United States
Environmental Protection
1=1 m m Agency
EPA/690/R-14/016F
Final
9-10-2014
Provisional Peer-Reviewed Toxicity Values for
Triethylene Glycol
(CASRN 112-27-6)
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
J. Phillip Kaiser, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Suryanarayana V. Vulimiri, BVSc, PhD, DABT
National Center for Environmental Assessment, Washington, DC
Zheng (Jenny) Li, PhD, DABT
National Center for Environmental Assessment, Washington, DC
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).
l
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iii
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 4
HUMAN STUDIES 13
Oral Exposures 13
Inhalation Exposures 13
ANIMAL STUDIES 13
Oral Exposures 13
Inhalation Exposures 23
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 25
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 25
Metabolism/Toxicokinetic Studies 26
Mode-of-Action/Mechanistic Studies 26
Immunotoxicity 26
Neurotoxicity 26
DERIVATION 01 PROVISIONAL VALUES 26
DERIVATION OF ORAL REFERENCE DOSES 28
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 28
Derivation of Chronic Provisional RfD (Chronic p-RfD) 32
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 33
Derivation of Chronic Provisional RfC (Chronic p-RfC) 33
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 33
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 34
Derivation of Provisional Oral Slope Factor (p-OSF) 34
Derivation of Provisional Inhalation Unit Risk (p-IUR) 34
APPENDIX A. SCREENING PROVISIONAL VALUES 35
APPENDIX B. DATA TABLES 36
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 38
APPENDIX E. REFERENCES 46
li
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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
POD[adj]
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
FEV1
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
111
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
TRIETHYLENE GLYCOL (CASRN 112-27-6)
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 toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
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 (http://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.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. 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.
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
Triethylene glycol
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INTRODUCTION
Triethylene glycol (TEG) is a liquid glycol that has a high boiling point and a very low
vapor pressure (HSDB. 2007). It is primarily used as an active ingredient in air sanitizers and
hospital disinfectants. Also, it is used as an inert ingredient in agricultural pesticide formulations
when a high boiling point and low volatility are important considerations (U.S. HP A. 2005). Its
properties are similar to those of diethylene glycol (DEG), but TEG has a higher boiling point,
viscosity, and specific gravity. Its uses, as indicated above, were approved by the EPA to be
eligible for registration under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
due to its low toxicity by the oral, dermal, and inhalation routes of exposure (U.S. HP A. 2005).
TEG is also approved by the U.S. Food and Drug Administration (FDA) as a preservative for
food packaging adhesives (21 CFR 175.105) and as a plasticizer in cellophane (21 CFR
177.1200) (U.S. HP A. 2005). The empirical formula for TEG is C6H14O4 (see Figure 1). A table
of physicochemical properties for TEG is provided below (see Table 1).
Figure 1. Triethylene Glycol Structure
Table 1. Physicochemical Properties of Triethylene Glycol (CASRN 112-27-6)a
Property (unit)
Value
Boiling point (°C)
285
Melting point (°C)
-7
Density (g/cm3)
1.1274 at 15°C/4°C
Vapor pressure (mm Hg at 25 °C)
1.32 x 10 3 (estimate)
pH (unitless)
ND
Solubility in water (g/100 mL at 25°C)
Miscible
Relative vapor density (air =1)
5.2b
Molecular weight (g/mol)
150.17
"HSDB (2007).
bNIQSH (1996).
ND = no data.
A summary of available toxicity values for TEG from U.S. EPA and other
agencies/organizations is provided in Table 2.
2
Triethylene glycol
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Table 2. Summary of Available Toxicity Values for Triethylene Glycol (CASRN 112-27-6)
Source/Parameter"
Value
(Applicability)
Notes
Reference
Date Accessed
Noncancer
ACGIH
NV
NA
ACGIH (2013)
NA
ATSDR
NV
NA
ATSDR (2013)
NA
Cal/EPA
NV
NA
Cal/EPA (2013)
3-26-2014b
NIOSH
NV
Values are available for other
countries but not the United
States. MAK = 1,000 mg/m3;
Peak limitation category: 11(2);
Pregnancy risk group: C
NIOSH (2010)
NA
OSHA
NV
NA
OSHA (2011):
OSHA (2006)
NA
IRIS
NV
NA
U.S. EPA
3-26-2014
Drinking water
NV
NA
U.S. EPA (2011a)
NA
HEAST
NV
NA
U.S. EPA (20lib)
NA
CARA HEEP
NV
NA
U.S. EPA (1994)
NA
WHO
NV
NA
WHO
3-26-2014
Cancer
IRIS
NV
NA
U.S. EPA
3-26-2014
HEAST
NV
NA
U.S. EPA (20lib)
NA
IARC
NV
NA
IARC (2013)
NA
NTP
NV
NA
NTP (2011)
NA
Cal/EPA
NV
NA
Cal/EPA (2014a.
2011)
NA
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities; HEAST = Health Effects Assessment Summary Tables; HEEP = Health and
Environmental Effects Profile; 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.
bThe Cal/EPA Office of Environmental Health Hazard Assessment (OEHHA) Toxicity Criteria Database
(http ://oehha. ca. gov/tcdb/index. asp) was also reviewed and found to contain no information on Methylene glycol.
MAK = maximum allowable concentration; NA = not applicable; NV = not available.
3
Triethylene glycol
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Literature searches were conducted on sources published from 1900 through
February 2014 for studies relevant to the derivation of provisional toxicity values for triethylene
glycol, CASRN 112-27-6. The following databases were searched by chemical name,
synonyms, or CASRN: ACGIH, ANEUPL, AT SDR, BIOSIS, Cal/EPA, CCRIS, CDAT,
ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX,
HAPAB, HERO, HMTC, HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed,
NIOSH, NTIS, NTP, OSHA, OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology
subset), RISKLINE, RTECS, TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA
HEEP, U.S. EPA OW, U.S. EPA's Declassified CBI database, and U.S. EPA
TSCATS/TSCATS2. The following databases were searched for relevant health information:
ACGIH, AT SDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA
OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide an overview of the relevant databases for TEG and include all
potentially relevant repeat-dose short-term-, subchronic-, and chronic-duration studies. Principal
studies are identified. Reference can be made to details provided in Tables 3A and 3B. The
phrase "statistical significance," used throughout the document, indicates ap-value of <0.05
unless otherwise specified.
4
Triethylene glycol
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-day)a
Acute0
ND
Short-termd
ND
Long-term6
ND
Chronicf
ND
2. Inhalation (mg/m3)a
Acute0
ND
Short-termd
Number and sexes
of subjects
evaluated, as well
as exposure
duration, are
unclear from the
study
0, 3-13
No exposure-related effects
13
DUB
NDr
Hamburger et al.
(1945)
PR
Number and sexes
of subjects
evaluated are
unclear from the
study, 3.5 weeks
0,4.4-9.1
No exposure-related effects
9.1
DUB
NDr
Puck et al.
(1945)
PR
Long-term0
326-336/0,
whole-body vapor
inhalation,
~2 months
o,
Concentrations
were greater
than or less than
2.5
No exposure-related effects
2.5
DUB
NDr
NMRU (1952)
PR
5
Triethylene glycol
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Long-term6
15-72 male and
female infants,
whole-body vapor
inhalation,
30-41 days
Not reported
No exposure-related effects
NDr
DUB
NDr
Krugman and
Ward (195 D
PR
1,000/0,
whole-body vapor
inhalation, 6 weeks
0, 1-10
No exposure-related effects
10
DUB
NDr
Bigg et al.
(1945)
PR
16/16, whole-body
vapor inhalation,
19 weeks
0, 1.8-3.3
No exposure-related effects
3.3
DUB
NDr
Harris and
Stokes (1945)
PR
Chronicf
ND
Animal
1. Oral (mg/kg-day)a
Short-term
20/20, F344 rat,
diet, 7 days/week,
14 days
M: 0, 1,132,
2,311, 5,9168
F: 0, 1,177,
2,411,6,209s
No treatment-related effects
6,209
DUB
NDr
Van Miller and
Ballantvne
(2001);
BtishvRun
(1989)
PR
8/8, CD-I mouse,
drinking water,
7 days/week,
14 days
0, 1,750, 4,375,
8,750, 13,125,
17,5008
Mortality, decreased body weight,
dehydration, and lethargy at
>8,750 mg/kg-day
4,375
DUB
8,750 (FEL)
NIP (1984)
NPR
Subchronic
5/group, sex
unspecified, mature
albino rat, drinking
water, 7 days/week,
30 days
0, 8,404, 16,958
(Adjusted)
Mortality at >8,404 mg/kg-day
NDr
DUB
8,404 (FEL)
Lauter and Vrla
(1940)
PR
6
Triethylene glycol
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Subchronic
5/group, sex
unspecified, young
albino rat, drinking
water, 7 days/week,
30 days
0,5,103,8,404
(Adjusted)
Weight loss, behavioral changes,
and mortality at >8,404 mg/kg-day
5,103
DUB
8,404 (FEL)
Lauter and Vrla
(1940)
PR
5/group, sex
unspecified, albino
rat, gavage,
7 days/week,
30 days
5.637, 10147,
11,274, 22,548
(Adjusted)
Overt signs of toxicity (hair loss
and diarrhea) at
>11,274 mg/kg-day
10147
DUB
11,274
Lauter and Vrla
(1940)
PR
20-30/20-30, F344
rat, diet, 90 days
M: 0, 748,
1,522, 3,8498
F: 0, 848, 1,699,
4,3608
No treatment-related effects
4,360
DUB
NDr
Van Miller and
Ballantvne
(2001); Union
Carbide (1990a)
PR
Chronic
12/0, Osborne-
Mendel rat, diet,
7 days/week,
2 years
0, 700, 1,401,
2,802
(Adjusted)
No treatment-related effects
2,802
DUB
NDr
Fitzhueh and
Nelson (1946)
PR
7-24/group, strain,
sex unspecified, rat,
drinking water,
7 days/week,
13 months
0, 158, 361,
2,999
(Adjusted)
No treatment-related effects
2,999
DUB
NDr
Robertson et al.
(1947)
PR
2-8, sex
unspecified, rhesus
macaque monkey,
diet, 7 days/week,
3-14 months
282, 564 (initial
measurements
used as control)
(Adjusted)
No treatment-related effects
564
DUB
NDr
Robertson et al.
(1947)
PR
7
Triethylene glycol
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Developmental
0/10 pregnant
female, CD-SD rat,
gavage, GDs 6-15
0, 563, 1,126,
2,815, 5,630,
11,260
Maternal: no treatment-related
effects
Developmental: decreased fetal
body weight at 11,260 mg/kg-day
Maternal: 11,260
Developmental:
5,630
NA
Maternal: NDr
Developmental:
11,260
Ballatttvnc and
Snellines (2005)
PR
(dose-range-
finding study)
0/25 pregnant
female, CD rat,
gavage, GDs 6-15
0, 1,126, 5,630,
11,260
Maternal: no treatment-related
effects
Developmental: decreased fetal
body weight per litter and
increased incidence of bilobed
thoracic centrum; both at
11,260 mg/kg-day
Maternal: 11,260
Developmental:
5,630
DUB
Maternal: NDr
Developmental:
11,260
Ballatttv nc and
Snellines (2005):
PR
Union Carbide
(1991);
individual litter
data are not
available for
incidence of
bilobed thoracic
centrum to run a
nested model in
BMDS
0/8 pregnant, CD-I
mouse, gavage,
GDs 6-15
0, 563, 1,126,
2,815, 5,630,
11,260
Maternal: no treatment-related
effects
Developmental: decreased fetal
body weight per litter at
>5,630 mg/kg-day
Maternal: 11,260
Developmental:
2,815
NA
Maternal: NDr
Developmental:
5,630
Ballatttv nc and
Snellines (2005)
PR
(dose-range-
findiim): Union
Carbide (1990a.
b)
8
Triethylene glycol
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Developmental
0/30 pregnant,
CD-I mouse,
gavage, GDs 6-15
0,563, 5,630,
11,260
Maternal: no treatment-related
effects
Developmental: decreased fetal
body weight per litter and
increased incidence of skeletal
variations; both at
>5,630 mg/kg-day
Maternal:
11,260
Developmental:
563
506 for
delayed
ossification of
the
supraoccipital
bone
Maternal: NDr
Developmental:
5,630
Ballantvne and
Snellintrs
(2005): Union
Carbide
(1990a): Union
Carbide (1990b)
PS, PR
0/50 pregnant, CD-
1 mouse, gavage,
GDs 7-14
0, 11,270
Maternal: none reported
Developmental: decreased fetal
weight at 11,270 mg/kg-day
Maternal: NDr
Developmental:
NDr
DUB
Maternal: NDr
Developmental:
11,270
Hardin et al.
