Document baEVvZ7rxgONJBNYLao4vEy43
Attachments to Letter to C. Auer dated May 4, 2000
Perfluoroctane Sulfonate Studies
AR026-Q!37
Repeated-Dose Toxicity
1) Ninety-Day Subacute Rhesus Monkey Toxicity Study, with Fluorad Fluorochemical Surfactant FC-95, International Research and Development Corporation, Project No. 137-092, December 18, 1978.
a) Study Report
b) Aborted Study: Ninety-Day Subacute Rhesus Monkey Toxicity Study, with Fluorad Fluorochemical Surfactant FC-95, International Research and Development Corporation, Project No. 137-087, January 2, 1979.
2) Ninety-Day Subacute Rat Toxicity Study, with Fluorad Fluorochemical Surfactant FC-95, International Research and Development Corporation, Project No. 137-085, November, 1978.
3) 104-week Dietary Chronic Study and Carcinogenicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) in Rats, Covance Laboratories Inc., Study Number 6329-183. In progress.
a) Summary Report - Week 53 undated
b) "Liver Slide Review," Marvin Case to John Butenhoff and Andrew Seacat dated April 5, 2000 relaying the results of an independent histopathologic review of liver slides from the study.
c) Second Draft Cell Proliferation Report, Pathology Associates International, August 24, 1999. [final interim report, to be incorporated in final report]
d) Study Report of Determination of Cyanide Insensitive Palmitoyl-CoA oxidation in samples from 3M Environmental Laboratory - Covance Studies 6329-183 and 6329-212, Centre For Xenobiotic Research, University of Dundee, Biomedical Research Center, Study Number XR0108, February 18, 1999.
4) Range-finder: 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222
a) Unaudited Draft Final Report, 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222 (draft not complete).
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Attachments to Letter to C. Auer dated May 4, 2000 Perfluoroctane Sulfonate Studies
b) Cell Proliferation Report, 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222 (draft to be incorporated in final report)
c) Protocol - Analytical Study, Quantitative Analysis of Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Following Administration of a 4-Week Capsule Toxicity Study, 3M Environmental Laboratory, AMDT-041598.1
d) Memorandum from Marvin Case, regarding histopathology review of liver tissue in Covance Study 6329-222, July 27, 1998
5) 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-223. In progress.
a) Undated report covering the 26-week dosing phase and one year of recovery.
b) John Butenhoff, "Dose-Setting Rationale for Six-Month Chronic Oral Study in Cynomolgus Monkeys," dated July 29, 1998 and followup Aug. 3, 1998.
c) Fecal Urobilinogen Analysis, Mayo Clinic, Porphyrins and Nutritional Chemistry Group, Test Code: 8308.
i) Summary Report from Dr. Joseph P. McConnell, dated March 16, 1999.
ii) General information from Mayo Clinic, Porphyrins and Nutritional Chemistry Group on Urobilinogen Analysis, dated January 14, 1999.
iii) Individual animal urobilinogen lab reports (raw data) from Mayo Clinic, Porphyrins and Nutritional Chemistry Group.
d) Pathology Report (Ancillary Study), Electron Microscopic Evaluation of Liver in Cynomolgus Monkeys, Pathology Associates International, Study No. EM99.76, July 13, 1999.
e) Pathology Review, Marv Case to Andrew Seacat, dated July 22, 1999 relaying the results of a histopathology review of slides.
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Attachments to Letter to C. Auer dated May 4, 2000 Perfluoroctane Sulfonate Studies
f) Laboratory Report, Interim Report of Preliminary Data for 26 Week Capsule Toxicology Study with PFOS in Cynomolgus Monkeys, 3M Environmental Laboratory, Report No. FACT-TOX-030, dated March 29, 1999.
6) Two Week Oral Rangefinding Toxicity Study of T-2509CoC in Rats, Safety Evaluation Laboratory, Riker Laboratories, Inc., Experiment No. 179RR023, 3M Reference no. T-2509.3 (FC-99 New Formula, L-4509, 25 % diethanolamine salt of perfluorooctanesulfonate in water), February 25, 1980.
7) [Submit
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00Z031
A T ^ I International Research and Development Corporation
SPONSOR: COMPOUND: SUBJECT:
3M Company
Fluorad Fluorochemical Surfactant FC-95
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
V/
Edwin I. Goiclenthal, Ph.D, Vice President and Director of 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
Date: December 18, 1978
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T A B L E OF C O N T E N T S
I. S y n o p s i s ....................................................... II. C o m p o u n d ....................................................... III. ClinicalStudies ...............................................
A. M e t h o d ............................................. 1. General Procedure..................................... 2. Compound Administration.............................. 3. Observations . .......................... . . . . . . 4. Clinical Laboratory Tests............................ a. H e m a t o l o g y ....................................... b. Biochemistry ..................................... c. U r i n a l y s i s ....................................... d. Statistical Analysis ............................
B. Results.................................................... 1. General Behavior, Appearance andSurvival............ a. Control........................................... b. 0.5 mg/kg/day..................................... c. 1.5 mg/kg/day..................................... d. 4.5 mg/kg/day. . ............................... 2. Body W e i g h t s .................. .................. 3. Laboratory Tests ..................................... a. One Month of theS t u d y ........................... b. Three Months of theStudy.........................
IV. PathologicalStudies ........................................... A. Methods.................................................... 1. Gross Pathology. . . . . . . . . . . . . . ......... 2. H i s t o p a t h o l o g y ....................................... B. Results.................................................... 1. Gross Pathology and OrganWeights..................... 2. H i s t o p a t h o l o g y .......................................
Iggg. 1 3
4 4 -4 4
5 5 5 5 6 6 6 6 6 7 7 8 8 8 8 9 10 10 10 10 11 11
11
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T A B L E OF C O N T E N T S (Continued)
Table No. 1. Individual Body W e i g h t s ................................ 2. Means and Significance of Hemtalogical Values . . . . .
3- 5. Individual Hematological Values ....................... 6. Summary of Mean Biochemical Values............
7- 9. Individual Biochemical Values .......................... 10. Summary of Mean Urinalysis V a l u e s .....................
11-13. Individual Urinalysis Values............................ 14. Necropsy O b s e r v a t i o n s .................................. 15. Absolute and Relative Organ Weights ................... 16. Microscopic Observations................................
If.se-
13 14-15 16-18 19-20 21-23 24-25 26-28 29 30 31-35
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I. SYNOPSIS Fluorad Fluorochemical Surfactant FC-95 was administered by gav-
age to rhesus monkeys at dosage levels of 0, (distilled water only) 0.5, 1.5 and 4.5 mg/kg/day for 90 days. Two male and two female monkeys were initiated at each dosage level and also in the control group. The monkeys were observed twice daily for general physical appearance, behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological and biochemical studies and urinaly sis were conducted once in the control period and at the end of the first and third month of the study.
The monkeys treated at the 4.5-mg/kg/day dosage level died or were sacrificed in extremis between week 5 and 7 of the study. These monkeys exhibited signs of toxicity in the gastrointestinal tract (anorexia, emesis, black stool and dehydration) from the first or second day of study. All the high-dose monkeys had decreased activ ity and before death showed marked to severe rigidity, convulsions, generalized body trembling, prostration and loss of body weight. The mean body weight decreased from 3.44 kg at the beginning of the study to 2.70 kg at week 5 of study. At 1 month of study all monkeys at the 4.5-mg/kg/day dosage level had decreased serum cholesterol values and serum alkaline phosphatase activity.
All monkeys at the 1 .5-mg/kg/day dosage level survived to the end of the study. The monkeys exhibited slightly decreased activity from the first week of the study which occasionally became moderate to marked. Monkeys at the 1.5-mg/kg/day dosage level occasionally had black stools, diarrhea, mucous in the stool and bloody stool and exhib ited dehydration or general body trembling at the end of study. The monkeys from this group had a slight decrease in mean body weight.
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In the laboratory tests, there was a decrease in the alkaline phospha tase activity and the concentration of inorganic phosphate in the serum at 3 months of study.
All monkeys at the 0.5-mg/kg/day dosage level survived to the end of the study. Monkeys at this dosage level exhibited an occasional soft stool, diarrhea, anorexia and emesis. Slightly decreased activ ity was noted in three monkeys at this dosage level. At 3 months of study a slight decrease in the serum alkaline phosphatase activity was noted.
No gross or microscopic pathological lesions which, were considered compound-related were seen in tissues other than the adrenals, pancreas, and submandibular salivary glands of male and female rhesus monkeys at the 4.5-mg/kg/day dosage level. Microscopically, the adre nals from male and female monkeys at the 4.5-mg/kg/day dosage level had compound-related marked diffuse lipid depletion; the pancreas from male and female monkeys at the 4.5-mg/kg/day dosage level had compoundrelated moderate diffuse atrophy of exocrine cells; the submandibular salivary glands from male and female monkeys had compound-related moderate diffuse atrophy of the serous alveolar cells.
No statistically significant variations in sex group mean weights of organs occurred between the control and experimental groups.
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II COMPOUND
The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below:
______________ Label_________________
Fluorad Fluorochemical Surfactant FC-95 3-M Stock No. 98-0207-0103-7 Lot 640 Net wt. 5 lbs. 2,2 kg.
