Jffl;	United States
iPilfEnvironmental Protectioi
if % Agency
EPA/690/R-10/001F
Final
10-01-2010
Provisional Peer-Reviewed Toxicity Values for
Acrylic Acid
(CASRN 79-10-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Harlal Choudhury, DVM, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
CONTRIBUTOR
Custodio V. Muianga, Ph.D., M.P.H.
National Center for Environmental Assessment, Cincinnati, OH
PRIMARY INTERNAL REVIEWERS
Debdas Mukerjee, Ph.D.
National Center for Environmental Assessment, Cincinnati, OH
Sanju Diwan
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300)
l
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	3
Human Studies	3
Animal Studies	4
Oral Exposure	4
Subchronic Studies	4
Chronic Studies	9
Reproductive/Developmental Studies	9
Inhalation Exposure	15
Subchronic Studies	15
Reproductive/Developmental Studies	17
Other Studies	21
Toxicokinetics	21
Other Routes	22
Genotoxicity	22
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR ACRYLIC ACID	22
Subchronic p-RfD	22
Chronic p-RfD	26
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC	26
INHALATION RfC VALUES FOR ACRYLIC ACID	26
Subchronic p-RfC	26
Chronic p-RfC	30
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR ACRYLIC ACID	30
Weight-of-Evidence Descriptor	30
Quantitative Estimates of Carcinogenic Risk	31
REFERENCES	31
APPENDIX A. BENCHMARK DOSE MODELING FOR INHALATION
SUBCHRONIC p-RfC	35
ii	Acrylic Acid

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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
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
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
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
ACRYLIC ACID (CASRN 79-10-7)
BACKGROUND
HISTORY
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 a
panel of six 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.
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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
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
Both RfD and RfC values are available for acrylic acid (chemical structure shown in
Figure 1) on IRIS (U.S. EPA, 2009a). The RfD of 0.5 mg/kg-day is based on a NOAEL of
53 mg/kg-day and a LOAEL of 240 mg/kg-day for reduced pup weight in a two-generation
reproductive study of rats exposed to acrylic acid in drinking water (BASF, 1993, later published
as Hellwig et al., 1997). The RfC of 0.001 mg/m3 is based on a LOAEL of 14.94 mg/m3
(LOAELhec = 0.33 mg/m3) for degeneration of the nasal olfactory epithelium in a subchronic
mouse inhalation study (Miller et al., 1981). Both assessments were posted on 2/17/94, and
neither was cited to a source document. The HEAST (U.S. EPA, 1997) lists a subchronic RfD of
"3
0.5 mg/kg-day and a subchronic RfC of 0.003 mg/m . These subchronic values are based on the
same studies, critical effects, and critical effect levels as the chronic values on IRIS
(U.S. EPA, 2009a). The Chemical Assessments and Related Activities (CARA) list (U.S. EPA,
1991, 1994a) includes a Health and Environmental Effects Profile (HEEP) for acrylic acid
(U.S. EPA, 1984) that did not attempt quantitative assessment due to inadequate data. Acrylic
acid is not on the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006). The
Agency for Toxic Substances and Disease Registry (ATSDR, 2009) has not prepared a
toxicological profile for acrylic acid. The World Health Organization (WHO, 1997) developed
an Environmental Health Criteria document for acrylic acid and lists guidance values of
0.054 mg/m3 for inhalation exposure and 9.9 mg/L for drinking water (associated with a
Tolerable Intake [TI] value of 3.1 mg/kg-day). The drinking water value is based on a NOAEL
of 78 mg/kg-day from a chronic rat study (Hellwig et al., 1993), and the inhalation value is based
"3
on the LOAEL of 15 mg/m from the above-mentioned subchronic mouse study (Miller et al.,
1981). The California Environmental Protection Agency (CalEPA, 2009a,b) has not derived
values for longer-term exposure to acrylic acid.
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Figure 1. Chemical Structure of Acrylic Acid
The American Conference of Governmental Industrial Hygienists (ACGIH, 2008) lists a
threshold limit value (TLV) for acrylic acid of 2 ppm as an 8-hour time-weighted average
(TWA) to prevent upper respiratory tract irritation. The National Institute of Occupational
Safety and Health (NIOSH, 2008) recommended exposure level (REL) is also 2 ppm (6 mg/m ).
The Occupational Safety and Health Administration (OSHA, 2009) has not derived occupational
exposure limits for acrylic acid. Interim Acute Exposure Guidelines (AEGL) ranging from
1.5 ppm (AEGL1, 10 minutes to 8 hours) to 480 ppm (AEGL3, 10 minutes) were derived for
acrylic acid in 2003 (U.S. EPA, 2009b). CalEPA (2009b) has derived an acute 1-hour REL of
6 mg/m3 for acrylic acid on the basis of respiratory irritation in rabbits, and it lists eyes and
respiratory tract as target organs.
A cancer assessment for acrylic acid is not available on IRIS (U.S. EPA, 2009a) or in the
HE AST (U.S. EPA, 1997). No assessment of the carcinogenic potential of acrylic acid has been
made in the HEEP (U.S. EPA, 1984) due to the lack of relevant studies. The International
Agency for Research on Cancer (IARC, 1999, 1987, 1979) lists acrylic acid as Group 3 (not
classifiable) with regard to carcinogenic potential in humans because of the lack of relevant data
for humans or animals. Acrylic acid is not included in the 11th Report on Carcinogens (National
Toxicology Program [NTP], 2005) and has not been studied for carcinogenicity by NTP (2009).
CalEPA (2009b) has not prepared a quantitative estimate of carcinogenic potential for acrylic
acid.
Literature searches were conducted from 1960s through October 2009 for studies relevant
to the derivation of provisional toxicity values for acrylic acid. Databases searched include
MEDLINE, TOXLINE (with NTIS), BIOSIS, TSCATS/TSCATS2, CCRIS, DART, GENETOX,
HSDB, RTECS, Chemical Abstracts, and Current Contents (last 6 months).
REVIEW OF PERTINENT DATA
HUMAN STUDIES
Schwartz et al. (1989) studied olfactory function in chemical workers exposed to vapors
of acrylic acid and other acrylates and methacrylates at a large manufacturing facility. The study
population included 731 (618 males and 113 females, mean age = 42.9 ± 11.3 years). Workers
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filled out questionnaires including medical history and history of smell or taste dysfunction, and
self-administered the University of Pennsylvania Smell Identification test (UPSIT) to assess
olfactory function. Cross-sectional (prevalence) and nested case-control studies were performed.
For the cross-sectional study, workers were categorized according to current exposure based on
job title: no chemical exposure (n = 319), exposure to chemicals other than acrylic acid,
acrylates, and methacrylates (n = 193), exposure to lower levels of acrylic acid, acrylates, and
methacrylates (n = 164), and exposure to higher levels of acrylic acid, acrylates, and
methacrylates (n = 55). UPSIT scores did not differ significantly across groups, with or without
control for age, ethnicity, and smoking status as potential confounders. The case-control study
was limited to workers who had been full-time employees at the plant for at least 6 months.
Cases (n = 77) were selected as subjects scoring at or below the 10th percentile (for their age) on
the UPSIT. Controls were matched 1:1 based on age, ethnicity, and gender. Cumulative
exposure scores were calculated for cases based on job history. Odds ratios (ORs) were
significantly increased for all workers, and, in particular, for workers who had never smoked,
with or without adjustment for multiple confounders (adjusted OR = 2.8 [1.1, 7.0] for all workers
and 13.5 [2.1, 87.6] for non smokers). ORs (crude or adjusted) increased with cumulative
exposure score. The results of the case-control study suggest an effect of acrylic acid, acrylates,
and methacrylates on olfactory function, but they cannot distinguish which of the chemicals may
have contributed to the observed effect.
Tucek et al. (2002) performed a prospective cohort study with an 8-year follow-up of
workers exposed to acrylic acid and many other chemicals in the production of acrylic acid and
its esters. The study cohort included 60 workers occupationally exposed to acrylic acid, its
esters, and other chemicals at a single facility in the Czech Republic for at least 5 years
(mean = 13 ± 5 years). Controls were 60 unexposed workers from the same plant. Mean subject
age was 40 ± 8 years for both groups. Exposure was measured at 15 workstations for selected
chemicals only (acrylic acid was not included) using personal passive dosimeters at regular
intervals. Health status of workers was assessed annually by general medical examination,
hematology, serum chemistry, urinalysis, serum immunology, selected tumor markers, and
spirometry. The study found no evidence of health-related changes in exposed workers that
could be related to exposure.
ANIMAL STUDIES
Throughout the discussion that follows, use of the term "significantly" refers to a
statistically significant deviation from controls.
Oral Exposure
Subchronic Studies—Fisher 344 rats (15/sex/group) were administered acrylic acid
(-97% pure) in drinking water at target doses of 0, 83, 250, or 750 mg/kg-day for 3 months
(DePass et al., 1983). Food and drinking water consumption and body weight were measured
weekly. Serum chemistry (cholesterol, glucose, urea nitrogen [BUN], alkaline phosphatase
[ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], and creatine
phosphokinase [CPK]), hematology (hemoglobin [Hgb], hematocrit [Hct], red blood cell count
[RBC], white blood cell count [WBC], and reticulocyte count), and urinalysis (specific gravity,
pH, protein, glucose, ketones, bilirubin, occult blood, and nitrite) were evaluated approximately
2 weeks prior to sacrifice. All test animals received gross pathological examination upon
sacrifice at the end of the treatment period, including measurement of relative and absolute
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weights of the liver, kidney, heart, spleen, brain, and testes. Microscopic examination of the
following organs and tissues was conducted for control and high-dose animals: pituitary, thyroid,
parathyroids, adrenals, heart, thymus, spleen, mesenteric lymph node, nasal cavity, trachea,
lungs, ovaries and oviducts, kidneys, urinary bladder, tongue, esophagus, stomach, duodenum,
colon, liver, pancreas, brain, eyes, skin, mammary gland, and sternum. Only organs with gross
lesions were examined microscopically in low- and mid-dose rats.
No mortality or clinical signs of toxicity were observed (DePass et al., 1983). As shown
in Table 1, mean body-weight gain was significantly reduced in high-dose males (-30%) and
mid- (-12%) and high-dose (-39%) females in comparison with controls. Food consumption was
significantly reduced in high-dose animals throughout the study. Water consumption was
significantly reduced in all treated male groups and in mid- and high-dose females. Changes in
organ weights appeared to occur in parallel to decreased body-weight gain (see Table 1). As
shown in Table 2, some minor changes in serum chemistry were also noted in mid- and
high-dose animals. There were no effects on hematological variables (data not shown). Based
on DePass et al. (1983), an increase in blood urea nitrogen (BUN) was observed for high-level
dose in male rats. In the female, a decrease in serum cholesterol and increases in BUN, glucose,
and alkaline phosphatase and aspartate transaminase were observed among the high dose levels.
Increases in BUN and alkaline phosphatase were dose related. The authors did not present
additional information on statistical significance or conclusions. Urinalysis revealed increased
urinary protein levels in the mid- and high-dose rats of both sexes (data not shown) and
decreased urinary pH in the high-dose females (median = 6.0 versus 7.0 in controls). No gross or
microscopic lesions were detected. The LOAEL for this study is 250 mg/kg-day based on
reduced body-weight gain in females. Other changes at this dose level included minor changes
in organ weights, serum chemistry, and urinalysis that may have been secondary to the effect on
body weight. In addition, DePass et al. (1983) reported that at 83 mg/kg-day the only effect was
a reduction of water consumption by male rats. There was no significant treatment related to
histopathologic changes. Many effects observed may have been the results of decreased water
consumption rather than specific toxic effect of acrylic acid. Organ weight effects in male rats
include significant reduction in absolute liver weight observed at high dose level. Other
statistically significant organ weight changes at the two lower dosage were probable chance
occurrences unrelated to treatment. The NOAEL for the study is 83 mg/kg-day.
Hellwig et al. (1993) performed gavage and drinking water studies with acrylic acid in
rats. In the gavage study, Wistar rats (10/sex/group) were administered acrylic acid (99% pure
stabilized with 200-ppm hydroquinine monomethylether) in water by gavage at doses of 0, 150,
or 375 mg/kg-day, 5 days/week, for 3 months. Body weight, food consumption, and drinking
water consumption were determined once per week. Animals were examined daily for clinical
signs of toxicity. All test animals received a gross pathological examination, which included
measurement of relative and absolute weights of the liver, kidney, spleen, testes, ovaries,
adrenals, and brain. Histopathological examination was made for gross lesions and tissues from
the esophagus, stomach, small intestine, liver, kidneys, urinary bladder, adrenals, tongue, and
buccal and nasal mucosa. The study authors reported slight-to-moderate retardation of growth in
high-dose males and indications of an effect on growth in high-dose females as well during the
first 3 weeks of the study (data not shown). Hellwig et al. (1993) presents results of the
hematological and urinanalytical examinations (Table 2 and Table 3 in the original article) at
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Table 1. Summary of Changes in Body and Organ Weights
in a 90-Day Drinking