(1987): Schuler
et al. (1986):
Schuler et al.
(1984)
PR
Reproductive
20/20 treated,
40/40 control, CD-I
mouse, drinking
water (breeding
protocol), 98 days
(cohabitation
period); final litters
and dams received
TEG in drinking
water for an
additional 21 days,
2 generations
0, 590, 3,300,
6,780
(Adjusted)
No treatment-related effects
6,780
DUB
NDr
Lamb (1997):
Bossert et al.
(1992):
Momssev et al.
(1989): NTP
(1984)
PR
9
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
2. Inhalation (mg/m3)a
Short-term
10/10, S-D rat,
whole-body aerosol
inhalation,
6 hours/day, 9 times
over 11 days
0, 101,411,987
Clinical chemistry changes
indicative of liver toxicity
accompanied by an increase in
liver weights greater than 10% at
411 mg/m3; mortality at
987 mg/m3.
101
DUB
411
Ballatttvne et al.
(2006)
PR
10/10, S-D rat,
nose-only aerosol
inhalation,
6 hours/day, 9 times
over 11 days
0,21, 106,212
No exposure-related effects
212
DUB
NDr
Ballatttv ne et al.
(2006)
PR
Subchronic
Number
unspecified, MZF,
strain unspecified,
rat, 24 hours/day,
41 days
Supersaturated
triethylene
glycol vapor
(-449 mg/m3)
No exposure-related effects.
-449
DUB
NDr
Maassen (1953)
PR
Chronic
24/12, strain
unspecified, rat,
24 hours/day,
6-13 months
Supersaturated
triethylene
glycol vapor (0,
~4 mg/m3)
No exposure-related effects.
~4
DUB
NDr
Robertson et al.
(1947)
PR
17/group, 8/control,
sex unspecified,
rhesus macaque
monkey,
24 hours/day,
13 months
Supersaturated
triethylene
glycol vapor
(0, ~4 mg/m3)
Decreased body weight; mortality
observed in both control and
exposed groups
NDr
DUB
NDr
Robertson et al.
(1947)
PR
10
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Table 3A. Summary of Potentially Relevant Data for Triethylene Glycol (CASRN 112-27-6)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL3
LOAEL3
Reference
(Comments)
Notesb
Chronic
8/group, 8/control,
sex unspecified,
rhesus macaque
monkey,
24 hours/day,
10 months
65-75%
saturated
triethylene
glycol vapor
(-2-3 mg/m3)
No exposure-related effects
~3
DUB
NDr
Robertson et al.
(19471
PR
Developmental
ND
Reproductive
ND
aDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an 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. All long-term exposure values (4 weeks and longer) are converted from a discontinuous to a continuous
exposure. Values from animal developmental studies are not adjusted to a continuous exposure.
bNotes: IRIS = utilized by IRIS, date of last update; PS = principal study; PR = peer reviewed; NPR = not peer reviewed; NA = not applicable.
cAcute = exposure for <24 hours (U.S. EPA. 20021.
dShort-term = repeated exposure for >24 hours <30 days (U.S. EPA. 20021.
eLong-term = repeated exposure for >30 days <10% life span (based on 70-year typical lifespan) (U.S. EPA. 20021.
Chronic = repeated exposure for >10% lifespan (U.S. EPA. 20021.
gDaily doses as reported by study authors.
DUB = data unamenable to BMDS; FEL = frank effect level; GD = Gestational Day; NA = not applicable; ND = no data; NDr = not determined; S-D = Sprague-Dawley.
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood gas partition coefficient.
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Table 3B. Summary of Potentially Relevant Cancer Data for Triethylene Glycol (CASRN 112-27-6)
Number of Male/Female
Species, Study Type, and
BMDL/
Reference
Category
Duration
Dosimetry3
Critical Effects
NOAELa
BMCLa
LOAELa
(Comments)
Notesb
Human
1. Oral (mg/kg-day)
Carcinogenicity
ND
2. Inhalation (mg/m3)
Carcinogenicity
ND
Animal
1. Oral3
Carcinogenicity
12/0, Osborne-Mendel rat,
HED: 0, 205, 410,
No carcinogenic effects
NA
DUB
NA
Fitzhueh and
PR
diet, 7 days/week, 2 years
820
Nelson (1946)
(Adjusted: 0, 700,
(small sample
1,401, 2,802)
size, only one
sex studied,
limited
analysis of
tissues and
organs)
2. Inhalation"
Carcinogenicity
ND
aDosimetry: Values are converted to a human equivalent dose (HED in mg/kg-day) for oral carcinogenic effects..
bPR = peer reviewed.
DUB = data unamenable to BMDS; NA = not applicable; ND = no data.
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HUMAN STUDIES
Oral Exposures
No studies have been identified.
Inhalation Exposures
In six human studies (NMRU. 1952; Krugman and Ward. 1951; Bigg et al.. 1945;
Hamburger et al.. 1945; Harris and Stokes. 1945; Puck et al.. 1945). patients in hospital wards
and workers in dormitories were continuously exposed to TEG via inhalation. The purpose of
these studies was to test the ability of TEG in controlling or reducing bacterial infections and
thus, these are not comprehensive toxicity studies. Across the studies, TEG concentrations
varied from 1 to 13 mg/m3 and subjects were continuously exposed for various lengths of time.
The studies by Bigg et al. (1945) and Hamburger et al. (1945) reported that no toxicological
effects were observed, but the extent and timing of the examinations is not apparent from the
studies. The studies by Puck et al. (1945). Naval Medical Research (NMRU. 1952). Harris and
Stokes (1945). and Krugman and Ward (1951) did not report any observation of toxicological
effects. For most of these studies, it is also unclear if healthy/uninfected people were exposed to
TEG. Due to the lack of information for these studies, they are not considered as principal
studies to derive a subchronic or chronic p-RfC.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure to TEG in animals have been evaluated in two short-term-
duration studies (Van Miller and Ballantvne. 2001; NTP. 1984). four sub chronic-duration studies
(Van Miller and Ballantvne. 2001; Lauter and Vrla. 1940). three chronic-duration studies
(Robertson et al.. 1947; Fitzhugh and Nelson. 1946). five developmental toxicity studies
(Ballantvne and Snettings. 2005; Schuler et al.. 1984). and one reproductive toxicity study
(Bossert et al.. 1992). Fitzhugh and Nelson (1946) also evaluated TEG for carcinogenicity.
Short-Term-Duration Studies
Van Miller and Ballantvne (2001) and BushyRun (1989)
F344 rats (20/sex/treatment group) were fed 0, 10,000, 20,000, or 50,000 ppm TEG
(purity >99%) in the diet for 14 days (Van Miller and Ballantvne. 2001). An unpublished report
of this study is also available (BushyRun. 1989). These dietary doses were calculated by the
study authors to be equivalent to 1,132, 2,311, and 5,916 mg/kg-day for males and 1,177, 2,411,
and 6,209 mg/kg-day for females (values as presented in the abstract, which were slightly
different than those presented in the tables from the study report; differences may be due to
rounding). Analytical measurements performed by the study authors indicated that TEG was
stable in the diet for at least 14 days in open glass feed jars and for at least 21 days in closed
polyethylene containers at ambient temperatures. All rats were observed daily for clinical signs
of toxicity, pharmacological effects, and mortality. Animals were weighed on Days 0, 7, and 14,
and food consumption was measured over Days 0-7 and 7-14. After 14 days, the study authors
placed 10 animals/sex/group in metabolism cages, and urine samples were collected over a
24-hour interval. Blood samples were collected from these animals and examined for
hematology and serum chemistry. The remaining 10 animals/sex/group were sacrificed, and
blood was collected for serum chemistry and complete necropsies were performed. Organ
weights for the liver, kidneys, heart, spleen, brain, adrenal glands, testes, and ovaries were
recorded. The following organs were examined histopathologically: brain, liver, kidneys,
pancreas, testes, ovaries, stomach, duodenum, jejunum, ileum, cecum, colon, urinary bladder,
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and sciatic nerve. Any lesions observed were described and recorded. Appropriate statistical
evaluations were conducted, including Levene's test for homogeneity of variance, pooled
variance Mest, analysis of variance (ANOVA), Kruskal-Wallis test, and Fisher's Exact test.
The study authors did not observe any deaths or treatment-related clinical signs in males
or females at any dose level. There were no treatment-related findings in body weight, food
consumption, hematology, serum chemistry, organ weights, or gross and microscopic pathology.
Urinalysis showed a statistically significant increase in urine volume (39-59%) and decrease in
urine pH in high-dose males and females. A statistically significant increase in urine volume
(22%) was also observed in males in the mid-dose group. Because these urinalysis findings were
not associated with any changes in serum chemistry or renal histopathology, the study authors
suggested that they were mostly related to the renal excretion of TEG or its metabolites
following absorption of large amounts of dietary TEG. Based on the lack of any adverse effects
in either sex, the NOAEL is 6,209 mg/kg-day and no LOAEL is determined.
NTP (1984)
NTP (1984) conducted a 14-day dose-range-finding study (unpublished) to aid the dose
selection process for a reproductive toxicity study of TEG (Bossert et al.. 1992) (included in
Table 3 and discussed below). CD-I mice (8/sex/treatment group) were administered 0, 1.0, 2.5,
5.0, 7.5, or 10.0%) TEG (97% pure) in the drinking water for 14 days. The study authors stated
that these were approximately equivalent to daily doses of 0, 1,750, 4,375, 8,750, 13,125, and
17,500 mg/kg-day, respectively. Animals were housed four per cage by sex. Clinical signs,
morbidity, and mortality were monitored twice daily. Body weight and water consumption were
measured weekly. At the end of Week 2, all test animals were sacrificed with no further data
collection. Statistical analyses were carried out using two-way ANOVA and the %2 test.
Treatment-related deaths occurred at doses >8,750 mg/kg-day and included two males at
8,750 mg/kg-day, one female at 13,125 mg/kg-day, and one female at 17,500 mg/kg-day.
Clinical signs observed in the animals from these treatment groups included dehydration,
lethargy, and piloerection. Mean final body weight and body-weight gain were also reduced by
>10%) in animals treated with >8,750 mg/kg-day. A LOAEL could not be determined because
the next highest dose (8,750 mg/kg-day) resulted not only in a reduction in body weight, but also
dehydration and death in both sexes. Therefore, 8,750 mg/kg-day is considered a frank effect
level (FEL). The NOAEL is 4,375 mg/kg-day.
Subchronic-Duration Studies
t auter and Vrla (1940): Drinking Water Study
In the first part of this study, the subchronic effects of TEG were investigated in young
and mature albino rats. The study authors administered TEG (purity unknown; stated to be
commercial grade) at concentrations of 5% or 10%> by volume (5.6%> or 11.3% by weight) in
drinking water to groups of five mature albino rats (sex unspecified) for 30 days. The estimated
daily doses are 8,404 and 16,958 mg/kg-day, respectively. Because body weight and water
consumption data over the course of the study were not provided, these doses are calculated for
this PPRTV assessment using an average body weight (0.2039 kg) and water consumption
(0.0306 kg/day) given for male and female rats for all rat strains by U.S. EPA (1988). The
control group consisted of 5 rats that were administered regular water; however, the control
animals appear to be younger rats based on reported final body weights. Treatment was followed
by a 15-day observation period. Additional information regarding experimental design was not
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provided by the study authors. All animals in the low-dose group showed signs of severe
toxicity, and three of the animals in this group died during the study. The two remaining animals
surviving to study completion recovered during the 15-day observation period. All animals in
the high-dose group showed signs of toxicity and died by Day 12. Based on mortality observed
at both doses tested in the study, an FEL of 8,404 mg/kg-day is established, and no NOAEL or
LOAEL is identified for adult rats.