Description white powder
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III. CLINICAL STUDIES
A. METHOD:
1. General Procedure:
Eight male (weighing from 2.55 to 3.55 kg) and eight female
(weighing from 2.70 to 3.75 kg) rhesus monkeys were initiated in this
study. The monkeys were purchased from Primate Imports, Port
Washington, New York. The monkeys were housed individually in hanging
wire mesh "squeeze-type" cages and maintained in a temperature-, humid
ity- and light-controlled environment. Purina Monkey Chow was fed
twice each day and fresh apples were fed 3 times a week. Water was
available ad libitum.
During the conditioning period, the monkeys were tattooed on
the inner surface of the thigh and intrapalpebral tuberculin tests
were conducted. Tuberculin tests also were conducted twice during the
treatment period. Complete physical examinations were conducted by the
staff veterinarian prior to initiation of compound administration.
Only monkeys in good health were selected.
This study was initiated on February 16, 1978. Terminal
sacrifices were conducted on May 17, 1978.
2. Compound Administration:
At the end of the conditioning period the monkeys were divided
into four groups on a random basis, so that the initial avera;
weights were similar:
Dosage Level (mg/kg/day)
Number of Monkeys
Male
Female
0 (Control) 0.5 1.5 4.5
22 22 22
22
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The monkeys in the control group were previously employed as the control group in an aborted 90 day study in monkeys on FC-95 (study 137-087). The test compound suspended in distilled water, was administered 7 days a week by gavage. All doses were given in the same volume of water. This volume of distilled water was given to the 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, 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. Food con sumption was estimated.
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, reticulocyte count^, platelet count, prothrombin time and activated partial thromboplastin time^ (APTT). Mean corpuscular hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentration were calculated.
b. Biochemistry: Biochemical studies included: the determinations of
fasting blood glucose, blood urea nitrogen, the activities of serum alkaline phosphatase, serum glutamic oxalacetic
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transaminase, and serum glutamic pyruvic transaminase, and the concentrations of cholesterol^, total protein^, albumin, sodium*, potassium*, chloride^, inorganic phosphate^, as well as the activities of Y-glutamyl transpeptidase** and creati nine phosphokinase*.
c. Urinalysis: Urinalysis included: measurement of volume, pH* and
specific gravity; description of color and appearance; qualitative tests for protein*, glucose*, ketones*, occult blood* and microscopic examination of the sediment.
d. Statistical Analysis: All statistical analyses compared the treatment groups
with the control group, by sex. Body weights (week 13), percent change in body weights bet
ween control period and 1, 2 and 3 months (sexes combined), hematologi cal, biochemical and urinalysis parameters (months 1 and 3) and absolute and relative organ weights (terminal sacrifice) were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or une qual variances) as described by Steel and Torrie*^ using Dunnett's* multiple comparison tables to judge significance of dif ferences. B. RESULTS:
1. General Behavior, Appearance and Survival: There was no mortality in the control, 0.5- and 1.5-mg/kg/day
dosage levels. Three monkeys at the 4.5-mg/kg/day dosage level died between week 5 and 6 of the study. The fourth monkey from this group was sacrificed in extremis in week 7 of the study,
a. Control: The monkeys from this group showed an occasional soft
stool or diarrhea (slight to severe). For one day Monkey 7358 had
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bloody diarrhea, anorexia and slight ataxia and for 3 days Monkey 7368 had anorexia. Emesis was noted rarely.
b. 0.5 mg/kg/day: Monkeys 7466 and 7504 exhibited occasional diarrhea or
soft stools. For Monkeys 7463 and 7483 the soft stools and diarrhea were frequent with occasional appearance of mucus in the stools. On one occasion bloody mucus in the stool and in the refuse pan was observed for Monkey 7483. Occasional anorexia and emesis were noted for Monkeys 7463, 7466 and 7504. Similarly, a slight intermittent decrease in activity was noted for Monkeys 7463, 7483 and 7504.
c. 1.5 mg/kg/day: All monkeys at this dosage level exhibited a slight
decrease in activity during the first week of study. For Monkey 7501 the decreased activity frequently was noted throughout the study and by week 13 had become moderate. Although no emesis, soft stools and diarrhea were noted for this monkey, slight general body trembling and mucus in the stool was observed in week 12, as well as slight dehydration in weeks 12 and 13. For Monkey 7501 and 7500 anorexia became persistent during weeks 12 and 13. For Monkey 7500 diarrhea and soft stool appeared along with mucus in the stool at week 2, black stool at week 8 and slight dehydration in week 12. This monkey exhib ited "bruising" around the right eye followed by "bruising" around both eyes at week 12.
For Monkey 7486 occasional soft stool and diarrhea were observed along with anorexia which became persistent in week 10. During weeks 10 and 11 slight dehydration was also noted. Monkey 7462 had occasional soft stool, emesis for 1 day each in weeks 1 and 3 and the decreased activity was observed in week 1 only.
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d. 4.5 mg/kg/day: At 4.5 mg/kg/day the monkeys showed apparent signs of
toxicity in the gastrointestinal tract from the first to the second day of the study (anorexia and partial anorexia, emesis, black stool and/or dehydration from slight to moderate). All had decreased acti vity from slight to severe. Before death they showed marked to severe rigidity, convulsions, moderate generalized body trembling and finally prostration. Monkey 7485 had petechial hemorrhages on the skin of the inguinal area, thorax and face and Monkey 7484 had pale gums after week 3 of the study.
2. Body Weights (Table 1): Changes in the body weights were similar for monkeys in the
control and at the 0.5-mg/kg/day dosage level. The male monkeys in the 1.5-mg/kg/day dosage level had a decrease in their body weight from 3.15 kg at the beginning of the study to 2.93 kg at the end of the study and from 3.22 kg to 2.75 kg for the female monkeys. The change in body weight for this group of monkeys was not statistically significant from the control group.
The monkeys at the 4.5-mg/kg/day dosage level showed a loss of the body weight after 2 weeks of the study. Their average body weight decreased from 3.44 kg -at the beginning of the study to 3.23 kg (week 2) - 3.13 kg (week 3) - 2.97 kg (week 4) - 2.70 kg (week 5) for both sexes. At week 6 and 7 of the study they died. There was no statistical evaluation of the body weights for monkeys at the 4.5mg/kg/day dosage level, because they were not alive at week 13, when the statistics were done.
3. Laboratory Tests (Tables 2-13): a . One Month of the Study: At 1 month of study there were no pathological changes in
values for monkeys from the control and 0.5-mg/kg/day dosage level.
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At the 1 ,5-mg/kg/day dosage level only Monkey 7501 had a slight decrease in the erythrocytes which was recovered in the third month of study.
Both the male and female monkeys at the 4.5-mg/kg/day dosage level had low values for serum cholesterol which were statisti cally significance.
Monkey 7484 had a decreased alkaline phosphatase activity (312 unit/1), serum potassium (3.6 meq/liter) and chloride concentration (102 meq/liter) and Monkey 7503 also had low serum chloride concentration (102 meq/liter).
Although the S.G.O.T. activity of male Monkeys 7484 and 7485 was in the highest expected normal range (115 units) the dif ferences between these values and that of the control were not sta tistically significant.
The only unusual changes in the urinalysis were the appearance of glucose from Monkey 7500 (1.5 mg/kg/day) and from Monkeys 7485 and 7503 (4.5 mg/kg/day). However, these monkeys had no pathological increase of the blood glucose,
b. Three Months of the Study: There was a statistically significant decrease in the
serum alkaline phosphatase activity for the male monkeys at the 0.5mg/kg/day dosage level and for two Monkeys, 7500 and 7501, at the 1.5mg/kg/day dosage level. These latter monkeys also had a decreased values of serum potassium concentrations. Monkey 7501 at 1.5mg/kg/day had very low serum cholesterol and Monkey 7500 at 1.5mg/kg/day had a slight decrease in the inorganic phosphate (4.2 mg/100 ml) concentration.
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IV. PATHOLOGICAL STUDIES A. METHODS : 1. Gross Pathology; After completion of ttie 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 representative 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 animals in the control and treatment groups. The following tissues were examined;
adrenals aorta 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 bone/bone marrow (rib
junction)
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
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B. RESULTS: 1. Gross Pathology (Table 14) and Organ Weights (Table 1 5 ) : No gross lesions considered compound-related were seen in male
and female rhesus monkeys which died or were sacrificed in extremis or were sacrificed after 90 days of study.
No statistically significent variations in sex group mean weights of organs occurred between the control and experimental groups.
2. Histopathology (Table 1 6 ) : All male and female monkeys.at the 4.5 mg/kg/day dosage level
had marked diffuse lipid depletion in the adrenals. One male and two females at the 4.5 mg/kg/day dosage level had moderate diffuse atrophy of the pancreatic exocrine cells. The lesion consisted of decreased cell size and loss of zymogen granules. Two male and one female monkeys at the 4.5 mg/kg/day dosage level had moderate diffuse atrophy of the serous alveolar cells characterized by decreased cell size and loss of cytoplasmic granules. These microscopic findings were consid ered compound-related.
