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Thirteen week toxicity study of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in fischer 344 rats
241
Toxicology Letters, 8 (1981)241-245 Elsevier/North-Holland Biomedical Press
THIRTEEN
WEEK TOXICITY
1,3,5TRIAZINE
(RDX)
STUDY
IN FISCHER
OF HEXAHYDRO-1,3&TRINITRO-
344 RATS
BARRY S. LEVINE, E. MARIANNA FUREDI, DONOVAN E. GORDON, JOHN M. BURNS and PAUL M. LISH Life Sciences Division, IIT Research Institute, Chicago, IL (U.S.A.)
(Received January 17th, 1981) (Accepted January 2Ist, 1981)
SUMMARY
Groups
of Fischer 344 rats received hexahydro-1,3,5-trinitro-1,3,5-triazine
13 weeks at doses of 0, 1, 10, 30, 100, 300 or 600 mg/kg/day. reductions
of
food
intake
triglyceride
levels, marginal
and
body
leukocytosis
weight
gain,
(RDX)
Toxicological
hyperreactivity
in the diet for up to
responses
to approach,
included decreased
slight serum
and mortality.
INTRODUCTION RDX
is a white
crystalline
material
used as an explosive.
Accidental
human
ingestion of RDX-based plastic explosives has resulted in grand ma1 seizures, gastrointestinal tract irritation, leukocytosis and elevated BUN levels [l-3]. Previous toxicity studies in rats, dogs and monkeys demonstrated similar responses to RDX intoxication. Van Oettingen et al. [4] observed hyperirritability, convulsions, body weight loss and mortality in rats and/or dogs following 6-10 weeks of RDX treatment. Convulsive episodes and/or tremors have also been seen in RDX-treated rhesus monkeys [5]. Subchronic dosing of RDX to mice produced hepatomegaly with marginal treatment-related periportal vacuolization in addition to behavioral changes and death [6]. The present investigation examines the dose-response relationships of RDX intoxication following dietary administration to rats for 13 weeks.
Abbreviation:
RDX, hexahydro-1,3,5-trinitro-1,3,5-triazine.
0378.4274/81/0000-0000/$02.50
Cc)Elsevier/North-Holland
Biomedical
Press
242
RDX,
84.7+-4.7070
purity
(military
grade),
was used
in this study.
All other
chemicals used were either analytical or reagent grade. The geometric median diameter of the RDX particles was 20 Km (by number) with ~90% 566 pm. Fischer 344 rats of both sexes (ARS Sprague Dawley, Madison, WI), 3-4 weeks old, were housed in an air-conditioned (21.--23°C) room at ambient relative humidity, 30-50%, and on a 12-h fixed light cycle. Food and water were provided ad lib. except during a 17-19-h fast prior to blood collection for helnatology and clinical biochemistry tests in test week 13 or routine killing after the l3-week exposure period. After one week of quarantine, the animals were randomly assigned, within sex, into 6 treatment groups. Ten animals per sex received either 10, 30, 100, 300 or 600 mg/kg/day of RDX for 13 weeks as a dietary admixture while 30 animals per sex served as controls. Toxicological end points included clinical signs, body weight, food consumption, hematology, clinical biochemistry, organ weights and tissue morphology. Glucose, BUN, SGPT, triglycerides, cholesterol, total protein, albumin and globulin were measured by standard clinical biochemistry microtechniques on a centrifugal analyzer. Hct, Hb, MCV, MCH, MCHC, RBCs, WBCs (total and differential), reticulocytes, and metHb were measured by conventional hematology methods including a particle size counter. Necropsies were conducted on all animals which either survived the 13 week test period or died during the study. Major organs of all killed animals were weighed. Approx. 25 tissues per animal were examined microscopically for the control, 30 and 100 mg/kg/day treatment groups. Major organs were examined histologically for the remaining test groups. One way analysis of variance tests by sex were conducted on all quantitative data with Dunnett’s t-test employed if pairwise comparisons were necessary
[7].
