United States
Environmental Protection
1=1 m m Agency
EPA/690/R-13/021F
Final
8-28-2013
Provisional Peer-Reviewed Toxicity Values for
Trinitrophenylmethylnitramine
(CASRN 479-45-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
John C. Lipscomb, PhD, DABT, Fellow ATS
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
Audrey Galizia, DrPH
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	ii
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	7
Oral Exposures	7
Inhalation Exposures	7
ANIMAL STUDIES	7
Oral Exposures	7
Inhalation Exposures	13
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	13
Tests Evaluating Genotoxicity and/or Mutagenicity	17
DERIVATION 01 PROVISIONAL VALUES	18
DERIVATION OF ORAL REFERENCE DOSES	19
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	19
Derivation of Chronic Provisional RfD (Chronic p-RfD)	22
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	23
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)	24
Derivation of Chronic Provisional RfC (Chronic p-RfC)	24
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	24
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	24
Derivation of Provisional Oral Slope Factor (p-OSF)	24
Derivation of Provisional Inhalation Unit Risk (p-IUR)	24
APPENDIX A. PROVISIONAL SCREENING VALUES	25
APPENDIX B. DATA TABLES	26
APPENDIX C. BMD OUTPUTS	30
APPENDIX D. REFERENCES	34
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower confidence limit
BMD
benchmark dose
BMDL
benchmark dose lower confidence limit
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
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
interspecies uncertainty factor
UFC
composite uncertainty factor
UFd
database uncertainty factor
UFh
intraspecies uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
TRINITROPHENYLMETHYLNITRAMINE (CASRN 479-45-8)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Trinitrophenylmethylnitramine (also known as tetryl) has many synonyms, including:
aniline, A-methyl-A,2,4,6-tetranitro-; benzeneamine, A-methyl-A,2,4,6-tetranitro-; CE;
A-methyl-A-2,4,6-tetranitrobenzeneamine; nitramine; picrylmethylnitramine; A-picryl-
A-m ethyl nitramine; picrylnitromethylamine; tetralit; tetralite; tetril; A-m ethyl-
A',2,4,6-tetranitroaniline; 2,4,6-tetryl; 2,4,6-trinitrophenyl-//-methylnitramine;
2,4,6-trinitrophenylmethylnitramine; A-2,4,6-tetranitro-A-methyl aniline; and
methylpicrylnitramine (HSDB, 2005) (see Figure 1). Tetryl was formerly used as a military
explosive, but is no longer used or manufactured in the United States (ATSDR, 1995). It is
explosive when exposed to heat or flame (ATSDR, 1995; IPCS, 1997). Table 1 provides a list of
tetryl's physicochemical properties.
0"
c-.
CH.
0"
N —
0 —
0"	0
Figure 1. Trinitrophenylmethylnitramine Structure
Table 1. Physicochemical Properties of Trinitrophenylmethylnitramine
(CASRN 479-45-8)a
Property (unit)
Value
Boiling point (°C)
187
Melting point (°C)
130-132
Density (g/cm3) (at 19°C)
1.57
Vapor pressure (Pa at 25°C)
1.2 x l0-7b
pH (unitless)
ND
Solubility in fresh water (mg/L at 20°C)
Solubility in salt water (mg/L at 25°C)
75
26
Relative vapor density (air = 1)
ND
Molecular weight (g/mol)
287.14
aValues from ATSDR (1995) and HSDB (2005).
bEstimated value—model not provided.
ND = no data.
A summary of available toxicity values for trinitrophenylmethylnitramine from U.S. EPA
and other agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Trinitrophenylmethylnitramine
(CASRN 479-45-8)
Source/Parameter"
Value
(Applicability)
Notes
Reference
Date
Accessed
Noncancer
ACGIH
8-hr TLV-TWA:
1.5 mg/m3
TLV-TWA based on upper
respiratory tract irritation
ACGIH (2013)
NA
ATSDR
NV
Developed a toxicological profile
for tetryl but did not recommend
any minimal risk level values for
oral or inhalation exposure
ATSDR (1995)
NA
Cal/EPA
NV
NA
Cal/EPA (2012)b
8-13-2013b
NIOSH
REL-TWA:
1.5 mg/m3
IDLH: 750 mg/m3
Skin designation
NIOSH (2010)
NA
OSHA
8-hr PEL-TWA:
1.5 mg/m3
Skin designation
OSHA (2006,
2011)
NA
IRIS
NV
NA
U.S. EPA
8-13-2013
Drinking Water
Standards and Health
Advisories List
NV
NA
U.S. EPA (2011a)
NA
HEAST
Subchronic RfD:
0.1 mg/kg-d
Chronic RfD:
0.01 mg/kg-d
Based on a LOAEL of 125 mg/kg-d
for liver, kidney, and spleen lesions
(in rabbits) over 9-month period
U.S. EPA (2003)
1-5-2011
NV
NA
U.S. EPA (2011b)
NA
CARA HEEP
NV
NA
U.S. EPA (1994)
NA
WHO
NV
NA
WHO
8-13-2013
Cancer
ACGIH
NV
NA
ACGIH (2013)
NA
IRIS
NV
NA
U.S. EPA
8-13-2013
HEAST
NV
NA
U.S. EPA (2011b)
NA
IARC
NV
NA
IARC (2013)
NA
NTP
NV
NA
NTP (2011)
NA
Cal/EPA
NV
NA
Cal/EPA (2009)
NA
aSources: Integrated Risk Information System (IRIS) database; Health Effects Assessment Summary Tables
(HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP); California
Environmental Protection Agency (Cal/EPA); American Conference of Governmental Industrial Hygienists
(ACGIH); Agency for Toxic Substances and Disease Registry (ATSDR); National Institute for Occupational Safety
and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical Assessments and Related
Activities (CARA) list; Health and Environmental Effects Profile (HEEP); World Health Organization (WHO).
IDLH= immediately dangerous to life or health; NA = not applicable; NV = not available; PEL-TWA = permissible
exposure level-time weighted average; REL-TWA = recommended exposure level-time weighted average;
TLV-TWA = threshold limit value-time weighted average.
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Literature searches were conducted on sources published from 1900 through
August 2013, for studies relevant to the derivation of provisional toxicity values for tetryl,
CASRN 479-45-8. The following databases were searched by chemical name, synonyms
(trinitrophenylmethylnitramine; aniline, A-methyl-A',2,4,6-tetranitro-; benzeneamine; A'-m ethyl-
A',2,4,6-tetranitro; CE; A'-m ethyl-A'-2,4,6-tetranitrobenzeneamine; nitramine;
picrylmethylnitramine; A'-picryl-A'-m ethyl nitramine; picrylnitromethylamine; tetralit; tetralite;
tetril; /l/-methyl-A',2,4,6-tetranitroaniline; 2,4,6-tetryl; 2,4,6-trinitrophenyl-//-methylnitramine;
2,4,6-trinitrophenylmethylnitramine; A'-2,4,6-tetranitro-A'-methylaniline; and
methylpicrylnitramine), or CASRN: ACGIH, ANEUPL, AT SDR, BIOSIS, Cal/EPA, CCRIS,
CD AT, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HERO, HMTC, HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID,
LactMed, NIOSH, NTIS, NTP, OSHA, OPP/RED, PESTAB, PPBIB, PPRTV, PubMed
(toxicology subset), RISKLINE, RTECS, TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST,
U.S. EPA HEEP, U.S. EPA OW, and U.S. EPA TSCATS/TSCATS2. The following databases
were searched for toxicity values or exposure limits: ACGIH, ATSDR, Cal/EPA, U.S. EPA
IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2,
NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 3 provides an overview of the relevant database for tetryl and includes all
potentially relevant repeated short-term, subchronic-, and chronic-duration studies. Principal
studies are identified. The phrase "statistical significance" as used throughout the document
indicates ap-value of <0.05.
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Table 3. Summary of Potentially Relevant Data for Trinitrophenylmethylnitramine (CASRN 479-45-8)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry"
Critical effects
NOAELa
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Human
None
Animal
1. Oral (mg/kg-d)a
Short-Term
5/5, F344 rat, diet, 14 d
0,31.8, 80, 121,
170.5, 349.7
(M); 0, 32.1,
82.5, 130.3,
178.9, 374.4 (F)
Increased methemoglobin at
121 mg/kg-d (M) and increased
reticulocytes and total bilirubin at
130 mg/kg-d (F).
80.0 (M)
DU
121.0 (M)
Reddy et al. (1994a,
1999)
PR (1999)
4, rat (sex, strain not
reported), gavage, d/wk not
reported, once or daily until
death
0; 1,000; 2,000
Rats died within 10 to 18 d at
1,000 mg/kg-d; effects on the liver,
kidney, and spleen at
2,000 mg/kg-d.
NDr
DU
NDr
Parmeggiani et al.
(1956, as cited in
ATSDR, 1995)
PR
4, rat (sex, strain not
reported), gavage, d/wk not
reported, 15 d
0, 250
Kidney lesions at 250 mg/kg-d
NDr
DU
250
Subchronic
15/15, F344, rat, diet, 90 d
0,13.0, 62.4,
179.6 (M);
0,14.2, 68.8,
199.0 (F)
Erythrocyte effects including
decreased hemoglobin, decreased
hematocrit, increased
reticulocyte count and increased
methemoglobin. Methemoglobin
chosen as critical effect:
significantly increased at mid and
high dose in males and females at
90 d.
NDr
25.5 (M),
31.1 (F)

Reddy et al.
