United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/013F
Final
9-10-2010
Provisional Peer-Reviewed Toxicity Values for
Ethoxyethanol Acetate
(CASRN 111-15-9)
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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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure (oral)
RfC
reference concentration (inhalation)
RfD
reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ETHOXYETHANOL ACETATE (CASRN 111-15-9)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by two
EPA scientists and external peer review by three independently selected scientific experts.
PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram consensus
review provided for IRIS values. This is because IRIS values are generally intended to be used
in all EPA programs, while PPRTVs are developed specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
There is no RfD, RfC, or carcinogenicity assessment for ethoxyethanol acetate (structure
shown in Figure 1) on IRIS (U.S. EPA, 2009). The HEAST (U.S. EPA, 1997) lists an RfD of
0.3 mg/kg-day for both subchronic and chronic exposure based on an oral acceptable daily intake
(ADI) of 0.3 mg/kg-day for ethoxyethanol acetate derived in a Health and Environmental Effects
Profile (HEEP) on 2-ethoxyethanol esters (U.S. EPA, 1985). The ADI was derived from an oral
NOAEL of 30.1 mg/kg-day estimated by route-to-route extrapolation from an inhalation NOEL
of 50 ppm for developmental toxicity in rats exposed for 6 hours/day on Gestation Days (GDs)
6-15 (Union Carbide Corporation, 1984; later published as Tyl et al., 1988). The Chemical
Assessments and Related Activities (CARA) database (U.S. EPA, 1994a, 1991a) lists no other
documents besides the aforementioned HEEP. There is no entry for ethoxyethanol acetate in the
Drinking Water Standards and Health Advisories list (U.S. EPA, 2006).
Figure 1. Chemical Structure of Ethoxyethanol Acetate
CalEPA (2009a,b,c) derived a chronic inhalation Reference Exposure Level (REL) of
0.3 mg/m3 (0.06 ppm) for ethoxyethanol acetate based on developmental toxicity in rabbits
(Tyl et al., 1988) but no chronic oral REL or cancer potency factor. There is no ATSDR (2009)
Toxicological Profile or World Health Organization (WHO, 2009) Environmental Health
Criteria Document for ethoxyethanol acetate. The carcinogenicity of ethoxyethanol acetate has
not been evaluated by the National Toxicology Program (NTP, 2009, 2005) or the International
Agency for Research on Cancer (IARC, 2009).
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Occupational health guidelines and standards are available for ethoxyethanol acetate.
ACGIH (2008, 2001) recommends a Threshold Limit Value-Time-Weighted Average
"3
(TLV-TWA) of 5 ppm (27 mg/m ) to minimize the potential for reproductive effects. The
TLV-TWA is based on testicular effects of ethoxyethanol acetate in mice and by analogy to the
TLV for 2-ethoxyethanol. The National Institute for Occupational Safety and Health (NIOSH,
2005) has set a Recommended Exposure Limit (REL) of 0.5 ppm (2.7 mg/m3) TWA. The
Occupational Safety and Health Administration (OSHA, 2009) has promulgated a Permissible
Exposure Limit (PEL) of 100 ppm (540 mg/m3) TWA. Sweeney et al. (2001) proposed an
-3
Occupational Exposure Limit (OEL) of 2 ppm (11 mg/m ), which was derived by using a
probabilistic physiologically based pharmacokinetic (PBPK) model to estimate aNOAEL in
humans from developmental toxicity data in rats.
Literature searches were conducted for studies relevant to the derivation of provisional
toxicity values for ethoxyethanol acetate. Databases searched include MEDLINE, TOXLINE
(BIOSIS and NTIS), TOXCENTER, CCRIS, DART/ETIC, TSCATS/TSCATS 2, GENETOX,
HSDB, RTECS, and Current Contents. The time period covered by most of the searches ranged
from the 1960s through early February 2010, although some searches covered earlier years.
Reviews by Environment Canada (2009) and Johnson (2002) were also examined for relevant
information.
REVIEW OF PERTINENT DATA
Human Studies
Epidemiology studies have noted hematological, reproductive, and developmental effects
in workers exposed to mixtures of glycol ethers, including ethoxyethanol acetate.
Leucopenia was observed in male shipyard painters exposed to mixed solvents containing
ethoxyethanol acetate (Kim et al., 1999). Air monitoring revealed that these workers were
"3
exposed to mean concentrations of ethoxyethanol acetate at 1.76-3.03 ppm (9.7-16.2 mg/m )
with peak exposures of up to 8.12-18.27 ppm (44-97 mg/m3). However, other solvents also
detected in the air samples at higher concentrations included methyl isobutyl ketone, xylene, and
toluene.
Workers at a silk-screening plant that used a cleaning solvent primarily composed of
ethoxyethanol acetate and small amounts of methyl isobutyl ketone and toluene to clean the
printing screens were evaluated for hematological effects (Loh et al., 2003). Women exposed to
a geometric mean concentration of ethoxyethanol acetate in the atmosphere at 9.34 ppm
(50.2 mg/m3) had a significant (p < 0.05) reduction in hemoglobin (Hgb) and hematocrit (Hct)
compared to the reference population, but men exposed to a geometric mean concentration of
4.87 ppm (27.0 mg/m3) of ethoxyethanol acetate in the atmosphere did not exhibit any significant
hematological changes. In follow-up surveys, the hematological effects observed in the female
workers were no longer significant or present after the implementation of engineering controls at
the factory for >1 year to decrease atmospheric concentrations, and protective measures
including wearing rubber gloves (Chen et al., 2007). Loh et al. (2008) reported that there is no
evidence based on evaluations of liver function profiles of the silk-screening workers that
ethoxyethanol acetate is hepatotoxic.
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No effects were observed on the menstrual patterns of women occupationally exposed to
a mean TWA concentration of 0.51 ppm (3 mg/m3) of ethoxyethanol acetate in the atmosphere at
a liquid crystal display manufacturing facility (Chia et al., 1997). Several epidemiological
studies have shown an association between maternal occupational exposure to glycol ether
mixtures including 2-ethoxyethanol, ethoxyethanol acetate, 2-methoxyethanol, and
2-methoxyethanol acetate and increased risk of spontaneous abortion, conception delays, and
congenital malformations (Cordier et al., 2001, 1997; Correa et al., 1996; Schenker, 1996, 1995;
Beaumont et al., 1995; Swan et al., 1995). However, in a review of some of these studies,
Maldonado et al. (2003) concluded that there is not enough evidence to determine whether
occupational exposure to glycol ethers causes human congenital malformation. In addition, the
relative contribution of ethoxyethanol acetate to the observed developmental effects among
workers exposed to glycol ether mixtures is not known.
Animal Studies
Oral Exposure
Subchronic Studies—In a study from the Japanese literature, Nagano et al. (1984, 1979)
administered ethoxyethanol acetate via gavage at 500, 1000, 2000, or 4000 mg/kg-day to groups
of five male JCL-ICR mice, 5 days/week, for 5 weeks. An additional 20 mice served as the
control group. Evaluations included hematology (white blood cell [WBC] count, red blood cell
[RBC] count, Hct, and Hgb content), testes weights, combined weights of seminal vesicles and
the coagulating gland, and histopathology of the testis. Three high-dose mice died prior to study
termination. The English language report of this study (Nagano et al., 1984) included no details
on the observed mortality and no mention of any effects on body weight. Dose-dependent
decreases in absolute and relative testicular weights were observed. Table 1 summarizes the
effects on organ weights. Decreased testicular weights were statistically significantly (p < 0.05)
different than controls at >1000 mg/kg-day, and absolute weight of combined vesicular and
coagulating glands was statistically significantly (p < 0.05) decreased compared to controls at
4000 mg/kg-day. Other significant findings include a reduction in WBC count at
>2000 mg/kg-day and a decrease in Hct at 4000 mg/kg-day (see Table 1). Nagano et al. (1984)
reported that histopathology revealed dose-related epithelial degeneration of the seminiferous
tubules; however, the authors provided no further details regarding incidence or severity of these
effects (data not shown). For the purposes of this review, the NOAEL and LOAEL are identified
as 500 and 1000 mg/kg-day, respectively, based on decreased testicular weight.
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Table 1. Organ Weights and Hematology in Mice Treated
with Ethoxyethanol Acetate by Gavage for 5 Weeks
Parameter
Dose (mg/kg-day)
0
500
1000
2000
4000
Number of mice
20
5
5
5
2a
Absolute testes weight (mg)
291 ±25b
269 ± 62
231 ±66c
173 ± 39c
83 ±7C
Relative testes weight (%)
0.76 ±0.08
0.69 ± 0.18
0.66 ± 0.1 ld
0.44 ± 0.10c
0.21 ±0.01c
Absolute vesicular and
coagulating glands weight
(mg)
376 ±59
366 ±80
341 ±52
369 ±36
299 ± 44d
Relative vesicular and
coagulating glands weight
(mg)
0.99 ±0.16
0.94 ±0.22
0.87 ±0.14
0.93 ±0.09
0.76 ±0.07
WBC count (per mm3)
3810±1572
2940 ± 482
3940±1380
2030 ± 606d
1100 ± 243c
RBC count (104/mm3)
764 ± 79
685 ± 84
701 ±60
719 ± 71
679 ± 32
Hct (%)
39.3 ±2.7
37.5 ±3.1
39.7 ±3.1
37.8 ± 1.7
35.0 ± 0.8d
Hgb (g/dl)
12.7 ±0.9
12.4 ±0.7
12.8 ± 1.0
12.6 ± 1.1
11.7 ± 1.0
a3/5 animals were dead before examination.
bMean ± standard deviation (SD).
Significantly different from controls (Student's /-test, p < 0.01).
Significantly different from controls (Student's t-test, p < 0.05).
Source: Nagano et al. (1979).
Reproductive/Developmental Studies—Following the NTP Reproductive Assessment
by Continuous Breeding (RACB) protocol, groups of 20 male and 20 female CD-I mice were
allowed access ad libitum to drinking water containing 0.5, 1, or 2% ethoxyethanol acetate for
18 weeks (7 days premating, 98 days continuous breeding, and 21 days postmating)
(Morrissey et al., 1989; Lamb et al., 1987; Gulati et al., 1985). Lamb et al. (1987) reported the
corresponding doses as 930, 1860, and 3000 mg/kg-day. An additional group of 40 male and
40 female mice served as controls. The selected test concentrations were based on an initial
range-finding study conducted by these researchers wherein ethoxyethanol acetate treatment
significantly affected body-weight gain in mice at 5%, and to a lesser degree, at 2.5% in the
drinking water. For the continuous breeding study, mice were monitored for survival, changes in
body weight, and water consumption. Reproductive performance was assessed by evaluating
fertility, pup survival, and sex ratio. At the high-dose, body weights were slightly reduced
(<10%), and water consumption was reduced by about 20%. Table 2 summarizes results based
on reproductive performance. The fertility index (number of fertile pairs per number of
cohabited pairs) was significantly reduced only at the high-dose. At >1860 mg/kg-day, the mean
number of litters per pair, the number of live pups per litter, and the adjusted live pup weights
were significantly reduced.
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Table 2. Reproductive Performance in Mice Treated with Ethoxyethanol
Acetate in Drinking Water During a Continuous Breeding Study
Reproductive Parameter
Dose (mg/kg-day)
0
930
1860
3000
Fertility index (%)a
95 (36/38)
95 (19/20)
100(19/19)
74 (14/19)b
Litters per pair
4.92 ± 0.05c
4.74 ±0.10
4.53 ±0.16d
1.64 ± 0.20d
Live pups per litter
Male
Female
Combined
5.77 ±0.24
5.52 ±0.22
11.29 ±0.43
5.77 ±0.34
5.40 ±0.34
11.17 ± 0.55
4.07 ± 0.37d
4.16 ± 0.3 ld
8.22 ± 0.62d
0.32 ± 0.41d
0.21 ±0.21d
0.54 ± 0.30d
Proportion of pups born alive
0.96 ±0.02
0.99 ±0.01
0.88 ± 0.04d
0.17 ± 0.09d
Live pup weight (g)
Male
Female
Combined
1.66 ±0.02
1.58 ±0.01
1.62 ±0.01
1.67 ±0.02
1.60 ±0.02
1.64 ±0.02
1.66 ±0.02
1.55 ±0.02
1.60 ±0.02
1.50 ± 0.13e
1.46f
1.59 ± 0.12e
Adjusted live pup weight (g)8
Male
Female
Combined
1.69 ±0.02
1.60 ±0.01
1.65 ±0.01
1.69 ±0.02
1.61 ±0.02
1.66 ±0.02
1.62 ± 0.02d
1.52 ± 0.02d
1.57 ± 0.02d
1.40 ± 0.06d'e
1.35 ± 0.09d'f
1.44 ± 0.05d'e
"Number of fertile pairs per number of cohabited pairs in parentheses.
bSignificantly different from controls (Fisher's exact test, p < 0.05).
°Mean ± standard error.
Significantly different from controls (Kruskal-Wallis test, p < 0.05).
eTen litters in this group contained no live pups.
fOnly one litter in this group contained live female pups.
8Means adjusted for total number of live and dead pups per litter by analysis of covariance.
Source: Gulati et al. (1985).
Based on the above findings, two additional studies were conducted as part of the NTP
RACB protocol including (1) a cross-over mating study to determine if males or females were
more sensitive to 2-ethoxyethanol treatment and (2) an assessment of the reproductive
performance of the second generation (Morrissey et al., 1989; Lamb et al., 1987; Gulati et al.,
1985).
The cross-over mating study was conducted using the animals that received
2% ethoxyethanol acetate (3000 mg/kg-day) in drinking water (Morrissey et al., 1989;
Lamb et al., 1987; Gulati et al., 1985). Exposed mice of each sex were mated with control. A
control group consisted of control males mated with control females. Test animals were
necropsied, and reproductive organs, liver, and kidneys were weighed. Sperm morphology and
vaginal cytology studies were also conducted. The litters of the crossover matings were
evaluated for litter size, sex ratio, and pup weights. Table 3 summarizes effects on body and
organ weights and results from sperm and vaginal cytology studies. There were no significant
changes in female body or organ weights. Male mice demonstrated statistically significant
(p < 0.05) decreases in body weight (magnitude was <10%) and absolute right testis weights
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(7%) compared to controls. When adjusted for body weight by analysis of covariance, the
change in testis weight was no longer significant. Sperm studies did not show any difference
between control and treated males based on count or motility, but there was a significant increase
in abnormal sperm compared with controls. There were no apparent effects on the estrous cycle
in females. Table 4 summarizes results based on reproductive performance. No significant
effects on fertility index, litter size, pup survival, or growth were observed among litters from
treated males mated with control females. However, the fertility index of treated females mated
with control males was significantly reduced compared to controls. In addition, there were
marked decreases in the number of live pups per litter and proportion of pups born alive to
treated female mice mated with control males. Based on these findings, female mice were
subjected to a detailed histological examination, which did not reveal any significant
