United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-G078
September. 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR RDX CYCLONITE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: oo NOT C,TE OR QUOTE
NOTICE
WASHINGTON, D.C. 20460
o This document 1s a preliminary draft. It has not been formally released
§> by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
<=> on Us technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSHER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for
emergency and remedial actions under the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA). Both published
literature and Information obtained for Agency Program Office files are
evaluated as they pertain to potential human health, aquatic life and
environmental effects of hazardous waste constituents. The literature
searched for In this document and the dates searched are Included In
"Appendix: Literature Searched." Literature search material Is current up
to 8 months previous to the final draft date listed on the front cover.
Final draft document dates (front cover) reflect the date the document 1s
sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include: Reference doses
(RfO's) for chronic and subchronlc exposures for both the Inhalation and
oral exposures. The subchronlc or partial lifetime RfD. Is an estimate of
an exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval which
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfO's Is the same as traditionally employed for chronic
estimates, except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfD's are not estimated. Instead,
a carcinogenic potency factor, or q-| (U.S. EPA, 1980) Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and
carclnogenlclty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification Is required In the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxldty
and cardnogenldty) represent two of six scores developed (the remaining
four reflect IgnltabllUy, reactivity, aquatic toxUUy, and acute mammalian
toxldty). Chemical-specific RQ's reflect the lowest of these six primary
criteria. The methodology for chronic toxldty and cancer based RQs are
defined 1n U.S. EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
RDX cyclonlte (1,3,5-tr1n1trohexahydro-l,3,5-trlazlne) Is a nonvolatile,
white crystalline compound at room temperature (Sax and Lewis, 1987). It Is
soluble In polar organic solvents, slightly soluble In water and Insoluble
In nonpolar organic solvents (Sax and Lewis, 1987; Spanggord et al.,
1980a). RDX 1s normally produced by the action of nitric add on hexamlne
(Ryon et al., 1984). During 1977, four U.S manufacturing facilities
produced between 10.2 and 52 million pounds of RDX (TSCAPP, 1989). The
primary manufacturing site was the Holston AAP In Klngsport, TN. RDX 1s
used as an explosive 1n armaments and munitions (Spanggord et al., 1980a).
The dominant fate process of RDX In translucent waters Is probably
direct photochemical degradation. The half-life for this process Is about 2
weeks {Spanggord et al.. 1980b). Sufficient data are lacking to predict the
significance of aerobic blodegradatlon. Limited data suggest that under the
proper conditions In lakes, ponds and groundwater, anaerobic degradation may
be significant. Volatilization from water or soil Is probably not
Important. Slow hydrolysis of RDX Is also a potential removal process
(Spanggord et al., 1980a; Hoffsommer and Rosen, 1973). When released to
soil, RDX displays moderate to high mobility and can be expected to leach
Into groundwater. This process depends greatly on the type of soil (Kayser
and Burllnson, 1988). If released to the atmosphere, RDX may be removed by
dry or wet deposition. Direct photochemical degradation of RDX 1n the
atmosphere may also occur.
RDX Is a man-made compound used In the manufacture of armaments and
munitions. RDX can enter the environment through wastewater discharge from
Its production, formulation and Incorporation Into munitions and through the
demilitarization or deepwater dumping of antiquated munitions (Hoffsommer
1v
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and Rosen, 1972; Hoffsommer et al., 1972; Ryon et al., 1984; Small and
Rosenblatt, 1974). RDX can also enter the environment by leaching from
waste lagoons Into soil and from the Improper disposal of contaminated
sludge (Oenklns et al., 1986). RDX may enter the atmosphere through the
release of contaminated partlculate matter formed during the Incineration of
ROX-conta1n1ng mixtures (Carroll et al., 1979; Ryon et al., 1984).
Exposure to RDX Is apparently limited to areas near where It Is manufac-
tured or used In munitions. Exposure can occur by the Inhalation of par-
tlculate matter produced during the Incineration of RDX-contalnlng mixtures.
Data on the toxlclty of RDX to aquatic organisms were obtained from
studies by Bentley et al. (1979) and Liu et al. (1984). RDX was more toxic
to fish {96-hour LC = 4.1-6.4 mg/l) than Invertebrates (48-hour
EC5Q = >100 mg/l) or algae (96-hr ECSQ = >32 mg/l) In acute
static toxlclty tests. The results of flowthrough toxlclty tests In
blueglll and fathead minnow were similar to those of static tests (96-hour
LC5Q = 6.6-7.6 mg/l); however, the toxlclty of RDX to catfish was
reduced slightly under flowthrough conditions (96-hour LC = 13
mg/i). The most sensitive life stage of fathead minnows exposed to RDX
was 7-day-old fry (96-hour LC5Q = 3.8 mg/l), followed In order by
60-day-old fry, 30-day-old fry, 1-hour-old fry and eggs. Chronic exposure
to >4.8 mg/l of RDX produced a transitory decrease In daphnld
reproduction. Although decreases were reported In the survival and percent
emergence of midges exposed to RDX at 1.3-21 mg/l, these effects did not
appear to be related to exposure. Fathead minnows chronically exposed to
6.3 mg/l of RDX had reduced survival during the first 60 days of the
experiment. RDX did not accumulate significantly In the tissues of
Invertebrates or fish; however, a 4-day BCF of 123 was calculated In algae.
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Balance experiments with 14C-RDX 1n rats suggest that absorption of
radioactivity from the gastrointestinal tract Is nearly complete {Schneider
et al., 1977). Plasma levels of RDX 1n rats and miniature swine
administered RDX by gavage plateaued after an Initial rise and did not peak
until 24 hours after treatment (Schneider et al., 1977), Indicating that
gastrointestinal absorption Is prolonged. In rats treated with RDX
suspended In saline, higher plasma levels were achieved with a 50 mg/kg dose
of a finely powdered sample compared with a 1QO mg/kg dose of a coarse
granular sample, demonstrating the effect of particle size on gastrointes-
tinal absorption (Schneider et al., 1977). RDX Is reported to be absorbed
from the stomach and lung but not through the skin (Taylor, 1975).
Distribution experiments In rats (Schneider et al., 1977, 1978; MacPhall
et al., 1985), miniature swine (Schneider et al., 1977) and mice (Guo et
al., 1985) Indicate that distribution Is rapid following oral or Intravenous
administration. Highest levels of RDX were found In the kidney of rats and
miniature swine (Schneider et al., 1977) and In the lung, liver and kidney
of mice (Guo et al., 1985). Continued oral exposure of rats did not result
In accumulation of RDX In any tissue (Schneider et al., 1978; MacPhall et
al., 1985).
RDX appears to be extensively metabolized and excreted as Indicated by
recovery of 43% of an oral dose of 14C-RDX as 14CO In rats (Schneider
et al., 1977). Urinary radioactivity accounted for 34% of the dose; only
3.6% of the urinary radioactivity constituted unmetabollzed compound. The
liver appears to be the principal dte of metabolism (Schneider et al.,
1977). Within 4 days of treatment, excretion accounted for =80% of the
administered dose.
v1
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In the only report of Inhalation exposure to ROX, 69 humans showed no
adverse effects after exposure to atmospheric concentrations ranging from
0-1.5 mg/m3 In an ammunition plant (Hathaway and Buck, 1977).
Subchronlc exposures of rats to RDX In the diet produced several dose
related effects. Levlne et al. (1981) noted that mean survival times of
F344 rats were Inversely related to concentrations of RDX In their diets.
Other dose-related effects seen Included reduced mean body weights and
reduced serum trlglycerlde levels. Dosjes ranged, from 10-600 mg/kg/day for
90 days. At 10 mg/kg/day, male body weights were reduced 6% compared with
controls. Cholakls et al. (1980) reported that administration of 28
mg/kg/day for 90 days In the diets of F344 rats produced no adverse effects
but saw a dose-related decrease In mean body weights at 40 mg/kg/day. von
Oettlngen et al. (1949) reported no adverse effects In rats fed RDX In the
diets at a dosage of 15 mg/kg/day for 10 weeks and for 12 weeks, but
Increased mortality and decreased weight gain at dosages of 25, 50 and 100
mg/kg/day.
In a subchronic study with B6C3F1 mice, Cholakls et al. (1980) reported
a dose-related Increase In mean liver weights that was significant at the
highest dose when the animals were exposed to 0, 80, 145 and 277 mg/kg/day
(TWA doses) for 90 days. The authors noted no significant effects In mice
receiving 145 mg/kg/day.
Subchronlc studies with other species have been done. In dogs, von
Oettlngen et al. (1949) saw a 20% weight loss compared with controls and
convulsions and behavior changes In dogs given 42.9 mg/kg/day for 42 days
(expanded dose). Hart (1974) observed no adverse effects when beagle dogs
were given <10 mg/kg/day for 90 days. Cynomulgus monkeys administered RDX
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by gavage for 90 days experienced no adverse effects at a dosage of 1
mg/kg/day but had disturbances of the central nervous system at 10 mg/kg/day
(Martin and Hart, 1974).
Three 2-year dietary studies are reported, one with B6C3F1 mice (L1sh et
al., 1984). one with F344 rats (Levlne et al., 1984} and one with Sprague-
Dawley rats (Hart, 1976). In mice, dosages of 1.5 mg/kg/day caused no
adverse effects while dosages of 7.0 mg/kg/day caused biochemical changes.
Doses of 35 mg/kg/day resulted 1n testlcular degeneration In the males and
higher renal weights and 107 (TWA dose) mg/kg/day produced decreased body
weights and Increased kidney and heart weights compared with controls.
Results with the rats Indicated that there were no adverse effects at a
dosage of 0.3 mg/kg/day while doses >1.5 mg/kg/day produced prostate
Inflammation and hemoslderosls 1n the males. Lower body weights compared
with controls were seen In rats given a dosage of 8 mg/kg/day. Effects seen
at 40 mg/kg/day Included Increased mortality and reduced body weights
compared with controls. No adverse effects at doses <10 mg/kg/day were
noted In a study with Sprague-Dawley rats, (Hart, 1976).
Acute exposures of rats by gavage resulted In LD values ranging from
71-200 mg/kg (von Oettlngen et al., 1949; Dllley et al., 1979; Cholakls et
al., 1980); reported ID values In mice administered by gavage range from
58-97 mg/kg (Dllley et al., 1979; Cholakls et al., 1980) with one outlier
value of 500 mg/kg reported by Spector, (1956).
Oral human exposures resulted 1n convulsions, seizures and unconscious-
ness several hours or days after exposure but no fatalities have been
reported.
The only carcinogenic effect reported was seen In female B6C3F1 mice
administered RDX at 0, 1.5, 7, 35 and 175/100 mg/kg/day for 105 weeks (Llsh
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et al., 1984). The animals receiving dosages >7 mg/kg/day had statistically
significant Increased Incidences of liver adenomas and carcinomas (combined)
compared with controls. This effect was not seen In the male mice. No
carcinogenic effects were seen In F344 rats at doses <40 mg/kg/day.
RDX was not mutagenlc In the Ames assay at concentrations <1 mg/plate
with metabolic activation and <2.5 mg/plate without activation (Hhong et
al., 1980; Cholakls et al.. 1980).
Based on U.S. EPA classification scheme RDX was assigned to Group C,
possible human carcinogen, on the basis of statistically significantly
Increased Incidence of liver tumors 1n female mice In the 2-year dietary
study by L1sh et al. (1984). From these data, a q^ of 5.4xlO~2
(mg/kg/day)'1 was estimated and a cancer-based RQ of 100 was derived.
In reproductive/teratology studies using Sprague-Dawley rats, RDX caused
reduction In fetal size and maternal lethality at concentrations of 20
mg/kg/day when given by gavage on days 6-15 of gestation (Angerhofer et al.
1986). In F344 rats, at concentrations of 20 mg/kg/day when given by gavage
on days 6-19 of gestation, RDX produced both embryotoxlclty and maternal
toxldty (Cholakls et al., 1980). F344 rats exposed to a dosage of 16
mg/kg/day 1n a 2-generatlon reproduction study showed signs of Impaired
lactation ability but no embryo or maternal toxldty.
Data were not sufficient for estimating an RfD for Inhalation exposure.
A previously verified RfD for oral exposure of 0.003 mg/kg/day based on a
NOEL of 0.3 mg/kg/day In a 2-year rat study (Levlne et al., 1984) was
adopted as the RfD for subchronlc and chronic oral exposure. Prostatlc
Inflammation and hemoslderosls of the spleen occurred at 1.5 mg/kg/day, the
next higher dose. An RQ of 1000 was based on prostatlc Inflammation and
hemoslderosls of the spleen In a 105-week oral rat study by Levlne et al.
(1984).
1x
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. CHEMICAL AND PHYSICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Reaction With Hydroxyl Radicals 4
2.1.2. Reaction With Ozone 4
2.1.3. Photolysis 4
2.1.4. Physical Removal Processes 4
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 5
2.2.4. Mlcroblal Degradation 5
2.2.5. Bloconcentratlon 6
2.2.6. Adsorption 6
2.2.7. Volatilization 6
2.3. SOIL 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Hydrolysis 7
2.3.3. Adsorption/Leaching 7
2.3.4. Volatilization 8
2.4. SUMMARY 8
3. EXPOSURE 9
3.1. WATER 9
3.2. FOOD 10
3.3. INHALATION 11
3.4. DERMAL 11
3.5. SUMMARY 11
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TABLE OF CONTENTS (cont.)
Page
4. ENVIRONMENTAL TOXICOLOGY 12
4.1. AQUATIC TOXICOLOGY 12
4.1.1. Acute Toxic Effects On Fauna 12
4.1.2. Chronic Effects On Fauna 14
4.1.3. Effects On Flora 18
4.1.4. Effects On Bacteria 19
4.2. TERRESTRIAL TOXICITY 19
4.2.1. Effects On Fauna 19
4.2.2 Effects On Flora 20
4.3. FIELD STUDIES 20
4.4. AQUATIC RISK ASSESSMENT 20
4.5. SUMMARY 20
5. PHARMACOKINETICS 23
5.1. ABSORPTION 23
5.2. DISTRIBUTION 24
5.3. METABOLISM 27
5.4. EXCRETION 27
5.5. SUMMARY 28
6. EFFECTS 30
6.1. SYSTEMIC TOXICITY 30
6.1.1 Inhalation Exposures 30
6.1.2. Oral Exposures 31
6.1.3. Other Relevant Information 40
6.2. CARCINOGENICITY 44
6.2.1. Inhalation 44
6.2.2. Oral 44
6.2.3. Other Relevant Information 46
6.3. MUTAGENICITY 46
6.4. TERATOGENICITY 47
6.5. OTHER REPRODUCTIVE EFFECTS 50
6.6. SUMMARY 51
7. EXISTING GUIDELINES AND STANDARDS 54
7.1. HUMAN 54
7.2. AQUATIC 54
xl
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TABLE OF CONTENTS (cent.)
Page
8. RISK ASSESSMENT 55
8.1. CARCINOGENICITY 55
8.1.1. Inhalation 55
8.1.2. Oral 55
8.1.3. Other Routes 55
8.1.4. Weight of Evidence 55
8.1.5. Quantitative Risk Assessment 56
8.2. SYSTEMIC TOXICITY 58
8.2.1. Inhalation Exposure 58
8.2.2. Oral Exposure 58
9. REPORTABLE QUANTITIES 62
9.1. BASED ON SYSTEMIC TOXICITY 62
9.2. BASED ON CARCINOGENICITY 65
10. REFERENCES 68
APPENDIX A A-l
APPENDIX B B-l
APPENDIX C C-l
APPENDIX D 0-1
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No.
5-1
6-1
9-1
9-2
9-3
LIST OF TABLES
TUIe
Concentrations (±S.D.) of ROX In Animal Tissues,
Incidence of Liver Adenoma/Carcinoma In B6C3F1 Mice Fed
CyclonHe for 105 Weeks
Oral Tox1c1ty Summary for ROX.
Oral Composite Scores for RDX.
RDX: Minimum Effective Dose (MED) and Reportable
Quantity (RQ)
9-4 Derivation of Potency Factor (F) for RDX.
Page
25
45
63
64
66
67
xlll
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List of Abbreviations
AAP Army ammunition plant
AEL Adverse-effects level
BCF Bloconcentratlon factor
CAS Chemical Abstract Service
CBC Complete blood cell
CNS Central nervous system
CS Composite score
CSF Cerebral spinal fluid
DMSO Dimethyl sulfoxlde
Concentration effective to 50% of recipients (and all other
subscripted concentration levels)
Frank effect level
Fischer 344
Genus mean acute value
Genus mean chronic value
Soil sorptlon coefficient
Octonol/water partition coefficient
Concentration lethal to 50% of recipients (and all other
subscripted concentration levels)
LD50 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
LOEC Lowest-observed-effect concentration
MED Minimum effective dose
HFO Mixed function oxldase
MTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEC No-ovserved-effect concentration
PEL
F344
GHAV
GMCV
Koc
Kow
xlv
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List of Abbreviations (cent.)
