iPs	United States
Environmental Protection
m»Agency
EPA/690/R-06/002F
Final
10-25-2006
Provisional Peer Reviewed Toxicity Values for
m-Aminophenol
(CASRN 591-27-5)
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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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and
Liability Act of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
NAAQS	National Ambient Air Quality Standards
NOAEL	no-ob served-adverse-effect level
NOAEL(ADJ)	NOAEL adjusted to continuous exposure duration
NOAEL(HEC)	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 inhalation reference concentration
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p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|imol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
m-AMINOPHENOL (CASRN 591-27-5)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) 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 (PPRTV) 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 Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program 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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. 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 manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
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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 RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript 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
w-Aminophenol is not listed on IRIS (U.S. EPA, 2006) or the Drinking Water Standards
and Health Advisories list (U.S. EPA, 2004). The HEAST (U.S. EPA, 1997) lists a subchronic
RfD value of 7E-1 mg/kg-day and a chronic RfD of 7E-2 mg/kg-day for w-aminophenol based
on altered weights for both the whole body and thyroid in rats exposed to w-aminophenol in their
diet for 13 weeks. The source document for this assessment was a Health and Environmental
Effects Profile (HEEP) for Aminophenols (U.S. EPA, 1985). No RfC or carcinogenic
assessment for w-aminophenol is available in the HEAST (U.S. EPA, 1997) or HEEP (U.S.
EPA, 1985). The HEEP is the only relevant document included in the CARA list (U.S. EPA,
1991, 1994). ATSDR (2006) has not produced a Toxicological Profile for w-aminophenol and
no Environmental Health Criteria document is available (WHO, 2006). Neither NTP (2006) nor
IARC (2006) has assessed the carcinogenicity of w-aminophenol. ACGIH (2005), NIOSH
(2006), and OSHA (2006) have not recommended occupational exposure limits for m-
aminophenol. Literature searches were conducted from 1984 through 2003 in TOXLINE
(supplemented with BIOSIS and NTIS updates), MEDLINE, CANCERLIT, TSCATS, RTECS,
CCRIS, DART, EMIC/ EMICBACK, HSDB, and GENETOX. Update literature searches from
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2003 through October 2005 were conducted in MEDLINE, TOXLINE (NTIS subfile),
TOXCENTER, TSCATS, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current
Contents. An additional update literature search of Medline (October 2005 to April 2006) was
conducted in April, 2006.
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of w-aminophenol to humans following chronic or
subchronic exposure by any route were located.
Animal Studies
No data were located on the toxicity to animals of inhaled w-aminophenol. Studies on
the oral toxicity of w-aminophenol are discussed below.
A combined subchronic toxicity and developmental toxicity study of w-aminophenol was
conducted in rats. Four groups of 35 Sprague-Dawley female rats were fed diets containing 0,
0.13, 0.25 or 0.98% w-aminophenol for 90 days (Re et al., 1984). From reported body weight
and food consumption data, average doses are estimated to be about 0, 120, 240 or 900 mg/kg-
day. Animals were observed daily for mortality and signs of toxicity. Food consumption and
body weights were recorded weekly. After 13 weeks, 10 females from each group were
randomly selected for sacrifice, necropsy and histopathology. Prior to necropsy, blood samples
were collected for hematology and clinical chemistry analyses (not further described). Organ
weights were recorded for the adrenals, kidneys, ovaries, liver, heart, thyroid, brain and pituitary.
Organs from rats in the high exposure (0.98%) and control groups that were prepared for
histologic examination were the following (organs with * were also evaluated from the low and
middle exposure groups): brain, thyroids with parathyroids*, heart, kidney*, intestines, urinary
bladder, skeletal muscle, uterus, pituitary, lungs, spleen, pancreas, ovaries*, adrenals*, eyes,
salivary gland, peribronchial lymph node, liver*, stomach, bone with marrow, mammary gland
and all gross abnormalities.
