United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/063F
Final
9-03-2009
Provisional Peer-Reviewed Toxicity Values for
2,4,6-Tribromophenol
(CASRN 118-79-6)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
2,4,6 TRIBROMOPHENOL (CASRN 118-79-6)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.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)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. 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 U.S. 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 U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. 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 U.S. 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 U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. 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 U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessment for 2,4,6-tribromophenol is available on
IRIS (U.S. EPA, 2009). There are no entries for 2,4,6-tribromophenol in the Chemical
Assessments and Related Activities list (CARA; U.S. EPA, 1991a, 1994), the Health Effects
Assessment Summary Tables (HEAST; U.S. EPA, 1997), or the Drinking Water Standards and
Health Advisories lists (U.S. EPA, 2006). The Agency for Toxic Substances Disease Registry
(ATSDR, 2009) has not published a Toxicological Profile for 2,4,6-tribromophenol. The World
Health Organization (WHO, 2005) has published a Concise International Chemical Assessment
Document (CICAD) for 2,4,6-tribromophenol and other simple brominated phenols, but found
the existing toxicity data inadequate for derivation of either oral or inhalation criteria to protect
human health. 2,4,6-Tribromophenol has been reviewed under the HPV Challenge Program, and
robust summaries from sponsors (e.g., Great Lakes Chemical Corporation, 2002) are available
online (U.S. EPA, 2008). Data summaries for 2,4,6-tribromophenol have been prepared under
the Organization for Economic Cooperation and Development-Screening Information Data
System (OECD-SIDS, 2006) program and are available online. The International Agency for
Research on Cancer (IARC, 2009) has not reviewed 2,4,6-tribromophenol with respect to
chronic toxicity or carcinogenicity in humans or animals. The chronic toxicity and
carcinogenicity of 2,4,6-tribromophenol have not been assessed by the National Toxicology
Program (NTP, 2005, 2009). The Occupational Safety and Health Administration
(OSHA, 2009), National Institute for Occupational Safety and Health (NIOSH, 2005), and the
American Conference of Governmental Industrial Hygienists (ACGIH, 2001, 2007) have not
established occupational exposure limits for 2,4,6-tribromophenol. The California
Environmental Protection Agency (CalEPA, 2002, 2005a, 2005b) has not derived a
Recommended Exposure Limit (REL) or cancer potency factor for 2,4,6-tribromophenol.
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Except as noted, literature searches were conducted from 1960s through June 2007 for
studies relevant to the derivation of provisional toxicity values for 2,4,6-tribromophenol.
Databases searched include MEDLINE, TOXLINE (Special), BIOSIS (August 2000 through
June 2007), TSCATS 1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and
Current Contents (December through June 2007). A final search of the literature was conducted
for the period from June, 2007 thru July, 2009.
REVIEW OF PERTINENT DATA
Human Studies
No studies regarding the toxicity of 2,4,6-tribromophenol in humans were identified.
Animal Studies
Oral Exposure
Subchronic Studies—Cij :CD Sprague-Dawley rats (12/sex/dose) were exposed orally to
2,4,6-tribromophenol (in corn oil) by gavage at daily doses of 0 (vehicle), 100, 300, or
1000 mg/kg-day in a combined repeat-dose and developmental/reproductive screening toxicity
test (OECD Test Guideline 422) (Tanaka et al., 1999). Males were exposed for 14 days prior to
mating (plus an additional 34 days; 48 days total) and females were exposed 14 days prior to
mating through Day 3 of lactation (41-45 days total). Females that did not mate successfully
were exposed for a total of 48 days. Only one female (from the control group) did not mate
successfully. Animals were observed daily, and clinical signs of toxicity, body weight, food
consumption, and water consumption were assessed for all animals throughout the study.
Comprehensive hematological and serum chemistry variables were assessed at study termination
for all males, but not for females. Absolute and relative organ weights were evaluated for brain,
thymus, liver, spleen, kidneys, adrenals, and reproductive tissues (testes and epididymis for
males; ovaries for females). Gross necropsies were conducted on all test animals.
Comprehensive histological examination of the digestive system was conducted for all test
groups. The thymus and urinary systems were evaluated histologically for all male test groups,
but only for control and high-dose females. Histological evaluation of the heart, spleen, testes,
ovaries, adrenals, and brain was performed only for control and high-dose animals of both sexes.
The reproductive variables assessed in the study, as well as conclusions regarding the
reproductive endpoints, are discussed in thq Reproductive/Developmental Studies section of this
document.
Table 1 shows the endpoints relevant to the assessment of systemic toxicity by
Tanaka et al. (1999). No parental mortality was observed. In comparison with controls, body
weight was statistically significantly decreased in the high-dose males beginning on Day 8 and at
every weekly measurement interval through the last measurement on Day 43 of the study (the
deficit from controls was approximately 10% throughout this period). Body weights were also
decreased among high-dose females relative to controls starting with Day 7 of gestation and
persisting through the last measurement on Day 4 of lactation, but the difference was not as
pronounced as in the males (deficit of approximately 6% throughout this period). Necropsy
body weights were significantly decreased in high-dose males (-12%; p < 0.0001, two-tailed
/-test) and females (- 5%;p < 0 .001, two-tailed Mest) with respect to controls (see Table 1). Food
consumption was reduced among high-dose animals of both sexes during the first week of the
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study, but not in subsequent weeks. A dose-related increase in the occurrence of excessive
salivation 5-35 minutes after dosing was observed among males and females exposed to 300 and
1000 mg/kg-day (data not shown by the researchers). This reaction to dosing was more common
at 1000 mg/kg-day than at 300 mg/kg-day and in males rather than females.
No treatment-related adverse effects on hematological variables were observed in males
(females were not assessed) (Tanaka et al., 1999). A statistically significant increase in
prothrombin clotting time in high-dose males relative to controls (15.6 ±1.2 seconds versus
14.2 ± 0.7 seconds) was not considered toxicologically relevant by the researchers because of the
small magnitude of change and because other indicators of potential adverse effects on clotting
(APPT [activated partial thromboplastin time] and fibrinogen) were unaffected by treatment.
Serum chemistry examination revealed statistically significant, dose-related increases in
creatinine in males dosed at 300 and 1000 mg/kg-day (indicative of renal dysfunction), an
increase in alkaline phosphatase (ALP) activity in males at 1000 mg/kg-day (possibly indicative
of an effect on the liver), and a number of other changes of uncertain biological significance in
high-dose males (small 10-15% increases in protein, albumin, albumin-to-globulin ratio [A/G],
and chloride [CI], and decreases in total bilirubin and potassium [K]) potentially related to
decreased body weight at this dose (Table 1). Creatinine was the only serum chemistry variable
that differed significantly from controls at the 300-mg/kg-day dose group. Blood urea nitrogen
(BUN) appeared to be elevated in the high-dose males, providing further support for a renal
effect, but it was not statistically increased due to high variability in the treated group. Clinical
chemistry was not evaluated in females.
There were statistically increased relative and absolute organ weights with respect to
controls for a number of organs in males and females only at the high dose (Table 1)
(Tanaka et al., 1999). With the possible exception of the changes in liver weight (increased
absolute and relative weights in both sexes) and thymus weight (decreased absolute weight in
males), the observed changes (increased relative organ weights) were consistent with, and likely
secondary to, the decrease in body weight in this dose group. Liver enlargement was visible
upon gross necropsy of high-dose males. Treatment-related histopathologic changes were noted
in thymus, kidney, and liver tissue. A statistically significant increase in the incidence of
hepatocellular hypertrophy (severity graded as slight -1 on a scale of 1 to 3) was noted in
high-dose males (12/12), but not females (0/11), with respect to controls (0/11). There was also
a significant decrease in the incidence of fatty change in liver sections from high-dose males.
