Document rBgQ0v2VN302x6zKX750NE0wJ

InternatioRneaslearcahndDevelopmenCtorporation 335 SPONSOR: COMPOUND: SUBJECT: 3M Company Fluorad4D Fluorochemical Surfactant FC-95 90-Day Subacute Rhesus Monkey Toxicity Study. Edwin 1. Go,4aeuthal, Ph.D. Vice Pres ut and Director IOtResearch 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 Larve Animal Toxicology Date:- January 2, 1979 137-087 InternatioRneaslearcahndDevelopmenCtorporation TA BL E 0 F C 0 N T E N T S 1. Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . II. Compound . . . . . . . . . . . . . . . . . . . . . . . . . . III. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . A. Methods . . . . . . . . . . . . . . . . . . . . . . . . 1. General Procedure . . . . . . . . . . . . . . . . . 2. Compound Administration . . . . . . . . . . . . . . 3. Observations . . . . . . . . . . . . . . . . . . . . 4. Clinical Laboratory Tests . . . . . . . . . . . . . a. Hematology . . . . . . . . . . . . . . . . . . . b. Biochemistry . . . . . . . . . . . . ... . . . . c. Urinalysis . . . . . . . . . . . . . 0 . * . d. Statistical Analysis . . . . . . . . . . . . . . B. Results . . . . . . . . . . . . . . . . . . . . . ... . 1. General Behavior, Appearance and Survival . . . . . 2. Body Weights . . . . . 0 * . . 0 0 0 . 0 0 0 0 . 3. Laboratory Tests . o o . o .. o .. . . . . a. Hematology . . . . . . . . . . . . . . . . . . . b. Biochemistry . . . . . 0 * 0 . . 0 . . * . * c. Urinalysis . . . . . . . . . . . . . . * . IV. Pathological Studies . . . . . . . . . . . . . . . . . . . . A. Methods . . . . . . . . . . . . . . . . . . . . . . . . 1. Gross Pathology . . . . . . . . . . . . . . 0 . 2. Histopathology . . . ... . . . . * . . . . . . . . . B. Results . . . . . . . . . . . . . . . . . . . . . . . . 1. Gross Pathology and Organ Weights . . . . . . . . . 2. Histopathology . . . . . . . . . . . . . . . . . . . Table No. 1. Individual Body Weights . . . ... . . . . . . . . . . . 2. Individual Hematological Values . . . . . . . . . . . . Page I 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 InternatioRneaslearcahndDevelopmenCtorporation T A B L E 0 F C'O N T E N T S (Continued) Table No. Cont. 3. Individual Biochemical Values . . . . . . . . . . . . . 4. Individual Urinalysi'sValues . . . . . . . . . . . . . . 5. Gross Necropsy Observations of Deaths . . . . . . . . . 6. -kbsolu@@e and Relative Organ 'Nlei,@,,ht.s . . . . . . . . . 7. Microscopl.c Observations . . . . . . . . . . . . . . . . Page 12 13 14-15 16-17 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 1 SYNOPSIS Fluoradt Fluorochemical Surfactant FC-95 was administered to rhesus monkeys, in aqueous suspension at dosage levels of 10, 30, 100 and 300 mcr/'Kg/dayfor 20 days. Two male and two female monkeys were initiated at each dosage level and also in a control group. The control group .7astreated only with distilled water. The monkeys were observea twice daily for general physical appearance and behavior and phar-nacotoxic S2L,07,ls'.llodywe4@,-htswere recorde@ll@,qeekly. Tiematolog-A*.calb,iochemical 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 oroups. 