treatment-related lesions. Gulati et al. (1985) concluded that the findings of the cross-over
mating study suggest that the reduction in the number of litters per fertile pair observed in the
continuous breeding study described above is attributable to effects in the female mice treated
with ethoxyethanol acetate, even though histopathology of reproductive organs was observed for
males (see below) and not females.
To assess the effects on the second generation, ethoxyethanol acetate was administered
again in the drinking water ad libitum at 0, 0.5, or 1% (0, 930, and 1860 mg/kg-day) to F1 mice
from weaning until mating at approximately 74 days of age (Morrissey et al., 1989; Lamb et al.,
1987; Gulati et al., 1985). Mating was only allowed between female and male offspring from the
same treatment group (20/sex/group). There were a limited number of live pups from dams
treated with 2% (3000 mg/kg-day) ethoxyethanol acetate for this evaluation. F1 adults were
evaluated for body weight, water consumption, and organ weights (reproductive organs, liver,
and kidneys). Mating and fertility indexes were also calculated. F2 litters were evaluated for
litter size, sex ratio, and pup weights. Table 5 summarizes effects in F1 adults on body and
organ weights and results from sperm and vaginal cytology studies. No significant effects on
growth were observed. F1 females from the high-dose group exhibited significant decreases in
absolute and adjusted (for body weight by analysis of covariance) group mean liver weights. In
F1 males, significant changes in organ weights include increased absolute and adjusted liver
weights among the low-dose group, and decreased absolute right cauda weight among the
high-dose group. Sperm studies did not reveal any significant effects on sperm motility or
morphology, but there was a decrease in sperm density among F1 mice in the high-dose
(1860 mg/kg-day) group that was significantly different from controls. There were no apparent
effects on the estrous cycle in females. Based on these effects, high-dose mice were subjected to
a detailed histological examination. No significant histological changes were observed among
females. However, degeneration of seminiferous tubules, interstitial cell hyperplasia, reduction
of sperm content, and accumulation of fluid and degenerated cells in the epididymis were noted
in males. Table 6 summarizes effects on reproductive performance. There was a 50% reduction
in the number of F1 pairs that were confirmed sperm positive at 1860 mg/kg-day. However, the
fertility indexes for the treated and control pairs were similar. There was a reduction in the
proportion of pups born alive at 1860 mg/kg-day compared to controls, but this difference is not
significant.
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Table 3. Body and Organ Weights in Mice Treated with Ethoxyethanol
Acetate in Drinking Water During a Cross-Mating Study
Parameter
Dose (mg/kg-day)
0
3000
Males
Females
Males
Females
Number of mice
40
36
20
15
Body weight (g)
41.6 ± 0.77a
40.0 ±0.99
38.8 ± 0.88b
37.1 ±0.90
Organ weights
Liver (g)
Absolute
Adjusted for body weight
2.16 ±0.05
2.10 ±0.03
2.25 ±0.06
2.21 ±0.05
2.08 ±0.08
2.19 ±0.05
2.07 ± 0.06
2.16 ±0.7
Kidneys (g)°
Absolute
Adjusted for body weight
0.79 ±0.02
0.78 ±0.02
0.58 ±0.01
0.58 ±0.01
0.77 ± 0.02
0.79 ±0.02
0.60 ± 0.02
0.62 ± 0.02
Right epididymis (mg)
Absolute
Adjusted for body weight
55.8 ± 1.0
55.4 ±0.9
N/A
53.4 ±1.1
54.3 ± 1.3
N/A
Right cauda (mg)
Absolute
Adjusted for body weight
19.6 ±0.4
19.5 ±0.4
N/A
18.9 ±0.4
19.1 ±0.5
N/A
Right testes (g)
Absolute
Adjusted for body weight
0.14 ±0.004
0.14 ±0.003
N/A
0.13 ±0.004d
0.13 ±0.005
N/A
Seminal vesicles (g)
Absolute
Adjusted for body weight
0.62 ± 0.02
0.61 ±0.02
N/A
0.57 ±0.03
0.59 ±0.03
N/A
Prostate gland (mg)
Absolute
Adjusted for body weight
31.7 ± 1.4
31.0 ± 1.2
N/A
31.3 ± 1.4
32.6 ± 1.7
N/A
Sperm
Motility (%)
95.3 ± 0.54e
N/A
93.3 ±0.99
N/A
Density (x 106 per gram caudal tissue)
1097 ± 54
N/A
1012 ±80
N/A
Morphology (% abnormal sperm)
3.03 ± 0.23e
N/A
5.80 ± 1.71b'e
N/A
Length of estrous cycle (days)
N/A
4.96 ± 0.10f
N/A
5.00 ± 0.10s
aMean ± standard error.
bSignificantly different from controls (F test, p < 0.05).
°Kidneys weighed with adrenal glands attached.
Significantly different from controls (F test, p < 0.01).
eNo sperm present for one animal in this group.
fEstrous cycle length could not be accurately estimated for 11 of 36 control females.
8Estrous cycle length could not be accurately estimated for 4 of 15 treated females.
N/A = not applicable.
Source: Gulati et al. (1985).
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Table 4. Reproductive Performance in Mice Treated with Ethoxyethanol Acetate in
Drinking Water During a Cross-Mating Study
Reproductive Parameter
Treatment Group
Control Male x
Control Female
Control Male x
High-Dose Female
High-Dose Male x
Control Female
Fertility index (%)a
59(10/17)
27 (4/15)b
74(14/19)
Live pups per litter
Male
Female
Combined
4.70±0.92c
3.40 ±0.70
8.10± 1.33
0.25 ±0.25d
0.25 ± 0.25d
0.50 ± 0.29d
3.07 ±0.58
4.50 ±0.86
7.57 ± 1.31
Proportion of pups born alive
0.85 ±0.11
0.07 ± 0.04d
0.87 ±0.08
Live pup weight (g)
Male
Female
Combined
1.69 ± 0.04e
1.66 ± 0.05s
1.69 ± 0.03s
2.04f
1.53f
1.78 ± 0.25e
1.77 ± 0.05s
1.62 ± 0.05s
1.70 ±0.05
Adjusted live pup weight (g)h
Male
Female
Combined
1.70 ± 0.06e
1.66 ± 0.06s
1.69 ± 0.06s
2.04 ± 0.16f
1.50 ± 0.18f
1.76 ± 0.12e
1.76 ± 0.04s
1.62 ± 0.05s
1.70 ±0.04
aNumber of fertile pairs per number of cohabited pairs in parentheses.
bSignificantly different from controls (Fisher's exact test, p < 0.01).
°Mean ± standard error.
Significantly different from controls (Kruskal-Wallis test, p < 0.05).
eTwo litters in this group contained no live pups.
fBased on only one litter.
8One litter in this group contained no live pups.
hLeast squares estimate of mean ± standard error adjusted for average litter size.
Source: Gulati et al. (1985).
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Table 5. Body and Organ Weights in Second Generation Mice Treated with
Ethoxyethanol Acetate in Drinking Water
Parameter
Dose (mg/kg-day)
0
930
1860
Males
Females
Males
Females
Males
Females
Number of mice
20
20
20
20
20
20
Body weight (g)
35.98 ±0.93a
32.5 ±0.45
36.9 ±0.69
32.6 ±0.71
35.5 ±0.91
31.1 ± 0.49
Organ weights
Liver (g)
Absolute
Adjusted for body weight
1.79	±0.06
1.80	±0.04
1.88 ±0.05
1.86 ±0.04
2.00 ± 0.05b
1.97 ± 0.04d
1.93 ±0.04
1.90 ±0.04
1.90 ±0.06
1.92 ± 0.04b
1.69 ± 0.05b
1.75 ± 0.04b
Kidneys (g)°
Absolute
Adjusted for body weight
0.69 ±0.02
0.69 ±0.02
0.49 ±0.01
0.49 ±0.01
0.71 ±0.02
0.70 ± 0.02
0.49 ±0.02
0.48 ±0.01
0.71 ±0.03
0.72 ± 0.02
0.48 ±0.01
0.48 ±0.01
Right epididymis (mg)
Absolute
Adjusted for body weight
51.2 ± 1.4
51.4 ± 1.5
N/A
49.0 ± 1.7
48.3 ± 1.4
N/A
46.1 ±2.0
46.8 ± 1.4
N/A
Right cauda (mg)
Absolute
Adjusted for body weight
18.8	±0.71
18.9	±0.58
N/A
17.2 ±0.64
16.9 ±0.58
N/A
15.0 ± 0.63d
15.2 ±0.58
N/A
Right testes (g)
Absolute
Adjusted for body weight
0.14 ±0.004
0.14 ±0.007
N/A
0.14 ±0.009
0.14 ±0.007
N/A
0.13 ±0.008
0.13 ±0.007
N/A
Seminal vesicles (g)
Absolute
Adjusted for body weight
0.44 ± 0.02
0.44 ± 0.02
N/A
0.44 ± 0.02
0.43 ±0.02
N/A
0.40 ± 0.02
0.40 ±0.17
N/A
Prostate gland (mg)
Absolute
Adjusted for body weight
24.2	± 1.4
24.3	± 1.2
N/A
21.3 ± 1.5
20.7 ± 1.2
N/A
20.7 ± 1.4
21.2 ± 1.2
N/A
Sperm
Motility (%)
91.0 ± 1.1
N/A
87.6 ±2.5
N/A
87.9 ±3.7
N/A
Density (*106 per
gram caudal tissue)
1378±101
N/A
1247 ± 92
N/A
973 ± 93b
N/A
Morphology
(% abnormal sperm)
4.24 ± 1.2
N/A
4.30 ±0.78
N/A
6.03 ± 1.47
N/A
Length of estrous cycle (days)
N/A
5.19 ± 0.2e
N/A
5.17 ± 0.1f
N/A
4.94 ± 0.2s
"Mean ± standard error.
bSignificantly different from controls (F test, p < 0.05).
°Kidneys weighed with adrenal glands attached.
Significantly different from controls (F test, p < 0.01).
eEstrous cycle length was > 7 days or could not be accurately estimated for 4 of 20 control females.
fEstrous cycle length was > 7 days or could not be accurately estimated for 2 of 20 low-dose females.
8Estrous cycle length could not be accurately estimated for 2 of 20 high-dose females.
N/A = not applicable.
Source: Gulati et al. (1985).
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Table 6. Reproductive Performance in Second Generation Mice Treated with
Ethoxyethanol Acetate in Drinking Water
Reproductive Parameter
Dose (mg/kg-day)
0
930
1860
Mating Index ("/<>)"
90 (18/20)
95 (19/20)
50 (10/20)
Fertility index (%)b
55 (11/20)
65 (13/20)
45 (9/20)
Live pups per litter
Male
Female
Combined
5.73 ± 0.65°
5.02 ±0.57
11.55 ± 0.61
4.92 ±0.68
5.31 ±0.72
10.23 ±0.96
4.00 ± 1.05
4.22 ±0.78
8.22 ± 1.53
Proportion of pups born alive
0.96 ±0.04
0.99 ±0.01
0.77 ±0.13
Live pup weight (g)
Male
Female
Combined
1.63 ±0.04
1.55 ±0.03
1.59 ±0.03
1.72 ±0.06
1.59 ± 0.04e
1.68 ±0.07
1.68 ± 0.06d
1.55 ±0.04
1.60 ±0.04
Adjusted live pup weight (g)f
Male
Female
Combined
1.69 ±0.03
1.59 ±0.03
1.65 ±0.03
1.69 ±0.03
1.58 ± 0.02e
1.65 ±0.03
1.66 ± 0.04d
1.52 ±0.03
1.57 ±0.04
aNumber with copulatory plugs per number of cohabited pairs in parentheses.
bNumber of fertile pairs per number of cohabited pairs in parentheses.
°Mean ± standard error.
dOne litter in this group contained no live male pups.
eOne litter in this group contained no live female pups.
fLeast squares estimate of mean ± standard error adjusted for average litter size.
Source: Gulati et al. (1985).
Based on the three companion mouse studies conducted under the NTP RACB protocol,
Gulati et al. (1985) concluded that ethoxyethanol acetate is a reproductive toxicant in mice based
on effects on reproductive performance in F0 mice characterized by decreases in fertility, the
number of litters per fertile pair, live pups per litter, proportion of pups born alive, and pup
weights at >1860 mg/kg-day. Gulati et al. (1985) also concluded that females appeared more
sensitive to these effects based on a nearly 50% decline in fertility and decreased number of live
pups per litter in the crossover mating study. Sperm parameters, testes weights, and an increased
incidence of abnormal sperm suggested modest effects on the male mice as well.
Second-generation animals also exhibited a slight reduction in fertility at 1860 mg/kg-day and
prominent histopathologic changes in the testes and epididymis of males. Based on these
findings, Lamb et al. (1987) identified a NOAEL of 930 mg/kg-day for reproductive toxicity.
For the purpose of this review, a NOAEL of 930 mg/kg-day and a LOAEL of 1860 mg/kg-day
are identified for reproductive toxicity.
Inhalation Exposure
Subchronic Studies—Truhaut et al. (1979) exposed a group of 40 male and 40 female
Wistar rats and a group of 2 male and 2 female New Zealand rabbits to ethoxyethanol acetate
(>99% purity) vapor at 200 ppm (1081 mg/m3), 4 hours/day, 5 days/week, for 10 months.
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Groups of 10 male and 10 female Wistar rats and 2 male and 2 female New Zealand rabbits
served as controls. Evaluations included body weight, hematology (RBC and WBC counts and
Hgb content), urinalysis (pH, protein, glucose, ketone bodies, and nitrites), gross pathology, and
detailed histopathology. Data showed no significant effects on growth or hematology, and
Truhaut et al. (1979) reported that no hematuria or ketonuria was observed. The authors reported
histological lesions described as "tubular nephritis with clear degeneration of the epithelium with
hyaline and granular tubular casts" in the kidneys of male rats and rabbits of both sexes (data not
shown). The authors did not observe any significant lesions in female rats, and they reported a
progressive restoration of the renal parenchyma in surviving animals following the exposure
period. Based on the evidence of renal damage in rabbits and male rats, a freestanding LOAEL
"3
of 200 ppm (1081 mg/m ) is identified for this study, although interpretation of these results is
limited by the small group sizes for rabbits and incomplete reporting of study details.
Carpenter (1947) exposed groups of three adult male dogs to 0 or 600 ppm (0 or
"3
3243 mg/m ) ethoxyethanol acetate vapor, 7 hours/day, 5 days/week, for 24 weeks. The
available study description was very brief. Evaluations included body weight, hematology
(complete blood counts and reticulocyte count), serum phosphorus, blood urea nitrogen,
sulfobromophthalein excretion, urinalysis (endpoints not specified), gross pathology, and
histopathology (liver, kidney, adrenal, thyroid, bladder, heart, intestine, lung, pancreas, spleen,
and testis). The author reported that no significant treatment-related effects were observed in
dogs exposed to ethoxyethanol acetate vapor for 24 weeks (data not shown). Although 600 ppm
(3243 mg/m3) appears to be a NOAEL for this study, the interpretation of these results is limited
by the small group sizes and incomplete reporting of study details.
Reproductive/Developmental Studies—Groups of Sprague-Dawley rats were exposed
to ethoxyethanol acetate vapor at 130, 390, or 600 ppm (703, 2108, or 3243 mg/m3), 7 hours/day,
on GDs 7-15 (Nelson et al., 1984; NIOSH, 1982). Group sizes were 15, 15, and 9 for the low-,
mid-, and high-concentrations, respectively. Data were compared to a pooled sham-exposed
control group of 34 rats. Evaluations included maternal body weights and number of resorption
sites and live fetuses. Upon sacrifice of the dams, fetuses were removed, weighed, sexed, and
examined for visceral abnormalities and skeletal defects. Nelson et al. (1984) reported that
maternal body weights were reduced at higher concentrations (data not shown). They considered
the weight reduction among dams at the higher exposure concentrations likely to be due to
increased resorptions among these groups (see below). The authors did not report corrected
maternal body weights based on gravid uterine weights. Table 7 summarizes pregnancy outcome
data. All implants were resorbed in the 600-ppm group. Mean number of resorptions per litter
were also significantly (p < 0.05) increased in the 390-ppm group. There were significant
decreases in fetal weights at 130 (<5%) and 390 (21%) ppm. Visceral and skeletal
malformations were significantly increased (on a litter basis) in the 390-ppm group, including
malformations of the heart, umbilicus, and ribs. One fetus from the 130-ppm group also
exhibited a heart malformation. Nelson et al. (1984) argued that as heart defects rarely occur
spontaneously and in the absence of a similar malformation in any control rat, this defect was
likely related to ethoxyethanol acetate treatment. There were also significant increases in the
incidences of visceral variations at 390 ppm and skeletal variations at 130 and 390 ppm. Nelson
et al. (1984) concluded that ethoxyethanol acetate was teratogenic at >130 ppm in rats. Based on
increased resorptions, decreased fetal weights, and increased incidences of malformations and
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Table 7. Developmental Effects in Rats Exposed to Ethoxyethanol Acetate Vapor