The remaining 25 rats from each group were mated to untreated male rats during week 14
(Re et al., 1984). Confirmed pregnant females (designated gestation day 0) were moved to
individual cages to resume test diet. Dams were observed daily for physical condition and signs
of toxicity; body weights were recorded on days 0, 6, 9, 12, 15 and 20 of gestation. Feed
consumption was determined for 10 dams per treatment group on gestation days 11 and 19.
Each female was sacrificed on gestation day 20 and uterus and ovaries were examined. The
numbers of live and dead fetuses and early and late resorptions were recorded, as were the total
number of corpora lutea on both ovaries. Live fetuses were removed, dried, weighed and
examined for external gross malformations and sex determination. One-third of the live fetuses
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of each litter were fixed for examination of soft tissue anomalies and the remaining two-thirds
were fixed and stored for examination for skeletal anomalies.
Dose-related reductions in food intake and body weight were noted in treated rats (Re et
al., 1984). Weekly food intake was 20% lower than controls during the first week of the study in
the high-dose group and similar deficits occurred throughout the study in this group. As a result,
body weights in this group were significantly reduced throughout the study, with the deficit from
controls increasing from 12% at the end of the first week to 21% after 13 weeks. Statistically
significant, but much less severe (on the order of 5%), reductions in food consumption and body
weight were also seen in the mid-dose group. Food intake and body weight in the low-dose
group were similar to controls. Hematological changes were found only in the high-dose group,
including significant decreases in red blood cell count (10%) and hemoglobin levels (4%).
Clinical chemistry variables were unaffected at any dose. Organ weight changes were observed
only in the thyroid, although the data were not presented in the publication. Relative thyroid
weight was reportedly increased in the high-dose group, probably secondary to the reduced body
weight in this group (absolute thyroid weight was apparently unchanged from controls in this
group). On the other hand, both relative and absolute thyroid weights were reported to be
significantly decreased in the low- and mid-dose groups. Gross changes were not seen in the
thyroid or other tissues at necropsy. Histopathological examination revealed reduced follicle
size and increased height of follicle epithelial cells (consistent with hypertrophy) in thyroids
from 9/10 rats in the high-dose group. Similar changes were also seen in several animals from
the mid-dose group (incidence not reported), but not in the low-dose group. Deposits of iron-
positive pigment were found in the spleen, liver and kidneys in a dose-related fashion.
Pigmentation in the liver was noted in 8/10 high-dose, 2/10 low- and mid-dose and 3/10 control
animals. Renal tubular pigmentation was observed in 8/10 high-dose, 1/10 mid-dose, 2/10 low-
dose and 1/10 control animals. Deposits in the spleen were seen in all control and high-dose
animals (not evaluated in low- or mid-dose groups), but the severity was only slight-to-moderate
in controls versus moderately severe-to-severe in the high-dose rats. The increased deposition of
iron pigments, together with the reductions in red blood cell count and hemoglobin in the high-
dose group, indicate a hemolytic anemia at this dose.
This study identified a LOAEL of 900 mg/kg-day (0.98% in the diet) based on evidence
of hemolytic anemia (increased incidence and/or severity of iron-positive pigmentation in the
spleen, liver and kidneys, along with reduced red blood cell count and hemoglobin). Body
weight was lower than controls in both the mid- and high-dose groups, but the change was
minimal in the mid-dose group and was secondary to reduced food intake at both doses
(suggesting an organoleptic, rather than toxic, effect). Histological changes in the thyroid
consistent with hypertrophy (reduced follicle size and increased follicular epithelial cell height)
were reported in both the mid- and high-dose groups (incidence reported only as "several"
animals in the mid-dose group). Thyroid hormone measurements were not made. However,
reported changes in thyroid weight were not consistent with a hyperthyroid effect. There was an
increase in relative, but not absolute thyroid weight in the high dose group, apparently secondary
to the decrease in body weight at this dose. In the mid-dose group, absolute and relative thyroid
weights were actually reduced. Therefore, the thyroid effects are considered to be adaptive
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rather than adverse. Thus, the 240 mg/kg-day dose (0.25%) is considered a NOAEL for m-
aminophenol.