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
SER Smooth endoplasmlc retlculum -
STEL Short-term exposure level
TLV Threshold limit value
TNT Trinitrotoluene
TWA Time-weighted average
xv
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
RDX 1s the common name for 1,3,5-trlnHrohexahydro-l,3.5-trlazlne. It
1s also known as cyclonUe, cyclotrlmethylenenltramlne, cyclotrlmethylene-
trlnltrarolne and hexogen (Chemllne, 1989; SANSS, 1989). The structure,
molecular weight, empirical formula and CAS number for 1.3,5-tMnHro-
hexahydro-l,3,5-tr1az1ne are as follows:
Molecular weight: 222.26
Empirical formula: C_H,N,n,
J D OUt)
CAS Registry number: 121-82-4
1.2. CHEMICAL AND PHYSICAL PROPERTIES
RDX 1s a white crystalline solid at room temperature (Sax and Lewis,
1987). A powerful chemical oxldant, It Is 1.5 times more powerful and
explosive than TNT (Sax and Lewis, 1967). It Is soluble In polar organic
solvents such as acetone, ether and methanol, and Insoluble In nonpolar
organic solvents such as carbon tetrachlorlde and carbon dlsulflde (Sax and
Lewis. 1987; Ulndholz et al., 1983). Selected physical properties for RDX
are as follows:
Melting point: 203.5°C Sax and Lewis, 1987
Density: 1.82 g/fflt Sax and Lewis, 1987
Vapor pressure
at 20°C: 4.1xlO~" mm Hg Spanggord et al.. 1980a
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Hater solubility
at 208C:
at 25°C:
Log Kow:
Conversion factor
at 25eC:
38.4
76 mq/4
0.87
Spanggord et al., 1983
Small and Rosenblatt, 1974
Hansch and Leo, 1985
1 ppm * 9.09 mg/m3
1 mg/m1 * 0.11 ppm
1.3. PRODUCTION DATA
The production of RDX was reported as 102 million pounds in 1972;
however, this figure is thought to represent 95% of the total produced
(Small and Rosenblatt. 1974). Thus, the actual 1972 production was an
estimated 107 million pounds. RDX is usually synthesized by the nitration
of hexamine and purified by recrystalllzation (Ryon et al., 1984). RDX is
produced for use at Army munitions plants but 1s not manufactured
commercially. Plants that produced RDX in 1977 and their production volumes
are as follows (TSCAPP, 1989):
IMC Chemical Group Spanish Fork, UT
IMC Libertyville, IN
Holston AAP Ktngsport, TN
Confidential Confidential
More recent data regarding the production of RDX were not located in the
available literature.
1.4. USE DATA
RDX is used mainly as an explosive for munitions, although it has been
used as a rat poison (Small and Rosenblatt, 1974; Windholz et al., 1983).
0.1-1 mi 11 ion pounds
1,000-10,000 pounds
10-50 mi 1 lion pounds
0.1-1 mi 11 ion pounds
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RDX 1s usually handled while wet or as a slurry In water to prevent
detonation during processing.
1.5. SUMMARY
RDX Is a nonvolatile, white crystalline compound at room temperature
{Sax and Lewis, 1987). It Is soluble In polar organic solvents, slightly
soluble In water and Insoluble 1n nonpolar organic solvents (Sax and Lewis,
1987; Spanggord et al., 1980a). RDX Is normally.produced by the action of
nitric acid on hexamlne (Ryon et al., 1984). During 1977, four U.S
manufacturing facilities produced between 10.2-52 million pounds of RDX
(TSCAPP, 1989). The primary manufacturing site was the Holston AAP In
Klngsport, TN. RDX Is used as an explosive In armaments and munitions
{Spanggord et al., 1980a).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Elsenrlch et al. (1981) report that organic compounds with a vapor
pressure
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2.2. WATER
2.2.1. Hydrolysis. Hydrolysis at environmentally significant pHs should
be slow. The rate constant for hydrolysis at pH 7 and 30°C was reportedly
4.7xlO~B s"1 (Spanggord et al., 1980a). This translates to a half-life
of 170 days In neutral waters. An 11.6% loss of RDX was observed In a
seawater solution stored In light-filtering bottles for 112 days (Hoffsommer
and Rosen, 1973). The loss was attributed to hydrolysis; however, no
control samples were used.
2.2.2. Oxidation. Pertinent data regarding the oxidation of RDX In water
were not located In the available literature cited 1n Appendix A.
2.2.3. Photolysis. The quantum yield of RDX Is 0.16 at a wavelength of
299 nm {Spanggord et al., 1983). The experimental half-lives for sunlight
photolysis of RDX In distilled water, Holston River, TN, water and
Searsvllle Pond water were 13, 14 and 9 days, respectively, In January, 1980
(Spanggord et al., 198Qb).
The rate constants for photolytlc transformation of RDX In a Louisiana
munitions plant wastewater lagoon were 0.016 cm/day (winter) and 0.076
cm/day (summer) at a depth of 50 cm. This translates to half-lives of 2000
and 456 days, respectively (Spanggord et al., 1983). This slow photolysis
rate can be attributed to the high absorptivity of light by the lagoon.
2.2.4. Mlcroblal Degradation. RDX resisted aerobic degradation during
studies 18-90 days long using Inoculum from various sources (Spanggord et
al., 1980a, 1983; McCormlck et al., 1981). In a 70 l biological treatment
simulator, RDX underwent 14% degradation In 5 days when an activated sludge
Inoculum was used (Small and Rosenblatt, 1974). ROX at concentrations of 50
or 100 ug/8, was completely removed after 4 days under anaerobic conditions
5940H -5- 07/28/89
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In nutrient broth cultures with a sewage sludge Inoculum (McCormkk et al.,
1981). Metabolites Identified 1n this study Include hydrazlnes, dimethyl
hydrazlnes, dlmethylnltrosamlnes, azoxymethane, formaldehyde and methane!.
In the laboratory, 13 ppm RDX 1n lagoon wastewater did not undergo anaerobic
degradation for 83 days while a yeast extract was repeatedly added as a
nutrient. After 90 days, the RDX concentration dropped to 2.9 ppm. After
92 days, the RDX concentration was 1.3 ppm (Spanggord et al., 1983}.
Subsequently, RDX-accllmated micro-organisms from these experiments were
Incubated with ROX In various nutrient-fed systems. Rapid degradation was
observed; In one case, 9.1 ppm RDX was reduced to 0.6 ppm In 5 days.
Anaerobic degradation also occured 1n the presence of a yeast extract
cometabolUe during dleaway studies using 10 ppm RDX 1n river water and pond
water (Spanggord et al., 1980a). Degradation was complete 1n 10 and 8 days,
respectively. These data suggest that under laboratory conditions, RDX can
undergo anaerobic blodegradatlon.
2.2.5. B1oconcentrat1on. The whole-body BCF In the blueglll, Lepomls
macrochlrus. was 24.8 (Ryon et al., 1984), suggesting that bloaccumulatlon
In aquatic organisms Is not an Important fate process.
2.2.6. Adsorption. K values for RDX In sediment from the Hols ton
oc
River, TN, ranged from 0.8-270 (Spanggord et al., 1980a, 1983). These values
suggest moderate to low adsorption to sediment and suspended organic
material (Swann et al., 1983); however, RDX was found In sediment at
concentrations <43,000 yg/g 1n a stream receiving high levels of munitions
wastes (Spanggord et al., 1983).
2.2.7. Volatilization. Based on RDX's water solubility. 38.4 mg/i at
20°C (Spanggord et al., 1983), and vapor pressure, 4.1xlO~9 mm Hg at 20°C
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(Spanggord et al., 1983), a Henry's Law constant of S.lxKT11 atm-raVmol
at 20° C can be calculated. This value suggests that volatilization of ROX
from water Is not an Important fate process.
2.3. SOIL
2.3.1. M1crob1a1 Degradation. Aerobic degradation for RDX Is not known to
occur (Spanggord et al., 1980a, 1983; McCormlck et al., 1981). Osman and
Klausmeler (1973) observed some loss of RDX during aerobic soil enrichment
studies, but there was no evidence that .this loss was due to
blodegradatlon. Under the proper conditions, anaerobic degradation of RDX
by acclimated microorganisms occurs (Spanggord et al., 1980a, 1983; Ryon et
al.. 1984), and this may be an Important fate process In soil.
Blodegradatlon of RDX In soil was suggested, but not quantified, during a
lyslmeter column study (Kayser and Burllnson, 1988).
2.3.2 Hydrolysis. Pertinent data regarding hydrolysis of RDX 1n soil
were not located In the available literature cited In Appendix A; however,
limited data for aquatic systems suggest the potential for removal from soil
via this mechanism.
2.3.3. Adsorption/Leaching. K values for RDX In sediment from the
OC
Holston River, TN, ranged from 0.8-270 (Spanggord et al., 1980ar 1983).
These K values suggest moderate to high mobility In soil (Swann et al.,
1983). In a 6-month study using 2-foot lyslmlter columns, Kayser and
Burllnson (1988) found that RDX movement varied considerably In four
different types of soils. These soils ranged In texture as well as ability
to fix compounds because of their various amounts of organic matter and 1on
exchange capacity. Half of the soils displayed a strong affinity for RDX
while the other half allowed RDX to leach through the column.
5940H -7- 10/03/89
-------
_9
2.3.4. Volatilization. The vapor pressure of ROX, 4.1x10 mm Hg at
20°C (Spanggord et al., 1980a), suggests that volatilization from soil Is
not an Important fate process.
2.4. SUMMARY
The dominant fate process of RDX In translucent waters Is probably
direct photochemical degradation. The half-life for this process Is a few
weeks (Spanggord et al., 1980b). Insufficient data are available to predict
the significance of aerobic blodegradatlon. Limited data suggest that under
the proper conditions In lakes, ponds and groundwater, anaerobic degradation
may be significant. Volatilization from water or soil Is probably not
Important. Slow hydrolysis of RDX Is also a potential removal process
(Spanggord et al., 1980a; Hoffsommer and Rosen, 1973). When released to
soil, RDX displays moderate to high mobility and can be expected to leach
Into groundwater. This process depends greatly on the type of soil (Kayser
and Burllnson, 1988). If released to the atmosphere, RDX may be removed by
dry or wet deposition. Direct photochemical degradation of RDX In the
atmosphere may also occur.
5940H -8- 07/28/89
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3. EXPOSURE
ROX Is a synthetic organic compound manufactured and processed predomi-
nantly by military armament plants as an explosive In munitions (Small and
Rosenblatt, 1974). RDX can enter the environment through wastewater dis-
charge from Us production, formulation and Incorporation Into munitions or
through the demilitarization of antiquated munitions (Hoffsommer and Rosen,
1972; Hoffsommer et al., 1972; Ryon et al., 1984). RDX can also enter the
environment by leaching from waste lagoons and from the Improper disposal of
contaminated sludge (Jenkins et al., 1986). RDX may be released to the
atmosphere In contaminated participate matter formed during the Incineration
of mixtures that contain RDX (Carroll et al., 1979; Ryon et al., 1984).
The National Occupational Exposure Survey, conducted between 1981 and
1983, estimated that 488 workers are occupatlonally exposed to RDX (NIOSH,
1984). The available monitoring data suggest that probable routes of
exposure for the general public Include Ingestlon of contaminated water and
Inhalation of contaminated partlculate matter produced 1n the Incineration
of RDX-conta1n1ng waste.
3.1. WATER
ROX concentrations of 0.1-0.15 mg/l were found In Brush Creek, IA,
which originates on an AAP (Small and Rosenblatt, 1974). RDX concentrations
In a stream near an AAP In Milan ranged from 0.1-109 mg/8, (mean 11.9
mg/i) (Ryon et al., 1984). RDX was detected In a river 1 mile from the
point of last discharge from the Holston AAP at a concentration of 79
iig/8. (Ryon et al., 1984). An on-s1te lagoon at an unspecified AAP
contained 6280 jig/a (Jenkins et al., 1986). ROX was not found 200 miles
off the Florida coast or 45 miles west of San Francisco; two sites where old
ships loaded with antiquated munitions were scuttled at sea (Hoffsommer et
al., 1972; Hoffsommer and Rosen, 1972)
5940H -9- 10/02/89
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A plume of RDX-contamlnated groundwater stretched 6.5 km near the
Cornhusker, IA, AAP. Concentrations ranged from 9 to >100 yg/a
(Spa"Iding and Fulton, 1988). In 4/39 groundwater samples taken at the Milan
AAP, detectable levels of RDX ranged from <20-780 yg/l {average 270
yg/l) (Ryon et al.. 1984). RDX was detected In 7/7 groundwater wells at
a munitions disposal site In concentrations of 1-47 yg/4 (Richard and
Junk, 1986). An unspecified AAP water supply well contained 70 yg/l
(Jenkins et al., 1986).
RDX was found In 5/5 sediment samples (2600-38.000 yg/g; average
11,080 ng/g) from an on-s1te lagoon at the Milan AAP (Ryon et al., 1984).
In the sediment of a nearby stream, RDX was found In 3/15 samples at
290-43,000 yg/g (average 15,160 ng/g). The sediment of a Louisiana AAP
wastewater lagoon contained 0.10-89 yg/g (Spanggord et al., 1983). RDX
was not found In five sediment samples taken near deepwater munitions dumps
In the Atlantic and Pacific Oceans (Hoffsommer et al., 1972)
RDX was quantitatively determined In the wastewater effluent of the
Holston AAP. Over a 6-month period In 1973, the concentration In various
effluent discharges ranged from <0.1-24.4 mg/i, with average concen-
trations ranging from 0.4-10.4 mg/l (Small and Rosenblatt, 1974). In
1979, the average dally discharge of RDX from this plant was 156 Ibs/day
(Ryon et al., 1984).
3.2. FOOD
Pertinent data regarding RDX 1n food were not located In the available
literature cited In Appendix A..
5940H -10- 10/02/89
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3.3. INHALATION
People living near plants where RDX 1s manufactured, formulated or
packed Into munitions may be exposed to RDX by Inhalation. RDX was found 1n
participate matter released during Incineration of waste munitions (Carroll
et al., 1979; Ryon et al., 1984).
3.4. DERMAL
Pertinent data regarding dermal exposure to RDX were not located In the
available literature cited 1n Appendix A..
3.5. SUMMARY
RDX Is a man-made compound used In the manufacture of armaments and
munitions. RDX can enter the environment through wastewater discharge from
Us production, formulation and Incorporation Into munitions and through the
demilitarization or deepwater dumping of antiquated munitions (Hoffsommer
and Rosen, 1972; Hoffsommer et al., 1972; Ryon et al., 1984; Small and
Rosenblatt, 1974). RDX can also enter the environment by leaching from
waste lagoons Into soil and from the Improper disposal of contaminated
sludge (Jenkins et al., 1986). RDX may be detected In groundwater when wash
waters are used to clean equipment and Interior surfaces at munition
manufacturing and demilitarization facilities. The wash water Is collected
In holding tanks and periodically pumped through carbon absorption columns
before being discharged to surface streams (Jenkins et al., 1986). RDX may
enter the atmosphere through the release of contaminated partlculate matter
formed during the Incineration of RDX-conta1n1ng mixtures (Carroll et al.,
1979; Ryon et al., 1984).
Exposure to RDX 1s apparently limited to areas near where It Is manufac-
tured or used In munitions. Exposure can occur by the Inhalation of par-
tlculate matter produced during the Incineration of RDX-contalnlng mixtures.
5940H -11- 10/03/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects On Fauna. RDX that had been dried and mixed
with acetone was used 1n static acute toxlclty tests conducted In a series
of freshwater Msn and aquatic Invertebrates (Bentley et al., 1979). The
Invertebrates tested were <1-day-old water fleas, Daphnla magna. juvenile
scud, Gammarus fasclatus. juvenile sowbugs, Asell us mllltarIs. and second
and third Instar midge larvae, Chlronomus tentans. For each Invertebrate
species, three groups of five animals were tested at each of the five or
more nominal exposure concentrations. Water temperature was maintained at
2Q*C. The 24- and 48-hour EC^ values for Immobilization exceeded 100
rag/i, the highest concentration tested. In all four Invertebrate species.
Fish were more sensitive than the Invertebrates to the toxic effects of ROX.
The ranges of 24-, 48- and 96-hour LC5Q values In fish were 7.5-14,
5.8-8,5 and 4.1-6.4 mg/l, respectively. There was little difference 1n
susceptibility among the species tested, which Included blueglll sunflsh,
Lepomls macrochlrus. rainbow trout, Salmo galrdnerl. channel catfish,
Ictalurus punctatus. and fathead minnow Plmephales promelas. For each
species, three groups of 10 fish were tested at each nominal concentration.
Water temperature was kept at 10°C for the trout and 20°C for the other
species. Life stage tests were conducted on fathead minnows. In these
tests, eggs were exposed to RDX for 144 hours, and 1-hour-old, 7-day-old,
30-day-old and 60-day-old fry were each exposed for 96 hours. Thirty
minnows of each life stage, In three groups of 10 each, were tested at each
nominal concentration. Water temperature for these tests was 25°C. The
LC for minnow eggs was >100 mg/l after 24- to 144-hour exposure. In
5940H -12- 07/28/89
-------
comparison, the 96-hour LC5Q In the static test was 4.1 rog/l. In the
other fish tested (blueglll sunMsh and fathead minnow; 30 of each exposed
to every concentration), 24- and 48-hour and Incipient LC5Q values were
>10, 6.6-7.6 and 5.2-6.4 mg/B., respectively. Incipient IC values In
fish were calculated at 264 hours.
4.1.2. Chronic Effects On Fauna.
4.1.2.1. TOXICITY Studies of chronic to*1dty were performed with
freshwater Invertebrates using a solution of RDX In DMSO solvent under
flowthrough conditions (Bentley et al., 1979). Both untreated and
DMSO-exposed controls were used. Water fleas, Daphnla magna. 20 per
aquarium, and midge larvae, Chlronomus tentans. 100 per aquarium, were
tested. Four replicates were employed at each exposure concentration.
Measured concentrations to which water fleas were exposed were 1.4, 2.2,
4.8, 9.5 and 20 mg/l. Survival of the first generation (up to day 21) was
not affected by treatment. The average number of young produced per
parthenogenetlc first-generation female was significantly reduced at >4.8
mg/i, between days 7 and 14, but not between days 14 and 21. In the second
generation, neither survival (up to day 42) nor reproduction differed from
controls. Based on first-generation reproductive effects, a NOEC of 2.2
mg/l and a LOEC of 4.8 mg/l were derived from this study. Midges were
exposed to measured RDX concentrations of 1.3, 2.2, 4.0, 10 and 21 mg/i.
No effect on the survival of larvae, pupae or adults, or the percent
emergence of adults was seen In the first generation (up to day 23). Only
Infertile eggs were produced by midges exposed to 1.3 and 4.0 mg/i, and no
eggs at all were produced at 10 mg/l. These effects did not appear to be
exposure-related since reproduction was unaffected by exposure to 21
mg/l. The second generation was Initiated from control eggs In the groups
5940H -14- 07/28/89
-------
o
that did not successfully reproduce. Although significant reductions In
second generation survival and percent emergence were found, 1t does not
appear that these effects were exposure-related; good dose-response
relationships were not attained, and effects were found In groups started
with control eggs even though these were actually being exposed to RDX for
the first time and first-generation effects had not been seen. Reproduction
was not affected In the second generation. The inconsistent results
obtained in this study preclude deriving effective concentration levels.
