chronic-
duration studies, no multigeneration reproduction study, and no early life-stage immunotoxicity
study.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFs
1
A UF of 1 was applied to account for subchronic to chronic extrapolation (UFs) because
developmental toxicity resulting from a narrow period of exposure was used as the critical effect.
The developmental period is recognized as a susceptible life stage when exposure during a time
window of development is more relevant to the induction of developmental effects than lifetime
exposure (U.S. EPA. 199lb)
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
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The confidence descriptors for the chronic p-RfD are described in Table 11.
Table 11. Confidence Descriptors for the Chronic p-RfD for DGME (CASRN 111-77-3)
Confidence Categories
Designation
Discussion
Confidence in study
H
Confidence in the co-orincioal studies (Yamano et al.. 1993; Hardin
et al.. 1986s) is hishbecause in each case, preliminary studies were
conducted to determine appropriate doses and comprehensive
developmental endpoints were examined. Each of the co-principal
studies identified sensitive effects at similar dose levels, and Yamano
et al. (1993) also identified a NOAEL. Dose-resDonse data are
available for both studies. Both studies were well reported.
Confidence in database
L
There is low confidence in the database. Although no peer-reviewed
subchronic-duration oral study is available, a 6-wk gavage study in
rats (Eastman Kodak. 1992s) provided a comprehensive evaluation of
systemic toxicity endpoints. Two peer-reviewed, adequately reported
developmental toxicity studies with dose-response data in rats are
available (Yamano et al.. 1993; Hardin et al.. 1986^. There are no
chronic-duration studies and no reproductive toxicity studies of
DGME. In addition, the lack of information on early life-stage
immunotoxicity is a significant weakness.
Confidence in chronic p-RfDa
L
The overall confidence in the chronic p-RfD is low.
H = high; L = low.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
There is a single subchronic-duration inhalation study available for DGME (Miller et al..
1985). This study exposed rats to DGME as a vapor for 13 weeks; however, no toxicity was
observed and a LOAEL was not identified. The study authors indicated that the highest exposure
concentration used (measured TWA =190 mg/m3) was equivalent to a maximally attainable
concentration based on the low vapor pressure of DGME. Furthermore, the test article had to be
preheated to approximately 60°C in order to generate a vapor. An acute inhalation study
reported no toxic effects in rats exposed to a substantially greater DGME concentration in air
(nominal concentration of 200,000 mg/m3) for 1 hour (Olin Corporation. 1977). However, no
details were provided regarding the method used to generate the chamber air concentrations and
measured concentrations were not reported for this study. Because there were no
treatment-related effects in either of these studies at apparent maximally obtainable
concentrations using extreme conditions for vapor generation, there is not enough information to
assessment human health hazard from environmental inhalation exposure to DGME. Therefore,
provisional sub chronic and chronic RfCs are not derived.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No studies were located examining possible associations between exposure to DGME
and cancer in humans or animals. Studies in animals (one 6-week study and several
developmental studies in rodents) are inadequate to assess the carcinogenicity of DGME.
Results from a single reverse mutation assay with DGME were negative. Table 12 identifies the
cancer weight-of-evidence (WOE) descriptor for DGME.
29 Diethylene Glycol Monomethyl Ether
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Table 12. Cancer Weight-Of-Evidence Descriptor for DGME (CASRN 111-77-3)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are no human data available.
"Likely to Be Carcinogenic to
Humans "
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
"Inadequate Information to Assess
Carcinogenic Potential"
Selected
Both
No carcinogenicity studies are
available that evaluated oral or
inhalation exposure.
"Not Likely to Be Carcinogenic to
Humans "
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
The lack of sufficient data on the carcinogenicity of DGME following oral exposure
precludes the derivation of a quantitative estimate (p-OSF) for oral exposure.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
The lack of data on the carcinogenicity of DGME following inhalation exposure
precludes the derivation of a quantitative estimate (p-IUR) for inhalation exposure.
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APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values are provided for DGME.
31 Diethylene Glycol Monomethyl Ether
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APPENDIX B. DATA TABLES
Table B-l. Selected Hematological Parameters of Female Virgin Wistar Rats
Exposed to DGME by Gavage for 11 Days3
Endpointb
Exposure Group (mg/kg-d)
0
125
150
500
1,000
2,000
3,000
4,000
Number of animals
5
5
5
5
5
5
5
5
RBCs (x 106/mm3)
8.30 ±
0.12
8.21 ±
0.19
(-1%)
8.25 ±
0.16
(-1%)
8.63 ±
0.14
(+4%)
8.19 ±
0.15
(-1%)
8.11 ±
0.09
(-2%)
8.03 ±
0.17
(-3%)
7.59 ±
0.11*
(-9%)
WBCs (x 103/mm3)
5.1 ±0.4
4.8 ±0.1
(-6%)
5.2 ±0.4
(+2%)
4.7 ±0.4
(-8%)
4.8 ±0.6
(-6%)
3.9 ±0.2
(-24%)
3.8 ±0.2
(-25%)
3.2 ±0.3*
(-37%)
Hb (g/dL)
15.5 ±
0.34
15.3 ±
0.41
(-1%)
15.5 ±
0.40
(0%)
15.2 ±
0.19
(-2%)
15.0 ±
0.47
(-3%)
14.8 ±
0.20
(-5%)
14.5 ±
0.13
(-6%)
13.5 ±
0.19*
(-13%)
Hematocrit (%)
44.9 ±
0.34
44.2 ±
0.79
(-2%)
44.6 ±
0.82
(-1%)
43.2 ±
0.44
(-4%)
43.9 ±
0.54
(-2%)
42.7 ±
0.67
(-5%)
41.4 ±
0.43*
(-8%)
39.6 ±
0.61*
(-12%)
"Yamano et al. (1993).
bValues expressed as mean ± SE (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's or
Scheffe's multiple comparison test).
Hb = hemoglobin; RBC = red blood cell; WBC = white blood cell
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Table B-2. Selected Clinical Chemistry Parameters in Female Virgin Wistar Rats
Exposed to DGME by Gavage for 11 Days"
Endpointb
Exposure Group (mg/kg-d)
0
125
250
500
1,000
2,000
3,000
4,000
Number of animals
5
5
5
5
5
5
5
5
BUN (mg/dL)
16.3 ±
0.65
17.0 ±
0.99
(+4%)
17.7 ±
1.40
(+9%)
15.3 ±
0.60
(-6%)
16.4 +
0.34
(+1%)
14.8 +
0.77
(-9%)
17.6 +
1.04
(+8%)
20.6 +
1.78*
(+26%)
Triglycerides (mg/dL)
33.9 ±
2.91
40.6 ±
2.95
(+20%)
47.0 ±
4.60
(+39%)
33.0 +
1.46
(-3%)
38.4 +
2.39
(+13%)
49.6 +
7.65
(+46%)
46.0 +
5.81
(+36%)
64.1 +
7.42*
(+89%)
Total protein (g/dL)
5.00 ±
0.11
4.90 ±
0.10
(-2%)
4.98 ±
0.06
(0%)
4.80 +
0.07
(-4%)
4.90 +
0.06
(-2%)
4.92 +
0.11
(-2%)
4.62 +
0.07*
(-8%)
4.48 +
0.07*
(-10%)
aYamano et al. (1993).
bValues expressed as mean ± SE (% change compared with control); % change from control = [(treatment
mean - control mean) + control mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's or
Scheffe's multiple comparison test).
