United States
Environmental Protection
1=1 m m Agency
EPA/690/R-13/007F
Final
2-11-2013
Provisional Peer-Reviewed Toxicity Values for
Diisopropyl Methylphosphonate
(CASRN 1445-75-6)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Chris Cubbison, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Suryanarayana V. Vulimiri, BVSc, PhD, DABT
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 iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVS 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 3
HUMAN STUDIES 8
Oral Exposures 8
Inhalation Exposures 8
ANIMAL STUDIES 8
Oral Exposures 8
Subchronic Studies 8
Chronic Studies 12
Developmental Studies 12
Reproductive Studies 13
Carcinogenicity Studies 16
Inhalation Exposures 16
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 16
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 16
Other Toxicity Studies (Exposures Other Than Oral or Inhalation) 17
Metabolic/Toxicokinetic Studies 17
Mode-of-Action/Mechanistic Studies 17
Immunotoxicity 17
Neurotoxicity 17
DERIVATION 01 PROVISIONAL VALUES 26
DERIVATION OF ORAL REFERENCE DOSES 27
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 27
Derivation of Chronic Provisional RfD (Chronic p-RfD) 30
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 30
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 30
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 31
APPENDIX A. PROVISIONAL SCREENING VALUES 32
APPENDIX B. DATA TABLES 33
APPENDIX C. BMD OUTPUTS 64
APPENDIX D. REFERENCES 65
in
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
DIISOPROPYL METHYLPHOSPHONATE (CASRN 1445-75-6)
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 (http://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 (www.epa.gov/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
Diisopropyl methylphosphonate (DIMP), CAS No. 1445-75-6, is an organophosphorus
compound (structure provided in Figure 1) that is a byproduct of the manufacture of the nerve
agent sarin (ATSDR, 1998). DIMP constitutes 2-3% of the crude sarin product (ATSDR, 1998).
It may also be used to simulate G-type chemical agents (HSDB, 2000). A table of the
physicochemical properties is provided below (see Table 1).
h3c ch3
Figure 1. DIMP Structure
Table 1. Physicochemical Properties of DIMP (CASRN 1445-75-6)3
Property (unit)
Value
Boiling point (°C at 10 mm Hg)
121.05
Melting point (°C)
No data
Density (g/mL at 25°C)
0.976
Vapor pressure (mm Hg at 25°C)
0.28
Solubility in water (g/1000 mL at 25°C)
160
Relative vapor density (air = 1)
0.976
Molecular weight (g/mol)
180.21
"Sources: HSDB, 2000; U.S. EPA, 1989.
A Reference Dose (RfD) of 8 x 10 2 mg/kg-day for DIMP is included on IRIS
(U.S. EPA, 1993), but a Reference Concentration (RfC) is not included. The Drinking Water
Standards and Health Advisories List (U.S. EPA, 2009) lists various health advisory values,
including an RfD of 8 x 10 2 mg/kg-day for DIMP. No RfD or RfC values are reported in the
Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 2011). The Chemical
Assessments and Related Activities (CARA) list does not include a Health and Environmental
Effects Profile (HEEP) that derived noncancer toxicity or potential carcinogenicity values for
DIMP (U.S. EPA, 1994). The toxicity of DIMP has been reviewed by the Agency for Toxic
Substances and Disease Registry (ATSDR, 1998). ATSDR recommends an
intermediate-duration oral Minimum Risk Level (MRL) of 0.8 mg/kg-day based on the lack of
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noticeable effects in dogs treated with DIMP for 90 days (Hart, 1980a). ATSDR also lists a
chronic-duration oral MRL of 0.6 mg/kg-day based on the lack of noticeable effects in mink
treated with DIMP for 13 months (Bucci et al., 2003). The toxicity of DIMP has not been
reviewed by the World Health Organization (WHO, 2011). The California Environmental
Protection Agency (CalEPA, 2008, 2009) has not derived toxicity values for exposure to DIMP.
No occupational exposure limits for DIMP have been derived or recommended by the American
Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute of
Occupational Safety and Health (NIOSH, 2011), or the Occupational Safety and Health
Administration (OSHA, 2011).
IRIS (U.S. EPA, 1993) reports a cancer weight-of-evidence (WOE) classification of
Group D ('Wo/ Classifiable as a Human Carcinogen") due to the lack of epidemiological studies
or animal bioassays for DIMP. The HEAST (U.S. EPA, 2011) does not report a cancer WOE
classification or an oral slope factor. The International Agency for Research on Cancer (IARC,
2011) has not reviewed the carcinogenic potential of DIMP. DIMP is not included in the
12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not derived a quantitative estimate
of carcinogenic potential for DIMP.
Literature searches were conducted on sources published from 1900 through
January 2012 for studies relevant to the derivation of provisional toxicity values for DIMP, CAS
No. 1445-75-6. Searches were conducted using EPA's Health and Environmental Research
Online (HERO) database of scientific literature. HERO searches the following databases:
AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy
Information Administration, Information Bridge, and Energy Citations Database; EBSCO:
Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for relevant
health information: ACGIH, ATSDR, CalEPA, 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 2 provides an overview of the relevant database for DIMP and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. Principal
studies are identified. The phrase "statistical significance," used throughout the document,
indicates ap-value of <0.05. Finally, studies that are not published in peer-refereed journals are
reported as unpublished studies in the text and Table 2.
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Table 2. Summary of Potentially Relevant Data for DIMP (CASRN 1445-75-6)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical effects
NO A EL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-d)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
2. Inhalation (mg/m3)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
Animal
1. Oral (mg/kg-d)a
Subchronic
32/32 per dose, S-D, rat,
diet, 7 d/wk, 90 d
Males: 0, 24.74,
74.58, 229.17;
Females: 0,
27.98, 92.31,
257.58
(Adjusted)
No adverse effects
257.58
NDr
NDr
Hart (1976a)
NPR
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Table 2.
Summary of Potentially Relevant Data for DIMP (CASRN 1445-75-6)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Subchronic
30 (29 at high dose)/30
per dose, ICR Swiss
Albino, mouse, diet,
7 d/wk, 90 d
Males: 0, 37.94,
108.18, 337.27;
Females: 0,
42.00, 142.59,
460.38
(Adjusted)
No adverse effects
460.38
NDr
NDr
Hart (1976b)
NPR
4/4 per dose, Beagle,
dog, diet, 7 d/wk, 90 d
Males: 0, 5.30,
40.43, 85.32;
Females: 0,
4.55,46.97,
92.78
(Adjusted)
No adverse effects
92.78
NDr
NDr
U.S. DOD
(1980); Hart
(1980a)
IRIS,
NPR
10/10 per dose, Ranch
Wild, brown mink,
diet, 90 d
Males: 0,6.8,
63.4,344.7,
747.1,1008.6;
Females: 0,9.0,
82.3,455.2,
907.7,1263.5
(Adjusted)
Increased Heinz bodies
344.7
NDr
747.1
Bucci et al.
(1994)
PS, PR
Chronic
ND/ND, S-D, rat,
drinking water, 7 d/wk,
26 wk
0.8° (Adjusted)
No adverse effects
0.8
NDr
NDr
U.S. DOD
(1978) as
reported by
U.S. EPA
(1993)
PR
Developmental
0/20 per dose,
CRL:COBS CD (SD)
BR rat, diet, GDs 6-15
0,7.4,21.6,
232.5
No adverse effects
232.5
NDr
NDr
Hart (1980b)
NPR
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Table 2. Summary of Potentially Relevant Data for DIMP (CASRN 1445-75-6)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Reproductive
10/20 per dose, S-D, CD
rat, diet, 3-generation
reproductive study dosed
through the end of
lactation, 13-wk
exposure for males and
19 wk exposure for
females
135d (Adjusted)
No adverse effects
135
NDr
NDr
U.S. DOD
(1980); Hart
(1980c)
NPR
6/24 per dose, dark
mink, diet, 1-generation
reproductive study,
12 mo
0, 11,37, 95
(Adjusted)
Mortality seen in low-, mid-, and
high-dose groups; significance is
questionable since no other effects were
seen and the mortality rate of first-year
mink in commercial fur ranch operations
is approximately 6% annually; however,
no mortality observed in the controls
NDr
NDr
NDr
U.S. DOD
(1979);
Aulerich et al.
(1979)
PR
9/35 per dose, Ranch
Wild, brown mink, diet,
2-generation
reproductive study
F0 males: 0,
14.94, 47.36,
284.79;
F0 females: 0,
25.61, 84.81,
460.72
(Adjusted)
F1 males: 0,
15.67, 45.00,
261.73;
F1 females: 0,
19.74, 56.50,
329.47
(Adjusted)
Hematological changes seen at the
highest dose in F0 females and F1 males
and females
56.5
NDr
329.5
Bucci et al.
(2003);
Concerns
regarding the
methodology
and data
interpretation of
the data have
been raised
(Calabrese,
2003a,b, 2005;
Colagiovanni,
2006; Calonge,
2006).
PR
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Table 2. Summary of Potentially Relevant Data for DIMP (CASRN 1445-75-6)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical effects
NOAEL3
BMDL/
BMCL3
LOAEL3
Reference
(Comments)
Notesb
Carcinogenicity
ND
2. Inhalation (mg/m3)3
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. 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.
bNotes: IRIS = Utilized by IRIS, date of last update; PS = principal study, PR = peer reviewed, NPR = not peer reviewed.
°U.S. EPA (1993) reported doses of 0, 0.0000044, 0.000044, 0.0736, and 7.36 mg/L, but only provided the adjusted value for the highest dose.
dU.S. EPA (1993) reported doses of 0, 300, and 3000 ppm, but only provided the adjusted value for the highest dose.
NA = Not applicable, ND = No data, NDr = Not determined, NR = Not reported, S-D = Sprague-Dawley.
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HUMAN STUDIES
Oral Exposures
No studies were identified on the oral exposure of DIMP to humans.
Inhalation Exposures
No studies were identified on the inhalation exposure of DIMP to humans.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure to DIMP in animals have been evaluated in four subchronic
(Hart, 1976a,b, 1980a; Bucci et al., 1994), one chronic (U.S. Department of Defense [DOD],
1978, as reported by U.S. EPA, 1993), one developmental (Hart, 1980b), and three reproductive
(U.S. DOD, 1979, as reported by U.S. EPA, 1993; Hart, 1980c, as reported by U.S. EPA, 1993;
Bucci et al., 2003) studies.
Subchronic Studies
Hart (1976a)
Hart (1976a) administered DIMP (88-95% pure) at concentrations of 0, 300, 1000, or
3000 ppm in the diet for 90 days to male and female Sprague-Dawley rats (32/sex/treatment
group). The data are available but are not published in a peer-refereed journal. Because this
proprietary study is summarized by IRIS (U.S. EPA, 1993), the Hart (1976a) study is considered
to be sufficiently peer-reviewed for use in this assessment. In the study, average daily doses are
estimated to be 0, 24.74, 74.58, or 229.17 mg/kg-day for males and 0, 27.98, 92.31, or
257.58 mg/kg-day for females based on the average body weights and food consumption
reported. Animals were obtained from ARS/Sprague Dawley (Madison, WI). Water was
provided ad libitum. Body weight and food consumption were measured weekly throughout the
study. Weekly examinations for overall appearance, behavior, and signs of toxicity were
performed. Hematocytology, blood biochemistry, acetylcholinesterase, and urinalysis
measurements were taken from 5 animals/sex/treatment group at 4 and 13 weeks. The following
endpoints were measured: erythrocyte count, packed cell volume, hemoglobin, leukocyte count,
differential leukocyte count, glucose, blood urea nitrogen, serum glutamic-pyruvic transaminase,
serum glutamic-oxaloacetic transaminase, serum alkaline phosphatase, sodium, potassium,
chloride, acetylcholinesterase (red blood cell [RBC], plasma, and brain), color, specific gravity,
pH, sugar, protein, ketones, and a microscopic examination of the sediment in the urine. The
following organs were removed and weighed at necropsy: liver, brain, thyroid, kidneys, adrenal
glands, heart, gonads, and spleen. Histopathological examinations were conducted on five
animals/sex in the control and high-dose groups.
No treatment-related mortality, or alterations of body weight, or food consumption were
seen during the course of the study (see Table B.l). Opacity of the eye lens was seen in 2-5 rats
per dose group (data not provided). However, the study authors reported that this is considered
normal and unrelated to DIMP exposure. There were sporadic, statistically significant changes
in the hematology and blood biochemistry results, but these are not considered to be
treatment-related by the authors, who stated that any statistically significant results were "of no
toxicologic importance" (see Tables B.2 and B.3 for males and females, respectively). No
significant findings were stated in the urinalysis report. An evaluation of the RBC, plasma, and
brain cholinesterase levels indicates a decrease in plasma cholinesterase levels after 13 weeks of
exposure in the low- and mid-dose groups and a statistically significant increase in plasma
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cholinesterase levels in high-dose males; however, no treatment-related effects were seen in the
RBC or brain cholinesterase levels (see Tables B.4 and B.5 for males and females, respectively).
It should be noted that plasma cholinesterase is considered a biomarker of exposure (ATSDR,
1998) and is not considered an adverse effect when other indications of neurotoxicity or liver
toxicity are lacking. Please see the section titled "Derivation of Oral Reference Doses" for a
discussion of the use of cholinesterase inhibition as a POD. There were no treatment-related
effects on organ weight; however, several pages of the document photocopy (the only obtainable
copy) were of poor quality, and the organ-weight data were unreadable. Due to the lack of
adverse effects, the NOAEL is considered to be 257.58 mg/kg-day; no LOAEL can be
determined.
Hart (1976b)
Hart (1976b) conducted a subchronic (90-day) oral toxicity study of DIMP using ICR
Swiss Albino mice. The data are available, but are not published in a peer-refereed journal.
Each treatment group and control group contained 30 mice per sex, except the high-dose group
of males that contained only 29 animals. DIMP was obtained from Richmond Organics
(Richmond, VA) with a reported purity of between 88-95%. The animals were fed 0, 210, 700,
or 2100 ppm DIMP in a diet of Purina Rodent Chow. Average daily doses are estimated to be 0,
37.94, 108.18, or 337.27 mg/kg-day for males and 0, 42.00, 142.59, or 460.38 mg/kg-day for
females based on the average body weights and food consumption reported in the study.
Animals were obtained from Flow Laboratories (Rockville, MD). Water was provided ad
libitum, and mice were housed five to a cage. Body weight and food consumption were
measured weekly throughout the course of the study. Weekly examinations for overall
appearance, behavior, and signs of toxicity were performed. Twenty mice per sex per group
were necropsied at 13 weeks. The remaining animals were maintained on the control diet for 2
or 4 weeks to evaluate possible recovery effects. The following organs were removed and
weighed at necropsy: heart, liver, thyroid, kidneys, adrenal glands, spleen, and gonads. The
following body parts were microscopically examined for abnormalities in five animals per sex in
the control and high-dose group: brain, pituitary, thyroid, heart, liver, spleen, kidneys, adrenals,
stomach, pancreas, small intestines, large intestines, mesenteric lymph node, testes or ovaries,
uterus or prostate, bone marrow, and urinary bladder. The study authors did not provide any
information on the statistical methods used.
