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International Research and Development Corporation
SPONSOR: 3M Company COMPOUND: Fluorad Fluorochemical FC-143 SUBJECT: Ninety Day Subacute Rhesus Monkey Toxicity Study.
Vice Preessiicdii:ne and Director or Research
Collaborators:
D. C. Jessup, Ph.D., Associate Director of Research
R. G. Geil, D.V.M., Vice President and Director of Pathology
J. S. Mehring, Ph.D., Director of Large Animal Toxicology
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Date :_____November 10, 1978
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T A B L E OF C O N T E N T S (Continued)
Table No. 5- 7. Individual Hematological Values ........................... 8. Means and Significance of Biochemical Values ............ 9-11. Individual Biochemical Values ............................. 12. Means and Significance of Urinalysis Values ..............
13-15. Individual Urinalysis Values ............................ 16. Summary of Gross Necropsy Observations .................. 17. Absolute and Relative Organ Weights ...................... 18. Microscopic Observations .................................
Page
18-20 21 22-24 25 26-28 29-30 31-32 33-39
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I. SYNOPSIS In a ninety day oral study in rhesus monkeys, Fluorad
Fluorochemical FC-143 was administered at dosage levels of 0 (control, treated only with 0.5% Methocel), 3, 10, 30 and 100 mg/kg/day. Two male and two female monkeys were initiated at each dosage level and also in a control group. The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urinalysis studies were conducted once in the control period, at the end of the first and third months of study.
The monkeys treated with the higher dose, (100 mg/kg/day) all died during weeks 2 through 5 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7-12. They all showed signs of toxicity in the gastrointestinal tract (anorexia, emesis, sometimes brown in color, black stools), pale face and gums, swollen face and eyes, slight to severe decreased activity and prostration. The monkeys of the 30 and 100 mg/kg/day dosage level showed body weight losses from the first week of the study.
Because of the early deaths of the monkeys at the 100 mg/kg/day dosage level, the clinical laboratory tests were not conducted.
The monkeys at the 30 mg/kg/day dosage level showed, in the first month of the study, slight increase in prothrombin time and in acti vated partial thromboplastin time (A.P.T.T.) values, as well as decreased alkaline phosphatase activity in the serum (statistically significant). Only one monkey from this dosage level in this period showed a low albumin value. At the end of the study, the only remaining monkey from the 30 mg/kg/day dosage level showed apparent anemia, low blood glucose, alkaline phosphatase, total protein and albumin values.
There was no mortality at the 10 mg/kg/day dosage level. One monkey had black stool on several days in week 12 and occasionally
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anorexia and one monkey exhibited pale face and gums. At this dosage level there was a very slight increase in the activated P.T.T. values in the female monkeys during the first month of the study (not sta tistically significant). There were no changes in the other indices and no changes in the body weight. In single monkeys from the 3 and 10 mg/kg/day dosage levels, there were trends toward decreased alkaline phosphatase in the serum.
In the control and the 3 mg/kg/day dosage level there was no mor tality, no changes in the body weights and no signs of toxicity. Soft stool, diarrhea or emesis were observed occasionally.
The mortality and the above mentioned signs of toxicity in the 30 and 100 mg/kg/day dosage levels were compound-related. There was a trend toward the same signs of toxicity in single monkeys at the 10 mg/kg/day dosage level. The 3 mg/kg/day dosage level seems to be free of signs of toxicity. There is an evident relationship between the administered doses and the degree of the toxicity.
No gross or microscopic lesions which were considered compoundrelated were seen in tissues other than the adrenals, bone marrow, spleen and lymph nodes for male and female monkeys at the 30 and 100 mg/kg/day dosage levels. Microscopically, the adrenals from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compoundrelated marked diffuse lipid depletion; the bone marrow from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compoundrelated slight to moderate hypocellularity; the spleen and lymph nodes from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compound related moderate atrophy of lymphoid follicles.
Statistically significant variations in sex group mean weights of a few organs occurred between the control and experimental groups. These variations were of unknown biological significance and were not accompanied by morphologic alterations.
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II. COMPOUND
The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below:
___________ Label______________
Description
Fluorad Fluorochemical FC-143 3M Stock No. 98-0211-0008-0 Lot 340
white powder
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111 CLINICAL s t u d i e s
A. METHODS :
1. General Procedure:
Ten male rhesus monkeys (weighing from 2.60 to 3.90 kilograms)
and 10 females (weighing from 2.95 to 3.80 kilograms) were initiated
on this study. The monkeys were purchased from Primate Imports
Corporation, Port Washington, N. Y. 11050. The monkeys were housed
individually in hanging wire mesh, "squeeze type" cages and maintained
in a temperature, humidity and light controlled enviroment. Purina
Monkey Chow was fed twice each day and fresh apples were fed 3 times
a week. Water was available a<i libitum.
During the conditioning period, the monkeys were tattooed on
the inner surface of the thigh and intrapalpebral tuberculin tests
were conducted. Tuberculin tests were conducted at bimonthly inter
vals during the treatment period. Also a complete physical examina
tion was conducted by the staff veterinarian prior to initiation of
compound administration. Only monkeys in good health were selected
for the study.
This study was initiated on January 11, 1978. Terminal sacri
fices were conducted on April 12, 1978.
2. Compound Administration;
At the end of the conditioning period the monkeys were divided
into five groups on a random basis, so that the initial average body
weights were similar:
Number of Monkeys
Male
Female
Dosage Level
22 22 22 22 22
Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 100 mg/kg/day
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The test compound, suspended in 0.5% Methocel, was admin istered by gavage, 7 days each week. All doses were given in a constant volume. Also the same volume of 0.5% Methocel was given to the vehicle control group. Individual daily doses were based upon the body weights obtained weekly.
3. Observations: The monkeys were observed twice daily for general physical
appearance and behavior and pharmacotoxic signs. Individual body weights were recorded weekly. General physical examinations were con ducted in the control period and monthly during the study.
4. Clinical Laboratory Tests; Blood and urine samples were obtained for analysis from all
monkeys once during the control period and at 1 and 3 months of study. The monkeys were fasted overnight prior to the collection of blood and urine samples.
a. Hematology: Hematological studies included: hemoglobin*, hematocrit^,
erythrocyte count, total-* and differential leucocyte counts, reti culocyte count^, platelet count, prothrombin time, activated partial thromboplastin time^ (A.P.T.T.). Mean corpuscular hemoglo bin, mean corpuscular volume and mean corpuscular hemoglobin con centration were calculated.
b. Biochemistry: Biochemical studies included: fasting blood glucose,
blood urea nitrogen, serum alkaline phosphatase, serum glutamic oxalacetic and pyruvic transaminase activities, cholesterol^, total protein^, albumin, sodium1**, potassium1**, chloride^, inorganic phosphate?, Y-glutamyl transpeptidase11 (y-G.T.P.) and creatinine phosphokinase^.
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c. Urinalysis: Urinalysis included: measurement of volume, p H ^ and
specific gravity; description of color and appearance; qualitative tests for protein^ f glucose^ t ketones^> occult blood^ and microscopic examination of the sediment.
d. Statistical Analysis: Analysis of body weights and clinical laboratory tests
were performed. All statistical analyses compared the treatment groups with the control group, by sex. The tests were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie^ using Dunnett's^ multiple comparison tables to judge significance of differences. B. RESULTS:
1. General Behavior, Appearance and Survival: There was no mortality in monkeys at 0, 3 and 10 mg/kg/day
dosage levels. The monkeys from the control and 3 mg/kg/day dosage levels
did not show any unusual behavior or signs of toxicity. Soft stool or moderate to marked diarrhea were noted occasionally. Frothy emesis was also noted occasionally.
At the 10 mg/kg/day dosage level the monkeys did not show any unusual signs of toxicity, except Monkey 7363. In week 7 its face appeared swollen and pale. It had been occasionally anorexic in week 4 and black stools appeared for several days in week 12 of the study.
At the 30 mg/kg/day dosage level, three monkeys died during weeks 7, 12 and 13 of the study. From week 4, the monkeys were anorexic. Slight to moderate and sometimes severe decreased activity was noted occasionally to frequently for the four monkeys. Emesis and ataxia were very rarely noted, for one monkey.
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Swollen face, eyes and vulva, as well as pallor of the face and gums were noted. From week 6, for two monkeys, black stools were noted. Monkey 7387 showed slight to moderate dehydration and ptosis of the eyelids.
All monkeys from the 100 mg/kg/day dosage level died during weeks 2 through 5 of study. They showed the same symptoms of toxicity as the previous group, but they appeared sooner in the study (from week 1) and were more marked: anorexia, frothy emesis (sometimes brown in color) pale face and gums, swollen face and eyes, decreased activity from slight to severe, prostration and body trembling.
2. Body Weights (Tables 1-3): Changes in body weight were similar for monkeys from the
control and the 3 and 10 mg/kg/day dosage levels. Monkeys at the 30 and 100 mg/kg/day dosage levels lost body weight after the first week of study. There was statistically significant decreases in the body weight for the male monkeys at the 30 mg/kg/day dosage level in week 13 of the study. The female monkeys of the same dosage level and the monkeys from the 100 mg/kg/day dosage level were dead in this period.
3. Laboratory Test (Tables 4-15): a. Hematology: There were no noteworthy changes in monkeys from the 3 and
10 mg/kg/day dosage levels. In the first month of the study there was a slight increase (not statistically significant) of the A.P.T.T. values in the females at the 10 mg/kg/day dosage level and a statisti cally significant increase of the A.P.T.T. and prothrombin time values in monkeys at the 30 mg/kg/day dosage level. In the third month of the study there was a high increase in the above mentioned indices for the one surviving monkey from the 30 mg/kg/day dosage level. The same monkey (#7455) had pronounced anemia as well.