No microscopic changes which were considered compound-related were seen in the adrenals, pancreas or submandibular salivary glands in male and female monkeys at the 0.5 and 1.5 mg/kg/day dosage levels. No microscopic lesions in tissues other than the adrenals, pancreas and submandibular salivary glands of male and female monkeys at the 4.5 mg/ kg/day dosage level were considered compound-related.
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References
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 Street, Hialeah, Florida.
6 General Diagnostics - Warner Chilcott Laboratories Revised April 1965.
7. General Diagnostics - Warner Chilcott Laboratories Revised January
. 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 Technical Bulletin 545, Sigma Chera. Co., St. Louis, Missouri. 1 2 . Sigma Technical Bulletin 520, Sigma Chem. Co., St. Louis, Missouri. 13. Bililabstix (Ames Reagent Strips). 14. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures
of Statistics, McGraw-Hill, New York, N. Y. 15. Dunnett, C. W . , New Tables for Multiple Comparisons With a Control,
Biometrics, Sept. 1964.
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FC-95:
TABI.E I
Group, Monkey Number
Sex
Control:
7355 7358 7368 7372
Mean
0.5 mg/kg/di!X: 7463 7483 7466 7504
Mean
1.5 mg/kg/day:
7462 7486 7500 7501
Mean
4.5 mg/kg/day:
7484 7485 7502 7503
Mean
M M F F
M M F F
M M F F-
M M F F
Ninety-Day Subacute Rhesus Monkey Toxicity Stiuly Individual Body Heights, Kilograms.
C o n t r o l _______________________________________ _______________Study Weeks -1 0 1 2 3 4 5 6 7
8
9
3.20 3.65 3.10 3.55
3.38
3.20 3.55 3.10 3.65
3.38
3.25 3.65 3.15 3.60
3.41
3.15 3.30 3.10 3.35
3.23
3.25 3.30 3.20 3.80
3.39
3.25 3.45 3.20 3.85
3.44
3.15 3.50 3.10 3.80
3.39
3.30 3.70 3.20 3.90
3.53
3.20 3.70 3.15 4.10
3.54
3.30 3.60 3.05 4.10
3.51
3.40 3.90 3.25 4.35
3.73
2.40 3.50 3.20 3.25
3.09
2.55 3.55 3.40 3.15
3.16
2.55 3.45 3.25 3.10
3.09
2.40 3.40 3.35 3.10
3.06
2.50 3.50 3.35 3.20
3.14
2.60 3.60 3.50 3.30
3.25
2.40 3.55 3.50 3.15
3.15
2.50 3.55 3.70 3.20
3.24
2.55 3.65 3.70 3.30
3.30
2.55 3.55 3.60 3.20
3.23
2.70 3.65 3.70 3.40
3,36
2.70 3.40 3.85 2.75
3.18
2.90 3.40 3.75 2.70
3.19
2.70 3.15 3.75 2.55
3.04
2.60 3.30 3.45 2.45
2.95
2.70 3.15 3.45 2.50
2.95
2.75 3.30 3.40 2.55
3.00
2.70 3.10 3.30 2.50
2.90
2.70 3.20 3.35 2.55
2.95
2.80 3.20 3.40 2.55
2.99
2.80 3.30 3.30 2.50
2.98
2.90 3.35 3.45 2.55
3.06
3.45 3.25 3.50 3.80
3.50
3.30 3.20 3.50 3.75
3.15 3.30
3.55 3.80
3.44 3.45
3.25 3.00 3.20 3.45
3.23
2.90 3.00 3.25 3.35
3.13
2.55 2.75 3.25 3.35
2.98
2.20 2.50* 3.10 2.80
2.70
2.15* Died 3.10 2.55*
3.10
Died
2.70 Died 2.70
2.65* Died Died
10
3.40 3.90 3.30 4.40 3.75
2.65 3.65 3.80 3.40 3.38
3.05 3.40 3.40 2.50 3.09
11
3.45 4.10 3.45 4.70 3.93
2.55 3.75 3.65 3.35 3.33
3.00 3.30 3.50 2.50 3.08
12
3.35 3.90 3.25 4.30 3.70
2.60 3.70 3.65 3.35 3.33
2.95 3.25 3.35 2.45 3.00
13
3.55 3.75 3.15 4.20 3.66
2.65 3.55 3.55 3.35 3.28
2.80 3.05 3.20 2.30 2.84
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`Terminal weight not Included in mean.
hd (B 0(0D
Co
FC-95: TABLE 2.
Hematology
Erythrocytes( 10/cmm
Hemoglobin, g/100 ml
Hematocrit,
%
Platelets, lO^/cam
Reticulocytes,
X
Prothrombin Time, sec
Activated P.T.T., sec
Leucocytes, loVcmm
MCVj
HCH, uug
MCHC, g/100 ml
BEST COPY AVAILABLE
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
MALES : Means and Significance of Hematological Values.
Study Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
4.93 4.67 4.63
12.3 12.4 12.3
35 37 39
129 181 205
0.5 0.3 0.2
11 11 12
29 24 25
7.03 10.59 8.67
71 79 84
25 27 27
36 34 32
5.36 4.81 4.34
12.7 13.8 12.4
38 37 39
140 226 226
0.9 0.3 0.3
11 12 11
28 25 22
10.29 10.41 7.06
70 77 80
24 29 26
34 37 33
5.04 4.66 4.45
12.3 13.2 11.6
37 37 36
114 161 223
0.6 0.2 0.1
11 11 11
29 24 28
8.22 8.39 9.04
73 80 81
25 28 26
34 36 32
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4.5 mg/kg/day
5.47 4.71
13.7 12.8 39 37 180 177 -
1.0 0.2
11 12
26 29
6.39 11.37
71 78
25 27
36 35
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FC-95: TABLE 2. Cont.
Heaatology
Crychrocytcs i 10/cmm
Hemoglobin, g/100 ml
Hematocrit,
Z
Platelets, lO^/cmm
Reticulocytes,
Z
Prothrombin Time, sec
Activated P.T.T., sec
Leucocytes, 10^/cmm
MOT. u5
MCH, uug
MCHC, g/100 ml
BEST COPY AVAILABLE
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
FEMALES: Means and Significance of Hematological Values.
Study Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control l 3
Control 1 3
5.66 5.02 4.71
13.1 14.1 12.0
39 40 38
176 151 232
0.4 0.2 0.1
11 11 12
27 27 25
7.39 8.77 4.62
68 79 81
23 28 26
34 36 32
5.56 4.56 4.79
12.6 13.4 12.2
38 38 39
164 177 236
0.8 0.1 0.1
10 11 11
27 27 29
10.31 7.82 9.09**
69 82 81
23 30 26
33 36 31
5.11 3.95 4.37
12.5 12.0 11.7
34 35 37
164 158 229
0.3 0.2 0.1
11 11 11
26 25 27
8.81 9.14 6.84*
67 88 85
25 31 27
37 35 32
Page 15
4.5 mg/kg/day
5.08 5.00
11.8 12.9
35 37
182 194
~ 0.8 0.1 "
11 12
27 28
12.71 11.28
68 75
" 23 26
34 35
-
137-092
`Significantly different from Control group mean, p<0.05. " Significantly different from Control group mean, p<0.01.
- - Not available
002049
FC-- 9 5 :
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
TABLE 3
Individual Hematological Values - Control.
Pro-
(.`roup,
1Erythro Hemo llemato- Plate Reticu thrombin Activated Leuco
Monkey
cytes globin crlt
lets locytes Time P.T.T. cytes
Number Sex 10 /ernia g/100 ml Z 103/cmm Z
sec sec 10^/cram
Neutrophils Lymplio- Eosino Mono Baso
Seg. Non-Seg. cytes phils cytes phils MtjV MCI! MC11C
ZZ
Z Z Z Z M MMg g/100 ml
Control :
7355
M
4.65
11.4
32
110 0.7
10
31
5.39
19 0
7358
M
5.20
13.2
38
147 0.2
11
27
8.66
13 0
7368
F 5.78
13.4
41
180 0.5
11
25
7.61
24 1
7372 F 5.53 12.7
36
172 0.3
11
28
7.17
12 0
80 84 74 87
0
1
0 69 25
36
3
0
0 73 25
35
1
0
0 71 23
33
1
0
0 65 23
35
Mean
5.29
12.7
37
152 0.4
11
28
7.21
17 0
82
1
0
0 70 24
35
0.5 oig/kg/day
7463
M
5.38
12.7
37
131 0.5
10
27
9.73
58 0
40
2
0
0 69 24
34
7483 M 5.34 12.7
38
148 1.2
11
28 10.84 47 0
50
3
0
0 71 24
33
7466 F 5.64 13.2
39
157 1.2
10
29
9.61
20 0
80
0
0
0 69 23
34
7504
F 5.47
11.9
37
170 0.3
10
25 11.00 28 0
72
0
0
0 68 22
32
Mean
5.46
12.6
38
152 0.8
10
27 10.30 38 0
61
1
0
0 69 23
33
1.5 mg/k/day
7462
M
5.03
12.2
37
101 0.2
11
28
7.28
16 0
83
1
0
0 74 24
33
7486
M
5.04
12.4
36
126 0.9
11
29
9.15
22 0
78
0
0
0 71 25
34
7500
F 4.96
12.4
32
142 0.2
11
26 10.07 53 0
43
3
1
0 65 25
39
7501
F 5.25
12.5
36
186 0.3
11
26
7.54
34 0
64
2
0
0 69 24
35
Mean
5.07
12.4
35
139 0.4
11
27
8.51
31 0
67
2
0
0 70 25
35
4.5 mg/kg/day
7484 M 5.40 12.9
36
197 0.8
11
27
6.72
20 0
79
0
0
1 67 24
36
7485 M 5.54 14.5
41
162 1.2
U
25
6.05
33 0
64
3
0
0 74 26
35
7502 F 5.27 12.7
35
191 0.5
10
25 13.89 34 0
63
2
0
1 66 24
36
7503
F 4.88
10.9
34
173 1.0
11
29 11.53 35 0
60
5
0
0 70 22
32
Mean
5.27
12.8
37
181 0.9
11
27
9.55
31 0
65
3
0
1 69 24
35
BEST COPY AVAILABLE
002050
I37-092
tl R> OQ (0
FC-95:
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
TABLE 6.
