Document Eq9kXLKBOEz5a6K28qLkbmR7n
f).R 7 2 6 -0 13<j International Research and Development Corporation
SPONSOR: COMPOUND: SUBJECT:
3M Company Fluorad Fluorochemical Surfactant FC-95 Ninety Day Subacute Rat Toxicity Study.
Collaborators:
D. C. Jessup, Ph.D., Associate Director of Research
R. G. Geil, D.V.M., Vice President and Director of Pathology
N. D. Jefferson, B.S., Acting Director of Small Animal Toxicology
R. J. Arceo, M.D. Staff Pathologist
Date: November 10, 1978
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International Research and Development Corporation
T A B L E OF C O N T E N T S
m o p s i s .................................................... i m p o u n d ............................... linicalStudies ............................................. . Method ..................................................
1. General Procedure...................... 2. Compound Administration............................. 3. Observations ....................................... 4. Laboratory T e s t s ..................
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. Serum Samples................................... 5. Statistical Analysis . . . . ....................... . Results............. 1. General Behavior, Appearance and Survival.......... 2. Body W e i g h t s .............. .. ...................... 3. Food C o n s u m p t i o n ................................... 4. 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 .................... athologicalStudies ........................................... . Methods................................... * ............ 1. Gross Pathology..................................... 2. Histopathology . . .................................. . Results................................................... 1. Gross Pathology and OrganWeights.................... 2. Histopathology..................................... a. Liver............................................ b. Stomach.......................................... c. Bone Marrow.......................... d . T h y m u s ......................................... e. Spleen ............................. . . . . . .
Page 1 3 4 4 4 4
5 5 5 5 5 6
6 6 6 8 8 8 8 9 9
10 10 10
10 10 10
11
11 11 11 11 11
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T A B L E OF C O N T E N T S (Continued)
f. Mesenteric Lymph N o d e s ......................... g. Small Intestine................................. h. Skeletal Muscle................................. 1. S k i n ................. ........................... Table No. 1. Group Mean Body Weights; Weight Ranges; andSurvival . . 2. Individual Weekly Body Weights ......................... 3. T-test Comparison Between Average Food Consumption of Control and Treated Groups............... 4. Mean Food Consumption................................... 5. Means and Significance of HematologicalValues . . . . . 6- 8. Individual Hematological Values.......................... 9. Means and Significance of Biochemical Values ........... 10-12. Individual Biochemical Values............................ 13. Means of Significance of Urinalysis Values ............ 14-16. Individual Urinalysis Values ............................ 17. Summary of Gross Necropsy Observations................. 18. Absolute and Relative Organ Weights..................... 19. Individual Organ Weights ............................... 20. Histomorphologic Observations......................... ..
laJ e , 11 12 12 12
14 15-16
17 18 19-20 21-26 27-28 29-34 35 36-41 42-43 44 45 46-51
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I. SYNOPSIS
Fluorochemical Surfactant
was fed in the diet at
levels of 30, 100, 300, 1,000 and 3,000-ppm to Charles River CD rats for
3 months. Five male and 5 female rats were Initiated at each dosage
level and in the control group. The rats were observed twice daily for
overt signs of toxicity and mortality. Individual body weights and sex
group food consumptions were recorded weekly. Hematological, biochemi
cal and urinalysis studies were conducted during the pretest period and
at 1 and 3 months of study.
At dosage levels of 300, 1,000 and 3,000 ppm, all rats died prior
to scheduled termination of the study. Overt signs of toxicity
including: emaciation, convulsions, altered posture, red material
(right eye and/or mouth), yellow material (anogenital region),
increased sensitivity to external stimuli and reduced motor activity
were evident prior to most deaths. Time of death was directly related
to the dosage level with the earliest deaths seen in the 3,000-ppm
treatment group.