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The statistically significant increase in the hematocrit in monkeys at the 10 mg/kg/day dosage level and in the platelet count in monkeys at the 3 mg/kg/day dosage level at 3 months of study, were within the normal physiological limits.
b. Biochemistry: There were no noteworthy changes in monkeys from the
control, 3 and 10 mg/kg/day dosage level. Only one monkey from the 3 mg/kg/day dosage level and one monkey from the 10 mg/kg/day dosage level showed trends toward decreases of alkaline phosphatase (432 and 474 units/1, respectively), without statistical significance.
In the first month of the study, decrease in serum alka line phosphatase was noted in monkeys at the 30 mg/kg/day dosage level (statistically significant) and in one monkey in the same dosage level, the albumin in the serum was lower (3.22 g/lOOml). The one surviving monkey (7455) from the 30 mg/kg/day dosage level showed decreasing of: blood sugar (66 mg/lOOml), total protein (5.52 g/lOOml) with albumin (2 g/lOOml) and alkaline phosphatase (360 units/1) and slightly elevated cholesterol (240 mg/lOOml).
c. Urinalysis: No changes considered to be related to compound were seen
in the urinalysis studies.
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IV. PATHOLOGICAL STUDIES A. METHODS : 1. Gross pathology: After completion of the compound administration period all surviving monkeys were anesthetized with Sernylan*, exsanguinated and necropsied. At necropsy, the heart, liver, adrenals, spleen, pituitary, kidneys, testes/ovaries and brain were weighed and repre sentative tissues were collected in buffered neutral 10% formalin. Eyes were fixed in Russell's fixative. The thyroid/parathyroid was weighed after fixation. Monkeys which died during the study were necropsied as above. 2. Histopathology ; Microscopic examination of formalin fixed hematoxylin and eosin stained paraffin sections was performed for all monkeys in the control and treatment groups. The following tissues were examined:
adrenals aorta bone brain esophagus eyes gallbladder heart (with coronary
vessels) duodenum ileum jejunum cecum colon rectum
kidneys liver lung skin mesenteric lymph node retropharyngeal lymph
node mammary gland nerve (with muscle) spleen pancreas prostate/uterus rib junction (bone
marrow) salivary gland
lumbar spinal cord pituitary stomach testes/ovaries thyroid parathyroid thymus trachea tonsil tongue urinary bladder vagina tattoo
and any other tissue(s) with lesions
*Phencyclidine HC1 - Bio-Ceutic Laboratories, Inc., St. Joseph, Missouri.
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1. Gross Pathology (Table 16) and Organ Weights (Table 17) : No gross lesions considered compound related were seen in male
and female rhesus monkeys which died on study or were sacrificed after 90 days of study.
Statistically significant variations in sex group mean weights of few organs occurred between the control and experimental groups. The following statistically significant organ weight variations occurred;
Organ
Dosage S Level e mg/kg/day x
Heart
10 F
Brain
10 F
Pituitary 3
M
Weight absolute,relative
absolute relative
Change decrease,decrease
decrease increase
P< 0.05,0.01
0.01 0.05
The biological significance of these variations is unknown. These organ weight variations were not accompanied by morphologic changes which were considered compound related.
2. Histopathology (Table 18): One male and two female rhesus monkeys at the 30 mg/kg/day dosage
level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had marked diffuse lipid depletion in the adrenals. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had slight to moderate hypocellularity of the bone marrow. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had moderate atrophy of lymphoid follicles in the spleen. One female at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had moderate atrophy of the lymphoid follicles in the lymph nodes.
No microscopic changes considered compound related were seen in the adrenals, bone marrow, spleen and lymph nodes of male and female rhesus monkeys at the 3 and 10 mg/kg/day dosage levels. No microscopic
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lesions in tissues other than the adrenals, bone marrow, spleen and lymph nodes at the 30 and 100 mg/kg/day dosage levels were considered compound-related.
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Reference 1. Coulter Hemoglobinometer. Coulter Electronics, 590 W. 20th
Street, Hialeah, Florida. 2. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. Mosby
Company, p. 1154. 3. Coulter Particle Size Counter, Model Zg, Coulter Electronics, 590 W.
20th Street, Hialeah, Florida. 4. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and
Reitman, Editors 6th Ed., 1963, The C. V. Mosby Company, p. 1132. 5. Coulter Particle Size Counter, Model A, Coulter Electronics, 590 W.
20th Steet, Hialeah, Florida. 6. General Diagnostics - Warner Chilcott Laboratories Revised April 1965. 7. General Diagnostics - Warner Chilcott Laboratories Revised Janurary 1967. 8. Technicon Auto Analyzer, 6/60 Micro Methodology. 9. Micro Auto Analyzer II, 6/60 Micro Methodology. 10. Atomic Absorption IL, Model 353 11. Sigma GGTP Procedure Bulletin //545. Sigma Chem. Co., St. Louis, Mo. 12. Bililabstix (Ames Reagent Strips). 13. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures
of Statistics, McGraw-Hill, New York, N. Y. 14. Dunnett, C. W., New Tables for Multiple Comparisons With a Control,
Biometrics, McGraw-Hill, New York, N. Y.
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FC-143: TABLE 1. Sex
M F
Group I (Control)
3.78
3.55
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Mean Body Weights of Monkeys Week 13 of Study.
Group II (3 mg/kg/day)
3.50
3.68
Group III (10 mg/kg/day)
3.68
3.78
Group IV (30 mg/kg/day)
2.30*
dead
Group V (100 mg/kg/day)
dead
dead
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*Statistical significance.
FC-143:
Ninety Day Subacute Rhesus Monkey Toxicity Study.
TABLE 2
Individual Body Weights, Kilograms
Group,
Monkey
Control
_______________________________________Week of Study
Number Sex 1 2 1 2 3 4 5 6 7 8 9 10 11 12 13
Control:
7362 7365
M M
7336 7386
F F
Mean
3 mg/kg/day:
7364 7366
M M
7384 7385
F F
Mean
10 mg/kg/day:
7363 7458
M M
7328 7383
F F
Mean
3.15 3.50
3.05 3.90
3.40
3.30 3.50
3.20 3.70
3.43
3.15 3.50
3.25 3.70
3.40
3.30 3.50
3.25 3.65
3.43
3.70 2.60
3.55 3.50
3.34
3.90 2.60
3.60 3.55
3.41
3.85 2.70
3.70 3.45
3.43
3.95 2.60
3.80 3.45
3.45
3.55 3.10
3.30 3.60
3.39
3.70 3.10
3.30 3.60
3.43
3.70 3.25
3.45 3.50
3.48
3.65 3.20
3.40 3.80
3.51
3.35 3.50
3.35 3.55
3.44
3.10 3.40
3.15 3.45
3.28
3.85 2.65
3.80 3.45
3.44
3.85 2.65
3.80 3.45
3.44
3.65 3.10
3.40 3.60
3.44
3.65 3.05
3.30 3.55
3.39
3.20 3.55
3.00 3.40
3.29
3.20 3.60
3.15 3.55
3.38
3.00 3.60
3.20 3.40
3.30
3.80 2.70
3.70 3.40
3.40
3.80 2.70
3.70 3.40
3.40
3.85 2.50
3.60 3.50
3.36
3.65 2.95
3.20 3.50
3.33
3.60 3.20
3.30 3.60
3.43
3.60 3.00
3.25 3.60
3.36
3.15 3.80
3.30 3.40
3.41
3.20 3.75
3.45 3.55
3.49
4.10 2.70
3.55 3.55
3.48
4.10 2.70
3.80 3.60
3.55
3.70 3.15
3.45 3.65
3.49
3.65 3.10
3.60 3.80
3.54
3.05 3.75 3. 30 3.40 3.38
4.05 2.45 3.55 3.40 3.36
3.75 3.10 3.50 3.65 3.50
3.20 3.80 3.35 3.50 3.46
4.05 2.55 3.70 3.30 3.40
3.85 3.25 3.40 3.75 3.56
3.40 4.00 3.35 3.50 3.56
4.20 2.50 3.90 3.40 3.50
3.90 3.25 3.60 3.75 3.63
3.50 4.05 3.60 3.50 3.66
4.30 2.70 3.75 3.60 3.59
3.90 3.45 3.75 3.80 3.73
Page 14
Oo
F*---<1
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FC-- 143 :
TABLE 2. Cont
Group,
Monkey
Control
Number Sex 1
2
Ninety Day Subacute Rhesus Monkey Toxicity Study Individual Body Weights, Kilograms.
____________________________________Week of Study 12 34 56 78
9
10 11 12 13
30 mg/kg/day:
7367 7455
M 3.40 M 3.50
7382 7387
F 3.25 F 3.70
Mean
3.46
100 mg/kg/day:
7361 7456 7335 7381
M 3.50 M 3.10 F 2.80 F 3.85
Mean
3.31
3.40 3. 30 3.30 3.75 3.44
3.85 3.10 2.95 3.80 3.43
3.25 3.20 3.20 3.50 3.29
3.50 2.60 2.70 3.55 3.09
3.25 3.05
3.20 3.55
3.26
3.10 2.85
3.05 3.50
3.13
2.95 2.65
3.00 3.45
3.01
2.65 2.45
2.85 3.10
2.76
2.30 2.50
2.80 2.95
2.64
3.30 2.70* 2.45 3.20
3.00 Died 2.05* 2.80
2.55
Died 2.60*
2.40* Died
Died
2.98 2.90 2.55
2.10* Died 2.55 2.60
2.80 2.80 2.85 2.85
2.73 2.75
2.70
2.80 2.70
2.73
2.70
2.80 2.65 2.72
2.65
2.80 2.50 2.65
2.50 2.30
2.60 2.25* Die, 2.25* Died
2.55 2.30
00173
(0L37-O9O
*Terminal weight not included in mean.
t) Pi 0n0>
FC-143:
TABLE 3.
Study Week
Sex
13 M F
Ninety Day Subacute Rhesus Monkey Toxicity Study. T-Test Comparison of Body Weights.