Individual Hematological Values - l Month.
Pro-
Group,
1Erythro Hemo Hemato Plate Reticu tbrombin Activated Leuco
Monkey
cytes globin crit
lets locytes Time P.T.T. cytes
Number Sex 10/cmm g/100 1 Z l/cmm X
sec sec 103/cram
Neutrophils Lympho Eosino Mono Baso
Seg. Non-Seg. cytes phils cytes phils MCV MCII MClIC
XX
Z Z Z Z P3 g g/100 ml
Control ;
7355 M 6.76
12.5
38
166 0.0
12
26
5.22
68 0
52
0
0
0 80 26
33
7358
M
6.60
12.3
36
196 0.5
10
21 15.95 61 0
36
5
0
0 78 27
36
7368
F 5.63
16.7
62
136 0.1
11
25 11.05 66 0
35
0
1
0 77 27
35
7372
F 6.60
13.6
37
168 0.2
11
28
6.68
23 0
72
5
0
0 80 29
36
Mean
6.86
13.2
38
166 0.2
11
25
9.68
69 0
68
3
0
0 79 27
35
0.5 mg/kg/day
7663 M 6.92
16.0
37
220 0.2
11
26 10.52 65 0
36
1
0
0 75 28
38
7683 M 6.69
13.5
37
232 0.3
12
26 10.29 53 0
67
0
0
0 79 29
36
7666
F 6.76
16.0
39
222 0.0
11
26
7.62
37 0
62
1
0
0 82 30
36
7506
F 6.38
12.7
36
131 0.1
11
29
8.22
60 0
58
2
0
0 82 29
35
Mean
6.68
13.6
37
201 0.2
11
26
9.11
69 0
50
1
0
0 80 29
36
1.5 mg/kg/day
7662 M 6.67
13.3
37
160 0.2
11
26
8.56
59 0
61
0
0
0 79 28
36
7686 M 6.66
13.1
37
161 0.2
11
26
8.23
67 0
51
1
1
0 80 28
35
7500 F 6.01
12.0
32
155 0.2
11
26 11.06 50 0
50
0
0
0 80 30
38
7501 F 3.89 12.0
37
160 0.1
11
23
7.21
68 0
50
2
0
0 95 31
32
Mean
6.30
12.6
36
159 0.2
11
26
8.76
51 0
68
1
0
0 86 29
35
6.5 mg/kg/day
7686 M 6.66* 12.0
36
206 0.0
12
32 11.83 82 0
17
0
1
0 73 26
35
7685 M 6.76 13.5
39
169 0.6
11
26 10.90 66 0
32
1
1
0 82 28
35
7502
F 6.20
12.7
35
202 0.1
11
27 12.90 60 0
60
0
0
0 83 30
36
7503 F 5.80 13.0
38
186 0.1
12
29
9.66
62 0
37
1
0
0 66 22
36
Mean
6.86
12.8
37
185 0.2
12
29 11.32 68 0
30
1
1
0 76 27
35
Ksimummt
002051
137-092
M i Anlsocy tosta
pj
00
(D
H>y5 :
Ninety-Day Subacute Rhesus Monkey Toxicity Study
TA Hit 5
Individual Hematological Values - 3 Months.
(*rou|jt
Erythro- Homo-
Monkey
cytes giubili
Number Sex 10/cmm g/100 ml
Heaatocrlt Z
Plate- Retimi-
lets locyte
10^/cmm
z
Prothrombin Activated
Time P.T.T. sec sec
Lcucocvtes I /c m m
Neutrophils Lympho- tosino- Nono- Huso-
Seg. Non-Seg. cytes
ZZ
Z
phi Is cytes phils MCV MCII MC11C
zZ Z m 3 HMg g/100 ml
Control :
7355 M 4.59
12.1
37
187 0.3
12
26
6.63
49 0
51
0
0
0 81 26
33
7358 M 4.67
12.5
40
222 0.0
11
23 10,70 20 0
76
3
l
0 86 27
31
7368 F 5.05 12.5
40
235 0.2
12
24
4.33
38 0
61
l
0
0 79 25
31
7372
F 4.36
11.5
36
228 0.0
11
25
4.91
27 0
66
7
0 83 26
32
Mean
4.67
12.2
38
218 0.1
12
25
6.64
34 0
63
3
0
0 82 26
32
0.5 nnt/kg/day:
7463
M
5.01
12.8
39
230 0.3
10
20
7.15
46 0
53
1
0
0 78 26
33
7483 M 4.66 12.0
38
222 0.2
11
24
6.96
42 0
54
4
0
0 82 26
32
7466
F 4.86
12.9
41
229 0.0
11
27
9.30
15 0
83
2
0
0 84 27
31
7504
F 4.72
11.5
37
242 0.1
11
31
8.82
33 0
66
1
0
0 78 24
31
Mean
4.81
12.3
39
231 0.2
11
26
8.06
34 0
64
2
0
0 81 26
32
1.5 mg/kR/day:
7462 M 4.30
11.3
35
230 0.1
11
29
7.71
18 0
81
1
0
0 81 26
32
7486 M 4.60
11.9
37
216 0.1
11
26 10.37 18 0
81
1
0
0 80 26
32
7500
F 4.12
11.1
35
234 0.1
11
26
7.22
34 0
64
2
0
0 85 27
32
7501
F 4.61
12.2
39
224 0.0
11
27
6.45
47 0
50
3
0
0 85 26
31
Mean
4.41
11.6
37
226 0.1
11
27
7.94
29 0
69
2
0
0 83 26
32
4.5 mg/kg/day:
7484 M Died 74B5 M Died 7502 F Died 7501 F Died
Mean
BEST COPY AVAILABLE
002052
137-092
ti OQ
fl>
00
FC-95:
TABLE 6.
Biochemistry
Glucose, mg/100 ml
B.U.N., mg/100 ml
Alkaline Phosphacase, int'l units/1
S.G.O.T., int'l units/1
S.G.P.T., int'l units/1
Cholesterol, mg/100 ml
Total Protein, g/100 ml
Albumin, ' g/100 ml
Sodium, meq/1
Potassium, meq/1
Chloride, meq/1
Inorganic Phosphace, mg/100 ml
Y - Glutamyl Transpeptidase Sigma units/ml
Creatinine Phosphokinase. Sigma units/ml
BEST copy AVAILABLE Page 19
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
MALES: Summary of Mean Biochemical Values.
Study Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control l 3
118 96 77
23.7 23.3 28.2
1070 1113 1095
22 56 56
40 42 35
183 198 162
8.33 8.46 7.85
4.96 4.75 4.70
150 161 153
4.9 4.9 4.2
112 117 112
6.8 8.1 7.4
56 42 56
25 62 20
106 .92
80
29.8 33.3 26.5
680 897 747
23 49 49
32 27 28
172 200 152
8.74 8.59 8.07
5.22 5.17 4.69
156 160 151
5.6 4.6 4.2
114 118 110
6.4 6.4 6.5
36 45 29
44 34 40
102 115 107
31.4 32.8 19.6
1035 1110
891
18 54 53
29 38 28
185 213 122
8.68 8.74 .8.38
5.36 5.22 4.98
156 160 150
5.4 4.7 4.8
116 121 111
6.0 8.5 6.0
50 55 45
11 67 40
4.3 mg/kg/day
116 99 -
19.6 29.1
-
1300 564 -
25 115 -
35 27
-
190 87** -
8.90 8.90
-
5.50 5.31
-
160 153 -
4.6 4.7
-
113 105 -
6.4 4.9*
-
46 26
-
13 55
Significantly different from Control group mean, p<0.05. Significantly different from Control group mean, p<0.01.
- Not available
002053
FC-95: TABLE 6. Cont.
Biochemistry
Glucose, mg/100 ml
B.U.N., mg/100 ml
Alkaline Phosphatase, int'l units/1
S.G.O.T., int'l units/1
S.G.P.T., int'l units/1
Cholesterol, mg/100 ml
Total Protein, g/100 ml
Albumin, g/100 ml
Sodium, meq/1
Potassium. meq/1
Chloride, meq/1
Inorganic Phosphate, mg/100 ml
Y - Glutamyl Transpeptidase Sigma units/ml
Creatinine Phosphokinase, Sigma unlts/mi
a m m m
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
Page 20
FEMALES: Summary of Mean Biochemical Values.