No treatment-related mortality was seen. Two male mice in the control group and 3 male
mice in the 210 mg/kg-day group escaped. One female mouse in the control was missexed.
Therefore, these animals were not available for evaluation. No treatment-related effects were
seen in body weight or food consumption (see Table B.6). The study authors did not report any
significant changes in the relative organ weights compared with the control. Data tables for the
organ weights could not be transcribed because several pages of the study photocopy were not
readable. Microscopic examination revealed no treatment-related effects. The planned recovery
experiments were deemed "noncontributory" because no toxic effects were seen during the
dosing period. The study authors concluded that DIMP does not cause toxic effects in mice at
the administered doses. Based on a lack of treatment-related effects, the NOAEL for this study
is 460.38 mg/kg-day; no LOAEL can be determined.
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Hart (1980a)
Hart (1980a) conducted a subchronic (90-day) oral toxicity study of DIMP using beagle
dogs. The data are available but are not published in a peer-refereed journal. Each treatment
group and control group contained 4 dogs per sex (5-6 months old). DIMP was obtained from
Richmond Organics (Richmond, VA) with a reported purity of between 88-96%. Animals were
fed 0-, 150-, 1500-, or 3000-ppm DIMP in the diet using PEG 400 as a vehicle. Average daily
doses are estimated to be 0, 5.30, 40.43 or 85.32 mg/kg-day for males and 0, 4.55, 46.97,
92.78 mg/kg-day for females based on the average body weights and food consumption reported
in the study. It should be noted that both IRIS and ATSDR reported 75 mg/kg-day for the
high-dose group. IRIS used the assumption that the dogs consumed 2.5% of their body weight;
the estimates for this assessment were based on the average food consumption reported by the
study authors. Animals were obtained from Hazleton Research Animals, Inc. (Cumberland,
VA). Water was provided ad libitum. All dogs were housed in individual cages with 12 hours of
light and 12 hours of darkness per day. Standard immunizations were given by the supplier.
Body weight was measured weekly throughout the course of the study. Food
consumption was determined twice per week. Daily examinations for each animal's overall
condition, behavior, and fecal consistency were performed. Instances of Giardia canis and
Isospora canis were reported, and all animals were treated with sulfamethazine and quinacrine
hydrochloride for 12 days. Hematology and blood chemistry were measured at 0, 4, 8, and
13 weeks. The following endpoints were measured: erythrocyte count, leukocyte count,
differential leukocyte count, hemoglobin, packed cell volume, clotting time, glucose, blood urea
nitrogen, serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase, serum
alkaline phosphatase, total protein, albumin/globulin ratio, creatinine, sodium, chloride, calcium,
uric acid, bilirubin, cholesterol, lactic dehydrogenase, acetylcholinesterase (RBC and plasma),
creatinine phosphokinase (CPK), total iron, triglycerides, carbon dioxide, phosphorus, albumin,
and potassium. The following organs were removed and weighed at necropsy: liver, brain,
thyroid, kidneys, adrenal glands, testes or ovaries, heart, and spleen. Statistical significance
between the treatment and control groups was determined using the Dunnett's Mest (p < 0.05);
calculations were performed by the American Statistical Association.
Body weight and food consumption remained normal throughout the course of the study
(see Table B.7). The hematology and clinical chemistry results are summarized in Tables B.8
and B.9 for males and females, respectively. After 4 weeks of treatment, an increase in clotting
time in males in the 39.08-mg/kg-day dose group was statistically different from the control, but
clotting time was not statistically elevated in males receiving the highest dose. Following
8 weeks of treatment, a decrease in phosphorous was seen in all of the treated males, but levels
were not statistically different by Week 13. No other changes in hematology or clinical
chemistry data were seen throughout the course of the study. The authors noted that RBC
cholinesterase measurements could not be used for comparisons due to technical difficulties with
the samples. Absolute and relative organ weights are provided in Tables B. 10 and B. 11,
respectively. The relative ovary weight was increased in all female treatment groups, but a level
of statistical significance was only achieved in the mid-dose group. There were no other dose
responses or histopathological results to indicate the adversity of this endpoint, nor were standard
deviations or individual data provided to determine the variability within each group. No other
relative or absolute organ weights were significantly different from the control group. Due to the
lack of treatment-related effects seen at the highest dose, a NOAEL of 92.78 mg/kg-day is
determined; no LOAEL can be determined.
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Bucci et al. (1994)
Bucci et al. (1994) is selected as the principal study for the derivation of the
subchronic p-RfD. Bucci et al. (1994) conducted a peer-reviewed, subchronic (90-day) oral
toxicity study on exposure to DIMP in Ranch Wild brown mink (Mustela vison). The
proprietary data (Bucci et al., 1992) were also available for review. Each dose group and the
3 control groups contained 10 mink per sex per group (12 months old). DIMP was obtained
from Lancaster Synthesis Inc., Ltd. (Windham, NH) with a reported purity of 95%. The animals
were fed 0-, 50-, 450-, 2700-, 5400-, or 8000-ppm DIMP in the diet. The study authors reported
average daily doses of 0, 6.8, 63.4, 344.7, 747.1, or 1008.6 mg/kg-day for males and 0, 9.0, 82.3,
455.2, 907.7, or 1263.5 mg/kg-day for females. Water was provided ad libitum. The control
groups consisted of one group that was fed ad libitum, one group that was fed to match the food
intake of the second highest dose group, and one group that was fed to match the food intake of
the highest dose group. The study authors reported that the study followed Good Laboratory
Practice (GLP) Standards. All mink were housed individually with 12.5 hours of light and
11.5 hours of darkness. The temperature was maintained at 23 ± 5°C and 30-70% relative
humidity. Body weight and food consumption were reported weekly. Clinical observations
were recorded twice daily. Hematology and clinical chemistry were determined from blood
samples taken on Weeks 0, 3, 7, and 13. The measured endpoints included the following:
hematocrit, hemoglobin, and erythrocyte counts, mean cell volume, mean corpuscular
hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte count, RBC morphology,
Heinz bodies, total leukocyte count, differential leukocyte count, and platelet count; in addition,
plasma and RBC cholinesterase, blood urea nitrogen, creatinine, glucose, total protein, albumin,
alanine aminotransferase, aspartate aminotransferase, sodium chloride, potassium, total
osmolality, total CO2, anion gap, total calcium, and inorganic phosphorus levels were measured.
Two male and two female mink from the 2700- and 8000-ppm groups were necropsied after a
4-week observation period. All other mink were necropsied at the end of the exposure period.
At necropsy, tissues samples were taken from all organ systems for microscopic examination.
The study authors reported that statistical significance was determined using the "repeated"
option of PROC GLM of SAS 1987 to account for the repeated measurements of each endpoint.
Additional details on the statistical methods of analysis were not provided.
The study authors reported a statistically significant reduction in the body weights of the
males and females in the high-dose group when compared with the controls (see Table B. 12).
The study authors concluded that these reductions in body weight were caused by decreased food
consumption due to taste aversion. This was supported by a similar decrease in body weight
seen in the control group with matched food consumption. The study authors noted that
matching the food consumption of the control group was only partially successful because the
mink in the control group tended to overcompensate when their food was available ad libitum.
Tables B.13 and B.14 show the reported changes in hematocrit, hemoglobin, erythrocyte count,
reticulocytes, Heinz bodies, and plasma cholinesterase levels recorded in females and males,
respectively. The study authors reported statistically significant decreases in hematocrit,
hemoglobin, erythrocyte, and plasma cholinesterase levels. There were also significant increases
in reticulocytes, and Heinz bodies, that started at Week 3 in females receiving 1263.5 mg/kg-day.
In females receiving 907.7 mg/kg-day, statistically significant reductions were seen in
hematocrit, hemoglobin, and plasma cholinesterase levels starting at Week 3. Statistically
significant increases were seen in the reticulocyte count at Week 3 and the number of Heinz
bodies starting at Week 7.
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In males, statistically significant decreases (hematocrit and erythrocytes) and increases
(reticulocytes) were seen in animals receiving 1008.6 mg/kg-day starting at Week 13 for
hematocrit, starting at Week 7 for erythrocytes and reticulocytes, and statistically significant
decreases (hemoglobin and plasma cholinesterase) and increases (Heinz bodies) starting at
Week 3 for hemoglobin, Heinz bodies, and plasma cholinesterase levels. In males receiving
747.1 mg/kg-day, statistically significant increases were seen at Week 3 for reticulocytes,
starting at Week 7 for Heinz bodies, and decreases starting at Week 3 for plasma cholinesterase
levels. In animals receiving 344.7 mg/kg-day, statistically significant reductions were found in
plasma cholinesterase levels starting at Week 7. As previously discussed, the plasma
cholinesterase level is considered a biomarker of exposure and is not considered an adverse
effect. The RBC acetylcholinesterase level was not affected by treatment with DIMP.
Erythrocyte morphology indicated mild-to-moderate dose- and time-dependent changes in both
male and female mink (data not reported). Platelet count and white blood cell (WBC) counts
were not biologically or statistically different from the controls. During a 4-week untreated
phase at the end of the study, animals in the mid- and high-dose groups showed no
treatment-related effects to any of the erythrocyte-related endpoints (see Table B.15).
Examination of the spleen revealed no statistically significant increase in the incidence or
severity of hematopoiesis in high-dose males and females; no effects were seen following the
4-week recovery phase (see Table B. 16). For this study, a NOAEL of 344.7 mg/kg-day and a
LOAEL of 747.1 mg/kg-day are determined based on the observed increased Heinz bodies.
Chronic Studies
There is one chronic study (U.S. DOD, 1978) summarized by IRIS (U.S. EPA, 1993)
where animals were administered adjusted daily doses of up to 0.8-mg/kg-day DIMP (purity not
reported) in the diet for 26 weeks; however, no adverse effects were reported. Therefore, the
information is provided in Table 2, but is not summarized again here.
Developmental Studies
Hart (1980b)
Hart (1980b) examined the developmental effects of prenatal exposure to DIMP in
CRL:COBS CD (SD) BR rats. The unpublished data are available but are not published in a
peer-refereed journal. In the study, all rats were obtained from Charles River Breeding
Laboratory (Portage, MI) and provided Purina laboratory chow and water ad libitum. The study
authors did not report whether the study was conducted in compliance with GLP guidelines.
DIMP (purity unspecified) was suspended in 100 mL of polyethylene glycol 400, blended with
10 kg of the basal diet, and incorporated into the diets of 20 pregnant rats per group at doses of 0,
100, 300, or 3000 ppm on Gestation Days (GDs) 6-15. Mean body weights (an average of the
body weights recorded on Days 6 and 16) and mean daily food consumption (Days 6-16) during
the treatment period were provided by the authors and used to estimate daily average doses of 0,
7.4, 21.6, and 232.5 mg/kg-day, respectively. The female rats were weighed on GDs 0, 6, 16,
and 20. Food consumption was measured on GDs 0-6, 6-16, and 16-20. All animals were
observed daily for changes in appearance, behavior, and condition. On GD 20, the adult females
were sacrificed, and the visceral and thoracic organs were examined. The number of
implantation sites and their placement in the uterine horns, live and dead fetuses, and resorption
sites were also evaluated in each pregnant female. All fetuses were removed and evaluated for
developmental abnormalities, including weight, crown-to-rump length, changes in the soft
tissues of the head, thoracic, and visceral organs, and skeletal abnormalities. This study is
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considered an acceptable developmental study because it uses an appropriate number of animals
and evaluates the offspring for treatment-related visceral and skeletal abnormalities
No treatment-related mortality was reported. Treatment with DIMP did not have any
effects on the mean body weight or food consumption (see Table B. 17). Table B. 18 summarizes
the reproductive indices. A statistically significant decrease in the number of implantation sites
was observed in the mid-dose group using a % test of independence (with Yates' correction for
continuity), but the number of implantation sites was normal in the high-dose group. The
authors also noted that no significant difference was observed in the mid-dose group when the
Wilcoxon rank sum test was used. No other treatment-related effects on reproduction were
noted. Examination of the offspring indicated a slight, though significant, increase in the number
of common skeletal abnormalities in animals that received the highest dose (see Table B.19).
The authors noted that this increase, while statistically significant, was not a treatment-related
effect for the following reasons: (1) while the increase was significant when using a 2 x 2
contingency table, the Wilcoxon rank sum test did not indicate a statistically significant effect;
and (2) the observed changes did not suggest a specific area of involvement. No other
treatment-related effects on development were noted. Therefore, a NOAEL of 232.5 mg/kg-day
is determined; no LOAEL can be determined.
Reproductive Studies
Three reproductive studies have been conducted with DIMP. Studies by Bucci et al.
(2003) and the U.S. DOD (1979)/Aulerich, et al. (1979) examined reproductive effects of DIMP
in mink while the U.S. DOD (1980)/Hart (1980c) study examined reproductive effects in rats.
Bucci et al. (2003)
Bucci et al. (2003) conducted a peer-reviewed, continuous breeding, reproductive toxicity
study on exposure to DIMP using Ranch Wild brown mink (Mustela vison). Each dose group
and the 2 control groups contained 9 male and 35 female mink (9 months old). DIMP was
obtained from Lancaster Synthesis Inc., Ltd. (Windham, NH) with a reported purity of between
97-99%. The animals were fed 0, 150, 450, or 2500 ppm in the diet. The study authors reported
the average daily dose to be 0, 14.94, 47.36, and 284.79 mg/kg-day in F0 males and 0, 25.61,
84.81, and 460.72 mg/kg-day in F0 females. Exposure began when the mink were 9.5 months
old. Harem mating occurred at 10.5 months of age, at which point, the F0 males were sacrificed.
The F1 generation was born approximately 1.75 months later. The study authors reported the
average daily doses as 0, 15.67, 45.00, and 261.73 mg/kg-day in F1 males and 0, 19.74, 56.50,
and 329.47 mg/kg-day in F1 females. F0 female mink were sacrificed after weaning was
completed (approximately 4 months). The F1 generation was administered feed that contained
DIMP at the same doses as the F0 generation. The F1 males were sacrificed after mating
(10.5 months of exposure, not including gestational exposure). F1 females were sacrificed after
weaning (13.5 months of exposure, not including gestational exposure). The F2 generation
males and females were sacrificed at the end of weaning. The study authors state that the study
was designed to follow the Health Effects Test Guidelines for Reproductive and Fertility Effects,
as published by the EPA's Office of Prevention, Pesticides, and Toxic Substances. The study
authors also report that the study was GLP compliant. All mink were obtained from the North
Branch Fur Farm (North Branch, MN). The study authors stated that realistic photoperiods were
maintained because they are critical for mink breeding patterns. Mink in both the F0 and F1
generations were vaccinated at 11 weeks of age for "common mink diseases." Body weight and
food consumption were measured weekly until mating and then on the day of whelping, 28 days
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after whelping, and on the day of sacrifice. The number of kits per litter, live kits per litter, litter
weights at birth, litter weights at 28 days after birth, and the sex ratios were measured in both the
F0 and F1 generations. Gross necropsy and microscopic examinations were conducted on all
parents and kits. The microscopic examination was limited to the reproductive organs of the
males and any lesions found in the kits. A total of 10 females per group had cholinesterase
levels measured in the brain. Male sperm count, motility, and morphology were measured using
IVOS Automated Semen Analyzers (Beverly, MA). The Krustal-Wallis nonparametric ANOVA
test using SAS was used to determine the statistical significance of the sperm count, motility, and
morphology data. The LABCAT system was used for statistical comparisons of the body
weight, food consumption, and hematological data.