In the second part of this study, the study authors administered TEG at concentrations of
3% or 5% by volume (3.4% or 5.6% by weight) in drinking water to groups of five 3-week-old
albino rats (sex unspecified) for 30 days. The study authors used the same control rats as
described above. The estimated daily doses are calculated for this PPRTV assessment as 5,103
and 8,404 mg/kg-day, respectively, based on average body weight and drinking water
consumption as discussed above (U.S. EPA. 1988). As with the adult rat study, treatment was
followed by a 15-day observation period. The study authors provided no further information on
the study design or data collected. All animals in the low-dose group survived to study
completion without signs of toxicity. The study authors noted that the young rats in the low-dose
group drank more than the adult rats. Treatment-related clinical signs were observed in high-
dose animals during the first 2 weeks of exposure. Body-weight gains were lagging during the
first 2 weeks, but improved afterwards. The study authors also stated that animal behavior
improved after the first 2 weeks of exposure. One animal in the high-dose group died on Day 15.
Based on the results from both parts of the study, the study authors concluded that exposure to
TEG at 5% in drinking water caused higher mortality in adult rats than in young rats. In young
rats, the NOAEL is 5,103 mg/kg-day, but no LOAEL can be determined because the next highest
dose of 8,404 mg/kg-day is an FEL.
t auter and Vrla (1940): (lavage Study
Four groups of five albino rats (sex and age unspecified, ranging in weight from
100-210 grams) received daily doses of TEG (stated to be commercial grade) via gavage for
30 consecutive days. No control group was reported. The dosing groups received 0.1 mL
TEG/kg body weight (bw)-day as a 5% aqueous solution, 3.0 mL TEG/kg BW-day as a
30% solution, 10.0 mL, or 20.0 mL TEG/kg BW-day of undiluted TEG. The corresponding
daily doses are calculated for this PPRTV assessment as 5.637, 101.47, 11,274, and
22,548 mg/kg-day, respectively. Treatment was followed by a 15-day observation period. Body
weights were measured during the treatment and posttreatment periods. This is the only
experimental design information provided by the study authors; however, the results section
indicates that there were more details related to study design that were not provided (such as
numbers of litters being delivered). No signs of toxicity or changes in body-weight gain were
observed in animals at the two lower doses (5.637 and 101.47 mg/kg-day). Animals exposed to
11,274 mg/kg-day showed signs of toxicity (hair loss and diarrhea) and decreased weight gain
during the first week; however, body-weight gain increased during the second week. All five of
the high-dose animals died within 3 days. The NOAEL is 101.47 mg/kg-day and the LOAEL is
11,274 mg/kg-day based on the overt signs of toxicity.
Van Miller andBallantyne (2001) and Union Carbide (1990a)
As presented in an unpublished report by Union Carbide (1990a). F344 rats were fed 0,
10,000, 20,000, or 50,000 ppm TEG (purity >99.45%) mixed in the diet for 90 days. Based on
these dietary concentrations, the study authors calculated daily TEG intakes of 0, 748, 1,522, and
3,849 mg/kg-day for males and 0, 848, 1,699, and 4,360 mg/kg-day for females, respectively.
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The sample sizes were 20/sex/group for the 10,000- and 20,000-ppm groups and 30/sex/group
for the control and 50,000-ppm groups. At the end of treatment, 20 rats/sex/treatment group
were sacrificed. Ten control and 10 high-dose rats/sex were retained for a 6-week recovery
period. Analytical measurements performed by the study authors indicated that TEG was stable
and homogeneous in the diet. The animals were observed daily for signs of toxicity. The study
authors performed detailed physical examinations once per week. Ophthalmoscopic
examinations were performed before treatment and at the end of the dosing period. Body weight
and food consumption were recorded weekly. Blood samples were collected on Day 30, at the
end of treatment, and at the end of the recovery period for hematology (hemoglobin
concentration, erythrocyte count, hematocrit, mean corpuscular volume [MCV], mean
corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelet
count, and total and differential leukocyte counts) and serum chemistry (glucose; urea nitrogen;
albumin globulin; total protein creatinine; total, conjugated, and unconjugated bilirubin;
phosphorus; sodium; potassium; calcium; chloride; aspartate and alanine aminotransferase;
alkaline phosphatase; y-glutamyl transferase; creatine kinase; lactate; and sorbitol
dehydrogenases). Urine samples were collected over a 24-hour period from 10 rats/sex in the
control and high-dose groups during Weeks 12-19. Urinalysis parameters included urine
volume, pH, specific gravity, color, microscopy, blood, protein, ketones, glucose, bilirubin, and
urobilinogen. At sacrifice, the following organs were removed and examined
histopathologically: brain, liver, kidneys, pancreas, testes, ovaries, stomach, duodenum, jejunum,
ileum, cecum, colon, urinary bladder, and sciatic nerve. Any observed lesions also were
examined. The study authors recorded organ weights for the liver, kidneys, heart, spleen, brain,
adrenal glands, testes, and ovaries. Appropriate statistical evaluations were conducted and
included Levene's test for homogeneity of variance, pooled variance Mest, ANOVA,
Kruskal-Wallis test, and Fisher's Exact test.
No deaths were observed. There were no treatment-related findings in clinical
observations, ophthalmic examination, clinical chemistry, necropsy, or histology. Although
some statistically significant decreases in body weights were noted in high-dose males and
females, they were not biologically significant (i.e., <10%). There were slight, but statistically
significant changes in hematology in high-dose males at the end of the treatment period. The
study authors postulated that these effects were probably due to a minor hemodilution following
the absorption of large amounts of TEG and its metabolites. Urinalysis showed a dose-related
decrease in urine pH in males at all dose levels and in females at the mid and high dose, reaching
statistical significance in both sexes at the high dose. A dose-related increase in urine volume
was also observed in males at the end of the dosing period, but this increase was statistically
significant only at the high dose. An increase in urine volume was observed in high-dose
females, but the increase was not statistically significant. Because the urinalysis findings were
not associated with any changes in serum chemistry or renal histopathology, the study authors
suggested that the findings were mostly related to the renal excretion of TEG or its metabolites
following absorption of large amounts of dietary TEG. Although some statistically significant
changes in relative organ weights occurred in high-dose males and females, none of the changes
are considered biologically significant (i.e., were <10% or not dose related). No gross or
microscopic lesions were observed. The study authors considered the NOAEL to be
1,522 mg/kg-day for males and 1,699 mg/kg-day for females; although they stated that there was
no specific organ or tissue toxicity in the study. However, the effects observed in the high-dose
animals were minimal and are not considered biologically significant. Therefore, the NOAEL is
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the highest dose tested (3,849 mg/kg-day for males and 4,360 mg/kg-day for females) with no
LOAEL identified.
Chronic-Duration Studies
Fitzhush and Nelson (1946)
Male Osborne-Mendel rats (12/group) were administered 0, 1, 2, or 4% TEG (purity not
reported) in the diet for 2 years. The equivalent daily doses are 0, 700, 1,401, and
2,802 mg/kg-day, respectively. These doses are calculated for this PPRTV assessment using an
average body weight (0.514 kg) and food consumption (0.036 kg/day) given for Osborne-Mendel
rats by U.S. EPA (1988). because although body weights and food consumption were observed
weekly, they were not reported over the course of the study. Eleven organs/tissues (lung, heart,
liver, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, and testis) were
routinely examined histologically; others were examined only in some animals. No data was
presented for the control group. No treatment-related effects were observed with respect to
mortality, food consumption, body-weight gain, and gross or microscopic lesions. As no effects
occurred at any dose tested, the NOAEL is 2,802 mg/kg-day, and no LOAEL is identified.
Robertson et al (1947): Rat Study
Rats of unspecified sex and strain were administered TEG ("purified" material with no
further information) in drinking water at daily concentrations of 0 (9 rats), 0.14 (7 rats),
0.32 (8 rats), or 2.66 (24 rats) mL/kg BW-day for 13 months, which are estimated to be
equivalent to 158, 361, and 2,999 mg/kg-day, respectively. Blood samples were collected at the
end of the exposure period and examined for total and differential leukocyte counts and red
blood cell counts. Body weights were measured monthly. Urine samples were examined
microscopically (specifics not provided). The study authors performed three sacrifices during
the study period (at 3, 8, and 13 months) and the animals were subjected to necropsy. No
statistical analysis was performed. No treatment-related effects were observed. Based on these
results, the NOAEL is 2,999 mg/kg-day, and no LOAEL is identified.
Robertson et al. (1947): Monkey Study
In this study, the authors administered TEG orally in eggnog at daily concentrations of
0.25 or 0.5 mL/kg body weight-day (approximately 50-100 times the quantity an animal could
absorb by breathing air saturated with glycol) to 10 rhesus macaque monkeys (sex unspecified).
It appears that there was no specific control group, but measurements taken in these animals
prior to treatment were used as the control values. The sample sizes were two animals for the
0.25 mL/kg-day group (treated for 12 months) and eight animals for the 0.5 mL/kg-day group
(two monkeys treated for each of the following durations: 3 months, 3.5 months, 12 months, and
14 months). The equivalent daily doses are calculated for this PPRTV assessment as 282 and
564 mg/kg-day, respectively. Body weight was measured weekly. Hematology (white blood
cell counts both total and differential, red blood cell counts, and hemoglobin) and urinalysis
(specifics not provided) were conducted at study initiation and at the end of treatment. At the
end of each treatment period, the animals were necropsied and selected tissues/organs were
examined histologically (full details were not provided, but the lungs, liver, kidneys, spleen,
bone marrow, stomach, and intestines were specified). No statistical analysis was performed.
There were no treatment-related findings in any of the animals. Based on these results, a
NOAEL of 564 mg/kg-day is identified and no LOAEL is determined.
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Developmental Studies
Battantym and Smlttnss (2005): Rat Developmental Dose-Range-Finding Study
The study authors administered undiluted TEG (purity >99%) at doses of 0, 563, 1,126,
2,815, 5,630, or 11,260 mg/kg-day to groups of 10 pregnant CD Sprague-Dawley female rats by
gavage on Gestational Days (GD) 6-15. The study authors examined the animals daily for
mortality and signs of toxicity and recorded body weights on GDs 0, 6, 9, 12, 15, 18, and 21.
Water consumption was measured over sequential 3-day intervals during gestation. The animals
were sacrificed on GD 21 and maternal liver, kidney, and gravid uterine weights were recorded.
The study authors also recorded the number of corpora lutea and implants. The maternal kidneys
were removed and a histological examination was performed. Fetuses were weighed, sexed, and
examined externally for malformations and variations. Appropriate statistical analyses were
conducted, including Mest, Levene's test, Kruskal-Wallis, ANOVA, Mann-Whitney U-test, and
Fisher's Exact test. The intended use of this study was as a dose-range-finding study only, and it
is not considered an acceptable developmental toxicity study because visceral and skeletal
examinations were not conducted.
There were no deaths in the control or treatment groups. There was a statistically
significant decrease in maternal body-weight gain observed in the 11,260 mg/kg-day-dose group
on GDs 6-9 (89.4% of controls). A decrease in maternal body-weight gain was also observed on
GDs 6-15 (80.3%) of controls) and GDs 0-21 (96.9%> controls), but these decreases did not reach
statistical significance. An increase in water consumption during treatment also was observed in
the two highest dose groups. No effects of treatment on maternal liver, kidney, or gravid uterine
weights were observed at any dose level. There were also no treatment-related effects on the
number of corpora lutea and implants. In the high-dose group, fetal body weights were reduced
in males (96.6%>) and females (94.5%>) compared to the control group (no indication of statistical
significance and the quantitative data were not available). Based on these findings, exposure
levels of 1,126, 5,630, and 11,260 mg/kg-day were selected for the definitive study. The
maternal NOAEL is 11,260 mg/kg-day, and no maternal LOAEL is identified based on the lack
of any biologically significant treatment-related effects. Based on decreased fetal body weight,
the developmental NOAEL is 5,630 mg/kg-day and the developmental LOAEL is
11,260 mg/kg-day.