In the teratology portion of the study, as in the pre-mating period described above, body
weights were significantly decreased in the high- and mid-dose groups (Re et al., 1984). The
deficit from controls was 16-20% in the high-dose group, but only 5-6% in the mid-dose group.
Food consumption was reduced in the high-dose group; food consumption data were not reported
for the mid-dose group. None of the dams died during the study and no other signs of maternal
toxicity were observed. No significant differences between control and treated groups were seen
for fertility, incidence of corpora lutea, total implantation sites, live fetuses, resorptions, dead
fetuses, male/female ratios, fetal weight or fetal variations or malformations. The high dose of
900 mg/kg-day is a NOAEL for developmental effects of w-aminophenol in this study.
Koizumi et al. (2002) compared the toxicity of w-aminophenol administered by gavage to
newborn and young Sprague-Dawley rats. Study protocols differed for the newborn and young
rats and are described independently here. Newborn rats (6/sex/dose) were given m-
aminophenol by gavage at doses of 0, 30, 80 or 240 mg/kg-day (range-finding study) or 0, 24, 80
or 240 mg/kg-day (main study) on postnatal days 4-21. In the range-finding study, rats were
examined during the exposure period for behavior, body weight, and physical development
(including abdominal fur appearance, incisor eruption and eye opening). The animals were
sacrificed on postnatal day 22 and evaluated for hematology effects [red blood cell (RBC) count,
hemoglobin (Hb), hematocrit (Ht), white blood cell count and platelet count], blood biochemistry
changes [total protein, total cholesterol, glucose, urea nitrogen (BUN), aspartate
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)], gross
findings and organ weight changes (organs not specified). In the main study, two groups of rats
were assigned to each dose. One group was sacrificed on postnatal day 22, while the other group
was withdrawn from treatment, maintained for a 9-week recovery period and sacrificed at 12
weeks of age. In the main study, the rats were subjected to the same clinical, hematological,
biochemical and gross pathology examinations as conducted in the range-finding study, as well
as the following evaluations: physical development parameters (preputial separation, vaginal
opening, reflex ontogeny); hematology [mean corpuscular volume (MCV), mean corpuscular
hemoglobin (MCH) and hemoglobin concentration (MCHC), platelet count, reticulocyte ratio,
differential leukocyte count and blood clotting parameters]; blood biochemistry [albumin,
albumin-globulin ratio, triglycerides, creatinine, gamma-glutamyl transferase (GGT), lactate
dehydrogenase (LDH), phospholipid, calcium, inorganic phosphorus, sodium, potassium,
chloride], organ weights (brain, pituitary, heart, thymus, liver, kidneys, spleen, adrenals,
thyroids, lungs, testes, epididymides, ovaries and uterus) and histopathology (all weighed organs,
as well as trachea, pancreas, lymph node, esophagus, submandibular gland, sublingual gland,
stomach, intestine, urinary bladder, eyeballs, spinal cord, sciatic nerve, seminal vesicles,
prostates, vagina, mammary gland, bone and bone marrow, skeletal muscle and skin).
Effects on treated animals were the same in both the range-finding and main studies.
Newborn rats receiving the highest dose showed clinical signs of toxicity (tremors in all animals
in the main study from dosing days 2 to 12, with incidence decreasing to 0 by days 16 and 17)
and significantly reduced body weight (when compared with controls) beginning on dosing day 8
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in males and on dosing day 4 in females. Terminal body weight in the high dose animals was
10% lower than controls in males and 13% lower in females. Because the newborn rats were
suckled by foster mothers, it is not possible to determine whether decreased food intake may
have contributed to the lower body weights. Hematological findings were unremarkable; the
only effect reported was a slight increase in reticulocyte ratio in high dose males (21.7% in
treated vs. 18.0% in controls; statistical significance not reported). Serum chemistry did not
reveal changes in ALT or AST. Total bilirubin was significantly increased in high-dose animals
of both sexes (26% increase over controls in males; 50% increase in females). Other findings
included a dose-related decrease in blood glucose in females (10% decrease from controls at 80
mg/kg-day; 21% decrease at 240 mg/kg-day), and a 25% decrease in BUN in high-dose females.