Bentley et al. (1979) performed a critical life stage toxicity test in
which the eggs and fry of channel catfish, Ictalurus punctatus. and fathead
minnows, Pimeghalej promelas. were exposed to RDX in DMSO for 30 days under
flowthrough conditions. Both untreated and OMSO-exposed controls were
Included In these studies. Eggs, 50/concentration for catfish and 40/con-
centratlon for minnows, were exposed within 48 hours of fertilization. The
eggs hatched within 3-8 days. In the catfish, 25 fry were selected from
each group for continued exposure. In the minnow, the number selected was
based on percent hatch. The tests were conducted at 22°C. Catfish were
exposed to mean measured concentrations of 0, 0.11, 0.71 and 2.3 mg/^ of
RDX. Other exposure levels were estimated to be 0.30 and 1.2 mg/l.
Percent hatch of eggs was not affected by exposure. Although survival after
30 days was reduced at ^1.2 mg/^, this was attributed to a diluter
malfunction early in the experiment that temporarily increased RDX
concentrations above the mean exposure levels; most mortality occurred
within 6 days of the malfunction. Body length at 30 days was unaffected by
exposure. Effective concentration levels could not be derived from this
study because of the diluter malfunction. Minnows were exposed to mean
5940H -15- 06/20/89
-------
measured concentrations of 0, 0.26, 1.2 and 5.8 mg/i. Other exposure
levels were estimated to be 0.76 and 3.0 mg/i. There were no effects on
percent hatch of eggs or survival at 30 days; body length was reduced
slightly, but significantly. In the 30-day-old fry exposed to 5.8 mg/i.
This concentration was taken to be the LOEC In this study; the NOEC was 3.0
mg/i.
The effect of chronic exposure to RDX In freshwater fish under flow-
through conditions was also studied by -Bentley et" al. (1979). In the first
test, fathead minnows, Plmephales promelas. were exposed to measured
concentrations of 0, 0.29, 0.64, 1.1, 2.7 and 4.9 mg/l of RDX In DHSO.
Both untreated and DMSO-exposed controls were Included 1n this study. The
study design was as follows: two aquaria, each containing 60 eggs, were
exposed at each concentration and, after hatching, two groups of 20 fry were
selected for continued exposure from each aquarium. On day 181, after most
fish had reached sexual maturity, each group was reduced to three males and
seven females. Groups of 50 eggs from the first seven spawns In each
aquarium were Incubated, and 20 fry from the first two egg groups In each
aquarium were selected for continued exposure. The total duration of
exposure for adult fish was 240 days. Water temperature was maintained at
25°C. There were no effects on percent hatch, survival at 30 days, or
length at 30 or 60 days. Survival at 60 days was reduced from 93-100% In
controls to 65-75% 1n the 4.9 mg/l group, but the difference was not
statistically significant. No mortality was recorded between day 60 and day
140, when the fish were all killed accidentally while being treated for
external parasites.
A second test was then conducted. The mean measured concentrations were
0, 0.43, 0.78, 1.5, 3.0 and 6.3 mg/i. Percent hatch was not affected by
ROX exposure. Survival was significantly reduced from 93-100% 1n controls
5940H -16- 07/28/89
-------
to c?25% at 30 days and 15% at 60 days 1n fish exposed to 6.3 mg/l.
Neither 30- nor 60-day survival was affected at lower concentrations.
Length was not Influenced by 30- or 60-day exposure. Between days 64 and
181, only four deaths occurred, suggesting that RDX was not cumulatively
toxic after 60 days. At 240 days, percent survival, length and wet weight
of both males and females were unchanged from controls. Also unaffected
were spawning activity, hatchabllHy j»f second-generation eggs, percent
survival, length and wet weight of second-generation fish after 30 days.
Water quality parameters were measured and found not to be affected by RDX
concentration In this study. A LOEC of 6.3 mg/l, based on reduced
survival during the first 60 days of the experiment, and a NOEC of 3.0
mg/i, were taken from this study.
4.1.2.2. BIOACCUWJLATION/BIOCONCENTRATION -- Exploratory bloconcen-
tratlon tests In fish and Invertebrates were conducted by Liu et al.
(1984). RDX, labeled with 14C and dissolved in DMSO, was added to
aquaria containing 50 annelid worms, LumbMculus varlegatus. 100 adult water
fleas, Daphnla magna. or 3 blueglll sunflsh, Lepomls macrochlrus, at a
nominal concentration of 0.3 mg/J, for 96 hours. These static tests were
performed at 20°C. Significant accumulation of RDX was not reported In any
of these species. Four-day BCF of 3.0 and 1.6 were found In worms and water
fleas, respectively. In bluegllls, the BCFs values were 1.9 In muscle
tissue and 3.1 In the viscera. These values are slightly less than the
equilibrium BCF values of 4-5 1n muscle and 9-10 In viscera reported by
Bentley et al. (1979) for bluegllls.
Bloaccumulatlon of RDX In fish was studied by Bentley et al. (1979).
Groups of 65 blueglll, Lepomls macrochlrus. 65 channel catfish, Ictalurus
5940H -17- 07/28/89
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pynctatus. and 130 fathead minnows, Pimephales promelas. were exposed to
t4C-RDX under flowthrbugh condlttons at mean measured concentrations of
0, 0.014 and 1.0 ing/^ for 28 days. A 14-day depuration period followed
exposure. Water was kept at a constant 18°C. Mortality was unusually high
(22-261) In bluegill and minnows exposed to either concentration of ROX, but
the cause could not be determined. Exposed catfish and controls of all
species were unaffected. Recovery of administered radioactivity was
complete (99-1011). Accumulation -and elimination of "C residues was
directly proportional to the concentration of '4C-RDX In the water.
Equilibrium between the rates of accumulation and elimination was reached
between 14 and 21 days in most cases, depending on the tissue and species in
question. RDX did not accumulate significantly in any of the species
tested. Equilibrium BCFs were =4-5 1n the muscle of fish exposed to 0.014
mg/^, and 3-4 1n the muscle of those exposed to 1.0 mg/^. In the
viscera, BCFs ranged from 6-11 at 0.014 mg/^, and 3-9 at 1.0 mg/^. The
results regarding elimination of radioactivity during the 14 days following
exposure were not as consistent. Although almost all radioactivity was
eliminated from the muscle and viscera of bluegills exposed to 0.014 mg/^,
almost none was eliminated from bluegllls exposed to 1 mg/^. In fish of
other species exposed to 1 mg/^, 70-87% was eliminated.
4.1.3. Effects On Flora.
4.1.3.1. Toxidty -- Bentley et al. (1979) investigated the acute
toxicity of RDX to several species of algae in static tests. RDX was dried
and mixed with acetone in these studies. Test species Included the
blue-green algae, Microcvstis aeruqinosa and Anabeana flos-aquar. the green
alga, Selenastrum capricornututn. and the diatom, Navlcula pelliculosa.
5940H -18- 06/20/89
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Chlorophyll a levels were monitored in all four species. Cell density was
also recorded by measurement of optical density In A. flos-aquar and by cell
counts for the other three species. The 96-hour EC50 values for changes
In chlorophyll a content and cell density were >32 mg/4, the highest
nominal exposure level, in all four species. S. caprlcornututn appeared to
be more sensitive to RDX than the other species; at 32 mg/4t cell density
was reduced 38% In this species but only 14-18% in the other species. The
decrease was also greater than In-other species at lower concentrations.
Percent reduction in chlorophyll a content was greater In this species than
others at 0.32-10 mg/^ but was similar in all four species at 32 mg/^
(17-23% decrease).
4.1.3.2. BIOCONCENTRATION -- RDX labelled with "C was used to
perform an exploratory bioconcentration test in the green alga, S.
capricornutum. (Liu et al., 1984). The algae were exposed to a nominal
concentration of 0.3 mg/^ of ROX for 96 hours under static conditions at
24°C. Relatively large amounts of radioactivity were recovered in the
tissues of the algae. The BCF was 123.0, which Is much higher than the
values reported for fish and invertebrates in the same study (1.6-3.1).
4.1.4. Effects On Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to RDX were not located in the available
literature cited in Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects On Fauna. Pertinent data regarding the effects of exposure
of terrestrial fauna to RDX were not located in the available literature
cited in Appendix A.
5940H
-19-
06/20/89
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4.2.2. Effects On Flora. Pertinent data regarding the effects of exposure
of terrestrial flora to RDX were not located In the available literature
cited 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of RDX on flora and fauna In the
field were not located In the available literature cited In Appendix A.
4.4. AQUATIC RISK ASSESSMENT
The lack of an adequate quantity of pertinent data regarding the effects
of exposure of aquatic fauna and flora to RDX prevented the development of a
freshwater criterion by the method of U.S. EPA (1986a,b). Available data are
displayed In Figure 4-1. The lowest LC,Q reported was 3.8 mg/l In
7-day-old fathead minnow fry. The lowest level at which effects were
reported In a chronic study was 4.8 mg/l In 0. Magna. Additional data
required for the development of a freshwater criterion Include the results
of acute assays with a nonarthropod and nonchordate species and an Insect or
species from a phylum not previously represented, another chronic study
using either a fish or an Invertebrate, an assay In which an aquatic plant
species Is exposed to measured concentrations of RDX and an estimate of the
maximum permissible tissue concentration In wildlife.
No data were located regarding the effects of exposure of marine fauna
and flora to RDX. Acute studies with representatives from eight families of
marine fauna and at least three chronic studies and one bloconcentratlon
study with marine fauna and flora are needed In order to develop a saltwater
criterion.
4.5. SUMMARY
Data on the toxlclty of RDX to aquatic organisms were obtained from
studies by Bentley et al. (1979) and Liu et al. (1984). RDX was more toxic
5940H -20- 07/28/89
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TEST TYPE
Family
#1
Chordate (Salmonid-fish)
12
Chordate (warmwater fish)
13
Chordate (fish or amphibian)
#4
Crustacean (planktonic)
#5
Crustacean (benthic)
16
Insectan
#7
non-Arthropod/ -Chordate
18
New Insectan or phylum
representative
#9
algae
#10
Vascular plant
GMAVa
(mg/L)
6.4
-6.75
5.56
38.73
100
38.73
NA
KA
32
NA
GMCV*
(mg/L)
NA
NA
4.35
3.25
NA
NA
NA
NA
NA
NA
BCFa
NA
10
11
NA
NA
NA
NA
NA
NA
NA
*NA-Not Available
FIGURE 4-1
Freshwater Aquatk Life From Exposure to
RDX.
of
5940H
-21-
07/28/89
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to fish (96-hour LCSO » 4.1-6.4 mg/^) than Invertebrates (48-hour
EC!Q * >100 mg/4) or algae (96-hour EC - >32 mg/£) in acute
static toxkity tests. The results of flowthrough toxiclty tests 1n
bluegill and fathead minnow were similar to those of static tests (96-hour
LC50 - 6.6-7.6 mg/*); however, the toxiclty of RDX to catfish was
reduced slightly under flowthrough conditions (96-hour LC50 - 13
mg/^). The most sensitive life stage of fathead minnows exposed to ROX
was 7-day-old fry (96-hour LC50 "*« 3.8 mg/^), followed in order by
60-day-old fry, 30-day-old fry, 1-hour-old fry and eggs. Chronic exposure
to .>4-8 nig/^ of RDX produced a transitory decrease In daphnid reproduc-
tion. Although decreases were reported in the survival and percent
emergence of midges exposed to RDX at 1.3-21 mg/l, these effects did not
appear to be exposure-related. Fathead minnows chronically exposed to 6.3
mg/^ of RDX had reduced survival during the first 60 days of the
experiment. RDX did not accumulate significantly in the tissues of
Invertebrates or fish; however, a 4-day BCF of 123 was calculated in algae.
5940H -22- 06/20/89
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5. PHARMACOKINETICS
5.1. ABSORPTION
Schneider et al. (1977) administered a SO rag/kg dose of 14C-RDX
dissolved In DMSO by gavage to 10 adult Sprague-Oawley rats (presumably both
males and females) and collected urine, feces and expired 1*CO_ for 4
days. The rats were then sacrificed to estimate whole carcass
radioactivity. Fecal radioactivity acounted for <3% of the administered
dose, while urinary radioactivity and- expired' 14CO accounted for 34%
and 43%, respectively. Radioactivity In the carcass accounted for 10% of
the administered dose. Overall recovery accounted for 90% of the
administered radioactivity. These data suggest that RDX and Us radioactive
metabolites produced 1n the gut are almost completely absorbed from the
gastrointestinal tract of rats.
In rats given a 100 ing/kg oral dose of coarse granular RDX as a slurry
1n Isotonlc saline and sampled at several Intervals within 24 hours, levels
of RDX In serum rose to 2.09 ug/mi within 4 hours and peaked at 3.0
yg/mi at 24 hours (Schneider et al., 1977). In rats similarly treated
with a finely powdered sample In saline at 50 tug/kg, 24-hour plasma levels
reached 4.7 ^g/mt, demonstrating the effect of particle size on rate of
absorption from an orally administered suspension.
In female miniature swine treated similarly with 100 mg/kg finely
powdered RDX In saline, serum RDX concentration Increased for the first hour
to =1.7 vg/mB., plateaued for the next 5 hours and Increased notably
from the sixth to the 24th hour to -4.7 ug/mi, suggesting that
gastrointestinal absorption In miniature swine was similar to that In the
rat.
5940H -23- 07/28/89
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MacPhail et al. (1985) reported that .RDX was absorbed Into blood within
1 hour of oral administration of 50 mg/kg In 2X carboxymethylcellulose to
4-5 adult female Sprague-Dawley rats. Levels 1n plasma rose rapidly In the
first hour but much slower over the next 23 hours. Peak levels appeared to
occur at 24 hours.
According to Taylor (1975), RDX Is absorbed from the stomach and lungs
but not through the skin. Further Information or documentation was not
provided.
5.2. DISTRIBUTION
RDX concentrations In tissues from rats and miniature swine In the
Schneider et al. (1977) studies described above are summarized In Table 5-1.
Highest levels were located In the kidney; however, RDX did not appear to
accumulate In a specific organ. Schneider and Andersen (1975) reported that
treatment of rats with slurries of RDX at 500 or 50 mg/kg by intraperitoneal
administration or at 100 mg/kg by gavage resulted 1n the same pattern of
tissue distribution with the levels in the tissues proportional to the dose
administered.
MacPhail et al. (1985) reported that concentrations of RDX in the brains
of adult female Sprague-Dawley rats peaked within 24 hours after oral
administration of 50 mg/kg In carboxymethylcellulose. The brain level of
RDX then decreased and was not detectable 72 hours after treatment. Plasma
levels plateaued 8 hours after dosing and remained relatively steady for the
next 16 hours; they began to fall and were almost undetectable by 3 days
after dosing.
MacPhail et al. (1985) administered RDX in carboxymethylcellulose to
adult (probably male) Sprague-Dawley rats (10/group) at concentrations of 1,
3 and 10 mg/kg for 30 days and measured RDX concentrations in plasma and
5940H -24- 06/20/89
-------
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whole brain at 15 and 30 days. Results showed that after 15 days of
treatment, RDX was not detectable In the plasma or brain of animals 1n the 1
and 3 mg/kg treatment groups; It was detectable In the plasma of only one
rat and In the brain of two rats In the highest dosage group. After 30
days, RDX was detected only 1n the brains of two rats at the highest dosage
level. The group mean brain concentration for this dose group was 0.27
pg/gm; there was no evidence of Increwed concentration In the brain with
continued duration of treatment.
Guo et al. (1985) administered an unspecified dose of 3H-RDX to male
mice (number and strain not given) by gavage or Intravenous Injection before
the mice were sacrificed and 3H-ROX concentrations In several organs, blood,
urine and feces were measured. Distribution was rapid following either
route of administration. After Intravenous administration, tissue concen-
trations were highest In lung, followed by heart, liver, kidney, brain,
spleen, testls, adipose tissue and muscle (In order of decreasing concentra-
tion); after gavage administration, tissue concentrations were highest In
liver, followed by kidney, muscle, lung, spleen, heart, brain, testls and
adipose tissue (In order of decreasing concentration). Tissue levels In all
mice decreased significantly 1n 12-24 hours. After gavage treatment, organ
radioactivity decreased to almost background levels In seven days. There
appeared to be no accumulation of RDX In any organ of the mouse.
Schneider et al. (1978) exposed Sprague-Dawley rats of both sexes to
RDX-saturated drinking water (50-70 ug/m!) for <90 days and sacrificed
the rats In groups of six at 30, 60 and 90 days to measure tissue concentra-
tions of the chemical. There appeared to be no RDX accumulation In any of
the tissues studied, Including heart, brain, liver, kidney, stomach and
colon.
5940H -26- 07/28/89
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5.3. METABOLISM
In the Schneider et al. (1977) rat study with a 50 mg/kg dose of
[14C]-RDX (see Section 5.1), expiration of 14CO_ accounted for 43% of
the administered radioactivity. Urinary radioactivity accounted for 34% of
the dose. On the basis of gas chromatographlc analysis of the urine of rats
treated orally with 100 mg/kg, the Investigators estimated that
unmetabollzed RDX accounted for only 3.6% of the total urinary radioac-
tivity. Levels of radioactivity much 1n excess of actual ROX levels were
also measured 1n the liver, prompting the Investigators to state that RDX
metabolites were present 1n the liver. They concluded that extensive
metabolism of RDX occurred In the liver. Schneider et al. (1977) cited work
Indicating that a single 50 mg/kg dose of RDX stimulated persistent SER
proliferation In the liver of rats (French et al., 1976) and that
phenobarbltal, a known liver mlcrosomal MFO-lnducer, Increased the rate of
ROX metabolism In the rat (Conney, 1967). The Investigators concluded that
RDX was extensively metabolized 1n the liver.