The study authors reported that 3.4% (6/175) of the female mink in the F0 generation
died, but the causes of death were unrelated to DIMP exposure. The authors noted that mink are
susceptible to physical changes due to increased stress that can lead to death. Approximately
10-15% of nursing dams are susceptible to "nursing disease," in which they are not able to
maintain the energy required to nurse their offspring. The authors reported that 4.6% (8/175) of
the F1 female mink died early, but, again, DIMP exposure was not determined as the cause of
death. Six out of eight of these deaths, which were distributed across the dose and control
groups, were associated with the stress of anesthetic administration. No significant differences
were seen in the body weights or food consumptions of the dose groups in comparison with the
control in either the F0 or F1 male and female mink (see Table B.20). No adverse clinical
observations were attributed to DIMP exposure. The authors reported no significant effects to
semen, litter size, percent live births, kit weight, or sex distribution (see Tables B.21 and B.22 for
female and male reproductive indices, respectively). The study report only provided the
hematological results of the high-dose females from the F0 and F1 generations. The authors
noted that treatment-related hematological effects were not seen in the females in the other dose
groups; however, these data were not reported. The authors noted that data on the hematological
effects in males were limited to the effects observed in the high-dose group, as discussed below.
F0 females showed significant decreases in the RBC count and increases in reticulocytes, mean
corpuscular volume (MCV), and Heinz bodies when compared with the control at the time of
necropsy. F1 females showed significant increases in Heinz bodies at 7.5 months of age and at
the time of necropsy. The high-dose males in the F2 generation showed significantly decreased
RBC counts (4.06 million/|iL compared with 4.51 million/|iL in the control). No other
hematological effects were seen in the F2 generation males or females. Plasma cholinesterase
levels were decreased in F1 males (14% decrease compared with control) at 4.5 months of age,
and whole blood cholinesterase was decreased in F1 males at 7.5 months of age (6% decrease
compared with control) (data not provided). F0 females showed significant decreases in plasma,
whole blood cell, and RBC cholinesterase levels at necropsy (see Table B.23). F1 females
showed significant decreases in plasma and whole blood cell cholinesterase levels at 4.5, 7.5, and
13.5 months of age, and decreases in RBC cholinesterase levels at 4.5 months of age (see
Table B.24). Brain cholinesterase was not found to be affected in any of the animals at terminal
sacrifice (see Tables B.23 and B.24; data in males not reported). For this study, a NOAEL of
56.5 mg/kg-day and a LOAEL of 329.5 mg/kg-day are determined based on the hematological
changes that were observed in the high-dose F1 females.
It should be noted that a number of concerns regarding the methodology and data
interpretation of the Bucci et al. (2003) study have been raised (Calabrese, 2003a,b, 2005;
Colagiovanni, 2006; Calonge, 2006). These include the use of medical intervention to increase
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the survival odds of many animals, expunging the data on 19 animals, and a number of protocol
and procedure deviations that question the study's compliance with GLP guidelines (Calabrese,
2005). Calabrese (2003a,b) evaluated the data on the animals that received intervention.
Following an accidental overdose of anesthesia, Bucci et al. (2003) provided medical
intervention for 24 F1 generation females (11 control and 13 treated animals). Despite
intervention, 5 of the 24 animals died (2 control and 3 treated animals). Comparison between the
surviving treated animals and the control animals that received intervention show that more of
the treated animals had abnormal physiological or clinical values (33% of controls [3/9] vs. 90%
of treated animals [9/10]) (see Table B.25) (Calabrese, 2003a). Among the animals that did not
survive, RBC damage was seen in three of the four treated animals but not in either of the control
animals. Calabrese (2003a) concluded that the intervention was more beneficial for the
DIMP-treated animals and possibly reduced the number of treatment-related effects that were
observed.
U.S. DOD (1979) and Aulerich et al. (1979)
The U.S. DOD commissioned a 1-generation reproductive toxicity study in mink given
DIMP in the diet (U.S. DOD, 1979) that is also cited as Aulerich et al. (1979) in the literature.
Four groups of immature dark variety mink (6 males; 24 females) were administered 0 (control),
50, 150, or 450 ppm (corresponding to 0, 11, 37, and 95 mg/kg-day as calculated by study
authors) daily in the diet for one 12 month reproductive cycle. Mortality and signs of
intoxication were recorded throughout the study. Body weights were measured every two
weeks. Food consumption was measured at two week intervals. Hematology measurements
included hematocrit, hemoglobin, and differential leukocyte counts. Following mating, newborn
kits were sexed and weighed on the day of welping and again at one month of age. Length of
gestation, litter size, sex ratio, kit mortality, weight gain of kits during lactation, and weight
changes of the dams were recorded. At study termination, blood samples were taken and the
mink were weighed and necropsied. Gross morphological changes were recorded and the
following organs were weighed and histologically examined: brain, liver, kidneys, spleen,
gonads, lungs, heart, adrenal glands as well as portions of the intestine, stomach, skeletal muscle,
adipose tissue, and integument. All parameters were analyzed by the study authors for statistical
significance using analysis of variance and Dunnett's t-test.
Mortality was elevated in female and male parent mink in all treatment groups but the
male sample size was too small to reach statistical significance. There were no statistically
significant differences compared to control values in body weight, percent change in body
weight, or feed consumption. Hematocrit was elevated in males at the two highest doses (37 and
95 mg/kg-day) but there were no changes in hemoglobin or in differential leukocyte counts.
There were no statistically significant differences in kit mortality. Kit weight at four
weeks and body weight of lactating females was unchanged with the exception of a 15%
elevation in kit weight seen only at the low dose (11 mg/kg-day). Reproductive success was
unaffected by treatment with DIMP. The study authors found no adverse effects on the
following parameters: welping rates, gestation length, fecundity, and kit weight at birth.
Additionally, gross and histopathological examination revealed no consistent pathological
changes and organ weights were not significantly changed from control values. The study
authors concluded that chronic treatment with DIMP in the diet failed to alter the reproductive
capacity of mink. The significance of the observed mortality in this study is questionable since
no other treatment-related effects were seen and there is about a 6% mortality rate in first-year
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mink within commercial fur ranch operations. Additionally, no mortality was observed at higher
administered oral doses in other mink studies (Bucci et al. 1994; 2003). Thus, neither a NOAEL
nor a LOAEL were identified due to the inherent uncertainty associated with this study.
U.S. DOD (1980) and Hart (1980c)
The U.S. DOD commissioned a 3-generation reproductive toxicity study in rats exposed
orally to DIMP (U.S. DOD, 1980) that is also cited as Hart (1980c) in the literature. Sprague-
Dawley CD rats (10 males and 20 females/dose group) were given daily doses of DIMP (0, 13.5,
or 135 mg/kg-day) in food. Two litters (designated a and b) were produced by each succeeding
generation. The first generation parents (F0) were weighed and food consumption estimated in
weeks 4, 9, 11 and 20. These animals were observed daily for mortality, weekly for general
appearance, and for anatomic observations at necropsy. Dosing began after weaning in each
generation. Observations of rat pups within each generation included the following: number of
live and dead pups at birth; sex and body weight; number and sex of surviving pups at postnatal
day (PND) 4; number, sex and body weights at PND 21; daily appearance observations and
anatomic observations at necropsy. Observations of the second generation were conducted on a
similar schedule. Observations of the third generation were as follows: newborn viability ratios
(live pups/total pups); pup viability ratios (pups at PND 4/pups at PND 0); lactation indices
(pups at PND 21/pups at PND 4) and gestation indices (females giving birth/females pregnant).
Treatment groups were compared with controls using 2x2 contingency tables with Chi-squared
correction for continuity. Treatment and control means for parent body weights, parent food
consumption, and pup weights were compared using Dunnett's t-test.
The authors reported no dose-related, statistically significant results that could be
attributed to daily treatment with DIMP over three successive generations of rats with two
matings per generation. There were a number of observations that differed statistically from the
untreated controls but the effects were not consistent between litters or generations. For
example, statistically significant pup loss was reported from PND 4 through PND 21 in the
treatment groups of the first mating within the third generation, but pup loss was not observed in
the second mating. In another example, food consumption and body weight were statistically
equivalent to controls in all groups except the F2b high-dose females that had significantly lower
values. Litter observations of the first breeding rats from the three generations were not
significantly different and the necropsy observations were "unremarkable and free of any dose-
dependent relationship." A NOAEL of 135 mg/kg-day was identified for this study. A LOAEL
was not identified.
Carcinogenicity Studies
No studies were identified on the carcinogenicity of DIMP to animals.
Inhalation Exposures
No studies were identified on the inhalation exposure of DIMP to animals.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
The majority of the genotoxicity and mutagenicity studies were negative or equivocal
(see Table 3 A). DIMP was negative for mutagenicity in bacteria and yeast (Hart, 1980d,e). In
the L5178Y TK+/- mouse lymphoma assay, equivocal results were obtained without metabolic
activation while negative results were reported in the presence of metabolic activation
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(U.S. DOD, 1991a). Assays using Chinese hamster ovary cells reported a significant increase in
chromosomal aberrations both with or without S9 metabolic activation, but neither SCEs nor
DNA damage were induced with or without S9 (U.S. DOD, 1991b,c,d). Increased SCEs were
seen in human lymphocytes obtained from 4 healthy donors (2 male and 2 female) following
incubation with >40-ppm DIMP (Li et al., 1998). Equivocal and negative results were reported
in micronucleus induction assays conducted in male B6C3Fi mice and male F344 rats,
respectively (U.S. DOD, 1991e,f). The assay was conducted twice in mice, and a small, though
significant, increase was reported the first time; however, negative results were reported the
second time. In addition, the maximum increase was noted as within the laboratory's historical
control limits. No increase in DNA damage was observed in male B6C3Fi mice following oral
exposure to 1000-mg/kg DIMP (U.S. DOD, 1991g). DNA damage was seen in the leukocytes,
but not the liver parenchymal cells, that were obtained from F344 rats that were orally treated
with DIMP (U.S. DOD, 1991h).
Other Toxicity Studies (Exposures Other Than Oral or Inhalation)
Ahlin et al. (1975) evaluated the effects of DIMP on the reproductive development of
male and female rats following subcutaneous exposure to DIMP (see Table 3B). No effect on
nipple formation was seen in either the male or female offspring. However, a number of
abnormalities were seen in the male offspring that indicate that DIMP may cause antiandrogenic
effects. These included the presence of female sex organs, undescended testicles, absence of
ventral prostatic glands, and decreased weight and alteration of the seminal vesicles.
Metabolic/Toxicokinetic Studies
Following the oral administration of DIMP to mice, rats, dogs, and mink (Bucci et al.,
1992; Hart, 1976c, 1980f) and subcutaneous injection to swine (Snodgrass and Metker, 1992),
DIMP was reported to be rapidly absorbed, metabolized to isopropyl methyl phosphonic acid
(IMPA), and excreted in the urine (see Table 3B). However, following dermal exposure to swine
(Snodgrass and Metker, 1992), DIMP is poorly absorbed (i.e., approximately 7%), but is rapidly
excreted. None of the studies found accumulation of DIMP in any of the organs.
Mode-of-Action/Mechanistic Studies
There is no suitable information to provide in this regard.
Immunotoxicity
The immunotoxicity of DIMP was evaluated in an in vitro study that used mouse
splenocytes and human peripheral blood lymphocytes (Li et al., 2000) (see Table 3B).
Following exposure to DIMP, both dose- and time-dependent decreases in lymphocytes were
observed, indicating that exposure to DIMP may result in a decrease in lymphocytic functions.
Neurotoxicity
The ability of DIMP to cause organophosphate-induced delayed neurotoxicity (OPIDN),
from acute exposure, was evaluated in adult, white Leghorn hens (Hart, 1980g). The data are
available but are not published in a peer-refereed journal. Although important details were not
reported, it is inferred that 20 hens/dose were pretreated with atropine and then received a single
dose of either 0-, 500-, 1000-, or 1500-mg DIMP/kg by oral gavage or with the positive,
neurotoxic control, tri-ortho cresyl phosphate. After a 21-day recovery period, the hens were
euthanized, and the left sciatic nerve was dissected and examined microscopically. Hens in the
low and middle dose groups received a second dose of DIMP followed by a second 21-day
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recovery period and examination of the sciatic nerve. Increased mortality was observed in mid-
and high-dose animals, and unsteady gait was observed to occur in a dose-dependent fashion.
However, microscopic examination indicated no DIMP-related effects on nerve fiber
degeneration. Hart (1980g) inexplicably discounted the unsteady gait of the hens as unrelated to
the neurotoxicity endpoint, sciatic nerve degeneration. The unsteady gait, at all doses of DIMP,
suggests that 500 mg/kg-day is a LOAEL for neurotoxicity.
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Table 3A. Summary of DIMP Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Ames assay;
Salmonella typhimurium strains TA
98, 100, 1535, 1537, and/or 1538 in
the presence or absence of S9
5.0 |iL/platc
Study was conducted in
duplicate with the same results
reached in each study
Hart (1980d)
SOS repair induction
ND
ND
ND
ND
ND
NA
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
Saccharomyces cerevisiae strain D4
in the presence or absence of S9
5.0 |iL/platc
Study was conducted in
duplicate with the same results
reached in each study
Hart (1980e)
Recombination
induction
ND
ND
ND
ND
ND
NA
Chromosomal
aberration
ND
ND
ND
ND
ND
NA
Chromosomal
malsegregation
ND
ND
ND
ND
ND
NA
Mitotic arrest
ND
ND
ND
ND
ND
NA
Genotoxicity studies in mammalian cells—in vitro
Mutation
L5178Y TK +/- mouse lymphoma
mutagenesis assay
NR
±
-
No comments
U.S. DOD
(1991a)°
Chromosomal
aberrations
Chinese hamster ovary cells
evaluated for clastogenic damage
5 or 15 (iL/mL
+
+
Increased chromosomal
aberrations were seen at
5 (iL/mL without activation
and at 15 (iL/mL with S9
activation
U.S. DOD
(1991b)°
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Table 3A. Summary of DIMP Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With Activation
Sister chromatid
exchange (SCE)
Chinese hamster ovary cells
NR
-
-
No comments
U.S. DOD
(1991c)°
Sister chromatid
exchange (SCE)
Human lymphocytes were obtained
from 4 healthy donors (2 males and
2 females, 24-33 yr old) and
evaluated for SCE following
incubation with DIMP
40 ppm
+
ND
No comments
Lietal. (1998)
DNA damage
Chinese hamster ovary cells
NR
-
-
No comments
U.S. DOD
(1991d)°
DNA adducts
ND
ND
ND
ND
ND
NA
Genotoxicity studies in mammals—in vivo
Chromosomal
aberrations
ND
ND
ND
ND
ND
NA
Micronucleus
Induction
Bone marrow from male B6C3Fi
mice were evaluated for micronuclei
1000 mg/kg
±
ND
The assay was conducted
twice; a small but significant
increase was noted the first
time; however, the maximum
response was noted to be
within the laboratory's
historical control limits; the
assay was repeated with no
observed increase in
micronuclei
U.S. DOD
(1991e)°
Micronucleus
Induction
Bone marrow from male F344 rat
evaluated for micronuclei
800 mg/kg
-
ND
No comments
U.S. DOD
(1991f)c
Sister chromatid
exchange (SCE)
ND
ND
ND
ND
ND
NA
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Table 3A. Summary of DIMP Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With Activation
DNA damage
Male B6C3F, mice treated with
DIMP; liver parenchymal cells and
leukocytes evaluated for DNA
damage
1000 mg/kg
ND
No comments
U.S. DOD
(1991g)°
DNA damage
F344 rats (sex unspecified) treated
with DIMP; liver parenchymal cells
evaluated for DNA damage
NR
ND
Results are questionable
because no increase in DNA
damage was seen in the
positive controls
U.S. DOD
(1991h)°
DNA damage
F344 rats (sex unspecified) treated
with DIMP; leukocytes evaluated for
DNA damage
NR
+
ND
No comments
U.S. DOD
(1991h)°
DNA adducts
ND
ND
ND
ND
ND
NA
Mouse biochemical or
visible specific locus
test
ND
ND
ND
ND
ND
NA
Dominant lethal
ND
ND
ND
ND
ND
NA
Genotoxicity studies in subcellular systems
DNA binding
ND
ND
ND
ND
ND
NA
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 determined, NR = Not reported, NR/Dr =
Not reported by the study author, but determined from data.