Battantym and Snellinss (2005) and Union Carbide (1991): Rat Developmental Study
Pregnant female CD rats (25/treatment group) were dosed daily by gavage with undiluted
TEG (purity >99%) over GDs 6-15 at 0, 1,126, 5,630, or 11,260 mg/kg-day (administered as
1.0, 5.0, and 10.0 mL/kg-day, respectively). Control animals received 10.0 mL/kg-day distilled
water. The original report for this study is also available (Union Carbide. 1991). The study
authors examined the animals daily for mortality and signs of toxicity. Body weight was
recorded on GDs 0, 6, 9, 12, 15, 18, and 21. Water and food consumption were measured over
sequential 3-day intervals during gestation. Pregnant rats were sacrificed on GD 21 and
necropsied. Examinations of the gravid uterus, ovaries, cervix, vagina, and abdominal and
thoracic cavities were performed. The following parameters were evaluated: liver weight,
kidney weight, gravid uterine weight, number of ovarian corpora lutea, and status of implantation
sites (i.e., resorptions, dead fetuses, and live fetuses). Maternal kidneys were examined
histologically. Fetuses were counted, weighed, sexed, and examined for external, soft tissue,
visceral (including craniofacial), and skeletal malformations and variations. Appropriate
statistical analyses were conducted, including Mest, Levene's test, Kruskal-Wallis, ANOVA,
Mann-Whitney U-test, and Fisher's Exact test.
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There were no treatment-related mortalities or clinical signs of toxicity during the study.
However, one pregnant dam in the 5,630 mg/kg-day group died on GD 11 of unknown causes.
Pregnancy rates were comparable among all dose groups (92, 96, 80, and 92% for the control,
low-, mid-, and high-dose groups, respectively). Statistically significant decreases in body
weights were observed in high-dose dams from GDs 9-18 and in the mid-dose dams on GD 18.
However, the differences were less than 10% and likely related to decreased food consumption.
Statistically significant increases in water consumption were observed in dams in both the mid-
(20%) and high-dose (40%) groups during treatment. There were no treatment-related effects on
maternal liver or gravid uterine weights. After correcting for the gravid uterine weight, there
was a slight (7%), but statistically significant, decrease in maternal body weight that was
accompanied by a slight (7.6%), but statistically significant, increase in relative kidney weight;
however, neither of the two effects is considered biologically significant (i.e., were <10%). In
addition, no treatment-related gross pathology or histopathology was observed in the kidneys.
Based on these observations, the study authors stated that the increases in water consumption and
relative kidney weight seen in the high-dose group were not associated with nephrotoxicity, and
these effects were likely associated with the renal excretion of TEG metabolites.
There were no treatment-related effects observed on the number of corpora lutea, pre-
and postimplantation loss, live fetuses/litter, or sex ratio. Fetal body weights per litter were
biologically significantly reduced in males and females at 11,260 mg/kg-day compared to the
controls (see Table B-l). For all doses tested, there were no treatment-related increases in the
incidence of any individual malformations, visceral or skeletal malformations, or total
malformations by fetuses or by litter. There were no increases in the incidence of external or
visceral variations. However, there was an increase in the incidence of bilobed thoracic centrum
that was statistically significant at 11,260 mg/kg-day (see Table B-2). The maternal NOAEL is
11,260 mg/kg-day, and no LOAEL is identified. The developmental NOAEL is
5,630 mg/kg-day with a LOAEL of 11,260 mg/kg-day based on reduced fetal body weight per
litter that was accompanied by an increase in the incidence of bilobed thoracic centrum.
Ballantyne and Snellings (2005), Union Carbide (1990a), and Union Carbide (1990b):
Mouse Developmental Dose-Ranging-Finding Study
Pregnant CD-I mice (8/treatment group) were administered undiluted TEG
(purity >99%) at doses of 0, 563, 1,126, 2,815, 5,630, or 11,260 mg/kg-day via gavage on
GDs 6-15. The study authors examined the animals daily for mortality and signs of toxicity and
recorded body weights on GDs 0, 6, 9, 12, 15, and 18. Water consumption was measured over
sequential 3-day intervals during gestation. The animals were sacrificed on GD 18, and maternal
liver, kidney, and gravid uterine weights were recorded. The study authors also recorded the
number of corpora lutea and implants. The maternal kidneys were removed and histological
examination was performed. Fetuses were weighed, sexed, and examined externally for
malformations and variations. Appropriate statistical analyses were conducted, including Mest,
Levene's test, Kruskal-Wallis, ANOVA, Mann-Whitney U-test, and Fisher's Exact test. This is
not considered an acceptable developmental toxicity study because visceral and skeletal
examinations were not conducted. However, its intended use was as a dose-range-finding study
only.
No deaths were reported. A significant increase in water consumption was observed at
11,260 mg/kg-day for GDs 6-9, 9-12, 12-15, and 6-15. Results for maternal body weights and
gravid uterine weights were not reported. Absolute and relative kidney weights were stated to be
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increased in the high-dose group, but the data were not biologically significant. Fetal body
weights were biologically significantly reduced at 11,260 mg/kg-day for males (94.8% of
controls) and females (93.9% of controls), and at 5,630 mg/kg-day for females (94.5% of
controls). Increased incidence of clubbed limbs was observed in six fetuses across the three
highest dose groups. Two fetuses from two litters at 2,815 and 5,630 mg/kg-day and a single
litter at 11,260 mg/kg-day had clubbed limbs. However, incidence of clubbed limbs was actually
decreased compared to controls in the definitive developmental study in mice reported by
Ballantvne and Snettings (2005) (see summary below). This observation suggests that the
incidence of clubbed limbs in mice from the dose-range-finding study may not be treatment
related, and thus was not considered as a potential critical effect and POD for derivation of a
subchronic or chronic provisional RfD (p-RfD).
Based on the findings in this study, dosages of 563, 5,630, and 11,260 mg/kg-day were
selected for the definitive study. Based on no observed effects, a maternal NOAEL of
11,260 mg/kg-day is identified, but a LOAEL could not be determined. Based on biologically
significantly decreased fetal body weight in female fetuses, the developmental NOAEL is
2,815 mg/kg-day and the LOAEL is 5,630 mg/kg-day.
Ballantvne and Snellings (2005), Union Carbide (1990a), and Union Carbide (1990b):
Mouse Developmental Study
The definitive mouse study reported in Ballantvne and Snettings (2005) is considered
the principal study for derivation of the subchronic and chronic p-RfDs. Timed-pregnant
CD-I mice (30/treatment group) were administered undiluted TEG (purity >99%) at doses of 0,
563, 5,630, or 11,260 mg/kg-day (0.5, 5.0, and 10.0 mL/kg-day) by gavage on GDs 6-15.
Control animals received 10.0 mL/kg-day distilled water. The original report for this study is
also available (Union Carbide. 1990a. b). The study authors examined the animals daily for
mortality and signs of toxicity. Body weight was recorded on GDs 0, 6, 9, 12, 15, and 18. Water
and food consumption were measured over sequential 3-day intervals during gestation. Pregnant
animals were sacrificed on GD 18 and necropsied. Examinations of the gravid uterus, ovaries,
cervix, vagina, and abdominal and thoracic cavities were performed. The following parameters
were evaluated: liver weight, kidney weight, gravid uterine weight, number of ovarian corpora
lutea, and status of implantation sites (i.e., resorptions, dead fetuses, and live fetuses). Maternal
kidneys were examined histologically. Fetuses were counted, weighed, sexed, and examined for
external, soft tissue, visceral (including craniofacial), and skeletal malformations and variations.
Appropriate statistical analyses were conducted, including Mest, Levene's test, Kruskal-Wallis,
ANOVA, Mann-Whitney U-test, and Fisher's Exact test. The study authors did not observe any
deaths in dams. One dam delivered early. Treatment-related clinical signs (hypoactivity and
audible/rapid breathing) were observed in two high-dose dams. There were no treatment-related
effects on pregnancy rate: 93.3% (controls), 96.7% (563 mg/kg-day), 93.3% (5,630 mg/kg-day),
and 90% (11,260 mg/kg-day). There were no treatment-related effects on maternal body
weights, body-weight gains, and food and water consumptions observed at any dose level. In
addition, no treatment-related effects were observed on maternal terminal body weight or body
weight corrected for gravid uterus weight. However, there was a dose-related decrease in gravid
uterine weight that was not statistically significant (see Table B-3). This was likely related to
decreased fetal weight. Dams in the high-dose group also exhibited slight (7%), statistically
significant but not biologically significant increases in relative kidney weights. There were no
treatment-related effects on maternal liver weight (absolute and relative) or absolute kidney
weight. The histology of the kidneys was normal.
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No treatment-related effects on gestational parameters, including corpora lutea, pre- and
postimplantation loss, live fetuses/litter, or sex ratio, were observed at any dose tested.
Dose-related, statistically significant decreases in fetal body weights per litter were observed at
5,630 and 11,260 mg/kg-day (see Table B-3). At all doses tested, there were no treatment-
related increases in the incidence of visceral or skeletal malformations or in the incidence of total
malformations by fetus or by litter. There were no increases in the incidence of external or
visceral variations. However, several individual fetal skeletal variations were seen that attained
statistical significance (see Table B-4). Mouse fetuses had delayed ossification in the cervical
region, and hind-limb proximal phalanges, as well as reduced caudal segments at
11,260 mg/kg-day. Delayed ossification also was observed in the supraoccipital and frontal
bones that was statistically significant for both effects at 5,630 mg/kg-day. The study authors
considered these patterns of delayed ossification consistent with reduced fetal body weights. The
maternal NOAEL is 11,260 mg/kg-day, and no maternal LOAEL is identified. Based on delayed
ossification of the supraoccipital and frontal bones and decreased fetal body weight, the
developmental NOAEL is 563 mg/kg-day and the developmental LOAEL is 5,630 mg/kg-day.
Schiller et al. (1984) and Hardin et al (1987)
Pregnant CD-I mice (50/treatment group) were administered TEG (99% pure) via gavage
in distilled water on GDs 7-14 at concentrations of 0 (distilled water; vehicle control) or
10 mL/kg body weight (Schuler et al.. 1984). The dose was calculated by the study authors to be
equivalent to 1 1,270 mg/kg-day. The proprietary data for this study also were available (Schuler
et al.. 1986). Schuler et al. (1986) and Schuler et al. (1984) evaluated TEG as part of a screening
assay for 15 glycol ethers; these data also were published by Hardin et al. (1987) as part of an
experimental design to test 60 chemicals in an abbreviated test to determine which chemicals
needed more conventional testing. All animals were observed twice daily during treatment, once
daily on GDs 14-17 (Hardin et al.. 1987). and then twice daily for signs of delivery. Maternal
body weights were recorded on GDs 7, 17, and 18 and on Postnatal Day (PND) 3. Signs of
toxicity were recorded daily. Dams were allowed to give birth, and the numbers of live born and
stillborn pups were recorded as soon as possible (within 12 hours). Total litter weights were
recorded on PNDs 1 and 3. Six reproductive endpoints were evaluated: pup survival in utero
(percentage of live litters/pregnant survivors); pup perinatal and postnatal survival (number of
live pups/litter, number of dead pups/litter, and pup survival to PND 3); and pup body weight
(weight at birth and at PND 3). Females that failed to deliver a litter by the presumed GD 22
were sacrificed and uteri were examined. Statistical evaluations were done using ANOVA and
Student's Mest. This is not considered an appropriate developmental toxicity study because
systematic examinations of pups (living or dead) for malformations were not performed.