There were statistically significant increases in the incidences of hyaline casts, tubular dilatation,
papillary necrosis, and lymphocyte infiltration of kidneys in high-dose males (slight-to-moderate
severity), but not females. Histological evaluation of thymus sections revealed slight atrophy in
3/12 high-dose males, but not in control, low-, or mid-dose males or in control or high-dose
females. This finding was not statistically significant, but it appears to be biologically relevant
given the statistically significant decrease in thymus weight observed in high-dose males.
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Table 1. Summary of Significant Findings Following Subchronic Oral (Gavage) Exposure of Rats to 2,4,6-Tribromophenola
Endpointb
Dose (mg/kg-day)
0
100
300
1000
Male
Female
Male
Female
Male
Female
Male
Female
No. examined0
12
11
12
12
12
12
12
11
Body weight (g)d
492 ± 34
332 ± 16
478 ±31
317 ±27
478 ± 36
333 ±22
422 ± 25e
307 ±15e
Absolute Organ Weights
Thymus (mg)
299 ±81
157 ±46
269 ± 52
134 ±48
269 ± 66
168 ±75
201± 57f
137 ±32
Liver (g)
13.99 ± 1.72
13.70 ±0.80
13.18 ± 1.31
13.48 ±2.07
14.20 ± 1.99
14.39 ± 1.76
16.23 ±2.32g
15.74 ± 1.28f
Relative Organ Weights (g%)
Brain
0.460 ± 0.042
0.613 ±0.034
0.465 ± 0.033
0.657 ± 0.067
0.473 ±0.041
0.602 ±0.038
0.522 ±0.032f
0.665 ± 0.025s
Liver
2.834 ±0.218
4.138 ±0.287
2.751 ±0.152
4.230 ±0.396
2.964 ±0.285
4.312 ±0.393
3.837 ±0.447f
5.117 ±0.265f
Kidney
0.678 ±0.054
0.649 ± 0.072
0.661 ±0.053
0.694 ± 0.078
0.679 ±0.083
0.666 ± 0.047
0.824 ±0.101f
0.772 ± 0.094f
Adrenals
12.257 ± 1.299
23.171 ± 1.572
11.807 ± 1.277
25.991 ±3.418
13.494 ± 1.966
25.988 ±4.091
15.304 ± 1.697f
27.315 ±3.415f
Testes
0.721 ±0.062
NA
0.733 ± 0.067
NA
0.729 ± 0.080
NA
0.794 ± 0.046s
NA
Histological Findings (observed/examined)
Liver
Fatty change
6/11
2/11
5/12
1/12
3/12
0/12
0/12f
0/11
Hepatocyte hypertrophy
0/11
0/11
0/12
0/12
0/12
0/12
12/12f
0/11
Kidney
Hyaline casts'1
1/11
1/11
1/12
NE
0/12
NE
8/12f
0/11
Dilatation, tubules
0/11
0/11
0/12
NE
0/12
NE
7/12f
0/11
Mineralization
1/11
3/11
0/12
NE
0/12
NE
1/12
1/11
Papillary necrosis
0/11
0/11
0/12
NE
0/12
NE
5/12f
0/11
Lymphocyte infiltration
1/11
0/11
1/12
NE
0
NE
6/128
0/11
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Table 1. Summary of Significant Findings Following Subchronic Oral (Gavage) Exposure of Rats to 2,4,6-Tribromophenola
Endpointb
Dose (mg/kg-day)
0
100
300
1000
Male
Female
Male
Female
Male
Female
Male
Female
Thymus (atrophy,)
0/11
0/11
0/12
NE
0/12
NE
3/12
0/11
Blood Chemistry (12 males/dose examined)
Protein (g/dL)
5.87 ±0.22
NE
5.84 ±0.14
NE
5.95 ±0.26
NE
6.45 ± 0.51f
NE
Albumin (g/dL)
3.36 ±0.13
NE
3.33 ±0.09
NE
3.39 ± 0.19
NE
3.88 ± 0.29f
NE
A/G
1.34 ± 0.06
NE
1.33 ±0.09
NE
1.33 ±0.10
NE
1.51 ± 0.08f
NE
Creatinine (mg/dL)
0.27 ±0.03
NE
0.30 ±0.04
NE
0.33 ± 0.07s
NE
0.47 ± 0.26f
NE
BUN (mg/dL)
13.3 ± 1.4
NE
13.6 ±2.1
NE
13.2 ±2.3
NE
20.9 ± 11.4
NE
Bilirubin (mg/dL)
0.05 ±0.01
NE
0.05 ±0.01
NE
0.04 ±0.01
NE
0.02 ± 0.01f
NE
ALP (U/L)
354 ±74
NE
440 ± 162
NE
342 ±102
NE
514 ±155s
NE
K (mmol/L)
4.46 ±0.29
NE
4.40 ±0.25
NE
4.38 ±0.30
NE
4.06 ± 0.25f
NE
CI (mmol/L)
106.6 ± 1.2
NE
107.6 ± 1.1
NE
107.8 ± 1.5
NE
119.0 ±3.6f
NE
3Tanaka et al., 1999
bValues are mean ± SD; NA = Not Applicable; NE = Not Evaluated
°The reason why <12 animals per dose were examined for some groups is not clear from the English translation of the study
dValues taken from Table 3 of Tanaka et al., 1999; these values differ from body weights depicted in Figures 1 and 2 of Tanaka et al., 1999
"Significant difference from control group, p < 0.001, two-sided t-test performed for this review
Significant difference from control group, p < 0.01 reported by Tanaka et al., 1999
Significant difference from control group, p < 0.05 reported by Tanaka et al., 1999
hComposition and specific location within the kidney were not addressed
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The increase in liver weight and hepatocellular hypertrophy, and the slightly elevated
serum ALP levels observed in the high-dose males, are indicative of an adaptive response of the
liver to 2,4,6-tribromophenol exposure, but do not suggest an adverse effect. In the thymus,
slight atrophy in some individuals and decreased mean absolute organ weight suggest a potential
chemical-related effect in high-dose males. The serum chemistry and microscopic evaluation of
urinary tract tissues made in this study (Tanaka et al., 1999) suggest that 2,4,6-tribromophenol
adversely affects the kidney in male rats. Significant incidences of several types of kidney
lesions, including hyaline casts, tubular dilatation, lymphocyte infiltration, and papillary
necrosis, were observed in the high-dose males only. The kidney observations appear congruent
with the chemically induced globulin accumulation (CIGA alpha2u) nephropathy specific to male
rats. However, chemicals known to produce alpha2u nephropathy typically produce minimal
changes in clinical chemistry and have little-to-no effect on glomerular function
(U.S. EPA, 1991b). A dose-related and statistically significant increase in serum creatinine was
observed in males exposed to 300 (22%) and 1000 (74%) mg/kg-day, suggesting a
treatment-related adverse effect on glomerular function, which, in turn, suggests that alpha2u
nephropathy may not be responsible for the observed kidney damage. Unfortunately, no serum
chemistries were assessed in females. Based on the dose-related increase in serum creatinine in
males and clinical signs (salivation) in both sexes, this study identifies a LOAEL of
300 mg/kg-day for 2,4,6-tribromophenol. The NOAEL is 100 mg/kg-day.
Chronic Studies—No chronic studies of 2,4,6-tribromophenol were identified.
Reproductive/Developmental Studies—As discussed in the Subchronic Studies section,
Tanaka et al. (1999) exposed groups of male and female rats by gavage to 2,4,6-tribromophenol
(0, 100, 300, or 1000 mg/kg-day) in a combined repeated-dose/reproductive/developmental
toxicity screening study (OECD Test Guideline 422). The reproductive variables assessed in the
study included numbers of pairs copulated, numbers of pregnant females, copulation index,
fertility index, mean days of estrous cycle, numbers of dams delivering live pups, mean duration
of gestation, mean number of total corpora lutea, mean number of total implants, mean number
of total pups born, mean number of total live pups born, mean sex ratio, mean stillbirths
(cannibalism evaluated separately), gestation index, mean implantation index, mean liver birth
index, and mean viability index (male and female) on Day 4. All of the reproductive variables
were presented as totals per dose-group as well as means per litter per dose-group where
appropriate. There were no treatment-related adverse effects on any endpoint except for neonatal
growth (decreased body weight relative to controls; both sexes; Days 0 and 4 of lactation) and
viability (Day 4 of lactation) in the 1000 mg/kg-day test group. Table 2 summarizes the results
for the viability endpoints. Data for pup body weight were not reported. Based on these
observations, the LOAEL for reproductive toxicity was 1000 mg/kg-day for decreased neonatal
viability (both sexes) on Day 4 of lactation and decreased neonatal body weight on Days 0 and 4
of lactation. The NOAEL is 300 mg/kg-day.