Information was obtained from ATSDR (1998). The original data are not available.
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Carcinogenicity other
than oral/inhalation
ND
ND
ND
NA
Other toxicity studies
(exposures other than
oral or inhalation)
In a 1-generation reproductive study, a total of
11 female rats (9 albino [strain unknown] and
2 piebald) were administered 50-60 mg/day
DIMP via subcutaneous injection on GDs 14-20;
offspring were sacrificed at birth or on
PNDs 10-91 and examined for abnormalities of
the genital organs (males only) and nipples
DIMP was well tolerated by the maternal rats;
in the male offspring, abnormalities of the male
genital organs were noted and included the
presence of female sex organs, undescended
testicles, absence of the ventral prostatic glands,
and decreased weight and alteration of the
seminal vesicles; no effect on nipple formation
was seen in the male or female offspring
At high
concentrations,
subcutaneous
injections of DIMP
may cause
antiandrogenic effects
in male offspring
Ahlin et al.
(1975)
Metabolism/
toxicokinetic
Radiolabeled 14C-DIMP (97% pure) was diluted
with DIMP and administered to rats (66 or
660 mg/kg) and mink (27 or 270 mg/kg) by
gavage; blood was collected through the first
24 hr following administration; urine and feces
were collected at 4, 8, 12, and 24 hr following
administration and once daily thereafter for 5 d;
collections were analyzed for radioactivity and
DIMP metabolites
DIMP was rapidly absorbed and removed from
the blood of the rats and mink, as indicated by
peak radioactivity blood levels in rats (2-3 hr)
and mink (2 hr), except for high-dose male mink
where the peak was seen at 4 hr; no significant
accumulation was seen in any organ; in both
rats and mink, the majority of the radioactivity
was recovered in the urine and was largely
(>97%) associated with the metabolite IMPA
Following oral
administration to rats
and mink, DIMP is
rapidly absorbed,
metabolized to IMPA,
and excreted in the
urine
Bucci et al.
(1992)
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Metabolism/
toxicokinetic
Radiolabeled 14C-DIMP (>99% pure) was
combined with DIMP (>97% pure) in 95% ethyl
alcohol resulting in DIMP concentrations of 0.4,
4, or 40 mg/mL; each solution contained
10 (iCi/mL of radiocarbon content; Yorkshire
Cross male swine (3/dose group) were
percutaneously treated with DIMP; an additional
3 animals were treated with 40 mg/mL 14C-DIMP
by subcutaneous injection; urine and feces were
collected 24 hr after treatment and daily thereafter
through the 7-d study; animals were sacrificed at
the end of study and the brain, heart, kidneys,
liver, lungs, spleen, adrenal glands, thyroid gland,
bladder, skin, bone, bone marrow, fat, skeletal
muscle, and blood were collected and analyzed
for residual 14C
Percutaneous administration of 14C-DIMP in
swine resulted in less than 7% of the dose being
absorbed through the 7-d study; the majority of
the absorbed dose (>80%) was eliminated in the
urine within 24 hr of treatment; no significant
accumulation was seen in any organ
Following subcutaneous injection, DIMP was
rapidly eliminated in the urine (91% within
24 hr); by Day 7, 99% of the dose had been
excreted in the urine; DIMP accumulation was
not seen in any organ
In swine, DIMP is
poorly absorbed
following dermal
application; following
dermal treatment or
subcutaneous
injection, DIMP does
not bioaccumulate
significantly and is
rapidly excreted
Snodgrass and
Metker (1992)
Metabolism/
toxicokinetic
A single oral dose (225 mg/kg) of radiolabeled
14C-DIMP (>99% pure) was administered to S-D
rats, Swiss Webster mice, and purebred beagle
dogs; blood, urine, feces, and expired carbon
dioxide were collected intermittently for the first
72 hr following the initial administration of
14C-DIMP and 14 d later and examined for 14C;
the major organs were also obtained at these
times and examined for residual 14C
Peak plasma levels occurred within 15 min
following exposure in mice and 2 hr following
exposure in rats and dogs; plasma radioactivity
quickly decreased in all animals with high levels
of radioactivity seen in all of the examined
tissues; in mice (15 min after administration)
and rats (2 hr after administration), the highest
levels were measured in the bladder, lungs,
liver, and kidneys; in dogs, the highest tissue
levels of radioactivity were recorded at 4 hr
after the administration of 14C-DIMP and were
found in the lungs, bone marrow, cecum, and
bladder; radioactivity levels rapidly decreased in
all tissues; urinary excretion was the major route
of elimination with over 90% of 14C
radioactivity recovered in all animals within
24 hr of administration
DIMP is rapidly
absorbed in rats, dogs,
and mice with
absorption occurring
more rapidly in mice;
DIMP is rapidly
eliminated through the
urine
Hart (1976c)
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Metabolic/ toxicokinetic
Urine collected in rats, mice, and dogs over 24 hr
was analyzed for radioactivity and DIMP
metabolites
Over 90% of the radioactivity of 14C-DIMP
administered to rats, mice, and dogs was
recovered in the urine; most of the recovered
radioactivity (93.2% in rat, 95.6% in mouse,
99.6% in dog) was associated with the
metabolite IMPA
In rat, mouse, and
dog, DIMP is
transformed to the
metabolite IMPA
Hart (1980f)
Mode of action/
mechanistic
ND
ND
ND
NA
Immunotoxicity
Splenic lymphocytes were harvested from
6-wk-old male CBA/N mice; cytotoxic T
lymphocytes (CTL) were induced from the mouse
splenocytes; human peripheral blood
lymphocytes (PBL) were obtained from
10 healthy donors (5 males and 5 females);
lymphocytes were treated with 0, 500, 1000, or
2000 ppm for 1 hr; using a separate assay,
lymphocytes were treated with DIMP for 3-5 hr
as follows: mouse splenocytes were treated with
0, 62.5, 125, 250, 500, 1000, or 2000 ppm; mouse
CTL were treated with 0, 250, 500, 1000, or
2000 ppm; human PBL were treated with 0, 125,
250, or 500 ppm; cell suspensions were use to
determine the effect of DIMP on natural killer
(NK) and CTL (mouse only) activities
Dose- and time-dependent decreases in mouse-
and human-derived lymphocytes were observed
Exposure to DIMP
may result in
decreased lymphocyte
function
Li et al. (2000)
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Neurotoxicity
White Leghorn hens (20/group) received 2 oral
doses of 0, 500, or 1000 mg/kg DIMP 3 wk apart;
an additional group of 20 hens received a single
dose of 1500 mg/kg DIMP; animals were
sacrificed 24 d (21 d in high-dose group)
following the last dose
For positive controls, 20 animals were exposed to
500 mg/kg Tri-o-cresyl phosphate (TOCP)
Increased mortality was seen in animals that
received the mid- and high-doses; a total of
5 animals in the low-dose group developed
signs of unsteady gait, but these signs were
determined to be unrelated to effects observed
in the positive control; in the mid-dose group,
2 animals developed an unsteady gait following
the administration of DIMP, but returned to
normal by the end of the initial observation
period; in the highest dose group, some animals
became prostrate following treatment with
DIMP, but most recovered; most high-dose
animals developed an unsteady gait within
1-3 d after treatment but recovered; the authors
noted that the unsteady gait was dissimilar to
the effects seen in the positive control animals
and unrelated to nerve fiber degeneration; no
effect on nerve fiber degeneration was seen
during the histopathological examination
Treatment with DIMP
did not cause nerve
fiber degeneration in
white Leghorn hens;
however, unsteady
gait was noted
Hart (1980g)
NA = Not applicable; ND = No data.
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of the noncancer reference and cancer values, respectively. IRIS data are indicated in the table, if
available.
Table 4. Summary of Noncancer Reference Values for DIMP (CASRN 1445-75-6)
Toxicity Type (Units)
Species/
Sex
Critical Effect
p-Reference
Value
POD Method
POD
UFC
Principal Study
Subchronic p-RfD (mg/kg-day)
Mink/M
Increased Heinz
bodies
1 x 10°
NOAEL
344.7
300
Bucci et al. (1994)
Chronic RfD (mg/kg-day)
IRIS (U.S. EPA, 1993)
Dog/M+F
No treatment-related
effects
8 x 10~2 (IRIS)
NOAEL
75a
1000
Hart (1980a)
Subchronic p-RfC (mg/m3)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Chronic p-RfC (mg/m3)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
aThe NOAEL reported by IRIS does not match the NOAEL reported for this study in Table 2 due to differences in dose conversion calculations applied to the
administered dose (3000 ppm).
NDr = Not determined.
Table 5. Summary of Cancer Values for DIMP (CASRN 1445-75-6)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
NDr
NDr
NDr
p-IUR
NDr
NDr
NDr
NDr
NDr = Not determined
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The study by Bucci et al. (1994) is selected as the principal study for the derivation of the
subchronic p-RfD. The critical effect is increased Heinz bodies in male mink given DIMP for
90 days with an associated NOAEL of 344.7 mg/kg-day. The details of this study are provided
in the "Review of Potentially Relevant Data" section. This study is published in a peer-reviewed
journal and was performed according to GLP guidelines. Benchmark dose (BMD) analysis is
not possible with these data because the number of blood samples available for each endpoint
was not reported. Consequently, the NOAEL/LOAEL approach is used. From the available
database of studies (see Table 2), Bucci et al. (1994; 2003) are the only studies that examined
animals that were administered doses sufficient to cause observable toxic effects. An increase in
Heinz bodies was reported in both sexes and represented the most sensitive effect. Heinz bodies
are inclusions seen in erythrocytes that are indicative of oxidative damage to hemoglobin. Their
occurrence can result in anemia. In addition, decreased hematocrit, hemoglobin, and erythrocyte
counts, and the increased reticulocyte count, indicate damage to RBC, providing further
supporting evidence of treatment-related effects (see Tables B.13 and B.14). Bucci et al. (2003)
was considered as a potential principal study, but serious questions about the methodology and
accusations of scientific misconduct (Calabrese, 2003 a,b; Colagiovanni, 2006; Calonge, 2006)
precluded further consideration of the study.
A decrease in plasma cholinesterase levels was observed in subchronic studies in rats (see
Tables B.4 and B.5; Hart, 1976a), dogs (see Tables B.8 and B.9; Hart, 1980a), and mink (see
Tables B.13 and B.14; Bucci et al., 1994). However, measures of brain cholinesterase, in test
animals, are the most direct evidence of a potential human health hazard. RBC cholinesterase
also provides a good estimate of potential hazards and is preferred over plasma cholinesterase.
Plasma cholinesterase is best used as part of a weight-of-evidence approach when RBC and brain
cholinesterase levels are not available (U.S. EPA, 2000). In this case, Hart (1976a) found that
the brain cholinesterase level was decreased in male and female rats administered
>74.58 mg/kg-day or >27.98 mg/kg-day, respectively, by 16-37% (see Tables B.4 and B.5);
however, these results are not dose-dependent or statistically significant and were only measured
in 5 rats per sex per treatment group (Hart, 1976a). In addition, brain cholinesterase levels were
not decreased in the mink (Bucci et al., 2003) (see Tables B.23 and B.24). There were no
clinical signs of neurotoxicity observed in any of these studies. A study performed on chickens
indicates that DIMP has a dose-dependent effect on gait when administered at doses that cause
mortality, but these doses did not result in the degeneration of the nerve fibers (Hart, 1980g).
Red blood cell cholinesterase was not changed in mink (Bucci et al., 1994) at the two
highest dose levels (907.7 and 1263.5 mg/kg-day) and was increased in mink by no more than
8% in a second study (Bucci et al. 2003). And while plasma cholinesterase was statistically
significantly decreased at lower doses than other endpoints, there was no dose response, with
male rats having an increase (rather than a decrease) in plasma cholinesterase at the highest dose,
and the results were highly variable at the different time points measured (Hart, 1980a). For the
reasons stated above, the observation of Heinz bodies in RBCs (Bucci et al., 1994) represented
the best choice of critical effect, and the NOAEL of 344.7 mg/kg-day was selected as the POD.
IRIS (U.S. EPA, 2011) used the Hart (1980a) subchronic study in beagle dogs to derive a
chronic RfD based on a NOAEL at the highest level tested. The Bucci et al. (1994) study,
selected here as the principal study, was not available to IRIS at the time (02/01/93 date of last
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revision). Nonetheless, there are several reasons it is superior to the Hart (1980a) study as the
choice of principal study. The Bucci et al. (1994) study employed more animals (10/sex/dose vs.
4/sex/dose) than the Hart (1980a) study; more doses were tested (5 doses vs. 3 doses); a greater
dose range was employed (6.8 to 1263.5 mg/kg-day vs. 4.6 to 92.8 mg/kg-day); a LOAEL and
NOAEL (versus a NOAEL only) were clearly identified; and it was published in a peer-refereed
journal.
No dosimetric adjustments are made as the study authors provided estimates of daily
consumption, presumably using the ppm in the diet, individual food consumption, and body
weight measurements.
The subchronic p-RfD for DIMP, based on the NOAELadj of 344.7 mg/kg-day
(Bucci et al., 1994), is derived as follows:
Subchronic p-RfD = NOAELadj + UF
= 344.7-300
= 1 x 10° mg/kg-day
Table 6 summarizes the uncertainty factors for the subchronic p-RfD for DIMP.
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Table 6. Uncertainty Factors for Subchronic p-RfD of DIMP
UF
Value
Justification
Notes
ufa
10
A UFa of 10 is applied for interspecies extrapolation to
account for potential toxicokinetic and toxicodynamic
differences between animal models and humans.