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 llth 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 -wasrelated to dosage level. 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 2 All deaths were considered as resulting from coinpoundeffect. A yellowish-brown liver colorati'onnoted at necropsy in several monkeys from the 100 and 300 mg/kg/day levels was the only @,=7rosfsinding @qhich was considered compound-related. No histomorpholo,,,,ibcasis for this find4.nLw.a-s observed. Other corossand microscopi-- lesions were of an a,yonal -iature or -@7e.-tehose -.qli4.acrhe com-@ionl7seen 4@-i monkeys. Or-an wej.ghts of treated monkeys were cons@4.dere@w4ill-hianorMal 14-mits. 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 3 CO@MPOLTND '@he c--mpound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below: Label Fluorad(DFlurochemical Surfactant FC-95 3M Stock No. 98-0207-0103-7 To 'N-@ewtt. 5 2,2 kg Description white powder 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 4 CLINICAL STUDIES A. METHODS: 1. General Procedure: Ten ma'Le (weighing from 3.05 to 3.80 kg) and ten female (wei,,Y,hinfarom 2-.75 to 4.10 ka) rhesus -ion'r-evosb-6ai-iedfro-nPrimat@ Imports, Port Washinooton,Neu,York were initiated into this study. The monke,,,st'ller'enouse,-4z.ridividuall-,i7n lianai-.,-icqire ,.iesl"isqueeze-@vpe cac,es and ma4@-f-ai-nedin a an4 rooo. Purinat) -',.IonkCehyow(Dwas fed twice each day and fresh apples were fed 3 times a wee!--. '.iaterwas available ad libitum. During the conditioning period the monkeys were tiittooedon 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 IV v Number Male 2 2 2 2 2 of Monkeys Female 2 2 2 2 2 Dosage Level mg/kg/day Control 10 30 100 300 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 5 The test compound, suspended in distilled water, was administered 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 aroup. iidividual daily doses were based upon the body weights, obtained weekly. 3. Observations: The monkeys were observed twice daily for general physical appearance, behavior and pharmacotox'@c siyns. Individtial bodv wei--,htswere recorded weeklv. General physical examinations were conducted 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: hemoglobinl, hematocrit.2 erythrocyte count3, total3 and differential leucocyte counts, reticulocyte count4, platelet count5, prothrombin time6, activated partial thromboplastin time7 (APTT). Mean corpuscular hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentration were calculated. b. Biochemistry, Biochemical studies included: blood glucose8, blood urea nitrogen8, serum alkaline phosphatase8, serum glutamic oxalacetic transaminase8, serum glutamic pyruvic transaminase8i cholesterol9, total protein9, albumin8, sodiumio, potassiumio, chloride9, inoraanic phosphate9 . Y-glutamyl transpeptidasell, creatinine phosphokinasel2. 