Weight changes were observed in several organs (brain, liver, kidney, spleen), but the changes
were seen primarily in the high-dose group and appeared to reflect decreased body weight in this
group. Histological evaluation revealed slight hypertrophy of thyroid follicular cells (in 4/6
males and 2/6 females) at 240 mg/kg-day (incidence, if any, in controls and other dose groups
not reported), with no other histology findings. Despite the evidence for hypertrophy, there were
no changes in thyroid weight in any group. Among the recovery groups sacrificed 9 weeks after
treatment ended, the only findings were slightly increased RBC (6%), Hb (5%) and Ht (7%) in
females in the 240 mg/kg-day group.
This study identified a NOAEL of 80 mg/kg-day and a LOAEL of 240 mg/kg-day for
newborn rats. The researchers considered the 240 mg/kg-day dose to be "unequivocally toxic."
Effects in the 240 mg/kg-day group included reduced body weight, tremors, changes in serum
bilirubin and reticulocyte ratio, and slight hypertrophy of thyroid follicular cells. Because the
rats were suckled by foster mothers and food consumption could not be monitored, it is uncertain
to what extent the reduction in body weight may have been related to an effect on food
consumption. The incidence of tremors, while high at the beginning of exposure (all rats
affected), decreased over the course of exposure and had declined to 0 by day 16 or 17 of
treatment, suggesting that the animals had developed tolerance to the exposure. The mild change
in reticulocyte ratio and elevated bilirubin at the high dose could be signs of mild or
compensated hemolytic anemia; however, no other hematology changes were noted in these
animals (RBC, Hb and Ht were not different from controls), nor was there evidence of
hemosiderin deposition. The mild thyroid follicular cell hypertrophy observed in this study may
reflect an adaptive response to m-aminophenol exposure, rather than an adverse effect. No
corresponding changes in thyroid weight were found, and other endpoints that would more
clearly identify a toxic effect on the thyroid (thyroid activity and thyroid hormone levels in
serum) were not monitored.
In a separate series of experiments, young (5-week old) rats were treated with m-
aminophenol by gavage for either 14 days (range-finding study) or 28 days (main study)
(Koizumi et al., 2002). In the range-finding study, groups of 5 rats/sex/dose were given 0, 80,
200 or 500 mg/kg-day m-aminophenol and sacrificed 24 hours after the last exposure. General
behavior, body weight and food consumption were monitored. Upon sacrifice, hematology
(RBC, Hb, Ht, MCV, MCH, MCHC, white blood cell count and platelet count), blood chemistry
(total protein, total cholesterol, glucose, triglycerides, BUN, creatinine, AST, ALT, ALP,
sodium, potassium, chloride), gross findings and organ weights (organs unspecified) were
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evaluated. In the main study, groups of 7 rats/sex/dose were administered daily doses of 0, 80,
240 or 720 mg/kg-day. Animals were sacrificed one day after the last treatment. Separate
control and high-dose recovery groups were maintained for 2 weeks after the 28-day exposure
and sacrificed at 11 weeks of age. Rats in the main study were examined for general behavior,
body weight and food consumption, and subjected to urinalysis, hematology, blood
biochemistry, necropsy, organ weight and histopathological evaluations. These evaluations were
not detailed, but were reported to comply with the Test Guideline of the Japanese Chemical
Control Act under Good Laboratory Practice conditions.