Page 16
Control
3.78 3.55
3 mg/kg/day
3.50 3.68
10 mg/kg/day
3.68 3.78
30 mg/kg/day
2.30a -
100 mg/kg/day
-
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*p<0.05 **p<0.01
aNot included in statistical analysis due to only one surviving animal.
- Line indicates animals had died prior to week 13.
001.740
FC-143: TABLE 4.
Hematology
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Means and Significance of Hematological Values.
Month of Study
Control
3 mg/kg/day 10 mg/kg/day
Erythrocytes, 10^/cmm
Hemoglobin, g/100 ml
Hematocrit, /e
Platelets, lO^/cmm
Reticulocytes, %
Prothrombin Time, sec
Activated P.T.T., sec
Leucocytes, 10 /cmm
Neutrophils, %
Lymphocytes, %
Eosinophils, %
Monocytes, %
Basophils, %
MCV,
MCH, uug MCHC, g/100 ml
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
1 3
4.46 4.90
11.7 12.9
38 37
253 210
0.2 0.3
12 11
28 26
9.49 9.40 .
24 16
75 80
1 3
0 1
0 0
86 75
27 26
31 36
4.26 4.74
11.4 12.7
37 37
233 285*
0.5 0.2
12 11
28 26
9.78 9.83
19 19
76 76
5* 3
0 2
0 0
86 78
27 27
31 35
4.71 5.47
12.1 13.3
39 40**
210 216
0.5 0.2
13 11
31 24
9.93 11.96
26 25
72 67
2 6
0 2
0 0
82 73
26 24
32 34
Page 17
30 mg/kg/day
4.53 3. 84a 11. 7 9 . 7a 36 30 a 219 261a 0.2 0.2a 15** 30a 35** 65a 8.44 10.14a 15 36 a 85 54a 0 3a 0 7a 0 0a 80 78a 26 25 a 32* 32a
*Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01-
aValue not used in statistical analysis due to only one animal surviving.
C01741
I'T-Wfl:
N i n e t y Day Si i l meul e Kl i csus Monkey T o x l e l t y S t u d y .
TARI.K '>
1ud1vtduat Hemal n|n)*|r,il Va 1uns ('mi 1rn) 1 .
Ornup,
Fry thro- Memo-
Monkey
e yl i'ii f; Inti III
Number Sex I0%nmi k/IOO ml
Hetnnloeilt 7.
I'l.iteletH 1(d/ciiim
Relleu1uey 1 its
t
rroilirumliiu T 1me see
A e l I v n l d I' . T. T sec
l.eiicn- Neul ntpli 1 1a
eytefi
Noll-Sn)* .
1(* / 1'IBIH *
7.
l.yni|din eyd*s %
CuntHil:
7162 7165
M 5.08 H 6.72
7116 F 5.27 7186 F 6.20
Menu
6.82
I J/ku/d.|y:
716/, 7166
M 6.50 M 6.6
7186 F 6.55 U S ') F 6 .1 0
Mean
6.61
10 iHg/kB/clay
7161 7618
M 5.26 M 5.29
7128 F 5.32 7181 F 5.06
Mean
5.22
1. nili/ku/Ojiy
7167 76 51
M 6.98 M 5.16
7182 7187
F 6.86 F 6.67
Mean
6.91
iOO j^ /J cg /c liiy :
7161 7656
M 6.75 M 5.16
7115 7381
F 5.66 F 6.82
Menu
5.10
11.0 11.9 12.8 11 .1 12.2
11.5 12.0 11.7 11.6 11.7
11.7 12.2 12.5 11.5 11.0
12.6 11.6 12.8 12.2 12.8
12.6 11.6 12.8 11.5 12.5
60 18 19 16 3
17 17 18 35 17
62 16 19 62 40
18 60 18 15 18
16 62 60 16 19
207 0.1 119 0 .1 226 0 .6 227 0 .5 265 0.6
155 0 . 6 297 0 .1 160 0 . 2 165 0 . 6 232 0.6
266 0 .6 261 0 .2 192 0 . 8 120 0 .6 210 0.5
163 0 .2 133 0 . 5 157 0 . 6 111 0 . 6 117 0 . 5
282 0 .1 196 0 . 2 185 0 . 2 115 0 . 5 195 0 . 1
n n 16 16 16
11 16 11 13 13
11 n ii n ii
12 12 n 16 11
12 11 16 16 11
29 10.96 16 1 10 16.79 27 0
29
7.86 18
u
21
12.09 59
0
27
11 .63 60
0
25
8 .9 8 62
0
29
7 .19 61
0
30 16.72 11 0
26
8 . 1 6 18
0
27
9.81 18
0
11
12.97 46
0
29
17.36 16*
0
11
7 .8 9 15
0
28
8 .2 2 67
0
36 11.61 10 0
28 10.86 61 0
26
8 . 6 5 21
(1
26
5.8.1 26
0
27
5.10 29
0
26
7.61 29
0
27
10.77 1(1
0
28
5.86 18
n
28
12.8
18
0
26
10.16 56
n
27
9.58 60
0
62 72 59 19 58
57 59 66 59 60
69 78 65 68 60
57 76 71 68 68
67 60 57 66 57
Iuim inn|>lil In'' 7.
Mono- Hasne V1e s ' pi,it'* MOV MOM hoik:
7. 7. | d imp. p / i n i l ml
1
0
0 79 26
ii
1
0
0 HI 25
it
1
0
0 76 26
13
1 1 0 81 26 i i
2
0
0 79 25
it
0 1 0 82 20 il
0
0
0 81 27
12
5
0
0 86
26
11
3 (1 0 86 27 11
2
0
0 81
27
12
5
0
0 8(1 26
11
6
0
0 68 21
I'l
0
0
0 71 21
12
6 1 0 81 27 2
6
0
0 76 25
11
2
0
0 76 25
11
3
0
0 78 26
16
|
(1
0 79 20
16
1
2
0 75 20
15
2 1 (1 77 26 16
3
0
n 76 26
16
0
1
1 78 ? s
11*
5
0
0 7 1 21
12
1
0
1 75 26
P
2
0
1 76 2'i
11
BEST COPY AVAfl ABLE 001742
delei'wlnnl Inn
' H k - (111 t I ' r r n l i n I I n i r n c y 1** men u s h a v e li nen .id j u s t r d l u r*(u,i| 100* .
F U - 141:
N i n e t y liny S u b a c u t e Khesus Monkey T o x i c i t y S t u d y .
TAIM.1% ft.
1iuilvirlu.il Ileumto Ini i ca I Valili* - I Monti.
Cri>ii|>,
Kiytlirn-
Memo-
Monkey
c v Lew
g l o b in
N u m b e r S e x M 1V f m m g / 1 0 0 ml
Mentaloet it 7
IMatelots 10 / c m m
KetIon-
loeytoH
X
1'niMirnnililn T 1ute sec
A e 1 1v a 1eil P.T.T. see
l.eiieo- Nell t rojili 11 h
oy t o s Soy,. Nou-Keg.
10 Votum %
%
l.yiupho-
cytos'
X
Fits I int Moio~ Has-
u 11** r y t e s a |tll I 1s ' '1 MOV non
7. 1 z
mo:
none r / I oo
Con im l:
7362 H 6.80 7365 H 6.71
11.9 11.9
7 336 7386
I- 6 . 2 0 I- 6 . 1 7
11.2 11.9
Mean
4 . 4 ft
11.7
3 nig/ky/<*>':
7366 M 6.35 7366 M 3.96
11.6 10.7
7386 7385
F 6.66 F 6.25
11.9 11.2
Mean
6.26
11.6
10 mg/kg/day ;
7363 77.58-
M M
6.62 6.81
12.1 11.3
7328 F 6.70 73B3 F 6.92
12.0 12.8
Mean
6.71
12.1
30 mg/k/il.iy
7367 M 6.59 7655 H 6.66
11.2 11.8
7382 7387
F 6.51 F 6.56
11.9 12.0
Mean
6.53
jOOJ5B/kj5Al.iji:
11.7
7361 M Died, week 5 7656 M Died, week 2
7775 7381
F Died, week 3 F Died, week 6
78 79 37 78 38
37 75 39 35 77
38 77 39 60 79
36 37 75 37 36
226 369 266 191 257
266 188 236 267 233
168 281 18) 209 210
175 237 268 237 219
0.2 0.2 0.2 0.3 0.2
0.5 0.6 0.2 0.9 0.5
1.0 0.3 0.5 0.1 0t5
0. 1 0.2 0.3 0.2 0.2
12 12 17 12 12
11 12 13 12 12
13 13 13 12 11
13 16 15 16 15
70
6.91 28
0
69
3
0
o 79 25
71
2R
1 6 . 5R 15
0
86
1
0
0 8 7 25
71
28
7.66 11
0
89
0
n
0 88 27
70
27
8.99 62
0
58
0
0
0 92 29
II
28
9 . 6 9 26
0
75
1
0
0 86 27
11
27
6.81 17
0
80
3
0
0 85 77
71
28
5 .8 3 16
0
78
6
0
0 88 27
II
28 17.07 22 1 73 3 1 0 87 27 71
29
9.61 18
0
73
9
II
0 82 26
12
28
9 . 7 8 19
0
76
5
0
0 86 27
II
27
8,08
62
0
31
17.98
11
0
57 87
1
0
0 86 28
72
1
0
1 77
21
11
31
7.01
35
0
63
2
1)
0 81 26
31
33
6.66
18
0
79
7
0
0 81
26
12
31
9.97
26
0
72
2
0
0 82 26
32
36
7.92
12
0
88
O
1)
0 78 26
71
37
ll.lt
27
0
73
0
(I
0 8 1 27
72
35
6.19
9
0
90
1
0
0 78 26
76
38
8.56
17
0
87
0
0
0 81
26
12
35
8.66
15
0
85
0
0
0 80 26
72
MST COPYAVAIlABLE
001743
117-090
Tli! il i Cf f l i n t l a l l e u c o c y t e m e a n s h a v e I n e n a d j u s t e d I o e q u a l IIMIfc.