When rats were treated with [14C]-RDX-saturated water for 1 week (5
rats) or 13 weeks (6 rats of both sexes), 30-50% of the radioactivity was
recovered as exhaled 14C02. 25-35% was found In the urine and 4-5% In
the feces. Of the total urinary radioactivity, unmetabollzed RDX
contributed only 3-5%, while the remainder was due to unidentified
metabolites (Schneider et al., 1978).
5.4. EXCRETION
In the Schneider et al. (1977) rat study (see Section 5.1.), the
Investigators reported that expired 14CO_ accounted for 43% of an oral
50 mg/kg dose of 14C-RDX. Expiration of 14CO remained fairly linear
through the first 3 days after treatment before stabilizing. Urinary
5940H -27- 07/28/89
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radioactivity accounted for 34% of the dose and remained fairly linear for 2
days, Urinary excretion was nearly complete by the third day. Fecal
excretion accounted for <3% of the administered radioactivity.
In the gavage study where 3H-RDX was administered to mice (Guo, 1985)
(see Section 5.2), more radioactivity was eliminated through urine than
feces after gavage administration, and 64.82% of the radioactivity was
eliminated through the urine and feces within 24 hours of administration.
5.5. SUMHARY
Balance experiments with 14C-ROX 1n rats suggest that absorption of
radioactivity from the gastrointestinal tract 1s nearly complete (Schneider
et al., 1977). Plasma levels of RDX In rats and miniature swine
administered RDX by gavage plateaued after an Initial rise and did not peak
until 24 hours after treatment (Schneider et al., 1977), Indicating that
gastrointestinal absorption Is prolonged. In rats treated with RDX
suspended In saline, higher plasma levels were achieved with a 50 mg/kg dose
of a finely powdered sample compared with a 100 mg/kg dose of a coarse
granular sample, demonstrating the effect of particle size on gastrointes-
tinal absorption (Schneider et al., 1977). RDX Is reported to be absorbed
from the stomach and lung but not through the skin (Taylor, 1975).
Distribution experiments In rats (Schneider et al., 1977, 1978; MacPhall
et al., 1985), miniature swine (Schneider et al., 1977) and mice (Guo et
al., 1985) Indicate that distribution Is rapid following oral or Intravenous
administration. Highest levels of RDX were found In the kidney of rats and
miniature swine (Schneider et al., 1977} and In the lung, liver and kidney
of mice (Guo et al., 1985). Continued oral exposure of rats did not result
In accumulation of RDX In any tissue (Schneider et al., 1978; MacPhall et
al., 1985).
5940H -28- 07/28/89
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RDX appears to be extensively metabo.11 zed and excreted as Indicated by
recovery of 43% of an oral dose of I4C-RDX as '4C02 In rats (Schneider
et al., 1977). Urinary radioactivity accounted for 341 of the dose and only
3.6% of the urinary radioactivity constituted unmetaboltzed compound. The
liver appears to be the principal site of metabolism (Schneider et al.,
1977). N1th1n 4 days of treatment, excretion accounted for »80% of the
administered dose.
5940H -29- 06/20/89
-------
radioactivity accounted for 34X of the dose and remained fairly linear for 2
days. Urinary excretion was nearly complete by the third day. Fecal
excretion accounted for <3X of the administered radioactivity.
In the gavage study where 3H-RDX was administered to mice (Quo, 1985)
(see Section 5.2), more radioactivity was eliminated through urine than
feces after gavage administration, and 64.82% of the radioactivity was
eliminated through the urine and feces within 24 hours of administration.
5.5. SUMMARY
Balance experiments with 14C-RDX 1n rats suggest that absorption of
radioactivity from the gastrointestinal tract Is nearly complete (Schneider
et al., 1977). Plasma levels of RDX 1n rats and miniature swine
administered RDX by gavage plateaued after an Initial rise and did not peak
until 24 hours after treatment (Schneider et al., 1977), Indicating that
gastrointestinal absorption 1s prolonged. In rats treated with RDX
suspended 1n saline, higher plasma levels were achieved with a 50 mg/kg dose
of a finely powdered sample compared with a 100 mg/kg dose of a coarse
granular sample, demonstrating the effect of particle size on gastrointes-
tinal absorption (Schneider et al., 1977). RDX 1s reported to be absorbed
from the stomach and lung but not through the skin (Taylor, 1975).
Distribution experiments In rats (Schneider et al., 1977, 1978; MacPhall
et al., 1985), miniature swine (Schneider et al., 1977) and mice (Quo et
al., 1985) Indicate that distribution Is rapid following oral or Intravenous
administration. Highest levels of RDX were found In the kidney of rats and
miniature swine (Schneider et al., 1977) and In the lung, liver and kidney
of mice (Guo et al., 1985). Continued oral exposure of rats did not result
In accumulation of RDX In any tissue (Schneider et al., 1978; MacPhall et
al., 1985).
5940H
-30-
06/20/89
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workers with regard to any parameter tested. The authors concluded that
there was no evidence for adverse health effects among workers with RDX
exposures of up to 1.57 mg/m3 or an average of 0.28 mg/m3.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC Schneider et al. (1978) provided RDX-saturated
drinking water (50-70 vg/mi) ad libitum for 90 days to a group of 18
male and female Sprague-Dawley rats to study tissue distribution during
subchronlc exposure. The total dally dose* was estimated by the
Investigators to be 5-8 mg/kg. A control group of 10 male and female rats
received distilled water. At 30-day Intervals, groups of six animals were
sacrificed and levels of RDX In selected tissues were measured. No signs of
toxlclty were observed during the study and the growth of treated rats was
similar to that of the controls. At necropsy, all organs appeared normal.
Schneider et al. (1978) gave 20 mg RDX/kg/day In an Isotonlc saline
slurry to a group of 30 male and female Sprague-Dawley rats by gavage for 90
days to study distribution during subchronlc treatment. Ten control rats
from both genders received Isotonlc saline by gavage. While eight of the
treated rats died between days 42 and 77, the deaths appeared to be due to
exacerbation of an underlying chronic respiratory disease rather than as a
direct result of the toxlclty of ROX. Treated rats exhibited no CNS signs.
No deaths occurred In the control group.
von Oettlngen et al. (1949) conducted two studies to measure the sub-
chronic toxlclty of dietary RDX 1n rats. A group of 45 rats (age, strain
and gender not reported) were divided Into three treatment groups and
received diets containing RDX concentrations adjusted to provide dosages of
15, 50 or 100 mg/kg/day for 10 weeks; the rats were then sacrificed.
5940H -31- 07/28/89
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Mortality, growth and clinical observations were recorded, but hematologlcal
or hlstologlcal observations were not. No control animals were reported In
this study. While no animals In the lowest dose group died, there was 60%
and 87% mortality 1n the middle- and high-dose groups, respectively. The
only abnormality observed In the dead animals was congestion of the lungs
and gastrointestinal tract. According to the authors, the rats that
received 15 mg/kg/day had a "normal" -weight Increase during the time of
treatment while the rats at the two higher dosages lost weight rapidly
during the first three weeks of exposure; their weights then fluctuated
below Initial weight levels until the final week of the study when the
weight of the animals at the highest dose was the same as It was at the
beginning of the treatment. The rats at the lowest dosage exhibited normal
behavior while those at the higher dose levels were Irritable, vicious and
suffered clonlc-tonlc convulsions.
For the second study, 80 rats, In treatment groups of 20, received diets
containing RDX adjusted to provide dosages of 0, 15, 25 or 50 mg/kg/day for
12 weeks. Behavior, weight, mortality and blood chemistry parameters were
recorded and surviving rats were sacrificed 5 days after cessation of the
treatment for Mstopathologlc examination of unspecified tissues. All
control rats and 19/20 low-dose rats survived. The death of the one
low-dose rat was probably not due to RDX exposure. Forty per cent of the
animals In each of the two high-dose groups died and autopsies of these
animals revealed lung and gastrointestinal tract congestion. Heights of
animals In the control group and 15 mg/kg dose groups Increased In a similar
manner while weights of rats 1n the two higher dose groups decreased for the
first four weeks and then Increased to almost the Initial weight (50 mg/kg
group) or higher than the Initial value (25 mg/kg group). Control animals
5940H -32- 07/28/89
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and those at the lowest dosage exhibited normal behavior while those at the
two higher dose groups were Irritable, vicious and had convulsions.
Behavior of survivors returned to normal during the 5 nonexposure days
before sacrifice. Blood chemistry patterns were similar In all groups.
Tissues of sacrificed rats had no significant abnormalities.
A 13-week study of the effects of orally administered RDX on F344
(Sprague-Oawley) rats was conducted by Levlne et al. (1981). Doses of 10,
30, 100, 300 and 600 mg/kg/day were "provided 'by adjusting the concen-
tration of RDX In the diets fed to test animals (10/sex/group) for 90 days.
A control group of 30 rats/sex received no RDX In their feed. Animals were
observed for mortality, toxic signs, body weight, food consumption and
clinical chemistry. All rats were necropsled at death or at the conclusion
of the study; major organs were weighed and about 25 selected organs and
tissues were prepared for microscopic examination. Results showed that
doses >100 mg/kg/day resulted 1n mortality. Irritability, reduced food
consumption and reduced body weight gain. Mean survival times were
Inveresly related to dose with no sex differences noted. Rats that were
given 10 mg/kg/day had at least a 10% reduction 1n serum trlglycerlde levels
and the magnitude of this effect was dose-related. Females at this dosage
had significant leukocytosls and males had a 6% reduction In mean body
weight gain compared with controls. Hales that received 30 mg/kg/day
exhibited a 13% reduction In body weight gain although food consumption was
comparable with that of controls. Animals that received RDX had no
histopathologlcal lesions at any dose level.
NacPhall et al. (1985) studied the behavioral effects of RDX when
administered to adult Sprague-Dawley rats for 30 days. Dosages of 0, 1, 3
and 10 mg/kg/day of RDX suspended In a 2% solution of carboxymethylcellulose
5940H -33- 07/28/89
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were given to groups of 24-72 male or female rats by gavage for 30 days.
Behavior and motor activity tests were given the day before the Initial
dose, then on days 16 and 31. There was no evidence of behavior
modification that was due to ROX administration.
A study of the subchronlc effects of RDX In the diets of F344 rats and
B6C3F1 mice was conducted by Cholakts et al. (1980). Dietary concentrations
were adjusted to provide dosages of 0.-10, 14. 20, 28 and 40 mg/kg/day In
treatment groups of 10 males and 10 females of each species. Animals were 5
weeks of age at the beginning of the study. Dosages were adjusted on the
basis of weekly food consumption and body weight measurements. The compound
was given for 90 days during which the animals were observed dally for signs
of toxldty, behavior changes and other abnormalities. Clinical pathology
measurements were taken from selected animals at selected Intervals. All
animals that died before the conclusion of the study were necropsled.
Animals that survived the study were sacrificed and necropsled on day 90.
Major organs were weighed and a comprehensive set of organs and tissues from
control and high-dose rats were subjected to microscopic examination.
Tissues from mice were not examined microscopically. The only consistent
lexicological effect seen In the rat study was a decrease In mean body
weights compared with those of controls In the rats given 40 mg/kg/day. The
decrease appeared to be dose-related and was statistically significant In
the male rats; It was also noted In the females. The food consumption of
male rats at the high-dose level was lower than that of controls for several
weeks during the study. There was one death In the-hlgh dose group but It
did not appear to be related to RDX administration. No other behavioral or
5940H -34- 07/28/89
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pharmacological signs were observed In the high-dose rats. Rats given 28
mg/kg/day RDX apparently were not affected by the treatment.
Cholakls et al. (1980) reported no differences In the treated mice
compared with controls with respect to change In body weight, food
consumption, behavior and clinical pathology; therefore, the study was
repeated at higher doses, using treatment groups of 10 male and 12 female
B3C3F1 mice. The mice were 5 weeks old at th& beginning of the study.
Diets were adjusted to provide dosages of 0, 40, 60 or 80 mg/kg/day for 2
weeks followed by 0, 320, 160 or 80 mg/kg/day, respectively, for 11 weeks
(TWA doses of 0, 277, 145 and 80 mg/kg/day for 91 days). Treated mice of
both sexes exhibited a dose-related Increase In mean absolute and relative
liver weights that were statistically significant at 277 mg/kg/day. A
dose-related but statistically nonsignificant Increase In absolute and
relative kidney weight was reported In treated male mice. Nice at the
highest dose had greater mortality than controls (27 and 0%, respectively);
deaths occurred during the llth week of the study except for one female that
died during week 6. Hale mice at the highest dosage became hyperactive and
nervous during weeks 7-8. Hlstopathologlcal lesions observed In the
high-dose group restricted to the males possibly attributable to RDX
Included mild focal myocardlal degeneration, hepatocellular vacuollzatlon,
Increased hepatocellular karyomegaly and mild tubular nephrosls.
According to von Oettlngen et al. (1949), seven female dogs (age and
breed not given) treated with 50 mg RDX/kg/day In a pellet of moistened food
6 days a week for 6 weeks (expanded dosage 42.9 mg/kg/day) exhibited no
significant changes In blood chemistry. They became excited and Irritable
several hours after the first dose and as exposure continued, they became
hyperactive and progressively convulsive. While five control dogs maintained
5940H
-35-
07/28/89
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a fairly constant weight for the duration of the study, treated dogs lost
weight after the first week. Although their food consumption was not
affected, treated dogs showed a 2OX weight loss at the end of the 6 weeks.
One treated dog died, but no deaths were noted among five control dogs. The
six surviving treated dogs were sacrificed and necropsled. All exhibited
dlstentlon of mesenterlc blood vessels and slight congestion of small
Intestine mucous membranes.
Hart (1974} studied the effects of oral administration of RDX In beagle
dogs {three males and three females/dose group) for 90 days. Ooses of 0.1,
1 and 10 mg/kg/day were given In small portions of moist dog food, and the
dogs were observed dally for changes In appearance, behavior and for signs
of toxIcHy. Dogs were weighed weekly, and hematologlcal, clinical
biochemistry and urlnalysls parameters were measured regularly. At
termination, the dogs were sacrificed and necropsled. Major organs were
weighed and subjected to hlstopathologlcal examination. There were some
cases of nausea and vomiting during the first 2 weeks of the study, but no
other toxic signs or changes In body weight were observed. One animal In
the 1 mg/kg/day dose-group died for reasons apparently not related to
exposure. Clinical pathology parameters, necropsies and microscopic studies
showed no effects that were due to RDX administration. The value of this
study 1s questionable because of the small number of dogs that were treated.
Martin and Hart (1974) conducted a study to determine the subchronlc
effects of RDX when administered orally to groups of cynomolgus monkeys for
90 days. Three monkeys/sex/treatment group were given doses of 0, 0.1, 1
and 10 mg/kg/day suspended In 1% methylcellulose by oral Intubation.
Monkeys were monitored dally for mortality, toxic signs and changes In
appearance and behavior. Weighings were conducted weekly and laboratory
5940H -36- 07/28/89
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tests, Including ophthalmologlcal examination, hematology, blood chemistry,
urlnanalysls and liver function, were made at regular Intervals. All
surviving animals were sacrificed and necropsled after 90 days of
treatment. Hlstopathologlcal examination was not performed. Weight loss
occurred 1n all groups. Including the control group, within the first week.
The Investigators attributed the weight loss to the stress of dally handling
and manipulation for gavage admlnlstatlen. The Vnvestlgators reported that
treated monkeys appeared not to regain lost weight as rapidly as controls,
suggesting an effect of RDX. The data Indicated considerable Individual
variation and no conclusion can be drawn. Of monkeys that received 10
mg/kg/day, five had disturbances of the central nervous system Involving
convulsions; four survived and recovered, but one was euthanized. An
Increase In the amount of Iron-positive material In liver cord cell
cytoplasm was reported In high-dose monkeys. The authors were unable to
explain the toxlcologlcal significance of this observation. There were no
effects on the other parameters monitored that were attributed to RDX.
Because the number of monkeys used 1n the study was small, statistical
significance was not performed.
6.1.2.2. CHRONIC A 2-year feeding study of RDX with 86C3F1 mice was
conducted by L1sh et al. (1984). Groups of 85 male and 85 female mice
received ROX mixed with feed at concentatlons adjusted to provide dosages of
0, 1.5, 7.0, 35 and 175 mg/kg/day for 105 weeks. Because mortality was high
at the Initial dosage of 175 mg/kg/day, this dose was reduced to 100
mg/kg/day after the first 10 weeks of the study, resulting In a 1HA dose for
this group of 107 mg/kg/day.
Dally observations for mortality, toxic signs and behavior abnormalities
were made. Body weights, food consumption, ophthalmology, hematology and
5940H -37- 07/28/89
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blood chemistry parameters were measured regularly. Palpations for masses
were conducted weekly. Ten mice/sex/treatment group were sacrificed at
weeks 26 and 53 and all animals that did not survive the study were
necropsled. Surviving mice were sacrificed and necropsled at week 105-106,
1 day following the last administration of RDX. Major organs were weighed
and selected tissues from some animals from each dose group were subjected
to microscopic examination. A moLe comprehensive hlstopathologlcal
examination was performed on mice from the control and high-dose groups.
Results showed that mice, at dosage levels >35.0 mg/kg/day, had Increased
mortality, body weight change, food consumption and hematology parameters
that were not significantly different from those of controls. The only
statistically significant effect (p value not reported) noted In the mice
that received 7.0 mg/kg/day was hypercholesterolemla In the females. At the
35 mg/kg/day dosage, males had significantly higher renal weights (p value
not reported) and an Increased Incidence of testlcular degeneration, while
females had a greater (not significant) Incidence of hepatomegaly compared
to controls. Mice that were exposed to the highest dosage had significantly
(p value not reported) reduced body weight gain over the 2-year period as
well as Increased kidney and heart weights, an Increased number of lung
hlstlocytes, an Increased Incidence of hepatomegaly and. In the males,
Increased Incidence of testlcular degeneration compared with controls.
Although the Increase In testlcular degeneration observed at 35 and 107
mg/kg/day was not statistically significant, the Investigators attributed It
to RDX.
Using the same protocol as Ush (1984), Levlne et al. (1984)
Investigated the effects of dietary concentrations of RDX on 344 rats.