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Table 2. Summary of Significant Reproductive/Developmental Endpoints Following Oral
(Gavage) Exposure of Rats to 2,4,6-Tribromophenol Prior to Mating and Throughout

Gestation and Early Lactationa

Dose (mg/kg-day)
0
100
300
1000
No. Live Pups on Day 4 (per litter mean ± SD)
Male
83 (7.3 ± 1.2)
87 (7.3 ± 2.8)
86 (7.2 ± 2.3)
42 (3.5 ± 2.4)b'°
Female
72 (6.5 ± 1.9)
84 (7.0 ± 2.2)
80 (6.7 ± 1.2)
49(4.1 ±2.9)b'd
Mean ± SD Day 4 Viability Index6
Male
92.6 ±8.6
88.6 ±23.7
97.4 ±6.3
53.3 ± 34.2°
Female
97.6 ±5.4
92.7 ± 15.5
94.0 ±9.6
50.4 ± 35.1°
"Tanaka et al., 1999
bNot clear whether the investigator's assessment of statistical significance applies to the total numbers, the means
or both
Significant difference from control group, p < 0,01
Significant difference from control group, p < 0.05
ePer litter: (Number of live pups on Day 4 number live pups born) x 100
A pilot teratology study was conducted in which 2,4,6-tribromophenol (purity not
reported) in corn oil was administered by gavage to groups of five Charles River CD female rats
at doses of 0, 10, 30, 100, 300, 1000, or 3000 mg/kg-day on Gestation Days (GD) 6-15
(International Research and Development Corporation, 1978a). The dams were observed for
clinical signs, changes in body weight, and mortality and were sacrificed on GD 20 for uterine
observations. Numbers of viable and nonviable fetuses, early and late resorptions, total
implantations, and corpora lutea were recorded, but the fetuses were not examined for skeletal or
visceral malformations. All rats in the 3000-mg/kg-day group died by GD 7. Significant effects
at the 1000-mg/kg-day dose included a 12.7% decrease, relative to controls, in maternal weight
gain between GD 6 and 12 and a 16% decrease in the number of live fetuses (13.7, 12.0, 13.6,
13.0, 13.6, and 11.5% at 0, 10, 30, 100, 300, and 1000 mg/kg-day, respectively; standard
deviations [SDs] not reported). Postimplantation loss was increased 500% at 1000 mg/kg-day,
but this effect was not clearly dose-related (increased 433, 100, 100, and 33% at 10, 30, 100, and
300 mg/kg-day, respectively). The LOAEL for maternal and fetal toxicity in this study is
1000 mg/kg-day for decreased maternal weight gain and decreased fetal viability. The NOAEL
is 300 mg/kg-day.
Inhalation Exposure
Subchronic Studies—Groups of five male and five female Charles River COBS rats
were exposed via whole-body inhalation to 2,4,6-tribromophenol (purity 99.5 to 99.1%) dust at
nominal concentrations of 0, 0.1, or 1 mg/L (mean analytical concentrations of 0, 0.10, or
0.92 mg/L (0, 100, or 920 mg/m3); mean gravimetric concentrations of 0, 0.15, or 0.98 mg/L) for
2 or 6 hours/day, 5 days/week, for 3 weeks (Industrial Biotest Laboratories, Inc., 1977). Particle
sizes ranged from 1-74 microns, with 78% of the particles <10 microns and 65% = 1-5 microns.
A mass median aerodynamic diameter (MMAD) was not reported and one cannot be estimated
from the data presented. Clinical signs, body weight, mortality, hematology (three/sex/group),
clinical chemistry (three/sex/group), urinalysis endpoints (three/sex/group), and gross pathology
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were evaluated in all groups. Animals were observed daily, body weights were measured
weekly, and clinical chemistry, urinalysis, and hematological variables were assessed on Study
Day 0 and at study termination. Histopathology was assessed in surviving animals in the control
and high-concentration groups. No statistical analyses were reported by the researchers.
Deaths occurred in the high-dose group (1/5 males and 1/5 females) after
10-11 exposures (Industrial Biotest Laboratories, Inc., 1977). No control or low-dose animals
died. Clinical signs of toxicity (primarily hypoactivity, salivation, lacrimation, and red nasal
discharge) were observed at both exposure concentrations. Hypoactivity and salivation were
observed in all high- and low-dose animals on every exposure day of the study. Mean terminal
body weights were markedly reduced in high-dose males (-30%) and females (-25%), in
comparison to controls; the animals in these groups actually lost weight during the course of the
study (the loss in weight occurred during the third week of the study). In the low-dose group,
terminal body weights did not differ significantly from controls, but body weight gain over the
course of the study was marginally reduced in females only (p = 0.045, two-tailed t-test
performed for this review). Hematology and urinalysis findings were unremarkable. Although
the researchers suggested that serum chemistry findings were likewise normal, there were
statistically significant (p < 0.05, two-tailed t-tests performed for this review) 1.5 to 3-fold
increases in BUN (males and females) and alanine aminotransferase (ALT) (males) in the
high-dose group; small group sizes (n = 2 or 3) limit the reliability of these data, however. At
gross necropsy, 4/5 males and 5/5 females in the high-dose group were visibly emaciated.
Pathologic changes were observed in the liver and kidneys of high-dose animals. Histologic
alterations included dilatation of renal tubules in 3/5 rats of each sex and a solitary area of
submassive hepatic necrosis in one female. Proteinaceous casts (unilateral) were observed in the
renal tubules of 2/5 high-dose males, but in none of the control males and in none of the females
(either control or high-dose). There were no treatment-related effects on the lungs or trachea of
high-dose rats in comparison with controls. The LOAEL for this study is 100 mg/m3 (lowest
dose tested) based on clinical signs of toxicity (especially hypoactivity and salivation) in males
and females and marginally decreased body weight gain in females. A NOAEL was not
identified.
Chronic Studies—No chronic inhalation studies were identified.
Reproductive/Developmental Studies—Pregnant Wistar rats (25/dose) were exposed
via whole-body inhalation to research-grade 2,4,6-tribromophenol (no further characterization) at
-3
nominal concentrations of 0, 0.03, 0.1, 0.3, or 1.0 mg/m , 24 hr/day, 7 days/wk, on Days 1-21 of
gestation (Lyubimov et al., 1998). No details regarding the methods for generating the test
atmosphere, particle sizes, or measurement of test concentrations were reported. CNS effects
were monitored in pregnant dams (Day 21 of gestation) and pups (postnatal days [PND] 30 and
60 by assessing skin pain threshold (SPT) and behavior in an open field (mobility, orientation,
horizontal and vertical movement, etc.), but these methods were not described in detail.
Maternal body weight, rectal temperature, lipid peroxidation (liver and placenta), total amino
nitrogen in the urine and blood, phenol excretion (urine), and serum hormone and enzyme levels
were recorded. Nonspecific immunological status of the dams was assessed by evaluating
phagocytosis and antimicrobial activity (test not specified) of the blood. On Day 21 of
pregnancy, 15 dams per dose group were sacrificed and examined for corpora lutea, numbers of
implants, resorptions, and live and dead fetuses. Half of the fetuses were examined for skeletal
variations and half were examined for visceral malformations. Groups of 10 dams per dose were
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allowed to deliver pups, which were then observed for two months and evaluated in the
aforementioned SPT and behavioral tests. These pups were sacrificed on PND 60 and relative
organ weights were determined for heart, liver, kidneys, spleen, adrenals, and reproductive
organs (ovaries and testes).