U) OQ fD
FC-143:
Ninety Day Su bacute Kliemis Monkey T o x i c i t y S t u d y .
TAIII.K 7.
liu llv id u a ) Denialinlof lent V alues - ) Months,
C.nmi,
Frylliro- Homo-
Monkey
tyli'H ftlob 1u
Number Sex 10 /cmiii r/ 100 ml
Heina t o C1 11
z
llel 1. u-
1' 1;i Lt*1e l s l o e v t l*s
10 /cmin
z
Prothrombin Act 1voted
Time
r.T.T.
sec sec
heuco- Neul ro|dt11s
cyl es Se,(. Nnn~S*j*.
10 Velum z
%
Lvmphocy t es
z
linn 1lie-
|>tll Is'
z
Mono-
cyl es
%
Huso-
|dil 1s*
7.
MTV
neu IMD\
MCIH' )/ IOO
iloiii rot :
7362 7 165
M 4.89 M 4.74
12.9 1 1. 1
71. r 4.72 7 186 1 4 .6 9
12.4 12.8
Nimm
4.9(1
12.9
3 mg/kg/tl.iy:
7 364 7366
M 4.86 H 4.46
12.9 12.0
7384 F 4.92 7)8 3 F 4.71
13.0 13.0
Me.in
4.74
12.7
10 mg/kg/ilnv
736) 74 58
M 5.04 M 5.70
13.6 12.6
732 7381
F 5.47 F 5.65
13.4 13.5
Mivin
5.47
0 mu/kg/ilny
13.3
7367 7455
M 01eil. week 7 M 3.84^ h 9.7
7382 7387
F IMeil, weck 11 I- Died, week 12
Heim
3.84 9.7
UM) mg/kti/d.-iy:
7361 7456
M Died, week 5 M O lid , week 2
7335 7381
F Died, week 3 F Dt cd. week A
37 37 16 w> 37
37 14 19 37 37
Alt 40 40 19 40
30
30
217 0 . 2 218 0 .3 170 0 .4 234 0 .3 210 0 .3
299 0.1 278 0 .2 313 0 .2 248 0 .2 285 0 .2
214 (1.2 218 0 .3 219 0 .3 212 0.1 216 0 .2
261 0 . 2
261 0 . 2
11 10 II 11 11
11 11 11 11 11
II 11 II II 11
30
30
32
7.82 20
0
25
12.84 10
II
25
8.41 16
0
2(1
8.51 18
i
26
9 . 4 0 16
0
24
7 .3 3 24
0
26
5.44 25
D
28
18.21 16
0
24
8 . 3 5 10
0
26
9 . 8 3 19
0
24
8.41 34
0
2J 20.18 4 0
23 10. 72 3) 0
27
8 .5 2 30
0
24
11.96 25
(1
65 10.14 36 0
65
10.14 36
0
74 85 79 80 80
71 74 76 82 76
60 94 51 64 67
54
54
4
2
i\ 76 LM
v>
4 1 0 70 ;v 14
4 1 0 76 ) i 16
0 1 0 77 7.7 lb
\ 1 1) 74 26 w.
4 1 0 76 27 15
0
0
1 /(. 71
15
5
3
(1 79 26
33
5 3 0 79 28 15
3 2 0 78 27 15
4
2
0 79 7 7
14
2
(1
0 70 22
32
11
s
0 73 24
34
4 1 0 fd> 24 r
6
2
0 73 24
34
3
7
0 78 24
12
3
7
0 78 25
32
BEST COPY A V A Il ABLE
n7-o<m
|*2+ P o l k l o c y t n s l s
r 2 Nuclea ted et y llirm yl es/IDO l e u c o c y t e s The d l f f e r c n l l u t l e u c o c y t e m e a n s h a v e b e e n nd}MKtc() t o e i j ua l 1002.
0) OQ (t>
F C - 143:. TABLE 8.
Biochemistry
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Means and Significance of Biochemical Values.
Month of Study
Control
3 mg/kg/day 10 mg/kg/day
Page 21 30 mg/kg/day
Glucose, mg/100 ml
B.U.N., mg/100 ml
Aik. Phos., int' 1 units/1
S.G.O.T., int'l units/1
S.G.P.T. i n t 'l units/1
Cholesterol, mg/100 ml
Total Protein, g/100 ml
Albumin, g/100 ml
Sodium, meq/liter
Potassium, meq/liter
Chloride, meq/liter
y-G.T.P. , Sigma units/ml
C.P.K., Sigma units/ml
Inorganic Phosphate, mg/100 ml
1 3 1 3 1 3
1 3
lb 3C
1 3 1 3 1 3 1 3 1 3 1 3 1 3
1 3
1 3
89 81 23.0 27.6 597 851
29 45
15 31
165 165
7.94 8.21 4.78 4.82 153 151 5.1 5.5 112 113 61 44
9 7
7.9 6.9
117* 96 21.2 20.2
847 783
35 41
21 31
154 141
8.23 8.24 5.05 5.12 152 154 5.1 5.6 110 112 49 38
14 6
7.2 6.3
104 88 22.5 22.0
601 743
34 35
34* 34
158 154
8.66 8.43 4.66 5.17 155 159** 5.2 6.0 113 114 47 51
16 9
7.0 7.3
122 66a 26.1 22.6a
365* 360a
59** 88a
44 46a
174 240a
8.36 5.52a 4.28 2.00a 152 150a 5.7 5.9a 112 113a 33 49 a
19* 10a
6.7 5.0a
*Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01.
aValue not used in statistical analysis due to only one animal surviving.
b I.U./l cSigma units/ml
001745
F C-143 :
Ninety Day Subacute Rhesus Monkey Toxicity Study.
TAHI.B 9 .
In d ivid u al Biochemical Values - Control 1.
Group,
Alk. l'h o s .
Monkey
01 ucose R.U.N.
in t'l
Number Sex mg/lUO ml mg/100 ml u n i t s / 1
S.C.O.T. In t'l
u n its/1
S.G.F.T. in t' l
u n its/1
Choies- Total terni Protein
m g/100 ml g / 100 ml
Albumin g / 100 ml
Fotas- r.blo- Inorganic Sodium sium r id e Phosphate moc|/l meq/1 me|/ l mg/100 ml
y-C.T.I*. Sl|>mn u/ntl
Creai In hie
l'hosphuk Lnnse KIgm.i m/ imI
Con t ro 1:
7362 7365
H H
7336 7386
F F
Mean
3 mg/kg/day:
7366 7366
M M
7386 7385
F F
Mean
10 mg/kg/day:
7363 7658
M M
7328 7383
F F
Mean
30 mg/kg/day:
7367 74 55
M M
7382 7387
F F
Mean
100 mg/kg/day
7361 7456
H M
7335 7381
F F
He an
94 82 79 85 85
m 71 96
107 96
89 180 98 98 116
108 110 132 117 117
93 100
75 119
97
41.0 16.7 24.0 21.0 25.7
19.0 28.7 22.0 22.0 22.9
27.2 26.2 20.0 27.3 26.7
26.9 26.0 27.9 23.8 25.7
29.0 23.0 28.0 22.1 25.5
780 659 915 960 829
880 580 5 70 1320 838
1167 806 776 581 833
970 687 641 978 819
598 799 570 1233 800
40 99 61 88 30 80 39 86 43 88
42 94 60 89 38 106 60 76 50 91
46 118 63 136 26 75 31 91 42 105
47 114 37 86 40 79 45 138 42 104
43 80 40 104 40 96 40 103 41 96
219 8 .6 8 123 9.50 185 9 . 5 2 190 8.52 179 9 .0 6
197 9 . 0 8 172 9 . 1 2 133 10.12 154 8 .72 164 9 .2 6
237 9.84 107 10.08 189 8 .4 8 168 8.32 175 9 . 1 8
150 9 .3 8 205 9.50 176 11.10 194 9 .4 4 181 9 .8 6
155 8 . 6 0 202 9 .0 0 151 8 . 9 8 124 9 . 6 0 158 9 .0 5
5.40 4.30 5.30 5.12 5.03
5.28 5.80 5.19 4.80 5.27
5.10 3.99 5.14 5.25 4.87
5.60 5.31 5.72 5.60 5.56
5.00 5.69 5.19 4.89 5.19
160 5.0 m 155 5 . 3 110
156 4 . 3 110 162 5 .0 111
158 4 . 9 111
155 4 . 3 108
157 4 .9
108
162 6 . 0 158 5 .2
113 116
158 5.1 111
167 6.2 150 4 .9
157 4.4 159 5 . 1
158 5.2
117 107
109 112
111
170 6 .2 163 5 .3
165 5.5 155 3.9
163 5.2
116 Ul
112 113
113
159 5 .9 157 4 .5
157 5 .2 159 5 .2
158 5 .2
116 109
111 112
112
6.5 6. 7 6.5 6.5 6.6
5.0 7-1 6.1 5.4 5.9
6.7 7.7 6.3 6.0 6.7
6.9 6.6 6.8 5.4 6.4
6.9 5. 7 5.6 6. 7 6.2
67 44 41 17 47
50 30 32 41 38
78 55 51 59 61
65 59 43 39 52
64 44 58 47 53
15 18 85 16 34
12 26 16 29 21
16 14 34 6A 32
15 9 18 16 15
17 22 20 10 17
Page 22
001746
137-090
ro-1Vi:
Ninety Day Subacute RIIPsua Monkey Toxicity Study.
TABLF. to
I n d i v i d u a l U iociiem lcal V alu e s - I Month.
Group,
Alk. Flios.
Monkey
Clucose
B.11.N.