Doses of 0, 0.3, 1.5, 8.0 and 40 mg/kg/day were fed to groups of 75 male and
5940H
-38-
07/28/89
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75 female rats for 105 weeks. No effects attributable to RDX admini-
stration were seen 1n the animals that received 0.3 mg/kg/day. Hale rats
administered 1.5 mg/kg/day had suppuratlve Inflammation of the prostate and
Increased amounts of a hemoslderln-llke pigment In the spleen. Rats of both
sexes given 8.0 mg/kg/day had body weights that were -5% lower than those
of controls. In addition, females had hepatomegaly and decreased total
serum protein levels. Rats at the highest dose of RDX had a statistically
significant higher rate of mortality compared with controls (80% and 50%,
respectively}, as well as reduced body weight gains, reduced food
consumption, hyperactlvlty, signs of liver and kidney damage and an
Increased Incidence of cataracts.
Hart (1976) conducted a 2-year study to determine the effects of diets
containing fine granular RDX at concentrations adjusted to provide dosages
of 0, 1.0, 3.1 and 10 mg/kg/day on Sprague-Dawley rats (100 males and 100
females/dose group). Rats were observed dally for mortality and weekly for
signs of toxic or pharmacologlc effects and changes In appearance and
behavior. The body weights and food consumption of 25 rats/treatment group
were monitored. Hematology, blood chemistry and urlnalysls parameters were
evaluated at regular Intervals on selected rats. Twenty rats/dose group
were sacrificed and necropsled after 52 weeks. All rats that survived the
study were sacrificed and necropsled after 104 weeks of treatment. Selected
organs were weighed and selected tissues were subjected to microscopic
examination. A more comprehensive hlstopathologlcal examination was
performed on rats from the control and high-dose groups. Treated rats
showed no apparent differences, compared with controls, In any of the
parameters evaluated.
5940H
-39-
07/28/89
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6.1.3. Other Relevant Information. The acute oral LD5Q for RDX 1n rats
was determined by von Oettlngen et al. (1949) to be 200 mg/kg when
administered as a ^% suspension In gum acacia. RDX was administered to 95
rats (age, sex and strain not given) by gavage 1n doses ranging from 25-400
mg/kg. Host deaths occured <24 hours after treatment. Autopsies revealed
moderate to severe congestion of the gastrointestinal tract and lungs.
The oral LDrQ for RDX In F344 rats- (combined sexes) was determined by
Cholakls et al. (1980) to be 118.1 mg/kg when administered by gavage \n a 1%
aqueous solution of methylcellulose. The response was not sex-related.
Signs of toxlclty In exposed animals Included gasping and labored breathing
and clonlc/tonlc convulsions.
Dllley et al. (1979) determined the oral L05Q for RDX 1n Sprague-
Dawley rats to be 71 mg/kg for males, and approximately that value In
females. All 10 females given 50 mg/kg survived, while 1/10 given 75 mg/kg
survived. Ten male and 10 female animals at each dose level were
administered ROX In corn oil by gavage. Signs of toxldty Included tremors
and convulsions. The acute oral LD5Q In Swiss-Webster mice was also
determined In this study using the same protocol. For male mice, the value
was 86 mg/kg; for female mice the value could not be determined because 5/10
animals at every dose level died.
The oral L05Q for RDX In B6C3F1 mice was determined by Cholakls el al.
(1980) to be 97.2, 58.9 and 80.3 mg/kg for males, females and combined sexes
when administered by gavage In an aqueous solution of 1% methylcellulose and
1% polysorbate 80. Signs of toxldty Included labored breathing and
clonlc/tonlc convulsions. The response appeared to be sex-related although
the authors stated that overlapping confidence limits do not support this
5940H -40- 07/28/89
-------
observation. Spector (1956) lists the acute oral LD5Q 1n mice as 500
mg/kg; In cats, as 100 mg/kg.
Schneider et al. (1977) noted that the acute oral toxlclty of RDX was
dependent on the physical form of the test sample. Without providing data,
these Investigators stated that the oral LD5Q of RDX dissolved in DMSO or
of finely powdered RDX suspended 1n saline was =100 mg/kg 1n Sprague-
Dawley rats. Coarsely granular RDX suspended In saline, however, yielded an
oral L05Q of =300 mg/kg.
The effects of acute administration of RDX to adult Sprague-Dawley rats
on behavior was studied by MacPhall et al. (1985). Doses of 1, 12.5, 25 and
50 mg/kg In 2% carboxymethylcellulose were given orally to groups of 24-72
male or female rats. Behavior tests were conducted 2 hours later and the
next day. Results showed that motor activity decreased with Increasing RDX.
dose with the lowest dose, causing a >50% decrease In activity compared to
controls. Activity levels were still depressed 24 hours after dosing.
Burdette et al. (1988) studied the effects of oral administration of RDX
on seizure activity of male Long Evans rats. ROX, In 2% carboxymethylcellu-
lose, was administered to groups of 10 rats orally at doses ranging from
0-60 mg/kg, and the animals were monitored for seizure activity for 24
hours. Plasma RDX concentrations were also monitored. Results showed that
spontaneous seizures occurred at dosages of >10 mg/kg and plasma concentra-
tions of 3.1 pg/mi. French et al. (1976) studied the change in liver
and kidney morphology in rats {number, strain and sex not reported) 24, 48
and 120 hours after oral administration of 100 mg/kg RDX. Changes in the
hepatocytes Involving mltochondrlal swelling, dilation of the rough
endoplasmic reticulum and the presence of concentric membrane arrays after
5940H -41- 07/28/89
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24 hours were noted. These effects persisted through the 120-hour observa-
tion. Proliferation of the SER of the liver had begun by 48 hours and
Increased dramatically by 120 hours. The effects of RDX on renal tissue
were minimal and transient at this dose level.
A study of the acute toxlclty of RDX In dogs was reported by von
Oettlngen et al. (1949). Dosages of 5 mg/kg and 15 mg/kg suspended In 10%
gum acacia were given to three dogs -{age, sex* and breed not given) by
stomach tube and physiological parameters. The dogs were observed for 240
minutes. No changes In any physiological functions measured (arterial and
venous blood pressures, respiratory rate, spinal CSF pressure and urine
nitrate content) were observed.
A study designed to assess the dermal toxlclty of RDX In New Zealand
albino rabbits showed that a single application of 2 g/kg In 1% carboxy-
methylcellulose caused no mortality, no clinical signs of toxlclty and a
small, transient, loss of body weight In eight male and five female animals
during a 14-day observation period (Furedl-Machacek et al., 1987).
Schneider et al. (1977) gave RDX 100 mg/kg In an Isotonlc saline slurry
to ten female miniature swine (21-60 kg) by gavage. Four animals convulsed
12-24 hours after dosing and two died at 22 hours. The lag time between
compound administration and onset of convulsions In the swine Is comparable
with the latent period before RDX convulsions In humans (Schneider et al.
(1977).
Gleason et al. (1969) suggested an acute fatal, oral dose of RDX 1n
humans as ranging from 5-500 mg/kg. According to Taylor (1975), Industrial
workers exposed to ROX experienced sudden convulsions or loss of
conslousness without convulsions. Some workers had headaches, dizziness,
nausea and vomiting before losing consciousness. Return to consciousness
5940H -42- 07/28/89
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was followed by Intermittent stupor, weakness and nausea. Recovery was
essentially complete. There were no fatalatles reported In 915,000 man-
years of RDX exposure In U.S. ordnance plants during World War II (HcConnell
and Fllnn, 1946).
Kaplan et al. (1965) reported case studies of five workers In an
ammunitions plant exposed to RDX through Inadequate ventilation 1n the
workplace. Possible routes of exposure Included Inhalation, 1ngest1on and
skin absorption. Five of 26 workers-engaged 1n the operation reported
convulsions or unconsciousness (or both) within 2 days (2 cases) or 2 weeks
(1 case) or unknown periods of time (2 cases) after the beginning of RDX
exposure. Premonitory signs of headache, dizziness and vomiting were not
always seen. Unconsciousness lasted from several minutes to 24 hours and
was followed by stupor, dlsorlentatlon, nausea,. vomiting and weakness for
varying lengths of time. Urlnanalysls and CBC counts were normal. After
supportive treatment, recovery was complete. Two men who were subsequently
reexposed to the compound had the Illness again.
Human exposures to RDX have been reported. A 3-year-old child suffered
clonlc-tonlc convulsions after Ingesting =1.23 g of the compound. He
recovered within several days (Woody et al., 1986).
Cases of soldiers who experienced effects from exposure to RDX have been
reported by Merrill (1968); Hollander and Colbach (1969) and Stone et al.
(1969). The soldiers were exposed to C-4, a plastic explosive used In
Vietnam, containing 91% RDX, either by conscious or accidental Ingestlon.
Signs of the Intoxication Included multiple generalized seizures, followed
by lethargy, severe nausea and vomiting, muscle twitching and loss of
memory. The seizures usually occurred without previous Indication of
sickness. At least 3/8 patients had consumed alcohol In the form of beer or
5940H -43- 07/28/89
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vodka with or before Ingesting C-4. Actual amounts of C-4 consumed were
only reported for three patients, and were 25 g, 25 g and 180 g; the other
exposures could not be quantified. There were no fatalities reported and
all patients recovered within several days except the case of 180 g
Ingestlon who had anemia and loss of recent memory after 30 days of
hosp1ta!1zat1on {Stone et al., 1969).
von Oettlngen et al. (1949) reported that no signs of Irritation were
seen when a 1 cm2 patch of wet gauze Covered with RDX was taped onto the
forearm of a volunteer for 48 hours.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhalation exposure to RDX were not located In the literature cited In
Appendix A.
6.2.2. Oral. In the 2-year study using mice reported by Llsh et al.
(1984) (see Section 6.1.2.2.), oral administration fed In the diet of 0,
1.5, 7.0, 35 and 175 mg/kg/day resulted In a statistically significant
Increase In the number of hepatocellular carcinomas combined with adenomas
In the females at doses >7.0 mg/kg/day when compared with controls (Table
6-1). The Investigators observed that the Incidence of hepatocellular
adenomas/carcinomas 1n the female control mice was unusually low; however,
the Incidence of these liver tumors was statistically significant when
compared with historical control Incidence of 7.954 from the NTP (n.d.). The
Incidence of combined alveolar-bronchial carcinoma/adenoma 1n male mice at
the highest dose level was Increased compared with controls but the Increase
was not statistically significant.
Levlne et al. (1984) (see Section 6.1.2.2.) observed no evidence for the
carclnogenlclty of RDX In F344 rats under the conditions of the study.
*
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TABLE 6-1
Incidence of Liver Adenoma/Carcinoma In B6C3F1 Nice
Fed Cyclonlte for 105 Weeks3
Sex/
Number b
F/65
F/62
F/64
F/64
F/31
M/63
M/60
M/62
M/59
M/37
Dose
(mg/kg/day)
0
1.5
7.0
35.0
175/100d
0
1.5
7.0
35.0
175/1 00d
QUALITY OF EVIDENCE
Tumor Incidence
(%)
1 (1-5)
5 (8.1)
9 (14.1)c
12 (18.8)c
6 (19.4)c
21 (33.3)
26 (43.3)
17 (27.4)
25 (42.4)
18 (48.6)
Strengths of Study: The compound was administered to both sexes at more than
two dose levels. Adequate number of animals/group; nat-
ural route of exposure; adequate duration of exposure;
compound 89-98% pure; MTD achieved.
Weakness of Study: Highest dose altered after 10 weeks due to excess
mortality In males and females.
Overall Adequacy: Adequate
aSource: Llsh et al.. 1984
bNumber of animals surviving >12 months
Clnc1dence significantly different from that of control group (p<0.05)
dBecause of toxldty. Initial dose of 175 was reduced to 100 after 10
weeks.
6200H -45- 07/28/89
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Groups of 75 rats/sex/group received diets that provided dosages of 0, 0.3,
1.5, 8 or 40 mg/kg/day for <24 months. Increased mortality and decreased
rate of body weight gain were observed at doses of 40 mg/kg/day, suggesting
that the MTD had been reached.
6.2.3. Other Relevant Information. Other relevant Information regarding
the carclnogenldty of RDX were not located In the available literature
cited 1n Appendix A.
6.3. MUTAGENICITY
ROX at concentrations <2.5 mg/plate was negative In the reverse mutation
assay In Salmonella typhlmurlum strains TA98, TA100, TA1535, TA1537 and
TA1538 with rat liver S-9 metabolic activation; 1t was also not mugatenlc
when tested In the Salmonella spot test at spot concentrations of 0.625 and
1.25 mg with the same strains (Whong et al., 1980). It was also not
mutagenlc to any of the five bacterial strains of S^ typhlmurlum when tested
with and without rat liver activation at concentrations <.012 mg/plate
(Simmon et al., 1977).
In a separate study, Cholakls et al. (1980) reported that RDX was not
mutagenlc to any of the five Salmonella tester strains at concentrations <1
mg/plate with and without metabolic activation (Arochlor-lnduced rat
liver). RDX was not mutagenlc In the rat dominant lethal mutation test at
doses <50 mg/kg/day.
Dllley et al. (1979) assayed the effect of various concentrations of ROX
In an unscheduled DNA synthesis assay. The ability of RDX dissolved 1n
dlmethylsulfoxlde to stimulate DNA synthesis In cultured WI-38 cells with
and without metabolic activation (mouse liver) was determined to be zero at
concentrations <4 mg/mB..
5940H -46- 10/03/89
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6.4. TERATOGENICITY
A study of the teratologlcal effects of RDX In Charles River Sprague-
Dawley rats was done by Angerhofer et al. (1986). In a pilot study, RDX
(90% pure) dosages of 10, 20, 40, 80 and 120 mg/kg/day were administered by
gavage to pregnant rats, six/dose group, on days 6-15 of gestastlon. The
test compound was suspended In 10X gum acacia In concentrations of 3%.
Total volume of the administered doses was not given. Only six control rats
received the vehicle, 4 mi/kg/day, on- the same schedule. Test animals
were observed dally for changes In appearance and behavior; all animals that
died before the end of the study were necropsled. On day 20 of gestation,
surviving animals were sacrificed and examined for gross pathological
changes; the uterus and ovaries were exposed and examined for number and
location of viable fetuses, nonvlable fetuses, resorptlons, total
Implantations and corporea lutea. Each fetus was weighed, measured, sexed
and examined for external malformations and visceral anomalies. All of the
rats that received >40 g/kg/day died before the end of their dosing
periods. These animals experienced convulsions before death and necropsy
findings Included bloody discharge around their mouths and noses. Dams
treated with 20 mg/kg/day had urogenltal discharge and red nasal discharge
throughout the dosing time. Those administered 10 mg/kg/day displayed no
effects from treatment. Pups born to treated dams from all test groups had
body weights that were significantly lower than those born to control dams.
In the definitive study, groups of at least 25 mated rats were given
dosages of 0, 2, 6 or 20 mg/kg/day on days 6-15 of gestation (Angerhofer et
al., 1986). Necropsies were performed on all animals that died or became
moribund before the end of the study. All surviving animals were sacrificed
5940H -47- 07/28/89
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on day 20 of gestation; uteri were exposed and scored for number of fetuses,
Implantation sites, resorptlons, and corpora lutea. Each uterus was excised
and weighed and this value subtracted from the terminal body weight to
determine the absolute body weight change during gestation. The fetuses
were removed, weighed, measured, sexed and scored for abnormalities;
one-half were then prepared for soft tissue examination and the others for
skeletal observation.
Of the dams receiving 20 mg/kg/day-, 16 of 51 (31%) did not survive.
These animals experienced urogenltal discharge, red nasal and oral
discharge, convulsions and prostration before death; necropsies of these
animals did not establish a specific cause of death. Some surviving dams at
this dose level exhibited nasal, oral and urogenltal discharge, convulsions,
hyperactlvlty and alopecia. These animals had body weights that were
significantly lower than controls on days 10, 13 and 16 of gestation but
which were more comparable with those of controls by day 20. The high-dose
group had a fertility Index of 74% compared with 64% In the controls and a
gestation Index of 94% compared with 100% 1n all other groups.
One dam from each of the other treatment groups (2 mg/kg/day and 6
mg/kg/day) did not survive the study. No overt signs were noted for these
deaths.
The fertility Indexes for controls and the 2 mg/kg/day dose group were
64% while that for the 6 mg/kg/day group was 74%. The gestation Indexes for
both of these groups was 100%.
Studies of fetal parameters showed no statistically significant
differences In Implantations per dam or fetuses per dam In treatment groups
compared with controls. All treatment groups had slightly higher Incidences
of resorptlon (6%) than the controls (5%), but the differences were not
5940H -48- 07/28/89
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statistically significant. The weights and lengths of fetuses In all
treated groups were significantly less than those of controls (p<0.05). The
differences, however, were slight and did not appear to be dose-related at 2
or 6 mg/kg/day. When the data were statistically reanalyzed using the
litter as the basis of comparison, reduced fetal length and body weight were
significant only at 20 mg/kg/day (U.S. EPA, 1988a). One of the conclusions
drawn by the authors of this study was 4hat oral dosages of RDX as low as 2
mg/kg/day can cause reduced fetal size In rat pups receiving the chemical
during the major period of organogenesls. U.S. EPA (1988a), however,
considered 20 mg/kg/day a LOAEL and 6 mg/kg/day a NOAEL for fetal effects In
this study.
Cholakls et al. (1980} studied the developmental effects of RDX on F344
rats and New Zealand rabbits. Treatment groups of 24 pregnant rats or 10
pregnant rabbits received doses of 0, 0.2, 2.0 or 20 mg/kg/day by gavage on
days 6-19 (rats) or 7-29 (rabbits) of gestation. The vehicle was aqueous 1%
methylcellulose and 1% polysorbate 80. Positive controls were given by
gavage 350 mg/kg hydroxyurea (rats) or 3 mg/kg/day of 6-am1nonlcot1nam1de
(rabbits). Animals were observed dally for signs of toxldty; body weights
and feed consumption were monitored frequently. Dams were weighed and
sacrificed on day 20 (rats) or day 30 (rabbits) of gestation. Uteri were
exposed and examined. The number and position of resorptlons, live fetuses
and corpora lutea were scored. Fetuses were counted, weighed, sexed and
examined for abnormalities. Selected fetuses were cleared and stained for
soft tissue and skeletal examination.