No mortality and no effects on maternal body-weight gain were reported (data not shown
by researchers) (Lyubimov et al., 1998). Dams exposed to the highest concentration had
significant decreases in mean orientation reactions (i.e., vertical head movements), relative to
controls (3.8 ± 0.59 versus 11.11 ± 2.73 in controls), but no other behavioral changes.
Significant increases in serum ALP (65.0 versus 29.0 mEQ in controls, no measure of error
reported), serum progesterone (93.5 ± 7.3 versus 61.3 ± 7.1 mg/L in controls), urinary total
amino nitrogen (-22% higher than controls), and total excretion of phenols (-23% higher than
controls) were also observed in dams exposed at the highest concentration. Data were not shown
for the aforementioned variables at the other exposure concentrations. There were no
treatment-related effects on immune function, serum corticosterone levels, or serum estradiol
concentrations (data not shown). Statistically significant dose-related increases in
embryolethality (combined pre- and postimplantation loss) were found at test concentrations of
"3
0.1 mg/m and above (approximately 7, 8, 18, 22, and 36% embryolethality for the control, 0.03,
0.1, 0.3, and 1.0 mg/m3 groups, respectively; data presented graphically in the original report).
"3
Fetal weight was significantly decreased at concentrations of 0.1 and 1 mg/m , but not at
0.3 mg/m . Delayed sternal ossification was reported in exposed groups; this manifest as a
significant decrease in the number of centers for sternal ossification (6.5 ± not reported,
3.85 ± 0.42, 4.98 ± 0.27, and 4.95 ± 0.27 in control, 0.1, 0.3, and 1.0 mg/m3 groups; data for
"3
0.03 mg/m were not reported). No other meaningful treatment-related findings regarding
skeletal or visceral malformations or other variables that were assessed are apparent from the
data presented in the report.
A somewhat detailed discussion of postnatal development and neurobehavioral effects is
presented in the report (Lyubimov et al., 1998), but the meaning of these findings is unclear.
The reported behavioral changes that had statistical significance (grooming behavior
and" emotionality") were not dose-related, and, in the case of'emotionality," which is defined by
the investigators as a measure of the number of defecations made during the observation period,
the mean and SDs were extremely small. Changes in relative organ weights are discussed for
2-month-old neonates, but no data are presented. With the possible exception of reduced relative
testes weight in high-dose males, the reported changes do not appear to be dose-related. In
addition to the absence of data to discern the magnitude of the reported changes, the lack of
absolute organ weights and the lack of organ histopathology preclude the assignment of meaning
to any of the reported findings with respect to organ weights.
Deficiencies in reporting of the study (Lyubimov et al., 1998) limit the utility of these
data for toxicity assessment. Using the data reported, the LOAEL for maternal toxicity in this
"3
study is 1.0 mg/m on the basis of increases in serum ALP and progesterone and urinary amino
nitrogen, and the NOAEL is 0.3 mg/m3. For fetotoxicity, the study appears to identify a LOAEL
3	3
of 0.1 mg/m for embryolethality and delayed sternal ossification, with a NOAEL of 0.03 mg/m .
These findings suggest that the developing fetus may be a sensitive target for
2,4,6-tribromophenol. However, the reliability of these data is uncertain due to inadequate
reporting of study methods and results.
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Other Studies
Toxicokinetics
Absorption, distribution, and elimination were evaluated in 11 rats (strain not reported)
that were treated with a single dose of 14C-2,4,6-tribromophenol (purity 99.98%) in aqueous
ethanol by gavage (Velsicol Chemical Corporation, 1977). Groups of 2-3 females and 2 males
were given 4.0-5.3 mg/kg and sacrificed 8, 17, 48, and 96 hours after treatment, respectively, for
measurement of radiocarbon in tissues. Blood radiocarbon was measured in four rats at 1, 2, 4,
8, 17, 24, and 48 hours after treatment. 2,4,6-Tribromophenol appears to have been rapidly
absorbed and readily excreted. Radiocarbon in the blood peaked 1 hour after dosing and then
decreased log-linearly to negligible levels within 24 hours. Blood level kinetics are apparently
first order and the elimination rate constant (ke) and half-life are calculated to be 0.3 and
2.03 hours, respectively. In tissues, the levels of radiocarbon reached maximum values 8 hours
following dosing, with the highest levels occurring in the blood, muscle, fat, kidneys, liver, and
lungs. The only tissues containing detectable residues after 48 hours were kidneys, liver, and
lungs. Tissues retained approximately 4.9% and 0.01% of the administered radiocarbon at 8 and
48 hours following treatment, respectively. Most of the administered radioactivity was
eliminated via urine (-70-90%) and feces (-4-6%) within 48 hours. Elimination of
radioactivity in the urine was proportional to the decreasing concentrations in the blood.
Accumulation of 2,4,6-tribromophenol (purity 99.3%) in adipose tissue was evaluated in
groups of 8 male Charles River rats (3 control and 5 test rats/group) by gas chromatography
(Industrial Biotest Laboratories, Inc., 1975). Rats were fed a diet containing 1000 ppm of
2,4,6-tribromophenol and then sacrificed after 7 days of exposure followed by 0, 7, or 14 days of
recovery or 21 days of exposure followed by 0, 14, or 42 days of recovery. Compared to control
values ranging from not detectable (<0.01 ppm) to 0.016 ppm, the fat tissue analysis showed,
increased 2,4,6-tribromophenol concentration at the end of the 7- and 14-day exposure periods
(0.56 and 0.30 ppm, respectively), as well as an increase (0.06 ppm) in 2/5 animals given 7 days
recovery after 7 days of treatment. None of the animals given 14-day or longer recovery periods
had detectable residue. No treatment-related changes in food consumption or body weight were
observed during the study.
Acute/Short-term Toxicity
Cij:CD Sprague-Dawley rats (5/sex/dose) were given a single oral dose of
2,4,6-tribromophenol (99.8% purity by weight) in corn oil by gavage at doses of 1000, 1300,
1690, 2197, or 2856 mg/kg and observed for 14 days (Tanaka et al., 1999). Hypoactivity was
observed at all doses and excessive salivation was observed in most treated animals. Mortality,
convulsions, tremors, and prone or lateral body position were observed in both sexes at doses
>1300 mg/kg. All deaths occurred within 1 day of exposure. The combined LD50 for both sexes
is 1486 mg/kg. No macroscopic abnormalities were observed at necropsy.
Spartan rats (5/sex/dose) were treated by gavage with a single dose of
2,4,6-tribromophenol (suspended in 0.5% Methocel) at 1585, 2512, 3980, 6308, 10,000, or
15,848 mg/kg and were observed for 14 days (International Research and Development
Corporation, 1974a). LD50 values of 5012 mg/kg for males and 5012 mg/kg for females were
calculated based on zero, one (male), one (female), nine (five males, four females), nine (four
males, five females) and nine (four males, five females) deaths in the low- to high-dose groups.
Clinical signs of toxicity, including nasal and ocular discharge (clear and porphyrin-containing),
lacrimation, decreased motor activity, tachypnea, and/or tachycardia, were observed in all dose
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groups. Ataxia, tremors, flaccidity, prostration, and/or cyanosis occurred at >6308 mg/kg. Gross
necropsy revealed a dose-related increase in congestion with some hemorrhage in lung, stomach,
and liver.
Charles River CD rats (5/sex/dose) were given a single oral dose (by gavage) of 631,
1000, 1585, 2512, 3980, or 6308 mg/kg and were observed for 14 days (International Research
and Development Corporation, 1978b). One female at 1585 mg/kg and all animals in the
higher-dose groups died. LD50 values were estimated to be 1995 mg/kg for males and
1819 mg/kg for females. No information on clinical signs of toxicity or pathology was reported.
Mortality was observed in guinea pigs given a single oral dose of 2,4,6-tribromophenol at
3000 mg/kg, but no mortality was observed following similar exposure to 1000 mg/kg
(Dow Chemical Company, 1946). No additional information (e.g., numbers tested and deceased,
observation period, animal sex, and strain) was reported.