(1994b, 1999)
PR, PS
20/0, rabbit, gavage, d/wk
not reported, 3 mo
25
Death in 18/20 rabbits; lung, liver,
kidney, spleen congestion
NDr
DU
NDr
Guarino and
Zambrano (1957, as
cited in ATSDR,
1995)
PR, no control
group
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Table 3. Summary of Potentially Relevant Data for Trinitrophenylmethylnitramine (CASRN 479-45-8)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry"
Critical effects
NOAEL3
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Subchronic
12, sex not reported, rabbit,
gavage, d/wk not reported,
120 days
0, 125
Decreased blood coagulability
NDr
DU
125
Daniele (1964, as
cited in ATSDR,
1995)
PR, study only
evaluated
blood
coagulability
12/0, rabbit, gavage, d/wk
not reported, 6-9 mo
(3 rabbits—6 mo;
9 rabbits—9 mo)
125
Effects on the liver, kidney, and
spleen
NDr
DU
NDr
Fati and Daniele
(1965, as cited in
ATSDR, 1995)
PR, no control
group
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
0/20, rat, gavage, every 3 d
for 30 d
0, 196
Stomach adenomas and mammary
hyperplasia in one rat from each
group (not statistically significant)
NDr
DU
NDr
Griswold et al.
(1968)
PR
2. Inhalation (mg/m3)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent dose
(HED in mg/kg-d) for oral carcinogenic effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous (weekly) exposure.
Values from animal developmental studies are not adjusted to a continuous exposure. Values for inhalation (cancer and noncancer), and oral (cancer only) are further
converted to an HEC/D. Values from animal developmental studies are not adjusted to a continuous exposure.
HED = avg. mg test article ^ avg. kg body weight ^ Number daily doses.
bNotes: IRIS = Utilized by IRIS, date of last update; PS = principal study, PR = peer reviewed, NPR = not peer reviewed.
DU = data unsuitable, NV = not available, ND = no data, NDr = not determinable, NI = not identified, NP = not provided, NR = not reported, NR/Dr = not reported but
determined from data, NS = not selected.
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HUMAN STUDIES
Oral Exposures
No studies investigating the effects of oral exposure to tetryl in humans have been
identified.
Inhalation Exposures
The effects of inhalation exposure of humans to tetryl are limited to case studies and
reports of workers exposed in occupational settings. According to numerous secondary sources
(HSDB, 2005; ATSDR, 1995; Talmage, 1999) and primary sources (Troup, 1946; Hardy and
Maloof, 1950; Bergman, 1952; Goh, 1984), these studies are lacking adequate quantitative
exposure estimates and consist of both inhalation and dermal exposures. During occupational
exposure to tetryl, workers are most commonly exposed to dusts via inhalation and direct skin
contact (Bergman, 1952; Goh, 1984; Hardy and Maloof, 1950; Troup, 1946). Dermal and ocular
irritation and dermal sensitization are the most common effects reported from tetryl exposure.
Tetryl also reacts with amino acids (Brownlie and Cumming, 1946) glutathione and hemoglobin
(Maroziene et al., 2001). In several case reports, workers developed rashes on the face, neck,
shoulders, forearms, and hands (Bergman, 1952; Goh, 1984; Hardy and Maloof, 1950; Troup,
1946). Swelling of the lips and hands were noted in one case (Goh, 1984), and discoloration of
the skin and hair in other cases (Goh, 1984; Bergman, 1952; Troup, 1946). A popular eruption
accompanied by gross edema and exfoliation have been noted (Hilton and Swanson, 1941;
Smith, 1916). In a case study of 1,258 workers exposed to tetryl, 944 workers (75%)
experienced dermatitis (Witkowski et al., 1942, as cited in Myers and Spinnato, 2007b). Yellow
staining on the hands, face, neck, and hair was also reported in workers exposed to tetryl (Hilton
and Swantson, 1941, as cited in Myers and Spinnato, 2007b). Respiratory effects including
asthma, tracheitis, burning and itching of the respiratory tract, sneezing, and inflammation of the
mucous membranes were reported due to inhalation exposure (Troup, 1946; Bergman, 1952). In
addition, clinical signs of toxicity were noted to the hematopoietic system including anemia,
malformed and variably sized red blood cells, decreased hemoglobin concentration, leukocytosis,
and leukopenia (Ruxton, 1917; Brabham., 1943; Probst et al., 1944; Hardy and Maloof, 1950).
Other reports of toxicity included menstrual changes, irritability, headache, general malaise,
lassitude, and sleeplessness (Hardy and Maloof, 1950; Bergman, 1952). As noted above, the
available studies did not report estimated exposure concentrations, and several cases involved
coexposure to multiple chemicals. Thus, these studies are not considered appropriate for
deriving a provisional inhalation reference concentration for tetryl.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to tetryl have been evaluated in two short-term
studies (Reddy et al., 1994a, 1999; Parmeggiani et al., 1956, as cited in ATSDR, 1995); four
subchronic-duration studies (Reddy et al., 1994b, 1999; Guarino and Zambrano, 1957, as cited in
ATSDR, 1995; Daniele, 1964, as cited in ATSDR, 1995; Fati and Daniele, 1965, as cited in
ATSDR, 1995), and one carcinogenicity study (a short-term screening assay of 30 days)
(Griswold et al., 1968).
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Short-Term Studies
Reddy et al., 1994a, 1999
Reddy et al. (1999) conducted a published peer-reviewed short-term toxicity study in rats.
Groups of 5 male and 5 female F344 rats were fed 0; 500; 1,250; 2,000; 2,500; or 5,000 ppm
tetryl (99.45% purity) in the diet for 14 days (Reddy et al., 1994a, 1999). These doses were
calculated by the study authors to be equivalent to 0, 31.8, 80.0 121.0, 170.5, and
349.7 mg/kg-day for males and 0, 32.1, 82.5, 130.3, 178.9, and 374.4 mg/kg-day for females.
The results of this study were originally compiled in an unpublished report by Reddy et al.
(1994a). All rats were observed daily for clinical signs, behavioral responses, and for mortality
and morbidity. Animals were weighed on days 0, 7, and 14, and food and water consumption
were measured twice weekly. Blood samples were collected at sacrifice and the following
hematology endpoints were measured: red and white blood cell counts, differential leukocyte
count, packed cell volume, platelet count, hemoglobin, and methemoglobin. Clinical chemistry
endpoints included sodium, potassium, total protein, albumin, calcium, phosphorus, total
bilirubin, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase,
glucose, alkaline phosphatase, triglycerides, and cholesterol. Organs weights were determined
for spleen, kidneys, testes with epididymides, brain, liver, adrenals, lungs, thymus, ovaries, and
heart, and various other tissues (unspecified) were also examined. Histopathology was
performed on all tissues and organs in the control and high dose animals; and on spleen, kidney,
and testes in all dose groups. Histopathology was examined by a certified pathologist and
inflammatory and degenerative lesions were graded according to a scale of 1 to 4 (minimal, mild,
moderate, or marked). Statistical evaluations were performed using ANOVA, F-test (p < 0.05)
and Dunnett's test.
No mortality, clinical signs of toxicity, or reduced food or water consumption were
observed (Reddy et al., 1994a, 1999). In males, a statistically significant decrease in body
weights and a statistically significant increase in relative kidney weights were reported at
349.7 mg/kg-day. In females, statistically significant increases in relative liver weights at 178.9
and 374.4 mg/kg-day, and increases in spleen weights were reported at 374.4 mg/kg-day. No
other significant changes in organ weights were noted. Analysis of hematological parameters in
males showed a statistically significant increase in reticulocytes at 121.0 mg/kg-day and in
methemoglobin at 121.0, 170.5, and 349.7 mg/kg-day. In females, a statistically significant
decrease in hemoglobin at 178.9 and 374.4 mg/kg-day, a decrease in hematocrit at
130.3 mg/kg-day, an increase in reticulocytes at 130.3 and 178.9 mg/kg-day, and an increase in
methemoglobin at 374.4 mg/kg-day were reported. Clinical chemistry results in males consisted
of statistically significant increases in total protein at 31.8, 80.0, 121.0, and 349.7 mg/kg-day,
increases in albumin at all doses, increases in calcium at 31.8 and 80.0 mg/kg-day, decreases in
alkaline phosphatase at 80.0, 121.0, 170.5, and 349.7 mg/kg-day, and increases in glucose at
170.5 mg/kg-day. In females, statistically significant increases in total protein and albumin were
observed at 82.5, 130.3, 178.9, and 374.4 mg/kg-day, increases in total bilirubin at 130.3, 178.9,
and 374.4 mg/kg-day, and decreases in sodium at 374.4 mg/kg-day. Histopathological analysis
of the tissues revealed an increased incidence of cytoplasmic droplets in the proximal renal
cortical tubular epithelial cells of male rats at doses of 80 mg/kg-day and higher. A LOAEL of
121.0 mg/kg-day is identified for this study based on increased methemoglobin in males. The
NOAEL is 80.0 mg/kg-day.
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Parmeggiani et al., 1956, as cited in ATSDR, 1995
Parmeggiani et al. (1956, as cited in ATSDR, 1995; in Italian) administered a single dose
of 1,000 or 2,000 mg/kg tetryl to groups of four rats, daily doses of 1,000 or 2,000 mg/kg-day to
groups of four rats until death, or daily doses of 250 mg/kg to a group of four rats for 15 days.
Groups of four rats were used as controls. The strain and sex of the rats were not reported.