S tudy Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
4.5 mg/kg/day
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
Control 1 3
107 163 88
23.6 25.2 28.7
1173 1092
831
16 46 36
23 23 29
180 198 165
7.70 7.66 7.49
4.71 4.86 4.77
156 155 152
4.8 4.7 4.6
111 111 113
6.4 6.5 6.5
38 41 32
10 50
5
139 98 97
22.0 25.5 21.5
1013 942 861
39 55 36
42 37 27
208 221 169
8.77 8.47 8.02
5.27 5.41 4.82
158 162 151
5.3 5.1 5.1
112 116 111
7.5 8.2 7.3
50 47 40
20 39 10
113 119 108
20.7 26.4 22.6
770 753 618
20 45 27
32 35 34
204 169 100
8.67 8.63 8.47
5.20 5.42 5.21
157 157 149
5.2 3.8 3.7
115 113 109
5.4 5.7 4.7
43 28 30
24 31*
7
144 164 -
22.4 31.6
-
875 615
-
37 75*
-
37 45
-
176 112* -
8.88 8.82*
-
5.16 5.39
-
159 156 -
5.3 4.3
-
116 110 -
6.4 5.6
-
34 30
-
27 49
.Significantly different from Control group mean, p<0.05. Significantly different from Control group mean, p<0.0l.
- Sot available
0020S4
FC-95:
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
TABLE 7
Individual Biochemical Values - Control.
Group,
Alkaline S.C.O.T. S.fi.P.T. Choies- Total
Potas- Chi- Inorganic y - filutumy) Creatinine
Monkey
Glucose B.U.N. Pltosphatase lnt'l
lnt'l
terol Protein Albumin Sodium sium ride Pitosphate Transjupt lilase Phos.
Number Sex oeg/100 ml mg/100 ml lnt'l u/1
u/1
u/1 mg/100 ml g/100 ml g/100 ml muq/1 meq/1 meq/l mg/100 ml Sigma u/ml Sigma u/ml
Control:
7355
M
119
20.2
1050
46 24
192 8.65
4.92
153 5.4 115
7.1
51
38
7358
M
117
27.2
1090
33 21
174 8.11
5.00
148 4.4 110
6.6
61
12
7368
F
117
26.9
1170
23 18
155 8.09
4.93
158 5.4 111
6.6
39
18
7372
F
97
22.2
1175
23 14
204 7.30
4.49
153 4.2 111
6.2
37
2
Mean
113 23.6
1121
31
19
181 8.04
4.84
153 4.9 112
6.6
47
18
0.5 mg/kg/day:
7663
M
123
26.5
635
33
29
182 7.94
4.96
149 4.4 111
5.2
35
81
7683
M
90
33.2
725
31
17
161 9.53
5.49
164 6.7 117
7.5
38
6
7666
F
121
19.1
1250
33
31
208 8.61
5.07
161 5.6 114
8.5
55
13
7506
F
156
26.9
775
51
46
208 8.93
5.46
155 5.0 109
6.4
44
27
Mean
123 25.9
846
37
31
190 8.75
5.25
157 5.4 113
6.9
43
32
1.5 mg/kg/day:
7662
M
96
29.9
800
36
17
196 8.26
5.00
150 4.6 111
5.9
46
9
7686
M
109
32.9
1270
22
20
174 9.10
5.71
162 6.2 120
6.2
55
13
7500
F
116
18.6
1080
29
19
172 8.82
5.18
162 5.4 118
5.4
51
33
7501
F
109
22.9
460
34
21
236 8.52
5.22
151 4.9 112
5.3
34
14
Mean
108 26.0
903
30
19
195 8.68
5.28
156 5.3 115
5.7
47
17
6.5 mg/kg/day;
7686
M
120
19.0
985
30
18
186 9.25
5.69
163 4.7 114
6.5
34
8
7685
H
112
20.2
1615
40
32
194 8.54
5.30
156 4.5 112
6.3
58
18
7502
F
137
23.6
965
36
22
182 8.90
5.17
160 5.0 116
6.7
33
36
7501
F
150
21.1
785 38
51
170 8.86
5.14
157 5.6 116
6.1
34
17
Mean
130 21.0
1088
36
31
183 8.89
5.33
159 5.0 115
6.4
40
20
BEST COPY AVAILABLE -
002055
137-092
FG-95*
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
TABLE 8
Individual Biochemical Values - 1 Month.
Croup
Monkey
Cllicose B.U.N.
Number Sex mg/100 ml iug/10 ml
Alkaline S.C.O.T . S.G.P.T.
Phosphatase lnt'l
lnt'l u/1
u/1
Sisma u/ral
Choles terol
mg/100 ml
Total
Potas Chlo Inorganic Y - Glutamyl Creatinine
Protein Albumin Sodium sium ride Phosphate TrunspeptJduse Phos.
g/100 ml g/100 ml meq/l meq/l meq/l mg/100 ml Sigma u/ral Sigma u/ml
Control :
7355
M
103
23.3
1146
40
39
212 8.36
5.19
164 5.0 119
8.9
40
32
7358
M
89
23.2
1080
72
45
184 8.55
4.30
157 4.7 114
7.3
43
91
7368
F
196
30.0
1158
51
25
188 8.13
5.16
157 5.0 109
6.7
42
50
7372
F
129
20.3
1026
41
20
208 7.19
4.55
152 4.3 113
6.2
40
50
Mean
129 24.2
1103
51
32
198 8.06
4.80
158 4.8 114
7.3
41
56
0.5 mg/kg/dayi
7463
M
82
30.8
924
58
31
208 8.06
5.36
159 4.5 121
5.8
4b
34
7483
H
101
35.8
870
40
22
192 9.12
4.97
161 4.6 115
7.0
43
34
7466
F
100
24.1
1164
48
38
230 8.45
5.30
165 5.7 118
8.7
46
30
7504
F
96
26.9
720
61
36
211 8.48
5.51
158 4.5 113
7.7
48
48
Mean
95 29.4
920
52
32
210 8.53
5.29
161 4.8 117
7.3
46
37
1.5 mg/kg/day:
7462
H
131
29.8
870
50
37
222 8.60
5.30
161 4.1 123
8.5
54
72
7486
M
98
35.8
1350
58
38
204 8.87
5.14
159 5.3 119
8.4
55
61
7500
F
125
23.9
816
40
39
154 8.55
5.15
159 3.9 113
6.1
35
31
7501
F
112
28.9
690
50
31
184 8.70
5.69
155 3.7 112
5.3
21
30
Mean
117 29.6
932
50
36
191 8.68
5.32
159 4.3 117
7.1
41
49
4.5 mg/kg/day:
7484
H
97
35.0
312
115 21
76 8.11
5.02
154 3.6 102'
4.6
15
32
7485
H
100
23.2
816
115 32
97 9.68
5.59
152 5.7 107
5.1
36
77
7502
F
172
26.2
564
80
54
128 8.90
5.69
163 4.2 118
6.3
26
77
7503
F
155
37.0
666
69 36
96 8.74
5.08
149 4.3 102
4.8
34
20
Mean
131 30.4
590
95 36
99 8.86
5.35
155 4.5 107
5.2
28
52
BEST COPY AVAILABLE
002056
137-092
OQ
CD
ho ho
FC-95:
Ninety-Day Subacute Khesus Monkey Toxicity Study.
TABLE 9.
Group,
Monkey
Glucose B.U.N.
Number Sex mg/100 ml mg/100 ml
Individual Biochemical Values - 3 Months.
Alkaline S.G.O.T. S.G.P.T. Choles- Total
Potas Cil1o- Inorganic y - Uluiawyi Creatinine
Phosphatase lnt'l
Sigma
terol Protein Albumin Sod1um sium rIde Phosphate Transpeplidase Phoa.
lnt'l u/l
u/1
u/uil mg/100 ml g/100 ml g/100 ml raeq/1 meq/1 meq/1 mg/100 ml Slguia u/ml Signa u/tnl
Control :
7355
M
83
34.1
1110
59 40
179 7.69
4.78
154 4.0 115
8.0
43
20
7358
M
70
22.3
1080
52 29
144 8.00
4.61
152 4.3 109
6.7
68
19
7 368
F
112
26.9
876
33 29
144 7.68
5.01
152 4.4 110
5.8
36
6
7372
F
63
30.4
786
39 29
185 7.30
4.53
151 4.8 115
7.1
27
3
Mean
82 28.4
963
46 32
163 7.67
4.73
152 4.4 112
6.9
44
12
0.5 mg/kg/day:
7463
M
83
22.8
690
42
26
160 7.62
4.97
152 4.2 111
5.8
40
9
7483
M
76
30.1
804
56
29
143 8.52
4.41
150 4.1 108
7.2
18
71
7466
F
106
18.1
978
32
27
178 8.11
4.80
153 5.5 110
8.4
38
6
7504
F
87
24.8
744
40
27
160 7.92
4.83
148 4.7 111
6.1
42
13
Mean
88 24.0
804
43
27
160 8.04
4.75
151 4.6 110
6.9
35
25
1.5 mg/kg/day:
7462
M
92
15.2
816
82
35
132 8.51
4.85
149 5.0 112
6.8
46
76
7486
M
121
23.9
966
23
20
112 8.24
5.11
151 4.5 109
5.1
43
4
7500
F
106
17.7
690
22
33
113 8.81
4.98
150 3.4 109
4.2
35
5
7501
F
110
27.5
546
32 34
87 8.12
5.44
148 3.9 109
5.1
24
8
Mean
107 21.1
755
40
31
111 8.42
5.10
150 4.2 110
5.3
37
23
A.5 mg/kg/day;
7484 7485 7502 7503
M M F F
Died Died Died Died
Mean
1ST COPY AVAILABLE
002057
137-092
PI
OfPD
to LO
FC--95 : TABLE 10.
