Document a10QeG4JM489d3YbzqyMENby

A R m -0138 International Research and Development Corporation r^ l SPONSOR: COMPOUND: SUBJECT: 3M Company Fluorad Fluorochemical Surfactant FC-95 90-Day Subacute Rhesus Monkey Toxicity Study. Edwin I. Vice Pres Director lenthal, Ph.D. hat and 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:___ January 2, 1979 137-087 002070 International Research and Development Corporation 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. Clinical Studies ............................................ A. M e t h o d s ............................................... 1. General Procedure ................................. 2. Compound Administration ........................... 3. Observations ....................................... 4. Clinical Laboratory Tests ......................... a. Hematology..................................... b. Biochemistry ................................... c. Urinalysis ................ . . . . . ........ d. Statistical Analysis ........................... B. R e s u l t s ............................................... 1. General Behavior, Appearance and Survival ........ 2. Body W e i g h t s ....................................... 3. Laboratory Tests ................................... a. Hematology..................................... b. Biochemistry ................................... c. Urinalysis ..................................... IV. Pathological Studies ....................................... A. M e t h o d s ............................................... 1. Gross Pathology ................................... 2. Histopathology ..................................... B. R e s u l t s ............................................... 1. Gross Pathology and Organ Weights ............ . . 2. Histopathology ..................................... Table No. 1. Individual Body W e i g h t s ............................... 2. Individual Hematological Values ....................... Page 1 3 4 4 4 4 5 5 5 5 6 6 6 6 7 7 7 7 7 8 8 8 8 9 9 9 10 11 137-087 002071 International Research and Development Corporation T A B L E OF C O N T E N T S (Continued) Table No. Cont. 3. Individual Biochemical Values ....................... 4. Individual Urinalysis Values ........................... 5. Gross Necropsy Observations ofDeaths ................. 6. Absolute and Relative Organ Weights .................. 7. Microscopic Observations ............................... Page 12 13 14-15 16-17 18-21 137-087 002072 International Research and Development Corporation Page 1 I. SYNOPSIS Fluorad Fluorocheraical Surfactant FC-95 was administered to rhesus monkeys, in aqueous suspension at dosage levels of 10, 30, 100 and 300 rog/kg/day for 20 days. Two male and two female monkeys were initiated at each dosage level and also in a control group. The control group was treated only with distilled water. The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urine studies were conducted only in the control period. The study was terminated after 20 days because of the early deaths of the monkeys in all treatment groups. The monkeys treated with 300 mg/kg/day died between the 2nd and 4th days after the initiation of the study. From the first through the second day, the following signs of toxicity were observed: anorexia, decreased activity (from slight to severe before death), emesis with some diarrhea, body stiffening, general body trembling and twitching, weakness, convulsions and prostration. The administration of 100 mg/kg/day of the test compound led to death of all monkeys between the 3rd and 5th day of study. The monkeys treated at 30 mg/kg/day died between the 7th and 10th day and those treated at 10 mg/kg/day died.between the 11th and 20th day of study. At each of these dosage levels the toxic symptoms were the same as for the monkeys at the 300-mg/kg/day dosage level. However, the time of appearance of the toxic symptoms was related to dosage level. 