According to ATSDR (1995), exposure was via gavage. No adverse effects were noted in the
rats administered a single dose of 1,000 mg/kg. The rats administered a single dose of
2,000 mg/kg showed effects on the liver, renal tubular epithelia swelling, and hemosiderosis and
atrophy of the spleen. Animals administered daily doses of 1,000 or 2,000 mg/kg died within 10
to 18 days. Weight loss, dyspnea, rough coat, and yellow pigmentation in the tail, ears and nose,
and limb paralysis and convulsions were observed in these rats. Histopathological examination
of the liver revealed changes in the hepatocytes and activation of Kupffer cells, and examination
of the kidney revealed swollen tubular epithelium, cytoplasmic changes, and nuclear pyknosis.
Moderate spleen hemosiderosis with lymphatic follicle atrophy was observed in rats at
2,000 mg/kg-day. The lower dose of 250 mg/kg-day also produced degenerative kidney lesions,
and may be considered a 15-day LOAEL.
Reddy et al., 1997
Reddy et al. (1997) administered tetryl by gavage in corn oil at 0; 500; or 1,000 mg/kg to
male F344 rats. After 24 hours, changes in enzymes, hematology, and histopathology were
studied. Ethoxy and pentoxy O-dealkylase activities showed a significant decrease at both doses,
and there was an increase in methemoglobin and a decrease in lymphocyte counts at both doses,
and an increase in glucose and serum urea nitrogen at 1,000 mg/kg only. Glycogen accumulated
in the livers and focal coagulative necrosis of the gastric mucosa was noted at both doses.
Wells et al. 1920, as cited in ATSDR, 1995
Wells et al. (1920, as cited in ATSDR, 1995) reported that 1 to 3 daily oral doses of tetryl
at 1,000 mg/kg by gavage in milk were lethal to rabbits. No information was reported on the
number, sex, or species of rabbits. Swelling and degeneration of the epithelium of the kidneys,
edema of the lungs and bronchi, and accumulation of hematic pigment in the spleen were
reported. No effects on the liver were observed. In another study by Wells et al. (1920, as cited
in Myers and Spinnato, 2007b), dogs were administered 100 mg/kg-day tetryl subcutaneously.
Hepatic lesions consisting of necrosis and fatty degeneration and kidney effects consisting of
swelling of the tubular epithelium, fatty deposits, necrosis, and albuminuria were reported.
Subchronic Studies
Reddy et al., 1994b, 1999
Reddy et al. (1994b, 1999) is considered the principal study for derivation of the
provisional subchronic and chronic p-RfDs. In a Good Laboratory Practice (GLP)-compliant
peer-reviewed, published study, groups of 15 male and 15 female F344 rats were fed 0; 200;
1,000; or 3,000 ppm tetryl (99.45% purity) in the diet for 90 days (Reddy et al., 1999). These
doses were calculated by the study authors to be equivalent to 0, 13.0, 62.4, and 179.6 mg/kg-day
for males and 0, 14.2, 68.8, and 199.0 mg/kg-day for females. Many of the results from
Reddy et al. (1999) were originally presented in an unpublished report by Reddy et al. (1994b).
The animals were housed in temperature (20-22°C) and humidity (40-60%) controlled
rooms on a 12:12 hour light:dark cycle and were housed individually in polycarbonate cages and
food and water were provided ad libitum. Five rats per group were killed on Day 45 and their
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hematology and clinical chemistry endpoints were measured, and 10 rats per group were
sacrificed at the end of the study (Day 90). Rats were observed daily for clinical signs and for
morbidity and mortality. Food and water consumption were measured twice weekly. Blood
samples were collected at Day 45 and Day 90. Hematology endpoints included red and white
blood cell counts, differential leukocyte count, packed cell volume, platelet count, hemoglobin,
and methemoglobin. Clinical chemistry endpoints included sodium, potassium, total protein,
albumin, calcium, phosphorus, total bilirubin, blood urea nitrogen, creatinine, alanine
aminotransferase, aspartate aminotransferase, glucose, alkaline phosphatase, triglycerides, and
cholesterol. Body weight was recorded, as were weights for brain, liver, spleen, kidneys,
adrenals, lungs, thymus, testes with epididymides, ovaries, and heart, as well as various other
unspecified organs. Histopathology was performed by a certified pathologist on all tissues and
organs in the control and high dose animals; histopathology of the spleen, kidneys, and testes
were carried out in all animals. Inflammatory and degenerative lesions were graded according to
a scale of 1 to 4 (minimal, mild, moderate, or marked). All animals were also examined for
ophthalmologic changes. Statistical evaluations were done using ANOVA, F-test (p < 0.05) and
Dunnett's test.
No deaths or clinical signs of toxicity were observed in the rats (Reddy et al., 1994b,
1999). Statistically significant decreases in food consumption were observed at all dose levels in
both males and females, and a statistically significant increase in water consumption was noted
only in the 199.0 mg/kg-day females. At the end of Week 6 (42 days), no significant changes
were noted in body weights in males and a significant decrease was noted in the
199.0 mg/kg-day females. At the end of the study, statistically significant decreases in body
weight were observed in the 179.6 mg/kg-day males and in the 68.8 and 199.0 mg/kg-day
females (see Tables B.l and B.2).
Relative organ weight changes after 90 days are shown in Tables B. 1 and B.2. Organ
weight changes were not evaluated at 45 days. The only statistically significant change in organ
weight at the lowest dose was an increase in relative kidney weights at 14.2 mg/kg-day in
females (5.4%); however, this change is not considered biologically significant because it is
<10%. Statistically significant increases were observed in relative liver weights of males at 62.4
and 179.6 mg/kg-day (10.4% and 28.3%, respectively) and of females at 68.8 and
199.0 mg/kg-day (10.1% and 21.4%, respectively). Statistically significant increases were also
observed in relative kidney weights of males at 62.4 and 179.6 mg/kg-day (12.5% and 19.4%,
respectively) and of females at 68.8 and 199.0 mg/kg-day (5.4% and 17.8%, respectively).
Absolute changes in organ weights (as presented in Reddy et al., 1994b) were as follows:
statistically significant increases in spleen weights in males at 179.6 mg/kg-day, statistically
significant decreases in brain weights in males at 179.6 mg/kg-day and in females at 68.8 and
199.0 mg/kg-day, statistically significant decreases in adrenal weights in females at
68.8 mg/kg-day, and statistically significant decreases in adrenal and thymus weights in males at
179.6 mg/kg-day and in females at 199.0 mg/kg-day. No changes were noted in absolute kidney
weights of either males or females at any dose and absolute liver weights were increased in
males at 179.6 mg/kg-day and in females at 199.0 mg/kg-day.
A number of effects of tetryl on hematological parameters were noted after 45 and
90 days in males (see Tables B.3 and B.4). These data demonstrate a pattern of dose-dependent
changes indicative of methemoglobinemia and hemolytic anemia including decreased
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hemoglobin and hematocrit and increased reticulocyte content. Similar effects were observed
after 45 days in females, however, increases in methemoglobin were observed at 45 days in
females at all doses and at 90 days at 68.8 and 199.0 mg/kg-day only.
Effects of tetryl on clinical chemistry parameters were noted after 45 and 90 days (see
Tables B.5 and B.6). After 90 days in males, statistically significant changes consisted of:
increases in blood urea nitrogen (BUN) at 62.4 mg/kg-day, decreases in alkaline phosphatase at
13.0, 62.4, and 179.6 mg/kg-day, increases in albumin and calcium at 62.4 and 179.6 mg/kg-day,
increases in cholesterol and total bilirubin at 13.0, 62.4, and 179.6 mg/kg-day, and increases in
total protein at 62.4 and 179.6 mg/kg-day. After 45 days in males, some of the same effects were
observed (increases in albumin, calcium, and total protein). However, at 45 days (and not at
90 days), a significant increase in potassium was noted in males at 179.6 mg/kg-day. After
90 days in females, statistically significant changes were as follows: increases in glucose at
68.8 mg/kg-day, decreases in alkaline phosphatase at 199.0 mg/kg-day, increases in aspartate
aminotransferase (AST) at 14.2 mg/kg-day, increases in albumin at 14.2, 68.8, and
199.0 mg/kg-day, decreases in triglycerides at 199.0 mg/kg-day, increases in cholesterol at 14.2,
68.8, and 199.0 mg/kg-day, increases in total bilirubin at 14.2 and 199.0 mg/kg-day, and
increases in total protein at 68.8 and 199.0 mg/kg-day. The only significant effect that was also
observed at 45 days in females was an increase in total bilirubin (which occurred at
199.0 mg/kg-day only). Increased creatinine was noted at 45 days (and not at 90 days) in
females at 68.8 and 199.0 mg/kg-day. According to the study authors, all other clinical
chemistry parameters were within normal limits (Reddy et al., 1999).
Histopathology at 90 days revealed that the spleens of both males and females were
characterized by prominent deposition of intra- and extracellular pigment (which was
characterized by the study authors as "probable hemosiderin") at 179.6 mg/kg-day in males and
199.0 mg/kg-day in females. At 179.6 mg/kg-day, males also exhibited excessive erythroid cell
hyperplasia. In the kidneys, pigment deposition was noted in the renal cortical epithelium at 62.4
and 179.6 mg/kg-day in males and 68.8 and 199.0 mg/kg-day in females. In males, a
dose-related increase in the severity of tubular degeneration and regeneration, hyaline casts, and
cytoplasmic droplets in proximal cortical tubular epithelial cells was noted. Cytoplasmic
droplets were observed in male rats at doses of 62.4 and 179.6 mg/kg-day. The study authors
reported that the immunohistochemical staining properties of the droplets were consistent with
alpha-2-u-globulin and were observed by the study authors to be morphologically similar to the
droplets observed in the 14-day (Reddy et al., 1994a, 1999) study, except for a diminished
intensity of eosinophilic staining.