Rats exposed to 720 mg/kg-day in the main experiment exhibited tremors and salivation
sporadically throughout the study. Timing of these effects in relation to daily dose
administration was not reported. Terminal body weights were significantly (p<0.01) lower than
controls in males at 720 mg/kg-day (12%). Body weights in females at this dose were also lower
than controls (10%), although the difference did not reach statistical significance. Females
treated at 720 mg/kg-day and sacrificed upon termination of exposure in the main study showed
signs of anemia, including significantly (p<0.05) decreased RBC (10% lower than control) and
Hb (8%> reduction) and increased reticulocyte ratio (77% increase). These effects were not
observed at doses up to 500 mg/kg-day in the range-finding study. Clinical chemistry
evaluations revealed significantly (p<0.05) increased ALT in animals of both sexes treated at 720
mg/kg-day (59% increase in males; 46% increase in females), increased total cholesterol in high
dose males (21% higher than controls) and decreased triglycerides in high dose males (47%
lower), potentially indicating effects on the liver. High dose animals of both sexes had increased
total bilirubin (2.2-fold higher than controls in males; 1.6-fold in females), likely resulting either
from liver toxicity or from hemolytic anemia. BUN was increased (24%) in high dose females,
suggesting possible renal toxicity.
Relative liver and kidney weights were significantly (p<0.01) increased in both sexes at
720 mg/kg-day only (22% and 16%, respectively, in males; 17% and 18%, respectively, in
females). However, absolute liver and kidney weights were not significantly different from
controls in either sex, so the relative organ weight changes may reflect only reduced body weight
at this dose. Similarly, relative brain and testes weights were increased in high dose males (18%
and 19%), respectively, p<0.01), but these changes were likely associated with body weight
reductions. In contrast, both absolute and relative thyroid weights were substantially increased
in both sexes treated at 720 mg/kg-day (54% and 77%, respectively, in males; 67% and 85%,
respectively, in females), suggesting a specific effect on the thyroid. In addition, absolute and
relative spleen weights were increased in females treated at this dose (39% and 50%,
respectively), possibly in response to the hemolytic anemia. Histopathology evaluation revealed
changes consistent with hemolytic action (pigment or hemosiderin deposition) in the liver,
kidneys and spleen (all 720 mg/kg-day animals of both sexes). Slight deposition of pigment in
the renal proximal tubular epithelium was observed in 6 of 7 females treated at 240 mg/kg-day.
Hypertrophy of thyroid follicular cells (5/7 females and 3/7 males) was observed in the 720
mg/kg-day animals and is consistent with the increase in thyroid weight in both sexes. Also at
this dose, the incidence of hyaline droplets in the proximal tubule epithelium of the kidney was
increased over controls in males (7/7 treated vs. 2/7 controls).
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Animals in the 720 mg/kg-day recovery group, sacrificed 2 weeks after treatment ended,
showed no thyroid follicular cell hypertrophy. Males in the recovery group had significantly
(p<0.05) decreased RBC (4% less than control), Hb (3%), and MCHC (2%), and increased MCV
(3% more than control) and reticulocyte ratio (41%). Females in the recovery group did not have
reduced RBC or Hb, but had significantly (p<0.05) increased hematocrit (8%), MCV (5%) and
MCH (4%) and decreased MCHC (2%). The incidence of pigment deposition in the liver and
kidneys of male rats in the 720 mg/kg-day recovery group was much lower than in the same dose
group sacrificed immediately after treatment ended (1/7 with deposits in liver and 0/7 in kidney
of recovery group compared with 7/7 each for liver and kidney in the immediate sacrifice group).
Similarly, the incidence of liver pigmentation in females was lower in the recovery group (2/7
vs. 7/7 in the immediate sacrifice group). However, both males and females of the recovery
group had hemosiderin deposition in the spleen (6/7 males and 7/7 females). The hematological
findings and histopathology suggest that the hemolytic effects persisted in the recovery group.