No notes
ufd
3
A UFd of 3 is applied because the database includes an
acceptable oral three-generation reproductive study in
rats (Hart, 1980c) and an acceptable oral developmental
study in rats (Hart, 1980b). However, there is clear
indication of the need for a repeated dose, subchronic- or
chronic-duration neurotoxicity study.
Uneven gaits were observed in
chickens; possible decrease in
brain cholinesterase levels in rats,
but not in mink; no clinical signs of
toxicity in rats, mice, or dogs, but
doses were not high enough in rats,
dogs, or mice to observe adverse
effects
UFh
10
A UFh of 10 is applied for intraspecies differences to
account for potentially susceptible individuals in the
absence of information on the variability of response to
humans.
No notes
ufl
1
A UFl of 1 is applied because the POD was developed
using a NOAEL.
No notes
UFS
1
A UFS of 1 is applied because a subchronic-duration
study was utilized.
No notes
UFC
<3000
300
A UFC of 300 is applied for derivation of the subchronic
p-RfD.
No notes
UFa for interspecies animal-to-human extrapolation.
UFd for deficiencies in the database.
UFh for sensitive human subgroups.
UFl for extrapolation from a LOAEL to a NOAEL.
UFS for extrapolation from subchronic to chronic duration.
UFC is the composite uncertainty factor.
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The confidence of the subchronic p-RfD for DIMP is medium, as explained in Table 7
below.
Table 7. Confidence Descriptors for Subchronic p-RfD for DIMP
Confidence Categories
Designation"
Discussion
Confidence in study
H
Confidence in the key study is high. Bucci et al. (1994) was
adequate in design for a 90-d study in mink. The study was
peer-reviewed and followed GLP guidelines. The study
included multiple effect levels, and both a NOAEL and LOAEL
are identified.
Confidence in database
M
The database includes subchronic toxicity studies on rat,
mouse, dog, and mink, (Hart, 1976a,b, 1980a; Bucci et al.,
1994), a developmental toxicity study on the rat (Hart, 1980b),
and one 3-generation reproductive study on the rat (Hart,
1980c). Of the four available subchronic studies, only the study
performed in mink was performed at a dose level sufficient to
cause observable toxic effects. The available evidence
indicates the need for a neurological study.
Confidence in subchronic p-RfDb
M
The overall confidence in the subchronic p-RfD is medium.
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)
A chronic RfD of 8 x 1CT2 mg/kg-day is available on IRIS (U.S. EPA, 1993) based on the
90-day feeding study in dogs (Hart 1980a, referenced as U.S. DOD, 1980 in IRIS). The IRIS
database should be checked to determine if any significant changes have been made.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No subchronic or chronic p-RfC can be derived because no inhalation studies on
exposure of humans or animals to DIMP were identified.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 8 identifies the cancer WOE descriptor for DIMP.
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Table 8. Cancer WOE Descriptor for DIMP
Possible WOE
Descriptor
Designation
Route of Entry (Oral,
Inhalation, or Both)
Comments
"Carcinogenic to
Humans "
NS
NA
No human carcinogenicity studies were
identified.
"Likely to Be
Carcinogenic to
Humans "
NS
NA
No animal carcinogenicity studies were
identified.
"Suggestive Evidence
of Carcinogenic
Potential"
NS
NA
No animal carcinogenicity studies were
identified.
"Inadequate
Information to Assess
Carcinogenic
Potential"
Selected
Both
This is selected due to the lack of any data
on carcinogenicity.
"Not Likely to Be
Carcinogenic to
Humans "
NS
NA
Although the genotoxicity studies were
negative or equivocal, there are no data to
indicate that DIMP is not carcinogenic to
humans or animals.
NS = Not selected; NA = Not applicable.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The lack of data on the carcinogenicity of DIMP precludes the derivation of quantitative
estimates for either oral (p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A. PROVISIONAL SCREENING VALUES
There are no screening values for DEVEP.
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APPENDIX B. DATA TABLES
Table B.l. Average Body Weights and Food Consumption of Male and Female Rats
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
300 (24.74)
1000 (74.58)
3000 (229.17)
Male
Mean body weight
(kg)
0.296
0.291
0.295
0.288
Food consumption
(kg/d)
0.022
0.024
0.022
0.022
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
300 (27.98)
1000 (92.31)
3000 (257.58)
Female
Body weight (kg)
0.195
0.193
0.195
0.198
Food consumption
(kg/d)
0.019
0.018
0.018
0.017
aSource: Hart (1976a).
Calculated from average body weights and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
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Table B.2. Selected Mean Hematology and Blood Chemistry Levels of Male Rats
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
300 (24.74)
1000 (74.58)
3000 (229.17)
N
5
5
5
5
Wk 4
PCV (%)
48.0 ± 1.4°
50.0 ±0.75 (104)
50.5 ±0.24 (105)
48.0 ± 1.2 (100)
Hemoglobin (gm %)
15.6 ±0.86
16.6 ±0.43 (106)
16.4 ±0.41 (105)
15.6 ±0.56 (100)
RBC (mm3 x 106)
6.19 ±0.32
6.85 ±0.21 (111)
6.76 ±0.16 (109)
6.06 ± 0.28 (98)
WBC (mm3 x 103)
11.5 ±0.93
13.1 ±0.58 (114)
12.1 ± 1.0(105)
10.8 ± 1.3 (94)
BUN (mg %)
18 ± 1.2
19 ±0.73 (106)
20 ±0.80 (111)
18 ±0.51 (100)
Glucose (mg %)
79 ±5.4
73 ± 6.8 (92)
79 ±6.5 (100)
72 ±3.0 (91)
Alkaline phosphatase
(i.u.)
168 ± 12
163 ± 6.5 (97)
177 ±22 (105)
140 ±11 (83)
SGPT (i.u.)
16 ± 1.2
18 ±0.85 (113)
15 ± 0.63 (94)
16 ±0.92 (100)
Wk 13
PCV (%)
50.5 ± 1.0
52.5 ±0.93 (104)
50.0 ± 0.72 (99)
52.0 ±2.3 (103)
Hemoglobin (gm %)
16.8 ±0.33
16.9 ±0.64 (101)
16.8 ±0.21 (100)
17.2 ±0.68 (102)
RBC (mm3 x 106)
7.62 ±0.31
7.76 ±0.39 (102)
7.53 ±0.24 (99)
7.52 ± 0.24 (99)
WBC (mm3 x 103)
12.1 ± 1.8
12.3 ±2.3 (102)
11.3 ±0.92 (93)
12.9 ± 1.7(107)
BUN (mg %)
18 ±0.87
23 ±3.9 (128)
21 ±3.0 (117)
19 ± 1.5 (106)
Glucose (mg %)
99 ±6.2
97 ±3.6 (98)
103 ± 10 (104)
102 ±6.4 (103)
Alkaline phosphatase
(i.u.)
109 ± 14
239 ± 12 (219)d
116 ±2.7 (106)
130 ±26 (119)
SGOT (i.u.)
261 ± 19
239 ± 20 (92)
263 ±28 (101)
245 ± 7.2 (94)
SGPT (i.u.)
26 ±2.2
30 ±3.3 (115)
30 ±4.8 (115)
24 ± 1.2(92)
Potassium (mEq/L)
8.9 ±0.86
8.1 ±0.28 (91)
8.3 ±0.56 (93)
10.5 ± 1.4 (118)
Sodium (mEq/L)
194 ±7.8
192 ± 5.8 (99)
194 ±5.3 (100)
196 ±7.4 (101)
aSource: Hart (1976a).
Calculated from average body weights and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°Mean ± S.E.(% of control).
dp < 0.01 by independent Student's t-test; not calculated by study authors.
PCV = Packed cell volume, BUN = Blood urea nitrogen, SGOT = Serum glutamic oxaloacetic transaminase,
SGPT = Serum glutamic pyruvic transaminase.
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Table B.3. Mean Hematology and Blood Chemistry Results of Female Rats
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
300 (27.98)
1000 (92.31)
3000 (257.58)
N
5
5
5
5
Wk 4
PCV (%)
46.5 ± 1.8
48.5 ± 1.1 (104)°
47.5 ± 1.0 (102)
46.0 ± 1.4 (99)
Hemoglobin (gm %)
14.7 ±0.58
16.7 ±0.43 (114)d
16.1 ±0.47 (110)
15.5 ±0.44 (105)
RBC (mm3 x 106)
5.72 ±0.46
6.92 ± 0.18 (121)d
6.43 ±0.20 (112)
6.42 ±0.14 (112)
WBC (mm3 x 103)
8.3 ± 1.3
8.9 ± 1.5 (107)
6.8 ±0.59 (82)
7.7 ±0.71 (93)
BUN (mg %)
19 ±0.87
20 ±0.86 (105)
21 ±2.3 (lll)d
20 ± 1.5 (105)
Glucose (mg %)
83 ±2.8
84 ±8.0 (101)
90 ±7.7 (108)
86 ± 5.5 (104)
Alkaline phosphatase (i.u.)
97 ±5.3
86 ± 5.3 (89)
95 ± 11 (98)
87 ± 14.0 (90)
SGPT (i.u.)
15 ±0.73
15 ± 1.4 (100)
13 ±0.81 (87)
12 ± 0.68 (80)d
Wk 13
PCV (%)
47.0 ±0.54
48.5 ±0.85 (103)
50.5 ± 1.4 (107)d
50.5 ±0.88 (107)e
Hemoglobin (gm %)
15.7 ±0.22
16.3 ± 0.27 (104)
16.8 ±0.40 (107)d
16.6 ±0.18 (106)d
RBC (mm3 x 106)
7.04 ±0.18
7.15 ±0.27 (102)
7.12 ±0.35 (101)
6.92 ± 0.20 (98)
WBC (mm3 x 103)
9.1 ± 1.1
8.6 ± 1.5 (95)
7.9 ±0.59 (87)
8.6 ± 1.2 (95)
BUN (mg %)
22 ± 1.2
21 ±0.71 (95)
18 ±0.51 (82)
21 ± 1.1 (95)
Glucose (mg %)
112 ±6.6
110 ± 11 (98)
93 ± 12 (83)
107 ±8.1 (96)
Alkaline phosphatase (i.u.)
108 ± 13
80 ± 6.0 (74)d
78 ± 4.6 (72)
68 ± 12 (63)
SGOT (i.u.)
226 ± 11
236 ±24 (104)
228 ±26 (101)
229 ±8.1 (101)
SGPT (i.u.)
18 ±0.45
17 ± 0.89 (94)
20 ±3.0 (111)
20 ± 0.68 (11 l)d
Potassium (mEq/L)
7.8 ±0.67
7.7 ±0.36 (99)
7.4 ± 0.27 (95)
8.8 ±0.19 (113)
Sodium (mEq/L)
187 ±8.3
186 ±9.1 (99)
180 ± 10 (96)
194 ±8.0 (104)
aSource: Hart (1976a).
Calculated from average body weights and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°Mean± S.E. (% of control).
dp < 0.05 by independent Student's t-test; not calculated by study authors.
ep < 0.01 by independent Student's t-test; not calculated by study authors.
35 Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.4. Cholinesterase Levels in Male Rats Exposed to DIMP for 90 Days"
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
Parameter
0
150 (24.74)
1500 (74.58)
3000 (229.17)
Wk 4
RBC (nU/mL)
207 ± 23
211 ±31 (102)
240 ±35 (116)
155 ±21 (75)
N
3
4
4
4
Plasma (|iU/mL)
673 ±211
523 ± 39 (78)
782 ±245 (116)
795 ±198 (118)
N
3
4
4
4
Wk 13
RBC (nU/mL)
189 ± 19
285 ±56 (151)
460 ± 19 (243)°
222 ±72 (117)
N
3
4
5
4
Plasma (|iU/mL)
925 ± 34
469 ±31 (51)°
564 ±27 (61)°
1229 ±64 (133)°
N
4
4
5
4
Brain (^U/mg tissue)
14.73 ±4.7
16.69 ±6.2 (113)
13.16 ±4.1 (89)
11.59 ±2.8 (79)
N
5
5
5
5
aSource: Hart (1976a).
Calculated from average body weight and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
cp < 0.01 by independent Student's t-test; not calculated by study authors.
U = amount of enzyme necessary to catalyze the conversion of 1 |iIVI of substrate per minute.
36
Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.5. Cholinesterase Levels in Female Rats Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (27.98)
1500 (92.31)
3000 (257.58)
Wk 4
RBC (nU/mL)
165 ±32
141 ±34 (85)
132 ±41 (80)
169 ± 13 (102)
N
4
4
4
3
Plasma (|iU/mL)
937 ± 207
1447 ± 353 (154)
1466 ±319 (156)
1401 ± 137 (150)
N
4
4
4
3
Wk 13
RBC (nU/mL)
143 ± 10
252 ± 86 (176)
134 ± 40 (94)
114 ±40 (80)
N
3
4
4
3
Plasma (nU/mL)
2361 ±29
2062 ± 147 (87)
1977 ±301 (84)
912 ±40 (34)°
N
3
5
4
3
Brain (|iU/mg tissue)
11.17 ± 1.4
7.29 ± 1.3 (65)
7.00 ± 1.2 (63)
9.36 ±2.4 (84)
N
5
5
5
5
aSource: Hart (1976a).
Calculated from average body weight and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
cp < 0.01 by independent Student's t-test; not calculated by study authors.
37
Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.6. Body Weights and Food Consumption of Male and Female Mice
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (37.94)
1500 (108.18)
3000 (337.27)
Male
N
4
4
4
4
Mean body weight (kg)0
0.032
0.031
0.033
0.032
Food consumption (kg/d)°
0.0056
0.0056
0.0051
0.0053
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (42.00)
1500 (142.59)
3000 (460.38)
Female
N
4
4
4
4
Mean body weight (kg)0
0.027
0.027
0.027
0.026
Food consumption (kg/d)°
0.0056
0.0054
0.0055
0.0057
aSource: Hart (1976b).
Calculated from average body weight and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
Data calculated from individual weekly animal data. If data were missing, the previously reported value was used
for that week.
38
Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.7. Mean Body Weights and Average Food Consumption of Male and Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
Male
N
4
4
4
4
Mean body weight (kg)0
10.9
11.6
11.5
10.9
Food consumption (kg/d)°
0.37
0.41
0.31
0.31
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
Female
N
4
4
4
4
Mean body weight (kg)0
9.7
9.9
9.9
9.7
Food consumption (kg/d)°
0.30
0.30
0.31
0.30
aSource: Hart (1980a).
Calculated from average body weights and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
Data calculated from individual weekly animal data. If data were missing, the previously reported value was used
for that week.