Water Study of Rats Exposed to Acrylic Acida



Dose (mg/kg-day)

0
83
250
750
Endpoint/Sex
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Male
Diet consumption
16.9
0.6
16.4
0.9
16.2
0.6
14.0d
0.6
(g/kg-day)








Water consumption
21.4
0.7
19.4°
1.3
17.5d
0.8
13.0d
0.7
(mL/rat-day)








Body-weight gain (g)
200.6
20.2
196.7
17.3
188.2
23.5
141.5d
21.5
Liver absolute (g)
11.08
0.89
11.17
0.85
11.30
1.64
9.33d
1.25
Liver relative (%)
3.40
0.14
3.50
1.15
3.61
0.38
3.52b
0.15
Kidney absolute (g)
2.15
0.13
2.14
0.16
2.20
0.18
2.06
0.22
Kidney relative (%)
0.66
0.02
0.67
0.03
0.71d
0.03
0.78d
0.04
Spleen absolute (g)
0.60
0.06
0.61
0.06
0.60
0.08
0.53°
0.05
Spleen relative (%)
0.18
0.01
0.19
0.02
0.19
0.02
0.20°
0.02
Heart absolute (g)
0.82
0.10
0.83
0.08
0.81
0.10
0.71°
0.09
Heart relative (%)
0.25
0.03
0.26
0.02
0.26
0.02
0.27
0.02
Brain absolute (g)
1.84
0.06
1.81
0.08
1.81
0.08
1.74°
0.08
Brain relative (%)
0.57
0.03
0.57
0.03
0.58
0.04
0.66d
0.05
Testes absolute (g)
2.72
0.32
2.73
0.14
2.82
0.14
2.72
0.17
Testes relative (%)
0.84
0.11
0.86
0.07
0.91d
0.07
1.04d
0.06

Mean
SD
Mean
SD
Mean
SD
Mean
SD
Female
Diet consumption
10.4
0.4
10.6
0.2
10.2
0.6
o
t"-
00
0.3
(g/kg-day)








Water consumption
15.0
0.7
14.9
0.8
11.8d
0.7
8.6d
0.5
(mL/rat-day)








Body-weight gain (g)
78.0
10.8
82.1
11.1
68.4b
9.8
48.0d
8.2
Liver absolute (g)
5.70
0.45
5.84
0.57
5.61
0.47
4.91d
0.50
Liver relative (%)
3.19
0.13
3.16
0.14
3.29
0.18
3.27
0.22
Kidney absolute (g)
1.24
0.08
1.29
0.08
1.37d
0.07
1.34°
0.10
Kidney relative (%)
0.69
0.03
0.70
0.04
0.80d
0.06
0.89d
0.04
Spleen absolute (g)
0.43
0.05
0.46
0.05
0.43
0.04
0.37d
0.04
Spleen relative (%)
0.24
0.02
0.25
0.02
0.25
0.02
0.24
0.02
Heart absolute (g)
0.54
0.07
0.55
0.06
0.54
0.05
0.45d
0.04
Heart relative (%)
0.30
0.03
0.30
0.02
0.32
0.02
0.30
0.02
Brain absolute (g)
1.65
0.14
1.66
0.10
1.68
0.08
1.61
0.12
Brain relative (%)
0.93
0.10
0.90
0.08
0.99
0.08
1.07d
0.09
aDePass etal. (1983)
bp < 0.05
cp < 0.01
dp< 0.001
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Table 2. Clinical Chemistry Values in Rats Exposed to Acrylic Acid
in Drinking Water for 90 Days"
Dose
(mg/kg-day)
Endpoint (Mean ± SD)
Cholesterol
(mg/dL)
BUN
(mg/dL)
Glucose
(mg/dL)
ALP
(Units/L)
AST
(Units/L)
ALT
(Units/L)
CPK
(Units/L)
Male
0
53 ±7.9
16 ± 3.1
114 ± 10.2
103 ± 8.60
62 ±8.5
28 ±4.6
98 ±34
83
56 ±6.5
16 ±2.6
118 ± 10.7
103 ±6.50
58 ±6.5
28 ±5.4
103 ±41.8
250
54 ± 8.0
16 ± 1.8
111 ± 10.7
103 ±7.80
58 ±6.8
28 ±4.4
91 ±29
750
60 ± 7.9
19 ± 3.8°
115 ±9.00
102 ± 10.5
62 ±9.8
32 ±4.9
134±120
Female
0
77 ± 10
16 ±2.5
100 ± 8.70
71 ± 11
54 ±6.6
22 ±2.1
67 ±21
83
76 ± 7.9
17 ±2.0
107 ± 6.00
73 ± 10
54 ±5.4
21 ±2.3
60 ±25
250
68 ± 7.0°
19 ± 2.8°
105 ±7.60
80 ± 13b
62 ± 14
23 ±4.1
148 ±163
750
55 ± 6.2d
24 ± 3.3d
109 ± 11.3b
85 ± 7.6d
60 ± 7.1b
24 ±3.8
88 ±59
aDePass etal. (1983)
bp < 0.05
cp < 0.01
dp< 0.001
various intervals did not indicate an obvious treatement-related pattern in any of the clino-
chemical, hematological or urinanalytical parameters monitored. Also, reports that the
differences were marginal, inconsistent or lacked a dose-effect relationship. Clinical signs
observed in most animals in both dose groups from 3 weeks onward included tympanites
(abdominal swelling) of the gastrointestinal tract, cyanosis, and dyspnea (shortness of breath).
Mortality occurred in 10/20 animals (5 males and 5 females) in the low-dose group and 15/20
animals (6 males, 9 females) in the high-dose group. The timing of mortality and clinical signs
specifically associated with animals that died were not discussed. Pathological examinations
revealed irritation in the forestomach and glandular stomach and purulent catarrhal rhinitis as
prominent effects of gavage treatment with acrylic acid. Necrotizing tubular nephrosis was
observed in most of the animals that died during the study. Table 3 summarizes the incidences
of these endpoints. Statistical analyses are not reported for the results of gross or microscopic
examinations. No results or conclusions regarding organ weights are reported. The lowest dose
tested in this study, 150 mg/kg-day, is a FEL based on increased mortality.
Concurrent with the gavage study described above, the same researchers conducted a
12-month drinking water study that included a satellite group that was sacrificed after 3 months
of exposure (Hellwig et al., 1993). Wistar rats (20/sex/group for the main group and
10/sex/group for the satellite groups) were administered acrylic acid (99% pure stabilized with
200-ppm hydroquinine monom ethyl ether) in drinking water at concentrations of 0, 120, 800,
2000, or 5000 ppm (equivalent to mean measured doses of 0, 9, 61, 140, or 331 mg/kg-day) for
3 months (satellite group) or 12 months (main group) (Hellwig et al., 1993). Food and drinking
water consumption and body weight were measured once per week, and animals were examined
daily for clinical signs of toxicity. Serum chemistries, hematological analyses, and urinalysis
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Table 3. Histological Findings in Rats Exposed to Acrylic Acid via Gavage for 3 Months"