137-087 002073 International Research and Development Corporation Page 2 All deaths were considered as resulting from compound effect. A yellowish-brown liver coloration noted at necropsy in several monkeys from the 100 and 300 mg/kg/day levels was the only gross finding which was considered compound-related. No histomorphologic basis for this finding was observed. Other gross and microscopic lesions were of an agonal nature or were those which are commonly seen in untreated monkeys. Organ weights of treated monkeys ware considered within nor mal limits. 137-087 002074 International Research and Development Corporation Page 3 il. COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below: _____________ Label_______________ Fluorad Flurochemical Surfactant FC-95 3M Stock No. 98-0207-0103-7 Lot 640 Net wt. 5 lbs. 2,2 kg Description white powder 137-087 002075 International Research and Development Corporation Page 4 m . CLINICAL STUDIES A. METHODS: 1. General Procedure: Ten mala (weighing from 3.05 to 3.80 kg) and ten female (weighing from 2.75 to .10 kg) rhesus monkeys obtained from Primate Imports, Port Washington, New York were initiated into this study. The monkeys were housed individually in hanging wire mesh "squeeze-type" cages and maintained in a temperature-, hum Hit*-- and light-controlled room. Purina Monkey Chow was fed twice each day and fresh apples were fed 3 times a weak. 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. Prior to initiation of compound administration complete physical examinations were conducted by a staff veterinarian. Only monkeys in good health were selected. This study was initiated on January 10, 1978. The study was terminated on January 30, 1978 because of the deaths of the monkeys. 2. Compound Administration: At the end of the conditioning period the monkeys were divided into 5 groups on a random basis, so that the initial average body weights were similar, as shown below: Group I II III IV V Number of Monkeys Male Female 22222 22222 Dosage Level mg/kg/day Cont1r0ol 10300 300 137-087 002076 International Research and Development Corporation Page 5 The test compound, suspended in distilled water, was adminis tered 7 days each week by gavage. All doses were contained in the same volume of water. Also the same 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 pharraacotoxic signs. Individual body weights were recorded weekly. General physical examinations were con ducted only in the control period, because of the early deaths of all treated monkeys. 4. Clinical Laboratory Tests: Blood and urine samples were obtained for analysis from all monkeys only in the control period. The monkeys were fasted overnight prior to the collection of blood and urine samples. a. Hematology; Hematological studies included: hemoglobin*, hematocrit,2 erythrocyte count, total and differential leucocyte counts, reticulo cyte count^, platelet count, prothrombin time, activated partial thromboplastin time^ (APTT). Mean corpuscular hemoglobin, mean cor puscular volume and mean corpuscular hemoglobin concentration were calculated. b. Biochemistry: Biochemical studies included: blood glucose, blood urea nitrogen, serum alkaline phosphatase, serum glutamic oxalacetic trans aminase, serum glutamic pyruvic transaminase, cholesterol, total protein, albumin, sodium*, potassium*, chloride, inorganic phosphate, Y-glutamyl transpeptidase**, creatinine phosphokinase*. 