Int ' 1
Number Sex m g/100 ml mg/100 ml uni t s / l
S.G.O.T. I n t11
lflllls/1
S.G.P.T. ln t'l
Choies- Total t e r n i P r o te in Albumin
mg/100 ml g / 100 ml g /1 0 0 ml
P o t a s Ch l o Sodium sium r id e mej/ 1 roeq/1 meq/l
Inorganic
Phosphate y- c .t . p . mg/100 ml Sigma u/ml
CreaiIn Ine Phosphokinase
Sigma u/mi
Control :
736Z
M
87
33.9
611
27
18
191 7.30
6.82
153 5.6
117
6.6
81
7 365
M
86
16.2 626
33
17
121 8 . 6 0
6.11
153 5.6
111
8.6
50
7336
F
87
23.9
672
25
15
162 7 .90
6.89
168 6 .2
109
8.6
68
7386
F
96
16.9
680
31
10
206 8.15
5.30
158 5 .6
112
8.1
66
Mi>an
89
23.0
597
29
15
165 7.96
6.78
153 5.1
112
7.9
61
3 mg/kg/day :
7366
M 112
18.0
9 70
30
36
173 8.15
5.20
150 6 .3
106
6.9
77
731.6
M 131
23. 3
693
39
19
168 8.05
5.62
156 6 . 9
110
6.6
26
7386
F 105
26.2
539
30
15
161 8 .7 0
6.85
152 5 . 8 111
7.5
67
7385 F 120
19.1
1185
60
13
153 8.0 0
6.72
152 5 . 2 116
7.8
67
Henn
117
10 mg/kg/day:
21.2
867
35
21
156 8 . 2 3
5.05
152 5 . 1 1 10
7.2
69
7363
M
98
26.9
552
60
35
219 9 .6 0
6.62
16) 6 . 3 118
6.9
65
7658
H
97
22.5
732
60
63
136 9 . 0 5
6.32
151 6 . 9
109
8.6
66
7328
F
98
22.7
660
23
19
165 8 .2 0
6.50
152 6 . 3 111
5.6
37
7383 F 126
20.0
680
31
37
132 8 . 0 0
5.19
156 5 .2 113
7.2
63
Meati
106
22.5
601
36
36
158 8.66
6.66
155 5 . 2
113
7.0
67
30 mg/kft/day:
7367
M 112
35.2
376
68
30
180 8 .2 0
6.70
157 6 . 0
110
6.6
60
76 55
M
86
21.0
322
61
80
177 8.55
3.22
168 5.2
112
6.9
60
7382 F 106
25.2
600
83
63
161 8 .1 5
6.21
169 5 . 9 1 11
6.0
28
7387 F 185
22.8
360
65
23
179 8 .5 5
5.00
153 5.6
116
7.2
26
Mean
122
26.1
365
59
66
176 B. 36
6.28
152 5. 7 112
6.7
33
100 mg/kR/day
7361 7656
M Died, week 5 M Died, week 2
7335 7381
F Died, week 3 F Died, week 6
8 11
7 11 9
6 7 39 7 16
7 20 26 16 16
25 16 17 18 19
Page 23
001747
37-090
hi:-IV:
Ninety Day Subacute Klicsus Monkey Toxicity Study.
TABLE I I .
In d iv id u a l Biochem ical Value - 3 Montila.
Croup,
Monkey
Glucose
Number Sex in g / 100 ml
Aik. Plios.
H.U.N.
in t'l
m g/100 ml u n i t a / 1
S.G.O.T. lot *1
unita/1
S.fi.P.T. S 1f.nia
uii I t s /m l
Cimi e s T o t a l terni Protein
mg/100 ml g / 1 0 0 ml
Albumin g / 1 0 0 ml
Potas Ohio-
Sod 1urn sium r i d e I1KM|/ l m eq/1 moq/1
Inorganic Plionphate y- g . t . i*. m g/100 mL Sigm.i u/mi
CroatInlne
Pbos|iboklnase Sigma u/ml
Control :
7362 7365
M M
95 77
61.9 17.6
7336 7386
F F
67 86
33.1 18.1
Mean
81 2 7 . 6
3 mg/kg/day:
7366 7366
M M
106 ill
17.1 18.1
7386 7385
F F
96 76
23.6 22.0
He an
96 20.2
10 mg/kg/day:
7363 7658
M M
87 88
26.9 21.1
7328 7383
F F
75 100
21.8 20.0
Mean
88 2 2 .0
30 mg/kg/day:
7367 7655
M M
Died, week 7 66 2 2.6
7382 7387
F F
Died, week 13 D ie d , week 12
Mean
66 22.6
100 mg/kg/day:
7361 7656
M M
Died, week 5 Died, week 2
7335 7381
F F
Died, week 3 Died, week 6
806 766 786 1068 851
1092 596 632 1016 783
936 936 626 676 763
360
360
55 66 67 30 39 26 39 2 7 65 31
61 28 39 33 39 33 63 29 61 31
62 62 38 31 30 25 30 37 35 36
88 46
88 46
197 7.59 135 9 . 1 8 150 8.31 177 7 .7 6 165 8.21
166 7. 72 126 8.09 132 8 . 9 3 162 8 .2 1 161 8 .26
196 8 .6 6 139 9 .7 1 155 7.93 128 7.62 156 8 .6 3
6.99 6.60 6.98 6.90 6.82
5.09 5.52 6.91 6.97 5.12
5.61 6.69 5.27 5.11 5.17
150 5.5 116
151 6.1
113
151 5 .1 153 5.1
116 109
151 5 . 5 113
153 5 .8 153 5.5
153 5.2 155 6 . 0
156 5 .6
112 109
112 116
112
166 7.0 159 6 .2
156 6 .8 158 5 .8
159 6 . 0
119 112
110 113
116
5.6 8.0 7. 3 6.7 6.9
7.0 5.3 6.5 6.6 6. 3
8.0 9.0 5.6 6.5 7. 3
260 5.52
2.00
150 5 .9
113
5.0
260 5.52
2.00
150 5.9 113
5.0
37 53 62 65 66
65 51 27 29 38
63 52 60 68 51
69
69
7 8 7 6 7
7 6 6 6 f>
7 12
7 9 9
10
10
Page 24
001748
137-090
FC-143:
TABLE 12.
Urinalysis
Volume, ml
PH
Specific Gravity
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Page 25
Month of Study
Means and Significance of Urinalysis Values.
Control
3 mg/kg/day 10 mg/kg/day
30 mg/kg/day
1 35
33 51
3 71 94 51
1 8.5 8.5 8.1 3 8.3 7.6 8.2
1
1.028
1.026
1.026
3
1.018
1.015
1.024
41 40a
8.1 6.6a
1.026 1.031
137-090
aValue not used in statistical analysis due to only one animal surviving.
001749
FC-141:
TABLE 13.
Group,
Color
Monkey
Vo 1unte
miti
Nunilie r Sex ml Appetir.
N in e ty Day Subacute Rhesus Monkey T o x i c i t y Study.
Individual Urinalysis Values - Control i.
Uric
Spec.
Oeetill
l.etieo- Erytliro-- Kpl.
T r i p l e Cal .
Ac Iti
pii Grav. P r o t e in (Mucose Blood Ketones c y t c s
cytes
C e l l U r ates Fltos. Oxnl . C r y s t a l s
Control :
7362 7365
M 100 M 28
7336 F 27 7386 F 70
Mean
56
3 mg/kg/dny :
7364 7366
M 25 M 25
7384 7385
Mean
F F
215 35
75
10 mg/kg/day:
7363 7458
M 20 M 50
7378 7181
Mt*in
F F
35 35
35
30 mg/kg/day:
7367 7455
7382 7387
Mean
M M
F F
20 35
20 48
31
100 mg/kg/day:
7361 7456
M 21 M 25
7335 7381
F 25 F 40
Moan
28
l.S-cl LS-cl
1.S-C l.S-cl
7.6 1.010 7.2 1.037
7.0 1.036 8.4 1.023
7.6 1.027
N N
N N
l.S-cl LS-cl
I.S-C LS-cl
7.8 1.032 7.2 1.035
8.3 1.026 8.3 1.020
7.9 1.028
N N
N N
LS-cl LS-cl
LS-cl LS-cl
7.7 1.020 7.5 1.036
7.8 1.036 8.2 1.020
7.8 1.028
LS-cl LS-cl
LS-cl LS-cl
7. 1 1.050 6.8 1.030
7.0 1.055 8.2 1.030
7.3 1.041
N N N N
N N N N
LS-cl LS-cl
LS-cl LS-cl
7.6 1.035 7.1 1.042
7.2 1.041 8.1 1.042
7.5 1.040
N N
N N
N tr N NNH
-
occ
occ F
occ
"
1-3
OCC F
occ
N N 1+ -
N A+ N
-
- - occ occ ore - occ occ occ H
N tr N N tr N
NNN NNN
-
-
-
occ F
FF
-
occ F
o c c ore
-
occ ore
occ
-
occ F
occ
N tr N N tr N
N tr N N 31 N
-
-
-
occ F
F
-
occ F
occ F
-
1-3 F
occ M
-
occ occ
occ
N tr N
-
1-3
1-3 occ
occ oce
N tr N - 1-3 1-3 occ F
NNN NNN
-
-
1-3 F
occ
-
oec K
occ oce
N tr N
- occ - F occ
N t r 3
-
-
occ F
occ F
N t r 1+ N 1+ 1+ -
1-3 - occ occ F - 1-3 occ occ M
M M F H
H H H M
M M F M
Page 26
001750
tr - Trace
1+ - Trace to s l i g h t 2F - S l i g h t t o moderate 3F - Moderate 4F - Marked
S - Straw LS - Light Straw l)S - Dark Straw I.Am - Light Andier OAm - Dark Amher cl - Cloudy
(' - Gl e u r
N - Ncgat i ve
F - Few L - Loaded M - Many R - Bare o r e - Orcas 1o n a 1
<}NS - Q u an tity not s u f f i c i e n t norm - Normal
- None seen
FC-141:
TABI.li 14
Uroup, Monkey Number
Sex
Volume ml
Color and
Appear.
Ninety Day Subacute Rhesus Monkey Toxicity Study.
I n d i v i d u a l U r i n a l y s i s Values - I Month.