137-087 InternatioRneaslearcahndDevelopmenCtorporation Page 6 c. Urinalysis: Urinalysis included: measurement of volume, pHl3 and spe- cific gravity; description of color and appearance; qualitative tests for proteinl3, *42lucosel3, ketones 'L3, occult blood13 and microscopic examination of the sedimenl,. d. StatisticalAnalysis: No statistical analysis on the laboratory tests was per- orr"edbecause the laboratory tests wera obtained 'L or the contr3l period only, however statistical analysis of body weights were conducted. B. RESULTS: 1. General Behavior, Appeara-,iceand Survival: The monkeys from the 300-mg/kg/day dosage level group died between the 2nd and 411-hday of the study. From the Ist or 2nd day the following signs of toxicity were observed: anorexia, decreased activity (slight to severe), emesis (frothy or food like emesis) and occasional 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 st.udy. The same toxic symptoms as the previous 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 InternatioRneaslearcahndDevelopmenCtorporation Page 7 weakness, prostration, general body trembling and tremoring and stiffening 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 InternatioRneaslearcahndDevelopmenCtorporation Page 8 IV. PATHOLOGICAL STUDIES A. NETHODS: 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 2. from this study. 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 gallbladder heart (with coronary vessels) duodenum ileum jejunum cecum colon rectum kidneys liver lung skin mesenteric lymph node retropharyngeal lymph node mammary gland nerve (with muscle) spleen pancreas prostate/uterus rib junction (bone marrow) salivary gland lumbar spinal cord pituitary stomach testes/ovaries thyroid parathyroid thymus trachea tonsil tongue urinary bladder vagina tattoo and any other tissue(s) with lesions 137-087 InternatioRneaslearcahndDevelopmenCtorporation 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 yellowish-broun discoloration was observed in several monkeys from the 100 and 300 mg/kg/day groups. other gross findinas in these monkeys were of agonal nature or were those which are co.T-Tonlyseen 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 FluoradOFluorochemical Surfactant TABLE 1. Group, Monkey Number Sex Control: 7355 m 7358 m 7368 F 7372 F Mean 10 mg/kg/day: 7347 m 7354 m 7369 F 7371 F @lean 30 mg/kg/day: 7349 m 7351 m 7370 F 7377 F Mean 100 mg/kg/day: 7356 m 7359 m 7373 F 7374 F Mean 300 mg/kg/day: 7357 m 7360 m 7375 F 7379 F Mean 9P--Day Subacute '-'.-les@ulsonkey Study. Individual Body Weights, Kilograms. Page 10 Control 1 2- 1 Week of Study 2 3 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 -i140. 