During Gestation



Exposure Concentration (mg/m3)
Parameter
0
703
2108
3243
Number pregnant/number mated
34/41
15/15
15/20
9/9
Mean number of implants per dam
12.7
14.5a
12.9
14.7a
Litters with resorptions (%)b
14 (42)
7 (47)
9(56)
9 (100)
Mean number of resorptions per litter
0.64
0.49
2.3a
14.7a
Resorptions (% of implants)b
23 (5)
8(4)
35 (17)
103 (100)
Mean number of live fetuses per litterb
12.2
14.0
10.8
0
Mean live fetal weights (g)




Female
3.46
3.31°
2.74°
N/A
Male
3.64
3.46°
2.85°
N/A
Incidence of visceral malformations




Total (based on number of litters)
0/34
1/15
3/15d

Total (based on number of fetuses)
0/270
1/142
7/116

Cardiac



N/A
IV septal defect
0/270
0/142
6/116
Ringed aortic arch
0/270
1/142
2/116

Rt.-sided ductus arteriosus
0/270
0/142
1/116

Umbilical hernia
0/270
0/142
2/116

Incidence of skeletal malformations




Total (based on number of litters)
0/34
0/15
3/15d

Total (based on number of fetuses)
0/137
0/69
4/59
N/A
Ribs




Wavy
0/137
0/69
2/59

Fused
0/137
0/69
1/59

Incidence of visceral variations




Total (based on number of litters)
26/34
14/15
15/15d
N/A
Total (based on number of fetuses)
79/270
47/142
58/116

Incidence of skeletal variations




Total (based on number of litters)
19/34
14/15e
15/15d
N/A
Total (based on number of fetuses)
37/137
39/69
56/59