BUN = blood urea nitrogen
Table B-3. Selected Relative Organ Weights in Female Virgin Wistar Rats Exposed
to DGME by Gavage for 11 Days3
Endpoint
Exposure Group (mg/kg-d)
0
125
250
500
1,000
2,000
3,000
4,000
Number of animals
5
5
5
5
5
5
5
5
Relative organ weight
Kidneyb
0.74 +
0.01
0.77 +
0.01
(+4%)
0.71 +
0.01
(-4%)
0.71 +
0.01
(-4%)
0.71 +
0.01
(-4%)
0.75 +
0.02
(+1%)
0.77 +
0.01
(+4%)
0.83 +
0.01*
(+12%)
Thymus0
114.49 +
3.46
119.44 +
7.89
(+4%)
115.37 +
7.85
(+1%)
124.11 +
6.15
(+8%)
101.26 +
8.75
(-12%)
85.46 +
2.24
(-25%)
49.56 +
2.15
(-57%)
35.62 +
1.77*
(-69%)
Pituitary0
6.64 +
0.47
6.23 +
0.24
(-6%)
6.14 +
0.60
(-8%)
5.81 +
0.52
(-13%)
5.73 +
0.27
(-14%)
5.34 +
0.16
(-20%)
5.05 +
0.24*
(-24%)
4.97 +
0.30*
(-25%)
aYamano et al. (1993).
bRelative organ weight (organ weight/body weight x 102) expressed as mean ± SE (% change compared with
control); % change from control = [(treatment mean - control mean) + control mean] x 100.
°Relative organ weight (organ weight/body weight x 105) expressed as mean ± standard error mean ± SE
(% change compared with control); % change from control = [(treatment mean - control mean) + control
mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's or
Scheffe's multiple comparison test).
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Table B-4. Selected Relative Organ Weights in Male Wistar Rats Exposed to
DGME by Gavage for up to 20 Days3
Exposure Duration (d)
Control
2,000 mg/kg-d
Day
1
2
5
20
1
2
5
20
Number of animals
4
4
4
8
4
4
4
8
Relative organ weightb
Liver
36.92 ±0.57
38.86 ±
0.63
34.96 ±
2.10
35.34 ±
4.31
37.17 ±
0.58
(+1%)
37.63 ±
1.13
(-3%)
31.88 ±
0.52*
(-9%)
31.90 ±
0.85*
(-10%)
Kidney
8.81 ±0.39
8.48 ±
0.19
8.06 ±
0.25
8.22 ±
0.79
8.36 ±
0.39
(-5%)
8.92 ±
0.18*
(+5%)
8.59 ±
0.42
(+7%)
8.01 ±
0.72
(-3%)
Spleen
3.31 ±0.26
3.47 ±
0.19
3.42 ±
0.27
2.28 ±
0.23
3.02 ±
0.33
(-9%)
3.58 ±
0.21
(+3%)
2.54 ±
0.17*
(-26%)
2.33 ±
0.17
(+2%)
Thymus
3.15 ±0.54
2.95 ±
0.54
2.36 ±
0.21
2.08 ±
0.45
2.30 ±
0.14*
(-27%)
2.92 ±
0.50
(-1%)
1.49 ±
0.35*
(-37%)
1.24 ±
0.24*
(-40%)
Testis
10.78 ±0.91
11.72 ±
1.21
12.54 ±
0.70
11.16 ±
0.69
11.17 ±
0.70
(+4%)
11.58 ±
0.55
(-1%)
10.52 ±
1.09*
(-16%)
9.09 ±
2.33*
(-19%)
"Kawamoto et al. (1990a).
bRelative organ weight (organ weight/body weight x 1,000) expressed as mean ± SD (% change compared with
control); % change control = [(treatment mean - control mean) control mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Student's unpaired
test).
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Table B-5. Average Body Weights and Food Consumption of Male Albino CD Rats
Exposed to DGME by Gavage for 6 Weeks3
Time Period
Exposure Group, mg/kg-db
0 (control)
643
1,286
2,571
Number of animals
10
10
10
10
Body weight (g)°
Day 0
234.6 ± 17.3
239.4 ± 12.2 (+2%)
233.2 + 8.4 (-1%)
235.9+ 16.1 (+1%)
Day 3
253.3 ± 19.6
259.1 ± 11.4 (+2%)
252.2 + 9.0 (0%)
236.6 + 18.9* (-7%)
Day 6
272.0 ± 18.6
280.2 ± 14.0 (+3%)
274.8 + 9.1 (+1%)
262.4 + 18.3 (-4%)
Day 13
311.4 ± 25.1
318.3 ± 12.0 (+2%)
312.7+ 13.5 (0%)
297.1 + 16.7 (-5%)
Day 20
328.8 ±29.1
332.0 ± 17.2 (+1%)
322.9 + 18.2 (-2%)
309.3 + 21.0 (-6%)
Day 27
363.3 ±31.3
367.6 ± 16.3 (+1%)
353.7 + 16.1 (-3%)
333.9 + 20.4* (-8%)
Day 34
387.3 ±36.3
391.1 ± 13.6 (+1%)
369.5 + 23.4 (-5%)
346.3 + 26.1* (-11%)
Day 41
405.0 ±38.5
409.6 ± 14.6 (+1%)
381.6+ 27.4* (-6%)
359.9+ 25.9* (-11%)
Food consumption (g/rat/d)°
Day 3
21.93 ± 1.93
25.57 ± 1.75 (+17%)
23.38+ 1.86 (+7%)
15.07 + 6.67* (-31%)
Day 6
22.26 ± 2.02
24.58 ± 1.58 (+10%)
23.54 + 1.62 (+6%)
19.90 + 4.25* (-11%)
Day 13
22.93 ± 2.73
25.02 ± 1.69 (+9%)
22.84 + 3.58 (0%)
21.44+ 1.80* (-6%)
Day 20
22.96 ±2.36
24.34 ± 1.40 (+6%)
22.78 + 2.46 (-1%)
20.01 + 2.35* (-13%)
Day 27
23.43 ±2.26
24.58 ± 1.37 (+5%)
22.75 + 1.78 (-3%)
20.47 + 1.95* (-13%)
Day 34
23.83 ±2.20
24.81 ± 1.37 (+4%)
22.86 + 1.68 (-4%)
20.71 + 1.85* (-13%)
Day 41
24.09 ±2.14
24.97±1.39 (+4%)
23.12+ 1.50 (-4%)
20.90 + 1.65* (-13%)
"Eastman Kodak (1992).
bADDs presented here were calculated using the following equation: Doseadd = dose x (days exposed + 7 days).