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.nv5 3.70 3.21 2.90 2.65 2.50* Died 2.40* Died 2.70 2.55* D4 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. Flteorad* Fluoroctiemical Stirfactant FC-95: TABI.E 2. Group, Erythro- Hk)nkey cites Number Sex 10 /cmm 90-Day Subacute Rheaus floitkeyToxicity Steitly. Individual Hematologfcal Values - Control Period. Ilemo globln g/100 ml flematocrit 2 Platelets 103/cm Retic- ulocytes 2 Prothrombin Time see Activated P.T.,r. I.ee Leuco- c@tc'" 10 Ne!!tr2L)II-tis Seg. Nt)ii--Seg. I.yn4ilifp-Ef,.qlllo-Flo cytefy plitis cy % Control: 7355 m 4.48 11.3 34 185 0.8 13 7358 m 4.56 12.0 38 219 1.8 12 7368 F 4.51 10.8 35 138 0.8 13 7372 F 5.10 ii.a 35 197 0.7 14 Flean 4.66 11.5 36 185 1.0 13 0 d a1: 7347 m 4.34 11.8 37 173 0.3 13 7354 m 5.04 12.6 39 167 0.2 13 7369 F 4.94 12.4 38 113 0.5 14 7371 p 4.96 12.1 39 236 0.6 13 Mean 4.82 12.2 38 172 0.4 13 30 mg/ K/day: 7349 m 4.69 11.6 38 107 0.3 13 7351 m 5.09 12.1 39 136- 0.4 14 7370 F 4.48 12.5 39 137 1.1 14 7377 r 4.41 11.1 35 171 0.3 14 14ean 4.67 11.8 38 136 0.5 14 100 mg/kglday: 7356 m 4.70 11.6 38 234 0.3 13 7359 m 4.99 12.5 38 189 0.6 14 7373 F 4.55 11.6 38 134 0.6 13 7374 p 4.51 11.4 36 318 0.8 14 Mean 4.69 11.8 38 219 0.6 14 22!1 - A/kl/d-y: 7357 N 4.46 11.0 35 172 0.4 13 7360 m 4.76 12.2 40 174 1.0 14 7375 F 4.01 11.7 36 278 0.6 13 7379 F 4.84 12.8 39 186 0.1 13 Mean 4.52 11.9 38 203 o.5 13 26 5.95 33 28 8.59 17 31 4.82 38 32 8.66 42 29 7.01 33 27 11.22 17 28 7.42 23 28 7.65 3t 33 6.79 68 29 8.27 35 31 6.76 33 31 10.80 68 3t 8.99 40 29 6.95 53 31 8.38 49 26 11.61 38 29 6.12 18 28 5.64 47 28 6.84 52 28 7.55 39 29 6.90 49 30 5.95 47 26 5.61 63 30 7.11 45 29 6.39 51 4) 0 0 (1 0 f 0 (1 0 0 0 1 0 0 0 0 0 0 0 66 78 62 54 64 81 76 68 32 64 65 32 59 41 49 61 82 49 45 59 48 53 35 52 47 1 0 5 0 0 0 4 0 3 0 2 0 1 0 1 0 0 1 0 2 0 0 1 0 4 0 2 0 1 0 0 0 3 0 2 0 2 2 1. 2 2 0 2 0 137-087 Fluoradm FluorochemtcAl StirfiictilFlCi-t95: TABI.E 3. Group, Monkey Glucose Number Sex mg/100 ml B.U.H. mg/100 mi 90-Day Subacute RiiestiFMionkey Toxicity Study. individual BlocliemtralVal.ties- Cc)ntrolPerlexi. Alk. Phc)s. S.C.O.T. int'l int'i units/i units/I S.G.F.T. lntli units/] Cliolesterol fng/100 ml Total. Protein Albtimin g/100 mi. g/100 MI PotaqSodium sium rlde ,q/t meq/1 meq/t Inorganic Pliosphate mg/100 ml Control, 7355 m 122 20.0 1023 46 245 7358 m 103 18.2 1185 so 93 7368 F 144 34.o 1116 30 90 ,7372 p 106 26.4 1023 41 76 Mean 11.9 24.7 1087 42 126 10 mg/kg/day: 7347 m 130 26.8 1140 42 102 7354 77 43.6 1020 52 140 7369 F Ill 32.0 924 50 94 7371 F 104 23.6 1080 30 109 Mean 106 31.5 1041 44 III 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 LOO mg/kg/day: 7356 m 107 25.1 1461 48 130 7359 H al 24.5 743 33 47 7373 p 100 23.9 1290 30 86 7374 F 117 25.1 910 36 100 Mean 101 24.7 1101 37 91 300 ma/kg/day: 7357 H 86 25.0 867 46 125 7360 66 27.8 itio 50 107 7375 F 84 28.0 1470 35 95 7379 p 145 26.2 1437 55 126 Mean 