Number of Rats with Lesions
0 (controls)
150 mg/kg-day
375 mg/kg-day
Site and Lesion
Males
Females
Males
Females
Males
Females
Stomach
Hyperemia of the mucosal apices
0
0
3
1
5
3
Erosion in glandular stomach
without cellular reaction
0
0
2
1
2
4
Subepithelial edema (forestomach),
especially in the region of the plica
marginata
0
0
0
1
3
0
Epithelial hyperplasia
(forestomach), especially in the
region of the plica marginata
0
0
1
1
3
1
Esophagus
Purulent mucus, intraluminal
0
0
0
0
0
1
Nasal cavity
Purulent catarrhal exudate
0
0
5
7
6
7
Mucosal atrophy/metaplasia
0
0
0
1
1
1
Pharyngeal duct
Purulent catarrhal exudate
0
0
5
6
6
6
Mucosal atrophy/metaplasia
0
0
2
5
5
5
Sinus maxillaries
Purulent catarrhal exudate
0
0
2
1
2
3
Kidneys
Ballooning degeneration/
fragmentation/necrosis of tubular
cells (cortex)
0
0
5
4
5
7
aHellwig et al. (1993)
were conducted on Weeks 4, 12, 26, and 51. All test animals received gross pathological
examination, which included measurement of body weight and relative and absolute weights of
the liver, kidney, spleen, testes, ovaries, adrenals, and brain. Histopathological examinations
were performed on all gross lesions. In the satellite groups, histopathological examinations were
conducted for controls and the two highest-dose groups, and they included examination of the
esophagus, stomach, small intestine, urinary bladder, adrenals, tongue, buccal mucosa, and nasal
mucosa. For the main groups, histopathological examinations were conducted for the liver and
kidneys of all animals in all test groups, and on a comprehensive list of tissues and organs for
controls and the two highest-dose groups.
No treatment-related mortality was observed in this study; the only death was a low-dose
male (Hellwig et al., 1993). Drinking water consumption was significantly reduced (-15 to 20%
relative to controls) in high-dose (331 mg/kg-day) males throughout the study and in
140-mg/kg-day males (-10% relative to controls) for the first 14 weeks of the study, suggesting
that palatability was an issue. Body-weight gain was reduced as well in high-dose males; the
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difference in body weight from controls ranged from 6-8% for most of the study. Neither
drinking water consumption nor body-weight gain differed from controls in treated females.
There were sporadic statistically significant (p < 0.05) changes between controls and rats
exposed to acrylic acid with regard to some hematological and urinalysis variables, but the
changes were marginal and were not consistent over time or dose-related. There were no effects
on serum chemistry (data not shown). In contrast with the 3-month gavage study, the
histopathology data showed no statistically significant treatment-related differences between
controls and animals exposed to acrylic acid at any dose, at either the 3-month or 12-month
sacrifices, suggesting that the effects observed in the gavage studies were due to irritation
associated with bolus doses. Because the small change in body weight observed in high-dose
males in this study is not considered biologically significant, the NOAEL for this study is
331 mg/kg-day (highest dose tested).
Chronic Studies—Wistar rats (50/sex/group) were administered acrylic acid (99% pure
stabilized with 200-ppm hydroquinine monomethylether) in drinking water at concentrations of
0, 120, 400, or 1200 ppm for 26 (males) or 28 (females) months (Hellwig et al., 1993). Based on
measured body weight and drinking water consumption, these concentrations are equivalent to
doses of 0, 8, 27, or 78 mg/kg-day. For the first 3 months of the study, body weight and drinking
water consumption were determined once per week. Body weight was then determined once
every 4 weeks, and drinking water consumption was determined once every 3 months. General
well-being of the animals was checked daily. Hematological variables were assessed following
12, 18, 26 (males), and 28 (females) months of exposure. All test animals received gross
pathological examination, including the measurement of body weights, and relative and absolute
weights of the liver, kidney, spleen, testes, ovaries, adrenals, and brain. Histopathological
examinations were performed on a comprehensive list of tissues and organs, including sections
from bone marrow (femur), vagina, coagulation gland, mandibular lymph node, tongue, and
buccal mucosa.
No treatment-related mortality or clinical signs of toxicity were observed
(Hellwig et al., 1993). There were no significant treatment-related effects on body weight or
water consumption. Hematology data showed no consistent and dose-related effects. No
significant gross pathological changes were observed. A slight increase in the incidence of
hepatocellular fatty deposits was observed in high-dose males (incidences of 5/50, 6/49, 6/50,
and 13/50) but not in females. This effect is not considered to be toxicologically relevant due to
the low incidence, lack of statistical significance, and the lack of histopathological alterations of
the liver in other studies (DePass et al., 1983). The histopathology data showed no other
significant treatment-related nonneoplastic or neoplastic findings. Based on these findings, the
NOAEL for this study is 78 mg/kg-day (highest dose tested).
Reproductive/Developmental Studies—In a two-generation reproductive study
(Hellwig et al., 1997), acrylic acid (98.9% pure) was administered in drinking water at
concentrations of 0, 500, 2500, or 5000 ppm to groups of 25 male and 25 female Wistar rats
(35 days old at the beginning of treatment). After at least 70 days of treatment, the
F0 parental-generation animals were mated within the dose groups to produce one litter. Litters
were culled to eight pups at Day 4 postparturition, and groups of 25 male and female Fi pups
were selected for the Fi parental generation and were mated after at least 98 days of treatment.
F2 litters were culled to eight pups and were raised to Day 21 postpartum. Acrylic acid treatment
was continuous throughout the premating, gestational, and lactational periods. Pups from both
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generations were necropsied at Days 4 and 21 postpartum. In addition to body weight, food, and
water consumption and general reproductive parameters, pups were monitored for behavior and
developmental milestones, and some pups were examined for visceral and skeletal abnormalities.
Other endpoints that were monitored include nesting, littering and lactation behavior, gripping
reflex, hearing startle reflex, pupillary reflex, pinna unfolding, auditory canal opening, and eye
opening.
The acrylic acid doses based on water intake were estimated to be 53, 240, and
460 mg/kg-day in the animals receiving 500, 2500, and 5000 ppm in drinking water, respectively
(Hellwig et al., 1997). A consistent finding throughout the study was decreased water
consumption at the two highest doses. Water consumption was reduced 11-14% at
460 mg/kg-day in the F0 parental animals compared with controls throughout premating,
gestation, and lactation but was not reduced in Fo animals receiving 240 mg/kg-day. Statistically
significant decreases in body weight were observed in F0 males receiving 460 mg/kg-day during
Study Weeks 12 through 20, but these changes were not large enough to be considered
biologically relevant (i.e., 6-7% less than control values; a decrease of 10% is typically
considered to be adverse). The body weights among Fo females were unaffected by treatment.
High-dose male and female Fi parents had significantly lower body weights than controls
(13-26%) less in males and 11—23% less in females) throughout the entire 23-week period.
Water consumption was consistently and significantly reduced in Fi male and female parents
exposed to 240 or 460 mg/kg-day. No changes in water consumption or body weight were
observed in F0 or Fi parents exposed to 53 mg/kg-day. Pups of both generations exposed to
240 and 460 mg/kg-day had significantly reduced body weight at weaning in comparison with
controls (see Table 4). Although these changes occurred at the end of the period of active
nursing and are associated with decreases in maternal water consumption, it is not clear that the
reduced weight compared with controls can be attributed only to reduced maternal water intake.
Table 4. Body Weight (g) at Weaning in Fi and F2 Rat Pups in a Two-Generation

Reproduction Study with Acrylic Acida


Dose (mg/kg-day)
Generation
0
53
240
460
Fi Pups (M/F)
52.3/50.1
52.1/49.4
46.6b/44.6b
34.2b/32.7b
F2 Pups (M/F)
50.4/48.4
51.5/48.4
44.6b/42.4b
34.5b/33.2b
aHellwig et al. (1997); values are means for males/females; standard deviations are not reported
hp < 0.01, Dunnett's Test
Slight reductions in the number of pups with eye opening or auditory canal opening on
time were statistically (p < 0.05) significant in some groups, but were within historical control
ranges for rats from this colony (Hellwig et al., 1997) and are not considered to be treatment-
related. There were no adverse treatment-related effects on reproductive function at any dose
tested. The only clearly treatment-related adverse effects identified by histopathological
examination were lesions in the forestomach and glandular stomach in Fo and Fi parental animals
exposed to 460 mg/kg-day. Minimal hyperkeratosis of the limiting ridge of the forestomach and
edema of the submucosa of the glandular stomach were reportedly observed in most animals of
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both sexes (data not shown). These lesions were not observed in rats exposed to doses of 53 or
240 mg/kg-day. The NOAEL for reproductive effects is 460 mg/kg-day (highest dose tested).
The NOAEL and LOAEL values for parental toxicity are 240 and 460 mg/kg-day, respectively,
for histological changes in the stomach and forestomach and reduced body-weight gain in the Fi
parents. The LOAEL for pup toxicity is 240 mg/kg-day on the basis of significant reduction in
body weight; the NOAEL for pup toxicity and the overall NOAEL for the study is 53 mg/kg-day.
In a one-generation reproduction study, Fischer 344 rats (10 males, 20 females per group)
were administered acrylic acid (-97% pure) in drinking water at target doses of 0, 83, 250, or
750 mg/kg-day for 13 weeks (DePass et al., 1983). Exposure was continued during a 15-day
period of cohabitation (one male, two females) and throughout gestation and lactation. Females
were placed into individual cages for nesting. Dates of parturition, litter size, number born live
and dead were recorded. Litter size was reduced to five male and five female pups on Day 5 of
lactation. Offspring were weighed as litters on Day 7 and individually on Day 21 postpartum.
Food and water consumption and body weight were measured daily. Following weaning, 10 rats
(5 males, 5 females) from each dose group of F0 and Fi were randomly selected for sacrifice and
necropsy. Liver, kidney, heart, brain, and testes were weighed, and tissues from these organs
from the high-dose and control groups were evaluated microscopically.
No clinical signs or unusual reproductive behaviors were observed (DePass et al., 1983).
Table 5 shows the results for body weight, food consumption, water consumption, and organ
weights of parental animals. Significant reductions in body-weight gain were observed in
parental males at 750 mg/kg-day and females at 250 and 750 mg/kg-day. Food consumption was
significantly decreased at 750 mg/kg-day in both sexes, while water consumption was
significantly decreased at 250 and 750 mg/kg-day in both sexes. Changes in organ weights
appeared to occur in parallel to decreased body-weight gain. No histopathological changes were
observed in any of these organs. In the high-dose group, there appeared to be low male and
female fertility and decreases from controls in the number of litters with live pups, the number of
live pups per litter, and the percent of pups weaned (see Table 6). None of these apparent
differences were statistically significant, but interpretation of these results is complicated by
unusually low control values for female fertility and number of live pups per litter. It is also
unclear how to reconcile the reported decrease in percent of high-dose pups weaned with 100%
survival of those pups through Day 21 of weaning. Mean body weight among high-dose pups of
both sexes was significantly lower than control values on Postnatal Days 7 and 21 (data for
Day 21 are shown in Table 7). Small—but significant—changes in organ weights were noted in
parallel with the decreased body weight. As with parental animals, no histological changes were
noted in any of these organs. Based on these findings, 250 mg/kg-day is a NOAEL for the study,
and 750 mg/kg-day is a LOAEL for reductions in parental and fetal body weight. Possible
reproductive effects were also seen at 750 mg/kg-day. Other reported developmental studies
(Singh et al., 1972) observed total body-weight reductions pertinent to gestational exposures to
acrylic acid monomers. No other developmental effects were observed in this study.
As part of a series of genetic toxicity tests of acrylic acid, a dominant-lethal assay was
conducted with male CD-I mice (McCarthy et al., 1992). Male mice (group sizes were not
explicitly reported, but, judging by the numbers of females reported in the results tables,
5-30 males/group were used) received either a single gavage dose of acrylic acid (>99.8% pure,
adjusted to pH = 6) in water (0, 32, 108, or 324 mg/kg) or five consecutive daily doses of 0, 16,
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Table 5. Body Weight, Food Consumption, Water Consumption, and

Organ Weights of Parental Rats Following Exposure to Acrylic Acid in

Drinking Water in a One-Generation Reproduction Study
a


Dose (mg/kg-day)

0
83
250
750

Mean
SD
Mean
SD
Mean
SD
Mean
SD
Males
Measured dose (g/kg-day)
0.0
0.0
0.085
0.006
0.25
0.02
0.73
0.05
Food consumption (g/rat-
16.1
0.2
16.8
0.3
16.2
0.3
14.0d
0.07
day)








Water consumption (mL/rat-
21.3
0.3
20.1
0.5
17.7d
0.5
12.9d
1.0
day)








Body-weight gain (g)
206.0
16.9
201.2
25.0
191.7
11.6
143.7d
23.0
Liver absolute (g)
12.09
1.67
12.66
0.77
12.05
0.64
9.61°
0.57
Liver relative (%)
3.18
0.28
3.46
0.17
3.30
0.16
3.20
0.09
Kidney absolute (g)
2.41
0.24
2.45
0.07
2.36
0.15
2.32°
0.39
Kidney relative (%)
0.63
0.03
0.67
0.02
0.64
0.04
0.77°
0.09
Spleen absolute (g)
0.63
0.09
0.64
0.05
0.66
0.06
0.66
0.12
Spleen relative (%)
0.17
0.02
0.17
0.01
0.18
0.01
0.22b
0.04
Heart absolute (g)
0.96
0.16
0.91
0.08
0.83
0.07
0.78
0.23
Heart relative (%)
0.25
0.03
0.25
0.01
0.23
0.02
0.26
0.06
Brain absolute (g)
1.87
0.19
1.86
0.05
1.89
0.08
1.71
0.26
Brain relative (%)
0.50
0.06
0.51
0.03
0.52
0.03
0.57
0.10
Testes absolute (g)
2.89
0.17
2.88
0.09
2.91
0.06
2.76
0.15
Testes relative (%)
0.77
0.07
0.79
0.06
0.80
0.02
0.92d
0.06

Mean
SD
Mean
SD
Mean
SD
Mean
SD
Females
Measured dose (g/kg-day)
0.0
0.0
0.083
0.003
0.25
0.01
0.72
0.04
Food consumption (g/rat-
10.5
0.1
10.7
0.4
0.4
0.4
8.7d
0.03
day)








Water consumption (mL/rat-
15.1
0.5
14.7
0.3
12.5d
0.9
8.8d
0.4
day)