Rats that received 20 mg/kg/day had 24% mortality (6 of 25), lower whole
body weights and liver weights compared with controls and signs of neuro-
toxlclty. There were fewer viable fetuses (81.4%) compared with controls
5940H -49- 07/28/89
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(93.2%) and more early resorptlons (15.3%) than controls (6.0%). There was
no evidence for teratogenlc effects and no adverse effects were reported at
0.2 or 2.0 mg/kg/day. The only effect seen In the rabbits was a slight
reduction 1n maternal weight gain at the highest RDX dose. There were no
effects on the number of fetuses/dam, Implants/dam, fetal weights or fetal
abnormalities and there appeared to be no specific teratologlc effects.
6.5. OTHER REPRODUCTIVE EFFECTS
A 2-generat1on reproduction study of RDX using F344 rats was reported by
Cholakls et al. (1980). The FQ generation consisted of 22 males and 22
females/treatment group that were fed diets adjusted to provide dosages of
0, 5, 16 or 50 mg/kg/day for 13 weeks and then mated. The F, animals were
maintained on the test diets for 13 weeks after weaning and then mated.
F_ pups were sacrificed after weaning and selected animals were
necropsled; some tissues were prepared for hlstopathologlcal evaluation.
Mortality In the high-dose group was 18% 1n the FQ generation compared
with 0% 1n controls (statistically significant, p value not given) and the
number of stillbirths In F, and F_ generations was significantly higher
than those of controls 1n this dose group (p value not given). The number
of Hveblrths was also decreased In the high-dose rats, compared with
controls. Rats from the high-dose group showed a consistent reduction In
body weight and food consumption In the F_ and F, generations. There
appeared to be no differences In gross necropsy observa- tlons of F pups
compared with controls. Reduced pup body weights at 25 days after birth
were reported at 16 and 50 mg/kg/day In offspring of the first FQ mating
but not In the second FQ mating or 1n subsequent generations. A
statistically significant Increase In the number of renal cortical cysts was
reported at 16 mg/kg/day In F? offspring of either sex examined
5940H -50- 07/28/89
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hlstopathologlcally. Although the authors concluded that reproductive
performance of rats 1n the low- and middle-dose groups was not affected by
treatment, the observation of lower body weights In the first FQ offspring
at weaning suggests Impaired lactation ability 1n the dams, which Is a
slight, but adverse, reproductive effect.
6.6. SUMMARY
In the only report of Inhalation exposure to' RDX, 69 humans showed no
adverse effects after exposure to atmospheric concentrations ranging from
3
0-1.5 mg/m In an ammunition plant (Hathaway and Buck, 1977).
Subchronlc exposures of rats to RDX In the diet produced several dose-
related effects. Levlne et al. (1981) noted that mean survival times of
F344 rats was Inversely related to concentrations of RDX In their diets.
Other dose-related effects seen were a reduction In mean body weights and
reduced serum trlglycerlde levels. Doses ranged from 10-600 mg/kg/day for
90 days. At 10 mg/kg/day, male body weights were reduced 6% compared with
controls. Cholakls et al. (1980) reported that administration of 28
mg/kg/day for 90 days In the diets of F344 rats produced no adverse effects
but saw a dose related decrease In mean body weights at 40 mg/kg/day. von
Oettlngen et al. (1949) reported no adverse effects 1n rats fed RDX 1n the
diets at a dosage of 15 mg/kg/day for 10 weeks and for 12 weeks, but
Increased mortality and decreased weight gain at dosages of 25, 50 and 100
mg/kg/day.
In a subchronic study with B6C3F1 mice, Cholakls et al. (1980) reported
a dose-related Increase In mean liver weights that was significant at the
highest dose when the animals were exposed to 0, 80, 145 and 277 mg/kg/day
(TWA doses) for 90 days. The authors noted no significant effects In mice
receiving 145 mg/kg/day.
5940H -51- 07/28/89
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Subchronlc studies with other species have been done. In dogs, von
Oettlngen et al. (1949) saw a 20% weight loss compared with controls and
convulsions and behavior changes In dogs given 42.9 mg/kg/day for 42 days
(expanded dose). Hart (1974) observed no adverse effects when beagle dogs
were given <10 mg/kg/day for 90 days. Cynomulgus monkeys administered RDX
by gavage for 90 days experienced no adverse effects at a dosage of 1
mg/kg/day but had disturbances of the central nervous system at 10 mg/kg/day
(Martin and Hart, 1974).
Three 2-year dietary studies are reported, one with B6C3F1 mice (Llsh et
al., 1984), one with F344 rats (Levlne et al., 1984) and one with
Sprague-Dawley rats (Hart, 1976). In mice, dosages of 1.5 mg/kg/day caused
no adverse effects, while dosages of 7.0 mg/kg/day caused biochemical
changes. Doses of 35 mg/kg/day resulted In testlcular degeneration In the
males and higher renal weights, and 107 (TWA dose) mg/kg/day produced
decreased body weights and Increased kidney and heart weights compared with
controls. Results with the rats Indicated that there were no adverse
effects at a dosage of 0.3 mg/kg/day while doses >1.5 mg/kg/day produced
prostate Inflammation and hemoslderosls In the males. Lower body weights
compared with controls were seen In rats given a dosage of 8 mg/kg/day.
Effects seen at 40 mg/kg/day Included Increased mortality and reduced body
weights compared with controls. No adverse effects at doses <10 mg/kg/day
were noted 1n a study with Sprague Dawley rats (Hart, 1976).
Acute exposures of rats by gavage resulted In L05Q values ranging from
71-200 mg/kg (von Oettlngen et al., 1949; Dllley et al., 1979; Cholakls et
al., 1980); reported LDrn values 1n mice administered by gavage range from
58-97 mg/kg (Dllley et al., 1979; Cholakls et al., 1980) with one outlier
value of 500 mg/kg reported by Spector (1956).
5940H -52- 07/28/89
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Oral human exposures resulted 1n convulsions, seizures and unconscious-
ness several hours or days after exposure but no fatalities have been
reported.
The only carcinogenic effect reported was seen 1n female B6C3F1 mice
administered ROX at 0, 1.5, 7, 35 and 175/100 mg/kg/day for 105 weeks (Llsh
et al., 1984). The animals receiving dosages >7 mg/kg/day had statistically
significant Increased Incidences of liver adenomas' and carcinomas (combined)
compared with controls. This effect was not seen In the male mice. No
carcinogenic effects were seen in F344 rats at doses <40 mg/kg/day.
RDX was not mutagenlc In the Ames assay at concentrations <1 mg/plate
with metabolic activation and <2.5 mg/plate without activation (Whong et
al., 1980; Cholakls et al., 1980).
In reproductive/teratology studies using Sprague-Dawley rats, RDX caused
reduction In fetal size and maternal mortality at concentrations of 20
mg/kg/day when given by gavage on days 6-15 of gestation (Angerhofer et al.
1986). In F344 rats, at concentrations of 20 mg/kg/day when given by gavage
on days 6-19 of gestation, RDX produced both embryotoxlclty and maternal
toxlcity (Cholakls et al., 1980). F344 rats exposed to a dosage of 16
mg/kg/day 1n a 2-generat1on reproduction study showed signs of Impaired
lactation ability but no embryo or maternal toxlcity.
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
A verified RfD for chronic oral exposure is 0.003 mg/kg/day (U.S. EPA,
1988b). The duration of this RfD presented In Section 8.2.2.2.
ACGIH (1988) recommended a TWA-TLV of 1.5 mg/m3 for occupational
exposure based on analogy to TNT (ACGIH, 1986). This value Is accompanied
by a "skin" notation, Indicating that dermal exposure Is potentially
hazardous. A STEL of 3 mg/m3 Is 1 fated, but ACGIH (1986, 1988) recommends
that this value dropped because data are Insufficient. OSHA (1989)
established a PEL for an 8-hour workday of 1.5 mg/m3 with a "skin"
notation, primarily to provide protection against neuropathic effects.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to RDX were not located In the available literature cited 'In
Appendix A.
5940H
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhalation exposure to RDX were not located In the available literature
cited In Appendix A.
8.1.2. Oral. RDX has been shown to be carglnogenlc to female B6C3F1 mice
when administered at dietary concentrations adjusted to provide dosages of
0, 1.5, 7, 35 and 175/100 mg/kg/day for 105 weeks (Llsh et a!., 1984).
Females at dosage levels >7 mg/kg/day had statistically significant
Increased Incidences of liver adenomas and carcinomas (combined) compared
with controls. This effect was not seen 1n male mice. This study was an
adequate carcinogenic study because the compound was given to both sexes at
more than two dose levels, there were an adequate number of animals In each
dose group (85 at start), the route was natural and length of exposure time
was adequate. The compound was 89-98% pure. The main weakness of the study
was that the highest dose had to be decreased after 10 weeks because of high
mortality In this dose group. Thus, the number of mice In this exposure
group was reduced before the conclusion of the study.
8.1.3. Other Routes. Pertinent data regarding the carclnogenlclty of RDX
by other routes of exposure or other data regarding the carclnogenlclty of
RDX were not located In the available literature cited In Appendix A.
8.1.4. Weight of Evidence. Data were not located regarding the
carclnogenlclty of RDX to humans. Oral administration of cyclonlte to
female B6C3F1 mice (Llsh et al., 1984) resulted In a statistically
significant Increased Incidence of liver adenomas and carcinomas
(combined). According to EPA guidelines (U.S. EPA, 1986c), the L1sh et al.
(1984) study constitutes limited evidence for carclnogenlclty In laboratory
5940H
-55-
07/28/89
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animals. Applying U.S. EPA classification scheme for carcinogenic risk
assessment adopted by the U.S. EPA (1986b), RDX Is assigned to U.S. EPA
Group C, possible human carcinogen.
8.1.5. Quantitative Risk Assessment.
8.1.5.1. INHALATION Data were not located regarding the
cardnogenlclty of Inhalation exposure to RDX. The development of liver
tumors In female mice In the 2-year dietary study (L1sh et al., 1984)
suggests that RDX may be carcinogenic-by any route of exposure, provided
absorption and distribution to the liver occurred. Pharmacoklnetlc data
(see Section 5.1) suggest that absorption from the lung occurs. In the
absence of adequate Inhalation data, It Is appropriate to adopt the q * of
5.4 x 10"2 (mg/kg/dayr1 derived for oral exposure (see Section 8.1.5.2)
as the slope factor for Inhalation exposure as well.
In estimating the concentration of RDX In air associated with specific
levels of Increased risk of cancer, H Is necessary to adjust for the ratio
of the extent of absorption from the respiratory tract to that from the
gastrointestinal tract. Pharmacoklnetlc data were Insufficient for
estimation of the extent of absorption of Inhaled RDX from the respiratory
tract. A default value of 50% Is assumed. The rat study by Schneider et
al. (1977) Indicated that absorption from the gastrointestinal tract was
nearly complete. A resp1ratory:gastro1ntest1nal absorption ratio of 0.5 Is
estimated. By applying the adjustment factor of 0.5 discussed above and by
assuming humans weigh 70 kg and Inhale 20 mVday, It Is estimated that an
air concentration of RDX of 1.3xlO~3 mg/m3 would be associated with an
Increased cancer risk of lxlO~s. Concentrations In air of 1.3xlO~4 and
1.3xlO"s mg/m3 are associated with Increased cancer risks of lx!0~6
and lxlO~7, respectively.
5940H
-56-
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8.1.5.2. ORAL A statistically significant and dose-related
Increased Incidence of combined adenomas and carcinomas was reported In
female B6C3F1 mice fed diets containing RDX for 2 years (L1sh et al.f
1984). There was no evidence of a carcinogenic effect In male mice In this
study nor evidence of cardnogenldty In F344 rats 1n a 2-year dietary study
(Levlne et al., 1984). RDX was assigned to U.S. EPA Group C, possible human
carcinogen, because of the positive results In the female mice.
The decision whether to estimate slope factors for Group C chemicals 1s
made on a chemical-by-chemical basis. In the case of RDX, the response In
the female mice was not only statistically significant but occurred In a
dose-related fashion, strengthening the position that the observed
carcinogenic response was due to exposure to RDX; therefore. It 1s
appropriate to estimate a slope factor for oral exposure to RDX using the
data From female mice. The data and calculations for the derivation are
presented In Appendix B. A q * of 5.4xlO~2 (mg/kg/day)'1 was derived
for oral exposure of humans to RDX.
From the q^ of 5.4xlO~2 (mg/kg/day)'1, H Is estimated that a
concentration of 6.5xlO~3 mg/8. In drinking water 1s associated with
Increased cancer risk to humans of lx!0~s. This estimate Is based on the
assumption that humans weigh 70 kg and drink 2 I of water/day (U.S. EPA,
1980). Drinking water concentrations of 6.5xlO~4 mg/l and 6.5xlQ~5
mg/8, are associated with Increased cancer risks of IxlQT6 and lxl(T7,
respectively.
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8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Hathaway and
Buck (1977) did not see any adverse effects on 69 workers exposed to
workroom atmospheric concentrations of RDX ranging from undetectable to 1.57
mg/ma with an average value of 0.28 mg/m3. This study cannot be used
for risk assessment because exposures were not sufficiently quantified, only
69 persons were evaluated, the study-was narrowly focused and did not
evaluate a sufficiently broad spectrum of potential toxlcologlcal effects
and no effects were seen.
8.2.1.2. CHRONIC EXPOSURES -- Pertinent data regarding the toxlclty of
Inhalation exposure to RDX were not located In the literature cited In
Appendix A; data are Insufficient for derivation of an RfD.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) - Of the
subchronlc studies of RDX that are reported, several cannot be used for RfD
derivation. Schneider et al. (1978) (rec #16) saw no adverse effects when
RDX-saturated drinking water at dally doses of 5-8 mg/kg was given to
Sprague-Dawley rats for 90 days. MacPhall et al. (1985) (rec #15) saw no
changes In behavior or motor activity In Sprague-Dawley rats that were given
<10 mg/kg/day for 30 days. Hart (1974) (rec #20) observed no adverse
effects after administration of 0.1, 1 or 10 mg/kg/day to beagle dogs for 90
days, A 10-week study with rats (von Oettlngen et al., 1949) had no
controls.
Other subchronlc studies In which adverse effects were noted are
appropriate for RfD consideration, von Oettlngen et al. (1949) (rec #18)
observed 40% mortality and abnormal behavior In a group of 20 rats that were
5940H -58- 07/28/89
-------
given 25 mg/kg/day but saw no adverse effects 1n rats treated at the next
lowest dosage, 15 mg/kg/day (rec #17). Levlne et al. (1981) (rec #8)
reported that F344 rats administered 10 mg/kg/day (the lowest dose used In
the study) for 90 days, had reduced serum trlglycerlde levels; females had
leukocytosls and males had reduced body weight gain. No animals had
hlstopathologlcal lesions. Cholakls et al. (1980) (rec #11} observed a
dose-related decrease In mean body weights 1n F344 rats that received 40
mg/kg/day for 90 days but reported no adverse effects 1n rats that received
28 mg/kg/day (rec #10).
RDX administered In the diets of B6C3F1 mice produced no adverse effects
at dosages of 145 mg/kg/day for 91 days but at dosages of 277 mg/kg/day,
caused greater mortality than controls and hyperactlvlty and nervousness In
males (Cholakls et al., 1980) (rec #13, 14).
von Oettlngen et al. (1949) (rec #19) observed a 20% weight loss,
hyperactlvlty, and convulsions In seven female dogs that were given 50
mg/kg/day, 6 days a week for 6 weeks. Cynomulgus monkeys were administered
RDX by gavage for 90 days and showed no adverse effects at doses of 0.1 and
1 mg/kg/day but five/six animals had disturbances of the CNS at 10 mg/kg/day
((Martin and Hart, 1974) (rec #21, 22). The weakness of this study Is that
only a small number of animals were exposed and hlstopathologlcal examina-
tion was not performed.
The monkey appears to be the species most sensitive to the CNS effects
of ROX according to the subchronlc studies. None of the subchronlc studies
reported adverse effects 1n rats, dogs or mice at doses <10 mg/kg/ day,
which Is the lowest adverse effect dose In the Martin and Hart (1974) (rec
#22) monkey study; the no effect dose In the study Is 1 mg/kg/day (rec
#21). U.S. EPA (1988a,b), however, concluded that monkeys and dogs appeared
5940H -59- 07/28/89
-------
to be no more sensitive than rats. Because this study Included only six
monkeys/group and hlstopathologlcal examination was not performed, confi-
dence In the 1 mg/kg/day as a NOEL Is low; therefore, the verified RfO for
chronic exposure, 0.003 mg/kg/day (U.S. EPA, 1988b), 1s adopted as
sufficiently protective for subchronlc exposure. Confidence In the key
study, the data base and the RfD Is high (U.S. EPA, 1988b).
8.2.2.2. CHRONIC EXPOSURES - Three chronic studies and three develop-
mental/reproduction studies are considered In th'e determination of an RfO
for chronic oral exposure. Levlne et al. (1984) reported suppuratlve
Inflammation of the prostate and hemoslderosls In the spleen In male F344
rats that were given 1.5 mg/kg/day for 105 weeks but did not see adverse
effects In rats treated with 0.3 mg/kg/day (rec #1 and 2). Hart (1976) (rec
#7) reported no adverse effects In Sprague-Oawley rats at 10 mg/kg/day, the
highest dose used. Developmental studies with RDX In F344 rats (Cholakls et
al., 1980) showed that embryotoxlclty and maternal toxldty occurred at dose
levels of 20 mg/kg/day when the compound was administered by gavage on days
6-19 of gestation (rec #26). A reproduction study (Cholakls et al., 1980)
showed that lactation was Impaired In dams administered 16 mg/kg/day J_n
utero. through growth period, pregnancy and pup weaning (rec #28). No
adverse effects on fetal or maternal parameters In F344 rats were seen at
dosages of 0.2 and 2.0 mg/kg/day (rec #25). In a developmental toxldty
study with Sprague-Oawley rats. Angerhofer et al. (1986) reported reduced
fetal body weight and length without maternal toxldty at exposures of 2
mg/kg/day, the lowest dose used, on days 6-15 of gestation. Subsequent
evaluation of the data by U.S. EPA (1988a), however, Indicated that fetal
effects were significant at 20 mg/kg/day, but not at 2 or 6 mg/kg/day.