137-087 002077 International Research and Development Corporation Page 6 c. Urinalysis: Urinalysis included: measurement of volume, p H ^ and spe cific gravity; description of color and appearance; qualitative tests for protein1^, glucose^, ketones1-^, occult blood1-^ and microscopic examination of the sediment. d . Statistical Analysis: No statistical analysis on the laboratory tests was per formed because the laboratory tests were obtained for the control period only, however statistical analysis of body weights were con ducted. B. RESULTS: 1. General Behavior, Appearance and Survival: The monkeys from the 300-mg/kg/day dosage level group died between the 2nd and 4th day of the study. From the 1st or 2nd day the following signs of toxicity were observed: anorexia, decreased acti vity (slight to severe), emesis (frothy or food like emesis) and occa sional diarrhea. Antemortem observations were body stiffening and stiffened limbs, general body trembling and twitching, convulsions and prostration. The monkeys at the 100-mg/kg/day dosage level died between the 3rd and the 5th day of the study. The same toxic symptoms as the pre vious group were noted from the 2nd day. The administration of 30 mg/kg/day led to the same indications of toxicity, but appeared some days later. The deaths also occurred later; from the 7th to the 10th day of the study. The monkeys at the 10-mg/kg/day dosage level died between day 11 and 20 of the study. The signs of toxicity which appeared in the second week of the study were: anorexia, diarrhea, decreased activity, emesis, marked 137-087 002078 International Research and Development Corporation Page 7 weakness, prostration, general body trembling and tremoring and stif fening of the limbs. One of the monkeys had black stools and one had erythema of the face. There were no deaths nor unusual behavior in the control group. Occasionally, soft stools were noted. 2. Body Weights (Table 1): The monkeys from all treated groups lost body weight when the terminal body weight was compared with the initial body weight. In the first week of the study, there was no statistically significant decrease in the body weight of monkeys at the 10- and 30mg/kg/day dosage levels. 3. Laboratory Tests: a. Hematology: The control period values are contained in Table 2. b. Biochemistry: The control period values are contained in Table 3. c. Urinalysis: The control period values are contained in Table 4. 137-087 002079 International Research and Development Corporation Page 8 I V. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology; All experimental monkeys died during the study period. 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 fixa tion. A new study was initiated (137-092) utilizing the control monkeys from this study. 2. Histopathology; Microscopic examination of the following formalin fixed hema toxylin and eosin stained paraffin sections was performed for all animals in the experimental groups: adrenals aorta bone brain esophagus eyes gallb ladder 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 137-087 002080 International Research and Development Corporation Page 9 B . RESULTS: 1. Gross Pathology (Table 5) and Organ Weights (Table 6 ) : All deaths which occurred during the course of study were con sidered due to compound effect. Significant compound related gross pathologic findings were limited to the liver where vellowish-brown discoloration was observed in several monkeys from the 100 and 300 mg/kg/day groups. Other gross findings in these monkeys were of agonal nature or were those which are commonly seen in untreated monkeys. While contemporary control organ weight values were not available for comparison, the organ weight values of these monkeys appeared to be within normal limits. 2. Histopathology (Table 7 ) : No consistent histopathologic changes which were considered to represent a direct compound effect were observed in any tissues examined microscopically. Many agonal changes, including congestion, hemorrhage and lipid depletion of the adrenal cortex, were seen in monkeys from all experimental groups. No microscopic basis was seen for the yellowish-brown discoloration noted at necropsy in several monkeys from the 100 and 300 mg/kg/day groups. 