Uric
Spec.
Ocelli t
Leuco Erythro lipl.
Triple Cal.
Ac 1il
pll Cruv. l'r u te In Glucose Ulood Ketones c y t e s
cytes
(*e 11 s U rates VUo h . Oxa 1. C r y s t a l s Hud er
Coin yol :
7162 7365
M M
7136 7386
F F
Moan
3 nig/kj'/duy:
7364 7366
It M
7384 7385
F F
Mean
10 mg/kg/duy :
736 3 7458
M M
7328 7383
P F
Meun
JO wg/kfi/diiy :
73b 7 7455
M M
7182 7387
F F
Mean
HW) mg/kg/duy:
7J61 7456
M M
7335 7381
F F
55 1.S-C 35 1.S-C 20 LS-C 30 LS-C 35
20 LS-C 20 LS-C 40 OS-cl 50 L S - c l 33
65 l.S -cl 35 LS-C 55 L S-el 50 LS-cl 51
30 LS-C 30 LS-r.l 60 LS-cl 45 LS-cl 41
Died, week 5 Oled, week 2 Oled, week 3 Oled, week 4
8.5 1.021 8.5 1.028 8.5 1.033 8.5 1.030 8.5 1.028
8.8 1.019 8.5 1.036 8.0 1.021 8.5 1.027 8.5 1.026
7.5 1.023 8.0 1.028 8.5 1.026 8.5 1.028 8. 1 1.026
7.5 1.024 8.0 1.026 8. 3 1.022 8.5 1.032 8.1 1.026
N N N N
N N 1+ H
N N N N
N N N N
NN NN N It N lr
NN NN N 41 NN
NN NH NN N tr
HN NN NN NN
N NNN-
NN2+ N-
NNNN-
NN NN-
occ occ occ M
-
- occ
F occ
-
1-3 F
FF
-
occ M
FM
occ F - occ F
H-12 - F - occ F
M occ F
occ occ M
OCC -
o cc
-
-
1-3
occ
F OCC
o cc F
occ occ
occ occ
M M
M M
- occ occ occ OCC occ M F -
occ
-F
F-
-
occ F
occ occ
-
-
-
-
-
-
-
-
-
M M M M
M M H M
M M M M
L M M M
Casts
Page 27
001751
tr - Trace 1+ - Trace t o s l i g h t
2+ - S l i g h t t o moderaLe
3t - Moderate
4i - Marked
s - Straw
I.S - Li Kill Straw OS - Oavk Straw I.Aiu - Light Ainhe r OAm - Oavk Amlier c l - Cloudy
C - Clear
N - Negative F - Few
L - Loaded
M - Many R - Rare uec - Occasional
QMS - Q u an tity not s u f f i c i e n t
norm - Normal - Hone se e n
FC-- 143:
TABLE 15.
Group, Monkey Number
Sex
Volume ml
Color and
Appear.
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Individual U r in a ly sis Values - 3 Months.
Urie
Spec.
Occult
Leuco E rythro K|l.
Triple Cal.
Arid
pll Grav. P r o t e in G lu cose Blood Ketones c y t e s
cytes
C ells Urates Phos. Oxal. Crystals Bactc
Control:
7362 7365
M M
7336 7386
F K
Mean
3 mg/kg/day:
7m 7366
M M
7 386 7 385
K F
Mean
10 mg/kg/day:
7363 7458
H M
7328 7383
F F
Mean
30 mg/kR/dny:
7367 7455
M M
7382 7387
F F
Moan
100 mg/kg/day:
7361 7456
M M
7335 7381
F F
110 I.S-C 40 LS-cl 85 I.S-C 50 l.S-C 71
50 LS-C 150 I.S-C 125 LS-C
50 1.S-C 94
40 LS-C 35 LS-cl 50 LS-C 80 LS-cl 51
Died, week 7 40 S-C Died, week 13 Died, week 12 40
Died, week 5 Died, week 2 Died, week 3 Died, week 4
8.2 1.012 8. 1 1.029 8.2 1.015 8.8 1.016 8.3 1.018
6.0 1.020 7.9 1.007 8. 1 1.010 8.5 1.021 7.6 1.015
8.0 1.027 8.7 1.022 9.0 1.029 7.0 1.019 8.2 1.024
6.6 1.031
6.6 1.031
N N N N
N N N N
N N N N
N
NN NN
NIF -
- occ F OCC 1-3 F
occ F-
NN
tr -
-
OCC F
occ F
N 3F N o c c - o c c F
FF
-
-
-
NN NN
NN N tr
tr N-
NN-
- - F occ -
-
occ F
occ -
- occ F occ 1-3 M
F FM
-
NN NN
NN NN
NN-
NN-
- occ F - -F
occ occ F occ occ F
occ OCC occ -
occ --
-
-
-
-
N It N 1-3 occ - F
M occ
-
M M M M
M M M M
M M M M
M
Casts
Page 28
001752
tr - Trace 1F - T r a ie t o s l i g h t 2F - S l i g h t to moderate 3F - Moderate
4 F - Marked
S - St raw I.S - Light St raw DS - Dark Straw I.Aiii - Light Amlier
DAm - Dark Anther el - Cloudy
/t
N - Negative F - Few 1. - le a d e d M - Many
R - Rare oec - Occasional
QNS - Quant i l y not s u f f i c i e n t norm - Normal
- Nunc seen
FC-li3: TABLE 16.
BEST COPY AVAI1ABLE Page 29
Ninety Day subacute Rhesus Monkey Toxicicy Study. Sunnary of Gross Necropsy Observations, Terminal Sacrifice.
0 mg/kt. dav
Site Lesion
N'o Gross lesions
>NU, V tl
.c! "" S"}i
Z Z!
CM J"V
C <--
*
30
r*. I1** r*s.
:terr.ai swelling, eye ares alopecia dehydrated emaciated red vaginal discharge scab, racial area
Lung mite lesion adhes ions dark red foci/reddish purple area yellow, white foci nodules
XX X
X
Heart nemorrkage, subendocardial gelatinized fat, endocardial atrophy
Lymph Nodes enlarged reddish black in color
X
Thymus atropr.y
Abdominal Cavity depletion or fat
itjmacn dark rad foci erosion, mucosa, pyloric portion mucosal hyperemia yellcvisn gelatinous material, fur.dic portion hemorrhage, fundic mucosa ulcers
Small Intestine greenisn-grav mucoid material dark red/brovn mucoid material liquid, blood tinged fluid reddish brown in color congestion, mucosa hemorrhage, mucosa
large Intestine congestion, mucosa h e m e r m a g e t mucosa dark reedish black foci semi solid, blood stained contents
3 ag/kg/dav 10 mg/kg/dav 30 mg/kg/dav 100 ns;kg/dav
V
X X V
X
X X XXXX XX
X XX
XX
x XX
X
VX X
XX X X
X x
X
X
x
xx
X
XX XX X
*Died on Study
001753
FC -i3: TA BLE 16. Cont
BESTCOPYAV4IMBLFage 30
N'inety Day Subacute Rhesus Monkey Toxicity Study.
Su.nmary of Gross Mecropsy Observations.
Pancreas accessory spleen
Liver cvsc brownish color accentuated lobulations granular surface yellowish mottling reddish yellow color
= w
>1*s
"1
SHi'1i
J Z Z
0 m g/kg/dav zz
?N
C
r** fs.
O
0r*-00
3 m g/kg/day
Z=
.y
a
X
vT> X
p*
10 n g /k z /d a v
zz
is.
-- i"*
r.XT3*.i
XNe f*.
X<r*-*i
30 m g/kg/dav
nC z
Si
sc
r in SJ rr**s
100 n g /k g /d av
SI Z
sc
sc
is.
SlCb
r-r-Xw> PV
X X XX X X X
Kidneys brownish discoloration
x
subcutaneous edema, abdomen subcutaneous hemorrhage, abdomen
L 3 '-0 :
''Died on Study
001754
FC-143:
N i n e t y Day S u b a c u t e K hesus Monkey T o x i c i t y S t u d y .
TAIII.K 17.
Absolute ((rants) nttd Relative (X Body Weight) Organ Weights, Terminili Sacrifice and Deal Its.
Croup, Moiitcy
Terminal Sacr 1flee
Conirol:
7162
7365
dean 73 Jb 7386
Menu 3 mg/kg/day: 7364 7166
Mean 7384 7385
Menu
10 mg/kg/daj:
7361 7458
Mean 7128 7383
Mean
-'ll
7455
Deaths: 30 mg/kg/day: 7367 7382 7387 100 mg/kg/day: 7361 7456 7335 7381
Sex
M M
F F
M M
F k'
M M
F F
M
M A* F
M II F F
Hotly Wt. kg
Spleen 8'
%
1.1ver gX
Adrenals g XxlO
K Icliu-ys 8X
VsLos/
B Ov.irlcs
fi" "
xlO
1.25 3.85 3.55 3.40 3.50 3.45
4.10 2.65 3.38 3.70 1.45 1.58
3.80 3.25 3.53 1.55 3.70 1.63
2.40
2.10 -5
2.25
2.40 2.70 2.05 2.60
2.15 7.87
5.11
5.03 3.87
4.45
0.07 0.20
0.14
0.15 0.11
0.13
4.67 1.87
3.2 ?
6.82 2.94
4.88
0.11 0.07
0.09
0.18 0.09
0.13
2.39 4.91
3.65
4.06 3.99
4.0)
0.06 0.15
0.11
0.11 0.11
0.11
1.50
0.15
70.73 79.15
74.94
84,79 77.77
81.28
2.18 2.06
2.12
2.49 2.22
2.36
91.40 63.17
77.29
102.64 67.25
84.95
2.23 2.38
2.31
2.77 1.95
2.16
87.25 82.30
84.78
81.00 85.35
84.18
2.30 2.53
2.41
2.34 2.31
2.12
70.76
2.95
1.45 3.01
1.97
0.07 0.13
0.09
1.65 1.76 2.49 3.05
0.07 0.07 0.12 0.12
75.33 112.87 85.17
3.59 5.02 3.79
/9.02 85.08 74.28 82.58
3.29 3.15 3.62 3.18
0.65 0.7 I
0.68
-
0.62 0.62a
0.20 0.18
0.19
-
0.18
0. IBa
0.77 0.82
0.80
0.7R 0.55
0.67
0.19 0.31
0.25
0.21 0.16
0.19
0.74 0.67
0.71
0.66 0.86
0.76
0.19 0.2!