"3
Spartan rats (5/sex) that were exposed by inhalation to 50 mg/L (50,000 mg/m ) of
2,4,6-tribromophenol for 4 hours and observed for 14 days showed clinical signs that included
decreased motor activity, slight dyspnea, erythema, ocular porphyrin discharge, and clear nasal
discharge (International Research and Development Corporation, 1974b). Clinical signs of
toxicity observed in Charles River rats (5/sex) during inhalation exposure to 1.63 mg/L
"3
(1630 mg/m ) for 4 hours included ptosis (drooping eyelids) and red nasal discharge; the nasal
discharge continued for 8-18 hours following exposure (Industrial Biotest
Laboratories, Inc., 1977).
Genotoxicity
2,4,6-Tribromophenol was not mutagenic in assays conducted by three different
laboratories with Salmonella typhimurium, Escherichia coli, or Saccharomyces cerevisiae.
2,4,6-Tribromophenol dissolved in dimethyl sulfoxide (DMSO) is not mutagenic in
preincubation assays with Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537
and Escherichia coli strain WP2uvrA (Tanaka et al., 1999). Assays were conducted both with
and without metabolic activation (rat liver S9) at six different concentrations up to 500 [j,g/plate
in Salmonella strains TA98, 100, and 1535, and up to 1000 [j,g/plate in TA1537. Toxicity was
observed at higher test concentrations, and the results at these concentrations are not reported. In
E. coli, assays were conducted with six different concentrations up to 5000 [j,g/plate, and toxicity
was observed only at 5000 [j,g/plate. All test results were negative. Positive and negative
controls responded appropriately. 2,4,6-Tribromophenol is not mutagenic in preincubation
assays with S. typhimurium strains TA98, TA100, TA1535, and TA1537 (Zeigler et al., 1987).
These assays were conducted with and without Aroclor 1254-induced rat and hamster liver
homogenate. 2,4,6-Tribromophenol was also not mutagenic in plate incorporation assays with
S. typhimurium strains TA98, TA100, TA1535, TA1537, TA1538, and Saccharomyces
cerevisiae strain D4 (Litton Bionetics, Inc., 1978). These assays were conducted with, and
without, Aroclor 1254-induced rat liver homogenate.
2,4,6-Tribromophenol dissolved in DMSO induced chromosomal aberrations in Chinese
hamster lung (CHL/IU) cells following short-term treatment (Tanaka et al., 1999). The lowest
effective concentrations are 0.050 mg/L in the absence of metabolic activation and 0.10 mg/L in
the presence of metabolic activation (phenobarbital and 5,6-benzoflavone-induced rat liver S9).
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These were the highest concentrations tested. No polyploidy was observed.
2,4,6-Tribromophenol did not induce chromosome fragmentation in Allium cepa root cells
(Levan and Tjio, 1948).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 2,4,6-TRIBROMOPHENOL
Subchronic p-RfD Derivation
The toxicity database for 2,4,6-tribromophenol is limited to a combination repeated-dose
reproductive/developmental screening toxicity study (Tanaka et al., 1999) and a pilot teratology
study (International Research and Development Corporation, 1978a), both of which were
conducted with rats. The repeated-dose study was conducted for 41-48 days. None of the
available studies examined fetuses for malformations. There are no human studies. Table 3
shows the dose-response information from the available animal studies.
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Table 3. Summary of Oral Noncancer Dose-Response Information
Species
Sex
Dose
(mg/kg-day)
Exposure
Regimen
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Subchronic Exposure
Rat
M,F
0, 100, 300, or
1000 mg/kg-day
Gavage, 14 days
prior to mating
through Day 3
of lactation
100
300
Increased serum creatinine
(M), clinical signs
(salivation)
OECD Guideline Study for
combined repeated-dose,
reproductive, and
developmental toxicity
screening.
Tanaka et al.,
1999
Reproductive/Developmental Toxicity
Rat
M,F
0, 100, 300, or
1000 mg/kg-day
Gavage, 14 days
prior to mating
through Day 3
of lactation
300
1000
Decreased neonatal
viability (both sexes) on
Day 4; decreased neonatal
body weight (Days 0 and
4)
OECD Guideline Study for
combined repeated-dose,
reproductive, and
developmental toxicity
screening; no exams for
fetal malformations.
Tanaka et al.,
1999
Rat
F
0, 10, 30, 100,
300, 1000, or
3000 mg/kg-day
Gavage, Days
6-15 gestation
300
1000
Decrease in maternal
weight gain between
Gestation Days 6 and 12
and a 16% decrease in the
mean number of live
fetuses per litter
Pilot study; no exams for
fetal malformations; 100%
mortality by GD 7 at
3000 mg/kg-day.
International
Research and
Development
Corporation,
1978a
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The observed treatment-related effects following the lowest repeated exposure in the
animal database were increased serum creatinine and clinical signs of toxicity (excessive
salivation) (Tanaka et al., 1999). These effects were observed at a concentration of
300 mg/kg-day. The next highest dose tested (1000 mg/kg-day) was associated with a larger
increase in serum creatinine, greater occurrence of salivation, histopathologic evidence of kidney
damage (males), increased absolute and relative liver weight, hepatocellular hypertrophy,
increased serum ALP, other serum chemistry changes in males (increased protein, albumin,
chloride, and decreased potassium), possible thymic atrophy in males (decreased thymus weight
and histological evidence of atrophy), and decreased body weight in both sexes. The observed
liver changes (increased liver weight, hepatocellular hypertrophy, and increased serum ALP
levels) appear to represent an adaptive response to exposure, rather than toxicity. Despite the
similarity in lesions and pattern of occurrence, the observed effects on the kidney in males may
not be alpha2U-related nephropathy; increased serum creatinine is indicative of an effect on
glomerular function that is not typical of alpha2U nephropathy. Unfortunately, no serum
chemistries were assessed in females, making further characterization of potential effects on the
kidney in females impossible.
Data from the reproductive phase of the combined study and from the pilot teratology
study are supportive of adverse effects at the 1000 mg/kg-day level of exposure. Decreases in
maternal weight gain during exposure and in neonatal growth and viability were observed in both
the screening reproductive and pilot teratology studies at 1000 mg/kg-day (Tanaka et al., 1999;
International Research and Development Corporation, 1978a;). No treatment-related effects
were observed at 300 mg/kg-day in either the reproductive phase of the combined study or in the
pilot teratology study.
These observations suggest that 300 mg/kg-day is a LOAEL for short-term oral exposure
on the basis of increased serum creatinine in male rats. The dose-related statistically significant
(p < 0.05) increase in creatinine in male rats (Tanaka et al., 1999) is the most sensitive
treatment-related endpoint in the database. Although clinical signs (salivation) were observed at
300 mg/kg-day, the data are not presented. The serum creatinine data are used as the basis for
benchmark dose (BMD) modeling. Table 4 summarizes the data set used in the BMD modeling.
Appendix B presents the results of the BMD model. A linear model with modeled variance
provided adequate fit to the data set and yields a BMDLisd of 92 mg/kg-day.
Table 4. Data Set for Increased Serum Creatinine in Male Ratsa
Dose (mg/kg-day)
0
100
300
1000
Mean
0.27
0.30
0.33
0.47
Standard Deviation
0.08
0.04
0.07
0.26
Number Animals
12
12
12
12
3Tanaka et al., 1999
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Applying a composite uncertainty factor (UF) of 1000 to the BMDLisd of 92 mg/kg-day
yields a subchronic p-RfD for 2,4,6-tribromophenol as follows:
Subchronic p-RfD = BMDLisd ^ Composite UF
= 92 mg/kg-day 1000
= 0.092, rounded to 0.09 mg/kg-day or 9 x 10"2 mg/kg-day
The Composite UF of 1000 is composed of the following:
•	A full UF of 10 is applied for interspecies extrapolation to account for potential
pharmacokinetic and pharmacodynamic differences between rats and humans.