°Values expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean) + control mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (statistical test not
reported).
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Table B-6. Selected Clinical Chemistry Parameters in Male Albino CD Rats Exposed to
DGME by Gavage for 6 Weeks"
ADD (mg/kg-d)b
Endpoint
0 (control)
643
1,286
2,571
Number of animals
10
9
10
8
BUN (mg/dL)°
11.3 ± 1.6
12.6 ± 2.4 (+12%)
11.5 ± 1.4 (+2%)
13.9 ±2.6* (+23%)
"Eastman Kodak (1992).
bADDs presented here were calculated using the following equation: Doseadd = dose x (days exposed + 7 days).
°Values expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean) + control mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (statistical test not
reported).
BUN = blood urea nitrogen
Table B-7. Selected Absolute and Relative Organ Weights in Male Albino CD Rats
Exposed to DGME by Gavage for 6 Weeks"
Endpoint
ADD (mg/kg-d)b
0 (control)
643
1,286
2,571
Number of animals
10
9
10
8
Absolute organ weights (g)°
Liver
10.587+ 1.392
11.561 + 1.239 (+9%)
10.552 + 0.690 (0%)
10.139 + 0.793 (-4%)
Kidney
2.834 + 0.418
3.011 + 0.151 (+6%)
2.954 + 0.324 (+4%)
2.877 + 0.342 (+2%)
Heart
1.142 + 0.152
1.244 + 0.131 (+9%)
1.204 + 0.092 (+5%)
1.132 + 0.101 (-1%)
Testes
3.075 + 0.167
3.199 + 0.311 (+4%)
3.208 + 0.300 (+4%)
2.251 + 0.240* (-27%)
Brain
2.009 + 0.099
1.951 + 0.087 (-3%)
1.915+ 0.134 (-5%)
1.822 + 0.195* (-9%)
Spleen
0.673 + 0.132
0.701 + 0.062 (+4%)
0.685+ 0.137 (+2%)
0.559 + 0.065* (-17%)
Relative organ weights (g/100 g)c
Liver
2.802 + 0.179
3.031 + 0.307* (+8%)
3.003 + 0.124* (+7%)
3.104 + 0.163* (+11%)
Kidney
0.750 + 0.063
0.789 + 0.046 (+5%)
0.642 + 0.089* (-14%)
0.879 + 0.075* (+17%)
Heart
0.303 + 0.019
0.327 + 0.026 (+8%)
0.343 + 0.034* (+13%)
0.347 + 0.033* (+15%)
Testes
0.820 + 0.064
0.839 + 0.083 (+2%)
0.915 + 0.090* (+12%)
0.689 + 0.066* (-16%)
Brain
0.535 + 0.040
0.512 + 0.031 (-4%)
0.547 + 0.049 (+2%)
0.559 + 0.056 (+4%)
Spleen
0.179 + 0.027
0.186+ 0.017 (+4%)
0.195+ 0.037 (+9%)
0.171 + 0.020 (-4%)
"Eastman Kodak (1992).
bADDs presented here were calculated using the following equation: Doseadd = dose x (days exposed + 7 days).
°Values expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean) + control mean] x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (statistical test not
reported).
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Table B-8. Selected Histopathological Findings from Male Albino CD Rats Exposed to
DGME by Gavage for 6 Weeks3
ADD (mg/kg-d)b
Endpoint0
0 (control)
643
1,286
2,571
Testes
Atrophy, seminiferous tubules
0/10
NDr
0/10
6/10*
Epididymides
Degenerated spermatozoa
0/10
NDr
NDr
3/10
Hypospermia
0/10
NDr
NDr
2/10
Kidneys
Proximal convoluted tubules, hyaline droplet
10/10
10/10
10/10
9/10
degeneration
Proteinaceous casts
0/10
0/10
0/10
9/10*
"Eastman Kodak (1992).
bADDs presented here were calculated using the following equation: Doseadd = dose x (days exposed 7 days).
°Values expressed as number of animals affected/number of animals exposed.
* Statistically significantly different from controls at p< 0.05, as calculated for this review (Fisher's exact test).
NDr = not determined
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Table B-9. Selected Reproductive Parameters of Female CD-I Mice Exposed
to DGME by Gavage on GDs 7-14a
Endpoint
Exposure Group (mg/kg-d)
0
4,000
Number of timed-pregnant animals
50
50
Number of deaths
0
5
Number of confirmed pregnancies
32
36b
Number of mice producing viable litters
31
5
Number of stillborn litters
0
9
Number of mated animals with totally resorbed litters
1
18
Number of nonpregnant animals
17°
14d
Reproductive index6
0.97
0.14*
Pre-exposure body weight of time-pregnant animals (GD 7) (g)f
28.3 ±2.5
28.1 ±3.1 (-1%)
Maternal body weight of dams prior to delivering on GD 18 (g)f
48.6 ± 4.6; n = 31
39.4 ±4.1* (-19%); n= 14
Maternal body weight gain (GDs 7-18) (g)f
19.7 ± 3.7; n = 31
10.2 ±3.5* (-48%); n = 14
Maternal body weight of dams producing viable litters on
PND 3 (g)f
33.9 ± 3.9; n = 31
28.2 ± 1.5* (-17%); n = 14^
aBioassav Svs (1983a).
includes four dams that died during the dosing period.
°One animal in the control group was not accounted for after GD 18.
includes one dam that died during the dosing period.
"Defined as the ratio of the number of animals producing viable litters divided by the number of mice ever
pregnant.
fValues expressed as mean ± SD (% change compared with control); % change control = [(treatment
mean - control mean) control mean] x 100.
gMaternal body weight on PND 3 was not measured for one animal (litter died).
'Statistically significantly different from controls atp< 0.05, as reported by the study authors (reproductive index:
X2; body-weight data: Model I ANOVA).
Gd = gestation day; PND = postnatal day
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Table B-10. Selected Litter Data of Female CD-I Mice Exposed to DGME
by Gavage on GDs 7-14a
Endpoint
Exposure Group (mg/kg-d)
0
4,000
Number of viable litters
31
5
Pup viability
Live pups/litterb
10.1 ±2.8
3.2 ±2.2* (-68%)
Dead pups/litterb
0.1 ±0.4
0.6 ± 0.5 (+500%)
Adjusted % dead pups/litter0
0.9 ±0.9
3.4 ±2.7* (+248%)
Live pups/litter on PND 3b
10.1 ±2.8
1.3±1.3* (—87%); « = 4d
Adjusted % pup viability/litter (PNDs l-3)e
10.0 ±0.1
4.5 + 3.6* (-55%); « = 4d
Litter weight (g)b
PND 1
16.1 ±3.7
4.6+ 2.9* (-71%)
PND 3
20.3 ±4.3
2.5 + 1.7* (-88%); « = 3f
Body weight gain PND 1-3
4.2 ±1.1
-4.2 + 2.6* (-200%); « = 3f
Adjusted % change in litter weight PNDs l-3g
5.1 ± 0.7
-7.6 + 2.1* (-249%); « = 3f
aBioassav Svs (1983a).
bValues expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean)/control mean] x 100.