Urinalysis Volume,
ml pH
Specific Gravity
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
MALES: Summary of Mean Urinalysis Values.
Study Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
Control 1 3
Control 1 3
Control 1 3
22 30 10
7.2 6.4 7.0*'
1.032 1.028 1.034a
22 25 33
8.3 5.5 7.2a
1.027 1.027 1.033a
28 40 75
8.5 5.9 8.0a
1.030 1.021 1.024
Page 24
4.5 mg/kg/day
58 38
8.4 6.4
1.034 1.033
--
137-092
a Significance not determined due to only one value in the Control group. - Not available
002058
FC-95:
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
TABLE 10. Cont.
FEMALES: Summary of Mean Urinalysis Values.
Urinalysis
Study Month
Control
0.5 mg/kg/day
1.5 mg/kg/day
Volume, ml
PH
Specific Gravity
Control 1 3
Control 1 3
Control 1 3
32 25 80
8.1 5.8 8.0
1.031 1.032 1.021
53 13 30
7.9 5.5 9.0
1.027 1.032 1.021
20 28 40
8.3 6.4 8.0
1.031 1.028 1.025
Page 25
4.5 mg/kg/day
30 23
8.8 6.5
-
1.027 1.036
-
137-092
- * Not available
002059
HC-95:
TABLE II.
Group, Monkey Number
Ninety-Day Subacute Khesus Monkey Toxicity Stuily
Individual Urinalysis Values - Control.
Color
Uric
Volume and
Spec.
Occult Ke Leuco Erythro Epl.
Triple Cal. Acid Bac
Sex ml Appear. pli Grav. Protein Glucose Blood tones cytes cytes Cells Urates Phos. Ox. Crystals teria Casts
Control :
7355 7358 7368 7372
M 25 LS-cl 7.7 1.029 N
NNN
occ F
FF
M 20 LS-cl 6.7 1.035 N
N N N-
- occ occ occ F
-
F
8 DS-cl 9.0 1.034
2+
N
3+ N -
301 1-3
F occ -
-
F 55 LS-cl 7.2 1.028 N
N
N
N-
1-3 occ
F occ -
-
0.5 mg/kg/day:
7463 7483 7466 7504
M 30 LS-cl 9.0 1.020 N
M 15 DS-cl 7.6 1.034 N
F 80 LS-cl 6.8 1.023 N
F 25
S-C 9.0 1.031
N
N tr N
F occ occ
N N N-
- - F occ F -
N
N
N-
occ occ
F occ occ
-
N N N-
- occ occ occ F
-
1.5 mg/kg/day:
7462 7486 7500 7501
M 25 LS-cl 8.0 1.033 N
M 30
S-C 9.0 1.027
N
F 30
S-C 7.7 1.024
N
F 10
S-C 8.8 1.037
N
NNN
F occ F
N
N
N-
occ -
F
F occ
-
N tr 1+ - occ occ F occ - -
N N N-
- occ
F
F occ
-
4.5 mg/kg/day:
7484 7485 7502 7503
M 105 M 12 F 30 F 30
LS-cl S-C
LS-C LS-C
7.7 1.034
9.0 1.033
8.8 1.028 8.8 1.025
N N N N
NNN
occ occ F occ
N N N-
- occ
F occ -
-
N tr 1+ -
- occ
F
F-
-
N tr N -
- occ
F occ F
-
M FMM-
M MMF-
M MF_ F-
F MF_ M-
c/*
002060
tr - Trace 1+ - Trace to slight 2+ - Slight to moderate 3+ - Moderate 4+ - Marked
S - Straw LS - Light Straw DS - Dark Straw LAm - Light Amber DAm - Dark Amber cl - Cloudy
C - Clear
N - Negative F - Few L - Loaded M - Many R - Rure
occ - Occasional QNS - Quantity not sufficient
None seen
hi tu
09
(D N> O'
FC-95:
TABLE 12
Croup, Monkey Number
Ninety-Day Subacute Rhesus Monkey Toxicity Stmly.
Individual Urinalysis Values - 1 Month.
Color
Uric
Volume and
Spec.
Occult Ke Leuco Erythro Elp.
Triple Cal. Acid Bac
Sex ml Appear. pH Grav. Protein Glucose Blood tones cytes cytes Cells Urates Phos. Ox. Crystals teria Casta
Control :
7355 7358 7368 7372
H
M F F
0.5 mg/kg/day:
7663 7683 7666 7506
M M F F
1.5 mg/kg/day;
7662 7686 7500 7501
M M F F
6.5 mg/kg/day:
7686 7685 7502 7503
M M F F
25 LS-C 6.8 1.030 35 LS-cl 6.0 1.025 15 S-cl 6.0 1.032 35 S-cl 5.5 1.032
25 LS-cl 5.5 1.026 25 LS-cl 5.5 1.029
6 LS-cl 5.5 1.028 20 LS-cl 5.5 1.035
30 LS-C 6.2 1.025 50 LS-cl 5.5 1.017 60 LS-cl 6.8 1.020 15 LS-cl 6.0 1.036
60 LS-cl 6.5 1.030 35 LS-cl 6.2 1.035
5 LS-cl 7.0 1.037 60 LS-cl 6.0 1.035
N N N N
N N N N
N N N
N
N
tr
N N
N
N
3+ 1-3
occ 1-3
F
F
N N 3+ -
occ 1-3
F
OCC
-
_
N
N
3+ 3-5
- occ
F
FM
-
N
N
N-
occ -
M
F occ
-
N N 3+ -
- occ F
FF
-
N N 3+ -
- occ F OCC F
-
N
N
3+ -
occ 1-3
F
FM
-
N N 3+ -
- occ
F OCC M
-
NN NN 1+ N
NN
3+ 3+ N occ 3+ occ
1-3 - occ - occ
1-3 occ
FF F occ F occ OCC F occ occ
-
-
N NN
1+ tr N N N 2+ 1+ 3+ 2+ -
occ occ
F
F
occ -
M F-
- 1-3 F
F-
- occ F occ -
-
M MM-
F-
F_ MM_ F-
F_
F_
M_
M-
F
M M
_
M-
1ST COPYAVAILABLE
002061
tr - Trace 1+ - Trace to slight 2+ - Slight to moderate 3+ - Moderate 4+ - Marked
S - Straw LS - Light Straw DS - Dark Straw LAia - Light Amber DAm - Dark Amber cl - Cloudy
C - Clear
N - Negative F - Few L - Loaded M - Many R - Rare
occ - Occasional QNS - Quantity not sufficient
None seen
hd fu oo n>
to
FC-95
TAUI.E 13.
Croup, Monkey Number
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
Individual Urinalysis Values - 3 Months.
Color
Triple Cal. Uric
Volume and
Spec.
Occult Ke- Leuco- Erythro- Epi. Urates Triple Cal. Ac Id Bac
Sex ml Appear. pH Grav. Protein Glucose Blood tones cytes cytes Cells Urates Plios. Ox. Crystals teria Casts
Control :
7355 7358 7368 7372
M
20
S-cl 7.0 1.036
N
N N 6+ - occ 8-10 F occ - -
H0
F
30
S-cl 7.5 1.026
N
N N 6+ -
- 1-3 M occ F -
F 130
S-cl 8.5 1.016
2+
H
6+ 1+ 1-3 occ 5-8 M
H-
-
0.5 mg/kg/day:
7663 7683 7666 7506
H
35
S-cl 7.3 1.028
N
H
30
S-cl 7.0 1.038
N
F 25
S-cl 9.0 1.021
N
F
35
S-cl 9.0 1.020
N
N
N
1+ occ occ
-
M occ H
-
N N 6+ -
- occ H
M OCC
-
N N N - - 5-8 M M F -
N 1+ N occ - 1-3 F F F -
1.5 ing/kg/day:
7662 7686 7500 7501
M
M
F F
50 100
55 25
S-cl 8.0 1.025 S-cl 8.0 1.023 S-cl 8.0 1.016 S-cl 8.0 1.033
N N N N
N N N - - 1-3 H F F _
NNN-
--
F FF _
N 6+ 3+ - - occ F OCC OCC _
N 6+ 3+
occ F
P OCC
6. 5 mii/ku/day:
7686 . 7685 7502 7503
M Died M Died F Died F Died
MMM-
M_ HMM-
H_ H M-
M
09
BEST COPY AVAILABLE
002062
137-092
tr - Trace 1+ - Trace to slight 2+ - Slight to moderate 3+ - Moderate 4+ - Marked
S - Straw LS - Light Straw DS - Dark Straw LAm - Light Amber DAm - Dark Amber cl - Cloudy C - Clear
N - Negative F - Few L - Loaded M - Many R - Rare
m e - Occasionili QNS - Quantity not .suff icient
None seen
d 03 OQ (D
0N05
FC-95: TABLE 14.