•	A full UF of 10 is applied for intraspecies differences in order to account for
potentially susceptible individuals in the absence of information on the variability
of response in humans.
•	A full UF of 10 is applied to account for database deficiencies. The toxicological
database for oral exposure to 2,4,6-tribromophenol is composed solely of two
studies conducted on only one species and lacks true subchronic, reproductive,
and developmental toxicity studies. Neither of the existing studies examined
fetuses for malformations.
A UF for LOAEL-to-NOAEL extrapolation is not applied because BMD modeling is
used to identify the POD; a UF for subchronic-to-chronic extrapolation is not applied because a
subchronic study was available.
Confidence in the principal study (Tanaka et al., 1999) is medium because the rats were
exposed for only 41-48 days (approximately half of the typical 90-day duration of a subchronic
toxicity study in rats), and females were not evaluated for clinical chemistry and hematology.
Confidence in the database is low. Toxicity is investigated in only one species—rats—and the
existing studies were designed as screening-level and, as such, employed small numbers of
animals and less-than-complete analyses. Also, as discussed above, neither of the existing
studies examined fetuses for malformations. Consequently, confidence in the subchronic p-RfD
is low.
Chronic p-RfD Derivation
There are no chronic toxicity studies for 2,4,6-tribromophenol, and, as discussed in the
previous section, there are only screening-level, repeated-dose, reproductive and developmental
toxicity studies. It is a commonly accepted practice to use a subchronic p-RfD as the basis for a
chronic RfD by applying an additional UF of 10 to account for the use of a subchronic study to
approximate a chronic duration of exposure. However, given that the subchronic p-RfD for
2,4,6-tribromophenol derived in the previous section already incorporates an UF of 1000 for
intraspecies variability, interspecies variability, and database uncertainties, employing an
additional UF of 10 to account for less-than-chronic duration would yield a total UF of 10,000.
Provisional reference values are usually not developed for studies that exceed a composite UF of
3000 because of the high level of uncertainty. Therefore, no chronic p-RfD is derived for
2,4,6-tribromophenol. However, Appendix A of this document contains a screening value that
may be useful in certain instances. Please see the Appendix A for details.
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FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR 2,4,6-TRIBROMOPHENOL
The relevant inhalation studies for 2,4,6-tribromophenol are restricted to two 21-day
studies (one with gestational exposure); neither of which is suitable for quantitative risk
assessment. Table 5 summarizes the data from these studies.
The study by Industrial Biotest Laboratories, Inc. (1977) used only two test
concentrations and does not establish a NOAEL. Clinical signs of toxicity, most notably
hypoactivity and excessive salivation, were observed at both test concentrations in males and
females. Body weight gain was marginally decreased in females at the low concentration. At
the high concentration, body weights were markedly reduced in both sexes and most of the
animals were visibly emaciated. Histopathologic examination and serum chemistry analyses
suggested effects on the liver and kidneys in rats at the high concentration. Histological
examination was not performed for the low-exposure animals. There are two further deficiencies
in this study that preclude its use in quantitative human risk assessment. Only the lungs and
trachea are examined microscopically, limiting the usefulness of the study in determining critical
respiratory endpoints. In addition, no information on aerodynamic particle sizes is reported,
making it impossible to determine the mass aerodynamic diameter variables necessary to
extrapolate from a particulate animal exposure concentration to a human equivalent
concentration (HEC).
The developmental toxicity study by Lyubimov et al. (1998) has many deficiencies in
reporting. The most important deficiency with respect to the quantification of dose is a complete
lack of discussion about how the test atmosphere was generated and whether the nominally
reported exposure concentrations were validated. If the reported nominal concentrations are
correct, then the LOAELs for maternal toxicity (1 mg/m3) and embryolethality (0.1 mg/m3)
observed in this study occur at concentrations 18 times and 180 times lower, respectively, than
the duration-adjusted LOAEL for adult toxicity (18 mg/m3) reported for rats in the 21-day
Industrial Biotest Laboratories, Inc. (1977) study. As in the previous study, no information on
particle sizes is reported. Therefore, it is not possible to know—with confidence—the conditions
and concentrations for animal exposure, and it is, therefore, not possible to extrapolate a HEC
from the available information. Based on these deficiencies, the study by Lyubimov et al. (1998)
is not useful for quantitative human health risk assessment.
In conclusion, there are no suitable inhalation data from which to derive a subchronic or a
chronic p-RfC for 2,4,6-tribromophenol.
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Table 5. Summary of Inhalation Noncancer Dose-Response Information
Species
Sex
Exposure
Concentration3
(mg/m3)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses
Comments
Reference
Short-term Exposure
Rat
M, F
Mean analytical
concentrations of
dust at 0, 100, or
920 mg/m3
adjusted to 0, 18
or 164 mg/m3
(mg/m3 x 6/24 x
5/7)
Whole-
body,
6 hr/day,
5 days/wk,
for 3 wk
Not
established
18
Clinical signs of toxicity
(hypoactivity and excessive
salivation) in males and females
and marginally decreased
body-weight gain in females
No information on MMAD or data
from which to generate MMAD
were provided.
Histopathologic examination of the
respiratory tract included only
lungs and trachea.
Industrial
Biotest
Laboratories,
Inc., 1977
Reproductive/Developmental Toxicity
Rat
F
Nominal: 0, 0.03,
0.1, 0.3, and
1.0 mg/m3
Whole
body
continuous,
Days 1-21
of gestation
Maternal
0.3
Fetal
0.03
Maternal
1.0
Fetal
0.1
Maternal: Increased serum ALP.
serum progesterone, urinary total
amino nitrogen, and urinary
excretion of total phenols
Fetal: Embrvolethalitv
(combined pre- and
postimplantation loss), delayed
sternal ossification
No information on generation of
the test atmosphere, measurement
of test concentrations or particle
size distribution was reported;
many deficiencies in methodology
and data reporting.
Lyubimov et al.,
1998
Concentrations cannot be adjusted to human equivalent concentrations (HEC) due to the lack of information on mean aerodynamic particle diameters for these studies
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PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
2,4,6-TRIBROMOPHENOL
Weight-of-Evidence Descriptor
No data have been located on the carcinogenicity of 2,4,6-tribromophenol in humans or
animals. The available toxicity studies were conducted for very short durations and, as such, are
not useful for assessing potential carcinogenicity. Mutagenicity data in bacteria and yeast are
negative—although positive results have been obtained for chromosomal aberrations in Chinese
hamster lung cells. In accordance with Guidelines for Carcinogen Risk Assessment and
Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens
(U.S. EPA, 2005), there is"Inadequate Information to Assess [the] Carcinogenic Potential" of
2,4,6-tribromophenol in humans.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Documentation
of the threshold limit values for chemical substances. 7th Edition. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2009. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxprofiles/index.asp.
CalEPA (California Environmental Protection Agency). 2002. Hot Spots Unit Risk and Cancer
Potency Values. Online, http://www.oehha.ca.gov/air/hot spots/pdf/TSDlookup2002.pdf.
CalEPA (California Environmental Protection Agency). 2005a. OEHHA/ARB Approved
Chronic Reference Exposure Levels and Target Organs. Online.
http ://www. arb. ca. gov/toxics/healthval/chronic.pdf.
CalEPA (California Environmental Protection Agency). 2005b. Air Chronic Reference
Exposure Levels Adopted by OEHHA as of February 2005.
Dow Chemical Company. 1946. Preliminary tests on the toxicity of 2,4,6-tribromophenol.
TSCA 8D Submission OTS0522208.
Great Lakes Chemical Corporation. 2002. IUCLID Data Set for 2,4,6-Tribromophenol.
Submitted to U.S. EPA under the HPV Challenge Program. Online.
http://www.epa.gov/chemrtk/pubs/summaries/tribomop/cl4177rs.pdf.
IARC (International Agency for Research on Cancer). 2009. Search IARC Monographs.
Online. http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php.