The study authors did not consider the changes in the clinical chemistry parameters at
13.0 mg/kg-day in males (decreases in alkaline phosphatase, increases in cholesterol and total
bilirubin) or 14.2 mg/kg-day in females (increases in albumin, cholesterol, and bilirubin) to be
biologically relevant because the values were within an accepted normal reference range
(Reddy et al., 1994b, 1999). The deposition of cytoplasmic droplets in the kidneys at 62.4 and
179.6 mg/kg-day in males and 68.8 and 199.0 mg/kg-day in females was not considered by the
study authors to be significantly detrimental to the kidney since they cleared with time.
However, the increased relative liver weights at 62.4 and 179.6 mg/kg-day in males and 68.8 and
199.0 mg/kg-day in females, the decrease in alkaline phosphatase in all dose groups in males and
at 199.0 mg/kg-day in females, the increase in serum cholesterol in all dose groups in males and
females, and the increase in total bilirubin in all dose groups in males and in the 14.2 and
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199.0 mg/kg-day dose groups in females represent sensitive markers of liver damage. The
increase in methemoglobin at 14.2 mg/kg-day in females at 45 days is also indicative of toxicity
in the context of the other adverse hematological effects seen at the higher doses and after the
longer 90-day duration. Since the effects seen at the low dose would not be considered adverse
without additional supporting evidence of blood and liver effects at the two higher doses, the
lowest doses of 13.0 mg/kg-day in males and 14.2 mg/kg-day in females are considered to be
"minimal" LOAELs, based on elevated serum total bilirubin and cholesterol in males and
females and increased serum methemoglobin in females and decreased alkaline phosphatase in
males. A NOAEL cannot be identified since the LOAEL was the lowest dose tested.
Guarino and Zambrano, 1957, as cited in ATSDR, 1995
Guarino and Zambrano (1957, as cited in ATSDR, 1995; in Italian) administered tetryl by
gavage at 25 mg/kg-day to 20 male rabbits for up to 3 months. No controls were used and no
information was provided regarding the strain of the rabbits or dosing regimen sufficient to
perform a duration adjustment. The mean survival time of the rabbits was 2 months, with
25 mg/kg-day lethal to 18 out of 20 rabbits. No information was provided regarding the cause of
death. Gross and microscopic signs of lung congestion were observed. Congestion and
yellowish color in the liver were noted and microscopic examination revealed epithelial swelling,
fatty infiltration, and necrotic foci. The kidneys were visibly congested, with lesions to the
parenchymal tissue and swelling and vacuolar degeneration of the convoluted tubules. The
spleens were also congested, with free erythrocytes in the splenic sinuses. A NOAEL or LOAEL
is not identified from this study since only one dose was administered, with no control group.
Daniele, 1964, as cited in ATSDR, 1995
A study of blood coagulability in rabbits administered tetryl by gavage at 0 (n = 3) and
125 mg/kg-day (n = 12) for 120 days was reported by Daniele (1964, as cited in ATSDR, 1995;
in Italian). No information was given to inform a duration adjustment. Blood coagulability was
evaluated through the measurement of several components of the coagulation pathway (e.g.,
platelets). Although the study authors do report some significant differences between treated and
control animals, experimental variability and the small number of animals tested make
interpretation difficult.
Fati and Daniele, 1965, as cited in ATSDR, 1995
Fati and Daniele (1965, as cited in ATSDR, 1995) administered tetryl by gavage at
125 mg/kg-day to 12 male rabbits for 6-9 months. Effects on the liver noted in the rabbits
exposed for 6 months consisted of hepatocyte changes, characterized by swelling, vacuolization,
cytoplasmic opacity and slight granularity, and focal inflammation without necrosis. In the
animals exposed for 9 months, additional hepatocyte changes, consisting of diffuse turbid
swelling, highly granular cytoplasm, polymorphic nuclei, and hyperchromia and pyknosis,
parenchymal necrosis, Kupffer cell hyperplasia, and vascular congestion were observed. No
effects on the kidneys were observed in rabbits exposed for 6 months. In rabbits exposed for
9 months, mild renal congestion was observed, and microscopic examination of the kidneys
found turbid swelling, vacuolar degeneration, narrowed and poorly distinguishable tubular
lumen, and cellular hypertrophy. This study provides suggestive evidence that the liver, kidney,
and spleen are target organs of tetryl toxicity in rabbits following subchronic oral exposure.
However, neither a NOAEL nor a LOAEL can be identified from this study since no control
group was employed.
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Chronic Studies
No chronic-duration studies on oral exposure to tetryl have been identified.
Developmental Studies
No developmental studies on oral exposure to tetryl have been identified.
Reproductive Studies
No reproductive studies on oral exposure to tetryl have been identified.
Carcinogenicity Studies
Griswold et al., 1968
Griswold et al. (1968) is a short-term screening assay in which groups of 20 female
Sprague-Dawley rats were administered 0 or 40 mg tetryl by gavage in sesame oil every 3 days
for 30 days (equivalent to 196 mg/kg per dose; duration adjusted to 65 mg/kg-day). Treatment
began when the rats were 40 days of age and the rats were weighed and inspected weekly for
tumors. The rats were killed after 9 months of observation but it was unclear whether the 30-day
dosing period was included in this time period. Histopathology of the mammary tissue, ovaries,
liver, intestinal tract, pituitary, and adrenal glands was performed. Adenoma of the stomach and
mammary hyperplasia were seen in one animal from each group, but these results were not
biologically or statistically significant.
Inhalation Exposures
Gell, 1944, as cited inATSDR, 1995
A single short-term study of the effects of exposure to tetryl smoke was reported by
Gell et al. (1944). In this study, 8 guinea pigs were exposed to a smoke of tetryl particles
30 minutes per day for 6 days (Gell, 1944, as cited in ATSDR, 1995). According to ATSDR
(1995), the tetryl particle smoke was generated by blowing air over a 10% solution of tetryl in
acetone. The study authors estimated the tetryl concentration in the chamber to be about
-3
400 mg/m and total absorption to be about 7-10 mg per animal. The guinea pigs were then
exposed intravenously to picryl protein antigens prepared from the sera of rabbits exposed to
analogs or metabolites of tetryl. One of these animals died and 6 out of 8 developed
anaphylactic sensitivity.
No other studies investigating the effects of inhalation exposure to tetryl in animals have
been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Maroziene et al. (2001) report the results of in vitro studies with human erythrocytes in
which they compared the effectiveness of several nitro aromatics in the production of
methemoglobinemia. Intact and lysed erythrocytes were incubated with nitro aromatic agents at
concentrations up to 300 |iM. Tetryl produced a significant increase in methemoglobinemia in
both intact and lysed erythrocytes, but the increase was more marked in lysed erythrocytes,
which the study authors attributed to protective mechanisms operative in intact erythrocytes.
After 2 hours of incubation, tetryl produced three- to five-times more methemoglobin than
trinitrotoluene or w-dinitrobenzene. While conjugation with glutathione was demonstrated, the
reaction product also demonstrated the ability to induce methemoglobin formation, though at a
potency of about 20% that of the parent compound.
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A few studies on genotoxicity, short-term toxicity and toxicokinetics of tetryl are
available. These are summarized in Tables 4A and 4B. No studies were identified regarding
chromosomal aberrations or malsegregation in prokaryotes; any effects in mammalian cells in
vitro; mammals in vivo; or genotoxicity in subcellular systems.
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Table 4A. Summary of Tetryl Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Salmonella typhimurium
TA98, TA100, TA1535,
TA1537, TA1538
1.0-333.3
(ig/plate
+ (TA98, TA100,
TA1537, TA1538)
- (TA1535)
+
Reduced mutagenicity in all activated strains
McGregor et al.
(1980)
Reverse
mutation
Salmonella typhimurium
TA98, TA100, TA1535,
TA1537, TA1538
2.5-30 (ig/plate
+ (TA100, TA1535)
- (TA98, TA1537)
+
Reduced mutagenicity in activated TA100
Whong et al.
(1980)
Reverse
mutation
Salmonella typhimurium
TA98, TA100,
40-200 (ig/plate
+
+
Reduced mutagenicity in both activated strains
Tan et al. (1992)
Reverse
mutation
Salmonella typhimurium
TA98, TA100
0-100 (ig/plate
+
+
Reduced mutagenicity in both activated strains
George et al.
(2001)
SOS repair
induction
E.Coli W3310/polA+,
p3478/polA~
100 |ig/platc-
10 mg/plate
-
-
NA
McGregor et al.
(1980)
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
Neurospora crassa N23,
12-9-17
5-80 (ig/plate
+
ND
Increased acl-3 reversions in the N23 strain in a
dose-dependent manner. No tetryl-induced
frame shift mutations in the 12-9-17 strain.
Whong et al.
(1980)
Recombination
induction
Saccharomyces cerevisiae D5
ND
+
-
NA
McGregor et al.
(1980)
Mitotic gene
conversion
Saccharomyces cerevisiae D4
5-30 (ig/plate
+
ND
Increased conversions were noted in both ade+
and trp+ with increased tetryl concentrations
Whong et al.
(1980)
aLowest effective dose for positive results, highest dose tested for negative results.
b+ = positive; ± = equivocal or weakly positive; - = negative; T = cytotoxicity; NA = not applicable; ND = no data; NDr = not determinable; NR = not reported;
NR/Dr = not reported but determined from data.
ND = no data.
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Table 4B. Other Studies
Test
Materials and Methods
Results
References
Short-term
studies
Rats exposed to 0; 500;1,000 mg/kgby
gavage and effects observed 24 hrs later.