95 26.8 1221 47 113 170 8.70 4.Bt 153 4.1 111 5.7 147 8.64 4.71 157 5.1 l@to 6.6 146 9.08 5.00 156 4.6 112 5.3 206 9.00 4.74 156 4.0 Ill. 5.0 167 8.86 4.82 156 4.5 III 5.7 182 7.92 5.49 165 5.7 112 8.4 226 9.88 5.60 165 7.0 lt6 7.5 149 8.14 5.07 154 5.8 1.12 5.8 143 a. 34 5.20 162 5.9 116 5.4 175 8.57 5.34 162 6.1 114 6.8 iso 8.70 5.01 159 5.3 113 7.0 213 8.64 5.20 158 5.7 113 5.8 151 9.22 4.80 159 4.8 110 5.6 194 9.40 5.12 153 4.1 110 4.8 185 8.99 5.03 157 5.0 112 5.8 214 9.10 5.45 163 5.5 110 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 Ill 6.5 ISO 9.28 5.26 160 5.6 il() 6.8 227 8.50 4.99 156 4.7 110 5.4 127 8.74 5.5t 157 4.6 III 5.7 183 8.98 5.44 162 4.5 III 6.1 179 8.88 5.30 159 4.9 it]. 6.0 137-087 Fluorocitemical StirfactantFC-95: TABLE 4. Group, Monkey Number Volume Sex ml Color and Appear. 90-Day Subacute Rliesustionkey T(ixtelty Stiitty. Individual Urinelysin Values. Spec. Occult leuco- Erytitro- Ept. Triple Cal. pil Grav. Protein Glucose Blood Ketones cytes cytes Cel.19 I)rites Pling. Oxal. Control: 7355 H 7358 H 30 S-cl 7.6 1.030 N 15 DS-ct 7.5 1.040 N 7368 7372 F 30 p 50 LS-C 7.0 1.021 N S-cl 7.5 1.032 N Mean 31 7.4 1.031 10 mit/kg/day: 7347 25 7354 m 10 7369 7371 F 20 r 32 Mean 22 S-el 7.6 1.044 N 8-cl 7.6 1.035 N S-el 6.3 1.031 N S-el 9.0 1.021 N 7.6 1.033 30 mg/kglday: 7349 3() S-el 7.6 1.023 m 7351 m 12 S-cl 7.2 1.040 N 7370 7377 F 40 LS-cl 8.2 1.009 N F 20 S-cl 7.8 1.027 N Mean 26 7.7 1,.025 100 mg/kg/day: 7356 m 14 7359 m 25 S-et 7.8 1.040 N t.S-cl 8.0 1.024 n 7373 F 13 7374 F 33 S-cl S-C 5.9 1.041 8.5 1.038 Mean 21 7.6 1.036 300 mg/kg/day: 7357 H 10 7360 m 35 7375 F 30 7379 F 30 Mean 26 S-cl 8.0 1.041 S-cl 6.5 1.031 N DS-cl 8.0 1.029 N S-C 7.3 1.040 N 7.5 1.035 N N N N N N N N N N N N F occ H occ oce occ orc occ occ occ F N N N N N N N N N 3+ - N - N - 1-3 nec occ occ - oce occ oce occ occ occ arc - p oce n N N N ii. - oce N - - F - occ F N 1+ N - N N 34- - act, F - O(IC oce - N tr N - occ - F - N N N - - F - N N N N N - N - - 04@r occ - occ - Oct, occ - N N tr - - N N N - - N N N - - N tr N - - F F - F F - Oct, - - act* occ - 137-087 Code: tr - Trace 1+ - Trace to slight 2+ - Slight to moderate 3+ - Moderate 4+ - Harked S - Straw LS - Light Straw DS - Dark Straw lAm - Light Amber DAm - Dark Amber cl - Cloudy C - Clear N - Negative QNS - fltiiiitityootntifficien F - Few L - Loaded norin - ti,)rma.1 N@,iiesecii H Ft-lily R Rare ot-C 0(*c,a4l-in.11 rt-0 rt Istr ILp I--- :r 0 cr a so -0 0 00 0 9 lp,a rt pr .1 01-11 ,.Itole, if 9* IV or 0 '4 0 0 14 0111 n 1- 1 1m4 9 m t@ 0 a 1-0 I* rt Ir "1. 0 rt I, 96 1% cr rt 0- 00'C" F@14 "0 "0 L o A ir C6 0 :or 00 0 10 eg "0 I o -o,-, "0'too @:lr 0 ft 96 npr C6 r, 0rt 0 a. to- IL n0 v 0 ft ti tt CL OM 0 004 gL Fos k : rt on 0 0 I-L r 12. 