0.20
0. 19 0.23
0.21
0.84
0.15
1.63 1.74
1.20
0.78 0.77 0.53
1.59 1.45 1.01 1.16
0.66 0.54 0.50 0.45
11.82 17.06
14.44
13.80 19.58
16.69
0 . 3b 0.44
0.40
0.41 0.56
0.48
19.76 12.40
16.08
17.60 14.44
16.02
0.48 0.47
0.47
0.48 0.42
0.45
16.84 16.54
16.69
15.32 13.56
14.44
0.44 0.51
0.48
0.43 0.37
0.40
16.85
0.70
16.34 19.03 15.96
21.88 14.77 15.40 18.28
0.78 0.85 0.71
0.91 0.55 0.75 0.70
0.85 1.21
2.04
0.28 0.77
0.28
0.01 0.08
0.06
0.82 0. 77
0. 0
1.66 0.85
2.26
0.18 0.16
0.17
0.09 0.03
0.06
0.49 0.46
0.48
1.75 1.99
1.87
0.29 0.19
0.14
0.05 0.06
0.05
0.82 1 .05
0.94
1.16
0.05
1.94 0.21
0.12
0.09 0.93
1.42
1.37 0.71 0. Ill 0.13
0.06 0.03 0.51 0.50
Page 31
001755
117-090
--
Croup mean relative organ v.-lights simun In this table were cn 1ni 1.( organ weight:-. *SI | ;nl f l e a n t 1v d i f f e r e n t f r o m C o n t r o l g r o u p mean, p-.-0.D5. **S Ijpil f l e a n t ly ill I Cerent from C o n t r o l gr oup mean, p - 0 . 0 1 .
ly averaging the !nd ivi timi 11 y cn leu 1aled re 1at 1ve
NoI Included In analysis. - *< l i n t a v a l I a b I e
Ml-1VI s
TAlll.K 17. Coni.
0roii|i, Monkey Number
Terminal S a c r i f i c e :
Control:
7 162 7165
Mein 7116 7111b
Menu 1 mg/kg/day: 7164 7166
Mean 7184 7185
fk'au 10 mg/kg/day: 7161 7458
Mean
7128 7181
Mean
10 mg/kg/day 3 : 7455 Heaths: 30 mg/kg/day:
7367 7382 7387 100 mft/kR/iJny: 7361 7456 7335 7381
N i n e t y Day S u b a c u t e R h e su s Monkey T o x i c i t y S tm ly .
Ab s o l ut e (Crams) aiul R e l a t i v e (Z Body Melglit) Organ Wei ght s, Terminal S a c r i f i c e nml De a t hs .
Body Wt.
Sex kg
_ J l e ^ r t ____
g .............
'X
Thyroid/
Pajralhjrrold
g""
' 2x10
_____ B r a i n g"
Z
M
3.75
11.69
0.36
M
3.85
18.17
0.47
3.55
14.93
0.42
F
1.40
15.30
0.45
K
3.50
14.75
0.42
3.45
15.03
0.44
1.050 0.296
0.673 -
0.819
0.8193
0.32 0.08
0.20 _
0.24
0.24
M
4.10
18.90
0.46
M
2.65
12.70
0.48
3.38
15.80
0.47
V
3.70
16.87
0.46
F
3.45
15.19
0.44
3.58
16.03
0.45
0.893 0.178
0.616
(J.694 0.543
0.619
0.22 0.14
0.18
0.19 0.16
0.17
M
3.80
15.10
0.40
M
3.25
14.14
0.44
1.211 0.488
0.32 0.15
3.53
14.62
0.42
0.850
0.23
F
3.55
11.85
0.31
F
3.70
U .69
0.12
0.461 0.537
o .n 0.15
3.63
11.77*
0.12**
0.499
0.14
M
2.40
10.50
0.44
0.292
0.12
M
2.10
10.39
0.49
F
2.25
11.93
0.53
F
2.25
10.21
0.45
M
7.40
14.54
0.61
M
2.70
15.55
0.58
F
2.05
11.44
0.56
F
2.60
12.95
0.50
0.532 0.543 0.845
0.791 0.718 0.479 0.417
U . 25 0.24 0.38
0.33 0.27 0.23 0.16
87.04 90.39
88.72
82.64 81.55
82.10
2.68 2.35
2.51
2.41 2.31
2.18
96.01 81.50
89.76
78.66 80.21
79.44
2.34 3.15
2.75
2.13 2.32
2.2 3
77.73 83.38 80.56 77.19 75.88 76.54**
75.01
2.05 2.57 2.31 2.17 2.05 2.11
3.13
82.27 83.22 91.45
92.43 95.42 74.28 86.20
3.92 3.70 4.06
3.85 3.53 3.62 3.32
I'l l ill I a r y g Zxlir
0.053 0.063
0.058
n.oso 0.073
0.06:!
0 . U. 0.16
0.16
0 . 15 0.71
0 . 18
Cl ,0HM 0.051
0.066
0.086 0.051
0.070
0.20 0.19
0.19*
0.2 1 0.15
0.19
0.063 0.047
0.055
_
0.071
0.07I3
0.17 0 . 14 0.16
0.19 O.IR3
0.049
0.20
(1.068 0.070 0.057
0.072 0.046 0.056 0.082
0.32 0.31 0.25
0.30 0.17 0.27 0.32
Page 32
001756
Croup mean r e l a t i v e organ w e i g h t s shown In l l i l s t a b l e were c a l c u l a t e d by a v e r a g i ng t he i n d i v i d u a l l y c a l c u l a t e d r e l ative organ weights. *SI go ITI cant l y d i f f e r e n t from Cont rol p.roup mean, p 0 , 0 5 . **S I gnl t l eant ly d i f f e r e n t from Cont rol group mean, p l l . t l l .
nNot Incl uded In a n a l y s i s . - - Not a v a i l a b l e
Page 33
FC-143: TABLE 18.
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
firoup. Monkey Number 7362
7365 7336 7386 7366 7385 7363 7328 7383 7367* 7382* 7387* 7361* 7381*
Tissue Lesion
Control U I Xl X X !* !
3 ag/Wdav X X U- U.
r
50 c-i
r-u r-
10 mg/kg/dav X X b. h.
oU"oV -rav*
30 mg/kg/day X X tu Cu
U*5 vrs n*
100 mg/kg/dav x X u. u. ** 50 u*. tri ri
cn r** r<-
Brain focal perivascular lymphoid
infiltrates
11 11
i1i1
1 3
11
i 1_ 1 1
i 1i1
Spinal cord
Peripheral nerve
Sarcocystis sp. in ocular muscle
focal lymphoid Infiltrates in sclera
focal lymphoid infiltrates in lacrimal gland
focal lymphoid infiltrate in palpebral conjunctiva
cystic tarsal gland
11 11
i1i1
111 1
i1 11
i1 i1
11 11
i1 i1
111 1
i1 11
i1i1
1 1111
x
x 3
1 11111
3
33 3
3
1
X
Pituitary diffuse congestion small parenchymal cyst
111111111
111 x
1 3 33
1 33
Thyroid foci of interstitial lymphoid infiltrates focal interstitial fibrosis diffuse congestion
111
1 11111111
32 3
11
2 2
3
3
Parathyroid diffuse congestion
1111
11
11
3
Tongue foci of inflammatory cell infil trates in lamina propria and mucosal epithelium foci of inflammatory cell infil trates in muscle Sarcocystis sp.
1
3 2
3
11
23 23
3 x
33
32 x
2
11 11
22 2
137-090
Code:
x - condition presenc a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - not available *Died or sacrificed in extremis
01757
FC-143: TABLE IS. Cont.
Ninety Dy Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Page 34
Tissue Lesion
to 0) XI c-.o>.<uu
3 JJ
1-0 3 OIZ
Control z Z be
in s0
10 S0 <n
en ps
en rs
er*ns
b. -0 30 en is.
foci of inflammatory cell infil trates in mucosal epithelium and tonsillar crypt
Sarcocystis sp. in muscle Gongylonema sp. in mucosal
epithelium atrophy of lymphoid follicles
3
42 X
3 X
3 ng/kg/dav Z Z Ok Ok
10 .ng.'kg/dav Z Z b. Ch
>0 <T in
vO 39 CO
en rs
en rs
en rs
en rs
en 00 00 en
<0 en r-
m rs
CM <rns
eono rs*
i
4333344
30 ag/kg/day Z Z be b.
in
* fs
4 esj
rs
1/3 10 00 30
rs
erns
en P'S
en rs
_1
23
4
100 mg/kg/dav Z Z b. be
* * * 4
>0
in *0 en OO
rs
en rs
en rs
en rs
.._
Adrenal foci of dystrophic mineraliza tion diffuse congestion diffuse lipid depletion foci of lymphoid infiltrates in sinusoids acidophilic degeneration of individual to small groups of cells
3322 3
1 32
2 23
32 2
33
2
343 555
2
3 55
43 55
23
Trachea
foci of inflammatory cell infil
trates in lamina propria
3
Salivary gland focal interstitial lymphoid infiltrates diffuse congestion decreased cell size, loss of cytoplasmic granules
1
23
2
1
34 3
1
223
3 23 33
11
33
Lung
acarlan pigment ''peribronchial,
peribronchiolar, perivas-
cular)
3 222
focal perivascular lymphoid
infiltrates
focal peribronchial/peribron
chiolar lymphoid aggregates
4434
lung mite in bronchiolar lumen X
X
interstitial pneumonia
34
4
diffuse congestion
foreign body pneumonia
5
focal hemorrhage
3
acute focal bronchopneumonia
4
numerous aggregates of pigment
laden alveolar macrophages
3222 3 334 3 3 34
5 3
?23 2 33
344 3 33
4
3 224
3 22 44
333
2 22
33 3 4 3
137-090
Code:
x - condition present a - autolyzed 1 not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - not available Died or sacrificed in extremis
0017S8
Page 35
FC-143: TABLE 18. Cont.