Enzyme changes, increase in methemoglobin, serum urea nitrogen, decrease
in lymphocytes.
Reddy et al. (1997, as cited
in Myers and Spinnato,
2007b)

Rabbits exposed 1-3 times per day to
1,000 mg/kg by gavage in milk
Dogs exposed to 100 mg/kg-d
subcutaneously.
Mortality; kidney, lung, and spleen effects.
Liver and kidney effects.
Wells et al. (1920, as cited
in ATSDR, 1995);
Wells et al. (1920, as cited
in Myers and Spinnato,
2007b)

Guinea pigs (n = 8) exposed to smoke of
tetryl particles 30 minutes per day for 6
days. Subsequently exposed to picryl protein
antigens.
One animal died, 6/8 showed anaphylactic sensitivity.
Gell (1944, as cited in
ATSDR, 1995)
Metabolism/
toxicokinetic
5 male Sprague-Dawley rats administered
25, 100, 300 mg/kg subcutaneously.
Highest amounts of tetryl found in blood, liver, muscle; highest tissue:blood
ratios found in brain, kidney, liver. \ -mcthy 1 -2.4.6-1ri nitroani 1 i nc identified
as major metabolite. Picric acid and picramic acid identified as urinary
metabolites. Elimination in both the urine and feces.
Myers and Spinnato
(2007a,b)
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Tests Evaluating Genotoxicity and/or Mutagenicity
McGregor et al., 1980; Whong et al, 1980; Tan et al, 1992; George et al, 2001
The genotoxic effects of tetryl were assessed in vitro in multiple Ames Reverse Mutation
assays utilizing Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538,
both with and without metabolic activation systems (McGregor et al., 1980; Whong et al., 1980;
Tan et al., 1992; George et al., 2001). Tetryl tested positive for mutagenicity showing an
increase in histidine revertants in all tested strains without metabolic activation. Studies indicate
that metabolic activation diminishes the mutagenic response of tetryl in all Salmonella
typhimurium tester strains.
No differential toxicity was noted between E. Coli polA+ and pol A tester strains with or
without metabolic activation following a DNA repair assay (McGregor et al., 1980). Results
indicate that tetryl does not induce DNA repair under the tested conditions.
In a forward mutation assay utilizing Neurospora crassa tester strains N23 and 12-9-17
(frameshift mutations), an increase in ad-3+ reversions (base pair) was reported in the
N23 strains in a dose-dependent manner, but frameshift mutations were not observed
(Whong et al., 1980).
Tetryl was assessed for genotoxicity following mitotic gene conversion and
recombination induction assays in Saccharomyces cerevisiae tester strains D4 and D5,
respectively (Whong et al., 1980; McGregor et al., 1980). Increased conversions were noted in
both ade and trp in a dose-dependent manner in the D4 strains (Whong et al., 1980). Clear
indications of mitotic recombination and other aberrations were also reported in the D5 strain
(McGregor et al., 1980).
Metabolism/Toxicokinetic Studies
Myers andSpinnato, 2007a,b
Myers and Spinnato (2007a,b) administered 25, 100, or 300 mg/kg tetryl dissolved in
dimethyl sulfoxide (DMSO) by subcutaneous injection to groups of 5 male Sprague-Dawley rats.
Tissue distribution data showed that the highest amounts of tetryl were found in the blood, liver,
and muscle. The brain, kidney, and liver had the highest tissue to blood ratios compared to the
other tissues. The major urinary metabolites identified were picric acid and picramic acid. The
major metabolite identified from microsomal fraction studies was TV-methyl-2,4,6-trinitroaniline
(NMPA), with two enzymes responsible for NMPA formation; one was a type of microsomal
NAD(P)H: quinine oxidoreductase that was NADH-specific and the other appeared to be
NADPH: cytochrome-P450 reductase (Myers and Spinnato, 2007a). Tetryl elimination occurred
in equal amounts in the urine and feces. The existing data for metabolism and toxicokinetics are
insufficient to support the development of a dosimetric model.
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present a summary of noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if
available.
Table 5. Summary of Noncancer Reference Values for Trinitrophenylmethylnitramine (CASRN 479-45-8)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD Method
PODhed
UFC
Principal Study
Subchronic p-RfD
(mg/kg-d)
Rat/M
Methemoglobinemia
2 x 1(T2
BMDL
6.1
300
Reddy etal. (1994b, 1999)
Chronic p-RfD
(mg/kg-d)
Rat/M
Methemoglobinemia
2 x 1(T3
BMDL
6.1
3,000
Reddy etal. (1994b, 1999)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
NDr = not determinable.
Table 6. Summary of Cancer Values for Trinitrophenylmethylnitramine (CASRN 479-45-8)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
p-IUR
NDr
NDr = not determinable.
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
No human studies are available on oral exposure to tetryl. Four subchronic animal oral
studies are available (Reddy et al., 1994b, 1999; Guarino and Zambrano, 1957, as cited in
ATSDR, 1995; Daniele, 1964, as cited in ATSDR, 1995; Fati and Daniele, 1965, as cited in
ATSDR, 1995). Reddy et al. (1994b, 1999) was chosen as the principal study since this study
was both GLP-compliant and subsequently published in the peer-reviewed literature. Study
design included a control group and three doses tested in both sexes, and the investigators
examined a large number of endpoints comprising weight changes, histopathology, clinical
chemistry, and hematology. The other three studies were older studies in Italian and cited in a
secondary source.
In Reddy et al. (1994b, 1999), groups of 10 male and 10 female F344 rats were fed 0;
200; 1,000; or 3,000 ppm tetryl in the diet for 90 days; initial body weights were reported to be
approximately 125 grams. These dietary concentrations were calculated by the study authors to
be equivalent to daily doses of 0, 13.0, 62.4, and 179.6 mg/kg-day for males and 0, 14.2, 68.8,
and 199.0 mg/kg-day for females. Several hematology and clinical chemistry endpoints were
evaluated at 45 and 90 days. Organ weights and histopathology were evaluated only at 90 days.
The brain, liver, spleen, kidneys, adrenals, lungs, thymus, testes with epididymides, ovaries, and
heart were weighed, and various other tissues were also examined. Histopathology was
performed on all tissues and organs in the 0 and 179.6 mg/kg-day dose groups in males and in
the 199.0 mg/kg-day dose group in females, with histopathology of the spleen, kidneys, and
testes carried out in the remaining dose groups as well.
Effects were observed on the blood, kidney, spleen, and liver (Reddy et al., 1994b, 1999).
The effects at 90 days in the middle- and high-dose groups (62.4 and 179.6 mg/kg-day in males
and 68.8 and 199.0 mg/kg-day in females) included hematological effects (decreased red blood
cell count, hemoglobin, and hematocrit and increased methemoglobin and reticulocytes),
pigment deposition in the renal cortical epithelium, increased relative spleen weights, and
increased liver weights and decreased alkaline phosphatase. In the low-dose groups
(13.0 mg/kg-day in males and 14.2 mg/kg-day in females), decreases in alkaline phosphatase in
males and increases in total bilirubin in males and females were observed. The pigment
deposition in the renal cortical epithelium and spleen may be related to erythrocyte damage and
hemolysis; and were consistent with methemoglobin induction.
The study authors did not consider the changes in the clinical chemistry parameters at
13.0 mg/kg-day in males (decreases in alkaline phosphatase, increases in cholesterol and total
bilirubin) or 14.2 mg/kg-day in females (increases in albumin, cholesterol, and total bilirubin) to
be biologically meaningful because the values were within an accepted normal reference range
(Reddy et al., 1994b, 1999). Given the decrease in feed intake and body weight, changes in
relative organ weights were not considered. However, absolute brain weight was increased and
absolute adrenal weight was decreased in females at 68.8 mg/kg-day. The increase in
methemoglobin was observed in both sexes, but was more pronounced in females.
Methemoglobin formation demonstrated a clear dose dependent increase with statistically
significant three-fold increases over controls evident at the lowest dose of 14.2 mg/kg-day in
females at 45 days. This effect is also indicative of toxicity in the context of the other adverse
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hematological effects seen at the higher doses and after the longer 90-day duration (increased
methemoglobin, decreased RBC count, decreased hemoglobin, decreased hematocrit, increased
reticulocytes, increased spleen weight).
Benchmark dose (BMD) analysis of the principal study was carried out on a number of
endpoints, including increased body weights, organ weights and increased methemoglobin in
both males and females and compared to other potential point of departure values. The EPA
Benchmark Dose Software (BMDS version 2.1.2) continuous-variable models with constant
variance (Hill, linear, power and polynomial) was fit to the data for each of these endpoints. The
majority of the modeled endpoints had goodness of fit values (p-values) <0.1, which indicates
that these models do not adequately fit these data. The only endpoints that had models with
/(-values >0.1 were body weights in males and methemoglobinemia. The male body weight data
are not used as the point-of-departure (POD) for the subchronic p-RfD because of the potential
contribution of decreased food intake. BMD modeling was successfully applied to 90 day and
45 day data describing methemoglobinemia in male and female rats. Several models had
/(-values >0.1 for methemoglobinemia in male and female rats; of these models the linear models
(linear, polynomial, power models) all had the lowest BMDL of 25.5 mg/kg-day, observed in
male rats exposed for 90 days (see Appendix C). This value was lower than the LOAEL
observed for absolute organ weight changes in females (68.8 mg/kg-day). Thus, the BMDL of
25.5 mg/kg-day for males is selected as the POD for derivation of the subchronic p-RfD. The
subchronic p-RfD for tetryl is derived as follows:
In EPA's Recommended Use of Body Weight3/4 as the Default Method in Derivation of
the Oral Reference Dose (U.S. EPA, 201 lc), the Agency endorses a hierarchy of approaches to
derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses body weight scaling to the 3/4 power (i.e.,
BW3 4) as a default to extrapolate doses of orally administered agents from all laboratory animals
to humans for the purpose of deriving a RfD under certain exposure conditions. More
specifically, the use of BW3 4 scaling for deriving a RfD is recommended when the observed
effects are associated with the parent compound or a stable metabolite, but not for portal-of-entry
effects or developmental endpoints.