93 00 In " 0 0 rv cr 03 4 on m to to fo a, (L COL 0 00 I. ti 0 te g tr @h po nn le l@ r. cl m .Vic n ft a in go be .14 r c so g3 4 P. 4 CL 0 m " a "0 0 Go 903 0.0 n IOL@0- gg 0 n -4 t-w ell 0.00 00.n .,o 0 rt 0 t- a o cr 0 00 rt rr 1 101 CL p@ am CL : totj n' C6 10, 1 rr rt tm ri et 0r a. I-L0 40 CL - 0 ri 0 cr ry I-- Its 0 0 0 ri 00 tr I- tr n a :11-1 n* 00 0 C6 lb m 0 0 ts 0 0 11 p 136 t3 bt Fitiorad(,.' vllioroclkclqlcal Surfactant: TABLE 6. 90-Day Stil,acuteRfiestinMonkey I'oxicII y S tit(ty. Absolute (Grams) and Relat[ve (% RnclyWetglit)organ Welglits,I)Patlis. Group, Monkey Number Body Wt. Spleen Liver Sex kg 9 2 9 Adrenil.9 g- 9 10 mg/kg/day: 7347 7354 7369 7371 30 mg/kglday: 7349 7351 7370 7377 100 mg/ka/day: 7356 7359 1373 7374 300 mg/ka/day.- 7357 7360 7375 7379 m 2.50 2.00 0.08 84.62 3.38 1.16 o.54 20.42 m 2.40 2.24 0.09 85.19 3.55 1.18 (1.49 14.05 F 2.55 2.03 0.08 73.21 2.87 1.119 0.58 15.33 F 3.25 1.46 0.04 89.12 2.74 1.51 0.46 I(s.87 m 2.90 2.17 0.07 98.89 3.41 1.48 o.51 18.07 m 3.10 1.99 0.06 99.69 3.22 1.39 ().45 16.57 F 2.65 2.09 0.08 73.99 2.79 ().911 0.35 16.34 F 2.50 1.30 0.05 65.68 2.63 1.2t 0.48 14.70 H 3.50 2.44 0.07 126.72 3.62 ().118 0.25 20.72 H 2.70 3.38 0.13 76.92 2.85 1.10 ().41 14.44 F 3.20 2.02 0.06 104.01 3.25 1.17 0.37 18.18 F 2.45 1.65 0.07 65.75 2.68 1,.16 0.47 15.27 m 2.80 2.60 0.09 82.97 2.96 t.fl2 0.36 11.06 m 3.40 2.fi2 0.08 90.53 2.66 1.()9 0.32 15.31 F 3.35 1.60 0.05 98.57 2.94 1.33 0.40 19.75 F 2.60 1.45 0.06 73.12 2.81 O.fis 0.31 14.70 137-087 Fitiorad* Fluorocitemical Stirfnctant: TARI.E 6. Cont. Group, Monkey Ntimber Sex 10 mg/kg/day: 7347 m 7354 m 7369 F 7371 F 30 mg/kg/da 7349 m 7351 m 7370 F 7377 100 mg/kg/day: 7356 m 7359 m 7373 F 7374 p 300 ma/ka/day: 7357 m 7360 H 7375 F 7379 F 90-Day Subacute Rheous Monkey Toxicity Study. Absolute (Grano) and Relative (% Body Weight) organ Welplitm, Deaths. Body Wt. Heart Thyroid kg 9 2 9 Zx]O 9 Brain 2.50 2.40 2.55 3.25 2.90 3.10 2.65 2.50 3.50 2.70 3.20 2.45 2.00 3.40 3.35 2.60 14.14 14.09 13.46 15.15 14.37 18.09 12.78 14.46 17.06 13.23 15.04 12.48 13.07 15.20 19.62 11.60 0.57 0.59 0.53 0.47 0.50 0.58 0.48 0.58 0.49 0.49 0.47 0.51 0.47 0.45 0.59 0.45 0.38 0.46 0.71 0.47 0.72 0.38 0.44 0.59 1.05 0.90 0.61 0.33 0.88 0.73 0.65 0.75 0.15 0.19 0.28 0.14 0.25 0.12 0.17 0.2to 0.30 0.33 0.19 0.13 0.31 0.21 0.19 0.29 79.12 3. 111.28 4. 74.90 2. 84.48 2. 85.03 2. 86.88 2. 81.33 3. 80.52 3. 89.07 2. 82.35 3. 80.78 2. 77.71 3. 96.22 3. 86.18 2. 95.96 2. 88.92 3. 137-087 not available gTqTTTTAT 3OU - ma=za 9 17 *282apouL 2q2lls - E 3mgrls alqiqzv=z 2ou - T 3useazd UCT37PUOO - x :Vpoo LBO-LET 83vz3TT;UT tTlqdoz3nva TvT3T3#za3ul Tvz@o; 839-IT;U,; pToqdmXl lv-;pzwo-;doqnt TV-JO; aswqzu@q Ivlp.