39
Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.8. Mean Hematology and Clinical Chemistry Levels of Male Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
N
4
4
4
4
WkO
PCV (%)
48
44 (92)°
42d (88)
44 (92)
HGB (g %)
15.7
14.8 (94)
14.2 (90)
15.0 (96)
RBC (mm3 x 106)
7.54
6.57 (87)
6.49 (86)
6.63 (88)
WBC (mm3 x 103)
7.7
7.9(103)
6.5 (84)
7.6 (99)
Clotting time (sec)
353
375 (106)
465 (132)
435 (123)
Glucose (mg/dL)
99
120 (121)
94 (95)
111 (112)
BUN (mg/dL)
12
10 (83)
14 (117)
10 (83)
SGOT (miu/mL)
40
40 (100)
36 (90)
31 (78)
SGPT (miu/mL)
32
37 (116)
29 (91)
32 (100)
Alkaline phosphatase (miu/mL)
152
112(74)
113 (74)
106 (70)
LDH (miu/mL)
225
238 (106)
213 (95)
158 (70)
Calcium (mg/dL)
11.9
11.6(97)
11.8(99)
11.4 (96)
Phosphorus (mg/dL)
6.8
6.0 (88)
6.3 (93)
6.4 (94)
Total protein (g/dL)
6.3
5.8 (92)
6.0 (95)
5.8 (92)
Albumin (g/dL)
3.5
3.2 (91)
2.9 (83)
2.9 (83)
Bilirubin (mg/dL)
0.2
0.3 (150)
0.3 (150)
0.3 (150)
Uric acid (mg/dL)
0.4
0.3 (75)
0.2 (50)
0.3 (75)
Cholesterol (mg/dL)
182
163 (90)
167 (92)
169 (93)
Plasma cholinesterase (mu/mL)
2359
2062 (87)
1775 (75)
2087 (88)
RBC cholinesterase (mu/mL)
685
798 (116)
815 (119)
523 (76)
Wk 4
PCV (%)
48
50 (104)
48 (100)
46 (96)
HGB (g %)
16.9
17.2 (102)
17.1 (101)
15.9 (94)
RBC (mm3 x 106)
6.91
7.00(101)
6.95 (101)
6.82 (99)
WBC (mm3 x 103)
9.1
10.3 (113)
10.9 (120)
9.9(109)
Clotting time (sec)
405
555 (137)
675d (167)
578 (143)
Glucose (mg/dL)
97
109 (112)
109(112)
106 (109)
BUN (mg/dL)
15
14 (93)
14 (93)
12 (80)
SGOT (miu/mL)
37
41 (111)
37 (100)
32 (86)
SGPT (miu/mL)
41
36 (88)
35 (85)
42 (102)
40 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.8. Mean Hematology and Clinical Chemistry Levels of Male Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
Alkaline phosphatase (miu/mL)
127
87 (69)
84 (66)
72 (57)
LDH (miu/mL)
87
98(113)
83 (95)
53 (61)
Calcium (mg/dL)
11.3
11.4(101)
11.4(101)
11.3 (100)
Phosphorus (mg/dL)
4.9
4.6 (94)
4.5 (92)
4.4 (90)
Total protein (g/dL)
6.3
5.9 (94)
6.1 (97)
6.0 (95)
Albumin (g/dL)
3.5
3.5 (100)
3.7 (106)
3.5 (100)
Bilirubin (mg/dL)
0.1
0.1 (100)
0.1 (100)
0.1 (100)
Uric acid (mg/dL)
0.4
0.8 (200)
0.3 (75)
0.3 (75)
Cholesterol (mg/dL)
164
141 (86)
167 (102)
153 (93)
Plasma cholinesterase (mu/mL)
NR
1862
1571
1750
RBC cholinesterase (mu/mL)
NR
2667
4804
4889
Wk 8
PCV (%)
48
48 (100)
48 (100)
48 (100)
HGB (g %)
16.9
16.9 (100)
17.1 (101)
17.6 (104)
RBC (mm3 x 106)
8.46
8.07 (95)
7.88 (93)
7.71 (91)
WBC (mm3 x 103)
12.3
14.5 (118)
13.5 (110)
11.2(91)
Clotting time (sec)
488
488 (100)
533 (109)
488 (100)
Glucose (mg/dL)
88
93 (106)
93 (106)
101 (115)
BUN (mg/dL)
18
15 (83)
14 (78)
13 (72)
SGOT (miu/mL)
35
46 (131)
45 (129)
40 (114)
SGPT (miu/mL)
38
35 (92)
36 (95)
42 (111)
Alkaline phosphatase (miu/mL)
124
77 (62)
74 (60)
71 (57)
LDH (miu/mL)
183
287 (157)
269 (147)
201 (110)
Calcium (mg/dL)
10.8
10.8 (100)
10.6 (98)
10.5 (97)
Phosphorus (mg/dL)
5.4
4.8d (89)
4.7d (87)
4.7d (87)
Total protein (g/dL)
6.9
6.6 (96)
6.6 (96)
6.5 (94)
Albumin (g/dL)
3.2
3.1 (97)
3.1 (97)
3.1 (97)
Bilirubin (mg/dL)
0.4
0.4 (100)
0.1 (25)
0.1 (25)
Uric acid (mg/dL)
0.4
0.6(150)
0.5 (125)
0.5 (125)
Cholesterol (mg/dL)
176
152 (86)
166 (94)
152 (86)
Plasma cholinesterase (mu/mL)
NR
2176
1692
1798
RBC cholinesterase (mu/mL)
NR
2688
3181
2709
41 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.8. Mean Hematology and Clinical Chemistry Levels of Male Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
Wk 13
PCV (%)
49
47 (96)c
47 (96)
49 (100)
HGB (g %)
16.6
15.8 (95)
15.6 (94)
16.4 (99)
RBC (mm3 x 106)
7.21
7.11 (99)
7.23 (100)
7.60 (105)
WBC (mm3 x 103)
11.0
10.6 (96)
10.7 (97)
9.4 (85)
Clotting time (sec)
458
570 (124)
518 (113)
480 (105)
Glucose (mg/dL)
89
99(111)
104(117)
105 (118)
BUN (mg/dL)
14
14 (100)
14 (100)
13 (93)
SGOT (miu/mL)
45
52 (116)
50(111)
49 (109)
SGPT (miu/mL)
44
44 (100)
36 (82)
44 (100)
Alkaline phosphatase (miu/mL)
82
53 (65)
51 (62)
48 (59)
LDH (miu/mL)
231
518 (224)
499 (216)
332 (144)
Calcium (mg/dL)
11.2
10.9 (97)
11.2(100)
11.0(98)
Phosphorus (mg/dL)
5.1
4.5 (88)
4.6 (90)
4.6 (90)
Total protein (g/dL)
6.6
6.3 (95)
6.6 (100)
6.4 (97)
Albumin (g/dL)
3.3
3.3 (100)
3.4 (103)
3.3 (100)
Bilirubin (mg/dL)
0.1
0.1 (100)
0.4 (400)
0.2 (200)
Uric acid (mg/dL)
0.6
1.1 (183)
0.9 (150)
0.6 (100)
Cholesterol (mg/dL)
156
145 (93)
170 (109)
142 (91)
Plasma cholinesterase (mu/mL)
2704
1888 (70)
1687 (62)
1839 (68)
RBC cholinesterase (mu/mL)
2688
2302 (86)
1982 (74)
3392 (126)
aSource: Hart (1980a).
Calculated from average body weight and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°Mean (% of control).
dp < 0.05 by Dunnett's /-test, conducted by the study author.
NR = Not reported.
42 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.9. Mean Hematology and Clinical Chemistry Levels of Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
N
4
4
4
4
WkO
PCV (%)
45
46 (102)c
48 (107)
45 (100)
HGB (g %)
15.2
15.1 (99)
16.4 (108)
15.1 (99)
RBC (mm3 x 106)
6.84
6.58 (96)
7.09 (104)
6.84 (100)
WBC (mm3 x 103)
5.7
6.4 (112)
6.7(118)
7.6 (133)
Clotting time (sec)
338
443 (131)
443 (131)
465 (138)
Glucose (mg/dL)
108
109 (101)
113 (105)
122(113)
BUN (mg/dL)
11
11 (100)
12 (109)
13 (118)
SGOT (miu/mL)
36
32 (89)
30 (83)
33 (92)
SGPT (miu/mL)
27
32(119)
33 (122)
37 (137)
Alkaline phosphatase (miu/mL)
110
107 (97)
99 (90)
103 (94)
LDH (miu/mL)
269
160 (59)
156 (58)
182 (68)
Calcium (mg/dL)
11.9
11.8(99)
11.8(99)
11.6 (97)
Phosphorus (mg/dL)
6.2
6.5 (105)
6.1 (98)
6.2 (100)
Total Protein (g/dL)
6.1
5.8 (95)
6.0 (98)
5.8 (95)
Albumin (g/dL)
3.4
3.1 (91)
3.1 (91)
2.9 (85)
Bilirubin (mg/dL)
0.4
0.3 (75)
0.2 (50)
0.2 (50)
Uric acid (mg/dL)
0.3
0.2 (67)
0.3 (100)
0.2 (67)
Cholesterol (mg/dL)
188
177 (94)
176 (94)
174 (93)
Plasma cholinesterase (mu/mL)
2324
1820 (78)
2296 (99)
2016 (87)
RBC cholinesterase (mu/mL)
1075
865 (80)
1018(95)
735 (68)
Wk 4
PCV (%)
49
48 (98)°
50 (102)
49 (100)
HGB (g %)
17.2
16.9 (98)
17.3 (101)
17.3 (101)
RBC (mm3 x 106)
7.04
6.84 (97)
6.90 (98)
7.07 (100)
WBC (mm3 x 103)
9.8
9.8 (100)
9.5 (97)
7.7 (79)
Clotting time (sec)
465
555 (119)
668 (144)
600 (129)
Glucose (mg/dL)
109
105 (96)
118
112
BUN (mg/dL)
13
14 (108)
15 (115)
14 (108)
SGOT(miu/mL)
37
37 (100)
39 (105)
30(81)
SGPT (miu/mL)
31
38 (123)
37 (119)
38 (123)
43 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.9. Mean Hematology and Clinical Chemistry Levels of Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
Alkaline phosphatase (miu/mL)
95
92 (97)
81 (85)
73 (77)
LDH (miu/mL)
83
105 (127)
54 (65)
46 (55)
Calcium (mg/dL)
11.4
11.5 (101)
11.7(103)
11.3 (99)
Phosphorus (mg/dL)
4.3
4.5 (105)
4.7 (109)
4.5 (105)
Total Protein (g/dL)
6.2
6.1 (98)
6.0 (97)
5.7 (92)
Albumin (g/dL)
3.7
3.7 (100)
3.7 (100)
3.5 (95)
Bilirubin (mg/dL)
0.1
0.1 (100)
0.1 (100)
0.1 (100)
Uric acid (mg/dL)
0.5
0.5 (100)
0.7 (140)
0.3 (60)
Cholesterol (mg/dL)
165
180 (109)
162 (98)
151 (92)
Plasma cholinesterase (mu/mL)
NR
1739
2003
1603
RBC cholinesterase (mu/mL)
NR
3772
4576
4016
Wk 8
PCV (%)
49
48 (98)°
50 (102)
49 (100)
HGB (g %)
17.8
17.0 (96)
17.7 (99)
17.7 (99)
RBC (mm3 x 106)
8.14
7.87 (97)
8.05 (99)
8.10(100)
WBC (mm3 x 103)
11.7
12.4 (106)
10.8 (92)
14.1 (121)
Clotting time (sec)
413
495 (120)
570 (138)
480(116)
Glucose (mg/dL)
92
91 (99)
103 (112)
102(111)
BUN (mg/dL)
15
15 (100)
16 (107)
15 (100)
SGOT (miu/mL)
39
34 (87)
42 (108)
44 (113)
SGPT (miu/mL)
34
41 (121)
40 (118)
46 (135)
Alk phos (miu/mL)
96
96 (100)
74 (77)
76 (79)
LDH (miu/mL)
175
175 (100)
234 (134)
256 (146)
Calcium (mg/dL)
11.0
10.8 (98)
11.1 (101)
10.6 (96)
Phosphorus (mg/dL)
4.6
4.8 (104)
4.5 (98)
4.5 (98)
Total protein (g/dL)
6.7
6.4 (96)
6.8(101)
6.6 (99)
Albumin (g/dL)
3.3
3.2 (97)
3.3 (100)
3.2 (97)
Bilirubin (mg/dL)
0.4
0.4 (100)
0.1 (25)
0.1 (25)
Uric acid (mg/dL)
1.2
0.5 (42)
0.4 (33)
0.4 (33)
Cholesterol (mg/dL)
175
191 (109)
173 (99)
166 (95)
Plasma cholinesterase (mu/mL)
NR
1890
2257
1846
RBC cholinesterase (mu/mL)
NR
2919
2478
2281
44 Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.9. Mean Hematology and Clinical Chemistry Levels of Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
Wk 13
PCV (%)
50
46 (92)°
49 (98)
48 (96)
HGB (g %)
16.9
15.5 (92)
16.6 (98)
16.5 (98)
RBC (mm3 x 106)
7.38
7.02 (95)
7.43 (101)
7.32 (99)
WBC (mm3 x 103)
9.8
10.2 (104)
11.3 (115)
9.8 (100)
Clotting time (sec)
458
638 (139)
540 (118)
600 (131)
Glucose (mg/dL)
88
101 (115)
103 (117)
104(118)
BUN (mg/dl)
13
14 (108)
15 (115)
15 (115)
SGOT (miu/mL)
42
54 (129)
51 (121)
46 (110)
SGPT (miu/mL)
35
38 (109)
41 (117)
43 (123)
Alkaline phosphatase (miu/mL)
63
69(110)
60 (95)
50 (79)
LDH (miu/mL)
232
620 (267)
422 (182)
362 (156)
Calcium (mg/dL)
11.1
11.1 (100)
11.4(103)
10.9 (98)
Phosphorus (mg/dL)
4.4
4.5 (102)
4.5 (102)
4.6(105)
Total protein (g/dL)
6.4
6.3 (98)
6.5 (102)
6.4 (100)
Albumin (g/dL)
3.4
3.4 (100)
3.1 (91)
3.3 (97)
Bilirubin (mg/dL)
0.1
0.1 (100)
0.3 (300)
0.2 (200)
Uric acid (mg/dL)
0.5
0.8 (160)
0.6 (120)
0.5 (100)
Cholesterol (mg/dL)
158
215 (136)
186 (118)
173 (109)
Plasma cholinesterase (mu/mL)
1779d
1919(108)
2284 (128)
1779 (100)
RBC cholinesterase (mu/mL)
243 ld
2302 (95)
2045 (84)
2045 (84)
aSource: Hart (1980a).
Calculated from average body weight and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°Mean (% of control).
dn = 2.
45 Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.10. Absolute Organ Weights of Male and Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
Male
N
4
4
4
4
Brain (g)
75.45
78.87 (105)°
80.40 (107)
79.65 (106)
Heart (g)
90.44
88.10 (97)
86.79 (96)
85.77 (95)
Liver (g)
296.2
314.6(106)
314.6(106)
296.4 (100)
Spleen (g)
61.89
63.54 (103)
63.49 (103)
56.38 (91)
Kidney (g)
57.49
59.18 (103)
60.05 (104)
62.04 (108)
Thyroids (g)
0.878
0.95 (108)
1.00(114)
0.86 (98)
Adrenals (g)
0.93
0.96 (103)
1.05 (113)
0.97 (104)
Testes (g)
22.09
23.78 (108)
22.59 (102)
18.40 (83)
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
Female
N
4
4
4
4
Brain (g)
73.32
75.19 (103)
70.43 (96)
73.58 (100)
Heart (g)
81.58
74.88 (92)
78.85 (97)
74.69 (92)
Liver (g)
262.4
283.8 (108)
283.2 (108)
276.0 (105)
Spleen (g)
58.06
50.06 (86)
55.76 (96)
69.12(119)
Kidney (g)
50.14
50.39 (100)
46.13 (92)
45.29 (90)
Thyroids (g)
0.84
0.89 (106)
0.77 (92)
0.83 (99)
Adrenals (g)
0.97
1.03 (106)
1.10(113)
0.88 (91)
Ovaries (g)
0.73
1.04 (142)
1.96 (268)
1.46 (200)
aSource: Hart (1980a).
bValues are calculated from average body weight and food consumption provided in study using the following
equation DoseADj= Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°Mean (% of control).