BEST COPY A V A I L A B L E 29
Ninety Day Subacute Rhesus Monkey Toxicity Study. Necropsy Observations, Terminal Sacrifice and Deaths.
S ite Lesion
Adrenals enlarged brown in c o lo r
C o n tro l
0.5 mg/kg/day
1.5 mg/kg/day
4 ,5 mg/kg/day
to XI - , u ave
o c "I ii 2 5
ir \
lfOA
r
X
CO m
mN
(b ha Z
vcN0On
M pe*n.
p*.
en
< P-H
X ha ha ha ha h. ha
ceosnj
PH
OT
r*H
oT NhO (PAH r.
<p>CO0rw oolAA*
O
lA r*
it
ChhTJO
pH.
*
lCOA
f*H
o*N
lA
orn
A PH.
x
Lung
y e llo w ish mice le s io n s
xx
xxx
x
XXX
dark red area
xx
yellow ish fo c i
x
x
p le u ra l adhesions
x
x
dark red raised focus
x
Mesentery nodule accessory sp lenic tissu e
x x
x
Thymus atrophied
xx
Stomach raised nodules edema, g lan d u lar mucosa
x
x
Soiall in testin e dark yellow th ick flu id ,
lumen
x
Large in testin e esophagostomum nodule void o f contents
x xxxxxxxx x
Ile o co lic o rific e congestion
x
L iv e r accentuated lobulations yellow ish focus/area
brown in c o lo r m ottled
xx
x
x X XX
X
X
M iscellaneous intram uscular subcutaneous hemorrhage, hindlim bs a b sce ss , r i g h t hand
x Died or s a c r ific e d in e x tre m is.
x
137-092
002063
TABLE 115.
Croup, Monkey Number Sex
Body Wt. kg
Control:
7355 7358
Mean
M
3.55 3.75
3.65
7368 7372
F 3.15 F 6.20
Mean
3.68
0.5 mg/kg/day;
7663 7683
Mean
M M
2.65 3.55
3.10
7666 7506
F 3.55 F 3.35
Mean
3.65
1.5 ing/kg/day:
7662 7686
M 2.80 M 3.05
Mean
7500 7501
F F
2.93
3.20 2.30
Mean
2,75
DLed on Study;
6.5 mg/kg/day:
7686 7685
M 2.15 M 2.50
7502 7503
F 2.65 F 2.55
Spleen g 7.
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Absolute: (Grams) and Relative: (7 Body Weight) Organ Weight:s, Terminal Sacrifice.
Liver 87
Adrenals 8 7x10
Kidneys g%
Testes
8 7. Ovaries
8 7x10*
Heart 87
Thyroid/ Parathyroid
8 7x10
Brain 87
Pituitary . 8 7x10*
3.70 6.01
3.86
2.81 6.03
3.62
0.10 0.11
0.11
0.09 0.10
0.09
87.69 68.68
77.99
59.58 95.60
77.59
2.66 1.83
2.15
1.89 2.28
2.08
0.77 0.79
0.78
0.85 0.80
0.83
0.22 0.21
0.21
0.27 0.19
0.23
15.67 16.60
16.06
15.06 16.25
15.66
0.66 0.66
0.66
0.68 0.39
0.63
1.06 1.60
1.22
0.35 0.30
0.33
0.03 0.06
0.03
1.11 0.71
0.91
16.69 16.83
16.76
13.39 16.96
15.17
0.61 0.60
0.60
0.63 0.60
0.61
0.557 0.885
0.721
0.485 0.857
0.671
0.16 0.24
0.20
0.15 0.20
0.18
85.21 91.63
88.52
71.29 88.03
79.66
2.40 2.45
2.42
2.26 2.10
2.18
0.069 0.068
0.059
0.061 0.071
0.066
0.14 0.18
0.16
0.19 0.17
0.18
2.68 2.19
2.66
6.07 6.85
6.66
0.10 0.06
0.08
0.11 0.16
0.13
81.09 86.79
83.96
92.19 87.28
89.76
3.06 2.66
2.75
2.60 2.61
2.60
0.61 0.58
0.60
0.81 0.59
0.70
0.23 0.16
0.20
0.23 0.18
0.20
11.66 15.32
13.68
16.16 12.75
16.65
0.66 0.63
0.66
0.65 0.38
0.62
0.65 0.95
0.70
0.67 0.11
0.39
0.02 0.03
0.02
1.89 0.33
1.11
9.35 15.01
12.18
16.11 13.00
13.56
0.35 0.62
0.39
0.60 0.39
0.39
0.444 0.580
0.512
0.693 0.747
0.720
0.17 0.16
0.17
0.20 0.22
0.21
83.26 86.83
85.05
89.28 76.26
82.77
3.14 2.45
2.79
2.51 2.28
2.40
0.062 0.070
0.056
0.065 0.062
0.066
0.16 0.20
0.18
0.18 0.19
0.18
3.39 2.66
2.92
3.51 1.55
2.53
0.12 0.08
0.10
0.11 0.07
0.09
80.63 85.38
83.01
86.15 16.03
50.09
2.88 2.80
2.86
2.63 0.70
1.66
0.65 0.80
0.73
0.91 0.79
0.85
0.23 0.26
0.25
0.28 0.36
0.31
11.82 13.79
12.81
16.76 10.77
13.77
0.62 0.65
0.66
0.52 0.67
0.50
0.59 1.77
1.18
0.32 0.11
0.22
0.02 0.06
0.06
1.00 0.68
0.76
11.70 16.85
13.28
15.68 9.66
12.57
0.62 0.69
0.65
0.68 0.42
0.45
0.627 0.902
0.765
0.772 0.814
0.793
0.22 0.30
0.26
0.24 0.35
0.30
87.56 87.53
87.55
77.43 74.35
75.89
3.13 2.87
3.00
2.42 3.23
2.83
0.056 0.086
0.071
0.055 0.056
0.056
0.20 0.28
0.24
0.17 0.24
0.21
1.22 2.06
2.21 1.25
0.06 0.08
0.08 0.05
80.55 79.73
86.20 78.66
3.75 3.19
3.25 3.08
1.65 1.82
1.16 1.70
0.67 0.73
0.63 0.67
15.73 18.17
15.08 16.97
0.73 0.73
0.57 0.59
0.56 0.62
0.15 0.08
0.03 0.03
0.57 0.31
11.13 12.33
15.20 11.65
0.52 0.49
0.57 0.45
0.805 0.37 81.29 0.824* 0.33" 77.60
0.709 0.27 77.11 0.668 0.26 81.33
3.78 3.10
2.91 3.19
0.060 0.060
0.500 0.070
0.28 0.16
1.89 0.27
BEST COPY AVAILABLE
002064
Group mean relative organ weights shown In this table were calculated by averaging the Individually calculated relative organ weights.
a - Weight of thyroids only.
137-092
hi fb OQ n>
GoO
FC-95: TABLE 16.
BEST COPY AVAILABLE " 8e 31
Ninety Day Subacute Rhesus Monkey Toxicity-Study.
Microscopic Observations.
Tissue Lesion
* >, u &DV 3=1 Ii
Brain
Spinal Cord
Peripheral Nerve
Eye foci of inflammatory cell infiltrates in palpebral/ocular conjunctiva foci of lymphoid infiltrates in lacrimal gland cystic tarsal glands
Pituitary large focus of lymphoid Infiltrate in pars nervosa
Adrenals foci of dystrophic mineralization focus of lymphoid infiltrate in medulla diffuse congestion acidophilic degeneration of individual to small groups of cells multifocal lipid depletion diffuse lipid depletion
Thyro id focus of Interstitial lymphoid infiltrates
Parathyroid
Tongue focal hyalin degeneration of muscle foci of inflammatory cell infiltrates in mucosal epithelium and lamina propria foci of inflammatory cell infiltrate in muscle Gongylonema sp. in mucosal epithelium
Trachea foci of inflammatory cell infiltrates in lamina propria foci of inflammatory cell Infiltrates in lamina propria and trachealis muscle
Esophagus foci of inflammatory cell infiltrates in lamina propria
Heart foci of interstitial lymphoid infiltrates small focus of myocardial necrosis
Control X 2b Cb
7358 M
m pmmx.
0M5D ipxn.
rsj r** Cl r*
l11i l1-l l1 1l l
222 3
l 11 3
33 2
333
11
1
2
-111
1 3
322
432 3 11
32 1
2 33
0.5 mg/kg/day z Urn 2b
n <0 Pv
=0 psxr*
nsOO xr*Tx
mpox.
11l1 11i1 11l1
1l 22
1.5 mg/kg/dav
XX
CMM3 XX*
s0
CO
pxxT.
o <poxn.