5940H -60- 07/28/89
-------
When New Zealand rabbHs were treated by gavage on days 7-29 of gesta-
tion, dose levels of 20 mg/kg/day caused decreased maternal weight gain;
yet, 2 mg/kg/day had no adverse effects (Cholakls et al., 1980) (rec #29,
30).
Administration of RDX In the diets of female B6C3F1 mice for 105 weeks
resulted 1n hypocholesterolemla at doses of 7 mg/kg/day and hepatomegaly at
35 mg/kg/day. Hales that received 35 mg/kg/day had higher renal weights and
an Increased Incidence of testlcular degeneration (Llsh et al., 1984) (rec
#5, 6).
The chronic data Indicate that rats are more sensitive than mice or
rabbits to the effects of oral RDX because they exhibit adverse effects at
lower dose levels. The lowest dosage at which an adverse effect was noted
was 1.5 mg/kg/day In male F344 rats (Levlne et al., 1984) (rec #2). The
highest dosage lower than 1.5 mg/kg/day at which no adverse effects were
seen Is 0.3 mg/kg/day (Levlne et al., 1984) (rec #1). Thus, 0.3 mg/kg/ day
Is selected as the basis for an RfD for chronic exposure to RDX. Appli-
cation of an uncertainty factor of 100 (10 to extrapolate from rats to
humans and 10 for Intraspedes variation) results In an RfD of 0.003
mg/kg/day. This Is the value reported In IRIS (U.S. EPA, 1988b). U.S. EPA
(1988b) considers confidence In the key study, the data base and the RfD to
be high.
5940H -61- 07/28/89
-------
9. REPORTABIE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The systemic toxIcUy of RDX was discussed In Chapter 6. For each study
considered for computation of candidate CSs, the lowest dosages associated
with the effects reported are summarized In Table 9-1. Effects noted In
chronic exposure studies In mice Included hypercholesterolemla, hepatomegaly
and testlcular degeneration (Llsh et al., 1984}.' Effects seen In chronic
rat studies Included suppuratlve Inflammation of the prostate,
hemoslderosls, hepatomegaly, decreased serum protein levels and Increased
mortality (Levlne et al., 1984). Developmental effects observed In rats
were reduced fetal body weight and length and fetal lethality at 20
mg/kg/day, but the fetal effects were accompanied by maternal lethality
(Angerhofer et al., 1986; Cholakls et al., 1980) and are not scored for
derivation of candidate CSs. Impaired lactation ability was reported In
rats at 16 mg/kg/day (Cholakls et al., 1980). Effects reported in
subchronlc studies not reported In these species In chronic studies Include
severe weight loss In dogs at 42.9 mg/kg/day (von Oettlngen et al., 1949)
and convulsions and CNS disturbances In monkeys at 10 mg/kg/day (Martin and
Hart, 1974).
Table 9-2 presents candidate CSs for the effects presented In Table 9-1.
CSs are calculated for the chronic and reproductive studies. A CS Is also
calculated for the subchronlc study with monkeys (Martin and Hart, 1974)
because It reported the lowest dose level at which disturbances of the
central nervous system, Including convulsions, were seen. A CS Is also
calculated for body weight loss In dogs In the subchronlc study by von
Oettlngen et al. (1949) because no chronic data were located regarding this
effect In this species. An uncertainty factor of 10 was not applied In the
5940H -62- 07/28/89
-------
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derivation of MED values for these subchronlc studies because there was no
evidence that the Intensity of the effects Increased with Increased duration
of exposure. The highest CS, 18.1, was calculated for prostatlc Inflamma-
tion and hemoslderosls of the spleen 1n rats exposed to 1.5 mg/kg/day for
105 weeks (Levlne et al., 1984). The CS of 18.1 corresponding to an RQ of
1000 Is chosen to represent the chronic (noncancer) toxldty of RDX (Table
9-3).
9.2. BASED ON CARCINOGENICITY
Data were not located regarding the cardnogenlcHy of RDX to humans.
Data from laboratory animals (see Section 6.2.2) consisted of well designed
and well conducted 2-year studies using mice (Llsh et al., 1984) and rats
(Levlne et al., 1984). There was no evidence of cardnogenlcHy In rats of
either sex or In the male mice; however, female mice developed a
dose-related and statistically significantly Increased Incidence of combined
liver adenomas and carcinomas. The positive response In the female mice was
responsible for assignment of RDX to U.S. EPA Group C, possible human
carcinogen.
Using the data presented In Table 9-4 and Appendix B and the multistage
model by Howe and Crump (1982), a human F factor of 0.2780798(mg/kg/day}~1
was estimated, which corresponds to a Potency Group of 3. Potency Group 3
compounds In U.S. EPA Group C are assigned a "low" hazard ranking, which
corresponds to an RQ of 100 for carclnogenlclty.
5940H
-65-
07/28/89
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TABLE 9-3
RDX
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Spedes/sex:
Dose8:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
oral
rat/male
18.2 mg/day
105 weeks
prostatic inflammation and hemosiderosis of spleen
3.61
5
18.1
1000
Levine et al., 1984
'Equivalent Human Dose
6200H
-66-
06/26/89
-------
TABLE 9-4
Derivation of Potency Factor
-------
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hexahydro-l,3,5-trinitro-l,3,5-triazine (ROX) and TNT/RDX mixtures in the
Fischer 344 rat. NTIS AD-A108447. 363 p.
Levine, B.S., E.M. Furedi, V.S. Rac, D.E. Gordon and P.M. Lish. 1984.
Determination fo the chronic mammalian toxicological effects of RDX: (Twenty
four month chronic toxiclty/carcinogenicity study of hexagydro-1,3,5-
trin1tro-1,3,5-tr1az1ne (RDX) in the Fischer 344 rat.) NTIS AD-A160774.
Vol. 1. 347 p.
5940H -72- 06/26/89
-------
llsh, P.M., B.S. Levlne, E.M. Furedl, J.M. Sagartz and V.S. Rac. 1984.
Determination of the chronic mammalian toxkologlcal effects of RDX. Twenty
four month chronic toxlclty/carcinogeniclty study of hexahydro-1,3,5-trlni-
tro-1,3,5 trlazine (RDX) in the B6C3F1 hybrid mouse. Phase 6. NTIS AD
A181766. 364 p.
L1u, D.H., R.J. Spanggord, H.C. Bailey, H.S. Oavitz and D. Jones. 1984.
Toxlclty of TNT wastewaters to aquatic organisms: Acute toxldty of LAP
wastewater and 2,4.6-trinitrotoluene. NTIS AD-A142144. 85 p.
MacPhall, R.C., Q.D. Walker and L.L. Cook. 1985. Neurotoxlcity of
cylortrimethylenetrinitramine (RDX). NTIS AD-A168-266. 65 p.
Mantel, N. and M.A. Schneideman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
Martin, and Hart*. 1974. Subacute toxicity of RDX and TNT 1n monkeys.
NTIS AD-A044 650.
McConnell, W.I. and R.T. FUnn. 1946. Summary of twenty two trinibtoto-
luene fatalatles in World War II. J. Ind. Hyg. 28: 76. (Cited In Taylor,
1975.)
McCormlck, N.G., J.H. Cornell and A.M. Kaplan. 1981. Biodegratlon of
hexahydro-1,3,5-tr1n1tro-l,3,5-triazine. Appl. Env. M1crob1ol. 42: 817-823.
*No Initials provided.
5940H
-73-
06/26/89
-------
Merrill, S.L. 1968. Ingestlon of an explosive material, composition C-4: A
report of two cases. USARV Medical Bull. 40: 5-11.
NIOSH (National Institute for Occupational Safety and Health). 1988.
National Occupational Exposure Survey (NOES).
NTP (National Toxicology Program), n.d. Historical control data. NTP
Bulletin 10.
OSHA (Occupational Safety and Health Administration). 1989. 29 CFR Part
1910. Air Contaminants: Final Rule. 54: 2577.
Osmon, J.I. and R.E. Klausmeler. 1973. The mlcroblal degradation of
expolslves. Dev. Ind. M1crob1ol. 14: 247-252.
Richard, J.J. and 6.A. Junk. 1986. Determination of munitions 1n water
using macroretlcular resins. Am. Chem. Soc. 58: 723-725.
Ryon, M.6., B.C. Pal, S.S. Talmage and R.H. Ross. 1984. Database assess-
ment of the health and environmental effects of munition production waste
production. Final Report. Oak Ridge, TN. Oak Ridge Natl. Lab. p. 22-23;
37; 101; 110-113; 116-117; 119; 123; 125; 127; 131; 133. NTIS DE84-016512.
SANSS (Structure and Nomenclature Search System). 1989. Online. 03/02/89.
Sax, N.I. and R.J. Lewis. 1987. Hawley's Condensed Chemical Dictionary.
11th ed. Van Nostrand Relnhold Co., New York, NY. p. 338.
b
5940H -74- 10/03/89
-------
Schneider, N.R. and M.E. Andersen. 1975. Toxldty and tissue distribution
of cyclotrlmethylenetrlnltramlne (RDX). Toxlcol. Appl. Pharmacol. 33: 198.
Schneider, N.R., S.L. Bradley and M.E. Anderson. 1977. Toxicology of
cyclotrlmethylenetrlnltramlne: Distribution and metabolism In the rat and
the miniature swine. Toxlcol. Appl. Pharmacol. 39: 531-541.
Schneider, N.R., S.L. Bradley and M.E. Andersen, 1978. The distribution
and metabolism of cyclotrlmethylenetrlnltramlne (RDX) 1n the rat after
subchronlc administration. Toxlcol. Appl. Pharmacol. 46: 163-172.
Simmon, V.F., R.J. Spanggord, S. Eckford and V. McClurg. 1977.
Mutagenlclty of some munition wastewater chemicals and chlorine test kit
reagents. Final Report. NTIS Doc. AD-A057-680. p. 1-37; 67-69.
Small M.J. and D.H. Rosenblatt. 1974. Munitions production products of
potential concern as waterborne pollutants Phase II. In; Tech. Rep. 7404.
Aberdeen, MD. U.S. Army Medical Bloenglneerlng Res. Devel. Lab. p. 3-96.
NTIS AD919031.
Spaldlng, R.F. and J.U. Fulton. 1988. Groundwater munition residues and
nitrate near Grand Island, Nebraska, U.S.A. J. Contam. Hydrol. 2: 139-153.
Spanggord, R.J., T. Mill, T.W. Chou, H.R. Mabey, J.H. Smith and S. Lee.
1980a. Environmental fate studies on certain munition wastewater
constituents. Final report Phase I Literature Review. Fort Detrlck, MO.
U.S. Army Med. Res. and Develop. Command. SRI Project No. LSU-7934.
5940H -75- 10/02/89
-------
Spanggord, R.J., T. Mill, T.W. Chou, H.R. Nabey, J.H. Smith and S. Lee.
1980b. Environmental fate studies on certain munition wastewater
constituents. Final report Phase II Laboratory studies. Fort Detrlck, MD.
U.S. Army Med. Res. Oevel. p. 89. SRI Project No. NTIS AD A099256.
LSU-7934.
Spanggord, R.J., W.R. Habey, T. Mill, et al. .1983. Environmental fate
studies on certain munitions wastewater constituents. Fort Detrlck, MD.
U.S. Army Ned. Res. Devel. SRI Project No. LSU-7934. NTIS AD A138550.
Spector, M.S. 1956. Handbook of Toxicology. Vol. 1. W.B. Saunders Co.,
Philadelphia, PA. (Cited In Taylor, 1975.)
Stone. H.J.. T.L. Paletta, E.M. Helman, J.I. Brude and J.H. Knepshleld.
1969. Toxic effects following Ingestlon of C-4 plastic explosive. Arch.
Intern. Med. 124: 726-730.
Swann, R.L., O.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J.
Dlshburger. 1983. A rapid method for the estimation of the environmental
parameters octanol/water partition coefficient, soil sorptlon constant,
water to air ratio and water solubility. Res. Rev. 85: 17-28.
Taylor, G.D. 1975. Military dog training aids: Toxlclty and treatment.
NTIS AD/A-006 438.
TSCAPP. 1989. Computer print-out of non-confidential production data from
TSCA Inventory. OPTS, CID, U.S. EPA, Washington, O.C.
5940H -76- 07/28/89
-------
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45:(231) 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic loxldty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Methodology for Evaluating Reportable Quantity
Adjustments Pursuant to CERCLA Section 102. Prepared by Carcinogen
Assessment Group, Office of health and Environmental Assessment for the
Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986c. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1988a. Health Advisory Document for Hexahydro-l,3,5-tr1n1tro-
1,3,5-tMazlne (RDX). Office of Drinking Water, Washington, DC.
5940H -77- 10/05/89
-------
U.S. EPA. 1988b. Integrated Risk Information System (IRIS): Reference Dose
(RfD) for Oral Exposure for Hexahydro-1,3,5-tr1n1tro-1,3,5-tr1az1ne (RDX).
Online. (Verification date 04/20/88.) Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA/QWRS (Environmental Protection Agency/Office of Water Regulations
and Standards). 1986. Guidelines for Deriving Numerical National Hater
Quality Criteria for the Protection of Aquatic Organisms and Their Uses.
U.S. EPA, Washington, DC. NTIS PB 85-227049/XAB. p. 22-58; 98.
von Oettlngen, W.F., D.D. Donahue, H. Yagoda, A.R. Monaco and M.R. Harris.
1949. Toxldty and potential dangers of cyclotrlmethylenetrlnltramlne
(RDX). J. Indus. Hyg. Toxlcol. 31: 21-31.
Whong, W.Z., N.D. Spedner and G.S. Edwards. 1980. Mutagenlc activity of
tetryl, a nltroaromatlc explosive, In three mlcroblal test systems.
Toxlcol. Lett. 5: 11-17.
Wlndholz, E.M. 1983. The Merck Index. 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 392-393.
Woody, R.C., G.L. Kearns, M.A. Brewster, C.P. Turley, G.B. Sharp and R.S.
Lake. 1986. The neurotoxlclty of cyclotrlmethylenetrlnltramlne (RDX) 1n a
child: A clinical and pharmacokenetlc evaluation. 0. Toxlcol. CUn.
Toxlcol. 24: 305-319.
5940H -78- 10/05/89
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APPENDIX A
This HEED Is based on data Identified by computerized literature
searches of the following:
CHENLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In Hay, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices. 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2A. John Wiley and Sons,
NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 28. John Wiley and Sons,
NY. p. 2879-3816.
Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2C. John Wiley and Sons,
NY. p. 3817-5112.
5940H A-l 07/28/89
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Grayson, M. and D. Eckroth, Ed. 1978-84. K1rk-0thmer Encyclopedia
of Chemical Technology, 3rd ed. John W.I ley and Sons. NY. 23 Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology. 3rd
edition. Publishing Sciences Group, Inc., MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC,
Lyons, France: WHO.
Jaber, H.M., M.R. Mabey, A.T. Lieu, T.U. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA-600/6-84-010. (NTIS PB84-243906) Menlo Park, CA: SRI Inter-
national.
NTP {National Toxicology Program). 1988. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials. 6th
edition. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Stanford, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (United States International Trade Commission). 1986.
Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC
Publication 1892. Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M. Ed. 1983. The Merck Index. 10th ed. Merck and Co.,
Inc., Rahway, NJ.
5940H A-2 07/28/89
-------
In addition, approximately 30 compendia of aquatic toxidty data were
reviewed, including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria Data
Book. Volume 3. Effects of Chemicals on Aquatic Life. Selected
Data from the Literature through 1968. Prepared for the U.S. EPA
under Contract No. 68-01-0007. Washington. DC.
Johnson, W.W. and M.T. Finley. 1980. Handbook of Acute Toxidty of
Chemicals to Fish and Aquatic Invertebrates. Summaries of Toxicity
Tests Conducted at Columbia National Fisheries Research Laboratory.
1965-1978. United States Dept. Interior, Fish and Wildlife Serv.
Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed.
Prepared for the Resources Agency of California, State Water Quality
Control Board. Publ. No. 3-A.
Pimental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003: NTIS PB 80-196876.
5940H A-3 06/09/89
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APPENDIX B
Cancer Data Sheets for Derivation of a qt for Oral Exposure
Compound: RDX
Reference: Ush et al., 1984
Specles/straln/sex: mouse, B6C3F1, female
Length of exposure (le) 105 weeks
Length of experiment (Le) » 105 weeks
Llfespan of animal (L) - 105 weeks
Tumor site and type: liver, adenoma/carcinoma
Route/vehicle: oral, diet
Animal
Dose8
(mg/kg/day)
0
K5
7.0
35
107"
Human qt « 0
TWA Animal
Body Weight"
(kq)
0.0356
0.0361
0.0368
0.0355
0.0318
.0535374 (mg/kg/day) '
Equivalent
Human Dosec
(mg/kg/day)
0
0.120
0.565
2.79
8.23
le
Incidence
No. Responding/No. Tested
(or Examined)
1/65
5/62
9/64
12/64
6/31
'Data provided by Investigators
"Calculated as average of body weight measurements taken every eighth week
throughout the experiment
'Estimated by multiplying the animal dose by the cube root of the ratio of
the animal to reference human body weight of 70 kg (U.S. EPA, 1980)
'Mice dosed at 175 mg/kg/day for 10 weeks followed by 100 mg/kg/day for 95
weeks
"Because a human dose was estimated and entered Into the Global 82 (Howe
and Crump, 1982) computer program, the 95% lower confidence limit on dose
and the qT are gor humans rather than for experimental animals.