°Values expressed as mean ± SD, after V(r + 0.5) data transformation, where r = % deaths/litter.
dOne of the viable litters from the exposed group did not survive until PND 3.
e% pup viability = (number of live pups at PND 3 + number of live pups PND 1) x 100. Values expressed as
mean ± SD, after ~h data transformation, where r = % pup viability.
fOne available litter was not weighed on PND 3 (no further details provided).
g% change in litter weight = (PND 3 weight - PND 1 weight) + PND 1 weight x 100. Values expressed as
mean ± SD, after ~h data transformation, where r = % change in litter weight.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Model IANOVA).
PND = postnatal day
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Table B-ll. Selected Maternal and Litter Data in Female Sprague-Dawley Rats
Exposed to DGME by Gavage on GDs 7-16a
Endpoint
Exposure Group (mg/kg-d)
0
1,000
1,495
2,235
3,345
5,175
Number of dams
9
9
9
9
9
9
Number of deaths
0
0
0
0
0
2
Number of viable
litters per confirmed
pregnancy
9/9
8/8
4/4
8/8
3/9*
0/5*
Maternal body weight (g)b
GD 7
207 ± 14
216 ± 12
(+4%)
215 ± 14
(+4%)
211 ± 10
(+2%)
210 ± 15
(+1%)
208 ± 14
(0%)
GD 12
246 ± 17
251 ± 11
(+2%)
254 ± 15
(+3%)
247 ± 16
(0%)
240 ± 22
(-2%)
228 ± 36
("7%)
GD 16
275 ± 23
276 ± 16
(0%)
282 ± 17
(+3%)
278 ± 16
(1%)
261 ±23
(-5%)
244 ± 29*
("11%)
GD 21
337 ±34
327 ± 30
(-3%)
337 ±30
(0%)
325 ± 19
("4%)
279 ± 28*
(-17%)
239 ±23*
(-29%)
Adjusted maternal
body weight gain
GDs 6-21 (g)b c
77 ± 18
76 ±22
(-1%)
77 ± 17
(0%)
72 ± 10
(-6%)
70 ± 18
(-9%)
54 ± 19*
(-30%)
Food consumption (g)b
GDs 7-12
123 ± 18
119 ± 11
(-3%)
123 ± 12
(0%)
116 ± 11
(-6%)
96 ± 20*
(-22%)
79 ±21*
(-36%)
GDs 12-17
133 ±21
134 ± 13
(+1%)
134 ± 15
(+1%)
134 ± 13
(+1%)
120 ± 14
(-10%)
109 ± 14
(-18%)
GDs 17-21
107 ± 10
111 ± 14
(+4%)
114 ± 18
(+7%)
116 ±9
(+8%)
109 ± 14
(+2%)
92 ± 16
(-14%)
Live fetuses/litterb
Number
12.1 ±3.0
9.5 ±3.3
(-21%)
11.5 ±4.4
(-5%)
10.8 ± 1.7
("11%)
3.3 ±0.6*
(-73%)
0*
(-100%)
Percent
91.2 ± 11.9
90.8 ±7.9
89.7 ± 12.6
87.1 ±9.8
9.2 ± 13.8*
0*
Fetal weight (g)b
Male
4.0 ±0.6
3.8 ±0.8
(-5%)
3.6 ±0.6
(-10%)
3.5 ±0.8
(-13%)
2.3 ± 1.3*
(-43%)
NA
Female
3.8 ±0.5
3.5 ±0.8
(-8%)
3.3 ±0.7
(-13%)
3.2 ±0.6*
(-16%)
2.4 ±0.5*
(-37%)
NA
"Hardin etal. (1986).
bValues expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
°Body-weight gain GDs 6-21 minus gravid uterus weight.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (nonparametric
m-ranking procedures, with corrections for multiple comparisons to the control).
GD = gestation day; NA = not applicable (100% mortality)
40 Diethylene Glycol Monomethyl Ether
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Table B-12. Skeletal and Visceral Malformations and Variation in Litters of
Sprague-Dawley Rats Exposed to DGME by Gavage on GDs 7-16a
Endpoint
Exposure Group (mg/kg-d)
0
1,000
1,495
2,235
3,345
Skeletal examination
Number of litters (fetuses) examined
9(55)
8 (38)
4(23)
8 (42)
3(6)
Number of litters (fetuses) with
malformations15 [% fetuses affected]
1 (1) [3]
1 (2) [5]
2 (4) [13]
6* (13) [34]
1 (1) [17]
Number of litters (fetuses) with
variations [% fetuses affected]
6 (11) [18]
5 (12) [13]
4 (18) [80]
8 (32) [76]
3 (6) [100]
Reduced cranial ossifications
2 (2) [3]
3 (8) [23]
4* (13) [60]
6* (15) [36]
3* (5) [83]
Vertebrae
Misaligned
0
2 (2) [5]
1 (1) [8]
8* (15) [36]
3* (4) [67]
Reduced ossification
2 (2) [3]
1 (1) [4]
2(5) [31]
6* (15) [36]
3* (6) [100]
Total
2 (2) [3]
3 (3) [9]
2(5) [31]
8* (20) [48]
3* (6) [100]
Visceral examination
Number of litters (fetuses) examined
9(54)
8 (38)
4(23)
8 (44)
3(5)
Number of litters (fetuses) with
cardiovascular malformations0 [%
fetuses affected]
0
1 (1) [2]
0
4* (7) [17]
2 (3) [50]
Number of litters (fetuses) with
cardiovascular variations (missing
innominate) [% fetuses affected]
0
0
0
4* (6) [15]
0
aHardinet al. (1986).
bTotal malformations represents the sum of missing thoracic vertebrae, abnormal cervical arch, rudimentary cervical
ribs, missing ribs, wavy/fused ribs (unilateral and bilateral), and cleft sternebrae.
Total cardiovascular malformations represents the sum of double aortic arch, right aortic arch, right ductus arteriosus,
and ventricular septal defect.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test; the
litter was the statistical unit of comparison).