RESULTS AND DISCUSSION
Hyperreactivity mg/kg/day
to approach
or greater
(Table
and
mortality
I). In addition,
were tremors
observed
at doses
and convulsions
of
100
were seen
prior to death for some of the animals receiving 600 mg/kg/day. Histopathological lesions of the nervous system, however, were not in evidence. Mean survival times were inversely correlated with dose level and a sex difference was not apparent (Table I). Additional clinical signs observed at the higher dose levels included lethargy, ataxia, vulva1 discharge for females and epistaxis. Although small thin uteri were observed for some of the animals which received 100 mg/kg/day and survived the 13-week test period, microscopic examination failed to detect any lesions. RDX caused a significant reduction in food consumption at doses of 100
243
TABLE
I
SUMMARY
OF THE EFFECTS
BODY WEIGHTS, B ?00 $d wx P0 vr/ EO 0
Test week
Test week
1
300
9
147.2
227.2 f 18.7
13 217.3
k21.3
1
301.6 ~23.2
16.0
17.9
17.6
18.5
f 1.0
t 1.0
f 1.7
11.3
160.7
170.7
11.6
11.9
+ 12.1
+ 0.6
f 1.4
137.7c
214.8
265.1
292.1
i- 15.5
rt 16.8
* 18.1
k 24.0
105.7
142.8
160.1
_c 6.2
+ 7.2
138.9
205.7’
+ 14.2
f 24.9
107.1
143.5
& 6.4
+ 9.0
f
7.0
276.1’
254.6’: +23.0
15.4
172.2 *
k25.0
159.0
170.0
9.4
+ 10.7
13
f 0.9
* 11.1
kO.5 11.6 kO.5
kO.5
17.4
17.8
19.0
f 1.0
f 1.9
13.2’
11.8
11.4
+ 0.4
-+ 1.1
14.4
16.8
17.8
20.4
+ 1.1
f 1.6
f 0.4
+ 1.7
11.2 kO.4
11.4
13.0 + 0.9
to.5
13.0
11.9 + 1.1
+ 1.1 kO.8
13.0
13.0 12.9 13.0
11.8
13.0
f 0.8
179.4c
219.0~
251.0:
13.3c
13.6~
16.5
* 13.9 103.oc
+ 16.7[9] 132.3c
f 27.0[5] 156.7
& 0.0[2] 173.2
+1.4 8.0c
+ 0.9[9]
f 2.3[5] 11.9
+ 0.7(2]
+ 6.8
+ 8.5191
+ 7.7[7]
f
*o.o
+ 0.9[91
z+ 1.8[7]
* 1.3[5]
M
138.3C
M
132.8c
F
7.9[5]
10.6~
5.4c
b
11.6
8.5
12.4
9.9
b
1.5
b
1.1
b
0.5
b
0.5
2 0.8
104.4c f
4.2~
b
+ 1.2
1.9 128.8~
2.4c
b
*0.5
* 13.0 F
9
143.5
M
M
5
+ 10.7
+ 6.0
ON r” T$ ‘5 2 2% _ e, z 2 e, 5 .;E
(g/day)”
109.9
f 11.1
600
OF RDX FOR 13 WEEKS
+ 8.0 M
F
5
+ 14.5
M
F 100
ADMINISTRATION
AND MORTALITY Food consumption
F 30
OF DIETARY
CONSUMPTlON
Body weight (g)”
F IO
FOOD
103.8C
2.4~
b
k-o.5
+ 7.6 a Mean + SD; N = 30 for control
group
and
10 for the test groups
unless
otherwise
noted
in square
brackets. b These animals
had previously
c Mean significantly
different
died. from appropriate
control
group
mean,
P10.05.
mg/kg/day or greater (Table I). This was observed for males throughout the 13 week test period whereas food consumption was similar for treated and control females by test week 5. As a corollary, dose-related reductions in body weight gains were observed for RDX-treated males and to a lesser extent females (Table I). These reductions were apparently responsible for a slight increase in relative but not absolute testes weights, as this has been previously observed under conditions of experimental food restriction [8, 91. Dose-related decreases in serum triglyceride levels were observed for RDX-treated rats (Table II). At the lowest dose level (10 mg/kg/day), reductions of 10% and 14% for males and females, respectively, were observed. Although not statistically
244
TABLE
II
EFFECT
OF
DIETARY
TRIGLYCERIDES,
Se*
M
191.7
f:
98.4
(IO’/mm’) liver
weights Relative weights
FOR
13
WIzF.zKS
ON
SERUM
+ 52.7 k25.6
100
30
165.7
k51.6
126.1
+33.0L
72.0
rt36.8
86.6
i24.3
70.0
i Il.4
48.8
+ 6.4 [51L
M
8.86+
1.01
9.23?
1.29
9.50*
1.36
lO.l7?