Significantly different from controls (Kruskal-Wallis test, p < 0.05).
Statistical analysis was not conducted for this endpoint.
Significantly different from controls (mixed model analysis of covariance using MLE, p < 0.05).
Statistical significance was evaluated using the litter as the experimental unit. Significantly different from
controls (Kruskal-Wallis test,/? < 0.01).
"Statistical significance was evaluated using the litter as the experimental unit. Significantly different from controls
(Kruskal-Wallis test, p < 0.05).
Source: Nelson etal. (1984).
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"3
variations among fetuses of treated dams, the low exposure level of 130 ppm (703 mg/m ) is
identified as a LOAEL for this study; a NOAEL is not identified.
Tyl et al. (1988) exposed groups of 30 pregnant Fischer 344 rats to ethoxyethanol acetate
(99.8% purity) vapor at 0, 50, 100, 200, or 300 ppm (0, 270, 541, 1081, or 1622 mg/m3),
6 hours/day on GDs 6-15. Evaluations of dams included clinical signs, food and water
consumption, body weights, hematology (RBC, WBC, and platelet counts, Hgb, Hct, mean
corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], and mean corpuscular
hemoglobin concentration [MCHC]), organ weights (liver, kidneys, thymus, spleen, uterus),
number of corpora lutea, number of resorption sites, and gross examination of reproductive,
abdominal, and thoracic organs and cavities. Fetuses were weighed and examined for external,
visceral, and skeletal malformations and variations. Table 8 summarizes maternal effects. Food
consumption and maternal body-weight gain were both significantly (p < 0.05) reduced at
>200 ppm during the exposure period. However, Tyl et al. (1988) reported that by study
termination, maternal body weight, as well as gravid uterine weight, was similar to controls (data
not reported). During the postexposure period, food consumption was significantly (p < 0.05)
reduced only at 300 ppm. Tyl et al. (1988) reported that treated dams exhibited periocular
wetness and encrustation; these data were not shown. Hematological changes included increased
(15%) WBC count and decreased (7-9%) platelet count at >200 ppm, and decreased RBC count,
Hgb, Hct, and MCV at >100 ppm. Tyl et al. (1988) reported that all maternal organ weights
were similar to controls except for increased absolute liver weights in all treatment groups and
increased relative liver weights at >100 ppm. Tyl et al. (1988) considered increased liver
weights to be an adaptive response rather than a pathological response because the liver is the
presumed site of metabolism.
The pregnancy rate was high and uniform across all treatment groups, and there was no
treatment-related effect on the number of corpora lutea (Tyl et al., 1988). Table 9 summarizes
significant developmental effects. There was a small significant increase in the number of
nonviable implantations per litter at 300 ppm. Fetal body weights were significantly reduced at
>200 ppm. Although no external malformations were observed, there were significant increases
in the incidences of visceral (cardiovascular and renal) malformations at 300 ppm and skeletal
(cervical rib) and total malformations at >200 ppm. The incidences of numerous individual
visceral (again, primarily cardiovascular and renal) and skeletal variations (and one external
variation) were increased as well. The most sensitive visceral variations were increased at
>100 ppm, while the most sensitive skeletal variations were increased at >50 ppm. Tyl et al.
(1988) did not consider 50 ppm to be a LOAEL because there were no other indications of
fetotoxicity at this level other than an increase in two indications of reduced ossification in the
rat fetal skeleton. Therefore, Tyl et al. (1988) identified a NOAEL of 50 ppm for rats in this
study. However, for the purpose of this review, based on evidence of a developmental delay at
50 ppm characterized by reduced ossification and increased incidence and severity of
"3
developmental effects at higher concentrations, the low concentration of 50 ppm (270 mg/m ) is
identified as a LOAEL for developmental toxicity; a NOAEL is not identified. Maternal effects
occurred with a LOAEL of 100 ppm (541 mg/m3) and NOAEL of 50 ppm (270 mg/m3), based on
decreases in RBC parameters (RBC count, Hgb, Hct) in dams.
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Table 8. Significant Maternal Changes in Rats and Rabbits Treated with Ethoxyethanol
Acetate Vapor via Inhalation During Gestation
Parameter
Exposure Concentration (mg/m3)
0
270
541
1081
1622
Rats
Number of dams pregnant at
termination
28
28
28
28
29
Maternal weight change (g)
GDs 6-15
25.5 ±4.5a
25.6 ±4.4
24.5 ±4.6
20.8 ± 4.1b
16.2 ± 3.6b
Maternal food intake (g/day)
GDs 6-15
15.82 ± 1.12
15.47 ± 1.17
15.38 ±0.91
14.75 ±0.79b
13.73 ±0.84b
Hematology
WBC count
6.7 ± 1.3
7.1 ±0.9
6.8 ± 1.0
7.8 ± 1.0b
8.1 ± 1.0b
RBC count
6.3 ±0.5
6.2 ±0.3
6.0 ± 0.3C
5.9 ± 0.4b
5.9 ± 0.5b
Hgb
12.6± 1.0
12.3 ±0.6
11.8 ± 0.8°
11.7 ± 1.0b
11.6 ± l.lb
Hct
34.6 ±2.7
33.6 ±2.0
32.4 ± 1.7°
32.0 ± 2.5b
31.8 ± 2.8b
MCV
54.6 ±0.6
54.3 ±0.6
54.1 ±0.7d
54.1 ±0.8C
54.1 ± 0.5°
Platelets
1072 ±98
1075 ± 74
1038 ±59
982 ±124b
1001± 79°
Rabbits
Number of does pregnant at
termination
22
21
23
19
19
Maternal weight change
GDs 6-9
GDs 6-18
-58 ± 60
12 ± 117
-77 ± 72
9 ± 125
-111 ±5d
-60 ±211
-173 ± 86b
-107±150
-241 ± lllc
-231 ± 130°
Hematology
MCV
66.5 ±2.5
66.4 ±2.0
66.1 ± 1.7
66.5 ±2.7
68.4 ± 2.5C
Platelets
487±102
471±117
417 ±13 8d
395 ±103°
257 ± 88b
aMean± SD.
bSignificantly difference from controls (/-test,/? < 0.001).
Significantly different from controls (/-test, p < 0.01).
Significantly different from controls (/-test, p < 0.05).
Source: Tyl et al. (1988).
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Table 9. Developmental Effects in Rats Exposed to Ethoxyethanol Acetate Vapor via
Inhalation During Gestation
Parameter
Exposure Concentration (mg/m3)
0
270
541
1081
1622
Number of dams pregnant at termination
28
28
28
28
29
Viable implants/litter3
Nonviable implants/litter3
10.4 ±2.6
0.1 ±0.4
10.9 ± 1.1
0.3 ±0.6
10.8 ± 1.9
0.4 ±0.6
10.3 ± 1.5
0.4 ±0.6
10.8 ± 1.2
0.5 ± 0.7b
Number of litters examined
28
28
28
28
29
Fetal body weights/litter (g)"
All fetuses
Male fetuses
Female fetuses
4.3	±0.19
4.4	±0.19
4.2 ±0.12
4.3	±0.10
4.4	±0.19
4.1 ± 0.19
4.3 ±0.10
4.5 ±0.14
4.2 ± 0.11
4.1	± 0.30°
4.2	± 0.24°
3.9 ± 0.32°
3.7 ± 0.12°
3.9 ± 0.11°
3.6 ± 0.13°
Malformations'1
Visceral
Skeletal
Total
5/28
2/27
7/28
3/28
4/28
6/28
2/28
5/28
6/28
7/28
15/28e
18/28e
26/29"
2 l/29e
27/29e
Most sensitive external variations'1
Cranial ecchymosis
7/28
11/28
11/28
7/28
22/29e
Most sensitive visceral variations'1
Irregular rugae on palate
Left subclavian branches distal to ductus
arteriosus
10/28
0/28
11/28
4/28
21/28e
6/28e
26/28e
7/28e
24/29e
16/29e
Most sensitive skeletal variations'1
Unossified anterior arch of atlas
Poorly ossified metatarsals (hindlimb)
9/27
7/27
20/28e
15/28e
24/28e
16/28e
27/28e
25/28e
29/29e
4/29
aMean± SD.
bSignificantly different from controls (Mann-Whitney U test, p < 0.05).
Significantly different from controls (Mann-Whitney U test, p < 0.001).
incidence based on number of litters.
"Significantly different from controls (Fisher's exact test, p < 0.05).
Source: Tyl et al. (1988).
In a companion rabbit study, Tyl et al. (1988) exposed groups of 24 pregnant New
Zealand white rabbits to ethoxyethanol acetate (99.8% purity) vapor at 0, 50, 100, 200, or
300 ppm (0, 270, 541, 1081, or 1622 mg/m3), 6 hours/day on GDs 6-18. Aside from not
measuring food and water consumption, rabbits were evaluated for the same endpoints as
outlined above in the companion rat study through GD 29. Table 8 summarizes maternal effects.
Rabbits experienced significant decreases in body-weight gain at >100 ppm during the first few
days of the exposure period (GDs 6-9), but only at 300 ppm, based on the full exposure period.
During the postexposure period, rabbits exposed to 300 ppm exhibited a significant increase in
weight gain over controls. Clinicals signs reported by the researchers included scant feces on
paperboard (indirect evidence of reduced feed consumption) at >100 ppm, and occult blood
predominately at >200 ppm. Tyl et al. (1988) reported that gravid uterine weights were 73.99%
of controls at 200 ppm and 18.77%) of controls at 300 ppm. These findings were consistent with
5/19 and 16/19 resorbed litters observed at 200 and 300 ppm, respectively, as reported by the
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authors. Tyl et al. (1988) also reported that absolute liver weights were significantly increased
(121.24%) at 300 ppm compared to controls. Tyl et al. (1988) noted that relative liver weights
were not significantly different from controls at this level. As mentioned above, Tyl et al. (1988)
considered increased liver weights to be an adaptive response rather than a pathological response
because the liver is the presumed site of metabolism. Hematological data showed changes
including significant elevation of MCV at 300 ppm and a dose-related decrease in the number of
platelets achieving significance at >100 ppm (see Table 8).
The pregnancy rate of rabbits at >200 ppm was slightly reduced compared to controls,
but this difference was not statistically significant (Tyl et al., 1988). Table 10 summarizes
developmental effects in rabbits. At the highest exposure level, there was a significant reduction
in corpora lutea per doe and a significant increase in early resorptions per litter. The number of
viable implants per litter was significantly reduced at 200 and 300 ppm in dose-related fashion,
and the number of nonviable implants per litter was increased accordingly at these same
concentrations. The number of litters with live fetuses was markedly reduced at both 200 ppm
and 300 ppm, with only three surviving litters at 300 ppm. The small number of litters in the
300-ppm group influenced the results of statistical testing of fetal data for this group. Fetal
weights per litter were comparable to controls at 50, 100, and 200 ppm but appeared to be
reduced by about 10% at 300 ppm compared to controls (difference was not significant).
External, visceral, and skeletal malformations were significantly increased on a litter basis at
200 and (in some cases) 300 ppm. Only 11 fetuses from three surviving litters were available for
examination at 300 ppm, and all were malformed. External malformations were predominantly
in the tail, which Tyl et al. (1988) notes as a finding to which New Zealand white rabbits are
predisposed. Visceral malformations included ventricular septal defects and absent postcaval
lung lobes and kidneys. Only one skeletal malformation was significantly increased in rabbits
exposed at the highest concentration—rudimentary 14th ribs. The data on developmental
variations showed that the most sensitive individual external and visceral variations occurred at
200 ppm, while the most sensitive skeletal variations were increased at 100 and 200 ppm.
Tyl et al. (1988) identified a NOAEL of 50 ppm in this study for rabbits for both maternal and
developmental toxicity. For the purpose of this review, a NOAEL of 50 ppm (270 mg/m3) and a
"3
LOAEL of 100 ppm (541 mg/m ) are identified based on decreased body weight and
hematological changes in dams and skeletal variations in fetuses.
Imperial Chemical Industries (1983a,b) conducted two inhalation studies with
ethoxyethanol acetate on groups of pregnant Dutch rabbits to assess maternal and developmental
effects. In this first study, groups of eight rabbits were exposed to ethoxyethanol acetate
(99% purity) vapor at mean measured exposure concentrations of 0, 111, 224, or 420 ppm
(0, 600, 1211, or 2270 mg/m3) (Imperial Chemical Industries, 1983a). In the second study,
larger groups (24/group) were exposed to mean measured exposure concentrations of 0, 25, 99,
or 412 ppm (0, 135, 535, or 2227 mg/m3) (Doe, 1984; Imperial Chemical Industries, 1983b). In
both studies, rabbits were exposed 6 hours/day on GDs 6-18. Maternal evaluations included
survival, body weight, food consumption, hematology (Hgb, Hct, total WBC count, RBC count,
MCV, MCH, MCHC), spleen and uterus weights, and a detailed pathological examination. In
addition, implantation loss was calculated based on numbers of corpora lutea, implantations, and
live fetuses. In both studies, fetuses were examined for weight and gross abnormalities.
However, examinations for visceral and skeletal abnormalities were only conducted in the
second study (Doe, 1984; Imperial Chemical Industries, 1983b).
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Table 10. Developmental Effects in Rabbits Exposed to Ethoxyethanol Acetate Vapor via
Inhalation During Gestation




Exposure Concentration (mg/m3)
Parameter
0
270
541
1081
1622
Number of does pregnant at termination
22
21
23
19
19
Corpora lutca/doc"
11.3 ±2.3
10.2 ± 1.5
11.0 ± 2.1
10.9 ±2.0
9.4 ± 2.4b
Viable implants/litter3
8.3 ±2.1
7.5 ±2.7
8.3 ±2.6
5.4 ± 4.1b
0.6 ± 1.6b
Nonviable implants/litter3
0.7 ±0.8
0.4 ±0.8
0.7 ± 1.0
3.5 ± 3.6b
6.8 ± 3.2b
Early resorptions/litter '
0.3 ±0.6
0.0 ±0.2
0.1 ±0.3
2.3 ±3.6
6.5 ± 3.4b
Number of litters with no live fetuses
0
0
1
5
16
Number of litters examined
22
21
22
14
3
Fetal body weights/litter (g)a





All fetuses
41.8 ±5.1
45.2 ±5.8
39.8 ±6.3
40.8 ±5.9
36.4 ± 1.3
Male fetuses
41.4 ±6.5
45.9 ±5.8
40.0 ±6.0
40.1 ± 6.0°
37.1 ±2.3
Female fetuses
41.5 ±5.6
43.8 ± 5.9°
39.7 ±7.2
41.0 ±6.7
37.4 ± 3.3°
Malformations'1





External
1/22
2/21
1/22
7/14e
3/3e
Visceral
9/22
12/21
11/22
12/14e
3/3
Skeletal
1/22
5/20
1/22
12/14e
2/3e
Total
10/22
15/21
12/22
14/14®
3/3
Most sensitive external variations'1





Blunt-tipped tail
0/22
1/21
1/22
5/14e
1/3
Most sensitive visceral variations'1





Irregular rugae on palate
11/22
11/21
14/22
13/14e
2/3
Incomplete septation of lung lobes
2/22
1/21
0/22
7/14e
3/3e
Partial fetal atelectasis
0/22
1/21
2/22
5/14e
0/3
Most sensitive skeletal variations'1





Extra thoracic centrum and arch (Number 13)
6/22
5/20
15/22e
13/14e
2/2
Extra ribs on thoracic centra and arch 13,
6/22
5/20
14/22e
13/14e
2/2
bilateral