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Table B-13. Selected Maternal and Litter Data in Female Sprague-Dawley Rats Exposed to
DGME by Gavage on GDs 7-16a
Endpoint
Exposure Group (mg/kg-d)
0
720
2,165
Number of viable litters per confirmed pregnancy
22/22
21/21
21/23
Maternal body weight (g)b
Day 7
213 ±7
213 ±9(0%)
212 ±11 (0%)
Day 12
248 ± 10
251 ± 13 (+1%)
245 ± 13 (-1%)
Day 16
278 ± 14
279 ± 17 (0%)
273 ± 17 (-2%)
Day 21
332 ± 18
332 ± 24 (0%)
308 ± 29* (-7%)
Food consumption (g)b
Days 7-12
120 ± 13
122 ± 14 (+2%)
111 ± 13*(-8%)
Days 12-17
128 ± 14
127 ± 25 (-1%)
128 ± 12 (0%)
Days 17-21
105 ± 10
109 ± 12 (+4%)
106 ± 23 (+1%)
Live fetuses/litterb
Number
11.4 ±2.0
10.8 ± 2.8 (-5%)
7.4 ±3.9* (-35%)
Percent
90.7 ±8.8
90.5 ± 10.0
60.5 ±31.5*
Fetal weight (g)b
Male
4.6 ±0.8
4.5 ± 0.8 (-2%)
3.5 ±0.8* (-24%)
Female
4.4 ±0.7
4.2 ± 0.7 (-4.5%)
3.2 ±0.9* (-27%)
Gross malformations
Number of litters (fetuses) examined
22 (252)
21 (226)
21 (171)
Number of litters (fetuses) with malformations
[% fetuses affected]
l(l)c
[0.4]
0
5 (5)^
[3]
aHardinet al. (1986).
bValues expressed as mean ± SD (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
°Acaudia, imperforate anus.
dAcaudia, imperforate anus (four fetuses); gross edema (one fetus).
"Litters with gross malformations differed significantly across groups (x2 = 7.93, degrees of freedom = 2. p < 0.05),
but control and 2,165 mg/kg-day groups did not differ significantly by Fischer's exact test (p< 0.10), as reported by
the study authors.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (nonparametric
m-ranking procedures, with corrections for multiple comparisons to the control).
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Table B-14. Skeletal Malformations in Litters of Sprague-Dawley Rats Exposed to
DGME by Gavage on GDs 7-16a
Endpoint
Exposure Group (mg/kg-d)
0
720
2,165
Number of litter (fetuses) examined
22 (123)
21 (111)
20 (89)
Number of litters (fetuses) with malformations15 [% fetuses
affected]
2 (6) [4]
9* (15) [15]
16* (45) [51]
Ribs
Rudimentary cervical
1 (2) [2]
5 (9) [8]
11* (16) [18]
Wavy/fused: unilateral
0
0
3 (3) [3]
Bilateral
1 (4) [3]
4 (6) [6]
13* (32) [36]
Total
2 (6) [4]
9* (15) [15]
16* (43) [48]
Number of litters (fetuses) with variations [% fetuses
affected]
14 (24) [18]
15 (33) [30]
20* (82) [94]
Reduced cranial ossification
4 (6) [4]
10* (17) [16]
16* (51) [56]
Sternebrae
Reduced ossification
1 (1) [1]
1 (1) [1]
11* (22) [28]
Total0
9 (13) [10]
12(14) [13]
17* (40) [47]
Vertebrae
Reduced ossification
0
0
15* (44) [58]
Misaligned centra
0
2 (4) [4]
19* (61) [74]
Extra
1 (1) [1]
0
10* (15) [21]
Total
1 (1) [1]
2 (4) [4]
19* (68) [81]
Ribs
Thoraco-lumbar
8 (10) [7]
3 (3) [4]
15* (35) [42]
Totald
8 (10) [7]
3 (3) [4]
16* (38) [45]
Appendicular skeleton
Reduced ossification
1 (1) [1]
6* (13) [12]
15* (41) [53]
aHardinet al. (1986).
bTotal malformations represents the sum of abnormal thoracic arch, missing sacrococcygeal vertebrae, rudimentary
cervical ribs, and wavy/fused ribs (unilateral and bilateral).
Total sternebrae variations represents the sum of reduced ossification and misaligned sternebrae.
dTotal rib variations represents the sum of reduced ossification and thoraco-lumbar variations.
'Statistically significantly different from controls atp< 0.05, as reported by the study authors (Fisher's exact test; the
litter was the statistical unit of comparison).
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Table B-15. Visceral Malformations in Litters of Sprague-Dawley Rats Exposed to
DGME by Gavage on GDs 7-16a
Endpoint
Exposure Group (mg/kg-d)
0
720
2,165
Number of litters (fetuses) examined
22 (129)
21 (115)
21 (82)
Number of litters (fetuses) with malformations15 [% fetuses affected]
3 (3) [3]
4 (4) [3]
16* (37) [50]
Cardiovascular
Double aortic arch0
0
0
7* (9) [12]
Right aortic arch
0
1(1) [1]
6* (6) [10]
Ventricular septal defect
0
0
14* (27) [39]
Totald
0
1(1) [1]
15* (33) [46]
Number of litters (fetuses) with variations6 [% fetuses affected]
5 (7) [6]
10 (14) [17]
12* (19) [25]
Urinary
Dilated renal pelvis
2 (4) [3]
8* (11) [14]
12* (17) [23]
Totalf
5 (7) [6]
9 (13) [16]
12* (18) [24]
aHardin et al. (1986).
bTotal malformations represents the sum of cardiovascular (double aortic arch, right aortic arch, right ductus
arteriosis, and ventricular septal defect), brain (hydrocephalus), eye (folded retina, anophthalmia, and
microphthalmia), and urinary (hydroureter and hydronephrosis) malformations.
0 Ascending aorta bifurcated to form a vascular ring around the trachea and esophagus, then reformed as a single
descending aorta.
dTotal cardiovascular malformations represents the sum of double aortic arch, right aortic arch, right ductus
arteriosis, and ventricular septal defect.
eTotal variations represents the sum of cardiovascular (missing innominate) and urinary (dilated renal pelvis and
dilated ureter) variations.
fTotal urinary variations represents the sum of dilated renal pelvis and dilated ureter.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test;
the litter was the statistical unit of comparison).
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Table B-16. Selected Litter Data of Pregnant Wistar Rats Exposed to DGME by Gavage
on GDs 1-lT
Endpoint
Exposure Group (mg/kg-d)
0
125
250
500
1,000
2,000
3,000
4,000
Number of dams
6
5
4
4
5
6
6
5
Number of live
fetuses'3
14.7 ±0.5
14.0 ±0.6
(-5%)
14.3 ±0.9
(-3%)
13.8 ±0.8
(-6%)
12.8 ± 1.1
(-13%)
5.2 ± 1.3°
(-65%)
0*
(-100%)
0*
(-100%)
Incidence of dead or resorbed fetuses (%)
Early stage
2.2
6.7
3.3
3.5
7.9
44.0
96.7
100.0*
Late stage
0
0
1.7
1.8
8.0
21.1*
3.3
0
Fetal weight (g)b
Male
3.2 ±0.08
3.1 ±0.06
(-3%)
3.1 ±0.06
(-3%)
3.4 ±0.38
(+6%)
2.7 ±0.07
(-13%)
2.2 ±0.04*
(-31%)
NDr°
NDr
Female
3.0 ±0.09
2.8 ±0.10
(-7%)
3.0 ±0.04
(0%)
3.2 ±0.39
(+7%)
2.5 ±0.06
(-17%)
2.2 ± 0.11
(-27%)
NDr
NDr
Number of litters
(fetuses) examined
6(88)
5(70)
4(57)
4(55)
4(64)
6(31)
NDr
NDr
Number of litters
(fetuses) with
external
malformations'1
[% fetuses affected]
0
0
0
0
1 (1) P]
2 (3) [13]
NDr
NDr
Number of litters
(fetuses) with
external anomalies6
[% fetuses affected]
0
0
0
0
0
3 (5) [18]
NDr
NDr
aYamano et al. (1993).
bValues expressed as litter mean ± SE (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
°NDr = not determined; all embryos resorbed at these exposure levels.
dMalformations observed included omphalocele, anasarca, and anury.