At the 30-ppm dosage level, neither male nor female rats showed
any compound related changes in appearance or behavior. Mean body
weights were slightly lower for the rats at the 30-ppm dosage level when
compared to the controls. At the 30-ppm dosage level, one female rat
showed a slightly elevated glucose level and one male rat showed a
slightly elevated alkaline phosphatase value at 1 month of study. At 3
months of study, one male rat at the 30-ppm dosage level showed slight
to moderate elevations in glucose, blood urea nitrogen and Y-glutamyl
transpeptidase activity.
At the 100-ppm dosage level at 3 months, body weight means when
compared to the controls were lower for males and for females. Food
consumption means when compared to the controls were lower
(statistically significant) for males and females. At the 100-ppm
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dosage level, slight Increases in creatinine phosphokinase (CPK) and alkaline phosphatase activity, slight to moderate Increases in glucose and blood urea nitrogen, and slight to marked increases in plasma glutamic oxalacetic and pyruvic transaminase activities (PGOT and PGPT) were seen at I month of study. At 3 months of study, slight to moderate decreases in hemoglobin, hematocrit and erythrocyte counts were seen for male and female rats and slight to moderate increases in PGOT and PGPT activities were seen for two. of the three surviving female rats at the 100-ppm dosage level*
Compound-related gross changes such as emaciation, areas of discol oration involving ths stomach and liver were observed among treated rats that died prior to sacrifice. Similar changes were also observed in the liver of a few rats sacrificed at termination of study from the 30- and 100-ppm groups.
Microscopically, compound-related lesions were observed among all test groups. Morphological changes consisting of centrilobular to midzonal cytoplasmic enlargement (hypertrophy) of hepatocytes were observed in the livers. Necrosis of liver cells was also present among these rats. The incidence and relative severity of the above lesions were more evident among male test rats.
In addition, especially among rats from the 300-, 1,000-, and 3,000' ppm dosage level that died prior to sacrifice, changes involving the primary (thymus, bone marrow) and secondary (spleen, mesenteric lymph nodes) lymphoid organs, stomach, intestines, muscle and skin, were observed and were all considered as compound related.
The other changes described in the tissues of these rats were lesions of naturally occurring diseases.
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II COMPOUND
The compound was received from 3M Company, Saint Paul, Minnesota
on October 24, 1977 as indicated below:
______ Label______________
Description
U U i.
Fluorochemical Surfactant
white powder 6 x 5 lb tins
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International Research and Development Corporation
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IH.
CLINICAL STUDIES
A. METHOD:
1. General Procedure:
Thirty male (196 to 232 g each) and 30 female (165 to 206 g
each) Charles River CD rats purchased as weanlings from The Charles
River Breeding Laboratories, Inc., Portage, Michigan were used in this
study. The rats were distributed among the groups, based upon a
computer-generated table of random numbers. The rats were housed indi
vidually in suspended wire-mesh cages and maintained in a temperature-,
humidity- and light-controlled room. During the pretest period, rats
were provided ground Purina Laboratory Chow and water ad libitum.
During the actual study, the rats were provided the appropriate test
diet and water d libitum.
This study was initiated November 2, 1977 and terminated by
sacrifice of all remaining rats on January 31, 1978.
2. Compound Administration:
The compound was mixed weekly with ground Purina Labora
tory Chow (i.e., ground basal diet) on a weight/weight basis to provide
dosage levels of 30, 100, 300, 1,000 and 3,000 ppm for feeding. Five
male and five female rats were used at each dosage level and in a
control group. Control rats received the ground basal diet. Diet
samples (100 each) were taken immediately after preparation of each diet
and after 7 days standing in weeks 1, 4 and 12. The samples were frozen
and subsequently shipped to the sponsor. Diets were prepared in the
following manner: before weighing, the compound was ground using a
mortar with pestle. The appropriate quantity of
' Fluorochemical
Surfactant
as mixed with 500 g of the ground basal diet in a Hobart
blender to provide the premix. The proper quantity of premix was sub
sequently blended in a twin-shell blender, equipped with an intensifier
bar, with the amount of ground Purina Laboratory Chow necessary to
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provide the appropriate quantity by group of prepared diet. Control rats received the ground basal diet.