This study identified a NOAEL of 240 mg/kg-day and a LOAEL of 720 mg/kg-day. The
researchers considered the 720 mg/kg-day dose to be "unequivocally toxic." Effects at 720
mg/kg-day included anemia, liver and kidney toxicity, tremors, decreased body weight and
thyroid changes. Evidence of hemolytic anemia included hematological findings (decreased
RBC and Hb, increased reticulocyte ratio in females), serum chemistry (significantly increased
bilirubin in both sexes) and histopathology (pigment deposition in liver and kidney, hemosiderin
deposits in spleen). Liver toxicity was suggested by modest increases in ALT, while slightly
increased BUN in females and tubular lesions in males (hyaline droplets) suggested possible
kidney effects. The authors suggested that the liver and kidney effects may have occurred
secondary to hemolytic toxicity. Although there was an increased incidence of pigment
deposition in the kidneys of females at 240 mg/kg-day, there were no accompanying
hematological findings, nor was serum bilirubin increased.
Kurata et al. (1987) investigated the ability of w-aminophenol to promote development of
tumors induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN). Over a 52-week period, three
groups of 25 male Fischer 344 rats were studied; two groups were initiated with 0.1% EHEN in
the drinking water for 2 weeks. Starting on week 3 and continuing through the end of the study,
one of the groups was fed a diet containing 0.8% w-aminophenol; the other group received a
basal diet throughout the study. The third group was fed the 0.8% w-aminophenol test diet
without EHEN-pretreatment. The 0.8% dietary concentration is estimated to provide
approximately 400 mg/kg-day of w-aminophenol, assuming a rat in a chronic study consumes a
quantity of food equivalent to 5% of his body weight per day. All rats were sacrificed in week
52; the body, liver and kidney weights were recorded. Liver and kidney sections were evaluated
by histology and the liver by immunohistochemical determinations for glutathione S-transferase
placental type (GST-P) positive foci. No liver or kidney lesions were seen in uninitiated rats
treated with w-aminophenol. w-Aminophenol did not promote development of preneoplastic
lesions in the liver of rats initiated with EHEN; rats receiving both compounds showed
significant decreases in the number of GST-P positive foci, in comparison to rats that received
EHEN alone. The incidence of hepatocellular carcinoma was similar in both groups.
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Other Studies
A teratology study conducted by parenteral exposure failed to find developmental effects
of w-aminophenol. Groups of pregnant Syrian golden hamsters (LKV strain) were given m-
aminophenol at dose levels of 0, 100, 150 or 200 mg/kg by intraperitoneal injection on gestation
day 8 (Rutkowski and Ferm, 1982). Dams were sacrificed on gestation day 13 and the uteri
removed and contents examined. w-Aminophenol was not toxic to the dams at these doses and
produced no clear evidence of a teratogenic effect. There were six malformed fetuses that were
observed at 150 mg/kg, but all were from the same litter and no malformations were seen at the
200 mg/kg dose.
w-Aminophenol was not mutagenic to Salmonella typhimurium or Escherichia coli
(Watanabe et al., 1991; Lavoie et al., 1979; Thompson et al., 1983; Hayashi, 1981; Elder, 1988;
Zeiger et al., 1988). In mammalian cells in vitro, w-aminophenol did not increase the frequency
of sister chromatid exchanges (SCE) in Chinese hamster (V79) cells (Wild et al., 1981; Elder,
1988) or human lymphocytes (Kirchner and Bayer, 1982) and did not induce unscheduled DNA
synthesis in cultured rat hepatocytes (Thompson et al., 1983). An abstract from a recent study
published in Chinese reported DNA damage (as measured by the comet assay) to human
peripheral blood lymphocytes and mouse spleen cells treated with w-aminophenol in vitro (Qu et
al., 2004). In vivo, w-aminophenol did not increase the incidences of micronuclei in bone
marrow cells in mice (Wild et al., 1981) or rats (Hossack and Richardson, 1977), SCE in Chinese
hamster bone marrow cells (Kirchner and Bayer, 1982) or sperm-head abnormalities in mice
(Wild et al., 1981). Results of a dominant lethal assay in rats were negative (CTFA, 1982; Elder,
1988).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR m-AMINOPHENOL
No studies examining the effects of w-aminophenol in orally exposed humans were
located. A long-term oral study reported no liver or kidney lesions in rats fed a diet containing
400 mg/kg-day for 52 weeks, but did not investigate other endpoints (Kurata et al., 1987). Re et
al. (1984) found no developmental effects produced by w-aminophenol in rats at oral doses up to
900 mg/kg-day. A teratology study conducted by parenteral exposure in hamsters also found no
evidence of developmental effects by w-aminophenol at i.p. doses up to 200 mg/kg-day
(Rutkowski and Ferm, 1982).