137-087 002081 Fluorad Fluorochemical Surfactant FC-95: TABLE 1. Group, Monkey Number Sex 90-Day Subacute Rhesus Monkey Toxicity Study. Individual Body Weights, Kilograms. Control Week of Study 1212 3 Page 10 Control: 7355 7358 M M 7368 7372 F F Mean 10 mg/kg/day: 734 7 7354 M M 7369 7371 F F Mean 30 mg/kg/day: 7349 7351 M M 7370 7377 F F Mean 100 mg/kg/day: 7356 7359 M M 7373 7374 F F Mean 300 mg/kg/day: 735 7 7360 M M 7375 7379 F F Mean 3.10 3. 70 3.05 3.55 3.35 3.40 3.05 3.10 3.85 3.35 3.45 3.65 3.05 3.50 3.41 3.80 3.10 3.80 2.85 3.39 3.00 3.60 4.05 2.70 3.34 3.10 3.75 3.10 3.60 3.39 3.40 3.10 3.10 4.00 3.40 3.45 3.70 3.10 3.30 3.39 3.80 3.10 3.80 2.80 3.38 3.05 3.65 4.10 2.75 3.39 3.10 3.70 3.10 3.60 3.38 3.20 3. 75 3.25 3.65 3.46 3.05 3.05 3.05 3.70 3.21 2.90 2.65 2.50* Died 2.40* Died 2. 70 2.55* Died 3.25* Died 2.75 3.05 3.05 2.60 2.95 2.91 2.90* Died 3.10* Died 2.65* Died 2.50* Died 3.50* Died 2.70* Died 3.20* Died 2.45* Died 2.80* Died 3.40* Died 3.35* Died 2.60* Died 137-087 *Terminal weight not included in mean. *,00208 Fluorad Fluorochemical Surtactant FC-95: 90-Day Subacute Rhesus Monkey Toxicity Study. Individual Hematological Values - Control Period. Croup, Erythro Monkey cytes Number Sex 10"/cmra Mmo globln g/100 ml Hemato Retlc- Prothrombin crit Platelets ulocytes Time X 10 -Vcmm Z sec Activated P.T.T. ;.ec Leuco cytes 10 3/cmm NeutrophIls Seg. Non-Seg. ZZ lympho Eosino Mono Baso cytes phils cytes phils Z Z ZZ MCH MCIIC pur g/100 ml Control: 7355 M 4.48 7358 M 4.56 7368 F 4.51 7372 F 5.10 Mean 4.66 10 tng/kg/day: 7147 M 4.34 7354 M 5.04 7369 F 4.94 7371 F 4.96 Mean 4.82 30 mR/kg/day: 7149 M 4.69 7351 M 5.09 7370 F 4.48 7377 F 4.41 Mean 4.67 100 mg/kg/day: 7366 M 4.70 7359 M 4.99 7373 F 4.55 7374 F 4.51 Mean 4.69 300 mg/kg/day: 7357 M 4.46 7360 M 4.76 7375 F 4.01 7379 F 4.84 Mean 4.52 11.3 12.0 10.8 11.8 11.5 11.8 12.6 12.4 12.1 12.2 11.6 12.1 12.5 11.1 11.8 11.6 12.5 11.6 11.4 11.8 11.0 12.2 11.7 12.8 11.9 34 38 35 35 36 37 39 38 39 38 38 39 39 35 38 38 38 38 36 38 35 40 36 39 38 185 0.8 219 1.8 138 0.8 197 0.7 185 1.0 173 0.3 167 0.2 113 0.5 236 0.6 172 0.4 107 13 137 171 136 0.3 0.4 1.1 0.3 0.5 234 0.3 189 0.6 134 0.6 318 0.8 219 0.6 172 0.4 174 1.0 278 0.6 186 0.1 203 0.5 13 12 13 14 13 13 13 14 13 13 13 14 14 14 14 13 14 13 14 14 13 14 13 13 13 26 5.95 33 0 66 l 0 0 76 25 33 28 8.59 17 0 78 5 0 0 83 26 32 31 4.82 38 0 62 0 0 0 78 24 31 32 8.66 42 0 54 4 0 0 69 23 34 29 7.01 33 0 64 3 0 0 77 25 33 27 11.22 17 0 81 2 0 0 85 27 32 28 7.42 23 0 76 1 0 0 77 25 32 28 7.65 31 0 68 l 0 0 77 25 33 33 6.79 68 0 32 0 0 0 79 24 31 29 8.27 35 0 64 1 0 0 80 25 32 31 6. 76 33 0 65 2 0 0 81 25 31 31 10.80 68 0 32 0 0 0 77 24 31 31 8.99 40 0 59 1 0 0 87 28 32 29 6.95 55 0 41 4 0 0 79 25 32 31 8.38 49 0 49 2 0 0 81 26 32 26 11.61 38 0 61 1 0 0 81 25 31 29 6.12 18 0 82 0 0 0 76 25 33 28 5.64 47 1 49 3 0 0 84 25 31 28 6.84 52 0 45 2 0 1 80 25 32 28 7.55 39 0 59 2 0 0 80 25 32 29 6.90 49 0 48 2 J 0 78 25 31 30 5.95 47 0 53 0 0 0 84 26 31 26 5.61 63 0 35 2 0 0 90 29 33 30 7.11 45 0 52 2 0 1 81 26 33 29 6.39 51 0 47 2 0 0 83 27 32 Page 11 002083 137-087 Fluorad Fluorochemlcal Surfactant FC-95: 90-Day Subacute Rhesus Monkey Toxicity Study. TABI.E 3 Ind lvidual Biochemical Values - Control Period. Group, Alk. Phos. S.G.O.T. S.G.P.T. Monkey Glucose B.U.N. Int'l Int'l Int'l Number Sex mg/100 ml mg/100 ml unlts/l unlts/l units/1 Choles Total Potas Chlo Inorganic y - Glutamyl Creatinine terol Protein Albumin Sodium sium ride Phosphate Transpeptidase Phosphokluase mg/100 ml g/100 ml g/100 ml meq/1 meq/1 meq/1 