3. Observations ; The rats were observed twice daily for overt signs of toxicity
and for mortality. Detailed observations were recorded weekly or daily when a specific condition existed. Individual body weights and food consumption were recorded weekly during the pretest and treatment periods.
4. Laboratory Tests; Once during the pretest period and at 1 month and 3 months of
the study, blood (orbital sinus puncture technique) and overnight urine samples were obtained from all surviving rats for analysis. Food and water were withheld prior to the collection of samples.
a. Hematology: Hematological studies included: hemoglobin*,
hematocrit^, total erythrocytes-*, reticulocytes^, and total and differential leucocyte counts.
b. Biochemistry: Biochemical studies included: fasting glucose, blood
urea nitrogen (BUN), plasma glutamic pyruvic (PGPT) and plasma glutamic oxalacetic (PGOT) transaminase activities, plasma alkaline phospha tase activity, y -glutamyl transpeptidase (y-GTP), creatinine phosphokinase (CPK)^ and calcium. Plasma alkaline phosphatase values were not obtained for the pretest (baseline) period because of interference from the anticoagulant.
c. Urinalysis: Urinalysis included: measurement of volume, pH, and
specific gravity; description of color and appearance; qualitative tests for protein, glucose, ketones, bilirubin, and occult blood; and microscopic examination of sediment.
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d. Serum Samples; Serum samples were obtained for all surviving rats at 13
weeks of study. The samples were pooled by sex and group, frozen, and subsequently shipped to the sponsor.
5. Statistical Analysis; All statistical analyses compared the treatment groups with
the control group, by sex. Body weights (week 13), food consumption (1-13 weeks), hematological, biochemical and urinalysis parameters (1 and 3 months) and absolute and relative organ weights (terminal) were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and T o r r i e ^ using Dunnett's ^ multiple comparison tables to judge the significance of differences. B. RESULTS:
1. General Behavior, Appearance and Survival; Control rats exhibited no behavioral anomalies related to the
testing procedure. Rats given the compound at 30 ppm of the diet exhibited no specific behavioral signs of toxicity and there was no mor tality. Changes in general behavior and appearance for male rats at the 100-ppm dosage level included the following: increased sensitivity to external stimuli and red material around the mouth were observed for one rat; increased sensitivity to external stimuli, leans to left and convulsions following handling were noted for a second rat; and one rat was cold to the touch (one day after collection of blood) and died. No compound-related signs of overt toxicity were noted for any of the females at 100-ppm dosage level.
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All rats la the 300-, 1,000- and 3,000-ppm dosage levels died
prior to the scheduled sacrifice. Most exhibited one or more of the
following signs of overt toxicity: emaciation, convulsions following
handling, altered posture (hunched back), red material around right
eye, yellow material around the anogenital region, increased sen
sitivity to external stimuli, reduced motor activity and moist red
material around the mouth or nose. At 300 ppm, death for males
occurred from day 13 through day 25 and for females from day 18
through day 28. At 1,000 ppm, death for males and females occurred
from day 8 through day 14. At 3,000 ppm, death for males and females
occurred from day 7 through day 8.
Observation
Number of Rats/Observation/Dosage Level
100 ppm 300 ppm
1,000 ppm 3,000 ppm
Emaciation
5 10 6
Convulsion
1 10
31
Altered position
(hunched back)
11
76
Red material
(right eye)
21
Yellow material
(anogenital region)
2
3
Increased sensitivity
2
2
Reduced motor activity
4
Moist red material
(mouth)
11
1
Survival (prior to sacrifice) after 3 months of compound admin-
istration was as follows:
Dosage Level
No. Surviving/No. Initiated
Male
Female
Control 30 ppm
100 ppm 300 ppm 1,000 ppm 3,000 ppm
\f/ ^
5/5 5/5 5/5 5/5 2/5 3/5 0/5 0/5 0/5 0/5 0/5 0/5
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2. Body Weights (Tables 1-2);
Comparison of mean body weights of the 30-ppm and 100-ppm
groups indicate a lower body weight gain at both dosage levels when
compared to the controls. Moderate to marked losses of body weight
were seen prior to death for rats at the 300-, 1,000- and 3,000-ppm
dosage level.