6204H
B-l
06/16/89
-------
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APPENDIX D
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO RDX
0.1. DISCUSSION
Dose/duration-response graphs for oral exposure to RDX generated by the
method of Crockett et al. (1985) using the computer software by Durkln and
Meylan (1988) developed under contract to ECAO-Clnn1nnat1 are presented In
Figures D-l and D-2. Data used to generate these graphs are presented in
Section D.2. In the generation of these, figures, all responses are
classified as adverse (FEL, AEL, or LOAEL) or non-adverse (NOEL or NOAEL)
for plotting. For oral exposure, the ordlnate expresses dosage as human
equivalent dose. The animal dosage in mg/kg/day 1s multiplied by the cube
root of the ratio of the animal :human body weight to adjust for species
differences In basal metabolic rate (Mantel and Schneiderman, 1975). The
result is then multiplied by 70 kg, the reference human body weight, to
express the human equivalent dose as mg/day for a 70 kg human.
The Boundary for Adverse Effects (solid line) is drawn by identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
line Is extended upward parallel to the dose axis. The starting point is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or
concentration equal to or lower than the previous one. This process is
continued to the lowest adverse effect dose or concentration. From this
point a line Is extended to the right parallel to the duration axis. The
Region of Adverse Effects lies above the Adverse Effects Boundary.
6201H D-l 06/22/89
-------
,l\
91
\
n
v
SI
0'
hi
a
z
ft.0001
(Oral Exposure)
0.001 0.01 0.1
HUNAN EQUIV DURATION (fraction lifcspan)
ENVELOP NETHOP
FIGURE D-l
Dose/Duration - Response Graph for Oral Exposure to RDX,
Envelope Method
KEY: F = FEL
A - AEL
n = NOAEL
N = NOEL
Solid Line - Adverse Effects Boundary
Dotted Line = No Adverse Effects Boundary
6201H
D-2
06/16/89
-------
ieeee
il
0'
in
I
1890 r
8.9001
-------
Using the envelope method, the Boundary for No Adverse Effects (dashed
line) Is drawn by Identifying the highest no adverse effects dose or
concentration. From this point, a line parallel to the duration axis Is
extended to the dose or concentration axis. The starting point Is then
connected to the next lower or equal no adverse effect dose or concentration
at a longer duration of exposure. When this process can no longer be
continued, a line 1s dropped parallel to the dose or concentration axis to
the duration axis. The No Adverse Effects Region lies below the No Adverse
Effects Boundary. At either ends of the graph between the Adverse Effects
and No Adverse Effects boundaries are Regions of Ambiguity. The area (1f
any) resulting from Intersection of the Adverse Effects and No Adverse
Effects boundaries Is defined as the Region of Contradiction.
In the censored data method, all no adverse effect points located In the
Region of Contradiction are dropped from consideration and the No Adverse
Effect boundary Is redrawn so that It does not Intersect the Adverse Effects
boundary and no Region of Contradiction Is generated. This method results
In the most conservative definition of the No Adverse Effects region.
Figure D-l presents the dose-duration response graph generated by the
envelope method. The Adverse Effects Boundary Is defined by four points,
corresponding to convulsions and death In miniature swine at one dose of 100
mg/day (Schneider et al., 1977) (rec #36), mouse LD5Q of 80 mg/kg
(Cholakls et al., 1980) (rec #31), convulsions and CNS disturbances 1n
monkeys at dosages of 10 mg/kg/day for 90 days (Hart, 1974) (rec #22),
maternal lethality at 2 mg/kg/day In rat developmental toxlclty studies
(Angerhofer et al., 1986; Cholakls et al., 1980) (rec #23, 26), reduced body
weight gain In a 90-day study In rats (Levlne et al., 1981) (rec #8) and
prostatlc Inflammation and splenic hemoslderosls seen In rats at 1.5
6201H
D-4
07/28/89
-------
mg/kg/day for 105 weeks (Levlne et al., 1984) (rec #2). The No Effects
Boundary Is defined by two points, one representing no effects seen In a
mouse study at dose levels <145 mg/kg for 90 days (Cholakls et al., 1980)
(rec #13) and the other representing the Hart (1976) study with rats In
which no adverse effects were seen at dosages <10 mg/kg/day (rec # 7). The
Region of contradiction contains NOAELs In 3-month studies In dogs (rec
#20), mice (rec #12, 13) and rats (rec #10, 17). .
When the graph 1s redrawn to eliminate the Region of Contradiction
(Figure 0-2), the No Adverse Effects Boundary Is defined by the points
representing the dose level of 10 mg/kg/day given to rats 1n a behavioral
study (McPhall et al., 1985) (rec #15), 50 mg/kg/day 1n a reproduction study
In rats (Cholakls et al., 1980) and 1.5 mg/kg/day given to mice for 105
weeks (L1sh et al., 1984) (rec #4).
D.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
D.2.1. Inhalation Exposure. Inhalation data were Insufficient to
generation of dose/duration-response graphs.
0.2.2. ORAL EXPOSURE
Chemical Name: RDX
CAS Number: 121-82-4
Document Title: Health and Environmental Effects Document on ROX
Document Number: pending
Document Date: pending
Document Type: HEED
6201H D-5 07/28/89
-------
RECORD #1
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Food
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose: 0.300
Duration Exposure: 105.0 Weeks
Duration Observation: 105.0 Weeks
150
0
DEATH
BODY
10
Comment: Doses given 0.3, 1.5, 8.0, 40 mg/kg/day.
effects seen at this dose
Citation: Levlne et al.. 1984
No
RECORD #2:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose: 1.500
Duration Exposure: 105.0 Weeks
Duration Observation: 105.0 Weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
150
75
OTHER
OTHER
5
Comment: Doses of 0.3, 1.5, 8, 40 mg/kg/day. Prostate
Inflammation 1n males at this dose. Effects
observed at 8.0 less severe that at 1.5-- In-
clude reduced body weight gain, hepatomegaly
Citation: Levlne et al., 1984
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Both
FEL
Food
Dose: 40.000
Duration Exposure: 105.0 Weeks
Duration Observation: 105.0 Weeks
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
150
NR
DEATH
BODY
10
Comment: Highest dose of the study 80% mortality
Citation: Levlne et al., 1984
6201H
D-6
07/28/89
-------
RECORD #4:
Species:
Sex:
Effect:
Route:
Mice
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 1.500
Duration Exposure: 105.0 Neeks
Duration Observation: 105.0 Weeks
170
0
WGTNS
BODY
4
Comment: Doses of 1.5, 7.0, 35, 175/100 mg/kg/day,
effects seen at this dose
Citation: Lish et al., 1984
No
RECORD #5:
Species:
Sex:
Effect:
Route:
Mice
Both
LOAEL
Food
Dose: 7.000
Duration Exposure: 105.0 Weeks
Duration Observation: 105.0 Weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
170
NR
METAB-
OTHER
2
Comment:
Citation:
Doses of 1.5, 7
cholesterolemia
, 35, 175/100 mg/kg/day hyper-
in females at this dose
Lish et al., 1984
RECORD #6:
Species: Mice
Sex: Both
Effect: AEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 35.000
Duration Exposure: 105
Duration Observation:
170
NR
DEGEN
TESTE
6
.0 Weeks
105.0 Weeks
Comment: Doses of 1.5, 7, 35, 175/100 mg/kg/day. At
this dose, hepatomegaly in females, testicu-
lar degeneration in males highest dose
produced high mortality, was reduced
Citation: Lish et al., 1984
6201H
D-7
06/22/89
-------
RECORD #7:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 10.000
Duration Exposure: 104.0 Weeks
Duration Observation: 104.0 Weeks
200
0
WGTNS
BODY
4
Comment: Doses of 1, 3.1, 10 mg/kg/day.
effects seen at any dose level
Citation: Hart, 1976
No adverse
RECORD #8:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose: 10.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
10
WGTDC
BODY
4
Comment: Doses of 10, 30, 100, 300, 600 mg/kg/day.
Body weight gain reduced 6% In males, also
biochemical changes 30 mg/kg/day produced
changes In body weights also
Citation: Levlne et al., 1981
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Dose: 100.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
NR
DEATH
BODY
10
Comment: Doses of 10, 30, 100, 300, 600 mg/kg/day High
mortality at this dose and at higher doses
Citation: Levlne et al., 1981
6201H
D-8
07/28/89
-------
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 28.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
20
0
WGTNS
BODY
4
Comment: Doses of 10, 14, 20, 28, 40 mg/kg/day. No
adverse effects seen at 10, 14, 20, and 28
mg/kg/day
Citation: Cholafcis et all, 1980
RECORD #11:
Species: Rats
Sex: Both
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 40.000
Duration Exposure: 90
Duration Observation:
20
NR
WGTDC
BODY
4
.0 Days
90.0 Days
Comment: Doses of 10, 14, 20, 28, and 40 mg/kg/day.
Dose related weight decrease compared to con-
trols at this dose. No other significant
adverse effects seen
Citation: Cholakis et al., 1980
RECORD #12:
Species:
Sex:
Effect:
Route:
Mice
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 40.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
20
0
HGTNS
BODY
4
Comment: Doses of 10, 14, 20, 28, 40 mg/kg/day. No ad-
verse effects seen at any dose level in mice
Citation: Cholakis et al., 1980
6201H
D-9
06/22/89
-------
RECORD #13:
Species:
Sex: .
Effect:
Route:
Mice
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 145.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
22
0
HGTNS
BODY
4
Comment: Doses of 40, 60, 80 mg/kg/day given for 2
weeks, then Increased to 320, 160, 80 mg/kg/
day (resp.) for 11 weeksTransformed doses of
277, 145, 80. NO adverse effects seen at
this flose
Citation: Cholakls et al., 1980
RECORD #14:
Species: Mice
Sex: Both
Effect: FEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 277.000
Duration Exposure: 90
Duration Observation:
22
6
DEATH
BODY
10
.0 Days
90.0 Days
Comment: Dose: 40 mg/kg/day for 2 wks, then 320 mg/kg/
day for 11 weeks: transformed to 277 mg/kg/day
In males, 401 mortality
Citation: Cholakls et al., 1980
RECORD #15:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Gavage
Dose: 10.000
Duration Exposure: 30.0 Days
Duration Observation: 31.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
0
BEHAV
CNS
8
Comment: Doses of 1, 3, 10 mg/kg/day. Behavior and
other CNS changes were endpoints. No adverse
effects seen at any dose level
Citation: MacPhail et al., 1985
6201H
D-10
06/22/89
-------
RECORD #16:
Species:
Sex:
Effect:
Route:
Rats
N.S.
NOAEL
Water
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose: 5.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
6
0
WGTNS
BODY
4
Comment: Drinking water saturated with RDX, total dose
5-8 mg/kg/day . No adverse effects seen
Citation: Schneider et a]., 1978
RECORD #17:
Species:
Sex:
Effect:
Route:
Rats
N.S.
NOAEL
Food
Dose: 15.000
Duration Exposure: 84.0 Days
Duration Observation: 89.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
0
DEATH
BODY
10
Comment: Doses of 15, 25, 50 mg/kg/day .
effects seen at this dose level
Citation: von Oettingen et al., 1949
No adverse
RECORD #18:
Species:
Sex:
Effect:
Route:
Rats
N.S.
FEL
Food
Dose: 25.000
Duration Exposure: 84.0 Days
Duration Observation: 89.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
8
DEATH
BODY
10
Comment: Doses of 15, 25, 50 mg/kg/day. Convulsions,
irritability, 40% mortality at this dose level
Citation: von Oettingen et al., 1949
6201H
D-ll
06/22/89
-------
RECORD #19:
RECORD #20:
Species:
Sex:
Effect"
Route:
Dogs
Female
AEL
Capsul
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 42.900
Duration Exposure: 42.0 Days
Duration Observation: 42.0 Days
7
7
HGTDC
BODY
4
Comment: Dose of 50 mg/kg/day 6 days/week, for 6 weeks:
transformed dose of 42.9 mg/kg/day for 42 days
1/7 dogs at this dose level died
Citation: von Oettingen et al., 1949
Species:
Sex:
Effect:
Route:
Dogs
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 10.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
6
0
ENZYM
N.S.
2
Comment: Doses of 0.1, 1, and 10 mg/kg/day 6 animals/
dose group. No adverse effects seen at any
dose level
Citation: Hart, 1974
RECORD #21 :
Species:
Sex:
Effect:
Route:
Monkeys
Both
NOAEL
Gavage
Dose: 1.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
6
0
ENZYM
N.S.
2
Comment: Doses of 0.1, 1, and 10 mg/kg/day by gavage
No adverse effects observed at dose levels of
0.1 and 1 mg/kg/day 6 animals/dose group
Citation: Hart, 1974
6201H
D-12
06/22/89
-------
RECORD #22:
Species:
Sex:
Effect:
Route:
Monkeys
Both
FEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 10.000
Duration Exposure: 90.0 Days
Duration Observation: 90.0 Days
6
5
NEURB
CMS
8
Comment:
Citation:
Doses of 0.1, 1,
had convulsions
this dose level
Hart: 1974
and 10 mg/kg/day. Animals
and disturbances of CNS at
6 animals/dose group
RECORD #23:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Dose: 20
Duration
Duration
.000
Exposure: 10.
Observation:
0 Days
20.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
26
16
DEATH
BODY
10
Comment: Doses of 2, 6, 20 mg/kg/day given on days 6-15
of gestation 31X mortality in dams. Fetal
weight and length less than controls
Citation: Angerhofer et al., 1986
6201H
D-13
06/22/89
-------
RECORD #24:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 40.000
Duration Exposure: 10.0 Days
Duration Observation: 20.0 Days
6
6
DEATH
BODY
10
Comment: Doses of 10, 20, 40, 80, 120 mg/kg/day given
on days 6-15 of gestation. All animals at
dose levels of 40, 80, and 120 mg/kg/day died
Citation: Angerhofer et al., 1986
RECORD #25:
Species:
Sex:
Effect:
Route:
Rats
Fema 1 e
NOAEL
Gavage
Dose: 2.000
Duration Exposure: 14
Duration Observation:
.0 Days
20.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
24
0
TOXDF
FETUS
8
Comment: Doses of 0.2, 2, and 20 mg/kg/day given on
days 6-19 of gestation. No adverse effects
seen at 0.2 and 2 mg/kg/day
Citation: Cholakis et al., 1980
RECORD #26:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Dose: 20.000
Duration Exposure: 14.0 Days
Duration Observation: 20.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
25
6
DEATH
BODY
10
Comment: Doses of 0.2, 2, and 20 mg/kg/day given on
days 6-19 of gestation. This dose produced
exbryo and maternal toxicity
Citation: Cholakis et al., 1980
6201H
D-14
06/22/89
-------
RECORD #27:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 5.000
Duration Exposure: 26.0 Weeks
Duration Observation: 26.0 Weeks
52
0
REPRO
OTHER
8
Comment: Doses of 5, 16, and 50 mg/kg/day given in a
two-generation study. No adverse effects seen
at this dose level
Citation: Cholakis et al .*', 1980
RECORD #28:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose: 16.000
Duration Exposure: 26.0 Weeks
Duration Observation: 26.0 Weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
26
26
REPRO
OTHER
8
Comment: Doses of 5, 16, 50 mg/kg/day in a two-genera-
tion study. At 16 mg/kg/day, dams have
impaired lactation ability
Citation: Cholakis et al., 1980
RECORD #29:
Species:
Sex:
Effect:
Route:
Rabbits
Female
NOAEL
Gavage
Dose: 2.000
Duration Exposure: 23.0 Days
Duration Observation: 30.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
0
0
TOXDF
FETUS
8
Comment: Doses of 0.2, 2.0, and 20 mg/kg/day given on
days 7-29 of gestation. No adverse effects
seen at 0.2 and 2 mg/kg/day
Citation: Cholakis et al., 1980
6201H
D-15
06/22/89
-------
RECORD #30:
Species:
Sex:
Effect:
Route:
Rabbits
Female
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose: 20.000
Duration Exposure: 23.0 Days
Duration Observation: 30.0 Days
10
10
WGTDC
BODY
4
Comment: Doses of 0.2, 2, and 20 mg/kg/day given on
days 7-29 of gestation. Materlan weight gain
reduced at this dose level. No fetal effects
observed
Citation: Cholakls et al.. 1980
RECORD #31:
Species:
Sex:
Effect:
Route:
Mice
Both
PEL
Gavage
Dose: 80.300
Duration Exposure: 1.0 Days
Duration Observation: 1.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR
NR
DEATH
BODY
10
Comment: 1050 for B6C3F1 mice
Citation: Cholakls et al., 1980
RECORD #32:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Dose: 118.000
Duration Exposure: 1.0 Days
Duration Observation: 1.0 Days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
NR
NR
DEATH
BODY
10
Comment: LQ$Q for F244 rats
Citation: Cholakls et al., 1980
6201H
D-16
07/28/89
-------
RECORD #33:
Species:
Sex:
Effect:
Route:
Rats
N.S.
PEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose: 200.000
Duration Exposure: 1.0 Days
Duration Observation: 1.0 Days
95
NR
DEATH
BODY
10
Comment: Dose range 25-400 mg/kg 1050 In rats
Citation: von OetUrrgen et ali, 1949
RECORD #34:
Species:
Sex:
Effect:
Route:
Rats
Hale
PEL
Gavage
Dose: 71
Duration
Duration
.000
Exposure: 1.0
Observation: 1
Days
.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
NR
DEATH
BODY
10
Comment: 1059 for male Sprague-Dawley rats
Citation: Dllley et a!., 1979
RECORD #35:
Species:
Sex:
Effect:
Route:
H1ce
F ema 1 e
PEL
Gavage
Dose: 86
Duration
Duration
.000
Exposure: 1
Observation
.0 Days
: 1.0 Days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR
NR
DEATH
BODY
10
Comment: (.050 for female Swiss Webster mice
Citation: Dllley et al., 1979
6201H
0-17
07/28/89
-------
RECORD #36: Species: Other/NOS Dose: 100.000
Sex: Female Duration Exposure: 1.0 Days
Effect: FEL ' Duration Observation: 1.0 Days
Route: Gavage
Number Exposed: 10
Number Responses: 2
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Comment: One dose given, 100 mg/kg 20X died, 40% had
convulsions
Citation: Schneider et al., 1977
6201H D-18 06/22/89
------- |