Because the above study aimed to screen chemicals for their potential to cause
reproductive toxicity in pregnant females, the bioassay was designed to employ doses of the test
chemicals that cause 10-20% maternal mortality. The study authors stated that this was
necessary to get confidence in the evaluation's findings, indicating that clear maternal toxicity
does not mean that reproductive toxicity will follow. For several chemicals including TEG, the
LD io could not be determined, and therefore, 10 mL/kg undiluted compound was established as
the maximum practicable dose. This 11,270 mg/kg-day dose of TEG produced 4% maternal
mortality (2/50), but 100% of the pregnant survivors produced viable litters (36/36; the study
report is unclear as to what happened to the other 12 animals). A statistically and biologically
significant decrease in mean pup birth weight (94% of controls) was observed at the
administered dose of TEG. There were no treatment-related effects on the number of alive or
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dead pups per litter or postnatal pup survival. No maternal NOAEL/LOAEL could be
determined due to the lack of effects measured and/or reported for the dams. No developmental
NOAEL could be determined and the developmental LOAEL is 11,270 mg/kg-day based on
decreased fetal body weight.
Reproductive Studies
Lamb (1997), Bossert et al. (1992), Morrissey et al. (1989), andNTP (1984)
Bossert et al. (1992) is the published version of the original study reported by NTP
(1984). It does not provide sufficient details on study design, but the study also has been
described by Morrissey et al. (1989) and a summary has been provided by Lamb (1997). The
Bossert et al. (1992) study was part of a series of studies evaluating glycol ethers and congeners
for structure-activity correlations using a reproductive assessment by continuous breeding
(RACB) study design.
Male and female CD-I mice were administered TEG (97% pure) in drinking water at
concentrations of 0, 0.3, 1.5, or 3% beginning 1 week prior to mating. Animals were randomly
grouped as mating pairs, cohabited, and treated at the same concentration continuously for
98 days (14 weeks). The doses were calculated by the study authors to be equivalent to 0, 590,
3,300, and 6,780 mg/kg-day (Bossert et al.. 1992). Doses selected were based upon the results of
the 14-day dose-range-finding study described earlier (NTP. 1984). The control group consisted
of 40 breeding pairs, and each TEG-treated group consisted of 20 breeding pairs. The
F0 females were allowed to deliver during the cohabitation period, and data collected during the
F0 cohabitation included the litter interval; number, sex, and weight of pups per litter; number of
litters per breeding pair; and the PND 0 dam body weight. Pups produced during the
F0 cohabitation period were evaluated (number alive and dead, sexed, and total litter weight) on
PND 0 (within 12 hours of birth) and then were euthanized. After the 98-day cohabitation, the
breeding pairs were separated. Dams were treated for an additional 21 days while delivering the
last litter. These last litters from the control and high-dose groups were used as the second
generation and received TEG in drinking water for a 21 day period (Morrissey et al.. 1989).
Parental F0 body weights and water consumption were measured for Weeks 1, 2, 5, 9, 13, and
18.
The final litters from the F0 control and high-dose TEG dams were allowed to grow until
74 ± 10 days of age while being maintained on the same TEG dietary concentrations to assess
the second-generation fertility. These F1 offspring were then mated to nonsiblings from the
same treatment group. F1 mice were weighed at birth (Day 0), PND 21, and PND 74 ± 10. They
were sacrificed and necropsied after the F2 pups were delivered and evaluated. Endpoints
examined for the F1 females included selected organ weights and histology. The endpoints
examined for F1 male reproductive function included selected organ weights and histology,
percentage motile sperm, epididymal sperm concentration, and percentage abnormal sperm.
F2 litters were evaluated for litter size, sex, and pup weight. Appropriate statistical analyses
were conducted as described in the RACB protocol. Although this is not a traditional
two-generation study design, it is considered an acceptable reproductive study because it
examined the reproductive effects of TEG in two generations.
In F0 animals, no treatment-related changes in physical appearance, body weight gain, or
fluid consumption were observed. Two F0 animals died in the control group and in each of the
mid- and high-dose groups. There were no treatment-related effects on the number of litters
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produced per pair, the number of live pups/litter, or proportion of pups born alive. There was a
statistically significant decrease in mean live pup weights in the mid- and high-dose groups after
adjusting for litter size, but the results are not considered biologically significant because they
were less than 5%. There were no treatment-related effects on reproduction in the F1 generation
study, including F2 litter size, proportion of F2 pups born alive, sex of the F2 pups born alive, or
adjusted F2 pup weight. Necropsy of the F1 animals found no treatment-related effects on body
or organ weights. Sperm assessment indicated that exposure of F1 males to 6,780 mg/kg-day of
TEG had no significant effects on sperm concentration, motility, and morphology. Based on the
lack of any biologically significant findings, the reproductive NOAEL is 6,780 mg/kg-day (the
highest dose tested), and no LOAEL is identified.
Carcinogenicity
Fitzhush and Nelson (1946)
Male Osborne-Mendel rats (12/group) were administered 1, 2, or 4% TEG (purity not
reported) in feed for 2 years. The equivalent daily doses calculated for this PPRTV assessment
are 0, 700, 1,401, and 2,802 mg/kg-day, respectively, based on an average body weight
(0.514 kg) and food consumption (0.036 kg/day) given for Osborne-Mendel rats by U.S. EPA
(1988). Human equivalent doses (HEDs) are estimated to be 0, 205, 410, and 820 mg/kg-day.
Body weights and food consumption were observed weekly. Eleven organs/tissues (lung, heart,
liver, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, and testis) were
routinely examined histologically in all animals with others examined only in some animals. No
treatment-related effects were observed for mortality, food consumption, body weight gain, and
gross or microscopic lesions.
Inhalation Exposures
The inhalation exposure effects of TEG in animals have been evaluated in two
short-term-duration studies (Ballantvnc et al.. 20061 one subchronic-duration study (Maassen,
1953). and three chronic-duration studies (Robertson et al.. 1947). No inhalation studies for the
developmental, reproductive, or carcinogenic effects of TEG in animals were identified in the
literature.
Short-Term-Duration Studies
Ballantyne et al. (2006)
In the Ballantvnc et al. (2006) study, Sprague-Dawley rats (10/sex/exposure group) were
administered concentrations of 0, 494, 2,011, or 4,824 mg/m3 TEG (99.9% pure) aerosols via
whole body inhalation for 6 hours/day, 5 days/week, over 11 days. These are equivalent to
human equivalent concentrations (HECs) of 0, 101,411, and 987 mg/m3 based on
extrarespiratory effects adjusting for continuous exposure and a blood-gas partition coefficient
of 1. Test concentrations within the chambers were determined by a gravimetric method at
30-minute intervals. The mass median aerodynamic diameter (MMAD) of TEG aerosol particles
was obtained using filters and a Sierra 8-stage cascade impactor (values ranged from
1.9-2.9 |im). At the terminus of the exposure period, animals were clinically examined, and
body weights, food and water consumption were measured. Samples from necropsied animals
were subjected to hematology, serum chemistry, and urine parameter evaluation, organ weights
were measured, and histological examination was conducted on what the study authors describe
as "multiple tissues and organs."
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All rats exposed at the highest inhalation concentration died between Days 2-5; these rats
had decreased body weight and body-weight gain and the following clinical signs of toxicity:
ataxia, prostration, labored breathing, swollen periocular tissues, ocular discharge, perinasal and
periocular encrustation, and blepharospasms (involuntary spasms of the eyelid). There was no
mortality in the two lower exposure groups; however, clinical signs of toxicity (periocular
swelling and perinasal encrustation) were observed on Days 2-5. On Day 2, body weight was
statistically and biologically (>10%) significantly decreased in males and females at 987 mg/m3.
On Day 5, body weight was statistically significantly decreased in males at >411 mg/m3 and
biologically significantly decreased at 987 mg/m3. Body weight was also statistically
significantly decreased in males on Days 8-12 at 411 mg/m3. Body weight gain was statistically
significantly decreased in males and females on Days 1-2 at 987 mg/m3, as well as in males on
Days 1-5. Food consumption was statistically significantly increased in females during the
entire study period at >101 mg/m3. Water consumption was statistically significantly increased
in males at 411 mg/m3. Water consumption was statistically significantly increased in females at
>101 mg/m3. Serum alkaline phosphatase and inorganic phosphorous were significantly
increased in females at >101 mg/m3. The following statistically significant clinical chemistry
changes were reported in females at 411 mg/m3: increased erythrocyte count, decreased mean
erythrocyte corpuscular volume, decreased serum glucose, decreased serum chloride, increased
alanine aminotransferase activity, increased urine volume, decreased urine osmolality, and
decreased urine pH. Alanine aminotransferase activity was statistically significantly increased in
males at 411 mg/m3. Urine volume was statistically significantly increased in males at
411 mg/m3. Urine pH and N-acetyl-P-D-glucosaminidase were both statistically significantly
decreased in males at 411 mg/m3. Absolute liver weight was statistically and biologically
(>10%) significantly increased in males at 411 mg/m3. Absolute kidney weight was biologically
(>10%>) significantly increased in males at 101 mg/m3. Absolute kidney weight was statistically
significantly increased in males at 411 mg/m3. Relative liver weight was statistically and
biologically (>10%) significantly increased in males and females at 411 mg/m3. Absolute kidney
weight was statistically significantly increased in males at >101 mg/m3 and in females at
411 mg/m3. The NOAEL is 101 mg/m3 and the LOAEL is 411 mg/m3 based on clinical
chemistry changes (i.e., increased serum alkaline phosphatase and alanine aminotransferase
activities) indicative of liver toxicity and accompanied by an increase in liver weights greater
than 10%.
Because whole body administration of TEG also allows for exposure through other routes
(e.g., oral exposure through preening), the study was repeated employing nose-only exposure
(Ballantvne et al.. 2006). Sprague-Dawley rats (10/sex/exposure group) were exposed to TEG
aerosol (MMAD range of 1.2-1.4 jam) at measured concentrations of 0, 102, 517, and
1,036 mg/m3. HECs of 0, 21, 106, and 212 mg/m3 are estimated based on extrarespiratory
effects adjusting for continuous exposure and a blood-gas partition coefficient of 1. Endpoints
examined were the same as those examined in the whole-body study described above. Although
two mid-dose animals (one male and one female) died, the deaths were not accompanied by any
signs of toxicity or any other abnormal findings and were not considered exposure-related. No
exposure-related effects were observed at any concentration. The NOAEL is 212 mg/m3 (the
highest concentration tested), and no LOAEL is identified. The study authors concluded that the
toxicity noted in the whole-body exposure study was likely due to oral exposure through
preening. However, it should be noted that lower concentrations were used for the nose-only
study.
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Subchronic-Duration Studies
Maassen (1953)
The Maassen (1953) study is reported in a foreign language, and a translation was not
available to review at the time of preparing this PPRTV assessment. Very limited information is
available in the secondary source (('EC. 2000). No exposure-related effects were observed in
rats (sex, strain, number unspecified) exposed continuously to supersaturated TEG vapour
(approximately 449 mg/m3) for 41 days. A NOAEL of 449 mg/m3 is identified based on lack of
effects; identification of a LOAEL is precluded.
Chronic-Duration Studies
Robertson et al. (1947): Rat Study
Robertson et al. (1947) housed 24 male and 12 female rats in a chamber containing
supersaturated TEG vapor in air (approximately 4 mg/m3), maintained by a glycostat device.
Four male and two female control rats were kept in a separate chamber containing normal air.
Animals remained in the respective chambers for 6 to 13 months. Due to breeding during the
test period, the populations increased in the TEG and control chambers to 60 and 14,
respectively. The study authors examined the parameters previously detailed in Robertson et al.
(1947) with the exception that interval sacrifices were performed at 3,4, 5, and 6 months.
The growth rates of adult and offspring rats exposed to TEG were similar to the growth
rates in the control group. The general health of the rats was not affected by the TEG exposure.