mg/100 ml Sigma ii/ml Sigma u/ml. Control: 7355 M 122 20.0 1023 46 245 7358 M 103 18.2 1185 50 93 7368 7372 F F 144 106 34.0 26.4 1116 1023 30 41 90 76 Mean 119 24.7 ' 1087 42 126 10 mg/kg/day: 7347 M 130 26.8 1140 42 102 7354 M 77 43.6 1020 52 140 7369 F 111 32.0 924 50 94 7371 F 104 23.6 1080 30 109 Mean 106 31.5 1041 44 111 30 mg/kg/day: 7349 M 110 23.0 1020 30 93 7351 M 96 22.6 765 32 102 7370 F 115 23.0 1524 60 121 7377 F 99 21.0 460 29 65 Mean 105 22.4 942 38 95 100 mg/kg/day: 7356 M 107 25.1 1461 48 130 7359 M 81 24.5 743 33 47 7373 F 100 23.9 1290 30 86 7374 F 117 25.1 910 36 100 Mean 101 24.7 1101 37 91 300 mg/kg/day: 7357 M 86 25.0 867 46 125 7360 M 66 27.8 1110 50 107 7375 F 84 28.0 1470 35 95 7379 F 145 26.2 1437 55 126 Mean 95 26.8 1221 47 113 170 8.70 4.81 153 4.1 111 5.7 147 8.64 4.71 15 7 5.1 n o 6.6 146 9.08 5.00 156 4.6 112 5.3 206 9.00 4.74 156 4.0 111 5.0 167 8.86 4.82 156 4.5 111 5.7 182 7.92 5.49 165 5.7 112 8.4 226 9.88 5.60 165 7.0 116 7.5 149 8.14 5.07 154 5.8 112 5.8 143 8.34 5.20 162 5.9 116 5.4 175 8.57 5.34 162 6.1 114 6.8 180 8.70 5.01 159 5.3 113 7.0 213 8.64 5.20 158 5.7 113 5.8 151 9.22 4.80 194 9.40 5.12 159 4.8 15 3 4.1 no no 5.6 4.8 185 8.99 5.03 157 5.0 112 5.8 214 9.10 5.45 163 5.5 n o 7.0 177 9.08 4.80 150 3.8 109 6.0 201 9.08 5.51 162 5.4 112 6.6 163 8.74 5.30 159 5.3 114 6.4 189 9.00 5.27 159 5.0 111 6.5 180 9.28 5.26 227 8.50 4.99 127 8.74 5.51 183 8.98 5.44 179 8.88 5.30 160 5.6 156 4.7 15 7 4.6 162 4.5 159 4.9 no no in in in 6.8 5.4 5.7 6.1 6.0 49 56 35 29 42 49 55 26 47 44 54 67 65 34 55 77 44 30 47 50 44 46 40 47 44 20 11 16 20 17 10 24 7 10 13 9 16 8 11 11 16 78 11 26 33 10 30 11 8 15 Pag 002084 137-087 Fluorad Flviorochemi ca1 Surfactant FC-95: 90-0ay Subacute Rhesus Monkey Toxicity Study. TABLE 4. Individual Urinalysis Values. Group, Color Uric Monkey Volume and Spec. Occult Leuco- Erythro- EpL. Triple Cal. Acid Number Sex ml Appear. pH Grav. Protein Glucose Blood Ketones cytes cytes Ce 1.1s Urates Phos. Oxal. Crystals Bacteria Casts Control: 7355 7358 M M 7368 7372 F F Mean 10 mR/kR/dav: 7347 7354 M M 7369 7371 F F Mean 30 mR/kR/dav: 7349 7351 M M 7370 7377 P F Mean 100 mR/kR/day: 7356 7359 M M 7373 7374 F F Mean 300 KiR/kR/day: 735 7 7360 M M 7375 7379 F F Mean 30 15 30 50 31 25 10 20 32 22 30 12 40 20 26 14 25 13 33 21 10 35 30 30 26 S-cl DS-cl LS-C S-cl 7.6 1.030 7.5 1.040 7.0 1.021 7-5 1.032 7.4 1.031 N N H H S-cl S-cl S-cl S-cl 7.6 1.044 7.6 1.035 6.3 1.031 9.0 1.021 7.6 1.033 N H N H S-cl S-cl LS-cl S-cl 7.6 1.023 7.2 1.040 8.2 1.009 7.8 1.027 7.7 1.025 N H N H S-cl LS-cl S-cl S-C 7.8 1.040 8.0 1.024 5.9 1.041 8.5 1.038 7.6 1.036 N H H N S-cl S-cl DS-cl S-C 8.0 1.041 6.5 1.031 8.0 1.029 7.3 1.040 7.5 1.035 N N N N HN NN NN NH NM" - - F occ - - " occ M occ occ - H- ore ore occ occ - N- - F -- - NH NN NN NH N3+ - NN- 1-3 occ occ occ - occ occ occ - occ occ occ occ - F occ - - - - - NN NN 11 - occ - F - - N - - - occ F - N 1+ N - NN 3+ - - occ F - F - occ. occ - - - - N tr N - OCC -F -' - NN N- - -F -- - - NN NN NN- - o c c occ - occ - - - o c c occ - - NN NN tr N- NN N- N tr N - - OC V. F F- - -F F- - - occ - - oer occ - - - - M M F F F F M F F F M F F M F F M M F F Page 13 002085 137-087 Code: 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 ore - Occasional QNS - Quantity not sufficient norm - Normal - None seen Fluor ad Fluorochemlcal Surfactant : TABLE 5. 