F
7.36+
1.17
9.07 t
I .62~
9.12?
1.12’
lI.93i
M
9.01 *
1.20
8.43f
2.77
8.92?
0.85
[2]~
0.16 [2] 1.76 151’
X.Xhi
0.64 121
(g)
F
5.05 + 0.39
5.14t
0.40 [9]
5.24?
0.40
5.88?
0.28 [SIC
liver
M
3.13*
0.27
3.02,
0.93
3.31 f
0.28
3.74t
0.10 [2]
F
3.09*
0.25
3.17i
0.19 (91
3.25i
0.22
3.69)
0.15 15)’
(%bw)
:’ X* SD; N= 30 for control
group
and IO for the test group5
h All rats at 300 and 600 my/kg/day died prior to blood weight5 were only recorded at sacrifice. ‘Mean
RDX
10
trigly-
Leukocytes
OF
LIVER WEIGHTS’.”
Dose (mg/kg/day)
cerides (mgoio)
Absolute
hND
0
Parameter Serum
ADMINISTRATION
LEUKOCYTES
significantly
different
from appropriate
control
unless otherwise
collection group
mean,
noted in square
brackets.
in Test Week 13.111 addition,
organ
P 5 0.05.
dose-response relationships suggested biological significance. significant, Reductions in serum triglyceride levels have been previously observed in rats treated with hepatotoxic chemicals which induce fatty infiltration of the liver [lo-121. Although slight hepatomegaly was apparent at 100 mg/kg/day (Table II), treatment-related microscopic lesions of the liver, including hepatocellular vacuolation indicative of fatty infiltration, were not observed. Slight but statistically significant leukocytosis was seen for females and appeared to be dose-related. Slight increases in leukocyte counts may have also occurred for RDX-treated males. None of these elevations were accompanied by any changes in the proportion of leukocyte cell types. No other clinical biochemistry or hematology parameters appeared to be altered by RDX. Multifocal degenerative testicular lesions were observed for single non-surviving males receiving either 300 or 600 mg/kg/day. The lesions were minimal to mild in severity and were not seen for control animals. Since these animals died 2-3 weeks after
initiation
of treatment,
the testicular
lesions
may
have
been
a secondary
response to general debilitation [13]. Blood clots and/or injected blood vessels of the brain were seen for a few animals receiving lethal doses, but were not supported by histological changes. There were no other gross or histopathological lesions which appeared to be associated with RDX treatment. Nontreatment-related lesions were regarded as incidental findings ascribed to naturally occurring diseases and have been previously reported as spontaneous lesions in F344 rats [14-161. ACKNOWLEDGMENT
This study was supported by U.S. Army Medical Command under Contract No. DAMD17-79-C-9161.
Research
and Development
245
REFERENCES 1 S.L. Merrill,
Ingestion
of an explosive
material,
Composition
C-4, U.S. Army
Vietnam
(USARV)
Med. Bull., 8 (1968) 5-10. 2 A.I. Hollander Army
Vietnam
3 W.S. Stone, ingestion 4 W.F.
and E.M.
Colbach,
(USARV)
Med. Bull. 14 (1969) 31-35.
T.L.
Paletta,
of C-4 plastic
Von Oettingen,
potential
dangers
5 E.R. Hart,
E.M.
Composition Heiman,
explosive, D.D.
Arch.
Donahue,
C-4 induced
J.I. Bruce and J.H. Int. Med.,
toxicity
A report
Knepshield,
of five cases, U.S.
Toxic effects
following
124 (1969) 726-730.
H. Yagoda,
A.R.
of cyclotrimethylenetrinitramine
Subacute
seizures:
Monaco
(RDX),
and M.R.
Harris,
.I. Ind. Hyg. Toxicol.,
of RDX and TNT in monkeys,
Litton
Bionetics,
Toxicity
and
31 (1949) 21-31.
Final Report,
Project
No. 1366 (1974). 6 J.M.
Cholakis
and L.C.K.
Inst. Final Report, 7 C.W.
Dunnett,
8 D. Scharer,
comparison
The effect of chronic in male rats, Toxicol.
10 B. Lombardi
and
factor
R.O.
Considerations
12 A.M. Hoyuba
Jr., H.L.
13 W.E. Ribelin,
15 D.G.
Digest. Atrophy
Coleman,
changes
S.W.
during
16 Pathology 79.
Appl.
study of RDX in mice, Midwest
for comparing
Res.
several treatments
with a control,
on organ weights of rats, Toxicology,
7 (1977) 45-56.