46 Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.ll. Relative Organ Weights of Male and Female Dogs
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (5.30)
1500 (40.43)
3000 (85.32)
Male0
N
4
4
4
4
Brain
0.657
0.643 (98)d
0.679 (103)
0.733 (112)
Heart
0.783
0.713 (91)
0.731 (93)
0.785 (100)
Liver
2.575
2.560 (99)
2.661 (103)
2.721 (106)
Spleen
0.549
0.511 (93)
0.536 (98)
0.517(94)
Kidney
0.492
0.480 (98)
0.509 (103)
0.570(116)
Thyroids
7.77
7.71 (99)
8.48 (109)
8.06 (104)
Adrenals
8.18
7.80 (95)
8.83 (108)
8.79 (107)
Testes
0.192
0.193 (101)
0.191 (99)
0.168 (88)
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
150 (4.55)
1500 (46.97)
3000 (92.78)
Female0
N
4
4
4
4
Brain
0.713
0.752 (105)
0.674 (95)
0.744 (104)
Heart
0.786
0.743 (95)
0.751 (96)
0.746 (95)
Liver
2.514
2.829 (113)
2.689 (107)
2.776(110)
Spleen
0.549
0.496 (90)
0.527 (96)
0.692 (126)
Kidney
0.485
0.505 (104)
0.439 (91)
0.449 (93)
Thyroids
8.08
8.75 (108)
7.27 (90)
8.34 (103)
Adrenals
9.36
10.24 (109)
10.38(111)
8.85 (95)
Ovaries
7.12
9.96 (140)
18.27e (257)
14.58 (205)
aSource: Hart (1980a).
bValues are calculated from average body weight and food consumption provided in study using the following
equation: DoseADj= Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
°g or mg/100 g body weight; authors do not differentiate which units go with which organs.
dMean (% of control).
ep < 0.05 by Dunnet's /-test; conducted by the study authors.
47 Diisopropyl methylphosphonate
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FINAL
2-11-2013
Table B.12. Body Weights and Food Consumption of Male and Female Ranch Wild Mink
Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (6.8)
450 (63.4)
2700 (344.7)
5400 (747.1)
8000 (1008.6)
Male
N
10
10
10
10
10
10
Feed consumed
(g/mink/d)
238.2
252.2 (106)°
246.1 (103)
235.6 (99)
240.2(101)
190.4 (80)
DIMP
consumed
(mg/mink/d)
0
14.4
129.9
690.3
1483.0
1711.7
Mean body
weight (g)
2084.1
2127.3 (102)
2047.5 (98)
2002.8 (96)
1985.1 (95)
1697.1 (81)
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (9.0)
450 (82.3)
2700 (455.2)
5400 (907.7)
8000 (1263.5)
Female
N
10
10
10
10
10
10
Feed consumed
(g/mink/d)
169.1
167.6 (99)
173.5 (103)
170.3 (101)
149.1 (88)
128.0 (76)
DIMP
consumed
(mg/mink/d)
0
9.6
91.6
499.0
920.9
1150.7
Mean body
weight (g)
1113.0
1062.5 (95)
1112.8 (100)
1096.3 (98)
1014.1 (91)
910.7 (82)
aSource: Bucci et al. (1994).
bDoses converted by authors.
°Mean (% of control).
48
Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.13. Hematology of Male Ranch Wild Mink Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (6.8)
450 (63.4)
2700 (344.7)
5400 (747.1)
8000 (1008.6)
N
10
10
10
10
10
10
WkO
Hematocrit (%)
45.31 ±2.86
46.76 ±3.94
(103)°
45.43 ±2.89
(100)
45.48 ±2.92
(100)
46.71 ±3.60
(103)
45.56 ±2.28
(101)
Hemoglobin
(g/dL)
15.52 ± 1.00
15.91 ± 1.42
(103)
15.43 ± 1.03
(99)
15.52 ±1.08
(100)
15.76 ± 1.14
(102)
15.48 ±0.81
(100)
Erythrocyte
Count (106/|iL)
7.95 ±0.75
8.35 ±0.82
(105)
8.00 ±0.76
(101)
7.96 ±0.64
(100)
8.25 ±0.56
(104)
8.02 ±0.50
(101)
Reticulocytes
(% x RBC)
2.16 ± 1.28
2.43 ±0.67
(113)
2.22 ±0.96
(103)
2.00 ± 0.67
(93)
2.14 ± 1.06
(99)
1.81 ±0.80
(84)
Heinz Bodies
(% x RBC)
0.00 ± 0
0.00 ± 0 (NA)
0.00 ± 0 (NA)
0.00 ± 0 (NA)
0.00 ± 0 (NA)
0.00 ± 0 (NA)
Plasma
Cholinesterase
(units/L)
1519.67 ±
144.84
1545.22 ±
247.56 (102)
1486.30 ±
297.67 (98)
1522.70 ±1
87.59 (100)
1595.40 ±
178.24 (105)
1503.70 ±
131.40 (99)
Wk 3
Hematocrit (%)
46.24 ± 1.49
47.53 ± 1.79
(103)
48.63 ±3.13
(105)
48.14 ±3.58
(104)
46.40 ±2.71
(100)
45.23 ±2.29
(98)
Hemoglobin
(g/dL)
15.36 ±0.61
15.79 ±0.58
(103)
15.96 ± 1.08
(104)
15.67 ± 1.13
(102)
15.27 ±0.93
(99)
14.89 ±0.78d
(97)
Erythrocyte
Count (l()'/|iL)
7.74 ±0.50
8.15 ±0.29
(105)
8.24 ±0.55
(106)
7.99 ±0.63
(103)
7.76 ±0.41
(100)
7.60 ±0.50
(98)
Reticulocytes
(% x RBC)
2.32 ±0.75
2.15 ±0.72
(93)
2.46 ±0.51
(106)
2.67 ± 1.01
(115)
3.61 ± 1.09d
(156)
2.75 ± 1.17
(119)
Heinz Bodies
(% x RBC)
0.07 ±0.11
0.04 ±0.07
(57)
0.07 ±0.08
(100)
0.56 ±0.86
(800)
1.98 ±2.42
(2829)
4.85 ± 9.99d
(6929)
Plasma
Cholinesterase
(units/L)
1469.10 ±
172.27
1563.90 ±
263.22 (106)
1393.70 ±
240.50 (95)
1029.80 ±
123.99 (70)
784.20 ±
120.96d (53)
733.30 ±
85.18d (50)
Wk 7
Hematocrit (%)
51.25 ±2.11
52.37 ±2.43
(102)
52.69 ±2.07
(103)
52.45 ±4.07
(102)
49.41 ±2.08
(96)
45.40 ±2.00
(89)
Hemoglobin
(g/dL)
16.31 ±0.81
16.43 ± 0.60
(101)
16.60 ±0.69
(102)
16.38 ± 1.36
(100)
15.69 ±0.51
(96)
14.71 ±0.58d
(90)
Erythrocyte
Count (106/|iL)
8.33 ±0.64
8.65 ±0.47
(104)
8.61 ±0.50
(103)
8.41 ±0.88
(101)
7.98 ±0.30
(96)
7.40 ± 0.37d
(89)
Reticulocytes
(% x RBC)
1.43 ±0.63
1.60 ±0.68
(112)
2.24 ±0.94
(157)
2.60 ± 1.47
(182)
2.23 ± 1.17
(156)
3.42 ± 1.42d
(239)
Heinz Bodies
(% x RBC)
0.13 ±0.24
0.32 ±0.53
(246)
0.41 ±0.96
(315)
0.32 ±0.69
(246)
3.26 ± 2.12d
(2508)
13.78 ±7.71d
(10,600)
49 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.13. Hematology of Male Ranch Wild Mink Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (6.8)
450 (63.4)
2700 (344.7)
5400 (747.1)
8000 (1008.6)
Plasma
Cholinesterase
(units/L)
1542.10 ±
157.93
1563.00 ±
248.98 (101)
1427.90 ±
273.63 (93)
982.00 ±
144.22d (64)
763.30 ±
115.5ld (49)
646.00 ±
73.66d (42)
Wk 13
Hematocrit (%)
48.15 ±2.11
48.29 ±2.44
(100)
48.58 ±2.53
(101)
48.14 ±2.20
(100)
48.33 ±3.51
(100)
44.01 ± 2.12d
(91)
Hemoglobin
(g/dL)
15.80 ±0.65
15.99 ±0.65
(101)
15.96 ±0.77
(101)
15.82 ± 1.04
(100)
15.95 ± 1.28
(101)
14.49 ±0.59d
(92)
Erythrocyte
Count (106/|iL)
8.13 ±0.57
8.39 ±0.56
(103)
8.33 ±0.48
(102)
8.05 ± 0.60
(99)
8.22 ±0.54
(101)
7.44 ± 0.44d
(92)
Reticulocytes
(% x RBC)
2.05 ±0.66
2.23 ± 1.06
(109)
2.14 ±0.54
(104)
2.22 ±0.88
(108)
2.96 ±0.57
(144)
4.48 ± 2.45d
(219)
Heinz Bodies
(% x RBC)
0.00 ±0.00
0.20 ±0.31
(NA)
0.03 ± 0.07
(NA)
0.70 ±0.73
(NA)
4.88 ± 5.62d
(NA)
14.45 ±8.48d
(NA)
Plasma
Cholinesterase
(units/L)
1446.70 ±
134.14
1460.70 ±
183.65 (101)
1340.50 ±
227.17 (93)
865.70 ±
87.24d (60)
722.10 ±
118.39d (50)
609.50 ±
117.00d (42)
aSource: Bucci et al. (1994, 1992).
'Doses converted by authors.
°Mean ± standard deviation (% of control).
dp < 0.05 by repeated measures using an incomplete block design in SAS; conducted by the study authors.
NA = Not applicable.
50
Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.14. Hematology of Female Ranch Wild Mink Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (9.0)
450 (82.3)
2700 (455.2)
5400 (907.7)
8000 (1263.5)
N
10
10
10
10
10
10
WeekO
Hematocrit (%)
48.68 ±3.11
44.74 ±2.90
(92)°
47.60 ± 1.85
(98)
48.64 ±3.36
(100)
48.18 ±3.55
(99)
47.15 ±2.93
(97)
Hemoglobin
(g/dL)
15.86 ±0.99
14.88 ±0.59
(94)
15.59 ±0.69
(98)
15.81 ± 1.13
(100)
15.63 ± 1.09
(99)
15.33 ±0.91
(97)
Erythrocyte
Count (106/|iL)
7.84 ±0.31
7.35 ±0.55
(94)
7.78 ±0.29
(99)
7.85 ±0.53
(100)
7.94 ±0.60
(101)
7.68 ±0.52
(98)
Reticulocytes
(%x RBC)
1.64 ±0.78
1.41 ±0.62
(86)
1.71 ±0.58
(104)
2.03 ±0.48
(124)
1.44 ±0.42
(88)
1.32 ±0.69
(80)
Heinz Bodies (%
x RBC)
0.01 ±0.03
0.01 ±0.03
(100)
0.00 ± 0 (0)
0.01 ±0.03
(100)
0.01 ±0.03
(100)
0.01 ±0.03
(100)
Plasma
Cholinesterase
(units/L)
1351.40 ±
130.25
1424.20 ±
202.24 (105)
1331.11 ±
213.68 (98)
1341.30 ±
165.79 (99)
1410.60 ±
178.55 (104)
1236.80 ±
111.33 (92)
Week 3
Hematocrit (%)
47.29 ±2.61
47.39 ±2.59
(100)
46.13 ± 1.41
(98)
46.69 ±2.99
(99)
44.74 ± 2.92d
(95)
43.79 ±2.62d
(93)
Hemoglobin
(g/dL)
15.63 ±0.76
15.44 ±0.91
(99)
15.25 ±0.37
(98)
15.33 ±0.88
(98)
14.77 ±0.99d
(94)
14.52 ± 0.83d
(93)
Erythrocyte
Count (106/|iL)
7.75 ±0.46
7.67 ±0.50
(99)
7.60 ± 0.24
(98)
7.59 ±0.42
(98)
7.37 ±0.61
(95)
7.11 ± 0.44d
(92)
Reticulocytes (%
x RBC)
1.80 ±0.71
1.87 ±0.71
(104)
1.76 ±0.63
(98)
2.19 ±0.59
(122)
3.21 ± 1.32d
(178)
3.10 ± 1.58d
(172)
Heinz Bodies (%
x RBC)
0.01 ±0.03
0.08 ±0.10
(800)
0.05 ±0.11
(500)
0.12 ± 0.14
(1200)
1.65 ± 1.65
(16,500)
9.24 ± 12.93d
(92,400)
Plasma
Cholinesterase
(units/L)
1332.60 ±
104.66
1342.80 ±
194.97(101)
1276.40 ±
203.54 (96)
872.40 ±
152.22d (65)
722.50 ±
101.14d (54)
620.40 ± 90.20d
(47)
Week 7
Hematocrit (%)
49.15 ±4.51
49.20 ±2.68
(100)
49.86 ±2.58
(101)
50.63 ± 1.49
(103)
46.33 ±3.88d
(94)
45.71 ±4.92d
(93)
Hemoglobin
(g/dL)
16.01 ±0.99
15.34 ±0.87
(96)
15.62 ±0.76
(98)
15.93 ±0.59
(100)
14.87 ± 1.27d
(93)
14.84 ± 1.45d
(93)
Erythrocyte
Count (106/|iL)
8.06 ±0.78
7.76 ± 0.47
(96)
8.00 ± 0.46
(99)
8.01 ±0.22
(99)
7.52 ±0.80
(93)
7.29 ± 0.95d
(90)
Reticulocytes (%
x RBC)
1.70 ±0.68
1.52 ±0.99
(89)
2.12 ±0.87
(125)
2.09 ±0.76
(123)
2.17 ±0.82
(128)
5.16 ± 2.19d
(304)
Heinz Bodies (%
x RBC)
0.19 ± 0.16
0.02 ±0.04
(11)
0.15 ±0.25
(79)
0.90 ±0.92
(474)
6.98 ± 6.03d
(3674)
20.56 ±8.22d
(10,821)
51 Diisopropyl methylphosphonate
-------
FINAL
2-11-2013
Table B.14. Hematology of Female Ranch Wild Mink Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
50 (9.0)
450 (82.3)
2700 (455.2)
5400 (907.7)
8000 (1263.5)
Plasma
Cholinesterase
(units/L)
1467.00 ±
205.92
1460.10 ±
213.82 (100)
1324.90 ±
123.12 (90)
874.20 ±
130.47d (60)
722.10 ±
118.17d (49)
541.40 ±90.84d
(37)
Week 13
Hematocrit (%)
47.41 ±3.75
47.12 ±2.12
(99)
46.44 ±2.84
(98)
46.30 ±3.87
(98)
44.51 ±2.26d
(94)
44.95 ±2.39d
(95)
Hemoglobin
(g/dL)
15.46 ± 1.03
15.29 ±0.72
(99)
15.00 ±0.95
(97)
15.25 ± 1.23
(99)
14.72 ±0.74d
(95)
14.92 ±0.76d
(97)
Erythrocyte
Count (106/|iL)
7.90 ±0.44
7.75 ± 0.45
(98)
7.75 ±0.50
(98)
7.61 ±0.61
(96)
7.41 ±0.32
(94)
7.51 ± 0.61d
(95)
Reticulocytes
(% x RBC)
1.98 ±0.77
1.83 ±0.54
(92)
2.13 ±0.92
(108)
2.33 ±0.97
(118)
3.27 ± 1.70
(165)
4.95 ± 2.62d
(250)
Heinz Bodies
(% x RBC)
0.02 ± 0.06
0.41 ±0.89
(2050)
0.17 ±0.16
(850)
1.70 ± 1.91
(8500)
14.01 ±9.22d
(70,050)
16.99 ±6.65d
(84,950)
Plasma
Cholinesterase
(units/L)
1395.10 ±
236.96
1387.30 ±
224.75 (99)
1252.10 ±
126.21d (90)
771.30 ±
128.77d (55)
646.60 ±
85.69d (46)
479.60 ±50.01d
(34)
aSource: Bucci et al. (1994, 1992).
bDoses converted by authors.