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations
Tissue Lesion
V3 rtl XU a. a a s -g -i
5sz
=
CN
\0
p*
Control x b.
m vO sO rs. p-.
be
'a oo r**
Heart
l
focal interstitial lymphoid
Infiltrates
3 33
focus of lymphoid infiltrate in
endocardium
focal subendocardial hemorrhage
atrophy of epicardial fat
3 ae/ke/d av X z b. b.
sO >3* sO 00 eo rv p* fN. re
l
233
10 mg/kg/d av X X b. be
m eo SO m
pr**
* SJ iSk ft
eo r*%
i1
1
3
30 ne /kg/d av X z be be
IT1 r-
C*N
r-
<pr*
r-.
p*i po* p*.
1
3
4
100 m g/kg/dav X X be be
**
sO
P-T pi
* m
*
r"> p-
S P*
1
22
3 44
Aorta
1l11
l111
111l
1111
11 1 1
S p leen
1l11
atrophy of lymphoid follicles
diffuse congestion
focal amyloidosis in lymphoid
follicles
increased amount of hemosiderin
pigment
l 111
l1 33
4 -* 4 4 334 3
3
44 44 44 34
3
Lymoh node
1 1 1 '1 1 1 1
atrophy of lymphoid follicles
increased amount of hemosiderin
pigment
3
neutrophil infiltrate in
sinuses
diffuse congestion
lymphoid hyperplasia
3
1111
11
4
3 3
4444
3
35 3
Esophagus
11
foci of inflammatory cell infil
trates in lamina propria
32
foci of interstitial lymphoid
infiltrates in muscularis
2
Gongylonema sp. in mucosal
epithelium
1 2 32
2
322 22 2 X
1
32
2
1 11 2
Stomach
foci of inflammatory cell infil-
trace in lamina propria
3u 33
diffuse congestion
foci of inflammatory cell infil-
traces in subaucosa
foci of inflammatory cell infil
trates in muscularis
foci of inflammatory cell infil-
crates in serosa
parasitic granuloma in omentum
focal mucosal hemorrhage
focal coagulation necrosis in
aiucosa
3344
4 3
4 34 3 2
4 43
3
3 X
2
33 33
2
137-090
Code :
x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - " not available *Died or sacrificed
3 24 3 3
3
G01759
FC -143: TABLE 18. Cont.
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Page 36
Tissue Lesion
Control
CO <u XI Z Z h* U*
a*
>1
ks
4
Z o
e
I
g2Z
<VrOn-
tSnOn
^
?nn
PS.
s0o0
^
3 ag/kg/day z z ft* a.
so >y m
psOn sm cn0 <X*>
rs. rs rs p^,
10 tng/kg/day
ZZ
fiu
Small intestine
1111
diffuse villous atrophy
focal hemorrhage
diffuse congestion
focal aggregate of brown pigment-
laden foamy macrophages in
mesentery
inflammatory cell infiltrates in
serosa
atrophy of lymph nodule
1
1 1111
30 ag/kg/dy
2ZSbfih
uin-i
if0*Nn0
*
fs
CrrOs>
100 ag/kg/day
ZZCfaEb
sm*O
r<*s
v--*O
rtns
pcr**nnsi
* pXpns
1
3 333
55 33 33
X
4 44
Cecum transmural inflammatory cell infiltrates diffuse congestion focal mucosai hemorrhage inflammatory cell infiltrates in serosa parasitic granuloma in muscularis atrophy of lymph nodule
1
1
11111
111
333
2
4 33 24
1
4
Colon
1111
diffuse congestion
parasitic granuloma in submucosa
transmural inflammatory cell
infiltrates
focal mucosal hemorrhage
atrophy of lymph nodule
111
1111
1
33 3
3
1
33 X
4
Rectum diffuse congestion Inflammatory cell infiltrates in muscularis atrophy of lymphoid nodule
Pancreas focal periductal lymphoid infiltrates focal interstitial lymphoid infiltrates diffuse congestion
Thymus
1111
1111
1111
1
32
1
33 32
111
3
1111
1111
1111
1 333
4
3 3
alia *>
33 3
137-090
Code;
x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - - not available *Died or sacrifie
001760
Page 37
F C - 143 TABLE 18. Cont.
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Tissue Lesion
Control 10 V XI z X Ch Eft*
in v> 33 en
r-*
Liver
portal inf lannatory cell infil
trates
333 3
parenchymal inflammatory cell
infiltrates
2 2 23
diffuse congestion
acidophilic degeneration of
individual to small groups
of hepatocytes
diffuse hepatocellular hyper
trophy with cytoplasmic
vacuolation
neutrophil infiltrates in
sinusoids
Group, Monkey Number 7362 7336 7364 7366 7385 7363 7328 7383 7367* 7382* 7361* 7335* 7381*
3 msc/kg/dav X X Sfte (he
T 00 <n r*
32 33 33
3
10 */kss/day X X Eft. Eft.
-3*
30 mx/kg/day X X Eh El*
m Pk, m c r** ps*
100 m g/kg/dav X X Eft. Efts
* sO IT PN.
332 2
2
1
2
332
4 33
3
32 33
3
33 3
Gallbladder
foci of inflammatory cell infil
trates in lamina propria
3343
3223
2333
laaa
aala
Kidney
focal interstitial lymphoid
infiltrates
22
2
multinucleated lining epithelium
in papillary ducts
XX
cyst in medulla
X
chronic interstitial nephritis
3
diffuse congestion
microlith in renal tubules
small foci of dystrophic miner-
alizar ion
2
334 2 X
23 23 X
2 22
433 22
22
3333 X
22
Urinary bladder
foci of inflammatory cell infil
trates in lamina propria
3 2 32
diffuse congestion
2323
11 33
i1
1
3
A 3 33
Testes prepuberal development chronic focal vasculitis focal perivascular lymphoid infiltrate
XX 4
XX
:< X 2
XX
XX
Ovaries small foci of dystrophic mineral ization diffuse congestion
1 2
11
11
1
2 3
11
137-090
Code :
x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 marked
6 - extreme - not available *Died or sacrifie
001761
Page 38
FC-143: TABLE 18. Cont.
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Tissue Lesion
Prostate focal interstitial lymphoid infiltrates focal lymphoid infiltrate in corpus cavemosum
Croup, s Monkey e Number X 7362 M I 7365 7336 7386 7366 7363 7383 7367* 7382* 7387* 7381*
Control
fa fa
3 ng/ktt/dav
X fa fa
5*fCsf0-f.)
0f0f 0U-01 n*. pv
10 m /k * /d * v
Z z fa fa
ieno ff
C0rr>N0-.
30 m g/kg/dav
X fa fa
tmn ri.
100 mg /k g /d a v fa fa
* n r-
* re*n
ruee*nnr.
11
33
23
23
2
3 22 3
Uterus diffuse congestion blood in uterine glands small foci of hemorrhage in endometrium brown pigment-laden macrophages in endometrium inflannatory cell infiltrates in endometrium proteinaceous fluid and inflam matory cells in uterine lumen
22 22
32
2
3 3
42
11
1
3
2
33
2
3
Vagina foci of lymphoid infiltrates in lamina propria and mucosal epithelium foci of lymphoid infiltrates in auscularis Sarcocyscis sp. focal lymphoid infiltrate in tunica adventitia diffuse congestion focal neutrophil infiltrate in aucosa
Skeletal muscle
1
Sarcocystis sp.
focal interstitial inflammatory
cell infiltrates
interstitial fibrosis
focal/aultifocal atrophy of muscle
increased sareolemma1 nuclei
34 2
11
33
2 x
44 3
3
23
25 3
1
x
3
Skin
brovu/black pigment in dermis
x xxx
dermal inflammatory cell infil
trates
2
diffuse acanthosis
33
diffuse congestion
hyperkeratos is
few large areas of hemorrhage
in subcutis
XXXX 33
33
3
3
XXXX 33
XXXX 333
XXXX
3 33
5
137-090
Code:
x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - m not available *Died or sacrificed in extremis
001762
Page 39
7382* V 7387* F 1 7361* M 7381* F 1
FC-U3: TABLE 18. Cont.
Sinety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Tissue Lesion
Control z z Ct* fcu
M lA
PA iS
seOn PS
m en fS
eo resn
3 mfc/ks/day z X fib Ct.
<vr en PS
seOn Ps
m PS
lA eo rns
10 rag/kg/dav z z a . Ct.
pa CO eo PA
<Pns
lA -rTs
CM PPAs
eo PPAs
3 0 mg/kg/dav zX UA P*s VA < Vrs PPAs
Mammary gland
brown pigment in dermis
XX
hyperkeratosis
33
dermal inflaamatory cell lnfll-
crates
3
inflammatory exudate in acinar
lumen/ducts
2
inflammatory cell infiltrates in
intralobular connective tissue
3
diffuse congestion
intraepidermal microabscess
X 3
3
2
1 X 3 33
23
XXX 33
3 33
2
XX 3 33
2
X 2
X
100 mg/kg/dav z Ct. #* VA eAn PS resn XXXX
3
Femur
Bone marrow (Rib junction) hypocellular marrow congestion
Miscellaneous acute focal cheilitis, lip
1
1
11i
1
1111
1111
11 1 1
344 3 3 34
4444 334 3
4
137-090
Code:
X - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight
4 - moderate 5 - marked 6 - extreme - not available Died or sacrificed in extremis
0176-3