"Anomaly observed was dorsum subcutaneous hematoma.
* Statistically significantly different from control (p < 0.05), as reported by the study authors (Dunnett's or
Scheffe's multiple comparison test; litter was statistical unit of comparison).
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Table B-17. Selected Effects on Pregnant Wistar Rats and Their Fetuses after
Exposure to DGME by Gavage on GDs 7-17a
Endpoint
Exposure Group (mg/kg-d)
0
200
600
1,800
Number of dams
14
14
14
14
Body weight (g)b
336 ±4.51
331 ±6.11 (-1%)
328 ± 6.23 (-2%)
317 ±4.69* (-6%)
Thymus weight (mg)b
228 ±7.32
208 ± 7.39 (-9%)
218 ± 11.45 (-4%)
181 ±8.02* (-21%)
Number of live fetuses/litterb
13.5 ±0.9
12.6 ± 1.0 (-7%)
12.9 ± 1.1 (-4%)
7.9 ±0.9* (-41%)
Percent dead or resorbed fetuses
Early stage
6.9
7.0
5.1
21.3*
Late stage
0
0
1.7
24.8*
Fetal weight (g)b
Male
3.3 ±0.17
2.9 ±0.14 (-12%)
2.6 ±0.12* (-21%)
2.1 ±0.06* (-36%)
Female
3.1 ±0.15
2.8 ±0.13 (-10%)
2.5 ±0.13* (-19%)
2.0 ± 0.05* (-35%)
aYamano et al. (1993).
bValues expressed as litter mean ± SE (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
* Statistically significantly different at p< 0.05), as reported by the study authors (Dunnett's or Scheffe's
multiple comparison test; litter was statistical unit of comparison).
Table B-18. External Malformations and Anomalies in Fetuses of Wistar Rats Exposed to
DGME by Gavage on GDs 7-17a
Endpoint
Exposure Group (mg/kg-d)
0
200
600
1,800
Number of litters examined
14
14
14
14
Number of litters (fetuses) examined
14(189)
14 (176)
14(181)
14(111)
Number of litters (fetuses) with
malformations'3 [% fetuses affected]
0
0
0
9* (12) [14.1]
Anasarca
0
0
0
7* (7) [8.7]
Anury
0
0
0
7* (8) [9.4]
Number of litters (fetuses) with
anomalies0 [% fetuses affected]
0
0
0
7* (15) [13.5]
Dorsum subcutaneous hematoma
0
0
0
7* (15) [13.5]
aYamano et al. (1993).
bMalformations observed included anasarca, anury, and peromelia.
0 Anomaly observed was dorsum subcutaneous hematoma.
* Statistically significantly different at p< 0.05), as reported by the study authors (statistical test not reported; litter
was the unit of comparison).
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Table B-19. Visceral Observations of Fetuses from Wistar Rat Dams Exposed to
DGME by Gavage on GDs 7-17a
Endpoint
Exposure Group (mg/kg-d)
0
200
600
1,800
Number of litters (fetuses) examined
14 (98)
14(91)
14 (93)
14 (59)
Number of litters (fetuses) with
visceral malformations15 [% fetuses
affected]
0
0
1 (1) [2.4]
9* (18) [28.0]
Right aortic arch
0
0
0
4* (5) [9.6]
Ventricular septal defect
0
0
1 (1) [2.4]
6* (13) [18.4]
% of litters (fetuses) with visceral
variations0 [% fetuses affected]
3 (4) [3.5]
5 (5) [5.0]
13* (32) [35.3]
14* (59) [100.0]
Thymic remnant in the neck
Unilateral
1 (1) [0.7]
2 (2) [2.0]
11* (20) [20.6]
5 (8) [11.1]
Bilateral
0
0
1 (2) [4.8]
14* (51) [88.9]
Total
1 (1) [0.7]
2 (2) [2.0]
12* (22) [25.4]
14* (59) [100.0]
Dilated renal pelvis
Unilateral
2 (3) [2.8]
2(2) [2.1]
6(10) [11.4]
11* (19) [36.4]
Bilateral
0
0
1 (1) [0.9]
6* (11) [16.4]
Total
2 (3) [2.8]
2(2) [2.1]
6 (11) [12.3]
13* (30) [52.8]
aYamano et al. (1993).
bMalformations observed included double aortic arch, right aortic arch, ventricular septal defect, and agenesis of
ductus arteriosus.
Variations observed included thymic remnant in the neck (unilateral and bilateral), dilated renal pelvis (unilateral
and bilateral), and kinked ureter.
* Statistically significantly different at p< 0.05), as reported by the study authors (statistical test not reported; litter
was the unit of comparison).
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Table B-20. Skeletal Observations of Fetuses from Wistar Rat Dams Exposed to
DGME by Gavage on GDs 7-17a
Endpoint
Exposure Group (mg/kg-d)
0
200
600
1,800
Number of litters (fetuses) examined
14(91)
14 (85)
14 (88)
14 (52)
Number of litters (fetuses) with
skeletal malformations'3 [% fetuses
affected]
0
0
0
5* (5) [13.9]
Agenesis of sacro-coccygeal
vertebrae
0
0
0
4* (4) [10.4]
Number of litters (fetuses) with
skeletal variations [% fetuses
affected]0
3 (3) [3.2]
1 (1) [1.2]
5 (6) [5.8]
14* (49) [96.2]
Splitting of vertebral bodies
Thoracic
0
0
0
14* (33) [69.9]
Lumbar
0
1 (1) [1.2]
1 (1) [1.0]
13* (38) [78.4]
Incomplete ossification of
occipitale
1 (1) [0.9]
0
2 (3) [2.8]
4* (44) [85.5]
Degree of ossificationd
Number of sternebrae ossified
4.2 ±0.22
3.6 ±0.19 (-14%)
2.8 ± 0.24* (-33%)
0.3 ±0.11* (-93%)
Number of proximal and middle phalanges ossified
Fore limb
3.6 ±0.34
3.2 ±0.22 (-11%)
2.9 ±0.17 (-19%)
1.6 ±0.12* (-56%)
Hind limb
3.9 ±0.04
3.8 ±0.08 (-3%)
3.5 ±0.11 (-10%)
2.0 ±0.19* (-49%)
Number of ossification centers of vertebrae
Thoracic
12.6 ±0.09
12.2 ± 0.08 (-3%)
11.7 ±0.15* (-7%)
9.0 ± 0.24* (-29%)
Lumbar
6.0
6.0 (0%)
6.0 (0%)
5.3 ±0.18* (-12%)
Sacral and caudal
6.7 ±0.22
5.9 ±0.19 (-12%)
4.2 ± 0.29* (-37%)
1.1 ±0.21* (-84%)
aYamano et al. (1993).
bMalformations observed included agenesis of digitorum pedis and manus and agenesis of sacro-coccygeal
vertebrae.