Body-weight gain (g)
85.2
8.5
87.4
8.4
78.2b
9.4
59.5d
8.6
Liver absolute (g)
7.25
0.82
8.51b
0.99
8.22
0.72
5.58°
0.32
Liver relative (%)
3.43
0.38
3.84b
0.22
4.00°
0.30
3.32
0.20
Kidney absolute (g)
1.50
0.12
1.69b
0.17
1.69b
0.09
1.47
0.09
Kidney relative (%)
0.72
0.07
0.77
0.04
0.83°
0.04
0.87d
0.04
Spleen absolute (g)
0.44
0.05
0.46
0.07
0.45
0.04
0.37b
0.03
Spleen relative (%)
0.21
0.03
0.21
0.03
0.22
0.02
0.22
0.02
Heart absolute (g)
0.64
0.10
0.71
0.08
0.68
0.06
0.54
0.09
Heart relative (%)
0.30
0.04
0.32
0.02
0.34
0.04
0.32
0.05
Brain absolute (g)
1.69
0.09
1.74
0.10
1.70
0.13
1.64
0.04
Brain relative (%)
0.80
0.05
0.79
0.03
0.83
0.04
0.98°
0.01
aDePass etal. (1983)
bp < 0.05
cp < 0.01
dp< 0.001
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Table 6. Reproductive Effects in Dams Following Exposure to Acrylic Acid in
Drinking Water in a One-Generation Reproduction Study"
Endpoint
Dose (mg/kg-day)
0
83
250
750
Fertility index (males)b
80
100
80
60
Fertility index (females)0
50
95
75
45
Gestation indexd
100
100
100
89
Gestation survival index6
100
100
100
100
5-Day survival indexf
100
100
100
100
21-Day survival index®
100
100
100
100
Pups born alive/litter11
6
8
9
4
Pups weaned/pups alive at birth11
100
100
100
42
aDePass etal. (1983)
bLitters sired per male mated (x 100)
deliveries per female mated (x 100)
dLitters with live pups/total pregnancies (/ 100)
ePups born viable/total pups delivered (/ 100); median per litter
fPups viable at Day 5/pups born viable (/ 100); median per litter
8Pups viable at Day 21/pups retained at Day 5 (/ 100); median per litter
hMedian
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Table 7. Body Weight, Food Consumption, Water Consumption, and

Organ Weights of Fi Male and Female Rat Pups on Day 21 Postpartum Following
Gestational and Lactational Exposure to Acrylic Acida



Dose (mg/kg-day)

0
83
250
750

Mean
SD
Mean
SD
Mean
SD
Mean
SD
Male
Mean body weight (g)
32.9
6.4
32.2
4.0
32.6
4.2
24.7°
4.0
Liver absolute (g)
1.14
0.12
1.32
0.20
1.15
0.14
0.80°
0.14
Liver relative (%)
3.55
0.05
3.87
0.27
3.65
0.21
3.06°
0.16
Kidney absolute (g)
0.36
0.05
0.39
0.03
0.35
0.04
0.24°
0.07
Kidney relative (%)
1.11
0.04
1.14
0.07
1.13
0.06
0.92
0.31
Spleen absolute (g)
0.18
0.02
0.18
0.02
0.18
0.03
0.12
0.02
Spleen relative (%)
0.55
0.10
0.53
0.04
0.58
0.03
0.48
0.06
Heart absolute (g)
0.12
0.03
0.14
0.03
0.12
0.03
0.14
0.12
Heart relative (%)
0.38
0.05
0.40
0.04
0.39
0.04
0.50
0.38
Brain absolute (g)
1.25
0.09
1.25
0.07
1.23
0.14
1.20
0.05
Brain relative (%)
3.89
0.21
3.73
0.48
3.91
0.34
4.63b
0.61
Testes absolute (g)
0.15
0.02
0.17
0.03
0.16
0.02
0.13
0.02
Testes relative (%)
0.47
0.02
0.49
0.04
0.51
0.02
0.50
0.03

Mean
SD
Mean
SD
Mean
SD
Mean
SD
Female
Mean body weight (g)
31.6
5.0
31.8
3.3
31.7
4.1
24. lc
4.3
Liver absolute (g)
1.02
0.15
1.34b
0.15
1.20
0.17
0.74b
0.20
Liver relative (%)
3.53
0.15
3.88
0.17
3.74
0.25
3.16
0.47
Kidney absolute (g)
0.34
0.04
0.40
0.05
0.37
0.04
0.29
0.04
Kidney relative (%)
1.16
0.08
1.15
0.05
1.15
0.08
1.25
0.22
Spleen absolute (g)
0.17
0.04
0.18
0.03
0.16
0.02
0.12
0.03
Spleen relative (%)
0.57
0.12
0.51
0.04
0.49
0.02
0.53
0.08
Heart absolute (g)
0.11
0.02
0.14b
0.02
0.12
0.02
0.07b
0.02
Heart relative (%)
0.37
0.03
0.42
0.04
0.37
0.04
0.30b
0.07
Brain absolute (g)
1.18
0.18
1.24
0.13
1.28
0.04
1.13
0.04
Brain relative (%)
1.03
0.86
3.61
0.30
4.04
0.33
4.98b
0.80
aDePass etal. (1983)
hp < 0.05
><0.01
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54, or 162 mg/kg-day, also administered by gavage in water. The doses used in the acute and
repeated-dose studies were based on preliminary toxicity studies. The maximum tolerated doses,
324 mg/kg-day for the acute study and 162 mg/kg-day for the repeated-dose study, did not result
in mortality (
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mouse was sacrificed in moribund condition after 5-6 weeks of exposure. No rats died during
the study. Female mice in the mid- and high-dose groups had significantly (p < 0.05) reduced
body-weight gain when compared to controls after 12 weeks of exposure—but not before (see
Table 8). There were no significant treatment-related effects on body-weight gain for male mice
or for rats of either sex. The authors reported that there were no significant treatment-related
effects on organ weights, organ-to-body weight ratios, hematology, or clinical chemistry in rats
or mice, or urinalysis in rats (data not shown). Male mice in the mid- and high-dose groups and
females in the high-dose group had lower mean hemoglobin levels than controls, but these levels
were considered to be in the normal range for mice of similar age and strain. The researchers
reported no gross pathological observations in rats or mice related to treatment. Lesions of the
nasal mucosa were observed during histopathological examination of rats and mice, primarily
degeneration of the olfactory epithelium (Table 9). The incidence and severity of these lesions
increased with exposure concentration. There were no other significant treatment-related
histopathological findings. For rats, the NOAEL and LOAEL values for the study are 25 ppm
3	3
(74.7 mg/m ) and 75 ppm (224 mg/m ) based on slight focal degeneration of the olfactory
epithelium. For mice, the low exposure level of 5 ppm (14.9 mg/m3) is a LOAEL for focal
degeneration of the nasal olfactory epithelium.
Table 8. Body-Weight Gains (Mean ± SD) of Rats and Mice
in a 13-Week Vapor Inhalation Study of Acrylic Acida
Weeks on
Test
Exposure Concentration (mg/m3)
Control
14.9
74.7
224
Control
14.9
74.7
224

Male Rats
Female Rats
3
91 ± 10
89 ±8
91 ± 9
84 ± 11
38 ±4
40 ±4
41 ± 3
40 ±4
6
157 ± 11
156 ±9
156 ± 10
148 ± 13
67 ±6
69 ±5
68 ±4
65 ±5
9
195 ± 14
192 ± 10
195 ±11
188 ± 15
81 ± 6
84 ±4
83 ±4
80 ±6
12
213 ± 15
210 ± 14
219 ± 13
210 ± 14
86 ±7
89 ±4
89 ±7
87 ±7

Male Mice
Female Mice
3
3.5 ± 1.7
4.0 ±0.7
3.7 ±0.6
4.5 ± 0.8b
5.0 ±1.1
5.5 ± 1.7
4.6 ±0.9
4.7 ± 1.0
6
4.5 ±0.8
6.6 ± 1.7b
5.8 ± 1.6
6.1 ± 1.0b
6.9 ±1.1
7.7 ± 1.0
6.2 ±0.7
6.8 ±0.9
9
6.3 ±2.0
8.3 ±2.6b
6.9 ± 1.5
7.6 ± 1.4
8.4 ± 1.0
10.1 ±2.7b
7.6 ± 1.0
8.4 ± 1.3
12
7.4 ±2.0
9.3 ±2.5b
7.5 ±2.0
8.5 ± 1.5
9.8 ± 1.3
8.9 ± 1.2
8.6 ± l.lb
8.7 ± l .lb
"Miller etal. (1981)
bStatistically significant deviation from control group mean using Dunnett's Test p < 0.05
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Table 9. Histopathological Observations in the Nasal Mucosa of Rats and Mice After
Exposure to Acrylic Acid in a 13-Week Vapor Inhalation Studya'b
Lesion Type
Exposure Concentration (mg/m3)
Sex/Species
0
14.9
74.7
224
0
14.9
74.7
224
Male Rats
Female Rats
Slight focal degeneration of the olfactory
epithelium
0/10
0/10
0/10
7/10
0/10
0/10
0/10
10/10