Hematology was likewise similar between control and treated animals. Necropsies showed no
exposure-related lesions. Based on this, a NOAEL of 4 mg/m3 is identified.
Robertson et al. (1947): Monkey Study
The study authors performed similar tests on rhesus macaque monkeys where
17 monkeys (sex unspecified) were exposed continuously by inhalation to approximately
4 mg/m3 supersaturated TEG vapor in air from one to 10 months, and 8 monkeys were kept in a
separate chamber containing normal air from 5 to 8 months. The study authors reported
decreased body weight, browning of the skin of the face, and crusting of the ears in exposed
monkeys. Hematology, blood chemistry, and urinalysis were similar between exposed and
control animals. There was high mortality or moribund sacrifices in both the exposed (7 of
17 monkeys) and control (5 of 8 monkeys) groups. Due to the lack of quantitative data, it is not
possible to identify a LOAEL or NOAEL for monkeys exposed to supersaturated TEG vapor in
air.
In a separate study, 8 rhesus macaque monkeys (sex unspecified) were exposed
continuously by inhalation to approximately 2-3 mg/m3 TEG vapor from 2 weeks to 10 months,
and 8 monkeys were kept in a separate chamber containing normal air for the same length of
time. No adverse reactions or histopathological changes (examined tissues were not specified by
the study authors) suggestive of toxicity from prolonged exposure to TEG were seen in the
exposed monkeys. Accordingly, a NOAEL of 3 mg/m3 is identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
TEG has been found to be negative in both genotoxicity and mutagenicity studies with
and without metabolic activation, including Salmonella typhimurium reverse mutation tests,
SOS-chromotest using Escherichia coli PQ37, forward mutation studies in Chinese hamster
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ovary (CHO) cells, chromosomal aberration tests in CHO cells, and sister chromatid exchange
(SCE) assays in CHO cells (Ballantvne and Snettings. 2007; U.S. EPA. 2005; Mersch-
Sundermann et al.. 1994).
Metabolism/Toxicokinetic Studies
An oral study by Mckennis (1962) that examined rats and rabbits found that TEG was
either excreted as unchanged compound or oxidized. TEG was primarily excreted via the urine.
Small amounts also were detected in the feces, and trace amounts were measured as exhaled
CO2. A total of 91-98% was excreted through all routes within 5 days of a single oral exposure
of 25% (weight/volume) TEG. The proposed metabolic pathway was TEG to hydroxy acid
followed by oxidation to ethylenedioxydiacetic acid (Mckennis. 1962).
Mode-of-Action/Mechanistic Studies
No studies have been identified.
Immunotoxicity
No studies have been identified.
Neurotoxicity
No studies have been identified.
DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present summaries of noncancer and cancer reference values, respectively.
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Table 4. Summary of Noncancer Provisional Reference Values for Triethylene Glycol (CASRN 112-27-6)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD Method
PODhed
UFc
Principal Study
Subchronic p-RfD
(mg/kg-day)
Mouse/Both
Delayed ossification of the
supraoccipital bone in fetal mice
2 x 10°
BMDLo5
70.8
30
Ballantvne and Snellines
(2005)
Chronic p-RfD (mg/kg-day)
Mouse/Both
Delayed ossification of the
supraoccipital bone in fetal mice
2 x 10°
BMDL05
70.8
30
Ballantvne and Snellines
(2005)
Subchronic p-RfC (mg/m3)
NDr
Chronic p-RfC (mg/m3)
NDr
NDr = not determined.
Table 5. Summary of Provisional Cancer Values for Triethylene Glycol (CASRN 112-27-6)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-day)"1
NDr
p-IUR (mg/m3)1
NDr
NDr = not determined.
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The definitive developmental toxicity study in mice by Ballantvne and Snettings (2005)
is selected as the principal study for derivation of the subchronic p-RfD. The critical effect is
delayed ossification of the supraoccipital bone in fetal mice. This study was presented in a
peer-revievved journal; was performed according to good laboratory practice (GLP) (Union
Carbide. 1990a. b); and otherwise meets the standards of study design and performance with
regard to numbers of animals, examination of potential toxicity endpoints, and presentation of
information. Details of the study are provided in the "Review of Potentially Relevant Data"
section.
Justification
There are four subchronic-duration studies available for consideration in the derivation of
the subchronic p-RfD (Van Miller and Ballantvne. 2001; I.autcr and Yrla. 1940). In addition,
there are five developmental toxicity studies (Ballantvne and Snettings. 2005; Schuler et at..
1984) and one reproductive toxicity study (Bossert et at.. 1992). I.autcr and Yrla (1940)
provided information on subchronic-duration exposure via drinking water in young and mature
rats and in a rat subchroni c-durati on gavage study. None of the studies reported in I.autcr and
Yrla (1940) are considered because the study reports provided insufficient information
concerning study design and results, and the numbers of animals used were small. The
subchroni c-durati on study by Van Milter and Ballantvne (2001) is considered to be of acceptable
quality; however, because of the lack of any effects observed at any dose tested, the study is not
selected as the principal study in light of effects observed in the developmental toxicity studies at
lower doses. The Schuler et at. (1984) developmental toxicity study is not considered due to
insufficient reporting and because only one high dose was tested. Ballantvne and Snettings
(2005) reported on four developmental toxicity studies. Two were dose-range-finding studies in
mice and rats and not fully comprehensive developmental toxicity studies. Not all the data were
provided in the dose-range-finding studies nor were the fetuses internally examined for
malformations. Thus, the dose-range-finding studies are not considered for subchronic p-RfD
derivation. Notably, there was a biologically significant increase (i.e., >5%) in the incidence of
clubbed limbs per litter in mice in the dose-range-finding study (Ballantvne and Snettings. 2005).
However, this effect does not show a clear dose-response and was actually decreased compared
to controls in mice from the definitive developmental study. These data suggest that the
increased incidence of clubbed limbs in the dose-range-finding study may not be treatment
related and was therefore not considered as a potential critical effect and POD. Because the
full/definitive developmental toxicity studies in mice and rats reported by Ballantvne and
Snettings (2005) tested more animals and are more comprehensive than the dose-range-finding
studies (e.g., evaluation of a full suite of developmental effects including visceral and skeletal
examinations and the number of live and dead fetuses), they are considered as potential principal
studies for derivation of the subchronic p-RfD.
In the Ballantvne and Snettings (2005) developmental toxicity studies in mice and rats,
the biological and/or statistically significant effects reported in the fetuses were decreased fetal
body weight per litter, as a total and by sex, and increased incidence of skeletal variations.
Based on the U.S. EPA's Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA.
1991) skeletal variations such as poorly ossified supraoccipital bone, poorly ossified frontal
bone, poorly ossified cervical centra, reduced caudal segments, and bilobed thoracic centrum are
considered biologically relevant endpoints. As described in Appendix C, all available
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continuous models in the U.S. EPA Benchmark Dose Software (BMDS version 2.1.2) are fit to
the number of litters with decreased fetal body weight in mice and rats and to the incidence data
for delayed ossification of the frontal bone and the supraoccipital bone in fetal mice, following
exposure to TEG on GDs 6-15. Although a 10% BMR is standard, a 5% BMR is used in this
case because the developmental effects (i.e., decreased fetal body weight and fetal skeletal
variations) were observed during a potentially sensitive life stage. For rats, the data for
decreased fetal body weight were not amenable to BMD modeling; thus, a NOAEL/LOAEL
approach was employed to identify a potential point of departure (POD). For decreased rat fetal
body weight in males, females, and males and females combined, the LOAEL is
11,260 mg/kg-day based on a biologically (>5%) and statistically significant decrease, with a
corresponding NOAEL of 5,630 mg/kg-day. For male mice, BMD modeling resulted in a
BMDLos of 1,274 mg/kg-day for decreased fetal body weight. The data for decreased fetal body
weight in female mice alone and male and female mice combined were not amenable to BMD
modeling due to increased variability in the data as indicated by a homogeneity variance p-walue
of less than 0.1. Thus, a LOAEL of 5,630 mg/kg-day for decreased fetal body weight is
identified with a corresponding NOAEL of 563 mg/kg-day. The dose-response trend and the
extent of change for decreased fetal body weight in mice were almost identical for all categories
(i.e., males alone, females alone, and males and females combined; see Table B-3). It is
therefore fair to reason that if the data for female mice and male and female mice combined were
amenable to BMD modeling, a similar BMDLos as was determined for decreased fetal body
weight in male mice (BMDLos = 1,274 mg/kg-day) would likely have been calculated. Taken
together, for decreased fetal body weight in rats and mice, the most sensitive potential POD
appears to be a NOAEL of 563 mg/kg-day in female mice alone and male and female mice
combined.
For increased incidence of delayed ossification of the frontal bone in litters of fetal mice,
BMD modeling using nested models resulted in a BMDLos of 847 mg/kg-day. A BMDLos of
506 mg/kg-day was identified for increased incidence of delayed ossification of the
supraoccipital bone in litters of fetal mice (see Table C-l). For increased incidence of bilobed
thoracic centrum in fetal rats, the individual litter data are not available to perform BMD
modeling using nested models; thus, a NOAEL/LOAEL approach was employed to identify a
POD. For increased incidence of bilobed thoracic centrum in fetal rats, the LOAEL is
11,260 mg/kg-day with a corresponding NOAEL of 5,630 mg/kg-day.
Increased incidence of fetal skeletal variations is a common developmental effect of TEG
toxicity observed in both mice and rats (Ballantvne and Snellings. 2005). Based on the
developmental effects from the Ballantvne and Snettings (2005) study, the most sensitive
potential POD from all available studies is the BMDLos of 506 mg/kg-day for increased
incidence of delayed ossification of the supraoccipital bone in litters of fetal mice. Thus,
delayed ossification of the supraoccipital bone in fetal mice is chosen as the critical effect,
with a BMDLos of 506 mg/kg-day as the POD.
Dosimetric Adjustments:
No dosimetric adjustments for duration are made because developmental toxicity studies
are not adjusted for continuous exposure.
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In U.S. EPA's Recommended Use of Body Weight4 as the Default Method in Derivation
of the Oral Reference Dose (U.S. EPA. 2011c) 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
human equivalent oral exposures, U.S. 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
TEG is not available for use in extrapolating doses from animals to humans. The selected
critical effect of delayed ossification of the supraoccipital bone in fetal mice is associated with
the parent compound or a stable metabolite. Furthermore, this fetal skeletal variation is not a
portal-of-entry effect. Therefore, scaling by BW3/4 is relevant for deriving human equivalent
doses (HEDs) for this effect.
Following U.S. EPA (2011c) guidance, the POD for delayed ossification of the
supraoccipital bone in fetal mice is converted to a HED through application of a dosimetric
adjustment factor (DAF)1 derived as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a BW„ of 0.025 kg for mice and a BWh of 70 kg for humans (U.S. EPA. 1988). the
resulting DAF is 0.14. Applying this DAF to the BMDLos identified for the critical effect in
fetal mice yields a BMDLoshed as follows:
BMDLoshed = 506 mg/kg-day x DAF
= 506 mg/kg-day x 0.14
= 70.8 mg/kg-day
The subchronic p-RfD for TEG, based on a BMDLoshed of 70.8 mg/kg-day for delayed
ossification of the supraoccipital bone in fetal mice, is derived as follows:
1 As described in detail in Recommended Use of Body Weight3'4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA. 2011c). rate-related processes scale across species in a manner related to both the direct
(BW11) and allometric scaling (BW3'4) aspects such that BW3'4 ^ BW1'1 = BW1'4, converted to a
DAF = BWa1'4 - BWt1'4.
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Subchronic p-RfD = BMDLoshed ^ UFc
= 70.8 mg/kg-day30
= 2 x 10° mg/kg-day
Table 6 summarizes the uncertainty factors for the subchronic p-RfD for TEG.
Table 6. Uncertainty Factors for the Subchronic p-RfD for TEG
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for uncertainty in characterizing the toxicodynamic
differences between mice and humans following oral TEG exposure. The toxicokinetic uncertainty
has been accounted for by calculation of a human equivalent dose (HED) through application of a
dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Body Weight4
as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 201 1c).