°Variations observed included cervical ribs, rudimentary lumbar ribs, splitting of vertebral bodies (thoracic and
lumbar), and incomplete ossification of occipitale.
dValues expressed as litter mean ± SE (% change compared with control); % change from control = [(treatment
mean - control mean) control mean] x 100.
* Statistically significantly different compared with controls at p < 0.05), as reported by the study authors
(dichotomous data statistical test not reported; continuous data: Dunnett's or Scheffe's multiple comparison test;
litter was statistical unit of comparison).
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Table B-21. Postnatal Observations of Offspring from Wistar Rat Dams Exposed to
DGME by Gavage on GDs 7-17a
Endpoint
Exposure Group (mg/kg-d)
0
200
600
1,800
Number of dams
8
8
8
8
Duration of gestation (days)b
22.1 ±0.13
22.4 ±0.18 (+1%)
22.5 ±0.19 (+2%)
23.8 ±0.25* (+8%)
Number of live pups/litterb
12.5 ±0.96
12.6 ± 0.60 (+1%)
11.6 ± 1.18 (-7%)
4.6 ± 0.82* (-63%)
Viability at PND 4°
92
94.1
62.4
5.4*
Viability at PND 21d
100
98.4
100
100
Number of litters (fetuses) examined
8(100)
8 (101)
8(93)
8(37)
Number of litters (fetuses) with
external malformations6 [% fetuses
affected]
0
1 (1) [0.9]
2 (2) [3.0]
1(1) [3.1]
aYamano et al. (1993).
bValues expressed as litter mean ± SE (% change compared with control); % change control = [(treatment
mean - control mean)/control mean] x 100.
°(Number of offspring on PND 4 number of offspring on PND 0) x 100.
d(Number of offspring on PND 21 number of offspring on PND 4) x 100.
"Malformations observed included anury.
* Statistically significantly different from controls at p< 0.05), as reported by the study authors (Dunnett's or
Scheffe's multiple comparison test; litter was statistical unit of comparison).
PND = postnatal day
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR DICHOTOMOUS DATA
The BMD modeling of dichotomous developmental toxicity data was conducted with the
U.S. EPA's BMDS (Version 2.5). For these data, all of the dichotomous models (i.e., Gamma,
Multistage, Logistic, Log-logistic, Probit, Log-probit, and Weibull models) available within the
software were fit using a BMR of 10% extra risk first. Adequacy of model fit was judged based
on the x2 goodness-of-fit p-value (p > 0.1), magnitude of scaled residuals in the vicinity of the
BMR, and visual inspection of the model fit. Among all models providing adequate fit, the
lowest BMDL was selected if the BMDLs estimated from different models varied greater than
three-fold; otherwise, the BMDL from the model with the lowest AIC was selected as a potential
POD from which to derive a p-RfD. Once the final model was selected, the same data set was fit
with the final model with a BMR of 5% extra risk to estimate BMDLos. The tables in
Appendix C present the results for the final model with BMR of 5% and results with BMRs of
10% extra risk for comparison purpose.
MODELING PROCEDURE FOR CONTINUOUS DATA
The BMD modeling of continuous data was conducted with the U.S. EPA's BMDS
(Version 2.5). For these data, all continuous models available within the software were fit using
a default BMR of 1 SD relative risk. For changes in adult body weight, a BMR of 10% change
relative to the control mean was also used. However, for changes in fetal body weight, a BMR
of 5% change relative to the control mean was used. An adequate fit was judged based on the
goodness-of-fit p-v alue (p > 0.1), magnitude of the scaled residuals in the vicinity of the BMR,
and visual inspection of the model fit. In addition to these three criteria forjudging adequacy of
model fit, a determination was made as to whether the variance across dose groups was constant.
If a constant variance model was deemed appropriate based on the statistical test provided in
BMDS (i.e., Test 2), the final BMD results were estimated from a constant variance model. If
the test for homogeneity of variance was rejected (p < 0.1), the model was run again while
modeling the variance as a power function of the mean to account for this nonconstant variance.
If this nonconstant variance model did not adequately fit the variance data (i.e., Test 3;/? < 0.1),
the data set was considered unsuitable for BMD modeling. Among all models providing
adequate fit, the lowest BMDL was selected if the BMDLs estimated from different models
varied greater than three-fold; otherwise, the BMDL from the model with the lowest AIC was
selected as a potential POD from which to derive a p-RfD.
Data sets for the most sensitive developmental endpoints observed in the coprincipal
studies of rats exposed orally to DGME during gestation (Yamano et al.. 1993; Hardin et al..
1986) were selected to determine potential PODs for the p-RfD, using BMD analysis. Data for
the endpoints are presented in Table 7. Several models provided adequate fit to the data.
BMDLs for models providing adequate fit were sufficiently close (differed by
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Table C-l. Modeling Results for Incidence Data for Number of Litters with Reduced
Cranial Ossification from Sprague-Dawley Rats Exposed to DGME by Gavage on
GDs 7-16a
Model
DF
x2
X2 Goodness-of-Fit
/>-Valucb
Scaled
Residuals0
AIC
BMDio
(mg/kg-d)
BMDLio
(mg/kg-d)
Gammad
0
0
NA
0.00
75.94
184.22
108.00
Logistic
1
0.56
0.46
-0.43
74.50
317.42
227.64
LogLogistic0
0
0
NA
0.00
75.94
252.76
58.25
LogProbit1
1
0.01
0.92
-0.02
73.952
294.35
191.51
Multistage (1-degree)'
1
0.01
0.93
0.02
73.950
164.11
107.95
Multistage (2-degree)f
0
0
NA
0.00
75.94
173.42
108.00
Probit
1
0.55
0.46
-0.41
74.50
311.58
231.94
Weibulld
0
0
NA
0.00
75.94
180.95
108.00
BMDos
(mg/kg-d)
BMDLos
(mg/kg-d)
Multistage (l-degree)ef
1
0.01
0.93
0.02
73.95
79.89
52.55
"Hardin et al. (1986)
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals for dose group near BMD.
dPower restricted to >1.
"Slope restricted to >1.
fBetas restricted to >0.
NA = not applicable
51
Diethylene Glycol Monomethyl Ether
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Multistage Model with BMR of 5% Extra Risk for the BMD and 0 95 Lower Confidence Limit for the BMDL
Multistage
0 8
0.6
0.4
0 -BMDL (BMD
500
1000
1500
2000
dose
12:18 08/11 2014
Figure C-l. Incidence of reduced cranial ossification in fetal rats for dams exposed to DGME
by gavage on GDs 7-16.