J.M.
of food restriction
Pharmacol.,
Interference
with secretion
on the pathogenesis
Greene,
G.W.
Ward,
R.A.
in the liver as a 15 (1966) l-20.
Fatty liver: Biochemical
and clinical
170.
Osbaldiston, Squire,
K.C.
lesions in aging F344 rats, Toxicol.
Arch.
Foster
and
J. Gerontol., Chu
Appl.
Forces
toxicity,
S.J.
Fischer 344 rats,
of the aging Fischer 344 rat, Armed
of triglycerides
of fatty liver, Lab. Invest.,
of rat testis as index of chemical Barthold,
toxicity
40 (1962) 571-586.
G.D. Dunne and S. Schenker,
Dis., 20 (1975) 1142-l
for 4 weeks on common
47 (1979) 15522.
Am. J. Pathol.,
aging in barrier-reared
Goodman,
nonneoplastic
The effect
Recknagel,
11 B. Lombardi,
14 G.L.
procedure
underfeeding
in toxic liver injury,
considerations,
toxicity
J. Dec., (1955) 1096~1121.
H. Oishi and K. Hiraga,
parameters common
90 day subchronic
No. 4513-B (1979).
A multiple
Am. Stat. Assoc. 9 S. Oishi,
Wong,
Project
and
Pharmacol.,
Institute
Pathol., A.M.
75 (1963) 17-23. Jonas,
Pathological
32 (1977) 258-278.
M.S.
Linhort,
Neoplastic
and
48 (1979) 237-248.
of Pathology
Study Set No. MLOO5-
Toxicology Letters, 8 (1981)241-245 Elsevier/North-Holland Biomedical Press
THIRTEEN
WEEK TOXICITY
1,3,5TRIAZINE
(RDX)
STUDY
IN FISCHER
OF HEXAHYDRO-1,3&TRINITRO-
344 RATS
BARRY S. LEVINE, E. MARIANNA FUREDI, DONOVAN E. GORDON, JOHN M. BURNS and PAUL M. LISH Life Sciences Division, IIT Research Institute, Chicago, IL (U.S.A.)
(Received January 17th, 1981) (Accepted January 2Ist, 1981)
SUMMARY
Groups
of Fischer 344 rats received hexahydro-1,3,5-trinitro-1,3,5-triazine
13 weeks at doses of 0, 1, 10, 30, 100, 300 or 600 mg/kg/day. reductions
of
food
intake
triglyceride
levels, marginal
and
body
leukocytosis
weight
gain,
(RDX)
Toxicological
hyperreactivity
in the diet for up to
responses
to approach,
included decreased
slight serum
and mortality.
INTRODUCTION RDX
is a white
crystalline
material
used as an explosive.
Accidental
human
ingestion of RDX-based plastic explosives has resulted in grand ma1 seizures, gastrointestinal tract irritation, leukocytosis and elevated BUN levels [l-3]. Previous toxicity studies in rats, dogs and monkeys demonstrated similar responses to RDX intoxication. Van Oettingen et al. [4] observed hyperirritability, convulsions, body weight loss and mortality in rats and/or dogs following 6-10 weeks of RDX treatment. Convulsive episodes and/or tremors have also been seen in RDX-treated rhesus monkeys [5]. Subchronic dosing of RDX to mice produced hepatomegaly with marginal treatment-related periportal vacuolization in addition to behavioral changes and death [6]. The present investigation examines the dose-response relationships of RDX intoxication following dietary administration to rats for 13 weeks.
Abbreviation:
RDX, hexahydro-1,3,5-trinitro-1,3,5-triazine.
0378.4274/81/0000-0000/$02.50
Cc)Elsevier/North-Holland
Biomedical
Press
242
RDX,
84.7+-4.7070
purity
(military
grade),
was used
in this study.