Poorly ossified sternebra 6
9/22
10/20
17/22e
ll/14e
0/2
Misshapen sternebrae
2/22
0/20
10/22e
6/14e
1/2
Split sternebrae
0/22
1/20
5/22e
1/14
0/2
Unossified sternebrae
6/22
7/20
16/22e
ll/14e
1/2
aMean± SD.
bSignificantly different from controls (Mann-Whitney U test, p < 0.05; Dunnett's test for viable implants/litter).
°At 50 ppm, n = 19; at 200 ppm; n = 13; and, at 300 ppm, n = 2.
incidence based on number of litters.
"Significantly different from controls (Fisher's exact test, p < 0.05).
Source: Tyl et al. (1988).
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Imperial Chemical Industries (1983a) observed a reduction in body-weight gain and food
consumption among all treatment groups compared to controls during the first few days of
exposure (GDs 5-10) (see Table 11). These differences only achieved statistical significance
(p < 0.05) at 420 ppm. Subsequent weight gain was comparable to controls. Food consumption
was significantly higher than controls at 420 ppm during the postexposure period (GDs 19-21).
Aside from a single rabbit exposed to 420 ppm that exhibited marked ataxia, loss of withdrawal
reflex, and slight head tremors, the study authors noted no other clinical signs. Postmortem
examination of the observably sick rabbit revealed 100% postimplantation loss but no indication
of the cause of the clinical signs. Mean gravid uterine weights at sacrifice were reduced among
all treatment groups compared to controls, but the difference was only significant at 420 ppm.
The data showed no significant maternal effects based on hematology, spleen weights, or
pathology. Table 11 summarizes litter data. There was a dose-related increase in group mean
percentage preimplantation loss that was statistically different from controls at 111 and
420 ppm—but not at 224 ppm. There were also apparent increases in postimplantation loss and
decreases in number of viable fetuses at 420 ppm, although the differences from controls were
not statistically significant. The number of early intrauterine deaths was significantly increased
at 420 ppm. Mean fetal weights per litter were significantly reduced in all treatment groups.
Imperial Chemical Industries (1983a) reported that gross fetal examination did not reveal any
significant abnormalities (data not shown). For the purpose of this review, a NOAEL of
224 ppm (1211 mg/m3) and a LOAEL of 420 ppm (2270 mg/m3) are identified for maternal
toxicity based on slight reductions in gestational body-weight gains. A LOAEL of 111 ppm
(600 mg/m3) (lowest concentration tested) is identified for developmental toxicity based on
reductions in mean fetal weights.
In the second study, reductions in maternal body-weight gain and food consumption were
observed among all treatment groups compared to controls (Doe, 1984; Imperial Chemical
Industries, 1983b) (see Table 12). Similar to the first study, these reductions were mainly
confined to the first few days of exposure (GDs 5-8). These differences only achieved statistical
significance (p < 0.05) at 412 ppm. Subsequent recovery towards control values was observed
for both body-weight gain and food consumption. During the postexposure period, body-weight
gain and food consumption were significantly increased over controls at 412 ppm. The data
showed no significant (p < 0.05) changes in spleen weights or pathology. Hematological
changes included a significant (p < 0.05) reduction in Hgb concentration at 412 ppm (see
Table 12). The other hematological parameters exhibited a dose-related reduction, but none
were significantly different from controls at any exposure level.
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Table 11. Important Maternal and Developmental Effects in Rabbits Exposed to
Ethoxyethanol Acetate Vapor During Gestation
Parameter
Exposure Concentration (mg/m3)
0
600
1211
2270
Number of does
5
5
7
6
Maternal body-weight gain (g)
GDs 5-10
GDs 0-20
23.8 ± 27.3a
103.6 ± 152.2
0.0 ±77.6
117.6 ±208.4
-46.6 ±90.5
140.7 ± 158.6
-115.2 ±71.5b
89.0 ± 110.3
Gravid uterine weight (g)
121.2 ± 46.1
113.7 ± 21.5
116.9 ± 42.0
70.7 ± 30.5C
Number of implantations
7.4 ± 1.1
7.0 ± 1.6
6.7 ±2.6
7.2 ± 1.9
Preimplantation loss
Mean ± SD
Percentage litters affected
0.0 ±0.0
0
15.0 ± 9.9b
80.0d
19.4 ±25.5
57.1
27.1 ±25.4C
83.3d
Postimplantation loss
Mean ± SD
Percentage litters affected
20.0 ±44.7
20.0
11.7 ± 16.2
40.0
11.3 ± 13.3
57.1
37.5 ±39.4
66.6
Number of viable fetuses
6.0 ±3.5
6.2 ± 1.9
6.0 ±2.4
4.3 ±3.0
Intrauterine deaths
Early
Late
0.0 ±0.0
1.4 ± 3.1
0.6 ±0.9
0.2 ±0.4
0.4 ±0.5
0.3 ±0.5
2.3 ±2.7C
0.5 ±0.8
Fetal weight/litter (g)
5.2 ± 0.2e
4.3 ± 0.4b
4.2 ± 0.3b
3.4 ± 0.6b'e
aMean± SD.
bSignificantly different from controls (Student's t-test, p < 0.01).
Significantly different from controls (Student's t-test, p < 0.05).
dSignificantly different from controls (Fisher's exact test, p < 0.05).
eOne rabbit had no live fetuses.
Source: Imperial Chemical Industries (1983a).
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Table 12. Significant Maternal and Developmental Effects in Rabbits Exposed to
Ethoxyethanol Acetate Vapor During Gestation
Parameter
Exposure Concentration (mg/m3)
0
135
535
2227
Number of pregnant does at
termination
16
15
17
19
Maternal body-weight gain (g)
GDs 5-8
GDs 5-18
-5.8 ± 25.6a
94.8 ± 109.8
-10.9 ±26.4
73.9 ± 91.5
-33.5 ±59.7
62.3 ± 117.0
-61.4 ± 55.4b
-1.5 ± 123,4C
Hematology
Number of animals examined
Hgb (g/dl)
Hct
RBC count (xl012/l)
WBC count (xl09/l)
13
12.6 ± 1.1
0.38 ±0.3
5.65 ±0.4
3.64 ± 1.9
14
12.5 ± 1.5
0.38 ±0.4
5.76 ±0.57
3.18 ±2.1
16
12.0 ±0.8
0.37 ±0.02
5.60 ±0.24
2.96 ± 1.6
18
11.8 ± 0.9°
0.37 ±0.03
5.50 ±0.41
2.92 ± 1.5
Number of implantations
7.3 ± 1.8
6.3 ±3.4
8.1 ±3.3
6.5 ±3.0
Preimplantation loss (%)d
14.0
19.1
8.2
12.3
Postimplantation loss (%)d
9.4
18.1
6.7
24.4C
Number of live fetuses/litter
6.6 ± 1.6
5.1 ±2.8
7.4 ± 3.0e
4.9 ± 3.2C
Total litter weight (g)
230 ± 63
194 ± 83f
223 ± 68e
179 ± 72c'f
Live fetal weight (g)
Number of fetuses
34.7 ±4.9
106
35.2 ± 5.9f
77
30.1 ±6. lbe
111
30.8 ± 4.2b'f
93
External and visceral defects
No. (%) showing any defects
No. (%) showing major defects
22 (20.8)
0
18 (23.4)
1(1.3)
30 (27.0)
2(1.8)
51 (54.8)8
3 (3.2)
Skeletal defects
No. (%) variants
No. (%) showing any defects
No. (%) showing major defects
50 (47.2)
23 (21.7)
1 (0.9)
40 (51.9)
14(18.2)
0
72 (64.9)8
37 (33.3)h
0
92 (98.9)8
91 (97.8)8
6 (6.5)h
aMean ± SD, unless otherwise noted.
bSignificantly different from controls (Student's t-test, p < 0.01).
Significantly different from controls (Student's t-test, p < 0.05).
Values reported as percentages.
"Excludes two mid-dose females who littered early and whose fetuses were partially eaten.
fExcludes four females with total resorptions (1 low-dose and 3 high-dose).
8Significantly different from controls (Fisher's exact test, p < 0.01).
hSignificantly different from controls (Fisher's exact test, p < 0.05).
Sources: Doe (1984); Imperial Chemical Industries (1983b).
Four rabbits (three from the 412-ppm group and one from the 25-ppm group) experienced
100% resorptions (Doe, 1984; Imperial Chemical Industries, 1983b). These animals
demonstrated vaginal bleeding, weight loss, lethargy, and fatty tissue in the excreta tray. There
was a significant increase in postimplantation loss at 412 ppm (see Table 12). Doe (1984)
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reported that when data based on the three rabbits that experienced 100% resorptions at this level
were excluded, there were no statistically significant differences in percentage postimplantation
loss. Other findings included significant decreases in the number of viable fetuses at 412 ppm
and significant reductions in live fetal weights at >99 ppm. Mean litter weights were only
significantly lower than controls at 412 ppm. While the researchers recognized that the
reduction in mean fetal weight at 99 ppm may be attributable in part to the higher proportion of
litters containing a large number of fetuses with subsequent intralitter competition, they
suggested that it may also be evidence of a slight fetotoxic effect at 99 ppm. The incidence of
external/visceral defects was significantly increased at 412 ppm, while the incidences of skeletal
defects and skeletal variations were increased at >99 ppm (see Table 12). External and visceral
defects included moderately dilated brain ventricles, malrotated forelimbs, and agenesis of the
right kidney. There was also a significant difference in the incidence of pale and reduced spleens
at 99 and 412 ppm. However, Imperial Chemical Industries (1983b) points out that this finding
is difficult to interpret and is of unknown biological significance. Skeletal defects included
misaligned vertical arches, additional hemivertebrae, increased numbers of thoracic ribs, and
retarded ossification in the vertebrae and sternebrae. Doe (1984) concluded that ethoxyethanol
acetate was teratogenic at 412 ppm. Based on these findings, the researchers identified 25 ppm
as a NOAEL, 99 ppm as fetotoxic, and 412 ppm (2227 mg/m3) as teratogenic. For the purposes
of this review, A NOAEL of 25 ppm (135 mg/m3) and a LOAEL of 99 ppm (535 mg/m3) are
identified for developmental toxicity based on reduced fetal body weights and increased skeletal
"3
variations and malformations. A NOAEL of 99 ppm (535 mg/m ) and a LOAEL of 412 ppm
(2227 mg/m3) are identified for maternal toxicity based on reduced weight gain and a marginal
reduction in blood Hgb concentration.
Other Studies
Genotoxicity
Ethoxyethanol acetate tested negative for mutagenicity in bacterial tests using Salmonella
typhimurium strains TA98, TA100, TA102, TA104, TA1535, TA1537, and TA1538 (JCIETIC,
2000 as cited in Environmental Canada, 2009; Slesinkski et al., 1988), Escherichia coli strain
WP2uvrA/pKM101 (JCIETIC, 2000 as cited in Environmental Canada, 2009), and Chinese
hamster ovary (CHO) cells at the HGPRT locus (Slesinski et al., 1988) with and without
metabolic activation. Slesinski et al. (1988) also reported negative findings in vitro for SCE in
CHO cells with and without activation. Positive results were obtained in the presence of
metabolic activation in CHO cells during a clastogenicity test (not further described;
Slesinski et al., 1988). In the absence of metabolic activation, results were only weakly positive.
In vivo, ethoxyethanol acetate was negative for micronuclei induction in mouse bone marrow
cells following intraperitoneal injection (Slesinski et al., 1988). An epidemiological
investigation evaluated the genotoxic potential of glycol ethers among workers at a varnish
production plant with known exposure to 2-ethoxyethanol, ethoxyethanol acetate, and
2-butoxyethanol (Sohnlein et al., 1993). No cytogenetic effects based on micronuclei induction
or SCE were observed.
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DERIVATION OF SUBCHRONIC AND CHRONIC PROVISIONAL ORAL
RfD VALUES FOR ETHOXYETHANOL ACETATE
Oral studies of ethoxyethanol acetate are limited to a subchronic study specifically
designed to evaluate effects on the male reproductive system (Nagano et al., 1984, 1979) and an
NTP reproductive toxicity study in mice following the RACB protocol (Morrissey et al., 1989;
Lamb et al., 1987; Gulati et al., 1985). There are no chronic oral data available for
ethoxyethanol acetate. Table 13 summarizes the available data. Nagano et al. (1984, 1979)
observed significant decreases in testes weights and a dose-related atrophy of the seminiferous
epithelium in male mice at >1000 mg/kg-day. Similar effects on the male reproductive system
were noted at >1860 mg/kg-day in the NTP study (degeneration of seminiferous tubules,
interstitial cell hyperplasia, reduction of sperm content, accumulation of fluid and degenerated
cells in the epididymis, increased incidence of abnormal sperm, decreased absolute testis
weights). The NTP evaluation also found functional effects on reproductive parameters at these
doses, including fewer litters per mated mouse pair, decreased numbers of pups per litter, and
depressed body weights of pups born alive. Based on a cross-over mating study, these
researchers concluded that the observed functional reproductive changes were due primarily to
an effect on the females.
Subchronic p-RfD
The lowest LOAEL by oral exposure was observed by Nagano et al. (1984, 1979), and it
was for reduced testicular weight at 1000 mg/kg-day. The corresponding NOAEL was
500 mg/kg-day. Dose-response modeling of the data for both absolute and relative testicular
weights (see Table 1) was attempted. BMD modeling was also attempted for the most sensitive
endpoints from the Gulati et al. (1985) study, including right cauda weights, sperm density,
estrous cycle length (see Table 5), and live pups per litter (see Table 6). Appendix A contains
details of the modeling. Data based on absolute testes weights, sperm density, and estrous cycle
length were not amenable to dose-response modeling (i.e., no adequate fit was achieved with any