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Industrial Biotest Laboratories, Inc. 1975. Report to Michigan Chemical Corporation.
Bioaccumulation study in fat tissue with 2,4,6-tribromophenol in albino rats. TSCA 8D
Submission 0TS0523301.
Industrial Biotest Laboratories, Inc. 1977. Report to Michigan Chemical Corporation. 21-Day
subacute dust inhalation toxicity study with 2,4,6-tribromophenol in albino rats. TSCA 8D
Submission OTS0523305; TSCA 8ECP Submission OTS0536719; TSCA 8E Submission
OTS0200291.
International Research and Development Corporation. 1974a. Acute oral toxicity (LD50) study
in albino rats. TSCA 8D Submission OTS0523299.
International Research and Development Corporation. 1974b. Acute inhalation toxicity in the
albino rat. TSCA 8D Submission OTS0523297.
International Research and Development Corporation. 1978a. Pilot teratogenicity study in rats.
TSCA 8D Submission OTS0523308.
International Research and Development Corporation. 1978b. Acute oral toxicity (LD50) study
in rats. TSCA 8E Submission OTS0200382; TSCA 8D Submission OTS0523310.
Levan, A. and J.H. Tjio. 1948. Induction of chromosome fragmentation by phenols. Hereditas.
34:453-484.
Litton Bionetics, Inc. 1978. Mutagenicity evaluation of 2,4,6-tribromophenol Lot #3287 in the
Ames Salmonella!microsome plate test. TSCA 8D Submission OTS0523309.
Lyubinov, A.V., V.V. Babin and A.I. Kartashov. 1998. Developmental neurotoxicity and
immunotoxicity of 2,4,6-tribromophenol in Wistar rats. Neurotoxicity. 19(2):303-312.
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to
Chemical Hazards. Online, http://www.cdc.gov/niosh/npg/.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. Online.
http://ntp.niehs.nih.gov/index.cfm?objectid=32BA9724-FlF6-975E-7FCE50709CB4C932.
NTP (National Toxicology Program). 2009. Management Status Report. Online.
http://ntp.niehs.nih.gov/?obi ectid=96A77AlC-123F-7908-7BA79AB04E206892.
OECD-SIDS. 2006. IUCLID Data Set. 2,4,6-Tribromophenol. Revised May 2003, Updated
January 2006, Printed February 2006.
OSHA (Occupational Safety and Health Administration). 2009. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
https://www.osha.gov/pls/oshaweb/owadisp.show docuinent?p table=STANDARDS&p id=999
2.
Tanaka, R., R. Yamada, K. Oba, et al. 1999. Combined repeat dose and
reproductive/developmental toxicity screening test of 2,4,6-tribromophenol by oral
administration in rats (Japanese) Toxicity testing reports of environmental chemicals no. 7.
Shizuoka, Japan: Ministry of Health & Welfare, Biosafety Research Centre.
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U.S. EPA. 1991a. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1991b. Alpha2u-Globulin: Association with chemically-induced renal toxicity and
neoplasia in the male rat. Risk Assessment Forum. Washington, D.C. EPA/625/3-91.019F.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
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],
EPA/630/R-00/001. Available at http://www.epa.gov/raf/publications/benchmark-dose-doc-
d raft, htm.
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment and Supplemental Guidance for
Assessing Susceptibility from Early-Life Exposure to Carcinogens. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/001F. Online.
http://www.epa.gov/raf/publications/pdfs/childrens supplement final.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. Online.
http://water.epa.gov/drink/standards/hascience.cfm.
U.S. EPA. 2009. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/iris/.
U.S. EPA. 2008. High Production Volume (HPV) Challenge Robust Summaries for
2,4,6-Tribromophenol. Online.
http ://www. epa. gov/chemrtk/pub s/summaries/tribomop/c 14177tc.htm.
Velsicol Chemical Corporation. 1977. Pharmacokinetic study of 2,4,6-tribromophenol in rats.
OTS0523314, 8D.
WHO (World Health Organization). 2005. Concise International Chemical Assessment
Document (CICAD) 66: 2,4,6-Tribromophenol and other simple brominated phenols. Published
under the joint sponsorship of the United Nations Environment Programme, the International
Labour Organization, and the World Health Organization, and produced within the framework of
the Inter-Organization Programme for the Sound Management of Chemicals. Online.
http://www.who.int/ipcs/publications/cicad/cicad 66 web version.pdf.
Zeigler, E., B. Anderson, S. Haworth 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. DERIVATION OF A CHRONIC SCREENING RfD
FOR 2,4,6-TRIBROMOPHEN OL
For reasons noted in the main PPRTV document, it is inappropriate to derive a chronic
p-RfD for 2,4,6-tribromophenol. However, information is available for this chemical, which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops
a"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Tanaka et al. (1999) observed that 300 mg/kg-day is a LOAEL for short-term oral
exposure on the basis of increased serum creatinine in male rats. The dose-related statistically
significant (p < 0.05) increase in creatinine in male rats (Tanaka et al., 1999) is the most sensitive
treatment-related endpoint in the database. The serum creatinine data are used as the basis for
benchmark dose (BMD) modeling. Table 4 of the main text summarizes the data set used in the
BMD modeling. Appendix B presents the results of the BMD model. A linear model with
modeled variance provided adequate fit to the data set and yields a BMDLisd of 92 mg/kg-day.
Applying a composite uncertainty factor (UF) of 10,000 to the BMDLisd of
92 mg/kg-day yields a chronic screening p-RfD for 2,4,6-tribromophenol as follows:
Chronic Screening p-RfD = BMDLisd Composite UF
= 92 mg/kg-day ^ 10,000
= 0.0092 mg/kg-day or 9 x 10 3 mg/kg-day
The Composite UF of 10,000 is composed of the following:
•	A full UF of 10 is applied for interspecies extrapolation to account for potential
pharmacokinetic and pharmacodynamic differences between rats and humans.
•	A UF of 10 is applied for intraspecies differences in order to account for
potentially susceptible individuals in the absence of information on the variability
of response in humans.
•	A UF of 10 is applied for extrapolation from sub chronic-to-chronic exposures in
order to account for additional effects that may be observed with longer exposure
periods.
•	A full UF of 10 is applied to account for database deficiencies. The toxicological
database for oral exposure to 2,4,6-tribromophenol is composed solely of two
studies conducted on only one species and lacks true subchronic, reproductive,
and developmental toxicity studies. Neither of the existing studies examined
fetuses for malformations.
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A UF for LOAEL-to-NOAEL extrapolation is not applied because BMD modeling was
used to identify the POD.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING FOR
CHRONIC SCREENING p-RfD
The data have been analyzed using all available models for continuous data in the BMD
dose software (BMDS) program (version 2.1) developed by the U.S. EPA (2000). Risk was
calculated as extra risk. For the continuous data, the original data were modeled with all the
continuous models available within the software with a default BMR of 1 SD. An adequate fit
was judged based on the goodness of fit p-walue (p > 0.1), scaled residual at the range of BMR,
and visual inspection of the model fit. In addition to the three criteria forjudging the adequate
model fit, whether the variance needed to be modeled, and if so, how it was modeled, also
determined final use of the model results. If a homogenous variance model was recommended
based on statistics (Test 2) provided from the BMD model runs, the final BMD results would be
estimated from a homogenous variance model. If the test for homogenous variance (Test 2) was
negative (i.e. ,p< 0. 1), the model was run again while applying the power model integrated into
the BMDS to account for nonhomogenous variance (known as nonhomogenous model). If the
nonhomogenous variance model did not provide an adequate fit to the variance data (Test 3:
p value <0.1), the data set would be considered unsuitable for BMD modeling. Among all the
models providing adequate data fit (goodness of fit p-w alue > 0.1), the lowest BMDL will be
selected if the BMDLs estimated from different models varies over a wide range (not quantified);
otherwise, the BMDL from the model with the lowest AIC would be considered appropriate for
the data set. Confidence bounds were automatically calculated by the BMDS using a maximum
likelihood profile method.