A validated human PBPK model for tetryl is not available for use in extrapolating doses
from animals to humans. The selected critical effect of erythrocyte changes, exemplified by
increased methemoglobin content, was associated with the parent compound. Furthermore, these
erythrocyte effects are not portal-of-entry or developmental effects. Therefore, scaling by BW3/4
is relevant for deriving human equivalent doses (HEDs) for these effects.
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Following U.S. EPA (201 lc) guidance, the POD for methemoglobinemia (BMDL
25.5 mg/kg-day) in adult male rats is converted to a HED through application of a dosimetric
adjustment factor (DAF)1 derived as follows:
DAF	=	(BWa1/4 - BWh1/4)
where
DAF	=	dosimetric adjustment factor
BWa	=	animal body weight
BWh	=	human body weight
Using a BWa of 0.25 kg for rats and a BWh of 70 kg for humans (U.S. EPA, 1988), the
resulting DAF is 0.24. Applying this DAF to the BMDL identified for the methemoglobinemia
in mature rats yields a BMDLni n as follows:
BMDLhed	= BMDL (mg/kg-day) x DAF
= 25.5 mg/kg-day x 0.24
= 6.1 mg/kg-day
The subchronic p-RfD for tetryl is derived as follows:
Subchronic p-RfD = BMDLhed UF
= 6.1 mg/kg-day -^300
= 2 x 10~2 mg/kg-day
The UFc for the subchronic p-RfD for tetryl is 300, as summarized in Table 7.
:As described in detail in Recommended Use of Body Weight3/4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA, 201 lc), rate-related processes scale across species in a manner related to both the direct
(BW1'1) and allometric scaling (BW3 4) aspects such that BW3 4 ^ B W1/1= BW converted to a
DAF = BWa'74 - BWhI/4.
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Table 7. Uncertainty Factors for Subchronic p-RfD of Trinitrophenylmethylnitramine"
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the toxicodynamic
differences between rats and humans following oral tetryl exposure. The toxicokinetic uncertainty has
been accounted for by calculation of a human equivalent dose (HED) through application of a
dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Body Weight3/4 as
the Default Method in Derivation of the Oral Reference Dose (U.S. EPA, 2011c).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation reproductive toxicity or
developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of tetryl in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 has been applied because a subchronic-duration study was selected as the principal study.
UFC
300

aReddy et al. (1999).
The confidence in the subchronic p-RfD for tetryl is low as explained in Table 8 below.
Table 8. Confidence Descriptors for Subchronic p-RfD for Trinitrophenylmethylnitramine
Confidence Categories
Designation"
Discussion
Confidence in study
H
The study by Reddy et al. (1994b, 1999) is a well-conducted study,
with a sufficient number of animals and examined many endpoints
Confidence in database
L
The database is lacking two-generation reproductive and
developmental toxicity studies
Confidence in subchronic
p-RfDb
L
The overall confidence is low
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
The principal study used to identify the critical effect of methemoglobinemia in male rats
was reported by Reddy et al. (1994b, 1999). Results from this GLP-compliant 90-day study
supported a BMDL value of 25.5 mg/kg-day, which was converted to a BMDLhed of
6.1 mg/kg-day by body weight scaling as described above, and serves as the POD for derivation
of the chronic p-RfD. The chronic p-RfD for tetryl is derived as follows:
Chronic p-RfD = BMDLhed ^ UF
= 6.1 mg/kg-day ^ 3,000
= 2 x 10~3 mg/kg-day
The UFc for the chronic p-RfD for tetryl is 3,000, as summarized in Table 9.
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Table 9. Uncertainty Factors for Chronic p-RfD of Trinitrophenylmethylnitramine"
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the toxicodynamic
differences between rats and humans following oral tetryl exposure. The toxicokinetic uncertainty
has been accounted for by calculation of a human equivalent dose (HED) through application of a
dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Body Weight3/4 as
the Default Method in Derivation of the Oral Reference Dose (U.S. EPA, 2011c).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation reproductive toxicity or
developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of tetryl in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
10
A UFS of 10 has been applied because a subchronic-duration study was selected as the principal
study.
UFC
3,000

aReddy et al. (1999).
The confidence in the chronic p-RfD for tetryl is low as explained in Table 10 below.
Table 10. Confidence Descriptors for Chronic p-RfD for Trinitrophenylmethylnitramine
Confidence Categories
Designation"
Discussion
Confidence in study
H
The study by Reddy et al. (1994b, 1999) is a well-conducted study,
with a sufficient number of animals and examined many endpoints
Confidence in database
L
The database is lacking two-generation reproductive and
developmental toxicity studies
Confidence in chronic
p-RfDb
L
The overall confidence is low
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The available data concerning health effects in humans following inhalation exposure to
tetryl are limited to case studies and reports of workers exposed in occupational settings, which
include exposures to multiple chemicals. These studies are lacking in adequate quantitative
exposure estimates (Troup, 1946; Hardy and Maloof, 1950; Bergman, 1952; Goh, 1984; ACGIH,
2013; ATSDR, 1995; Talmage et al., 1999). Since levels of exposure to tetryl were not provided
in these studies, NOAELS or LOAELs could not be established and health effects data in these
workers are unsuitable for the derivation of an RfC. No subchronic or chronic animal studies on
the toxicity of tetryl by inhalation exposure were identified.
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Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
No subchronic p-RfC can be derived because no inhalation studies on exposure to tetryl
were identified.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
No chronic p-RfC can be derived because no inhalation studies on exposure to tetryl were
identified.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
There are no human data available on the carcinogenicity of tetryl. There is only one
short-term screening assay (Griswold et al., 1968) in which rats were exposed for 30 days and
then evaluated 10 months later. The EPA has not classified tetryl for carcinogenicity, and no
other agencies have reviewed or classified the carcinogenic potential of the chemical (IARC,
2013; NTP, 2011; Cal/EPA, 2009). While there are no data on the carcinogenicity of tetryl from
in vivo bioassays, it is important to note that there are in vitro data that demonstrate mutagenic
activity (McGregor et al., 1980; Whong et al., 1980; Tan et al., 1992; George et al., 2001). Thus,
the data taken together indicate the cancer weight-of-evidence descriptor for tetryl as
"inadequate information to assess carcinogenic potential'.
Table 11 identifies the cancer weight-of-evidence descriptor for tetryl.
Table 11. Cancer WOE Descriptor for Trinitrophenylmethylnitramine
Possible WOE Descriptor
Designation
Route of Entry (Oral,
Inhalation, or Both)
Comments
"Carcinogenic to Humans "
NA
NA
There are no human data available.
"Likely to Be Carcinogenic to
Humans "
NA
NA
There is not enough evidence to
support this statement.
"Suggestive Evidence of
Carcinogenic Potential"
NA
NA
There is not enough evidence to
support this statement.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
There are no human or animal
carcinogenicity data available.
"Not Likely to Be
Carcinogenic to Humans"
NA
NA
There is not enough evidence to
support this statement.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
The available data do not support derivation of any oral cancer values.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
The available data do not support derivation of any inhalation cancer values.
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APPENDIX A. PROVISIONAL SCREENING VALUES
Appendix A is not applicable.
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APPENDIX B. DATA TABLES
Table Bl. Effect of Tetryl on Body Weights and Organ-to-Body Weight Ratios
(Relative Organ Weights) After 90 Days on Males3
Concentration (ppm) diet
0
200
1,000
3,000
(mg/kg-d)
0
13.0
62.4
179.6
Body weight (g)
304.19 ±4.78
305.04 ±4.12
297.37 ±3.89
279.95 ±4.71*
Kidneys (%)
0.72 ±0.01
0.75 ±0.01
0.81 ±0.04*
0.86 ±0.01*
Lungs(%)
0.47 ±0.01
0.48 ±0.03
0.48 ±0.02
0.51 ±0.01
Liver (%)
3.07 ±0.04
3.06 ±0.05
3.39 ±0.04*
3.94 ±0.03*
Heart (%)
0.33 ±0.01
0.35 ±0.01
0.32 ±0.01
0.33 ±0.01
Brain (%)
0.63 ±0.01
0.63 ±0.01
0.64 ±0.01
0.66 ±0.01
Spleen (%)
0.20 ±0.00
0.20 ± 0.00
0.21 ±0.00
0.25 ± 0.00*
Adrenals (%)
0.02 ±0.00
0.02 ± 0.00
0.02 ± 0.00
0.03 ± 0.00
Thymus (%)
0.09 ±0.01
0.08 ±0.00
0.09 ±0.01
0.09 ±0.01
Gonads(%)
1.67 ±0.09
1.76 ±0.08
1.67 ±0.07
1.72 ±0.06
aReddy et al. (1999).