model). Model fit based on relative testes weights was achieved after dropping the high-dose
group, which had experienced a high incidence of early mortality (Nagano et al., 1984, 1979).
As shown in Table 14, modeling of the data based on reduced relative testes weights in mice
(Nagano et al., 1984, 1979) resulted in the lowest BMDLisd value across the endpoints where
model fit was achieved (relative testes weight, absolute and adjusted right cauda weights, and
live pups per litter). The BMDisd was 663 mg/kg-day, and the BMDLisd was 499 mg/kg-day.
The BMDLisd (499 mg/kg-day) based on gavage dosing 5 days/week was converted to an
equivalent continuous (7 days/week) dose of 356 mg/kg-day. The BMDLisd of 499 mg/kg-day,
which is virtually identical to the NOAEL of 500 mg/kg-day, was selected as the point of
departure (POD) for derivation of the subchronic p-RfD value.
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Table 13. Summary of Oral Noncancer Dose-Response Information
Species
(«/sex/
group)
Exposure
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Duration-adjusted"
NOAEL
(mg/kg-day)
Duration-adjusted"
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Mouse
(20/sex/
group)
0, 930, 1860,
or 3000
mg/kg-day in
drinking
water
continuously
for 126 days
930
1860
930
1860
Decreased mean
number of litters per
pair, number of live
pups per litter, and
adjusted live pup
weights.
Cross-mating study
suggested that
decreased reproductive
performance was due
primarily to an effect on
females, even though
pathological effects
were observed on the
male (and not female)
reproductive tract.
Morrissey et al.,
1989; Lamb et al.,
1987; Gulati et al.,
1985
Mouse
(5
males/
group)
0, 500, 1000,
2000, or 4000
mg/kg-day
via gavage
5 days/week
for 5 weeks
500
1000
357
714
Decreased testicular
weight.
Study was specifically
designed to assess
effects on the male
reproductive system.
Nagano et al.,
1984, 1979
aAdjusted to continuous exposure.
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Table 14. Summary of BMDs and BMDLs for Endpoints in Mice Treated Orally with Ethoxyethanol Acetate
Endpoint
bmd1sd
(mg/kg-day)
BMDL1sd
(mg/kg-day)
BMDL1sdadj
(mg/kg-day)
Reference
Absolute testes weight
NAa
Nagano et al. (1979)
Relative testes weight
663
499
356
Nagano et al. (1979)
Absolute right cauda weight
1412
992
992
Gulati et al. (1985)
Body-weight-adjusted right cauda weight
1271
917
917
Gulati et al. (1985)
Sperm density
Inadequate for modeling (no significant trend, p > 0.05)
Gulati et al. (1985)
Length of estrous cycle
NA
Gulati et al. (1985)
Live pups per litter
1279
676
676
Gulati et al. (1985)
aNo model adequately fit the data.
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A subchronic p-RfD of 1 mg/kg-day was derived for ethoxyethanol acetate by dividing
the duration-adjusted BMDLisd of 356 mg/kg-day (Nagano et al., 1984, 1979) by an uncertainty
factor (UF) of 300, as shown below:
Subchronic p-RfD = BMDLisd ^ UF
= 356 mg/kg-day 300
= 1 mg/kg-day
The composite UF of 300 is composed of the following UFs:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
•	UFd: The database for oral exposure to ethoxyethanol acetate consists of a single
subchronic toxicity study in mice specifically evaluating the effects on the male
reproductive system and an NTP reproductive evaluation in mice. A factor of 3(10°5)
is applied for database inadequacies because data for evaluating developmental
toxicity are insufficient and might have identified toxic effects at lower levels.
•	UFl: A factor of 1 is applied, additional UF is not warranted when the POD is based
on BMDLisd
•	UFS: A factor of 1 is applied; additional UF for subchronic duration is not warranted
when the POD is based on subchronic exposure.
Confidence in the principal study (Nagano et al., 1984, 1979) is medium. Evaluations
were limited to the male reproductive tract, size of treated groups was small, and reporting of
histopathology results was qualitative. However, a wide range of doses were tested, organ
weight data were provided, and a NOAEL and LOAEL were identified. Confidence in the
database is medium. Reproductive toxicity has been evaluated based on a multigenerational
study in mice that followed a continuous breeding protocol. This study demonstrated
reproductive effects to be a sensitive endpoint for ethoxyethanol acetate and supported the
findings of Nagano et al. (1979, 1984). However, the database is limited because studies are
available on only a single species (mouse), and no multigenerational developmental toxicity
studies are available (developmental effects were a sensitive endpoint for ethoxyethanol acetate
in inhalation studies). Thus, confidence in the subchronic p-RfD is medium.
Chronic p-RfD
To derive the chronic p-RfD in the absence of chronic data, the POD from the subchronic
p-RfD is used along with a composite UF that includes the same areas of uncertainty enumerated
above for the subchronic p-RfD, as well as the application of a subchronic to chronic UF of 10,
as follows:
The composite UF of 3000 is composed of the following UFs:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
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•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
•	UFd: The database for oral exposure to ethoxyethanol acetate consists of a single
subchronic toxicity study in mice specifically evaluating the effects on the male
reproductive system and an NTP reproductive evaluation in mice. A factor of 3(10°5)
is applied for database inadequacies because data for evaluating developmental
toxicity are insufficient and might have identified toxic effects at lower levels.
•	UFl: A factor of 1 is applied, additional UF is not warranted when the POD is based
on BMDLisd
•	UFs: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure because data for evaluating response after
chronic exposure are not available.
This results in a total UF of 3000 for derivation of the chronic p-RfD.
A chronic p-RfD of 0.1 mg/kg-day for ethoxyethanol acetate based on the
duration-adjusted BMDLisd of 356 mg/kg-day in mice (Nagano et al., 1984, 1979) is derived as
follows:
Chronic p-RfD = BMDLisd ^UF
= 356 -3000
= 0.1 mg/kg-day
As discussed for the subchronic p-RfD, confidence in the principal study is medium.
Confidence in the database is reduced to low due to the absence of chronic data. Overall
confidence in the chronic p-RfD is low.
DERIVATION OF SUBCHRONIC AND CHRONIC PROVISIONAL INHALATION
RfC VALUES FOR ETHOXYETHANOL ACETATE
Human inhalation data are limited to epidemiology studies among workers exposed to
mixed atmospheres of glycol ethers. These data suggest that the critical effects in humans
associated with exposure to glycol ethers are hematological, reproductive, and developmental.
These data also suggest that in addition to the inhalation route, potential human health effects
may occur from exposure via the dermal route. However, due to concurrent exposures to
multiple chemicals, the relative contribution of ethoxyethanol acetate to the observed effects
reported in the epidemiology studies is unknown. Therefore, these data are inadequate for
deriving the p-RfC.
Animal data also suggest that ethoxyethanol acetate produces hematological (reduced
hemoglobin and increased WBC levels) and developmental effects. Inhalation studies of
ethoxyethanol acetate include subchronic studies in rats, rabbits, and dogs (Truhaut et al., 1979;
Carpenter, 1947) and developmental studies in rats and rabbits (Tyl et al., 1988; Doe, 1984;
Nelson et al., 1984; Imperial Chemical Industries, 1983a,b). Table 15 summarizes these data.
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Table 15. Summary of Inhalation Noncancer Dose-Response Information
Species
(«/sex/group)
Exposure
NOAEL"
(mg/m3)
LOAEL"
(mg/m3)
Responses at the LOAEL
Comments
Reference
Subchronic toxicity
Rat
(40/sex/group)
0 or 1081 mg/m3
4	hours/day,
5	days/week for
10 months
NA
1081
HEC: 129
Renal tubular nephritis with clear
degeneration of the epithelium
with hyaline and granular tubular
casts (males only).
Study limited by incomplete
reporting of study details.
Truhaut et al.,
1979
Rabbit
(2/sex/group)
0 or 1081 mg/m3
4	hours/day,
5	days/week for
10 months
NA
1081
HEC: 129
Renal tubular nephritis with clear
degeneration of the epithelium
with hyaline and granular tubular
casts.
Study limited by small group size
and incomplete reporting of study
details.
Truhaut et al.,
1979
Dog
(3/group)
0 or 3243 mg/m3
7 hours/day,
5 days/week for
24 weeks
3243
HEC: 676
NA
NA
Study limited by small group size
and incomplete reporting of study
details.
Carpenter, 1947
Developmental toxicity
Rat
(9-15 pregnant
females/group)
0, 703,2108, or
3243 mg/m3
7 hours/day on
GDs 7-15
Developmental:
NA
Developmental:
703
HEC: 205
Decreased fetal weight and
increased fetal skeletal variations;
cardiovascular malformation.
Increased resorptions and visceral
and skeletal malformations at
higher exposure concentrations.
Data are inadequate for assessing
maternal effects.
Nelson et al.,
1984
Rat
(30 pregnant
females/group)
0, 270, 541, 1081,
or 1622 mg/m3
6 hours/day on
GDs 6-15
Maternal:
270
HEC: 68
Developmental:
NA
Maternal:
541
HEC: 135
Developmental:
270
HEC: 68
Maternal: decreased red cell
parameters (RBC count, Hgb, Hct).
Developmental: increased fetal
skeletal variations.
Increased nonviable implants,
decreased fetal body weights, and
increased malformations and
variations at higher exposure
concentrations.
Tyletal., 1988
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Table 15. Summary of Inhalation Noncancer Dose-Response Information
Species
(«/sex/group)
Exposure
NOAEL3
(mg/m3)
LOAEL"
(mg/m3)
Responses at the LOAEL
Comments
Reference
Rabbit
(24 pregnant
females/group)
0, 270, 541, 1081,
or 1622 mg/m3
6 hours/day on
GDs 6-18.
Maternal and
developmental:
270
HEC: 68
Maternal and
developmental:
541
HEC: 135
Maternal: reduced gestational
body-weight gains and
hematological changes.
Developmental: increased fetal
skeletal variations.
Increased resorptions, decreased
viable implants, decreased fetal
weight, and increased
malformations and variations at
higher exposure concentrations.
Tyletal., 1988
Rabbit
(8 pregnant
females/group)
0, 600, 1211, or
2270 mg/m3
6 hours/day on
GDs 6-18
Maternal:
1211
HEC: 303
Developmental:
NA
Maternal:
2270
HEC: 568
Developmental:
600
HEC: 150
Maternal: reduced gestational
body-weight gain.
Developmental: decreased fetal
body weight.
Increased preimplantation loss at
higher exposure concentrations.
Preliminary study with no fetal
evaluations for malformations or
variations.
Imperial Chemical
Industries, 1983a
Rabbit
(24 pregnant
females/group)
0, 135, 535, or
2227 mg/m3
6 hours/day on
GDs 6-18
Maternal:
535
HEC: 134
Developmental:
135
HEC: 34
Maternal:
2227
HEC: 557
Developmental:
535
HEC: 134
Maternal: reduced gestational
body-weight gain and marginal
reduction in blood Hgb
concentration.
Developmental: decreased fetal
body weights and increased fetal
skeletal variations.
Decreased fetal survival and
increased fetal malformations
observed at higher exposure
concentrations.
Doe, 1984;
Imperial Chemical
Industries, 1983b
aHEC calculated as follows: NOAELheC = NOAEL x exposure hours/24 hours x exposure days/7 days x dosimetric adjustment. For nonrespiratory effects, the
chemical is treated as a Category 3 gas (U.S. EPA, 1994b) and the dosimetric adjustment is the ratio of the animal:humanblood:gas partition coefficients for
ethoxyethanol acetate (in the absence of experimental values, a default value of 1 was used).
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To provide a basis for comparing the studies, LOAEL and NOAEL values were adjusted
for continuous exposure and then converted to human equivalent concentrations (HECs). First,
exposure is adjusted to equivalent continuous exposure according to the below equation:
LOAELadj = LOAEL (mg/m3) x hours per day/24 x days per week/7
EPA currently performs this adjustment to continuous exposure for gestational exposure studies,
as for other types of studies (U.S. EPA, 2002). Then, treating ethoxyethanol acetate as a
Category 3 gas for effects on extrarespiratory endpoints, the dosimetric adjustments are made
using the ratio of animal :human blood:gas partition coefficients for ethoxyethanol acetate
(U.S. EPA, 1994b). Johanson and Dynesius (1988) attempted to experimentally determine a
human blood:gas partition coefficient for ethoxyethanol acetate but could not, apparently due to
rapid hydrolysis of the chemical by blood esterases. Gargas et al. (2000) used a saline:air
partition coefficient of 3822 reported by Johanson and Dynesius (1988) for ethoxyethanol acetate
as the blood:air partition coefficient for both rats and humans in their PBPK model. In the
absence of species-specific blood:air partition coefficients for rats and humans, the default ratio
of 1.0 is used to perform the dosimetric adjustment. For each study, the duration-adjusted effect