Oipxn*
4.5 mg/kg/day
XX
2b
* X Xr*x
tinf XxT
H
CM 9mP.
*Cl Oirxn.
11l1 11l1 11l1 11l1
ll11 ll1 1 ll11
l1 2
11 - 1
11l1
X
l111
1l
2 3
11i1
1 2
2
22 3
1111
2 332 4444 2332 5555 1111
1-l-
1 3
1
2
2
X
2232
---1
1 3
1
2
2
2223
1-11 111
4
3
111 2
3322
1 323
2
1
4 32
11 32
111 1
11
22
Code: 137-092
x - condition present 1 - not remarkable 2 - very slight
3 - slight 4 - moderate 5 - marked
6 - extreme - * not available * - died or sacrificed in extremis
002065
FC-95: TABLE 16. Cone.
BEST COPY AVAILABLE
Ninety Day Subacuta Rhesus Monkey Toxicity Study. Microscopic Observations.
Page 32
Tissue Lesion
*. u a. a V
3 JA JS
Su aS S:
L' Z Z
Control
ZSSfab
VI s 0 N
m
r*. f**
p
Aorta
Salivary Gland foci of interstitial lymphoid infiltrates decreased cell size, loss of cytoplasmic granules dilated ducts
Lung acute focal bronchitis focal perivascular neutrophil infiltrates focal aggregates of alveolar macrophages acarian pigment (peribronchiolar, peribronchial, perivascular foci of perivascular lymphoid infiltrates foci of peribronchial/peribronchiolar lymphoid aggregates lung mite in bronchiolar lumen acute focal bronchopneumonia chronic focal pleuritis interstitial pneumonia focal accumulation of blood and neutrophils in alveoli focal hemorrhage, focal interstitial fibrosis
Tonsil keratin-filled cyst foci of Inflammatory cell infiltrates in mucosal epithelium and lamina propria foci of inflammatory cell infiltrates in surface epithelium and tonsillar crypts
Thymus
Lymph Nodes diffuse reticuloendothelial cell hyperplasia
Scomach foci of inflammatory cell infiltrates in lamina propria foci of inflammatory cell infiltrates in lamina propria and submucosa foci of inflammatory cell infiltrates in lamina propria and serosa
Small Intestine multifocal cystic dilatation of duodenal glands
1111 2232
3
22 22 33 33
3
43 34 1111 -111 1
43 5
lili
0.5 mg/kg/day
z X (h b
1111 11
32
3 4
3
32 2 2 3
332
X
3 3
3
X
3 1111 1111
232 4
lili
1.5 mg/kg/dav 4.5 mg/kg/dav
Z X b fa
ZZ^b^S.
1111 ii
22
^r%p*ptnism 1111
i
44 4
2222 3
3333
2222
32 2
X
33
--
1
- 1-
3 1111 1111
42 3
3 1111
3 - - -111
3 11
23
1 a1 4
Code: 137-092
X - condition present
1 - not remarkable 2 - very slight
3 - slight 4 - moderate 5 - marked
6 - extreme - - not available
* - died or sacrificed in extremis
002066
TABLE 16. Coot.
BEST COPY AVAILABLE Page 33
Ninecy Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Tissue Lesion
z-.4>>s
u a
I
2 U \
ose
Control x s u. o.
mi/"i 3im/0"! xm<3 rmr-s r* r* r. r**
Cecum parasitic granuloma in mesentery parasitic granuloma in submucosa parasitic granuloma in muscularis foci of inflammatory cell infiltrates in submucosa, serosa and mesentery
Colon focal mucosal hemorrhage parasitic granuloma in muscularis and submucosa parasitic granuloma in serosa and mesentery foci of Inflammatory cell infiltrates in muscularis and serosa foci of inflammatory cell infHoraces in submucosa, muscularis and serosa foci of inflammatory cell Infiltrates in muscularis, serosa and mesentery parasitic granuloma in mesentery parasitic granuloma in muscularis chronic focal serositis
Rectum
foci of inflammatory cell infiltrates in muscularis
Liver portal inflammatory cell infiltrates multifocal bile duct proliferation acidophilic degeneration of individual to small groups of hpatocytes parenchymal Inflammatory cell infiltrates diffuse congestion neutrophilic infiltrate in sinusoids brown pigment in Kupffer cells focal/multifocal cytoplasmic vacuolation of hepatocytes small focus of heptocellular necrosis
Gallbladder foci of inflammatory cell infiltrates in lamina propria foci of inflammatory cell infiltrates in lamina propria and muscularis foci of hemorrhage in lamina propria and muscularis
Pancreas focal lymphoid infiltrates in perlpancreatic fat tissue decreased cell size, loss of zymogen granules focal interstitial lymphoid infiltrates
1 11 3
1111
322
2
3 33
2
3332
111
3
Code: 137-092
x - condition present 1 - not remarkable 2 - very slight
3 - slight 4 - moderate 5 - marked
0.5 mg/kg/day x r c.
f*O> f> xsO O r<>r* f<sr. r* i*-/.
1.5 mg/kg/day x x s* u.
4.5 mg/kg/day
x x &h i
<< r u"i
< JN
>r **ry- mO oir-n*
x 3 1 11 x
3
1 11 2
22
2
3
2223
233 3
1i
11
X
3
1111
3
222
3 3
4 2 3 22 2
ii
x
x x 3
1111
23
3
44
4
3
3
aa
33 4 1
23
32
6 - extreme m not available * m died or sacrificed in extremis
a - autolyzed
444 3
002067
FC-95: TABLE 16. Cont.
BEST COPY AVAILABLE Page 34
Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations.
Tissue Lesion
ayy
S
Spleen diffuse atrophy of lymphoid follicles
Kidney multinucleated lining epithelium in papillary ducts focal interstitial lymphoid infiltrates focus of glomerular fibrosis diffuse congestion microlith in renal tubules cystic glomeruli
Urinary Bladder foci of inflammatory cell infiltrates in lamina propria foci of inflammatory cell infiltrates in lamina propria and muscularis foci of inflammatory cell infiltrates in lamina propria and serosa
Prostate .foci of interstitial lymphoid Infiltrates lymphoid nodules/infiltrates in corpus cavernosum Sarcocystis sp. in muscle
Uterus inflammatory exudate in lumen of uterine glands small foci of hemorrhage in endometrium inflammatory cell infiltrates in endometrium focus of lymphoid infiltrates in serosa
Tesces prepuberal development
Ovaries small foci of dystrophic mineralization
Vagina foci of lymphoid infiltrates in mucosal epithelium and lamina propria foci of lymphoid infiltrates in muscularis focus of mucosal epithelium necrosis
Skeletal muscle Sarcocystis sp. foci of interstitial inflammatory cell infiltrates small foci of necrosis
Control
ac X u. au
ao ao CM in c P*.
rx* rx
0.5 mg/kg/day
XX
fa
en o
ofon
>o M3
T 3
T -T lA
P-. n fX fx
1111
1111
X 2232
X
1 33 3
XXX 2233
X -
223
1
2 3
33 3 2-
1
2
xx
1 '3
xx
1 2
43 22 2
11
32 3
43 22
111
2
1.5 mg/kg/day
X X 2fa fa
CM
xaoO
O 3
x3* m
r*x. Px.
3 m
rx
4,5 mg/kg/day
2 X fa
X <n m r*. px px.
1111
11 33
X 322
3 X
2322
2 22 4333 XX
11 3
4 11
X 1
2 2
xx 22
1
2 xx
11
32 2
1 11 X
34 11 1
2
Code: 137-092
x - condition present 1 - not remarkable 2 - very slight
3 - slight 4 - moderate 5 - marked
6 - extreme - not available * - died or sacrificed in extremis
002068
FC-95: TABLE 16. Cont.
BEST COPY AVAILABLE ,
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Microscopic Observations.
Tissue Lesion
Skin brown/black pigment in dermis dermal inflammatory cell infiltraces focus of subcutaneous hemorrhage hyperkeratosis focal hemorrhage in dermis multifocal foreign body granulomas
Mammary Gland dermal inflammatory cell infiltrates inflammatory exudate in ducts intraepidermal microabscess dilated ducts brown pigment in dermis hyperkeratosis
Bone/Bone marrow (Rib Junction) hypocellular marrow diffuse congestion
Control
X * Ok Sb
uwr**t
c/oI
co m
rmNs
p* p*. p-. p>*
0 .5 mg/kg/day x r s* a.
C-l f> SO -T >T sO vSTi
1*^ P. Pe
1 .5 mg/kg/day X X au Ci.
SM s>oC wo --o
P. ps, p. P*
4,5 mg/kg/day x x c*. is.
m M^ O iOn r. r* n.
XXXX
4
XXXX 22
3
X
XXXX
3
XX XX 2
33
2 32
X
XXXX
33
3
1111
32 3 22
X XXXX
33
1111
22
X
XX
X
34 3
1111
2
X X XX
3
1 4
3
3
Code: 137-092
X - condition present 1 - not remarkable 2 - very slight
3 - slight 4 - moderate 5 - marked
6 - extreme - not available * - died or sacrificed in extremis
002069