There were three studies considered for use in developing the provisional RfD (p-RfD)
values for w-aminophenol: a 90-day diet study in rats (Re et al., 1984), a 28-day gavage study in
young rats (Koizumi et al., 2002) and an 18-day gavage study in newborn rats (Koizumi et al.,
2002). In the 90-day rat study, Re et al. (1984) identified a NOAEL of 240 mg/kg-day and
LOAEL of 900 mg/kg-day for hemolytic anemia. Other effects in the 900 mg/kg-day group
were decreased body weight (associated with reduced food intake) and thyroid histological
changes (hypertrophy) suggestive of hyperactivity but not clearly adverse. Findings of the 28-
day gavage study (Koizumi et al., 2002) were similar. In this study, the NOAEL was 240
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mg/kg-day and the LOAEL was 720 mg/kg-day. Effects at 720 mg/kg-day included hemolytic
anemia, some evidence of liver and kidney toxicity that may have been secondary to the anemia,
decreased body weight, and thyroid changes (hypertrophy together with increased thyroid
weight) indicative of hyperactivity. This study also found clinical signs (salivation and tremors)
in the treated animals that probably reflected the bolus dosing used in this study.
The 18-day newborn rat study (Koizumi et al., 2002) identified a NOAEL of 80 mg/kg-
day and a LOAEL of 240 mg/kg-day. Effects at 240 mg/kg-day included reduced body weight
and tremors. The decrease in body weight started early in the study, achieving statistical
significance at 8-11 days. The deficit from controls was 10-13% over most of the study.
Tremors seen at this dose were likely associated with the gavage route of exposure and were seen
less often as the study progressed, suggesting the animals developed tolerance. The results of
this study suggest that the newborn rats were more sensitive to m-aminophenol than the older
rats used in the 24-day and 90-day studies. The 240 mg/kg-day dose that produced body weight
effects and tremors in the 18-day newborn study was a NOAEL in the 24-day and 90-day
studies. Therefore, the 18-day newborn study was chosen as the critical study for both the
subchronic and chronic p-RfDs. The body weight and tremor data from the newborn rat study
are not amenable to benchmark dose modeling, because the authors did not provide adequate
information for modeling of the data (in-life body weight data were only presented graphically
and with no measure of variance; terminal body weight data were collected after overnight
starvation following the last dosing and this seems to have increased variability in the data [body
weight differences were of similar magnitude to in-life measures but were no longer statistically
significant]; terminal body weights were presented as mean plus some measure of variance, but
the latter was not identified [e.g., standard error vs. standard deviation] and this information is
needed to perform the modeling; tremors were seen in all animals at the high dose and
(presumably) none at any lower doses, so the data provide no indication of the dose-response
beyond that provided by the NOAEL/LOAEL). Because the data were not suitable for modeling,
the NOAEL (80 mg/kg-day) from the newborn rat study was chosen as the point of departure for
both the subchronic and chronic p-RfDs.
The subchronic p-RfD of 0.3 mg/kg-day for w-aminophenol is derived by dividing the
newborn rat oral NOAEL of 80 mg/kg-day from the Koizumi et al. (2002) newborn study by an
uncertainty factor of 300 as follows:
Subchronic p-RfD = NOAEL / UF
= 80 mg/kg-day/300
= 0.3 or 3E-1 mg/kg-day
The uncertainty factor of 300 includes a factor of 10 for extrapolation from rats to humans, 3 for
protection of sensitive individuals, and 10 for deficiencies in the subchronic toxicity database,
including lack of longer-term or developmental toxicity data in a second species, absence of a
systematic study of neurotoxicity, and lack of a multigeneration reproduction study. A reduced,
3-fold uncertainty factor for protection of sensitive individuals is applied because the point of
departure was identified in a sensitive subpopulation (newborn rats).