UFd
1
A UFd of 1 is applied because the database includes one acceptable two-generation reproductive
toxicity studv in mice (Bossert et al.. 1992) and two acceptable developmental toxicity studies in
rats and mice (Ballatityne and Snellines. 2005).
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of TEG in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because developmental toxicity resulting from a narrow period of exposure
(i.e., delayed ossification of the supraoccipital bone in fetal mice) 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. 1991).
UFC
30
Composite Uncertainty Factor = UFA x UFD x UFH x UFL x UFS
The confidence in the subchronic p-RfD for TEG is high as explained in Table 7 below.
Table 7. Confidence Descriptors for the Subchronic p-RfD for TEG
Confidence Categories
Designation3
Discussion
Confidence in study
H
The confidence in the principal study is high because preliminary studies
were conducted to determine appropriate doses, and comprehensive
developmental endpoints were examined. Rats appeared to be less
sensitive than mice, but data in rats also indicate decreased fetal body
weight and skeletal variations.
Confidence in database
H
There is high confidence in the database because there were short-term-,
subchronic-, and chronic-duration studies, as well as developmental
(several) and reproductive toxicity studies.
Confidence in
subchronic p-RfDb
H
The overall confidence in the subchronic p-RfD is high.
aL = low; M = medium; H = high.
bThe overall confidence cannot be greater than the lowest entry in the table.
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Derivation of Chronic Provisional RfD (Chronic p-RfD)
In addition to all the studies considered for the derivation of the subchronic p-RfD (noted
above), there were three chronic-duration studies (Robertson et al.. 1947; Fitzhugh and Nelson.
1946). Fitzhugh and Nelson (1946) provided insufficient data, including no details on the
control group and no reported effects in rats at any dose tested, and Robertson et al. (1947)
examined chronic effects in both rats and monkeys. However, neither of these studies is
considered sufficient due to the lack of reporting details on study design and results, as well as
the small number of animals used throughout. Based on the lack of any sufficient
chronic-duration studies, and for the reasons detailed above under the derivation of subchronic
p-RfD, the definitive developmental study in mice by Ballantvne and Snettings (2005) is also
selected as the principal study for derivation of the chronic p-RfD. The BMDLoshed of
70.8 mg/kg-day for delayed ossification of the supraoccipital bone in fetal mice is again used as
the POD, and the chronic p-RfD is derived as follows:
Chronic p-RfD = BMDLoshed ^ UFc
= 70.8 mg/kg-day30
= 2 x 10° mg/kg-day
Table 8 summarizes the uncertainty factors for the chronic p-RfD for TEG.
Table 8. Uncertainty Factors for the Chronic p-RfD for TEG
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for uncertainty in characterizing the toxicodynamic
differences between mice and humans following oral TEG exposure. The toxicokinetic uncertainty
has been accounted for by calculation of a human equivalent dose (HED) through application of a
dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Body Weight3/4
as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 201 1c).
UFd
1
A UFd of 1 is selected because there is one acceptable two-generation reproduction study in mice
(Bossert et al.. 1992) and two acceptable developmental studies in rats and mice (Ballantvne and
Snellines. 2005).
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of TEG in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because developmental toxicity resulting from a narrow period of exposure
(i.e., delayed ossification of the supraoccipital bone in fetal mice) 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. 1991).
UFC
30
Composite Uncertainty Factor = UFA x UFD x UFH x UFL x UFS
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The confidence of the chronic p-RfD for TEG is high as explained in Table 9 below.
Table 9. Confidence Descriptors for the Chronic p-RfD for TEG
Confidence Categories
Designation3
Discussion
Confidence in study
H
The confidence in the principal study is high because preliminary studies
were conducted to determine appropriate doses, and comprehensive
developmental endpoints were examined. Rats appeared to be less
sensitive than mice, but data in rats also indicate decreased fetal body
weight and skeletal variations.
Confidence in database
H
There is high confidence in the database because there were short-term-,
subchronic-, and chronic-duration studies, as well as developmental
(several) and reproductive toxicity studies.
Confidence in chronic
p-RfDb
H
The overall confidence in the subchronic p-RfD is high.
aL = low; M = medium; H = high.
bThe overall confidence cannot be greater than the lowest entry in the table.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
There are no inhalation studies of sufficient quality to derive a subchronic p-RfC. Two
short-term-duration studies are available that evaluated whole-body and one nose-only exposure
(Ballantvne et al.. 2006). but they are of insufficient duration (only 9 days). There is a single
subchronic-duration study available (Maassen. 1953). This study is in a foreign language and
only evaluated one concentration stated to be a saturated atmosphere. Due to the lack of a
sufficient subchronic-duration study, no subchronic p-RfC can be derived.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
Chronic-duration inhalation studies were conducted in rats and monkeys (Robertson et
al.. 1947). The studies were not conducted according to proper standards, and study details were
not sufficiently documented. Small numbers of animals were exposed for various times in
chambers containing TEG vapor with no indication that the concentrations were measured or
how the vapors were generated. The rats varied in age from 6 weeks to 6 months, but data were
not separated by age. Rats were sacrificed throughout the study duration, but it was not clear
whether it was due to morbidity or planned interim sacrifice. Control and exposed animals (rats
and monkeys), however, were not generally sacrificed during the same time span. In one of the
monkey studies, there was high mortality or moribund sacrifices in both the supersaturated
exposed (7 of 17 monkeys) and control (5 of 8 monkeys) groups. Few details for each study are
provided and only a few endpoints were measured and/or reported. Furthermore, the animals in
the studies by Robertson et al. (1947) were exposed to a single concentration of TEG. Based on
the lack of information available and the low quality of chronic-duration studies, no chronic
p-RfC can be derived.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 10 identifies the cancer weight-of-evidence (WOE) descriptor for TEG.
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Table 10. Cancer WOE Descriptor for TEG
Possible WOE
Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to
Humans "
NS
NA
There are no human data to support this.
"Likely to Be
Carcinogenic to
Humans "
NS
NA
There are no sufficient animal studies to support
this.
"Suggestive Evidence
of Carcinogenic
Potential"
NS
NA
There are no sufficient animal studies to support
this.
"Inadequate
Information to Assess
Carcinogenic
Potential"
Selected
Both
There is one study that looked for tumors after
2 years of dietary treatment up to a
concentration of 4% TEG (2,802 mg/kg-day) in
male rats (Fitzhusjh and Nelson, 1946) with no
tumors reported. However, only 12 animals per
treatment group were used, there was no
information on any control group, and only a
few organs/tissues were routinely examined. No
carcinogenicity studies are available that
evaluated inhalation exposure.
"Not Likely to Be
Carcinogenic to
Humans "
NS
NA
No evidence of noncarcinogenicity is 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 TEG 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 TEG 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 screening values for TEG are identified.
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APPENDIX B. DATA TABLES
Table B-l. Developmental Cesarean Section Observations in Rats After Treatment with
TEGa
Observation
Exposure Group (mg/kg-day)
0
1,126
5,630
11,260
Number animals pregnant
25
25
25
25
Total number of litters
22
24
19
23
Mean fetal weight/litter (g)b
5.280 ±0.373
5.333 ±0.234
(101)
5.304 ±0.398
(100)
4.990 ±0.327
(95)*
Male mean fetal weight/litter (g)b
5.426 ±0.368
5.465 ±0.229
(101)
5.433 ±0.432
(100)
5.115 ±0.323
(94)**
Female mean fetal weight/litter (g)b
5.126 ±0.386
5.204 ± 0.260
(102)
5.173 ±0.400
(101)
4.846 ±0.332
(95)*
a6allantvne and Spellings (2005).
bMean ± SD (% of controls).
*p < 0.05, **p < 0.01.
Table B-2. Select Developmental Observations in Rats After Treatment with TEGa
Observations
Exposure Group (mg/kg-day)
0
1,126
5,630
11,260
Number of fetuses (litters) examined
325 (22)
356 (24)
281 (19)
362 (23)
Number of fetuses (litters) with malformations
22 (8)
22 (10)
22 (10)
49 (14)
Number of fetuses (litters) with variations
324 (22)
353 (24)
281 (19)
362 (23)
Number of fetuses (litters) with thoracic centrum no. 10 bilobed
9(6)
5(5)
14 (9)
23 (15)*
Number of fetuses (litters) with poorly ossified thoracic centrum
no. 10
5(5)
9(6)
9(3)
16 (12)
a6allantvne and Snellings (2005).
*p < 0.05.
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Table B-3. Developmental Cesarean Section Observations in Mice After Treatment with
TEGa
Observation
Exposure Group (mg/kg-day)
0
563b
5,630
11,260
Number animals pregnant
30
30
30
30
Total number of litters
27
28
26
25
Gravid uterine weight (g)
20.73 ±6.06
20.30 ±4.90 (98)
19.63 ±6.06 (95)
18.56 ±4.98 (90)
Mean fetal weight/litter (g)°
1.429 ± 0.115
1.416 ±0.097 (99)
1.350 ±0.066 (94)*
1.303 ±0.098 (91)**
Male mean fetal weight/litter (g)°
1.463 ±0.114
1.442 ±0.116 (99)
1.384 ±0.074 (95)*
1.332 ±0.106 (91)**
Female mean fetal weight/litter (g)°
1.391 ±0.118
1.395 ±0.092 (100)
1.321 ±0.066 (95)*
1.271 ±0.102 (91)**
a6allantvne and Spellings (2005).
bThe tables from which information was obtained in the publication had the low dose incorrectly labeled as 1,126;
however, because the rest of the document and the proprietary data (Union Carbide. 1990a. b) indicated
563 mg/kg-day is the lowest dose tested in mice, 563 mg/kg-day is used here.
°Mean ± SD (% of controls).
*p < 0.05, **p < 0.01.
Table B-4. Select Developmental Observations in Mice After Treatment with TEGa
Observations
Exposure Group (mg/kg-day)
0
563
5,630
11,260
Number of fetuses (litters) examined
310(27)
316(28)
310 (26)
283 (25)
Number of fetuses (litters) with malformations
13 (12)
10(7)
6(5)
15(6)
Number of fetuses (litters) with variations
310(27)
315 (28)
310 (26)
283 (25)
Number of fetuses (litters) with frontal bone poorly ossified
36(13)
48 (20)
60 (21*)
67 (22*)
Number of fetuses (litters) with supraoccipital bone poorly
ossified
45 (17)
54 (20)
83 (24*)
85 (23*)
Number of fetuses (litters) with poorly ossified cervical centra—
no 1, 2, 3, and/or 4
7(6)
9(7)
14 (9)
26 (14*)
Number of fetuses (litters) with reduced caudal segments
11(5)
22 (8)
24 (12)
46 (14*)
Number of fetuses (litters) with hind limb proximal phalanges,
some unossified
17(11)
32(14)
31 (13)
63 (19*)
Number of fetuses (litters) with hind limb proximal phalanges,
some poorly ossified
18(11)
23 (9)
35 (18)
47 (18*)
a6allantvne and Snellings (2005).
*p < 0.05.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR CONTINUOUS DATA
The benchmark dose (BMD) modeling of continuous data was conducted with
U.S. EPA's BMD software (BMDS, version 2.1.2). For decreased fetal body weight data, all
continuous models available within the software were fit using a default benchmark response
(BMR) of 5% relative risk. An adequate fit was judged based on the %2 goodness-of-fit />value
(p > 0.1), magnitude of the scaled residuals in the vicinity of the BMR, and visual inspection of
the model fit. I addition to these three criteria forjudging adequacy of model fit, a determination
was made as to whether the variance across dose groups was homogeneous. If a homogeneous
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 homogeneous 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 nonhomogeneous variance. If
this nonhomogeneous variance model did not adequately fit the data (i.e., Test 3; p < 0.1), the
data set was considered unsuitable for BMD modeling. Among all models providing adequate
fit, the lowest benchmark dose lower confidence limit (BMDL) was selected if the BMDLs
estimated from different models varied greater than 3-fold; otherwise, the BMDL from the model
with the lowest Akaike's information criterion (AIC) was selected as a potential POD from
which to derive a p-RfD.