°Mean ± standard deviation (% of control).
dp < 0.05 by repeated measures using an incomplete block design in SAS; conducted by the study authors.
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Table B.15. Plasma and Red Blood Cell Cholinesterase (ChE) Levels in Mink Exposed to
DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
2700 (344.7)
8000 (1008.6)
Male
Sample size
3
3
3
HCT (decimal)0
0.462
0.481 (104)
0.441 (95)
Whole blood ChE (U/L)d
2165±175
1972 ±260 (91)
1729 ± 37 (80)
Plasma ChE (U/L)d
1365 ±37
563 ±76 (41)
512 ± 140 (38)
RBC AChE (U/L)4 e
3097 ±359
3492 ± 145 (113)
3272 ± 130 (106)
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
2700 (455.2)
8000 (1263.5)
Female
Sample size
3
3
3
HCT (decimal)0
0.450
0.451 (100)
0.434 (96)
Whole blood ChE (U/L)d
2216 ±28
2057 ± 294 (93)
1624 ± 436 (73)
Plasma ChE (U/L)d
987 ± 58
495 ± 63 (50)
322 ± 20 (33)
RBC AChE (U/L)40
3718± 157
3958 ± 474 (106)
3322 ± 1110(89)
aSource: Bucci et al. (1994).
bDoses converted by authors.
°Values expressed as mean (% of control)
dValues expressed as mean ± SD (% of control).
eRed blood cell acetylcholinesterase content (RBC AChe) was calculated using the formula: RBC AChE = Whole
blood ChE - [Plasma ChE x (1 - HCT)] - HCT.
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Table B.16. Hematopoiesis in the Spleens of Mink Exposed to DIMP for 90 Days"
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
8000 (1008.6)
8000 (1008.6)
Recovery Group0
Male
Increased hematopoiesisd
6/10 (1.0)
7/8 (1.7)
0/2 (NA)
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
8000 (1263.5)
8000 (1263.5)
Recovery Group
Female
Increased hematopoiesisd
4/10 (1.5)
7/8 (1.6)
0/2 (NA)
aSource: Bucci et al. (1994).
bDoses converted by authors.
°Two animals from the high-dose group of each sex were observed for 1 additional month after the cessation of
treatment.
dValues expressed as the number of animals affected/number examined (average severity grade; maximum = 4).
NA = Not applicable.
54
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Table B.17. Body Weight and Food Consumption in Female Sprague-Dawley Rats
Exposed by Diet to DIMP on GDs 6-15a
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
100 (7.4)
300 (21.6)
3000 (232.5)
Mean Body Weight (g)
Day 0C
Mean
214 ± 17
219 ± 17(102)
217 ± 19(101)
217 ± 15 (101)
N
13
14
11
15
Day 6C
Mean
240 ± 19
245 ± 16 (102)
242 ± 19(101)
247 ± 13 (103)
N
13
14
11
15
Day 16°
Mean
281 ±22
299 ± 27 (106)
286 ± 25 (102)
295 ± 19(105)
N
13
14
11
15
Day 20°
Mean
337 ±28
346 ±40 (103)
341 ±34 (101)
346 ±29 (103)
N
13
14
11
15
Mean Daily Food Consumption (g)
Days 0-6°
Mean
20 ±7
22 ±9 (110)
18 ± 2 (90)
19 ± 1 (95)
N
10
13
11
15
Day 6-16°
Mean
18 ± 1
20 ±2 (111)
19 ±3 (106)
21 ±2 (117)
N
5
11
7
8
Day 16-20°
Mean
25 ±5
23 ± 4 (92)
25 ±4 (100)
26 ± 3 (104)
N
13
14
11
15
aSource: Hart (1980b).
bDoses are converted from ppm to mg/kg-day using the following equation: DoscAI,[ = Doseppm x Food
Consumption per Day x (1 -f- Body Weight) x (Days Dosed ^ Total Days).
°Values expressed as mean ± SD (% of control).
55
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Table B.18. Reproductive Effects in Female Sprague-Dawley Rats
Exposed to DIMP by Diet on GDs 6-15a
Parameter
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
0
100 (7.4)
300 (21.6)
3000 (232.5)
Pregnancy ratio0
14/20
14/20
11/20
15/20
Implantation sitesd'e
86/67
78/90
50f/68f
91/91
Resorptions/live fetuses
13/140
16/152
7/110
9/173
Average fetal weight (g)f
3.7
3.9
3.8
3.9
Average fetal length (cm/
3.1
3.1
3.1
3.1
Mean live litter size (pups)
11
11
10
12
aSource: Hart (1980b).
bDoses are converted from ppm to mg/kg-day using the following equation: Doscadj = Dose x Food Consumption
per Day x (1 Body Weight) x (Days Dosed Total Days).
°Number pregnant/ number mated.
dBased on average of litter means.
eLeft horn/right horn.
Significantly different from controls (p < 0.05) based on a 2 x 2 contingency table with the Yate's correction; not
significant for p > 0.05 based on Wilcoxon rank sum test as reported by the study author.
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Table B.19. Skeletal Effects in Sprague-Dawley Rats
Exposed to DIMP In Utero on GDs 6-15a
Exposure Group, ppm (Adjusted Daily Dose, mg/kg-d)b
Parameter
0
100 (7.4)
300 (21.6)
3000 (232.5)
Number examined0
100
102
75
114
Number normal
73
69
58
67
Number with common skeletal
variations'1
27
33
15
45e
Number with unusual changesf
0
2
4
3
aSource: Hart (1980b).
bDoses are converted from ppm to mg/kg-day using the following equation: DoscAI,[ = Doseppm x Food Consumption
per Day x (1 Body Weight) x (Days Dosed Total Days).
°The author examined two-thirds of the fetuses in each litter.
dThe author note that these are changes that are frequently observed in 21-day-old rat fetuses of this strain and
source in their laboratory and typically include unilateral and bilateral ribs; reduced ossification of interparietal,
hyoid, and supraoccipital bones; and nonfused thoracic vertebral centra.
"Significantly different from control (p < 0.05) based on a 2 x 2 contingency table; not significant forp > 0.05 based
on Wilcoxon rank sum test as reported by the study author.
fUnusual changes include malformed maxilla or mandible; reduced ossification of sternebrae, pubes, sacral vertebral
arches, right ischium, parietal bone, or maxilla; wavy ribs; nonossified hyoid; and nonossified distal phalanges of the
hind extremities.
57
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Table B.20. Mean Body Weights and Food Consumption of Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (14.94)
450 (47.36)
2500 (284.79)
F0 Male
Mean body weight (kg)
2.274
2.199 (97)°
2.244 (99)
2.227 (98)
Food consumed (g/lOOg bw)
9.8
9.2 (94)
9.9(101)
10.5 (107)
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (15.67)
450 (45.00)
2500 (261.73)
F1 Male
Mean body weight (kg)
2.400
2.343 (98)
2.425 (101)
2.302 (96)
Food consumed (g/lOOg bw)
9.4
9.3 (99)
9.2 (98)
9.4 (100)
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (25.61)
450 (84.81)
2500 (460.72)
F0 Female
Mean body weight (kg)
1.142
1.156(101)
1.137 (100)
1.132 (99)
Food consumed (g/lOOg bw)
18.6
15.8(85)
17.7 (95)
16.9(91)
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (19.74)
450 (56.50)
2500 (329.47)
F1 Female
Mean body weight (kg)
1.208
1.212(100)
1.210(100)
1.188 (98)
Food consumed (g/lOOg bw)
11.5
11.7(102)
11.5 (100)
11.9(103)
aSource: Bucci et al. (2003).
bReported by study authors.
°Mean (% of control).
58
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Table B.21. Breeding Outcomes of F0 Female Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (25.61)
450 (84.81)
2500 (460.72)
F0 Female
Number of dams
35
35
35
35
Number of litters
32
19
32
29
Total kits
226
134
232
217
Mean kits per litter
7.06
7.05
7.25
7.48
Mean live kits per litter
6.50
6.53
6.63
6.38
Litter biomass (g)
75.36
71.84
74.81
73.26
Mean individual weight (g)
10.97
10.13
10.59
10.46
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (19.74)
450 (56.50)
2500 (329.47)
F1 Female
Number of dams
35
35
35
35
Number of litters
28
22
23
23
Total kits
188
147
144
144
Mean kits per litter
6.71
6.68
6.26
6.26
Mean live kits per litter
5.75
4.95
4.83
5.70
Litter biomass (g)
67.27
63.54
61.37
65.40
Mean individual weight (g)
10.37
9.54
9.54
10.43
aSource: Bucci et al. (2003).
bReported by study authors.
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Table B.22. Sperm Evaluation of Male Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
150 (14.94)
450 (47.36)
2500 (284.79)
Sperm count
1244.9 ±418.0C
(« = 13)
1417.2 ±699.8
{n =13)
1434.3 ±657.4
in = 12)
1561.5 ± 1945.9
in = 13)
Motility
99.8 ±0.6
(,n = 10)
100 ±0
(n = 9)
96.6 ± 1.3
(n = 9)
99.9 ±0.3
in = 9)
Abnormal morphology (%)
0.3 ±0.3
(n = 13)
0.1 ±0.2
(n = 13)
0.3 ±0.4
in = 12)
0.2 ±0.2
in = 12)
aSource: Bucci et al. (2003).
bReported by study authors.
°Mean ± standard deviation.
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Table B.23. Hematologic Changes in F0 Female Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
2500 (460.72)°
F0 Females
N
35
35
Study initiation
(9.5 mo of age)
RBC (x 106hL)
7.59
7.72
Reticulocytes (% of RBCs)
3.1
3.3
MCV (|im3)
62
61
Heinz bodies (% of RBC)
0.0
0.0
Plasma cholinesterase (U/I)
1109
1040
Whole blood cholinesterase (U/I)
4378
4355
RBC cholinesterase (U/I)
8118
8099
Study termination
(13.5 mo of age)
RBC (x 106hL)
7.79
7.38d
Reticulocytes (% of RBCs)
1.8
4.1e
MCV (|im3)
58
60d
Heinz bodies (% of RBC)
0.0
2.8e
Plasma cholinesterase (U/I)
1426
860e
Whole blood cholinesterase (U/I)
3725
3115e
RBC cholinesterase (U/I)
6479
604 le
Brain cholinesterase (|imol/g/min)
6.53 (n = 10)
7.13 («= 10)
aSource: Bucci et al. (2003).
bReported by study authors.
°A11 groups were measured, but only results for the high-dose group were reported.
Statistically different from control (p < 0.05).
"Statistically different from control (p < 0.01).
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Table B.24. Hematologic Changes in F1 Female Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
2500 (329.47)°
F1 Females
N
35
35
4.5 mo of age
RBC (x 106hL)
7.97
7.94
Reticulocytes (% of RBCs)
3.1
3.1
MCV (nm3)
60
60
Heinz bodies (% of RBC)
0.0
0.0
Plasma cholinesterase (U/I)
1279
999d
Whole blood cholinesterase (U/I)
4589
4285d
RBC Cholinesterase (U/I)
8207
7859e
Brain cholinesterase (|imol/g/min)
--
~
7.5 mo of age
RBC (x 106hL)
8.45
6.36
Reticulocytes (% of RBCs)
3.4
3.9
MCV (nm3)
60
61
Heinz bodies (% of RBC)
0.0
0.2e
Plasma Cholinesterase (U/I)
1133
894d
Whole blood Cholinesterase (U/I)
4793
4572d
RBC cholinesterase (U/I)
8301
8174
Brain cholinesterase (|imol/g/min)
--
~
13.5 mo of age
RBC (x 106hL)
8.29
6.20
Reticulocytes (% of RBCs)
1.7
2.0
MCV (nm3)
61
61
Heinz bodies (% of RBC)
0.1
1.3d
Plasma cholinesterase (U/I)
1310
905d
Whole blood cholinesterase (U/I)
4335
3966e
RBC cholinesterase (U/I)
7332
7103
Brain cholinesterase (|imol/g/min)
7.24 (n = 10)
6.81 («= 10)
aSource: Bucci et al. (2003).
bReported by study authors.
°A11 groups were measured, but only results for the high-dose group were reported.
Statistically different from control (p < 0.01).
"Statistically different from control (p < 0.05).
62 Diisopropyl methylphosphonate
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Table B.25. Abnormal Clinical Responses in F1 Female Ranch Wild Mink
After Dietary Exposure to DIMPa
Parameter
Exposure Group, % (Adjusted Daily Dose, mg/kg-d)b
0
0
150 (19.74)
450 (56.50)
2500 (329.47)
Abnormality
Level 1
2/4 (3)°
1/5 (3)
3/3 (6)
2/3 (9)
4/4 (9)
Abnormality
Level 2
0/4
0/5
1/3 (1)
2/3 (6)
3/4 (6)
Abnormality
Level 3
0/4
0/5
1/3 (1)
1/3 (2)
1/4 (4)
aSource: Calabrese (2003a).
bAdjusted daily doses reported by Bucci et al. (2003).
°Number of mink with abnormal responses/number of mink that survived intervention (number of abnormal
responses).
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APPENDIX C. BMD OUTPUTS
There are no BMD outputs for DIMP.
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CalEPA (California Environmental Protection Agency). (2009) OEHHA toxicity criteria
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Snodgrass, HL; Metker, LM. (1992) Dermal penetration of 14C-labeled diisopropyl
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methylphosphonate (DIMP) in their drinking water for 26 weeks. U.S. Army Armament
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Michigan State University, Poultry Science Department, East Lansing, MI; Report No.
AD-A087-257/2. As cited in U.S. EPA (1993).
U.S. DOD (Department of Defense). (1980) Three-generation reproduction study in
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