%Tzopuaqns Twoo; *3w=lT;ul PTOqdmAT TVIITZSZ*3ul TT*O; 67*0-z*vu TITP-2900im TWOO; TTWUI c E x x x x2 E x xx E I z c E ly z c c rc z rz c z c cc E z c E z rz E c c x x x x x x x x xx x x x x x x 9*Swqdoxom -ZTTOOATV ;0 983838.ZSSI Ltlda=.z*diq sloonn q2oome twloTq@wzq 0292211;ul PTOqdmAl zwlnorwATiod lv*o; TII*O; TT*O; 02W=TT;ul TIVO -1 "02@RT;u7 TTTZTZAZVZUT sTslmzo-;qzaa2q zvlo,;iq-.ziqxTazT= 2-1 vmap* lw*o; UOT269juco Von;;-;p 02TRzaamaq TV=; pToqdmAl 021.zzll;ul 2wTorq*uozq-Tzed/IvTq=ozq-;zad Iv-4c; 2umd7d tmlzwov rz z c c z E c z *72daid watmwl tr; 82IZ21';;Ul P'TOqd"l TWOO; x 63;012 10.193901043 QZTA 27901-00U TWOO; 032VT *Swtl=meiq ITZO; x x x x xxx s Onss';2 TIMB-ZPT LIOBB*z*w 821-12TT;UT PT*qdmil Tvzo; x UOIIVZTITIVUTM oTqdoi2s,&p TV=; OIXRT 02 TIMS uoT2aldap p-;dtlson;;-;p Twus.1py I ItT P.;Ozsqzvlma IIIIIII IIT IIIIT I x x x E c E IT T I I IIT III IT T III T I IT T II PTOZAql U072vzTlwz'su'm geor@mou sawd SZBAO TvmAqzusawd TTTMB *Tqdcz2lCP TWOO; TIMI UT asvu=omsq lv=; llvms 4-zv2Tn2Ti SOAZ IT I IIIT T -T IT T I *ATZDVUUOO UT 82VZ21T;U7 ansg-;2 PTOqdMAI IVOO; *&zau Iviatid-;zacl IT IIII IIItIII p4o* lvutds IIT T T T IIIT T IT II ABP/FIJ/N O-OE 4WP/XA/ft 051- n 14 Vp/%-/YM-OC AWP/NA/2- 07 *sr,2vs(l'guOT3wA48sqo 2Tdo*wo.%zTH 'ApnzS 427*lzol. Ao'IUOW snoeql 02nzwqnS AVG-06 91 UTTsl uo-;Swl ansg-;l nm :2uw2zw;.Xns TTOTmeqzozonla spuzontal Fluorade pluorochemical Surfactant: TABLE 7. Cant. 90-Day Subacute Rhasus Monkey Toxicity Study. Microscopic observations, I)aaths. Page 19 Tissue lasion Aorta 10 mg/kzlday 30 ug/kg/day 100 mg/kg/dav 300 mg/kx/dav me m z sk xz m m lb. 9. x x m a@ %o a, en .4 P, c Spleen diffuse congestion atrophy of lymphatic follicles 333 3 3 3 33 3 3334 4 3 434 3 Magenteric lymph node atrophy of lymphatic follicles focal hemorrhage 1 1 4 4 333 33 4 1 34 Retropharyngeal lymph node congestion atrophy of lymphatic follicles Thycyst 1 1111 - 3 33 111 -- I x Bout marrow (rib junction) 111 1 Bone 111 1 Submandibular salivary gland diffuse atrophy of serous alveolar calls for-&Iinterstitial lvmhoid infiltrate 4 32 1 4 43 4 23 3 22333322 Esophagus focal lymphoid infiltrate in lamina prapria &cute focal soophagitis focal hemorrhage in Lamina propris focal neutrophil infiltrate in auto@& and lamina prapria Goncylanitma op. 13 1 3 3 3 111 1 222 Tongue 11 1 focal hemorrhage 2 3 focal lymphoid infiltrate in lamina propria 2 2 32 3 3 focal interstitial lymphoid infiltrate in muscul&rls 2 focal neutraphil infiltrate in sucosal epithelium 3 3 3 small focal necrosis in sucosal epithelium 3 3 focal edema 3 focal interstitialn*utrophil ixlfiltratain muscularis 4 3 focal noutraphil infiltrate in 1-tna preprl& 4 Tonsil focal neutraphil infiltrate in tonsillar epithelium 2 atrophy of lymphatic follicle 3 23 2 233 137-067 Code: x - condition present 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - uarked 6 *=rem - not available Fluoraddb Fluorochamical Surfactant: TABLE 7. Cant. go-Day Subacute Rh*sus Monkey Toxicity Study. Microscopic observati=n, Deaths. Page 20 Tissue Lesion S tomeh focal lywhoid infiltrate in submucos& focal submucceal ads= focal subsuccoal hemorrhage lamina propria/ 10 ms/kg/day -a a, Ln %c 30 mg/kg/dav x m b. D. a, 0 r, -C r, r@ 4Pn- rP,, r, 100 mg/kg/dav x %c a, m L--, U*i r@ P, e, r, e, P, P, 300 