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
Table B.2. Effect of Tetryl on Body Weights and Organ-to-Body Weight Ratios
(Relative Organ Weights) After 90 Days on Females"
Concentration (ppm) diet
0
200
1,000
3,000
(mg/kg-d)
0
14.2
68.8
199.0
Body weight (g)
171.55 ±2.13
168.44 ±2.52
163.70 ±2.49*
153.33 ± 1.00*
Kidneys (%)
0.73 ±0.01
0.77 ±0.01*
0.77 ±0.01*
0.86 ±0.01*
Lungs(%)
0.59 ±0.02
0.57 ±0.02
0.57 ±0.01
0.62 ± 0.02
Liver (%)
2.76 ±0.04
2.87 ±0.04
3.04 ±0.04*
3.35 ±0.03*
Heart (%)
0.40 ±0.01
0.38 ±0.01
0.39 ±0.01
0.43 ± 0.02
Brain (%)
1.07 ±0.02
1.06 ±0.04
1.05 ±0.02
1.10 ±0.01
Spleen (%)
0.26 ±0.01
0.25 ± 0.00
0.27 ± 0.00
0.30 ±0.01*
Adrenals (%)
0.05 ±0.00
0.05 ± 0.00
0.04 ± 0.00
0.05 ± 0.00
Thymus (%)
0.14 ±0.01
0.13 ±0.01
0.13 ±0.01
0.13 ±0.01
Gonads(%)
0.10 ±0.01
0.08 ±0.00
0.13 ±0.05
0.09 ±0.00
aReddy et al. (1999).
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
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Table B.3. Effect of Tetryl on Hematological Parameters after 45 or 90 Days on Males"
Concentration (ppm) diet
Sample at 45
or 90 days
0
200
1,000
3,000
(mg/kg-d)
0
13.0
62.4
179.6
RBC (x106/|iL)
45
90
8.66 ±0.12
9.34 ±0.19
8.87 ±0.30
9.31 ±0.23
8.71 ±0.15
9.27 ±0.18
8.50 ±0.20
8.94 ±0.18*
Hemoglobin (g/dL)
45
90
15.44 ±0.29
15.83 ±0.23
15.40 ±0.78
15.61 ±0.41
14.90 ±0.43
15.31 ±0.23*
14.12 ±0.48*
14.22 ±0.25*
Hematocrit (%)
45
90
44.90 ±0.97
48.37 ±0.79
45.20 ± 1.71
48.05 ± 1.14
43.94 ± 1.19
47.15 ± 1.23*
43.14 ±0.80
44.98 ±0.95*
WBC (xl03/|iL)
45
90
4.58 ±0.58
4.35 ±0.64
4.20	±0.58
4.21	±0.68
4.20 ±0.87
4.30 ±0.63
4.10 ±0.81
4.43 ±0.58
Platelets (x 10 7|iL)
45
90
700.60 ± 92.44
733.70 ±87.65
789.00 ±34.55
728.30 ±43.06
844.20 ± 37.25*
745.10 ±83.61
946.20 ±73.40
856.70 ±45.82*
Reticulocytes (%)
45
90
2.42 ±0.29
1.96 ±0.19
2.26 ±0.34
1.88 ±0.20
2.84 ±0.26
2.05 ±0.13
4.16 ± 0.15*
3.35 ±0.18*
MetHb (%)
45
90
0.42 ±0.31
0.50 ±0.40
0.88 ±0.48
0.58 ±0.32
1.36	±0.33*
1.37	±0.27*
2.44 ±0.46*
2.67 ±0.54*
aReddy et al. (1999).
n = 5 rats per dose group at 45 d;n = 10 rats per dose group at 90 d.
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
RBC = red blood cells; WBC = white blood cells; MetHB = methemoglobin.
Table B.4. Effect of Tetryl on Hematological Parameters after 45 or 90 Days on Females3
Concentration (ppm) diet
Sample at 45
or 90 days
0
200
1,000
3,000
(mg/kg-d)
0
14.2
68.8
199.0
RBC (><106/|iL)
45
90
8.15 ±0.21
8.24 ±0.21
7.99 ±0.16
8.23 ± 0.27
7.94 ±0.18
8.12 ± 0.19
7.80 ±0.25*
7.70 ±0.34*
Hemoglobin (g/dL)
45
90
15.66 ±0.25
15.66 ±0.35
14.96 ±0.42
15.66 ±0.58
14.66 ±0.40*
15.16 ±0.32*
14.36 ±0.68*
14.53 ±0.44*
Hematocrit (%)
45
90
43.72 ±2.01
44.61 ± 1.58
42.42 ± 1.00
44.55 ± 1.41
43.72 ± 1.83
43.85 ± 1.41
42.88 ± 1.68
43.22 ± 1.49
WBC (xl03/|iL)
45
90
4.18 ±0.49
4.14 ±0.70
4.04 ±0.96
3.41 ±0.57*
4.70 ±0.33
3.69 ±0.57
4.78 ±0.73
3.71 ±0.56
Platelets (x 107|iL)
45
90
778.60 ± 62.07
742.50 ± 32.03
778.40 ± 64.76
758.10 ±60.50
716.6 ± 125.3
811.40 ±71.07*
796.40 ± 82.38
853.40 ±53.81*
Reticulocytes (%)
45
90
2.02 ±0.25
1.71 ±0.28
1.94 ±0.27
1.77 ±0.22
2.32 ± 0.11
2.06 ±0.28*
3.68 ±0.43*
2.63 ±0.37*
MetHb
45
90
0.28 ±0.25
0.59 ±0.33
0.90 ±0.31*
0.68 ±0.33
1.10 ±0.27*
1.09 ±0.33*
1.96 ±0.41*
2.23 ±0.34*
aReddy et al. (1999).
n = 5 rats per dose group at 45 d; n = 10 rats per dose group at 90 d.
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
RBC = red blood cells; WBC = white blood cells; MetHB = methemoglobin.
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Table B.5. Effect of Tetryl on Clinical Chemistry After 45 and 90 Days on Males"
Concentration (ppm) diet
Sample at 45
or 90 d
0
200
1,000
3,000
(mg/kg-d)
0
13.0
62.4
179.6
Glucose (mg/dL)
45
90
194.60 ±21.85
185.60 ± 18.06
183.60 ± 15.88
187.50 ± 19.46
185.20 ± 19.61
187.50 ± 15.66
175.20 ±9.65
180.00 ± 17.99
BUN (mg/dL)
45
90
19.60 ± 1.52
20.20 ± 0.92
18.40 ±3.13
20.60 ± 2.22
20.40 ± 1.52
22.20 ± 1.03*
18.00 ± 1.22
21.0 ± 1.15
Creatinine (mg/dL)
45
90
0.60 ± 0.07
0.62 ± 0.04
0.56 ±0.05
0.62 ± 0.04
0.62 ± 0.04
0.61 ±0.03
0.60 ± 0.00
0.60 ±0.05
Alkaline phosphatase
(IU/L)
45
90
135.80 ±8.78
104.90 ±6.87
134.00 ± 14.61
93.70 ±6.60*
123.80 ± 10.03
88.30 ±8.71*
119.60 ± 12.56
80.90 ±6.38*
AST (IU/L)
45
90
126.80 ± 16.18
157.0 ±43.60
113.60 ± 12.22
150.30 ±29.70
134.40 ±39.30
164.60 ±21.88
111.60 ± 19.83
175.50 ±30.75
ALT (IU/L)
45
90
53.80 ± 12.68
85.10 ±28.73
45.80 ±6.80
83.80 ± 17.78
51.60 ±23.20
80.40 ± 16.30
38.60 ±8.56
66.50 ± 11.00
Potassium (mEq/L)
45
90
4.74 ±0.51
4.65 ±0.31
4.70 ±0.59
4.80 ±0.38
4.82 ±0.44
4.62 ±0.38
5.62 ±0.54*
5.00 ±0.24
Albumin (g/dL)
45
90
4.38 ±0.08
4.72 ±0.16
4.64 ±0.26
4.82 ±0.12
4.78 ±0.16*
5.00 ± 0.11*
5.04 ±0.09*
5.12 ± 0.21*
Calcium (mg/dL)
45
90
10.64 ±0.15
10.47 ±0.12
10.80 ±0.07
10.60 ±0.18
11.02 ±0.16*
10.67 ±0.18*
11.14 ± 0.15*
10.70 ±0.21*
Phosphorus (mg/dL)
45
90
9.82 ±0.52
9.05 ±0.55
9.64 ± 0.60
8.95 ± 0.66
9.84 ±0.43
8.59 ±0.97
10.82 ± 1.01
8.97 ±0.89
Triglycerides (mg/dL)
45
90
99.80 ±23.55
104.40 ± 27.63
88.60 ±44.81
103.40 ±30.56
97.00 ± 28.22
119.40 ±28.89
64.20 ± 24.80
89.30 ±32.15
Cholesterol13 (mg/dL)
90
58.60 ±7.06
66.40 ± 4.77*
79.10 ±4.65*
105.40 ±7.57*
Sodium (mEq/L)
45
90
137.60 ± 1.52
143.00 ±0.94
139.00 ± 1.00
143.50 ± 1.08
139.00 ± 1.22
143.00 ±0.82
138.40 ±0.55
142.30 ±0.67
Total bilirubin (mg/dL)
45
90
0.14 ±0.09
0.05 ±0.05
0.14 ±0.09
0.10 ±0.00*
0.12 ±0.04
0.09 ±0.03*
0.18 ±0.04
0.10 ±0.00*
Total protein (g/dL)
45
90
6.30 ±0.14
6.81 ±0.21
6.60 ±0.21*
6.88 ±0.13
6.88 ±0.13*
7.22 ±0.23*
7.12 ±0.18*
7.39 ±0.30*
aReddy et al. (1999, 1994b).
n = 5 rats per dose group at 45 d; n = 10 rats per dose group at 90 d.
bCholesterol was only measured at Day 90.