Male Mice
Female Mice
Focal degeneration of the olfactory epithelium
in the dorso-medial aspect of the nasal
passages with partial replacement by an
epithelium resembling respiratory epithelium
-slight-to -moderate
1/10
1/10
0/11
10/10
0/10
0/10
0/10
10/12
Focal degeneration of olfactory epithelium in
the dorso-medial aspect of the nasal passages
-slight
-very slight
-ungraded due to autolysis
0/10
1/10
0/10
0/10
1/10
0/10
10/11
1/11
0/11
0/10
0/10
0/10
0/10
0/10
0/10
0/10
4/10
0/10
9/10
0/10
0/10
1/12
0/12
1/12
Focal infiltration of inflammatory cells in the
mucosa and submucosa in regions having
degeneration of the mucosa
-slight
-very slight
0/10
0/10
0/10
0/10
0/11
1/11
0/10
10/10
0/10
0/10
0/10
0/10
2/10
0/10
0/12
10/12
Focal hyperplasia of submucosal glands in
regions having degeneration of the mucosa
-very slight
0/10
0/10
0/11
10/10
0/10
0/10
0/10
10/12
a Miller etal. (1981)
bHistopathological examinations were performed for 10 rats and 10 mice of each exposure group as well as for
any animals that died or were sacrificed moribund prior to scheduled sacrifice
Reproductive/Developmental Studies—In a preliminary developmental toxicity study,
pregnant Sprague-Dawley rats (5 females/group) were exposed by whole-body inhalation to
acrylic acid vapor (99.74% pure) at mean measured concentrations of 0, 217.6 or 438.9 ppm
"3
(0, 641, or 1290 mg/m for 6 hours/day, for 10 consecutive days on Gestation Days (GD) 6-15
(Klimisch and Hellwig, 1991). This study was conducted in order to determine appropriate
concentrations of test substance to be used in the main study summarized below. Body weight
and food consumption were determined prior to the test, then every 3 days during the testing
period until Day 20. All rats were sacrificed on Day 20 and received gross pathological
examination that included determination of uterine weight, number of implantation sites, and the
number of live and dead fetuses. A histological examination of the nasal mucosa was conducted
for all adults. Weight and crown-rump length were recorded for each fetus as well as any
external malformations.
No dams died during the study (Klimisch and Hellwig, 1991). Body weight and food
consumption were decreased throughout the entire exposure period in high-dose rats. At the low
dose, body-weight gain and food consumption were decreased only during the first 3 days of
exposure. All treated animals showed clinical signs of toxicity. In the low-dose group, signs
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included eyelid closure, eye discharge, and slightly red noses. Clinical signs were more
pronounced in the high-dose group, with increased restlessness and more frequent snout rubbing.
Body weight minus uterus weight, body-weight gain minus uterus weight, and placental weight
were significantly (p < 0.05) decreased in high-dose rats in comparison with controls. Terminal
placental weights were also significantly decreased in the low-dose group. Slight degeneration
of the nasal olfactory epithelium with metaplasia of the respiratory epithelium and hyperplasia of
the submucosal gland was observed during histopathological examination in both dose groups
(data not shown). Due to the limited number of pregnancies and fetuses present, embryonic and
fetal toxicity assessments were not conducted. Based on these findings, the study authors
concluded that maternal toxicity was present at both concentrations tested and identified the low
"3
concentration of 217.6 ppm (641 mg/m ) as a LOAEL for clinical signs of toxicity, reduced
placental weight, and degeneration of the nasal olfactory epithelium.
In the full developmental toxicity study, pregnant Sprague-Dawley rats
(30 females/group) were exposed to acrylic acid vapor at mean measured concentrations of 0,
39.4, 114.0, or 356.2 ppm (0, 116, 336, or 1050 mg/m3) for 6 hours/day, 5 days/week on
GD 6-15 (Klimisch and Hellwig, 1991). As in the pretest, body weight and food consumption
were determined prior to the test, and then every 2 days during the testing period until Day 20.
All rats were sacrificed on Day 20 and received gross pathological examination that included
weight of the uterus, number of implantation sites, and number of live and dead fetuses. Fetuses
were weighed and measured. One-third of the fetuses were stained and examined for internal
malformations. The remaining two-thirds were examined for skeletal malformations.
No maternal deaths were observed during the study (Klimisch and Hellwig, 1991).
Animals in the high-dose group had a watery discharge from the eyes and nose, and had restless
behavior that continued for 1-2 hours after exposure. As shown in Table 10, there were
small—but significant—reductions in maternal body weight and body-weight gain in comparison
to controls, primarily in the high-dose group, but, also, to a lesser extent in the mid- and
low-dose groups. Food consumption was reduced in a dose-related manner and was statistically
significant during the first few days of exposure in the mid-dose group and throughout the
duration of the study in the high-dose group. The data showed no treatment-related effects on
the number of corpora lutea, implantations, or live and dead fetuses. No fetal mortality was
observed during the study. Mean fetal body weights were significantly higher than control
values in the mid- and high-dose groups, but this change was not considered to be toxicologically
relevant. Fetal length was not affected by treatment. The data showed no treatment-related
external, internal, or skeletal anomalies. Based on these findings, the NOAEL and LOAEL
3	3
values for maternal toxicity are 39.4 ppm (116 mg/m ) and 114 ppm (336 mg/m ), respectively,
based on reduced body weight. The NOAEL for developmental toxicity is the highest dose
tested: 356.2 ppm (1050 mg/m3).
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Table 10. Effects on Body and Uterine Weight (Mean ± SD) in Pregnant
Female Rats Exposed to Acrylic Acid Vapors"
Endpoint
Exposure Concentration (mg/m3)
0
116
336
1050
Body weight (Day 0)
216 (9.4)b
216 (11.3)
214 (7.7)
215 (9.9)
Body weight (Day 6)
243 (10.1)
243 (16.1)
242 (9.5)
242 (12.7)
Body weight (Day 15)
288 (9.6)
284 (19.2)
283 (14.4)
261 (16.3)f
-9%g
Body weight (Day 20)
354 (19.9)
349 (33.3)
346 (27.0)
333 (26.1)f
-5.9%8
Uterus weight (Day 20)
64 (18.8)
66 (25.5)
68 (23.6)
65 (21.1)
BWE-uterus°
290 (12.0)
283 (17.8)
278 (16.6)f
-4.1%8
267 (13 4)f
-7.9%8
BWE-BWS-uterusd
74(11.5)
67 (11.2)e
-9.5%8
65 (13. l)f
-12.2% g
52 (9.5)f
-29.7% g
aKlimisch and Hellwig (1991)
bFigures in parenthesis indicate standard deviations
°B WE-uterus = body weight on Day 20 minus uterus weight
dBWE-BWS-uterus = body-weight gain between Day 0 and Day 20 minus uterus weight
ep < 0.05
{p < 0.01
8Percent difference from controls
As part of a larger study designed to address the embryotoxicity of acrylates, pregnant
Sprague-Dawley rats (20-24 per group) were exposed by whole-body inhalation to 0, 50, 100,
200, or 300-ppm acrylic acid (>99% pure) (0, 147, 295, 589, or 884 mg/m3) for 6 hours/day on
GD 6-20 (Saillenfait et al., 1999). Measured exposure concentrations were within 5% of target
concentrations, as confirmed by laboratory analysis of the test atmospheres. Body weight and
food consumption were measured periodically. Dams were euthanized on GD 21, and number of
implantation sites, resorptions, and dead and live fetuses were recorded. Live fetuses were
weighed, sexed, and examined for external anomalies. Half of the fetuses were examined for
internal tissue malformations; the other half were stained and examined for skeletal anomalies.
There was no mortality (Saillenfait et al., 1999). Maternal body-weight gain during
gestation (GD 6-21) was significantly (p < 0.05) reduced in comparison with control values
among dams exposed to 200- or 300-ppm acrylic acid (Table 11). Food consumption during
gestation (GD 6-21) was significantly reduced in the 100-, 200-, and 300-ppm groups (Table
11). The data showed no toxicologically relevant effects on the mean number of implantation
sites, number of resorptions, number of live fetuses or sex of fetuses. There was a
concentration-related decrease in mean fetal body weight per litter that was statistically
significant at 300 ppm for males, females, and both sexes combined (Table 12). The data
showed no toxicologically relevant effects on the number of external, internal, or skeletal
malformations. The NOAEL for maternal toxicity in this study is 100 ppm (295 mg/m3). The
"3
LOAEL for maternal toxicity is 200 ppm (589 mg/m ) based on decreased body-weight gain
during GD 6-21. The NOAEL and LOAEL for fetal toxicity are 200-ppm (589 mg/m3) and
"3
300-ppm (884 mg/m ), respectively, for decreased fetal body weight.
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Table 11. Effects of Exposure to Acrylic Acid Vapors on
Pregnant Sprague-Dawley Rats"
Acrylic Acid
Concentration
(ppm/6 hr/day)
No. of Dams
Body Weight
(g) on GD 6
Body Weight Gain (g) on GD
Absolute
Weight Gain
(g)b
6-13
13-21
6-21
0
24
272 ± 16
30 ±7
102 ± 29
131 ± 32
27 ± 13
50
20
265 ± 15
25 ± 11
108 ± 25
132 ±25
29 ±9
100
22
269 ± 12
25 ±8
101 ± 18
126 ± 22
21 ± 12
200
21
269 ± 14
18 ± 6°
87 ± 19
105 ± 21°
5 ± 12°
300
23
268 ± 16
12 ± 8°
75 ± 15°
88 ± 18°
-13 ± 14°

Food Consumption (g/dam/day) on GD
0-6
6-13
13-21
6-21
0
24

22 ±2
23 ±2
26 ±3
25 ±3
50
20

23 ±2
21 ± 2d
26 ±2
24 ±2
100
22

23 ±2
21 ± 2d
25 ±2
23 ± ld
200
21

23 ±2
19 ± 1°
23 ± 2°
21 ± r
300
23

23 ±2
18 ± 2°
20 ± 2°
19 ± 2°
aSaillenfait et al. (1999); values are mean± SD
b(Day 21 body weight)—(gravid uterus weight)—(Day 6 body weight)
Significant difference from control value, p < 0.01, Dunnett's Test
Significant difference from control value, p < 0.05, Dunnett's Test
Table 12. Effects of Gestational Exposure to Acrylic Acid Vapors
on Sprague-Dawley Rats"
Concentration
(ppm/6 hr/day)
No. Litters
Mean Fetal Body Weight (g) per Litter
All
Males
Females
0
24
5.73 ± 0.20
5.89 ±0.25
5.58 ±0.18
50
20
5.72 ±0.39
5.89 ±0.34
5.52 ±0.39
100
22
5.60 ±0.31
5.75 ±0.29
5.47 ±0.32
200
21
5.38 ±0.32
5.73 ±0.35
5.42 ±0.34
300
23
5.22 ± 0.37b
5.36 ± 0.40b
5.09 ± 0.34b
aSaillenfait et al. (1999); values are mean± SD
Significant difference from control value, p < 0.01, Dunnett's Test
In a range-finding study in rabbits, groups of eight pregnant New Zealand white rabbits
were exposed to 0-, 30-, 60-, 125-, or 250-ppm acrylic acid (>99% pure) on GD 10-23
(Neeper-Bradley et al., 1997). Test concentrations were analytically verified. From each group,
three animals were necropsied on GD 23 (last day of exposure), and the remaining animals were
examined on GD 29. Clinical signs of nasal irritation were significantly increased in the
250-ppm group and observed to a lesser extent in the 125-ppm group. Body weight on GD 29
was reduced in a dose-related fashion in all treated groups; the difference from controls was
statistically significant in all groups except those exposed to 60 ppm. Histopathological
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examination of the does revealed lesions in the nasal turbinates in all treated groups, ranging
from rhinitis to squamous metaplasia, epithelial erosion, and ulceration of the epithelium;
severity of the nasal lesions increased with increasing exposure concentration.
In the full developmental study (Neeper-Bradley et al., 1997), groups of 16 pregnant
rabbits were exposed to 0-, 25-, 75-, or 225-ppm acrylic acid (>99% pure) (0, 73.7, 221, or
"3
663 mg/m ) 6 hours per day on GD 6-18. Test concentrations were analytically verified. Signs
of nasal irritation (perinasal encrustacean, perinasal wetness, and nasal congestion) were
significantly increased in the high-dose group (225 ppm). Nasal congestion was also observed in
one mid-dose animal. The maternal body weight data showed no effect of treatment at any
exposure level. Histological examination of maternal tissues was not performed. The data
showed no exposure-related adverse effects on the number of corpora lutea and total, viable, or
nonviable implantations; preimplantation loss; fetal length or weight; or on morphological
abnormalities (external, skeletal, or soft tissue). The NOAEL for maternal toxicity in this study
3	3
is 75 ppm (221 mg/m ). The LOAEL for maternal toxicity is 225 ppm (663 mg/m ) based on
nasal irritation. The high exposure level of 225 ppm (663 mg/m3) is a NOAEL for
developmental toxicity in this study.
OTHER STUDIES
Toxicokinetics
Toxicokinetic studies of acrylic acid with mice and rats demonstrate that (1) acrylic acid
is rapidly absorbed, metabolized, and excreted in a similar manner, regardless of the route of
exposure; and (2) the disposition of acrylic acid is qualitatively and quantitatively similar in mice
and rats.
Sprague-Dawley rats were exposed to acrylic acid either by nose-only inhalation
(1 ^-acrylic acid at a maximum dose of 26 mg/kg for one minute) or by gastric intubation
(aqueous solution of nC-acrylic acid; dose equivalent to that used in inhalation experiment)
(Kutzman et al., 1982). Rats in the inhalation study were euthanized 1.5 or 65 minutes after
exposure. Rats in the oral study were killed at 1.5, 10, 20, 40, or 65 minutes after exposure. An
examination of the radioactivity in organs at the various time points indicated that regardless of
the route of exposure, the gastrointestinal tract was the primary site of absorption and the
percentage of radioactivity expired by the lungs (approximately 60%) and in the urine
(approximately 6%) was similar.
The absorption, distribution, metabolism, and elimination of acrylic acid were studied
following oral (40 or 150 mg/kg) or dermal administration (10 or 40 mg/kg) of 14C-acrylic acid
to male C3H mice and F344 rats (Black et al., 1995). In all cases, acrylic acid was rapidly
absorbed, metabolized, and eliminated. In the oral studies with both species, approximately 80%
of the administered dose was exhaled as 14C02, 3% was eliminated in the urine, and 1% was
eliminated in the feces. In the dermal studies with both species, 12—26% of the applied dose was
absorbed; the rest was presumed to be evaporated. For both species, 80% of the absorbed
radioactivity was exhaled within 24 hours; less than 0.5% of the administered dose was excreted
in the urine and feces. In both species and following both oral and dermal exposure, acrylic acid
was rapidly distributed to the plasma, liver, kidneys, and fat; elimination from these
compartments was rapid, but was slower from the fat.
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Other Routes
No increase in skin tumors developed in a group of 40 male C3H/HeJ mice that received
applications to the skin of 25 mL of 1% acrylic acid (-0.2 mg acrylic acid per mouse or
6.7 mg/kg) 3 times weekly for life compared to acetone controls (DePass et al., 1984). A similar
study observed no increase in skin tumors in male or female C3H or ICR mice treated with doses
up to 100 mL of 1% acrylic acid (-1.0 mg per mouse or 37.9 mg/kg) in acetone 3 times weekly
for 21 months (Hoechst-Celanese, 1990). There was a statistically significant increase in the
incidence of lymphosarcoma in female C3H mice in the high-dose group (7/50 vs. 0/50 in
acetone controls) of this study, but it is unclear if this resulted from treatment.
Genotoxicity
Acrylic acid was negative in mutagenicity tests in S. typhimurium (strains TA100,
TA1535, TA1537, TA1538, and TA98) with or without metabolic activation (Zeiger et al., 1987;
Lijinsky and Andrews, 1980). A test for mutagenicity of acrylic acid at the tk locus in L5178Y
mouse lymphoma cells without exogenous activation was positive, but, because it was primarily
small-colony mutants that were induced, the researchers suggested the positive results were due
to a clastogenic mechanism rather than induction of point mutations (Moore et al., 1988).
Acrylic acid gave positive results for induction of chromosomal aberrations in mouse lymphoma
cells in this study (Moore et al., 1988). McCarthy et al. (1992) reported negative results for
acrylic acid in a test for mutagenic activity at the HGPRT locus in Chinese hamster ovary (CHO)
cells but positive results for chromosomal aberrations in CHO cells—with or without activation.
However, acrylic acid did not induce micronucleus formation in Syrian hamster embryo (SHE)
cells (Wiegand et al., 1989), and results were negative in assays for both mutagenicity and
clastogenicity in vivo (Drosophila sex-linked recessive lethal, dominant lethal in mice,
chromosomal aberrations in mouse bone marrow cells) (McCarthy et al., 1992). Assays for
DNA damage (unscheduled DNA synthesis) in cultured rat hepatocytes and SHE cells were
negative (McCarthy et al., 1992; Wiegand et al., 1989), as was an assay for morphological
transformation in SHE cells (Wiegand et al., 1989).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RFD
VALUES FOR ACRYLIC ACID
SUBCHRONIC p-RfD
Table 13 summarizes the available oral toxicity database for acrylic acid. For the 90-day
gavage study (Hellwig et al., 1993) in Wistar rats, the endpoint incidences were summarized but
no statistical analysis were reported and no conclusions regarding organ weights were reported.
There was no discussion on timing of mortality and clinical signs reported associated with
animals that died. This effect could possibly be related to bolus dosing. The reported frank
effect level (FEL) of 107 mg/kg-day based on mortality does not give support for use as POD for
deriving RfD value.
The 12-month drinking water study (Hellwig et al., 1993) in Wistar rats for both sexes,
contained a satellite group that was sacrificed after 90-day exposure. Results of tests performed
(feed consumption, drinking water and body weight, hematological, clinical chemistry,
pathological and histological examination) showed statistical significance in some cases. The
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Table 13. Summary of Oral Noncancer Dose-Response Information for Acrylic Acid
Species and Study
Type (rt/Scx/Group)
Exposure (Doses, Route,
Frequency, Duration)
NOAEL
(mg/kg-
day)
LOAEL
(mg/kg-
day)
Duration-
Adjusted"
LOAEL
(mg/kg-
day)
Responses at the LOAEL
Comments
Reference
Subchronic Studies
F344 rat
(15/sex/group)
0, 83, 250, 750mg/kg-d, drinking
water, 90 days
83
250
250
Reduced body-weight gain in
females