mg/kg/dev w@ a, VN e, 1"0 34 2 3 3 42 3 3 23 3 3 3 3 4 5 3 Small intestine atrophy of lymphatic nodule - 1 2 2 1111 1 11 323 3 2 large intestine microgranulom in muscularis atrophy of lymphatic nodule focal lymphoid infiltrate in sub==oga focal hemorrhage in murosa submeotal congestion 2 3 3 32 4 23 2 4- x 3 22 pancr"s foral interstiti&l/pariductal lymphaid infiltrate 1 'a a 11 1 aa a 22 3 323 3 Liver diffuse congestion portal infl@twy call infiltrate focal bile duct proliferation @=all necrotic focus dark brown pigmnt-laden tupffer calls parasitic granul large focal cytoplasmic vacualation of hapatocytas 4 4444444 444 44 & 4 4 3 222 33 2 23 3 2 3 x 4 Gallbladder focal lymphoid infiltrate in lamina prcpr:La a a a 1 a Ia a& a 11a 1 2 2 Kidney cyst x diffus*. congestion 34 4334344 33 44 focal lywhoid infiltrate in commetive tissue 3 3 focal interstitial lymphoid infiltrate 2 2 2 3 3 @4 2 3 2 2 3 23 multinucleatod 14-ing epithelium in papillary duct x x =Lcrolith in renal tubules 2 x ectopic adrenal rest x Urinary bladder I- 1 11 focal lymphoid infiltrate in lamina prapria 2 2 33 3 3 focal noutraphil infiltrate in lamina propris 1- 3 3 3 Testis prepuberal development interstitialfibrosis 137-087 Code: xx 4 xx 1 x x - contition present I - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 extreme - not available a autolyzed xx Fluoradg Fluarochemical Surfactant: TABLE 7. Ccvnt. 90-Day Subacute RhasuB Monkey Toxicity StudyMicroscopic oba*rvations, Deaths. eage zi Tissue Lesion 02 v NJ i0 x 10 ma/ka/dav x x im am -e Ch -tAnt W% tn %oan Pen 30 ms/kz/day_ m m DW bw 0% o-4 0 w- .I0n1 tn 4" r. el en 100 mg/kg/day m m b. ow %o m en * UN LIN 01 r, en 300 mz/kst/d!Z x x ift ow "% 0 wi ok w@ %a P-. P- tn tn on cn ovary small focal dystrophic minaralization x x z Prostate 1 focal interstitial lymphoid infiltrate 3 2 3 uterus 1 1 *Ty-throcytes and inflammatory calls in lumn of andomtrial glands 2 2 focal bamrrhagt in andomtrim 2 Vasina focal lymphaid infiltrate in lamina propria 43 33 3 3 Skeletal muscle Sarcoeystis op. Skin focal aggregates of dark brown pigment in dermis focal lymphaid infiltrate in darmis diffuse acauthmis 1 11 1 1 1 1 11 1 1 1 11 1 x 2 xx z x x xx x x xx x z x 32 2 3 3 M@ry &land focal anmegates of dark brown pigment in dermis focal lymphoid infiltrate in intra- and interlobular commetive tissue epidermal inclusion cyst h"*rkerataxis - protaimescus fluid in dilated ducts focal lywhaid infiltrate in dermis accessory nipple 1 xx x2 x x xx x x xx x x x 3 23 3 x 4 33 2 2 2 Skin (tattoo) focal aggregates of black/dark pipwnt in dermis focal hemorrhage in dermis focal hemorrhage in subeutis brown 1 xx xx x x x 3 3 Izx z x x z x 3 miscellaneous focal lymphaid infiltrate, corpus spongiosum congestion and hosomhage. chin skin 3 4 137-087 Code: x - condition present 1 - not rimarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 *ztrom - not available a autelyzed