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File:
C:/BMDS250/Data/Diethyleneglycolmonomethylether/Hardin/cranial_oss/mst_cranial_oss_multi1.(d)
gnuplot Plotting File:
C:/BMDS250/Data/Diethyleneglycolmonomethylether/Hardin/cranial_oss/mst_cranial_oss_multi1.pit
Mon Aug if 12:18:17 2014
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 500
52 Diethylene Glycol Monomethyl Ether
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Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.173867
Beta(1) = 0.000652942
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background 1 -0.58
Beta(1) -0.58 1
Parameter Estimates
Variable
Background
Beta(1)
Estimate
0.180071
0.000642014
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
- Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-34.9714
-34.975
-43.5968
73 . 95
# Param's Deviance Test d.f.
3
2 0.00723248 1
1 17.2509 2
P-value
0.9322
0.0001795
Dose
Est. Prob.
goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
720.0000
2165.0000
ChiA2
0 .01
0.1801
0.4836
0.7958
d.f.
3 . 962
10.155
15.915
4 .000
10.000
16.000
22.000
21.000
20.000
0 . 021
-0.068
0 .047
P-value
0.9323
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0 . 05
Extra risk
0 . 95
7 9. 8944
52.5523
140.161
Taken together, (52.5523, 140.161) is a 90% two-sided confidence interval for the BMD
53
Diethylene Glycol Monomethyl Ether
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For number of litters with dilated renal pelvis from S-D rats, all models provided
adequate fit to the data. BMDLs for models providing adequate fit were judged to be sufficiently
close (differed by -Valueb
Scaled
Residuals0
AIC
BMDio
(mg/kg-d)
BMDLio
(mg/kg-d)
Gammad
1
0.52
0.47
-0.19
74.51
274.09
175.15
Logistic
1
2.05
0.15
1.09
76.08
546.91
393.28
LogLogistic®
1
0.1
0.75
-0.05
74.09
196.17
105.81
LogProbit1
1
1.47
0.23
0.93
75.42
466.22
304.73
Multistage (1-degree)6
1
0.52
0.47
-0.19
74.51
274.08
175.15
Multistage (2-degree)6
1
0.52
0.47
-0.19
74.51
274.08
175.15
Probit
1
1.91
0.17
1.08
75.93
517.85
378.99
Weibulld
1
0.52
0.47
-0.19
74.51
274.08
175.15
BMDos
(mg/kg-d)
BMDLos
(mg/kg-d)
LogLogistic6
1
0.1
0.75
-0.05
74.09
92.92
50.12
"Hardin et al. (1986).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals for dose group near BMD.
dPower restricted to >1.
"Slope restricted to >1.
54
Diethylene Glycol Monomethyl Ether
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Log-Logistic Model, with BMR of 5% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the B
Log-Logistic
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
I3MDL
BMD
0
500
1000
1500
2000
dose
12:29 08/11 2014
Figure C-2. Incidence of dilated renal pelvis in fetal rats for dams exposed to DGME by
gavage on GDs 7-16.
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/BMDS250/Data/Diethyleneglycolmonomethylether/Hardin/renal_pelvis_dilation/lnl_renal_pelvis_dil
ation_Lnl-BMR10-Restrict.(d)
gnuplot Plotting File:
C:/BMDS250/Data/Diethyleneglycolmonomethylether/Hardin/renal_pelvis_dilation/lnl_renal_pelvis_dil
ation_Lnl-BMR10-Restrict.pit
Mon Aug 11 12:29:47 2014
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 500
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
55 Diethylene Glycol Monomethyl Ether
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User has chosen the log transformed model
Default Initial Parameter Values
background = 0.0909091
intercept = -7.42199
slope = 1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -slope
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
background intercept
background 1 -0.44
intercept -0.44 1
Parameter Estimates
Variable
background
intercept
slope
Estimate
0.0938427
-7.4762
1
Std. Err.
- Indicates that this value is not calculated.
Analysis of Deviance Table
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.9982
-35.0468
-41.1835
# Param's Deviance Test d.f.
3
2 0.097356 1
1 12.3706 2
P-value
0.755
0.002059
AIC:
74 . 0937
goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0.0938
2 . 065
2 .000
22
-0.047
720.0000
0.3563
7.483
8 .000
21
0.236
2165.0000
0.5930
12.452
12.000
21
-0.201
Chi A2
0.10
d.f.
P-value
0.7541
Benchmark Dose Computation
Specified effect = 0.05
Risk Type = Extra risk
Confidence level = 0.95
BMD = 92.9219
BMDL = 50.1218
56
Diethylene Glycol Monomethyl Ether
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For data on thymus remnants in the neck in fetuses from Wistar rat dams, all models
(except for the 1-degree multistage) provided adequate fit to the data. BMDLs for models
providing adequate fit were sufficiently close (differed by 1.
"Slope restricted to >1.
fBetas restricted to >0.
57
Diethylene Glycol Monomethyl Ether
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Logistic Model, with BMR of 5% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
1
0.8
o>
it=
<
c
o
0.6
0.4
0.2
0
Logistic
BMDL BMD
0 200 400 600 800 1000 1200 1400 1600 1800
dose
12:51 08/11 2014
Figure C-3. Incidence of thymic remnant in the neck in fetal rats for dams exposed to DGME
by gavage on GDs 7-17.
BMBS Meetel ten
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/BMDS25O/Data/Diethyleneglycolmonomethylether/Yamano/thymic_remnant_neck/log_thymicremnant_Log-
BMR05.(d)
gnuplot Plotting File:
G:/BMDS250/Data/Diethyleneglycolmonomethylether/Yamano/thymic_remnant_neck/log_thymicremnant_Log-
BMR05.pit
Mon Aug 11 12:51:21 2014
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 500
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
58 Diethylene Glycol Monomethyl Ether
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09-29-2015
background = 0 Specified
intercept = -1.68894
slope = 0.00304839
Asymptotic Correlation Matrix of Parameter Estimates
intercept
slope
The model parameter(s) -background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept
1
-0.83
slope
-0.83
1
Parameter Estimates
Variable
intercept
slope
Model
Full model
Fitted model
Reduced model
Estimate
-3.07755
0.00793681
Std. Err.
0.839219
0.00206455
Analysis of Deviance Table
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
-4.72239 -1.43271
0.00389037 0.0119833
Log(likelihood) # Param'
-15.0857 4
-15.2854 2
-38.7805 1
Deviance Test d.f.
P-value
0.399343
47.3896
0.819
<.0001
AIC: 34.5708
goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0440
0 . 617
1.000
14
0.499
200.0000
0.1839
2 . 575
2 .000
14
-0.396
600.0000
0.8435
11.809
12.000
14
0.140
1800.0000
1.0000
14.000
14.000
14
0 .014
Chi^2 = 0.43 d.f. = 2 P-value = 0.8080
Benchmark Dose Computation
Specified effect = 0.05
Risk Type = Extra risk
Confidence level = 0.95
BMD = 99.0554
BMDL = 55.4101
59
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