90-Day Subacute Rhesus Monkey Toxicity Study. Gross Necropsy Observations of Deaths . Page 14 Tissue Lesion a a> o uoLi zeO zeS 10 mg/kg/day z Z u. Urn r*. m oimpnff. OvC' PN. rnr*-. External scant body fat accessory nipple red fluid around mouth skin, dark red areas, chin area emaciated foamy material around mouth x Lungs yellow foci purplish/dark red foci adhesions to, and between parietal pleura congestion, edema yellowish cite lesions reddish purple discoloration emphysema failed to collapse; yellow air filled focus X X XX X Trachea, Bronchi bloody fluid Heart hemorrhage, subendocardial dark red foci, subendocardial/papillary muscle X X Esophagus hyperemia Abdominal Cavity mesenteric vessels congested esophagostomum nodules X Thymus involuted Stomach light brown mucoid contents clear frothy mucoid contents distended with normal ingests hemorrhage, pyloric area slightly thickened mucosa congestion dark red foci X X X Small Intestine yellow/pale mucoid material dark red areas pasty/pale yellow ingesta thickened, mucosa blood stained ingesta green mucoid material and gas X X 30 mg/kg/day Z Z u. U< & r-* fimn* Pfron-v PPPr*>-*. 100 mg/kg/dav ZZ mrvmD* cri*nn. rn p* nPn*-. 300 mg/kg/dav z= Q rp*n. PN. P. x XX XX X X X x X.. XX XX X X X XX X X X X X X X X x X X XX X X xx X X X X X X 137-087 002086 FluoTad Fluorochemical Surfactant: TABLE 5. Cont. 90-Day Subacute Rhesus Monkey Toxicity Study. Gross Necropsy Observations of Deaths. Page 15 7379 Tissue Lesion Large Intestines hemorrhage, mucosa petechiae, colon semi fluid contents thickened mucosa congestion mucosa tapeworm in lumen esophagostomum nodules raised reddish foci, mucosa lieo-Colic Orifice congested Gallbladder distended with dark green bile Liver white linear area dark red yellowish brownish discoloration nodule accentuated lobulations Kidney hydronephrosis pale congestion a >, u 3o Jci Xi .10 mg/kg/dav X Z b. b. 30 mg/kg/dav X X b. b. O' mH tOv. mPv Pmv 100 mg/kg/dav X X b, b. vlAO oIT>* Ptnv *Pv m m r-i ci N NNN 300 mg/kg/dav X X b. b. Pinv ipnv mpv m X X X X x X X X X X X X X X X X X X X X 137-087 002087 Fluorad*'/ Fluoroclicmical Surfactant : TABLE 6. 90-Day Subacute Rlieaus Monkey Toxicity Study. Absolute (Grams)i and Relative (% Bndy Weight) Organ Wo 1glits, Deaths. Group, Monkey Humber Testes/ Body P. Z Wt. Splecri Liver Adrenals Kidneys Ovarles Sex kg g Z g % g 7x10 R Z g ZxlO 10 mg/kg/day: 7347 7354 H 2.50 2.00 0.08 84.62 3.38 1. 36 0.54 20.42 0.82 1.34 0.05 M 2.40 2.24 0.09 85.19 3.55 1. 18 0.49 14.05 0.59 3.10 0.13 7369 7371 F 2.55 2.03 0.08 73.21 2.87 1.49 0.58 15.33 0.60 0.26 1.02 F 3.25 1.46 0.04 89.12 2.74 1.51 0.46 16.87 0.52 0.15 0.46 30 mg/kg/day: 7349 7351 M 2.90 2.17 0.07 98.89 3.41 1.48 0.51 18.07 0.62 3.02 0.10 M 3.10 1.99 0.06 99.69 3.22 1.19 0.45 16.57 0.53 1.17 0.04 7370 7377 F 2.65 2.09 0.08 73.99 2.79 0.94 0.35 16.34 0.62 0.17 0.64 F 2.50 1.30 0.05 65.68 2.63 1.21 0.48 14.70 0.59 0.21 0.84 100 mg/kg/day: 7356 7359 M 3.50 2.44 0.07 126.72 3.62 0.88 0.25 20.72 0.59 3.88 0.11 M 2.70 3.38 0.13 76.92 2.85 1.10 0.41 14.44 0.53 0.78 0.03 7373 7374 F 3.20 2.02 0.06 104.07 3.25 1.17 0.37 18.18 0.57 0.18 0.56 T 2.45 1.65 0.07 65.75 2.68 1. 16 0.47 15.27 0.62 0.12 0.49 300 mg/kg/day: 7357 7360 7375 7379 M 2.80 2.60 0.09 82.97 2.96 1.02 0.36 13.06 0.47 0.63 0.02 M 3.40 2.62 0.08 90.53 2.66 1.09 0.32 15.31 0.45 1.48 0.04 F 3.35 1.60 0.05 98.57 2.94 1.33 0.40 19.75 0.59 0.32 0.96 F 2.60 1.45 0.06 73.12 2.81 0.85 0.33 14.70 0.57 0.09 0.35 Page 16 002088 137-087 Fluorad Fluorochemlcal Surfactant: TABl.E 6. Cont. Group, Monkey Number 10 mg/kg/day: 7347 7354 7369 7371 30 mR/kg/day: 7349 7351 7370 7377 100 mg/kg/day: 7356 7359 7373 7374 300 mg/kR/day: 7357 7360 7375 7379 Sex M M F F M M F F M M F F M M F F 90-Day Subacute Rhesus Monkey Toxicity Study. Absolute (Grams) and Relative (X Body Weight) Organ Weights, Deaths. Body Wt. kg Heart g* Thyroid g ZxlO g Brain t 2.50 2.40 2.55 3.25 2.90 3.10 2.65 2.50 3.50 2.70 3.20 2.45 2.80 3.40 3.35 2.60 14.14 14.09 13.46 15.15 0.57 0.59 0.53 0.47 14.37 18.09 12.78 14.46 0.50 0.58 0.48 0.58 17.06 13.23 15.04 12.48 0.49 0.49 0.47 0.51 13.07 15.20 19.62 11.60 0.47 0.45 0.59 0.45 0.38 0.46 0.71 0.47 0.15 0.19 0.28 0.14 0.72 0.38 0.44 0.59 0.25 0.12 0.17 