level is multiplied by the corresponding dosimetric adjustment to calculate the HEC:
LOAELhec = LOAELadj x Dosimetric Adjustment
where:
Dosimetric Adjustment = ratio of animal :human blood:gas partition coefficients (default =1)
Table 15 includes the HECs.
Maternal effects mainly characterized by decreased gestational weight gains and
hematological effects have been observed at HEC >135 mg/m3 ethoxyethanol acetate vapor
following inhalation exposure during gestation in rabbits and rats (Tyl et al., 1988; Doe, 1984;
Imperial Chemical Industries, 1983a,b). Evidence of a treatment-related delay in development
"3
characterized by retarded ossification has been observed in rats at HEC >68 mg/m (Tyl et al.,
1988). At higher concentrations, developmental effects including decreased fetal survival,
depressed fetal weights, and increases in the incidence and severity of developmental
malformations and variations have been observed in both rats and rabbits (Tyl et al., 1988;
Nelson et al., 1984; Doe, 1984; Imperial Chemical Industries, 1983a,b).
Dose-response modeling was performed on the incidence data (see Table 9) for delayed
skeletal ossification in rats (Tyl et al., 1988). BMD modeling was also performed for skeletal
variations in rats (see Table 7) and rabbits (see Table 12) in the studies by Nelson et al. (1984)
and Doe (1984), respectively. Doe (1984) only reported the incidence of skeletal defects in
rabbits based on individual fetuses, whereas Nelson et al. (1984) and Tyl et al. (1988) reported
data in rats for both fetuses and litters. When possible, incidence of affected litters, rather than
individual fetuses, was modeled for developmental variants to take into account potential litter
effects. The litter is considered the experimental unit in developmental toxicity studies, and
statistical analyses are generally performed based on incidence per litter or number of litters
affected (U.S. EPA, 1991b). Appendix B contains details of the modeling and plots of the best
fitting models.
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For comparison across endpoints, the BMCLio values, which were calculated using the
experimental exposure concentrations, were adjusted for continuous exposure and converted to
HECs, as described above for the LOAEL values:
BMCLioadj = BMCLio x hours per day/24 x days per week/7
BMCLiohec = BMCLioadj x Dosimetric Adjustment
As shown in Table 16, modeling of the data based on the incidence of unossified anterior
arch of atlas in rats as reported by Tyl et al. (1988) resulted in the lowest BMCLhec estimate.
The BMC io and BMCLio for the incidence of unossified interior arch of atlas in rats are 36 and
3	3
26 mg/m , respectively. The corresponding BMCLiohec value is 6.5 mg/m . Modeling of the
data on total skeletal variations in rats from Nelson et al. (1984) produced similar results
(BMCio = 112.5 mg/m3, BMCLio = 26 mg/m3, BMCLiohec = 7.6 mg/m3).
In addition to providing a slightly lower POD for derivation of the p-RfC, the Tyl et al.
(1988) study is preferable as the basis for the p-RfC because there is less uncertainty in the
modeling results. Uncertainty in the modeling results from Nelson et al. (1984) is relatively high
because the data set included only two dose groups other than controls; only one of those showed
a fractional incidence (the other was 100%), and the fractional incidence in the low-dose group
was very high (93%), leaving no data points to inform the curve in the vicinity of the BMR (10%
extra risk). Relative to the Nelson el. (1984) study, the Tyl et al. (1988) study included more
dose groups, more dose groups with fractional responses, larger group sizes, a broader range of
exposure concentrations (low concentration of 270 mg/m3 versus 703 mg/m3), and a broader
range of responses (low response incidence of 71% versus 93%). Therefore, the BMCLiohec of
6.5 mg/m3 based on unossified anterior arch in rats reported by Tyl et al. (1988) is selected as the
POD for derivation of the subchronic and chronic p-RfC values.
-3
The provisional subchronic and chronic p-RfC of 0.06 mg/m for ethoxyethanol
acetate, based on the BMCLiohec of 6.5 mg/m3 for unossified anterior arch in fetal rats exposed
during gestation (Tyl et al., 1988), is derived as follows:
Subchronic and Chronic p-RfC = BMCLiohec ^ UF
= 6.5 mg/m3 -M00
= 0.06 or 6 x 10"2 mg/m3
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Table 16. BMCs and BMCLs Based on Incidence of Skeletal Variations in Rats and Rabbits
Exposed to Ethoxyethanol Acetate via Inhalation
Endpoint
BMC10
(mg/m3)
BMCL10
(mg/m3)
BMCLio adj
(mg/m3)
BMCLiohec
(mg/m3)
Reference
Litter incidence of combined
skeletal variations (rats)
112.5
26
7.6
7.6
Nelson et al. (1984)
Litter incidence of unossified
anterior arch (rats)
36
26
6.5
6.5
Tyletal. (1988)
Litter incidence of poorly ossified
metatarsals (rats)
121
97
24
24
Tyletal. (1988)
Fetal incidence of skeletal variants
(rabbits)
133
109
27
27
Doe (1984); Imperial Chemical
Industries (1983b)
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The composite UF of 100 is composed of the following:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
•	UFa: A partial UF of 3 (10°5) is applied for interspecies extrapolation to account for
potential pharmacodynamic differences between rats and humans. Converting the rat
data to HECs by the dosimetric equations accounts for pharmacokinetic differences
between rats and humans; thus, it was not necessary to use the full UF of 10 for
interspecies extrapolation.
•	UFd: The database includes limited subchronic studies in rats, rabbits, and dogs and
developmental studies in rats and rabbits. A factor of 3 (10°5) is applied for database
inadequacies, including a lack of a multigeneration reproduction study following
inhalation exposure.
•	UFs: A factor of 1 is applied to derive the chronic p-RfC, as an additional factor for
extrapolation from subchronic-to-chronic exposure duration is not warranted when
developmental toxicity data are used.
•	UFl: A factor of 1 is applied; as an additional factor is not warranted when the POD
is based on BMCLiohec.
Confidence in the principal study (Tyl et al., 1988) is high. This study included an
appropriate number of animals and exposure levels and investigated a suitable range of
endpoints. Confidence in the database is medium. The database includes multiple high-quality
developmental toxicity studies in two species. Reproduction has not been evaluated following
inhalation exposure; a continuous breeding study in mice by oral exposure showed that
ethoxyethanol acetate can act as a reproductive toxicant. Subchronic studies are available in rats,
rabbits, and dogs but were all limited by incomplete reporting of study methods and results.
Medium confidence in the subchronic and chronic p-RfC value follows.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR ETHOXYETHANOL ACETATE
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the] Carcinogenic Potential" of ethoxyethanol acetate. No
information was located on the carcinogenicity of ethoxyethanol acetate in humans or animals.
Genotoxicity data for ethoxyethanol acetate were primarily negative.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for ethoxyethanol acetate is precluded
by the lack of suitable data.
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APPENDIX A. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC AND CHRONIC RfD
Model Fitting Procedure for Continuous Data
The model fitting procedure for continuous data using the EPA benchmark dose software
(BMDS) is as follows. The simplest model (linear) is first applied to the data while assuming
constant variance. If the data are consistent with the assumption of constant variance (p> 0.1),
then the fit of the linear model to the means is evaluated, and the polynomial, power, and Hill
models are fit to the data while assuming constant variance. Adequate model fit is judged by
three criteria: goodness-of-fit/>-value (p > 0.1), visual inspection of the dose-response curve, and
scaled residual at the data point (except the control) closest to the predefined benchmark
response (BMR). Among all of the models providing adequate fit to the data, the lowest 95%
lower confidence limit of benchmark dose (BMDL) is selected as the POD when the difference
between the BMDLs estimated from these models is more than 3-fold (unless it appears to be an
outlier); otherwise, the BMDL from the model with the lowest Akaike Information Criterion
(AIC) is chosen. If the test for constant variance is negative, the linear model is run again while
applying the power model integrated into the BMDS to account for nonhomogenous variance. If
the nonhomogenous variance model provides an adequate fit (p> 0.1) to the variance data, then
the fit of the linear model to the means is evaluated, and the polynomial, power, and Hill models
are fit to the data and evaluated while the variance model is applied. Model fit and POD
selection proceed as described earlier. If the test for constant variance is negative and the
nonhomogenous variance model does not provide an adequate fit to the variance data, then the
data set is considered unsuitable for modeling. The models are run with a BMR of 1 SD from
the control mean, as recommended by EPA (2000).
Model Fitting Results for Testicular Atrophy in Mice (Nagano et al., 1984,1979)
Following the above procedure, the continuous models in the EPA BMDS (version 2.1.1)
were fit to the data shown in Table 1 for testicular weight in mice (based on both absolute and
relative testes weights). The results based on absolute testes weights are shown in Table A-l.
The assumption of constant variance did not hold, and the nonhomogenous variance model did
not provide adequate fit based on absolute testes weights. Due to the deaths of three of the five
high-dose animals, the mean testes weight for the high-dose group was based on only two
animals. Therefore, the procedure for continuous data was also applied to absolute testes
weights excluding the high-dose group. Again, the assumption of constant variance did not hold,
and the nonhomogenous variance model did not provide adequate fit.
Table A-2 shows the results based on relative testes weights. The assumption of constant
variance did not hold, and the nonhomogenous variance model did not provide adequate fit based
on relative testes weights. As mentioned above, only two animals were examined in the high-
dose group. Excluding the high-dose group, the constant variance model provided adequate fit to
the variance data, and the linear model provided the best fit to the means. There were
insufficient data points to fit the Hill model. Figure A-l shows the fit of the linear model to the
data. The resulting benchmark dose (BMDisd) and associated 95% lower confidence limit
(BMDLisd) are 663 and 499 mg/kg-day, respectively.
Model Fitting Results for Changes in Right Cauda Weights, Sperm Density, Length of
Estrous Cycle, and Number of Live Pups per Litter in Mice (Gulati et al., 1985)
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Following the above procedure, the continuous models in the EPA BMDS (version 2.1.1)
were fit to the data shown in Table 5 for decreases in right cauda weights in mice (based on both
absolute and body-weight-adjusted right cauda weights), sperm density, and estrous cycle
duration, and to the data shown in Table 6 for reduced number of live litters per pair. Table A-3
shows the results based on right cauda weights. The constant variance model provided adequate
fit to the variance data based on both absolute and adjusted right cauda weights. Only the linear
model fit the means data based on the absolute right cauda weights. The BMDisd and BMDLisd
estimates are 1412 and 992 mg/kg-day, respectively. Figure A-2 shows the fit of the linear
model to the data for absolute right cauda weight. All models based on the adjusted right cauda
weights defaulted to the linear model, with the resulting BMDisd and BMDLisd of 1272 and 917
mg/kg-day, respectively (see Table A-3). Figure A-3 shows the fit of the linear model to the data
for adjusted right cauda weight.
Table A-4 shows the results based on the decreased sperm density and shortened estrous
cycle length. As shown, data on sperm density were inadequate for modeling (no statistically
significant trend,/? < 0.05). For estrous cycle length, the assumption of constant variance did not
hold, and the nonhomogenous variance model did not provide adequate fit.
Table A-5 shows the results based on the number of live pups (males and females
combined) per litter. The assumption of constant variance did not hold, but the nonhomogenous
variance model provided adequate fit to the variance data. All models defaulted to the linear
model. Figure A-4 shows the fit of the linear model to the data is shown. The resulting BMDisd
and BMDLisd are 1279 and 676 mg/kg-day, respectively.
Table A-l.
Model Predictions for Testicular Atrophy