Results of Model Fitting for 2,4,6-Tribromophenol
BMD modeling was conducted for the increased incidence of serum creatinine in male
rats observed in the Tanaka et al. (1999) study. Table B-l shows the BMD modeling results for
the data set. As shown in Table B-l, the linear model with constant variance fit the means but
not the variance. Running the linear model with modeled variance provides adequate fit to both
the means and the variance and, therefore, is chosen as the basis for BMD derivation. Figure B-l
illustrates the best-fitting model. Complete model runs are appended.
Table B-l. Model Predictions for Increased Serum Creatinine in Male Rats
Model
Variance
/j-Value"
Means
/j-Value"
AIC
bmd1sd
(mg/kg-day)
BMDL1sd
(mg/kg-day)
All dose groups
Linear (constant variance)13
<0.0001
0.977
-141.006
NA
NA
Linear (modeled variance)0
0.8892
0.8339
-205.141
143.115
92.1898
aValues <0.10 fail to meet conventional goodness-of-fit criteria
bCoefficients restricted to be positive
Coefficients restricted to be positive
NA = not applicable; model does not fit the data adequately
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Linear Model with 0.95 Confidence Level
Linear
0.65
0.6
0.55
0.5
0.45
0.4
0.35
0.3
0.25
BMDL
BMP
200
0
400
600
800
1000
Dose
10:31 02/052008
Figure B-l. Fit of Linear Model with Nonhomogeneous (Modeled) Variance to Data on
Increased Serum Creatinine in Male Rats from Tanaka et al., 1999
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of mg/kg-day.
BMDL computation failed for one or more points on the curve, therefore, the BMDL curve is not plotted.
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BMD Model Runs for Tanaka et al. 1999
Serum Creatinine in Male SD Rats
Polynomial Model. (Version: 2.12; Date: 02/20/2007)
Input Data File: C:\BMDS\TANAKA99.(d)
Gnuplot Plotting File: C:\BMDS\TANAKA99.plt
Tue Feb 05 10:28:53 2008
BMDS MODEL RUN
The form of the response function is:
Y[dose] = beta_0 + beta_l-dose + beta_2-doseA2 +
Dependent variable = MEAN
Independent variable = dose
rho is set to 0
The polynomial coefficients are restricted to be positive
A constant variance model is fit
Total number of dose groups = 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
Default Initial Parameter Values
alpha =	0.01875
rho =	0 Specified
beta_0 = 0.273934
beta_l = 0.000195902
Asymptotic Correlation Matrix of Parameter Estimates
( """ The model parameter(s) -rho
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
alpha	beta_0	beta_l
alpha 1	-2.7e-011	3.8e-011
beta_0 -2.7e-011	1	-0.67
beta_l 3.8e-011	-0.67	1
Parameter Estimates
Confidence Interval
Vari able
Upper Conf. Limit
al pha
0.0240865
beta_0
0.323762
Estimate
0.0172037
0.273934
Std. Err.
0.00351169
0.0254227
95.0% Wald
Lower Conf. Limit
0.0103209
0.224107
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beta_l
0.000290919
0.000195902
4.84792e-005
0.000100884
Table of Data and Estimated Values of Interest
Dose
Res.
Obs Mean
Est Mean Obs Std Dev Est Std Dev Scaled
0
100
300
1000
12
12
12
12
0.27
0.3
0.33
0.47
0.274
0.294
0.333
0.47
0.03
0.04
0.07
0.26
0.131
0.131
0.131
0.131
-0.104
0.171
-0.0714
0.00433
Model Descriptions for likelihoods calculated
Model Al:
Model A2:
Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Yij =
Var{e(ij) }
Mu(i) + e(ij)
= Sigma(i)A2
Model A3:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model
Al
A2
A3
fi tted
R
Log(li keli hood)
73.525750
106.869482
73.525750
73.503155
66.475642
# Param'
5
8
5
3
2
AIC
-137.051499
-197.738964
-137.051499
-141.006311
-128.951283
Explanation of Tests
Test 1: Do responses and/or variances differ among Dose levels?
(A2 vs . R)
Test 2
Test 3
Test 4
Are Variances Homogeneous? (Al vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test -2-log(Likelihood Ratio) Test df	p-value
Test 1
Test 2
Test 3
Test 4
80.7877
66.6875
66.6875
0.0451889
6
3
3
2
<.0001
<.0001
<.0001
0.9777
The p-value for Test 1 is less than .05. There appears to be a
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difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. Consider running a
non-homogeneous variance model
The p-value for Test 3 is less than .1. You may want to consider a
different variance model
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMD =	669.534
BMDL =	464.636
Linear Model with 0.95 Confidence Level
0.65
0.6
0.55
CD
£ 0.5
o
§" 0.45
cd
| 0.4
0.35
0.3
0.25
0	200	400	600	800	1000
Dose
10:28 02/05 2008
l	Linear
BIVD Lower Bound
BIVDL
BIVD
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Polynomial Model. (Version: 2.12; Date: 02/20/2007)
Input Data File: C:\BMDS\TANAKA99.(d)
Gnuplot Plotting File: C:\BMDS\TANAKA99.plt
Tue Feb 05 10:31:17 2008
BMDS MODEL RUN
The form of the response function is:
Y[dose] = beta_0 + beta_l-dose + beta_2-doseA2 + ...
Dependent variable = MEAN
Independent variable = dose
The polynomial coefficients are restricted to be positive
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i))
Total number of dose groups = 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
- rho)
Default Initial Parameter Values
lalpha = -3.97656
rho =	0
beta_0 = 0.273934
beta_l = 0.000195902
Asymptotic Correlation Matrix of Parameter Estimates
1alpha
rho
beta_0
beta_l
1alpha
1
0.98
-0.0046
0.016
rho
0.98
1
-0.0034
0.014
beta_0
-0.0046
-0.0034
1
-0.49
beta_l
0.016
0.014
-0.49
1
Confidence Interval
Vari able
Upper Conf. Limit
1alpha
4.93273
rho
9.48954
beta_0
0.287028
beta_l
0.000303115
Estimate
2.85154
7.61417
0.272686
0.000206555
Parameter Estimates
Std. Err.
1.06185
0.95684
0.00731748
4.92665e-005
95.0% Wald
Lower Conf. Limit
0.770343
5.7388
0.258344
0.000109994
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Table of Data and Estimated Values of Interest
Dose
Res.
Obs Mean
Est Mean Obs Std Dev Est Std Dev Scaled
0
100
300
1000
12
12
12
12
0.27
0.3
0.33
0.47
0.273
0.293
0.335
0.479
0.03
0.04
0.07
0.26
0.0296
0.039
0.0645
0.253
-0.315
0.591
-0.25
-0.127
Model Descriptions for likelihoods calculated
Model Al:
Model A2:
Model A3:
Yij =
Var{e(ij) }
Mu(i) + e(ij)
= SigmaA2
Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)A2
Yij,
Mu(i) + e(ij)
Var{e(ij)} = exp(lalpha + rho-1n(Mu(i)))
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model
Al
A2
A3
fi tted
R
Log(li keli hood)
73.525750
106.869482
106.752006
106.570308
66.475642
#
Param
5
8
6
4
2
AIC
-137.051499
-197.738964
-201.504012
-205.140616
-128.951283
Explanation of Tests
Test 1: Do responses and/or variances differ among Dose levels?
(A2 vs . R)
Test 2
Test 3
Test 4
Are Variances Homogeneous? (Al vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test -2-log(Likelihood Ratio) Test df
Test
Test
Test
Test
1
2
3
4
80.7877
66.6875
0.234952
0.363396
6
3
2
2
p-value
<.0001
<.0001
0.8892
0.8339
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. A non-homogeneous variance
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model appears to be appropriate
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =
Risk Type
Confidence level =
Estimated standard deviations from the control mean
0.95
1
BMD
143.115
BMDL
92.1898
BMDL computation failed for one or more point on the BMDL curve.
The BMDL curve will not be plotted
31

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