DePass et al.,
1983
Wistar rat
(10/sex/group)
0, 150, 375 mg/kg-d, gavage
(water), 5d/wk, 90 days
None
150
(FEL)
107
(FEL)
Mortality was observed in five
males and five females; 15/20
died at the high dose
Forestomach and
stomach irritation;
necrotizing tubular
nephrosis was
observed in all
animals that died
Hellwig et al.,
1993
Wistar rat
(20/sex/main group;
10/sex/satellite
group)
0, 120, 800, 2000, 5000 ppm (0, 9,
61, 140, 331 mg/kg-d), drinking
water, 3 months (satellite group) or
12 months (main group)
331
None
None
None

Hellwig et al.,
1993
Chronic Studies
Wistar rat
(50/sex/group)
0, 120, 400, 1200 ppm (0, 8, 27, 78
mg/kg-d), drinking water,
26 months (male), 28 months
(female)
78
None
None
None
No effect on tumor
incidence, but the
maximum tolerated
dose apparently
was not achieved
Hellwig et al.,
1993
Developmental/Reproductive Toxicity Studies
Wistar rat, two-
generation
reproduction study
(25/sex/group)
0, 500, 2500, 5000 ppm (0, 53,
240, 460 mg/kg-d), drinking water,
70-98 days premating, during
mating, gestation, and lactation
Parental:
240
Pups:
53
Parental:
460
Pups:
240
Parental:
460
Pups:
240
Parental: Lesions in stomach
and forestomach; body-weight
reduction in Fi parents
Pups: Reduction in pup body
weight
The NOAEL for
reproduction was
460 mg/kg-day
Hellwig et al.,
1997
F344 rat, one-
generation
reproduction study
(10 M, 20 F/group)
0, 83, 250, 750 mg/kg-d, drinking
water, 13 wks premating, during
mating, and throughout gestation
and lactation
Parental
and pup:
250
Parental
and pup:
750
Parental
and pup:
750
Parental: Reduced body-
weight gain
Pup: Reduced body weight

DePass et al.,
1983
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Table 13. Summary of Oral Noncancer Dose-Response Information for Acrylic Acid
Species and Study
Type (rt/Scx/Group)
Exposure (Doses, Route,
Frequency, Duration)
NOAEL
(mg/kg-
day)
LOAEL
(mg/kg-
day)
Duration-
Adjusted"
LOAEL
(mg/kg-
day)
Responses at the LOAEL
Comments
Reference
CD-I mouse,
dominant-lethal assay
(5-30 M/9-59
F/group)
0, 16, 54, 162, gavage,
five consecutive daily doses; or 0,
32, 108, 324 mg/kg, gavage, one
dose
5 doses:
162
1 dose:
324
None
None
None
No effects on %
dead implants or %
dominant lethal
McCarthy et
al., 1992
aAdjusted to continuous exposure
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difference between groups in the clinico-chemical, hematological and urinalyical examination at
various intervals showed non-obvious treatment related patterns in parameters monitored. The
differences were marginal, inconsistent or lacked a dose-effect relationship. The small change in
body weight observed in high-dose males was not considered biologically significant. A
NOAEL of 331 mg/kg-day (highest dose tested) was identified (six times higher than the
NOAEL identified at Hellwig et al. (1997) study.
The 26/28-month drinking water carcinogenicity study (Hellwig et al., 1983) did not
reveal any clear toxic or oncogenic effects of acrylic acid with exception of slightly reduce
consumption of water, which was not statistically significant. Based on these findings, the
NOAEL for this study is 78 mg/kg-day (highest dose tested). Overall, no treatment-related
mortality was observed in 90-day, 12-month, or 2-year studies in which Wistar and F344 rats
were exposed to acrylic acid via drinking water. This study gives no relevant information for
toxicity values assessment in comparison to Hellwig et al. (1997).
The McCarthy et al. (1992) identified a NOAEL value for reproduction in the acute and
repeated-dose studies of 324 mg/kg-days and 162 mg/kg-day respectively. This study was not
suitable for POD and is less relevant for humans compared to other studies (Hellwig et al., 1993;
Hellwig et al., 1997).
The study by Hellwig et al. (1997) (principal study) had an adequate number of animals
(25/Sex/rats). It was well described with a clear dosing regimen, sampling strategy and culling
of animals. The study was well performed, with four dosing levels including a control group, a
range of tissues examined endpoints and exposure levels. Treatment-related differences between
controls and animals exposed to acrylic acid observed were statistically significant. The
identified NOAEL for pup toxicity was 53 mg/kg-day, lowest compared to other NOAELs
identified in other studies (DePass et al., 1983; Hellwig et al., 1993; McCarthy et al., 1992).
The NOAEL of 53 mg/kg-day is the appropriate point of departure (POD) for deriving
the subchronic p-RfD for acrylic acid. Other studies (DePass et al., 1983) reported a NOAEL
(83 mg/kg-day) and a LOAEL (250 mg/kg-day) that are comparable to the selected POD.
Benchmark dose modeling cannot be conducted for reduced pup body weight in the critical study
due to the absence of standard deviations or standard errors in the study report.
Using the NOAEL of 53 mg/kg-day from the two-generation reproduction study in
Wistar rats (Hellwig et al., 1997) as the POD, a subchronic p-RfD is derived for acrylic acid as
follows:
Subchronic p-RfD = NOAEL UF
= 53 mg/kg-day -^300
= 0.2 or 2 x 10"1 mg/kg-day
The composite uncertainty factor (UF) of 100 is composed of the following UFs:
•	UFa: A factor of 10 is applied for animal-to-human extrapolation, as data for
evaluating relative interspecies sensitivity are insufficient.
•	UFr: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation, as data for evaluating susceptible human response are insufficient.
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•	UFd: A factor of 3 is applied due to the absence of a developmental toxicity study
by oral exposure.
•	UFl: A factor of 1 is applied because the POD was developed using a NOAEL.
•	UFS: A factor of 1 is applied because further adjustments for duration of exposure
are not warranted when developmental toxicity data are used to develop a POD
(U.S. EPA, 1991).
Confidence in the principal study is high because a sufficient number of animals were
used, appropriate endpoints were measured, and reporting was generally adequate. It is noted,
however, that BMD modeling could not be performed because no measure of variation was
reported for the critical endpoint of pup body weight. Confidence in the database is high. The
database contains three subchronic studies in two strains of rat, a chronic rat study, one- and
two-generation reproduction studies in rats, and a dominant lethal assay in mice by oral
exposure. The database also includes developmental toxicity studies in rats and rabbits by
inhalation exposure. All of these studies are of good quality and present consistent findings.
High confidence in the subchronic p-RfD follows.
CHRONIC p-RfD
A chronic RfD of 0.5 mg/kg-day for acrylic acid is available on IRIS (U.S. EPA, 2009a),
and it is based on the two-generation reproduction study in rats (Hellwig et al., 1997). As for the
subchronic p-RfD presented above, the chronic RfD was calculated from the NOAEL of
53 mg/kg-day for reduced pup weight and a composite UF of 100 (10 each for extrapolation
from rats to humans and protection of sensitive individuals). This assessment was posted to IRIS
on 2/17/1994.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RFC VALUES FOR ACRYLIC ACID
SUBCHRONIC p-RfC
Table 14 summarizes the available inhalation toxicity database for acrylic acid. Nasal
irritation and decreased body weight are the only critical effects that have been observed in rats,
mice, and rabbits following subchronic and gestational exposure to acrylic acid by the inhalation
route. Degeneration of the nasal olfactory epithelium observed histopathologically is the most
3	3
sensitive endpoint, with the lowest database LOAEL of 14.9 mg/m (LOAEL[hec] = 0.33 mg/m )
observed in a subchronic inhalation study conducted with B6C3Fi mice (Miller et al., 1981). A
subchronic LOAEL (3.9 mg/m3, Miller et al., 1981) in rats and maternal (84mg/m3) fetal LOAEL
(221 mg/m3) reported in Klimish and Hellwig (1991) and Saillenfait et al. (1999) were
comparable to the selected POD. The data sets for focal degeneration of the nasal olfactory
epithelium in male and female mice (Table 15) were amenable to benchmark dose modeling.
Details of benchmark dose modeling for the data sets shown in Table 15 are given in
Appendix A. The data set for female mice yielded a lower benchmark concentration (BMCio)
"3
and associated 95% lower confidence limit (BMCLio) values of 5.58 and 0.76 mg/m ,
respectively compared to male data. The logprobit model was selected on the basis of the lowest
BMCLio from the range of 0.76 to 6.09 mg/m3.
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Table 14. Summary of Inhalation Noncancer Dose-Response Information for Acrylic Acida
Species and
Study Type
(rt/Scx/Group)
Exposure
(Concentrations,
Frequency,
Duration)
NOAEL
(mg/m3)
LOAEL
(mg/m3)
NOAELjhec]
(mg/m3)
LOAELjhec]
(mg/m3)
Responses at the
LOAEL
Comments
Reference
Subchronic Toxicity
F344 rat
(15/sex/group)
0, 5, 25, 75 ppm
(0, 14.9, 74.7, 224
mg/m3), 6 h/d, 5
d/wk, 13 wks
74.7
224
1.3
3.9
Slight focal degeneration
of the nasal olfactory
epithelium