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A chronic p-RfD of 0.08 mg/kg-day for w-aminophenol is similarly derived, but uses a
higher uncertainty factor of 10 for deficiencies in the chronic toxicity database (total UF = 3000):
Chronic p-RfD = NOAEL / UF
= 240 mg/kg-day / 3000
= 0.08 or 8E-2 mg/kg-day
A single long-term oral study was conducted as part of a tumor promotion assay, but investigated
only liver and kidney pathology and no other endpoints (Kurata et al., 1987). Therefore, the 90-
day study of Re et al (1984) is selected as the basis for the provisional chronic RfD. The NOAEL
in this study is 240 mg/kg-day, with a LOAEL of 900 mg/kg-day for hemolytic anemia and
possible thyroid effects (equivocal). An aggregate uncertainty factor (UF) of 3000 is applied,
yielding an RfD of 0.08 mg/kg-day. The UF of 3000 includes factors of 10 for interspecies
extrapolation (UFA), 3 (10°5) for extrapolation to sensitive humans (UFH), 10 for data base
deficiencies (UFD) andlO for sub chronic-to-chronic exposure duration extrapolation (UFS). The
reduced factor of 3 for UFH is the same as for the provisional subchronic RfD. A full 10-fold
database factor is applied because of the lack of a multi-generation reproductive toxicity study, a
second developmental study and an adequate longer-term toxicity in a second species. A full 10-
fold factor is required for UFS because the chronic study (Kurata et al, 1987) does not address the
effect of continued exposure duration on either hemolytic anemia or thyroid effects. Also, the
neonatal rat study (Koizumi et al., 2002) is not used as the basis for the chronic p-RfD because
the NOAEL of 80 mg/kg-day is not, in itself, subject to a duration adjustment factor (i.e., UFS),
as it is only relevant for neonates. The subchronic NOAEL, although higher, results in a lower
RfD when adjusted for chronic exposure.
Confidence in the principal study is low. The study included an adequate number of dose
groups, and an adequate array of endpoints was investigated. However, the number of animals
per dose group was minimal, a single sex was tested, and the thyroid effects were not evaluated
or described fully. Confidence in the database is low for the subchronic data and low for the
chronic data. Only a single subchronic toxicity study, one developmental study and one neonatal
toxicity study are available. The chronic study evaluated only liver and kidney effects. No
adequate chronic oral studies were located, and no systematic studies of neurotoxicity or
reproductive effects are available. Overall confidence in both the subchronic and chronic p-RfD
is low.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR m-AMINOPHENOL
No chronic or subchronic inhalation studies examining the effects of w-aminophenol in
humans or animals were located, precluding derivation of provisional RfC (p-RfC) values for m-
aminophenol.
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PROVISIONAL CARCINOGENICITY ASSESSMENT FOR m-AMINOPHENOL
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
inadequate information to assess the carcinogenic potential of w-aminophenol. No data in
humans are available to assess the carcinogenic potential of w-aminophenol. w-Aminophenol
has not been tested for complete carcinogenicity in animals, but did not promote development of
tumors initiated by EHEN in rats. m-Aminophenol tested negative in mutagenicity assays using
S. typhimurium and E. coli, and in assays for induction of SCE and unscheduled DNA synthesis
in vitro. In in vivo assays, m-aminophenol has tested negative for micronuclei in mice and rats,
induction of SCE in hamster, sperm-head abnormalities in mice and dominant lethal
mutagenicity in rats. There is a single report of DNA damage (as measured by comet assay) in
human lymphocytes and mouse spleen cells after m-aminophenol treatment in vitro (Qu et al.,
2004).
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