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase.
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Table B.6. Effect of Tetryl on Clinical Chemistry After 45 and 90 Days on Females"
Concentration (ppm) diet
Sample at 45
or 90 d
0
200
1,000
3,000
(mg/kg-d)
0
14.2
68.8
199.0
Glucose (mg/dL)
45
90
154.80 ±21.04
125.10 ± 17.64
166.00 ± 5.00
138.80 ± 15.42
161.40 ± 17.87
145.30 ±18.66*
130.20 ±20.35
130.00 ± 17.31
BUN (mg/dL)
45
90
18.40 ±3.21
18.30 ±2.21
17.60 ± 1.67
19.00 ± 1.89
17.00 ± 1.00
20.20 ±2.39
17.20 ± 1.92
20.20 ±2.97
Creatinine (mg/dL)
45
90
0.52 ±0.04
0.54 ±0.05
0.54 ±0.05
0.55 ±0.05
0.64 ±0.05*
0.56 ±0.05
0.60 ±0.00*
0.57 ±0.05
Alkaline phosphatase
(IU/L)
45
90
123.20 ± 10.83
76.50 ± 11.40
122.50 ±26.31
74.00 ± 15.32
122.40 ±24.57
67.90 ±8.02
116.00 ± 16.84
63.30 ±9.35*
AST (IU/L)
45
90
106.20 ± 26.44
132.00 ±27.94
95.20 ± 11.12
180.20 ±65.81*
182.20 ±92.88
160.70 ±37.69
147.20 ±33.94
159.30 ±33.04
ALT (IU/L)
45
90
37.40 ±4.28
55.20 ± 19.23
35.60 ±5.68
85.40 ±46.21
60.20 ±35.15
79.80 ±30.14
38.20 ±6.38
59.00 ± 16.42
Potassium (mEq/L)
45
90
4.58 ±0.37
4.03 ± 0.25
4.52 ±0.49
4.49 ±0.50
4.30 ±0.16
4.48 ±0.45
4.54 ±0.45
4.56 ±0.86
Albumin (g/dL)
45
90
4.38 ±0.08
4.42 ±0.15
4.22 ±0.16
4.67 ±0.23*
4.68 ±0.13
4.72 ±0.12*
4.58 ±0.33
4.96 ±0.21*
Calcium (mg/dL)
45
90
10.66 ±0.21
10.04 ±0.24
10.60 ±0.20
10.23 ±0.23
10.96 ±0.13
10.18 ±0.21
10.70 ±0.21
10.34 ±0.43
Phosphorus (mg/dL)
45
90
8.90 ± 1.27
8.31 ±0.97
8.38 ±0.52
8.63 ± 1.10
10.02 ± 1.42
8.57 ±0.98
9.44 ± 1.69
9.12 ±0.99
Triglycerides (mg/dL)
45
90
39.60 ±8.82
40.60 ± 13.93
38.80 ± 10.85
44.60 ± 15.14
47.60 ± 14.54
36.20 ± 13.31
29.40 ±3.58
25.40 ±3.86*
Cholesterol13 (mg/dL)
90
102.70 ±6.80
112.90 ±8.85*
123.00 ±8.91*
131.50 ± 10.22*
Sodium (mEq/L)
45
90
138.40 ± 1.67
142.70 ±0.82
138.60 ±0.55
142.90 ±0.74
139.60 ± 1.82
142.80 ± 1.14
139.60 ±0.55
143.50 ± 1.08
Total bilirubin (mg/dL)
45
90
0.18 ±0.04
0.11 ±0.03
0.14 ±0.05
0.19 ± 0.10*
0.20 ±0.00
0.16 ±0.07
0.26 ±0.05*
0.22 ±0.04*
Total protein (g/dL)
45
90
6.20 ±0.32
6.18 ± 0.19
6.04 ±0.15
6.37 ±0.28
6.52 ±0.08
6.52 ±0.20*
6.28 ±0.04
6.71 ±0.33*
aReddy et al. (1999, 1994b).
n = 5 rats per dose group at 45 d; n = 10 rats per dose group at 90 d.
bCholesterol was only measured at Day 90.
Data are mean ± standard deviation.
* Significantly different from the control group (p < 0.05) by the Dunnett's test.
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APPENDIX C. BMD OUTPUTS
Table C.l. Tetryl 90 Day Male Methemoglobinemia Data
Continuous
Model Name
BMD
(mg/kg-d)
BMDL
(mg/kg-d)
p-Value Test 4
AIC
Scaled Residual
of Interest
Hill
33.9864
17.1635
NA
-28.344925
-3.10 x 10~07
Linear
31.103
25.486
0.5277
-31.066295
-0.641
Polynomial
31.103
25.486
0.5277
-31.066295
-0.641
Power
31.103
25.486
0.5277
-31.066295
-0.641
Polynomial Model with 0.95 Confidence Level
Polynomial
3
2.5
2
5
1
0.5
BMDL
BMD
0
0
20
40
60
80
100
120
140
160
180
dose
08:32 02/16 2012
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Polynomial Model. (Version: 2.16; Date: 05/26/2010)
Input Data File: C:/Documents and
Settings/jlipscom/Desktop/Benchmark/BMDS220/Data/lin_tetrylmale90ditiehb_Opt. (d)
Gnuplot Plotting File: C:/Documents and
Settings/jlipscom/Desktop/Benchmark/BMDS220/Data/lin_tetrylmale90dmehb_Opt.pit
Thu Feb 16 09:16:18 2012
BMDS Model Run
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*dose/s2 + ...
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 =	0.156725
rho =	0 Specified
beta_0 =	0.497816
beta 1 = 0.0122696
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 1
alpha
1
1.le-010
-7.7e-011
beta_0
1.le-010
1
-0.67
beta_l
-7.7e-011
-0. 67
1
Variable
Limit
0.20946
alpha
beta 0
0.656935
beta 1
Parameter Estimates
Estimate	Std. Err.
0.145634	0.0325648
0.497816	0.0811846
0.0122696	0.000851996
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf.
0.0818084
0.338697
0.0105997
0.0139394
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0	10	0.5	0.498	0.4	0.382	0.0181
13	10	0.58	0.657	0.32	0.382	-0.641
62.4	10	1.37	1.26	0.27	0.382	0.883
179.6 10	2.67	2.7	0.54	0.382	-0.26
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Model Descriptions for likelihoods calculated
Model A1:	Yij
Var{e(ij)}
Model A2:	Yij
Var{e(ij)}
Mu(i) + e(i j)
SigmaA2
Mu(i) + e(i j )
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
Var{e(i)}
Model
A1
A2
A3
fitted
R
= Mu + e(i)
= SigmaA2
Likelihoods of Interest
Log(likelihood)	# Param's	AIC
19.172462	5	-28.344925
21.919655	8	-27.839310
19.172462	5	-28.344925
18.533147	3	-31.066295
-17.908395	2	39.816789
Test 1:
Test
Test
Test
Explanation of Tests
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adeguately 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.)
Test
Test 1
Test 2
Test 3
Test 4
Tests of Interest
-2*log(Likelihood Ratio) Test df
79.6561
5.49439
5.49439
1.27863
p-value
<.0001
0.139
0.139
0.5277
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 greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3 is greater than .
to be appropriate here
The p-value for Test 4 is greater than .
to adeguately describe the data
Benchmark Dose Computation
The modeled variance appears
The model chosen seems
Specified effect
Risk Type
Confidence level
BMD
BMDL
Estimated standard deviations from the control mean
0.95
31.103
25.486
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Table C.2. Tetryl 90 Day Female Methemoglobinemia Data
Model Name
BMD
(mg/kg-d)
BMDL
(mg/kg-d)
/7-Value
Test 1: Lack
Dose
Response?
/7-Value
Test 3:
Good
Variance
Model?
/7-Value for
Fit: Does
the Model
for the
Mean Fit?
AIC
Scaled
Residual of
Interest
Exponential


<0.0001
0.9996
0.5198
Array
Array
Hill
45.6563
27.3945
<0.0001
0.9996
NA
-42.295529
-0.0122
Linear
38.1113
31.0666
<0.0001
0.9996
0.8649
-46.006495
0.00214
Polynomial
38.1113
31.0666
<0.0001
0.9996
0.8649
-46.006495
0.00214
Power
45.6278
31.3902
<0.0001
0.9996
0.9724
-44.295671
-0.0116
Table C.3. Tetryl 45 Day Male Methemoglobinemia Data
Model Name
BMD
(mg/kg-day)
BMDL
(mg/kg-day)
/7-Value for
Fit: Does the
Model for the
Mean Fit?
AIC
Scaled
Residual of
Interest
Exponential


0.06406
Array
Array
Hill
22.4966
10.9077
0.2656
-11.657626
0.861
Linear
36.5918
27.5312
0.3018
-12.501205
0.789
Polynomial
36.5918
27.5312
0.3018
-12.501205
0.789
Power
36.5918
27.5312
0.3018
-12.501205
0.789
Table C.4. Tetryl 45 Day Female Methemoglobinemia Data
Model Name
BMD
(mg/kg-day)
BMDL
(mg/kg-day)
/7-Value for
Fit: Does the
Model for the
Mean Fit?
AIC
Scaled
Residual of
Interest
Exponential


0.008342
Array
Array
Hill
23.6864
8.11893
0.01679
-16.816854
1.74
Linear
46.4202
34.5036
0.02789
-17.375309
0.346
Polynomial
46.4202
34.5036
0.02789
-17.375309
0.346
Power
46.4202
34.5036
0.02789
-17.375309
0.346
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