Miller et al.,
1981
B6C3Fi mouse
(15/sex/group)
0, 5, 25, 75 ppm
(0, 14.9, 74.7, 224
mg/m3), 6 h/d, 5
d/wk, 13 wks
None
14.9
None
0.33
Decreased mean body-
weight gain and focal
degeneration of the nasal
olfactory epithelium

Miller et al.,
1981
Reproductive/Developmental Toxicity
SD rat
(30 F/ group)
0, 39.4, 114.0,
356.2 ppm (0, 116,
336, 1050 mg/m3),
6 h/d, GDs 6-15
Maternal:
116
Fetal:
1050
Maternal:
336
Fetal:
None
Maternal:
29
Fetal:
262
Maternal:
84
Fetal:
None
Maternal: Reduced body-
weight gain on GDs 15-
20.
No effects were
observed on indices
of fertility or fetal
development
Klimisch and
Hellwig, 1991
SD rat
(20-24 F/ group)
0, 50, 100, 200,
300 (0, 147, 295,
589, 884 mg/m3), 6
h/d, GDs 6-20
Maternal:
295
Fetal:
589
Maternal:
589
Fetal:
884
Maternal:
74
Fetal:
147
Maternal:
147
Fetal:
221
Maternal: Decreased
body-weight gain on GDs
6-21:
Fetal: Decreased body
weight

Saillenfait et al.,
1999
New Zealand
rabbit
(16 F/ group)
0, 25, 75, 225 ppm
(0, 73.7, 221,663
mg/m3), 6 h/d,
GDs 6-18
Maternal:
221
Fetal:
663
Maternal:
663
Fetal:
None
Maternal:
31
Fetal:
166
Maternal:
94
Fetal:
None
Maternal: Nasal
congestion and irritation
No effects on fetal
development were
observed
Neeper-Bradley
et al., 1997
aHEC calculated as follows: NOAEL[Hec] = NOAEL x exposure hours/24 hours x exposure days/7 days x dosimetric adjustment
For systemic effects, the dosimetric adjustment is the ratio of the animal:human blood:gas partition coefficients for acrylic acid (in the absence of experimental
values, a default value of 1 was used)
For respiratory effects, the dosimetric adjustment is the RGDR for the affected portion of the respiratory tract (extrathoracic for acrylic acid), calculated as the
ratio of the animal:human minute volume/surface area ratios using default values from EPA (1994b)
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Table 15. BMD Dataset for Incidence of Focal Degeneration

of the Nasal Olfactory Epithelium in Mice"