in Mice Based on Absolute Testes Weights


Variance
Means

bmd1sd
BMDLiSD
Model
p-V aluea
p-V aluea
AIC
(mg/kg-day)
(mg/kg-day)
All dose groups
Linear (constant variance)13
0.002
0.889
311.0
684
541
Linear (modeled variance)13
0.001
0.875
312.8
724
507
Without high-dose group
Linear (constant variance)13
0.014
0.916
296.0
646
488
Linear (modeled variance)13
0.031
0.430
295.8
551
371
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bCoefficients restricted to be negative.
Sources: Nagano et al. (1984, 1979).
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Table A-2. Model Predictions for Testicular Atrophy
in Mice Based on Relative Testes Weights
Model
Variance
p-\aluea
Means
/7-Valuea
AIC
bmd1sd
(mg/kg-day)
BMDLisd
(mg/kg-day)
All dose groups
Linear (constant variance)15
0.008
0.642
-128.9
684
541
Linear (modeled variance)13
0.008
0.508
-128.2
785
576
Without high-dose group
Linear (constant variance)b
0.144
0.500
-119.9
663
499
1-degree polynomial (constant
variance)15
0.144
0.500
-119.9
663
499
2-degree polynomial (constant
variance)13
0.144
0.533
-118.8
901
526
3-degree polynomial (constant
variance)15
0.144
0.604
-119.0
921
530
Power (constant variance)0
0.144
0.477
-118.7
898
523
Hill (constant variance)0
0.144
NAd
-116.7
898
522
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bCoefficients restricted to be negative.
°Power restricted to >1.
dNot available; insufficient degrees of freedom.
Sources: Nagano etal. (1984, 1979).
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Table A-3. Model Predictions for Decreased Right Cauda Weights in Mice
Model
Variance
/7-Valuea
Means
/7-Valuea
AIC
bmd1sd
(mg/kg-day)
BMDLisd
(mg/kg-day)
Absolute Right Cauda Weight
Linear (constant variance)b
0.8415
0.7039
193.1
1412
992
2-degree polynomial (constant
variance)13
0.8415
NA°
195.0
1501
1000
Power (constant variance)d
0.8415
NA
195.0
1490
1000
Hill (constant variance/
NA
Body-Weight-Adjusted Right Cauda Weight
Linear (constant variance)b
1
0.8285
177.4
1271
917
2-degree polynomial (constant
variance)13
1
0.8285
177.4
1271
917
Power (constant variance)d
1
0.8285
177.4
1271
917
Hill (constant variance)d
NA
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
bCoefficients restricted to be negative.
°Not available; insufficient degrees of freedom.
dPower restricted to >1.
Sources: Gulati et al. (1985).
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Table A-4. Model Predictions for Decreased Sperm Density and Shortened
Estrous Cycle Length in Mice
Model
Variance
p-\aluea
Means
/7-Valuea
AIC
bmd1sd
(mg/kg-day)
BMDLisd
(mg/kg-day)
Sperm Density
Linear (constant variance)15
No significant trend (Test 1 p-valuc = 0.053)
Estrous Cycle Length
Linear (constant variance)15
0.005501
0.6111
32.2
5615
2179
Linear (modeled variance)13
0.3678
0.001695
34.2
5618
2150
2-degree polynomial (modeled
variance)13
0.3678
0.002365
33.6
3069
1924
Power (modeled variance)0
0.09448
0.01323
32.5
1972
1870
Hill (modeled variance)0
NAd
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bCoefficients restricted to be negative.
°Power restricted to >1.
dNot available; insufficient degrees of freedom.
Sources: Gulati et al. (1985).
Table A-5. Model Predictions for Decreased Numbers of
Live Mouse Pups Per Litter
Model
Variance
/7-Valuea
Means
p-V aluea
AIC
bmd1sd
(mg/kg-day)
BMDLiSD
(mg/kg-day)
Linear (constant variance)15
0.04581
0.7678
117.3
1845
1048
Linear (modeled variance)b
0.5295
0.6888
113.6
1279
676
2-degree polynomial (modeled
variance)13
0.5295
0.6888
113.6
1279
676
Power (modeled variance)0
0.5295
0.6888
113.6
1279
676
Hill (modeled variance)0
NAd
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bCoefficients restricted to be negative.
°Power restricted to >1.
dNot available; insufficient degrees of freedom.
Sources: Gulati et al. (1985).
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Linear Model wth 0.95 Confidence Level
Linear
0.9
0.7
0.6
0.5
0.4
0.3
BMDL
BMD
0
500
1000
1500
2000
Dose
10:4611/182009
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of
mg/kg-day (5 day/week).
Sources: Nagano et al. (1984, 1979).
Figure A-l. Fit of Linear Model to Data for Relative Testes Weights in Mice
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Linear Model with 0.95 Confidence Level
Linear
20
19
18
17
16
15
14
BMDL
BMD
0
500
1000
1500
Dose
13:0011/18 2009
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of
mg/kg-day.
Source: Gulati et al. (1985).
Figure A-2. Fit of Linear Model to Data for Absolute Right Cauda Weights in Mice
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Linear Model with 0.95 Confidence Level
Linear
20
19
18
17
16
15
14
BMDL
BMD
0
500
1000
1500
13:0011/18 2009
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of
mg/kg-day.
Source: Gulati et al. (1985).
Figure A-3. Fit of Linear Model to Data for Body-Weight-Adjusted Right Cauda Weights
in Mice
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Linear Model with 0.95 Confidence Level
Linear
13
12
11
10
9
8
7
6
5
BMDL
BMD
4
0
500
1000
1500
Dose
08:4911/30 2009
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of
mg/kg-day.
Source: Gulati et al. (1985).
Figure A-4. Fit of Linear Model to Data for Number of Live Mice Pups
(Male and Female Combined) per Litter
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC AND CHRONIC RfC
Model Fitting Procedure for Quantal Noncancer Data
The model fitting procedure for dichotomous noncancer data is as follows. All available
dichotomous models in the EPA BMDS (version 2.1.1) are fit to the incidence data using the
extra risk option. The multistage model is run for all polynomial degrees up to n-1 (where n is
the number of dose groups including control). Adequate model fit is judged by three criteria:
goodness-of-fit p-value (p > 0.1), visual inspection of the dose-response curve, and scaled
residual at the data point (except the control) closest to the predefined BMR. Among all of the
models providing adequate fit to the data, the lowest BMCL is selected as the POD when the
difference between the BMCLs estimated from these models are more than 3-fold (unless it
appears to be an outlier); otherwise, the BMCL from the model with the lowest AIC is chosen.
In accordance with EPA (2000) guidance, BMCs and BMCLs associated with an extra risk of
10% benchmark response (BMR) are calculated for all models.
Model Fitting Results for Skeletal Variations in Rats (Nelson et al., 1984)
Following the above procedure, the quantal models in the EPA BMDS (version 2.1.1)
were fit to the litter incidence data shown in Table 7 for the total number of skeletal variations
observed in rats. No live fetuses were born to rats exposed at the highest concentration;
therefore, data are only available for the control, low- and mid-exposure groups. Table B-l
shows the modeling results. There were insufficient degrees of freedom available to fit the
gamma, log logistic, log probit, or weibull models. The remaining models (logistic, 1-degree
multistage, 2-degree multistage, probit, and quantal-linear) all provided adequate fit. The
BMCLio estimates for these models differed by less than 3-fold. The AIC for the 2-degree
multistage model (AIC = 58.0102, BMCio = 166 mg/m3, BMCLio = 18 mg/m3) was just slightly
lower than that of the probit model (AIC = 58.0106, BMCio = 59 mg/m3, BMCLio = 34 mg/m3).
Given the proximity of the AIC values for these models, the BMCio and BMCLio values were
averaged across both models to give representative values of 112.5 mg/m3 (BMCio) and 26
mg/m (BMCLio) for this endpoint. Figures B-l and B-2 show the fit of the 2-degree multistage
and probit models to these data.
The excellent fit of the 2-degree multistage, probit, and other models requiring few
enough parameters to the Nelson et al. (1984) skeletal variation data is misleading, as it reflects
primarily the lack of information in the data set. There is high uncertainty with these modeling
results. This is because the data set included only two dose groups other than controls; only one
of those showed a fractional incidence (the other was 100%), and the fractional incidence in the
low-dose group was very high (93%), leaving no data points to inform the curve in the vicinity of
the BMR (10% extra risk).
Model Fitting Results for Skeletal Variations in Rats (Tyl et al., 1988)
Following the above procedure, the quantal models in the EPA BMDS (version 2.1.1)
were fit to the litter incidence data shown in Table 9 for the most sensitive skeletal variations in
rats (unossified anterior arch of atlas and poorly ossified hindlimb metatarsals). Table B-2
shows the modeling results based on unossified anterior arch of atlas in rats. Adequate model fit
was achieved with all models. The BMCLs differed by approximately 3-fold. The log-logistic
model gave the lowest BMCL estimate but appears to be an outlier, as the BMCL estimates from
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all of the other models fall within approximately a factor of 2 of each other. Moreover, there is
high uncertainty in the BMCL estimate from the log-logistic model. Although this model gave
the lowest BMCL estimate, it also gave the highest BMC estimate, and the spread between them
was much larger than for any of the other models. Therefore, the log-logistic model was not
considered further for this endpoint. In accordance with EPA (2000) guidance, the lowest AIC
was selected from among the remaining models. The gamma, 1-degree multistage, and quantal -
linear models all converged on the same parameters. The resulting benchmark concentration
(BMCio) and associated 95% lower confidence limit (BMCLio) are 36 and 26 mg/m3,
respectively. Figure B-3 shows the fit of the gamma model to these data.
Table B-3 shows the modeling results for poorly ossified metatarsals of the hindlimb in
rats. For this data set, adequate model fit could only be achieved by dropping the highest
exposure group. The incidence of poorly ossified metatarsals was very low in the high exposure
group because almost all of the fetuses at this level exhibited totally unossified metatarsals (a
progression of effect from the poorly ossified variation but quantified by the researchers
separately). After dropping the high exposure level, all of the models provided adequate fit.
BMCLs from the models differed by a factor of 3 (rounded). The log-logistic model provided
the lowest BMCL estimate, but as for unossified atlas arch discussed above, this appears to
reflect primarily greater uncertainty in the log-logistic results, as the spread between the BMC
and BMCL for the log-logistic was much larger than for any of the other models. In addition, the
BMCL estimate based on the log-logistic appears to be an outlier in comparison with the BMCL
estimates based on the other models, which are all within a factor of 2 of each other. Therefore,
the log-logistic was not considered any further for this endpoint, and in accordance with EPA
(2000) guidance, the lowest AIC was selected from among the remaining models. For incidence
data based on poorly ossified hindlimb metatarsals in rats, the probit model provided the best fit.
The resulting BMCio and associated BMCLio are 121 and 97 mg/m3, respectively. Figure B-4
shows the fit of the probit model to these data.
Model Fitting Results for Skeletal Variations in Rabbits (Doe, 1984; Imperial Chemical
Industries, 1983b)
Following the above procedure, the quantal models in the EPA BMDS (version 2.1.1)
were fit to the fetal incidence data shown in Table 12 for the number of fetuses with skeletal
variants. Table B-4 shows the modeling results. There were insufficient degrees of freedom
available to fit the 3-degree multistage model. All other models provided adequate fit to the
data. The BMCL estimates differed by a factor of more than 3, with the 1-degree multistage and
quantal-linear models converging with the lowest BMCL estimate. However, these models
provide relatively poor fit to the data, as shown by low goodness-of-fitp-walue, high AIC, high
scaled residuals at 3 of the 4 data points, and visual inspection. Furthermore, the BMCL
estimate from these models appears to be an outlier, as the BMCL estimates from the remaining
models are all within a factor of 2.5 of each other. Therefore, the quantal-linear/1-degree
multistage model was not considered further for this endpoint. In accordance with EPA (2000)
guidance, the lowest AIC was selected among these remaining models. The probit model had
the lowest AIC. Figure B-5 shows the fit of the probit model to these data. The resulting BMCio
and BMCLio are 133 and 109 mg/m3, respectively.
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Table B-l. Model Predictions for the Total Number
of Skeletal Variations in Rats
Model
Degrees
of
Freedom
2
X
x2
Goodness-of-Fit
/>-Valuc
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma (power >1)
0
0
NAb
60.010
294.91
17.97
Logistic
1
0.01
0.9253
58.027
52.48
26.97
Log logistic (slope >1)
0
0
NA
60.010
531.75
1.34
Log probit (slope > 1)
0
0
NA
60.010
391.23
23.02
Multistage (degree = I, betas > 0)
1
0.02
0.8802
58.052
38.04
17.87
Multistage (degree = 2, betas >
0)
1
0
0.9996
58.0102
165.99
17.97
Probit
1
0
0.9888
58.0106
58.67
34.32
Weibull (power > 1)
0
0
NA
60.010
156.06
17.97
Quantal-linear
1
0.02
0.8802
58.052
38.04
17.87
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
hNot available; insufficient degrees of freedom.
Source: Nelson etal. (1984).
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Table B-2. Model Predictions for the Skeletal Variation

Unossified Anterior Arch of Atlas in Rats


Model
Degrees of
Freedom
2
X
x2
Goodness-of-Fit
/>-Valuc
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma (power > 1)
3
0.28
0.96
103.9
35.69
26.11
Logistic
3
1.3
0.73
104.7
61.21
46.73
Log logistic (slope >1)
2
0.74
0.69
106.6
87.50
17.19
Log probit (slope > 1)
2
0.51
0.78
106.2
82.53
43.04
Multistage (degree = 1, betas >
0)
3
0.28
0.96
103.9
35.69
26.11
Multistage (degree = 2, betas >
0)
2
0.3
0.86
105.9
37.24
26.13
Multistage (degree = 3, betas >
0)
2
0.29
0.86
105.8
37.47
26.20
Multistage (degree = 4, betas >
0)
2
0.27
0.87
105.8
37.55
26.28
Probit
3
2.17
0.54
105.5
67.83
53.27
Weibull (power > 1)
2
0.28
0.87
105.9
35.81
26.11
Quantal-linear
3
0.28
0.96
103.9
35.69
26.11
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
Sources: Tyl et al. (1988).
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Table B-3. Model Predictions for the Skeletal Variation Poorly Ossified
Hindlimb Metatarsals in Rats, After Excluding the High Exposure Group
Model
Degrees of
Freedom
x2
y2 Goodness
of Fit
/>-Valuc
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma (power >1)
1
1.54
0.21
134.4
106.96
51.36
Logistic
2
1.35
0.51
132.2
121.17
94.48
Log logistic (slope >1)
1
2.13
0.14
135.0
135.17
31.01
Log probit (slope > 1)
1
2.08
0.15
134.9
140.43
92.48
Multistage (degree = 1, betas > 0)
2
1.66
0.44
132.5
71.46
50.96
Multistage (degree = 2, betas > 0)
1
1.25
0.26
134.1
101.77
52.27
Multistage (degree = 3, betas > 0)
1
1.02
0.31
133.9
97.02
53.02
Probit
2
1.26
0.53
132.1
121.48
96.95
Weibull (power > 1)
1
1.46
0.23
134.3
111.19
51.62
Quantal-linear
2
1.66
0.44
132.5
71.46
50.96
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
Sources: Tyl et al. (1988).
Table B-4. Model Predictions for the Number of Rabbit Fetuses with


Skeletal Variations



Model
Degrees of
Freedom
x2
X2 Goodness
of Fit
/>-Valuc
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma (power >1)
1
0.24
0.6219
414.5
273.00
116.26
Logistic
2
1.34
0.5128
413.6
120.98
97.33
Log logistic (slope >1)
1
0.36
0.5465
414.6
345.98
220.31
Log probit (slope > 1)
1
0.39
0.5307
414.6
342.78
215.05
Multistage (degree = 1, betas > 0)
2
4.23
0.1204
417.0
84.89
65.79
Multistage (degree = 2, betas > 0)
1
0.03
0.8683
414.2
188.05
91.17
Multistage (degree = 3, betas > 0)
0
0
NAb
416.2
149.82
85.35
Probit
2
0.45
0.7995
412.7
132.65
108.51
Weibull (power > 1)
1
0.12
0.7303
414.3
230.83
107.88
Quantal-linear
2
4.23
0.1204
417.0
84.89
65.79
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
hNot available; insufficient degrees of freedom.
Sources: Doe (1984); Imperial Chemical Industries (1983b).
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Multistage Model with 0.95 Confidence Level
Multistage
0	500	1000	1500	2000
08:21 11/19 2009	Dose
BMC and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Source: Nelson et al. (1984).
Figure B-l. Fit of 2-Degree Multistage Model to Litter Data on Incidence of
Total Skeletal Variations in Rats
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Probit Model with 0.95 Confidence Level
Probit
0	500	1000	1500	2000
Dose
08:21 11/19 2009
BMC and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Source: Nelson et al. (1984).
Figure B-2. Fit of Probit Model to Litter Data on Incidence of
Total Skeletal Variations in Rats
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Gamma Multi-Hit Model with 0.95 Confidence Level
Gamma Multi-Hit
0.9
0.7
0.6
0.5
0.4
0.3
0.2
EiMDL
BMD
0
200
400
600
800
1000
1200
1400
1600
Dose!
13:46 05/14 2009
BMC and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Source: Tyl et al. (1988).
Figure B-3. Fit of Gamma Multihit Model to Data on Litter Incidence of
Unossified Anterior Arch of Atlas in Rats
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Probit
BMDL
Probit Model with 0.95 Confidence Level
0	200	400	600	800	1000
Dose
14:43 05/142009
BMC and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Source: Tyl et al. (1988).
Figure B-4. Fit of Probit Model to Data on Litter Incidence of
Poorly Ossified Hindlimb Metatarsals in Rats
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Probit Model with 0.95 Confidence Level
Probit
1
0.9
0.8
0.7
0.6
0.5
0.4
BMDL
BMD
0
500
1000
1500
2000
Dose
10:0211/23 2009
BMC and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Sources: Doe (1984); Imperial Chemical Industries (1983b).
Figure B-5. Fit of Probit Model to Data on Fetal Incidence of
Skeletal Variants in Rabbits
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