Group mean body weights after 90 days of compound administra
tion were as follows:
Dosage Level
Group Mean Body Weights, g
Male
Female
Control 30 ppm
100 ppm
472 431 (- 8.7) 393 (-16.7)
264 243 (- 8.0) 221 (-16.3)
3. Food Consumption (Tables 3-4):
Group mean averages for food consumption declined consistently
as the dosage level was increased.
Dosage Level
Control 30 ppm 1
100 ppm 300 ppm \A 1,000 ppm* 3,000 ppm*
Average Food
Consumption
(grams/rat/day)
Male
Female
27.4 26.0 23.9 12.8
7.5 5.0
19.7 19.0 15.8
9.3 6.6 4.2
values for 1 week only
4. Laboratory Tests (Tables 5-8):
a. Hematology:
At the 30-ppm dosage level (1 and 3 months) and at the
100-ppm dosage level (1 month) hematologic values were within the
expected range. For the 100-ppm dosage level at 3 months, the two surviving
male rats had lower erythrocyte, hemoglobin, hematocrit and leucocyte
counts (differences when compared to controls were statistically
significant, p<0.01). The three surviving female rats had slightly
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lower hemoglobin and reticulocyte counts (statistically significant, p<0.05) as well as slightly lower erythrocyte, hematocrit and leuco cyte counts. All other hematologic values of male and female rats at this dosage level were within the expected range.
b. Biochemistry; One control rat showed moderately elevated PGOT and PGPT
activity at 3 months of study. At the 30-ppm dosage level, one female rat showed a
slightly elevated glucose level and one male rat showed a slightly elevated alkaline phosphatase value at 1 month of study. At 3 months of study, one male rat at the 30-ppm dosage level showed slight to moderate elevations in glucose, blood urea nitrogen and Y-glutamyl transpeptidase activity.
At the 100-ppm dosage level, slight to moderate increases in glucose (3 males, 1 female) and blood urea nitrogen (5 males, 4 females) were seen at 1 month of study. Also noted at 1 month of study, for 3 males and 2 females at the 100-ppm dosage level, were slight to marked increases in PGOT and PGPT. The creatinine phosphokinase (CPK) levels generally were slightly increased for rats at the 100-ppm dosage level at 1 month of study. Alkaline phosphatase acti vity also was slightly elevated for a few rats at the 100-ppm dosage level at 1 month of study. The group mean glucose values for males, blood urea nitrogen values for males and females, and CPK and alkaline phosphatase values for females at the 100-ppm dosage level were signi ficantly higher (p<0.05) than the control means at 1 month of study.
At 3 months of study, 2 of the 3 surviving female rats at the 100-ppm dosage level showed slight to moderate increases in PGOT and PGPT activity. One of these females also showed a slight eleva tion in CPK activity.
c. Urinalysis: No changes considered to be related to compound were seen
in the urinalysis studies.