Exposure Concentrations (mg/m3)
Sex
0
14.9
74.7
224
Male
1/10
2/10
11/11
10/10
Female
0/10
4/10
9/10
11/11
aMiller et al. (1981); incidences are based on very slight to moderate focal degeneration of the nasal olfactory
epithelium of the dorso-medial aspect of the nasal passages with or without partial replacement with respiratory
epithelium
-3
The BMCLio of 0.76 mg/m for the increased incidence of focal degeneration of the nasal
olfactory epithelium in female mice is the appropriate POD for deriving a subchronic p-RfC for
acrylic acid. Given that the effect of interest associated with the POD is an extrathoracic
respiratory effect, acrylic acid was treated as a Category 1 gas, and the following dosimetric
adjustments were made to convert the rodent BMCLio to a human equivalent concentration
(HEC) (U.S. EPA, 1994b). First, the duration-adjusted BMCLio was calculated:
BMCLio[adj] = BMCLio x hours/day x days/week
= 0.76 mg/m3 x 6/24 hrs/day x 5/7 days/week
= 0.14 mg/m3
Next, the Regional Gas Deposition Ratio (RGDR) for the extrathoracic region was calculated, as
follows (Equation 4-18 and default values from U.S. EPA, 1994b):
RGDRet = (Vf. ^ SAF.TLnmfi = 0.137
(Ve SAetX uman
Where:	Ve = Minute volume (L/min)
= 0.028 L/min for female B6C3Fi mice and 13.8 L/min for
humans
SAet = Surface area of the extrathoracic region (cm )
= 3 cm2 for mice, 200 cm2 for humans
"3
The BMCLio[hec] of 0.02 mg/m was subsequently derived as
BMCLio[hec] = RGDRet x BMCLio[adj]
= 0.137 x 0.14 mg/m3
= 0.02 mg/m3
To derive the subchronic p-RfC for acrylic acid, a composite UF of 30 was applied to the
BMCLio[hec], as follows:
Subchronic p-RfC =BMCL10[hec] ^UF
= 0.02 mg/m3 - 100
= 0.0002 or 2 x 10"4 mg/m3
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The composite UF of 30 is composed of the following:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation, as data for evaluating susceptible human response are insufficient.
•	UFa: A factor of 3 (10°5) is applied for pharmacodynamic differences between
rats and humans. No additional UF for pharmacokinetic differences is required
because dosimetric equations were used to derive a BMCL[Hec] from the mouse
exposure concentration and conditions.
•	UFd: A factor of 3 is applied because the database lacks a two-generation toxicity
study by inhalation exposure.
•	UFl: A factor of 1 for extrapolation from a LOAEL to a NOAEL was applied
because BMD modeling was used.
Confidence in the principal study is medium. The study (Miller et al., 1981) was well
conducted, and it identifies a LOAEL for a mild occurrence of the most sensitive endpoint.
Confidence in the study is medium because a NOAEL is not identified, a small number of
animals were used, and there is a limited description of the nasal lesion reported. Confidence in
the database is high. Subchronic inhalation studies in two species and developmental toxicity
studies in two species are available and of acceptable quality. Reproductive toxicity has been
studied by oral exposure. Medium confidence in the subchronic p-RfC follows.
"3
The subchronic p-RfC of 0.0002 mg/m for acrylic acid derived here is lower than the
chronic RfC of 0.001 mg/m3 available on IRIS—even though the key study and endpoint are the
same. This is due to use of the BMD modeling approach to determine the POD for the
subchronic p-RfC assessment, rather than the NOAEL/LOAEL approach used in the IRIS RfC
assessment.
CHRONIC p-RfC
A chronic RfC of 0.001 mg/m3 for acrylic acid is available on IRIS (U.S. EPA, 2009a),
and it is based on the subchronic study in mice (Miller et al., 1981). The chronic RfC was
calculated from the LOAEL of 14.9 mg/m3 (LOAELjhec] = 0.33 mg/m3) for degeneration of the
nasal olfactory epithelium and a UF of 300 (10 for protection of sensitive individuals, 10 for
interspecies extrapolation using the dosimetric adjustments for a LOAEL for a mild effect, and 3
for extrapolation from subchronic to chronic duration given rapid metabolism and limited
progression of effect from short-term to subchronic exposure). This assessment was posted to
IRIS on 2/17/1994.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR ACRYLIC ACID
WEIGHT-OF-EVIDENCE DESCRIPTOR
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), the
available data for acrylic acid provide "Inadequate Information to Assess [the] Carcinogenic
Potential" No information was located regarding carcinogenicity in humans following oral or
inhalation exposure to acrylic acid. The only available animal study conducted by the oral route
of exposure presents no evidence for increased tumors in rats following chronic exposure to
acrylic acid in drinking water (Hellwig et al., 1993), but it appears not to have reached the
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maximum tolerated dose. Dermal application studies with mice yielded negative (DePass et al.,
1984) or equivocal (Hoechst-Celanese, 1990) results. Acrylic acid was clastogenic in several in
vitro assays in mammalian cells (McCarthy et al., 1992; Moore et al., 1988), but it was negative
in others (Wiegand et al., 1989) and in clastogenicity assays conducted in vivo (McCarthy et al.,
1992). Acrylic acid did not produce point mutations in bacteria (Zeiger et al., 1987; Lijinsky and
Andrews, 1980) or mammalian systems (McCarthy et al., 1992; Moore et al., 19881), DNA
damage in mammalian cells (McCarthy et al., 1992; Wiegand et al., 1989), or morphological
transformation in mammalian cells (Wiegand et al., 1989).
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
The available data do not support derivation of oral or inhalation slope factors for acrylic
acid.
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values for chemical substances and physical agents and biological exposure indices. Cincinnati,
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Andersen, M; Sarangapani, R; Gentry R; et al. (2000) Application of a hybrid CFD-PBPK nasal
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BASF (Badische Anilin- und Sodafabrik). (1993) Reproduction toxicity study with acrylic acid
in rats: Continuous administration in the drinking water over 2 generations (1 litter in the first
and 1 litter in the second generation). Project No. 71R0114/92011. BASF Aktiengesellschaft,
Dept. of Toxicology, Rhein, FRG. (Cited in U.S. EPA, 2009a).
Black, KA; Beskitt, JL; Finch, L; et al. (1995) Disposition and metabolism of acrylic acid in
C3H mice and Fischer 344 rats after oral or cutaneous administration. J. Toxicol. Environ.
Health. 45(3): 291-311.
CalEPA (California Environmental Protection Agency). (2009a) Office of Environmental
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http://www.oehha.ca.gov/air/chronic_rels/index.html.
CalEPA (California Environmental Protection Agency). (2009b) Office of Environmental
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http://www.oehha.ca.gov/risk/ChemicalDB/index.asp.
1 The positive result in the mouse lymphoma cell assay was attributed to clastogenicity rather than point mutation by
the study authors.
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DePass, LR; Woodside, MD; Garman, RH; et al. (1983) Subchronic and reproductive
toxicology studies on acrylic acid in the drinking water of the rat. Drug Chem. Toxicol.
6(1): 1-20.
DePass, LR; Fowler, EH; Meckley, DR; et al. (1984) Dermal oncogenicity bioassays of acrylic
acid, ethyl acryl ate, and butyl acryl ate. J.Toxicol. Environ. Health. 14(2-3): 115-120.
Hellwig, J; Deckardt, K; Freisberg, KO. (1993) Subchronic and chronic studies of the effects of
oral administration of acrylic acid to rats. Food Chem. Toxicol. 31(1): 1-18.
Hellwig, J; Gembardt, C; Murphy, SR. (1997) Acrylic acid: Two-generation reproduction
toxicity study in Wistar rats with continuous administration in the drinking water. Food Chem.
Toxicol. 35(9):859-868.
Hoechst-Celanese. (1990) Support document: Chronic dermal oncogenicity study with acrylic
acid in [C3H/HeN HsD BR] and [HsD: (ICR) BR] mice with letter. Produced December 5,
1990; submitted to EPA December 10, 1990. OPTS Fiche # 0510541-3. EPADoc#89-
910000139S. TSCATS# 431151.
IARC (International Agency for Research on Cancer). (1979) Acrylic acid. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon, France. 19:47-72.
IARC (International Agency for Research on Cancer). (1987) Overall Evaluations of
Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. IARC Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon, France. Supplement
7:56.
IARC (International Agency for Research on Cancer). (1999) Acrylic acid. Re-evaluation of
Some Organic Chemicals, Hydrazine and Hydrogen Peroxide (Part 3). IARC Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon, France.
71(3):1223-1230.
Klimisch, HJ; Hellwig, J. (1991) The prenatal inhalation toxicity of acrylic acid in rats.
Fundam. Appl. Toxicol. 16(4):656-666.
Kutzman, RS; Meyer, GJ; Wolf, AP. (1982) The biodistribution and metabolic fate of acrylic
acid in the rat after acute inhalation exposure or stomach intubation. J. Toxicol. Environ.
Health. 10(6): 969-979.
Lijinsky, W; Andrews AW. (1980) Mutagenicity of vinyl compounds in salmonella
typhimurium. Teratog. Carcinog. Mutagen. 1:259-267.
McCarthy, KL; Thomas, WC; Aardema, MJ; et al. (1992) Genetic toxicology of acrylic acid.
Food Chem. Toxicol. 30(6):505-515.
Miller, RR; Ayres, JA; Jersey GC; et al. (1981) Inhalation toxicity of acrylic acid. Fund. Appl.
Toxicol. 1:271-277.
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Moore, MM; Amtower, A; Doerr, CL; et al. (1988) Genotoxicity of acrylic acid, methyl
acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate in L5178Y mouse
lymphoma cells. Environ. Mol. Mutagen. 11(1):49—63.
Neeper-Bradley, TL; Fowler, EH; Pritts, IM; et al. (1997) Developmental toxicity study of
inhaled acrylic acid in New Zealand White rabbits. Food Chem. Toxicol. 35(9):869-880.
NIOSH (National Institute for Occupational Safety and Health). (2008) NIOSH Pocket Guide
to Chemical Hazards. Index by CASRN. Online, http://www2.cdc.gov/nioshtic-
2/nioshtic2.htm.
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.gov/.
NTP (National Toxicology Program). (2009) Management Status Report. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://www.ntp.niehs.nih.gov/index.cfm?objectid=78CC7E4C-
F1F6-975E-72940974DE301C3F.
OSHA (Occupational Safety and Health Administration). (2009) OSHA Standard 1915.1000
for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online, http://www.osha.gov/
pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9992.
Saillenfait, AM; Bonnet, P; Gallissot, F; et al. (1999) Relative developmental toxicities of
acrylates in rats following inhalation exposure. Toxicol. Sci. 48(2):240-254.
Schwartz, BS; Dotty, R; Monroe, C; et al. (1989) Olfactory function in chemical workers
exposed to acrylate and methyl methacrylate vapors. Am. J. Pub. Health 79:613-618.
Singh, AR; Lawrence, WH; Autian, J. (1972) Embryonic-Fetal Toxicity and Teratogenic
Effects of a Group of Methacrylate Esters in Rats. J. Dental Res. 51(6): 1632-1638.
Tucek, M; Tenglerov, J; Kollarova, B; et al. (2002) Effect of acrylate chemistry on human
health. Int. Arch. Occup. Enivon. Health. 75 (Suppl):S67-S72.
U.S. EPA. (1984) Health and Environmental Effects Profile for 2-Propenoic Acid (Acrylic
Acid). Prepared by Environmental Criteria and Assessment Office, Cincinnati, OH for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. (1991) Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. (1994a) Chemical Assessments and Related Activities (CARA). Office of Health
and Environmental Assessment, Washington, DC. December.
U.S. EPA. (1994b) Methods of Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry. Office of Research and Development, National Center for
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U.S. EPA. (1997) Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. (2000) Benchmark Dose Technical Guidance Document. External Review Draft.
Risk Assessment Forum. EPA/630/R-00/001. October.
U.S. EPA. (2005) Guidelines for Carcinogen Risk Assessment. U.S. Environmental Protection
Agency, Risk Assessment Forum, Washington, DC. EPA/630/P-03/001B. Online.
http://www.thecre.com/pdf/20050404_cancer.pdf.
U.S. EPA. (2006) 2006 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-06-013. Washington, DC. Available at
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf.
U.S. EPA. (2009a) Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
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U.S. EPA. (2009b) Acute Exposure Guideline Levels. Results for Acrylic Acid. Online.
http://www.epa.gov/oppt/aegl/pubs/results23.htm.
WHO (World Health Organization). (1997) Acrylic Acid. Environmental Health Criteria 191.
Geneva, Switzerland.
Wiegand, HJ; Schiffmann, D; Henschler, D. (1989) Non-genotoxicity of acrylic acid and
//-butyl acrylate in a mammalian cell system she cells. Arch. Toxicol. 63(3):250-251.
Zeiger, E; Anderson, B; Haworth, S; et al. (1987) Salmonella mutagenicity tests III. Results
from the testing of 255 chemicals. Environ. Mutagen. 9(Suppl 9): 1-110.
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APPENDIX A. BENCHMARK DOSE MODELING FOR
INHALATION SUBCHRONIC P-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) 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 benchmark response
(BMR). Among all 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 is 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, benchmark concentrations (BMCs)
and lower bounds on the BMC (BMCLs) associated with an extra risk of 10% are calculated for
all models.
Model Fitting Results for Focal Degeneration of the Nasal Olfactory Epithelium of Female
Mice (Miller et al., 1981)
Applying the procedure outlined above to the data for focal degeneration of the nasal
olfactory epithelium in female mice (Table 14), model fit was achieved with all models.
Table A-l shows the modeling results. BMCLs from models providing adequate fit differed by
more than 3-fold. In accordance with EPA (2000) guidance, the lowest BMCL from a model
with adequate fit has been selected for use as the POD. For this data set, the log-probit model
provided the lowest BMCL (Figure A-l); the benchmark concentration (BMCio) and associated
"3
95% lower confidence limit (BMCLio) values are 5.58 and 0.76 mg/m , respectively.
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Table A-l. Model Predictions for Focal Degeneration of
the Nasal Olfactory Epithelium in Female Mice"
Model
Degrees of
Freedom
2
X
X2 Goodness
of Fit
/>-Valucb
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma0
3
0.04
1.00
22.00
3.26
1.96
Logistic
2
2.65
0.27
27.67
10.76
6.09
Log Logisticd
2
0.2
0.91
24.28
5.63
0.97
Log Probitd
2
0.1
0.95
24.13
5.58
0.76
Multistage 1 degree6
3
0.04
1.00
22.00
3.26
1.96
Multistage 2 degree6
3
0.04
1.00
22.00
3.26
1.96
Multistage 3 degree6
2
0.04
0.98
24.00
3.29
1.97
Probit
2
2.65
0.27
27.56
10.65
6.58
Weibulf
3
0.04
1.00
22.00
3.26
1.96
Quantal-Linear
3
0.04
1.00
22.00
3.26
1.96
Abbreviations: AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the
dose/concentration associated with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit
on the BMD/BMC
"Miller etal. (1981)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
°Power restricted to >1
dSlope restricted to >1
"Betas restricted to >0
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LogProbit Model wth 0.95 Confidence Level
0	50	100	150	200
Dose
12:03 12/01 2009
BMC and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg/m3
Figure A-l. Fit of Log-Probit Model to Data on Focal Degeneration of the Nasal Olfactory
Epithelium in Female Mice (Miller et al., 1981)
Probit Model. (Version: 3.1; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\lnpAAFemalenonconverttoHECAAFlogprobitNONHEC.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\lnpAAFemalenonconverttoHECAAFlogprobitNONHEC.pit
Tue Dec 01 12:03:30 2009
BMDS Model Run
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNormf .) is the cumulative normal distribution function
Dependent variable = Percent
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Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial	(and Specified) Parameter Values
background =	0
intercept =	-2.16744
slope =	0.744322
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept	slope
intercept 1	-0.97
slope -0.97	1
Parameter Estimates
Interval
Variable
Limit
background
intercept
0.582775
slope
1.7357
Estimate
0
-3. 04482
1.02558
Std. Err.
NA
1.25617
0.362312
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-5.50686
0.315466
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood) # Param's Deviance Test d.f.
-9.98095
-10.0657
-27. 8185
0.169492
35.6752
P-value
0.9187
<.0001
AIC:
24.1314
Goodness of Fit
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Dose
Est. Prob.
Expected
Observed
Size
Scaled
Residual
0.0000
14.9000
74.7000
224.0000
0.0000
0.3919
0.9161
0.9939
0.000
3.919
9.161
10.933
0.000
4.000
9.000
11.000
10
10
10
11
0. 000
0. 052
-0.183
0.260
Chi^2 = 0.10
d.f. = 2
P-value = 0.94 93
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	5.58051
BMDL =	0.758842
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Model Fitting Results for Focal Degeneration of the Nasal Olfactory Epithelium in Male
Mice (Miller et al., 1981)
Applying the procedure described above to the data for focal degeneration of the nasal
olfactory epithelium in male mice (Table 14), model fit (indicated by goodness-of-fit/?-value)
was achieved with all models. Table A-2 shows the modeling results. However, further
inspection revealed that model fit at the data point closest to the BMR (low-dose group) was
poor (scaled residual of 1.38) for the one-degree multistage and quantal linear models, which
also predicted BMC and BMCL values well below the other models. Therefore, these models
have been rejected from further consideration. Among the remaining models, the BMCLs varied
by less than 3-fold. In accordance with EPA (2000) guidance, the BMCL from the model with
the lowest AIC was selected to use as the POD. For this data set, the 3-degree multistage model
(Figure A-2) provided the lowest AIC; the resulting benchmark concentration (BMCio) and
"3
associated 95% lower confidence limit (BMCLio) are 14.36 and 3.27 mg/m , respectively.
Table A-2. Model Predictions for Focal Degeneration
of the Nasal Olfactory Epithelium in Male Mice"
Model
Degrees of
Freedom
2
X
y2 Goodness
of Fit
/>-Valucb
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Gamma0
1
0
1.00
22.51
14.61
5.23
Logistic
2
0.34
0.84
20.92
9.81
5.26
Log Logisticd
1
0
1.00
22.51
14.76
7.60
Log Probitd
1
0
1.00
22.51
14.69
7.50
Multistage 1 degree6
2
3.05
0.22
24.65
3.39
1.90
Multistage 2 degree6
2
0.21
0.90
20.80
11.03
3.49
Multistage 3 degree6
2
0
1.00
20.51
14.36
3.52
Probit
2
0.33
0.85
20.88
9.25
4.97
Weibulf
1
0
1.00
22.51
14.37
4.67
Quantal-Linear
2
3.05
0.22
24.65
3.39
1.90
Abbreviations: AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the
dose/concentration associated with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit
on the BMD/BMC
"Miller etal. (1981)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
°Power restricted to >1
dSlope restricted to >1
"Betas restricted to >0
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FINAL
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Multistage Model with 0.95 Confidence Level
0.6
0.4
0.2
o : -H
EMDL
14:27 12/01 2009
50
100
Dose
150
200
BMC and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg/m
Figure A-2. Fit of 3-Degree Multistage Model to Data on Focal Degeneration of the
Nasal Olfactory Epithelium in Male Mice (Miller et al., 1981)
Multistage Model. (Version: 3.0; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\mstAAMaleNONHECAAMaleMultistage3.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\mstAAMaleNONHECAAMaleMultistage3.pit
Tue Dec 01 14:27:12 2009
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2-beta3* doseA3)]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Cone
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
40
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FINAL
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Degree of polynomial
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background =	1
Beta (1) = 4.52028e+017
Beta(2) =	0
Beta(3) =	0
the user,
Background
Beta (2)
Beta (3)
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(l)
have been estimated at a boundary point, or have been specified by
and do not appear in	the correlation matrix )
Background Beta (2)	Beta(3)
1 -0.079	0.015
-0.079 1	-1
0.015 -1	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Beta(3)
Estimate
0.0999991
0
6.80291e-007
3.55614e-005
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-8 .25485
-8.25486
-27. 8185
# Param's Deviance	Test d.f.	P-value
4
3 7.2014 6e-006	1	0.9979
1 39.1274	3	<.0001
AIC:
22.5097
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.1000	1.000	1.000	10	0.000
14.9000	0.2000	2.000	2.000	10	-0.000
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FINAL
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74.7000	1.0000	11.000 11.000	11	0.002
224.0000	1.0000	10.000 10.000	10	0.000
Chi^2 = 0.00	d.f. = 1	P-value = 0.9985
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	14.35 62
BMDL =	3.27487
BMDU =	27.518
Taken together, (3.27487, 27.518 ) is a 90	% two-sided confidence
interval for the BMD
42
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