MODELING PROCEDURE FOR NESTED DICHOTOMOUS DATA
The BMD modeling of nested dichotomous data was conducted with U.S. EPA's BMDS
(version 2.1.2). For delayed ossification of the supraoccipital bone and frontal bone, the nested
logistic (NLogistic) dichotomous model was fit using a standard BMR of 5% extra risk for
developmental endpoints. For both delayed ossification endpoints, the NLogistic model was fit
with and without litter size as a covariate and with and without intralitter correlations. Adequacy
of model fit was judged based on the %2 goodness-of-fitp-value (p> 0.1), magnitude of scaled
residuals in the vicinity of the BMR, and visual inspection of the model fit.
DELAYED OSSIFICATION OF THE SUPRAOCCIPITAL BONE IN FETAL MICE
TREATED WITH TEG FROM GESTATIONAL DAYS 6-15 (Ballantvne and Snellings.
\ gtt&MWWW IMWWWWWWiBWWWWiWgBWWiWgWWiWWWWWiWWWiWgirf^y^hlJIljl
2005)
The NLogistic dichotomous model in BMDS (version 2.1.2) was fit to the data for
delayed ossification of the supraoccipital bone in fetal mice treated with TEG from GDs 6-15
(Ballantvne and Snellings. 2005) (see Table B-4). For delayed ossification of the supraoccipital
bone, a BMR of a 5% change relative to the control mean was used. As assessed by the
X2 goodness-of-fit statistic, AIC score, and visual inspection, the NLogistic model provided an
optimal fit (see Table C-l and Figure C-l). Including litter size as a covariate and using
intralitter correlations had significant effects on the AIC scores. The best fitting NLogistic
model as indicated by the lowest AIC was obtained with estimating intralitter correlations and
not including litter size as a covariate. The estimated dose associated with 5% extra risk
(BMD05) and the 95% lower confidence limit on this dose (BMDL05) were 825 and
506 mg/kg-day, respectively.
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Table C-l. Model Prediction for Delayed Ossification of the
Supraoccipital Bone in Fetal Mice"
Model
BMDos
BMDLos
X2/7-Value
AIC
Conclusion
NLogistic
825
506
0.474
721.73
Provided an optimal fit
a6allantvne and Spellings (2005).
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Nested Logistic Model with 0.95 Confidence Level
2000
4000
6000
dose
8000
10000
13:23 11/14 2012
Figure C-l NLogistic Model Fit for Delayed Ossification of the Supraoccipital Bone in
Fetal Mice (Ballantviie and Snellings, 2005).
NLogistic Model. (Version: 2.15; Date: 10/28/2009)
Input Data File: C:/Documents and Settings/JKaiser/Desktop/modeling
results/nln_nested_supra_teg_Nln-BMR10-Restrict.(d)
Wed Nov 14 13:23:12 2012
BMDS Model Run
The probability function is:
Prob. = alpha + thetal*Rij + [1 - alpha - thetal*Rij]/
[1+exp(-beta-theta2*Rij-rho*log(Dose))],
where Rij is the litter specific covariate.
Restrict Power rho >= 1.
Total number of observations = 106
Total number of records with missing values = 0
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Total number of specified parameters = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User specifies the following parameters:
thetal = 0
theta2 = 0
Default Initial Parameter Values
alpha =
beta =
thetal =
theta2 =
rho =
phil =
phi 2 =
phi 3 =
phi 4 =
0.316508
-9.65973
0
0
1
0.326483
0.312191
0.244159
0.138021
Specified
Specified
Parameter Estimates
Variable Estimate Std. Err.
alpha 0.316507 *
beta -9.65974 *
rho 1 *
phil 0.326483 *
phi2 0.312191 *
phi3 0.244159 *
phi4 0.138021 *
* - Indicates that this value is not calculated.
Log-likelihood: -354.866 AIC: 721.732
Litter Data
Lit.-Spec.
Litter
Scaled
Dose
Cov.
Est. Prob.
Size
Expected
Observed
Residual
0.0000
2.0000
0.317
1
0.317
0
-0.6805
0.0000
4.0000
0.317
2
0. 633
1
0.4844
0.0000
9.0000
0.317
4
1.266
3
1.3249
0.0000
9.0000
0.317
4
1.266
4
2.0890
0.0000
9.0000
0.317
4
1.266
0
-0.9673
0.0000
10.0000
0.317
5
1.583
0
-1.0020
0.0000
10.0000
0.317
5
1.583
5
2.1639
0.0000
11.0000
0.317
5
1.583
0
-1.0020
0.0000
11.0000
0.317
5
1.583
1
-0.3689
0.0000
11.0000
0.317
5
1.583
1
-0.3689
0.0000
11.0000
0.317
5
1.583
0
-1.0020
0.0000
11.0000
0.317
5
1.583
1
-0.3689
0.0000
12.0000
0.317
6
1. 899
3
0.5956
0.0000
12.0000
0.317
6
1. 899
0
-1.0274
0.0000
12.0000
0.317
6
1. 899
0
-1.0274
0.0000
12.0000
0.317
6
1. 899
0
-1.0274
41
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. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
. 0000
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12.0000
12.0000
12.0000
13.0000
14.0000
14.0000
14.0000
15.0000
16.0000
16.0000
16.0000
0.317
0.317
0.317
0.317
0.317
0.317
0.317
0.317
0.317
0.317
0.317
1. 899
1. 899
1. 899
1. 899
2.216
2.216
2.216
2.216
2.532
2.532
2.532
-0.4864
1.1366
0.5956
1.1366
-0.1018
-0.5742
-1.0467
0.3706
-1.0619
0.1962
0.6156
8.0000
8.0000
9.0000
9.0000
9.0000
10.0000
10.0000
10.0000
10.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
12.0000
12.0000
12.0000
12.0000
13.0000
13.0000
13.0000
13.0000
14.0000
14.0000
14.0000
14.0000
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
0.340
1.361
1.361
1.361
1.361
1.361
1.701
1.701
1.701
1.701
1.701
1.701
1.701
1.701
1.701
1.701
1.701
2.041
2.041
2.041
2.041
2.041
2.041
2.041
2.041
2.381
2.381
2.381
2.381
1.2431
-0.2736
-0.2736
-0.2736
2.0015
-1.0707
0.1882
0.8176
1.4471
-1.0707
2.0766
-0.4413
-1.0707
-1.0707
-1.0707
1.4471
-0.0222
1.0547
-1.0991
-0.0222
-0.0222
1.5932
-0.0222
0.5162
-1.1208
0.2911
-0.6502
-1.1208
9.0000
10.0000
10.0000
10.0000
10.0000
10.0000
10.0000
10.0000
11.0000
11.0000
11.0000
12.0000
12.0000
12.0000
12.0000
12.0000
12.0000
13.0000
13.0000
13.0000
14.0000
14.0000
14.0000
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
0. 497
1. 989
2.486
2.486
2.486
2.486
2.486
2.486
2.486
2.486
2.486
2.486
2.983
2.983
2.983
2.983
2.983
2.983
2.983
2.983
2.983
3.480
3.480
3.480
0.7685
-1.5814
-0.3090
-1.5814
-0.9452
0.9634
1.5996
-0.9452
0.9634
-0.9452
0.3272
0.5573
-0.5385
-1.6343
1.1052
0.5573
1.1052
1.1052
1.1052
0.5573
-0.2311
-1.1941
-0.7126
42
Triethylene glycol
-------
5630.0000
5630.0000
5630.0000
14.0000
15.0000
16.0000
0. 497
0. 497
0. 497
3.480
3.480
3. 977
1.2134
0.7319
-1.2790
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
6.0000
8.0000
9.0000
9.0000
10.0000
10.0000
10.0000
10.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
12.0000
12.0000
13.0000
13.0000
13.0000
14.0000
14.0000
14.0000
14.0000
15.0000
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
0.602
1.807
2.409
2.409
2.409
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.613
3.613
3.613
3.613
3.613
4.216
4.216
4.216
4.216
4.216
-1.8867
0.5077
0.5077
0.5077
1. 4586
0.7252
0.7252
-0.7417
0.7252
-0.0082
0.7252
-1. 4751
0.7252
-1.4751
1. 4586
0.8896
0.2480
-0.3936
-0.3936
-1.0352
1.0191
-2.4078
-0.1232
-0.6944
0.4479
Combine litters with adjacent levels of the litter-specific covariate
within dose groups until the expected count exceeds 3.0, to help improve
the fit of the X^2 statistic to chi-square.
Grouped Data
Dose
Mean
Lit.-Spec. Cov.
Expected Observed
Scaled
Residual
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
3.0000
4.0000
9.0000
10.0000
11.0000
11.0000
11.0000
12.0000
12.0000
12.0000
12.0000
13.0000
14.0000
14.0000
15.0000
16.0000
0. 950
1.266
4.115
3.165
3.165
3.165
1. 899
3.798
3.798
3.798
1. 899
2.216
4.431
2.216
2.532
5.064
0.0568
1.3249
-0.0471
0.8216
-0.5216
-0.9694
0.5956
-1.4529
-1.0704
1.2249
1.1366
-0.1018
-1.1462
0.3706
-1.0619
0.5741
563.
563.
563.
563.
563.
0000
0000
0000
0000
0000
16.0000
8.0000
9.0000
10.0000
10.0000
1.361
2.722
4.423
3. 402
3. 402
1.2431
-0.3870
0.2357
0.7112
0.2661
43
-------
FINAL
9-10-2014
563.
563.
563.
563.
563.
563.
563.
563.
563.
563.
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
11.0000
11.0000
11.0000
11.0000
12.0000
12.0000
13.0000
13.0000
14.0000
14.0000
3. 402
3. 402
3. 402
2.041
4.082
4.082
4.082
4.423
4.763
2.381
1.1563
-1.5142
0.2661
-0.0222
-0.0314
-0.0314
1.1108
-0.5041
-0.2539
-1.1208
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
5630.
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
14.0000
9.0000
10.0000
10.0000
10.0000
10.0000
11.0000
11.0000
12.0000
12.0000
12.0000
13.0000
13.0000
14.0000
14.0000
14.0000
14.0000
15.0000
1. 989
2.486
4.971
4.971
4.971
2.486
4.971
2.983
5.966
5.966
5.966
5.966
3.480
3.480
3.480
3.480
3.480
3. 977
3
0
2
5
6
4
4
4
2
9
10
9
3
1
2
6
5
1
0.7685
-1.5814
-1.3367
0.0129
0.4627
0.9634
-0.4370
0.5573
-1.5364
1.1756
1.5630
1.1756
-0.2311
-1.1941
-0.7126
1.2134
0.7319
-1.2790
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
11260.
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
0000
16.0000
6.0000
8.0000
9.0000
10.0000
10.0000
10.0000
10.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
11.0000
12.0000
12.0000
13.0000
13.0000
13.0000
14.0000
14.0000
14.0000
14.0000
1.807
2.409
2.409
5.420
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.011
3.613
3.613
3.613
3.613
3.613
4.216
4.216
4.216
4.216
4.216
-1.8867
0.5077
0.5077
1.4390
0.7252
0.7252
-0.7417
0.7252
-0.0082
0.7252
-1.4751
0.7252
-1. 4751
1. 4586
0.8896
0.2480
-0.3936
-0.3936
-1.0352
1.0191
-2.4078
-0.1232
-0.6944
0.4479
Chi-square =
67.10
DF
67
P-value
0.4735
To calculate the BMD and BMDL, the litter specific covariate is fixed
at the mean litter specific covariate of all the data: 11.500000
Benchmark Dose Computation
Specified effect = 0.05
44
Triethylene glycol
-------
FINAL
9-10-2014
Risk Type
Confidence level
BMD
BMDL
Extra risk
0. 95
824.936
506.316
45
Triethylene glycol
-------
FINAL
9-10-2014
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49
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