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IV. p a t h o l o g i c a l STUDIES A. METHODS ; L. Gross Pathology: After 90 days of compound administration, five rats/sex in the control and 30-ppm groups, and two and three female rats in the 100ppm groups were sacrificed with carbon dioxide and necropsied. At necropsy, organs and tissues were examined for gross abnormalities and collected in 10Z neutral buffered formalin (eyes in Russell's fixative). Liver samples, obtained from all of the rats at terminal sacrifice, were frozen and subsequently shipped to the sponsor. All rats that died prior to termination, were also necropsied, and tissues were collected as above. 2. Histopathology; Microscopic examination of formalin-fixed, hematoxylin and eosin stained, paraffin sections was performed for all rats in the control, 30-, 100-, 300-, 1,000- and 3,000-ppm dosage levels. The following tissues were examined histologically:
brain with cervical cord lumbar spinal cord peripheral nerve eyes pituitary thyroid parathyriod adrenals lung heart with
coronary vessels
aorta spleen mesenteric lymph nodes thymus bone with marrow
(sternum) salivary gland stomach small Intestine
(3 levels) colon
pancreas liver kidneys urinary bladder testes ovaries prostate uterus skin (mammary gland) and all tissues
with gross lesions
B. RESULTS:
1. Gross Pathology (Table 17) and Organ Weights (Tables 18-19):
Compound-related gross necropsy lesions and/or observations
were present among rats in all experimental groups. The livers of
these rats showed varying degrees of discoloration"and/or enlargement,
while in the stomach, foci of discoloration in glandular mucosa,
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presumably hemorrhages were also observed. In addition to the above gross observation, emaciation was evident especially among rats that died prior to sacrifice (300-, 1,000- and 3,000-ppm levels).
2. Histopathology (Table 20): Compound-related lesions were observed histologically in the
following organs and tissues. a. IiiZE! Slight to marked, focal necrosis of liver cells
with no lobular distribution was seen among rats at the 100-ppm and higher treatment levels. The above lesion was accompanied by focal to multifocal, very slight to slight, cytoplasmic enlargement (hypertrophy) of hepatocytes in the centrilobular to midzonal regions of the affected liver lobules in all test groups, especially amone male rats. There was a slight increase in cytoplasmic vaculoation of hepatocytes in 30-ppm treated rats, but this finding was not evident at the higher dose levels; therefore, this lesion was considered insignificant.
b. Stomach: Mucosal hyperkeratosis and/or acanthosis was observed in the forestomach (nonglandular portion) while mucosal hemorrhages and/or erosions were observed in the glandular portion.
c. Bone Marrow; Hypocellularity was noted. d. Thymus: Depletion in number ans size of lympoid follicles was noted. e. Spleen: Decrease in size of the organ (atrophy) with a corresponding decrease in size and number of lymphoid follicles and cells was observed. f. Mesenteric Lymph Nodes: Depletion in size and number of lymphoid follicles was noted. g. Small Intestine (duodenum, jejunum, ileum): Decreased atrophy in the height and thickness of the villi were noted.
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h. Skeletal Muscle: Atrophy was evident. i. Skin; Epidermal hyperkeratosis and/or acanthosis was noted. The findings in the stomach, lymphoid organs, intestine, muscle and skin, were prominent among all rats (300-, 1,000- and 3,000-ppm levels) that died prior to sacrifice.
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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 ZB , 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. Technicon Auto Analyzer 6/60 Micro Methodology.
6. Sigma GGTP Procedure Bulletin #545. Sigma Chemical Co., St. Louis, Missouri.
7. Micro Auto Analyzer II, 6/60 Micro Methodology.
8. Photovolt PV4, Photovolt Corporation.
9. Multistix (Ames Reagent Strips).
10. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y.
11. Dunnett, C. W., New Tables for Multiple Comparisons With a Control, Biometrics, Sept. 1964.
137-085
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Fl iioi'uuhuiiiliin I
TAIII.K I.
Week 1
Si inly
Cimimi lienil Hiilly Weight 171 . Hnugcu
SurV 1V.l1
N in e ty liny Siihm ute
Croup flenn Hmly Weights, Crnm:
Menu Hmly
Wr.
30 ppm
Weight Knngus
SurV 1Vili
Menu Hmly Wt.