0.24 1.05 0.90 0.61 0.33 0.30 0.33 0.19 0.13 0.88 0.73 0.65 0.75 0.31 0.21 0.19 0.29 79.12 111.28 74.90 84.48 3.16 4.64 2.94 2.60 85.03 86.88 81.33 80.52 2.93 2.80 3.07 3.22 89.07 82.35 80.78 77.71 2.54 3.05 2.52 3.17 96.22 86.18 95.96 88.92 3.44 2.53 2.86 3.42 Pituitary g ZxW 0.050 0.038 0.077 0.082 0.20 0.16 0.30 0.25 0.038 0.048 0.051 _ 0.064 0.066 0.051 0.13 0.18 0.20 _ 0.24 0.21 0.21 0.050 - 0.070 0.058 0.18 - 0.21 0.22 Page 17 002089 137-087 not available Fluorad Fluorochemical Surfactant: TABLE 7. Tissue Lesion Brain Page 18 90-Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations, Deaths. 10 W K X OP*i-N*Jo|o3 <pmr -- X empn- BV u. h tOer*on*' ^fer*n4. 30 mg/kg/day X X (u to O' cnn* Wermn- errOn- epppn- 100 mg/kg/day X X to to teri*non* rem-n* erer*-nn* ner*sn-.. 300 mg/kg/dav X X to to f-* ehn* esp*no*, err1nn*- o *ere'n- 11 111 11111111111 Spinal cord - - 1111111111 111- Peripheral nerve focal lymphoid infiltrate in connective tissue 11111 11111 111 1 3 Eyes Pituitary small focal hemorrhage in pars nervosa small focal dystrophic mineralization small parenchymal cysts Thyroid Parathyroid 111111 111111111 1 111 1 1 111 1 32 XX X 33 X 1 1 1 111111 111 1111 111- 11 1 11 1- 1- 1- 1 Adrenal diffuse lipid depletion 555555555555A 555 small to large focal dystrophic mineralization X XXX X X X focal lymphoid infiltrate accessory adrenal tissue congestion A3 X 3A 33A 2 2 2 2 2 2 focal hemorrhage large focal necrosis with cholesterol clefts A X Trachea focal lymphoid infiltrate in lamina propria 11 2 33332 33 2 332 2 2 Lung acarian pigment focal perlbronehial/peribronchiolar lymphoid infiltrate focal hemorrhage diffuse congestion focal edema lung mite in bronchiolar lumen bronchiectas is interstitial inflammatory cell infiltrate focal perivascular lymphoid infiltrate focal bronchiolar smooth muscle hypertrophy focal aggregates of alveolar macrophages XXXXX XX XXX XXX XX X 332 2 2 2 332 33332 32 32 2 2 32 332 A A A 3 3A 3 2A XX XX 3 XX XX XX 3 3A A 33 3 3 Heart small focal myocardial necrosis focal interstitial lymphoid Infiltrate focal subendocardial hemorrhage focal subepicardial lymphoid Infiltrate focal interstitial neutrophil infiltrate 1 1 11 22 3 22 2 2 33 3 3 33 A5 3 A 33 3 332 22 3 137-087 Code: x - condition present 1 - not remarkable 2 - very slight 3 - slight A - -moderate 5 - marked 6 - extreme - not available OQ2090 Fluorad Fluorochemical Surfactant : TABLE 7. Cont. 90-Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations, Deaths. Page 19 7356 M |g Tissue Lesion Aorta muK > hi . j jj 10 mg/kg/day X X ft- to r- amfr Oso* -r*4* sr* mr-. mr-'* 30 mg/kg/day X XIfc y f* <r r* inn r* Nm r* N rr*>s sig/kg/dav X b- U. * fn atf in pv N r-s r-a S 300 mg/kg/dav X X Us U. fm* N WnC3 DnrI*T* f<r0nv-\ 11 111 1 11 1 1 1 11 11 1 Spleen diffuse congestion atrophy of lymphatic follicles 11 333 3 3 3 333 3334 4 3 4343 Mesenteric lymph node atrophy of lymphatic follicles focal hemorrhage Retropharyngeal lymph node congestion atrophy of lymphatic follicles Thymus cyst 11 1 11 1 A 4 33333 34 4 1 1111 3 33 _1 1. 11 - 111 XX _1 1 1 _1 1 1 1 Bone marrow (rib junction) 1 1 111 11 1 1 1 11 1 11 1 Bone -111111111111111 Submandibular salivary gland diffuse atrophy of serous alveolar cells focal interstitial lymphoid infiltrate 11 4 4 43 4 32 23 3 223333 22 Esophagus focal lymphoid infiltrate in lamina propria acute focal esophagitis focal hemorrhage in lamina propria focal neutrophil infiltrate in mucosa and lamina propria Gongylonema ap. 1 3 11 1 3 111 11 222 3 3 X Tongue 11 1 11 1 11 focal hemorrhage 23 focal lymphoid infiltrate in lamina propria 2 232 3 3 focal interstitial lymphoid infiltrate in muscularis 2 focal neutrophil infiltrate in mucosal epithelium 33 3 small focal necrosis in mucosal epithelium 33 focal edema 3 focal interstitial