All other
chemicals used were either analytical or reagent grade. The geometric median diameter of the RDX particles was 20 Km (by number) with ~90% 566 pm. Fischer 344 rats of both sexes (ARS Sprague Dawley, Madison, WI), 3-4 weeks old, were housed in an air-conditioned (21.--23°C) room at ambient relative humidity, 30-50%, and on a 12-h fixed light cycle. Food and water were provided ad lib. except during a 17-19-h fast prior to blood collection for helnatology and clinical biochemistry tests in test week 13 or routine killing after the l3-week exposure period. After one week of quarantine, the animals were randomly assigned, within sex, into 6 treatment groups. Ten animals per sex received either 10, 30, 100, 300 or 600 mg/kg/day of RDX for 13 weeks as a dietary admixture while 30 animals per sex served as controls. Toxicological end points included clinical signs, body weight, food consumption, hematology, clinical biochemistry, organ weights and tissue morphology. Glucose, BUN, SGPT, triglycerides, cholesterol, total protein, albumin and globulin were measured by standard clinical biochemistry microtechniques on a centrifugal analyzer. Hct, Hb, MCV, MCH, MCHC, RBCs, WBCs (total and differential), reticulocytes, and metHb were measured by conventional hematology methods including a particle size counter. Necropsies were conducted on all animals which either survived the 13 week test period or died during the study. Major organs of all killed animals were weighed. Approx. 25 tissues per animal were examined microscopically for the control, 30 and 100 mg/kg/day treatment groups. Major organs were examined histologically for the remaining test groups. One way analysis of variance tests by sex were conducted on all quantitative data with Dunnett’s t-test employed if pairwise comparisons were necessary
[7].
RESULTS AND DISCUSSION
Hyperreactivity mg/kg/day
to approach
or greater
(Table
and
mortality
I). In addition,
were tremors
observed
at doses
and convulsions
of
100
were seen
prior to death for some of the animals receiving 600 mg/kg/day. Histopathological lesions of the nervous system, however, were not in evidence. Mean survival times were inversely correlated with dose level and a sex difference was not apparent (Table I). Additional clinical signs observed at the higher dose levels included lethargy, ataxia, vulva1 discharge for females and epistaxis. Although small thin uteri were observed for some of the animals which received 100 mg/kg/day and survived the 13-week test period, microscopic examination failed to detect any lesions. RDX caused a significant reduction in food consumption at doses of 100
243
TABLE
I
SUMMARY
OF THE EFFECTS
BODY WEIGHTS, B ?00 $d wx P0 vr/ EO 0
Test week
Test week
1
300
9
147.2
227.2 f 18.7
13 217.3
k21.3
1
301.6 ~23.2
16.0
17.9
17.6
18.5
f 1.0
t 1.0
f 1.7
11.3
160.7
170.7
11.6
11.9
+ 12.1
+ 0.6
f 1.4
137.7c
214.8
265.1
292.1
i- 15.5
rt 16.8
* 18.1
k 24.0
105.7
142.8
160.1
_c 6.2
+ 7.2
138.9
205.7’
+ 14.2
f 24.9
107.1
143.5
& 6.4
+ 9.0
f
7.0
276.1’
254.6’: +23.0
15.4
172.2 *
k25.0
159.0
170.0
9.4
+ 10.7
13
f 0.9
* 11.1
kO.5 11.6 kO.5
kO.5
17.4
17.8
19.0
f 1.0
f 1.9
13.2’
11.8
11.4
+ 0.4
-+ 1.1
14.4
16.8
17.8
20.4
+ 1.1
f 1.6
f 0.4
+ 1.7
11.2 kO.4
11.4
13.0 + 0.9
to.5
13.0
11.9 + 1.1
+ 1.1 kO.8
13.0
13.0 12.9 13.0
11.8
13.0
f 0.8
179.4c
219.0~
251.0:
13.3c
13.6~
16.5
* 13.9 103.oc
+ 16.7[9] 132.3c
f 27.0[5] 156.7
& 0.0[2] 173.2
+1.4 8.0c
+ 0.9[9]
f 2.3[5] 11.9
+ 0.7(2]
+ 6.8
+ 8.5191
+ 7.7[7]
f
*o.o
+ 0.9[91
z+ 1.8[7]
* 1.3[5]
M
138.3C
M
132.8c
F
7.9[5]
10.6~
5.4c
b
11.6
8.5
12.4
9.9
b
1.5
b
1.1
b
0.5
b
0.5
2 0.8
104.4c f
4.2~
b
+ 1.2
1.9 128.8~
2.4c
b
*0.5
* 13.0 F
9
143.5
M
M
5
+ 10.7
+ 6.0
ON r” T$ ‘5 2 2% _ e, z 2 e, 5 .;E
(g/day)”
109.9
f 11.1
600
OF RDX FOR 13 WEEKS
+ 8.0 M
F
5
+ 14.5
M
F 100
ADMINISTRATION
AND MORTALITY Food consumption
F 30
OF DIETARY
CONSUMPTlON
Body weight (g)”
F IO
FOOD
103.8C
2.4~
b
k-o.5
+ 7.6 a Mean + SD; N = 30 for control
group
and
10 for the test groups
unless
otherwise
noted
in square
brackets. b These animals
had previously
c Mean significantly
different
died. from appropriate
control
group
mean,
P10.05.
mg/kg/day or greater (Table I). This was observed for males throughout the 13 week test period whereas food consumption was similar for treated and control females by test week 5. As a corollary, dose-related reductions in body weight gains were observed for RDX-treated males and to a lesser extent females (Table I). These reductions were apparently responsible for a slight increase in relative but not absolute testes weights, as this has been previously observed under conditions of experimental food restriction [8, 91. Dose-related decreases in serum triglyceride levels were observed for RDX-treated rats (Table II). At the lowest dose level (10 mg/kg/day), reductions of 10% and 14% for males and females, respectively, were observed. Although not statistically
244
TABLE
II
EFFECT
OF
DIETARY
TRIGLYCERIDES,
Se*
M
191.7
f:
98.4
(IO’/mm’) liver
weights Relative weights
FOR
13
WIzF.zKS
ON
SERUM
+ 52.7 k25.6
100
30
165.7
k51.6
126.1
+33.0L
72.0
rt36.8
86.6
i24.3
70.0
i Il.4
48.8
+ 6.4 [51L
M
8.86+
1.01
9.23?
1.29
9.50*
1.36
lO.l7?
F
7.36+
1.17
9.07 t
I .62~
9.12?
1.12’
lI.93i
M
9.01 *
1.20
8.43f
2.77
8.92?
0.85
[2]~
0.16 [2] 1.76 151’
X.Xhi
0.64 121
(g)
F
5.05 + 0.39
5.14t
0.40 [9]
5.24?
0.40
5.88?
0.28 [SIC
liver
M
3.13*
0.27
3.02,
0.93
3.31 f
0.28
3.74t
0.10 [2]
F
3.09*
0.25
3.17i
0.19 (91
3.25i
0.22
3.69)
0.15 15)’
(%bw)
:’ X* SD; N= 30 for control
group
and IO for the test group5
h All rats at 300 and 600 my/kg/day died prior to blood weight5 were only recorded at sacrifice. ‘Mean
RDX
10
trigly-
Leukocytes
OF
LIVER WEIGHTS’.”
Dose (mg/kg/day)
cerides (mgoio)
Absolute
hND
0
Parameter Serum
ADMINISTRATION
LEUKOCYTES
significantly
different
from appropriate
control
unless otherwise
collection group
mean,
noted in square
brackets.
in Test Week 13.111 addition,
organ
P 5 0.05.
dose-response relationships suggested biological significance. significant, Reductions in serum triglyceride levels have been previously observed in rats treated with hepatotoxic chemicals which induce fatty infiltration of the liver [lo-121. Although slight hepatomegaly was apparent at 100 mg/kg/day (Table II), treatment-related microscopic lesions of the liver, including hepatocellular vacuolation indicative of fatty infiltration, were not observed. Slight but statistically significant leukocytosis was seen for females and appeared to be dose-related. Slight increases in leukocyte counts may have also occurred for RDX-treated males. None of these elevations were accompanied by any changes in the proportion of leukocyte cell types. No other clinical biochemistry or hematology parameters appeared to be altered by RDX. Multifocal degenerative testicular lesions were observed for single non-surviving males receiving either 300 or 600 mg/kg/day. The lesions were minimal to mild in severity and were not seen for control animals. Since these animals died 2-3 weeks after
initiation
of treatment,
the testicular
lesions
may
have
been
a secondary
response to general debilitation [13]. Blood clots and/or injected blood vessels of the brain were seen for a few animals receiving lethal doses, but were not supported by histological changes. There were no other gross or histopathological lesions which appeared to be associated with RDX treatment. Nontreatment-related lesions were regarded as incidental findings ascribed to naturally occurring diseases and have been previously reported as spontaneous lesions in F344 rats [14-161. ACKNOWLEDGMENT
This study was supported by U.S. Army Medical Command under Contract No. DAMD17-79-C-9161.
Research
and Development
245
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