neutrophil infiltrate in muscularis 43 focal neutrophil infiltrate in lamina propria 4 Tonsil focal neutrophil Infiltrate in tonsillar epithelium atrophy of lymphatic follicle 2 3 23 _ 2 233 137-087 Code; x - condition present 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - not available 002091 Fluorad Fluorochemica1 Surfactant- TABLE 7. Cant. 90-Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations, Deaths. Page 20 Tissue Lesion - --..... - 10 mg/kg/day CO V K z z (fa (fa >- k. . x o1 r-. -mr- rtm-n O' r> P-1 h* crn- z2 30 mg/kg/dav z z As {fa O' rr3>** *m* mf- orr*n. 1rfr-"*>.. 7359 M 7360 M 100 mg/kg/da v z Kh b, \mC rr*o. rv- m r*. mrv mr- 300 mg/kg/da v z Jfa b- rnr- ITl rrr>-. Or-'. n r* Stomach . focal lymphoid infiltrate in lamina propria/ subaueosa focal submucosal edema focal submucosal hemorrhage 34 A 23 34 5 233 3 233 33 3 Small intestine atrophy of lymphatic nodule 11 1111 1 11 2 2 323 32 Large Intestine microgranuloma in muscularis atrophy of lymphatic nodule focal lymphoid infiltrate in submucosa focal hemorrhage in mucosa submucosal congestion Pancreas focal interstitial/periductal lymphoid infiltrate 1 11 1 1 1 X 23 32 23 3 2 2 32 4 4 1 'a A 11 1A a A 22 3 3 23 3 Liver diffuse congestion portal inflasnatory cell infiltrate focal bile duct proliferation small necrotic focus dark brown pigment-laden Kupffer cells parasitic granulomas large focal cytoplasmic vacuolation of hepatocytes 44 44444 44 444 44 44 3 222 33 2 23 3 2 3 X 4 Gallbladder focal lymphoid infiltrate in lamina propria -A A A 1 A 1 A AAA 11A 1 22 Kidney cyst diffuse congestion 34 43 focal lymphoid infiltrate in connective tissue 3 focal interstitial lymphoid infiltrate 22 23 3 multinucleated lining epithelium in papillary duct microlith in renal tubules ectopic adrenal rest X X 3 43 4 23 X X 443 223 X 3 44 3 23 X Urinary bladder 1 focal lymphoid infiltrate in lamina propria 2 focal neutrophil infiltrate in lamina propria 1 11 2 3333 1_ 33 3 Testis prepuberal development interstitial fibrosis 137-087 Code: XX 4 XX 1 X x - eontition present 1 - not resunrkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - - not available a - autolyzed XX 002092 Pittorad's FluoroChemical Surfactant: TABLE 7. Cont. 90-Day Subacute Rheaua Monkey Toxicity Study. Microscopic Observations, Deaths. Page 21 Tissue Lesion n I 1 >, b * -g os 10 mg/kg/day X X fr* fa so mf a tt nn fa \OC' e* fa fp*n cf an 30 mg/kg/day x X fr frk O' a %n Of a fa. fa ff af f an fsi f an 100 mg/kg/day Z X fr b xO vr> Om ' rf a> sf a mf a n f* rf a> mf a 300 mg/kg/dav X X b fr* ftenan fa Os o m f. f s O' fs Ovary small focal dystrophic mineralization 1 X 1 X 1 X 11 Prostate focal interstitial lymphoid Infiltrate `3 Uterus erythrocytes and inflammatory cells in lumen of endometrial glands focal hemorrhage in endometrium 1 2 1 2 1 2 1 3 11 1 2 Vagina focal lymphoid Infiltrate in lamina propria A3 33 3 1 3 Skeletal muscle Sarcocystis sp. Ill 11X111111111 X Skin focal aggregates of dark brown pigment in dermis focal lymphoid infiltrate in dermis diffuse acanthosis Masnary gland focal aggregates of dark brown pigment in dermis focal lymphoid infiltrate in lntra- and Interlobular connective tissue epidermal inclusion cyst hyperkeratosis proteinaceous fluid in dilated duets focal lymphoid Infiltrate in dermis accessory nipple Skin (tattoo) focal aggregates of black/dark brown pigment in dermis focal hemorrhage in dermis focal hesurrhage in aubcutis xxxx 1 xxxxxxxxxx 32 2 33 X xxxxxxxxxx X X 3 A X 1 XXXX 23 X 3 33 2 1 X X X XX X X 33 xxxxxxxx 3 Miscellaneous focal lymphoid infiltrate, corpus spongiosum congestion and hemorrhage, chin akin 3 A 137-087 Code: x - condition present 1 - not r'emarkable 2 - very slight 3 - slight A - moderate 5 - marked 6 - extreme - a not available a - autolysed 002093