100 ppm
Wulglit Sill*Knngc8 vivai
_l 220 212-228 0 245 213-259 l 101 276- 130 2 12 1 302-358 3 S', 2 308- 376 4 KiH 346-405 5 180 352-406 (> 41b 380-444 7 434 400-466 8 444 414-483 9 451 418-487 1U 463 437-495 11 475 448-518 12 486 458-526 13 472 438-523
FKHAI.ES :
-1 186 168-197 0 191 lb8-207 1 219 190-236 2 219 186-236 3 233 207-244 4 241 212-264 5 252 222-278 6 262 224-286 7 266 230-290 8 271 276-297 9 267 2 33-298
111 27'. 274-310 II 281, 242-710 12 306 24 1- 194 11 264 224-298
5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5
5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5
215 206-227 5/5 219 227-265 5/5 294 272-328 5/5 303 274-332 5/5 330 303-360 5/5 351 311-787 5/5 356 328-392 5/5 389 360-420 5/5 404 370-440 5/5 411 376-448 5/5 422 386-455 5/5 429 399-458 5/5 440 410-476 5/5 444 418-466 5/5 431 408-464 5/5
186 172-199 5/5 192 180-208 5/5 220 206-240 5/5 224 204-244 5/5 231 213-255 5/5 235 216-262 5/5 246 232-264 5/5 256 238-276 5/5 256 238-280 5/5 254 234-285 5/5 254 236-278 5/5 252 238-274 5/5 264 244-290 5/5 260 240-284 5/5 24 3 228-262 5/5
217 212-224 5/5 226 200-252 5/5 2/6 246-306 5/5 291 244-330 5/5 701 258-350 5/5 707 262-359 5/5 308 278-362 3/5 324 275-363 3/5 351 280-390 3/5 373 284-420 3/5 388 282-442 3/5 391 292-457 3/5 398 120-476 2/5 412 344-480 2/5 393 320-466 2/5
188 170-206 5/5 198 182-222 5/5 212 190-234 5/5 204 182-226 5/5 202 192-214 5/5 210 195-215 5/5 217 208-222 1/5 222 212-234 3/5 221 212-214 3/5 224 217-235 1/5 227 217-245 3/5 225 216-241 3/5 216 230-244 3/5 234 225-250 3/5 221 206-238 3/5
002110
Kilt T i i x l c l l y Sillily
i ; Wo I (lit Kh iik o i; ; aiul S u r v l v n l .
3011 ppm flollll Hod y U e l lit S u r Ut. Rnnes viviil
___ LJ101L-J'IL" ___
Hun il Hody W eight S u r U t. Kongos vlv.ll
___ 1!J>_________
Nein
Body Wo l u llt S u r -
U l. Kongo
v I vhI
202 196-214 5/5 223 210-250 5/5 217 200-244 5/5 207 200-224 4/5 192 187-200 3/5
0/5
217 207-232 5/5 231 212-251 5/5 186 164-204 5/5
0/5
219 216-223 245 237-252 159 156-164
5/5 5/5 3/5 0/5
187 165-202 5/5 197 175-215 5/5 176 164-188 5/5 166 150-182 5/5 166 152-178 4/5
0/5
178 172-188 5/5 180 179-181 5/5 142 120-150 5/5
0/5
179 169-192 187 177-198 135 126-140
5/5 5/5 3/5 0/5
BEST COPY AVAILABLE
Fluorochemical Surfactant
BEST COPY AVAILMTE 3
Miaecy Day Subacuta Rat Toxicity Study.
TABLE 2.
Individual Weekly Body Weights, Grans.
Group,
Precase
Week of Study
Sac Mo. Sex -1 0 - 2 3 4 5 6 7 3 9 10 11 12 13
Control:
73886 73887 73888 73889 73890
M 222 249 314 330 354 372 396 424 438 452 453 464 484 482 466 X 225 248 286 302 328 346 352 380 400 414 418 437 44fl 464 456 X 228 259 330 358 376 405 406 444 466 483 487 495 513 526 523 X 212 233 3C0 322 342 367 372 404 424 422 442 441 448 458 438
M 212 235 276 302 308 352 374 428 440 451 456 476 476 498 477
73891 73892 73893 73894
73895
F 194 200 230 230 240 251 262 278 280 285 270 279 294 394 268 F 179 184 208 210 230 227 238 248 252 246 248 256 260 262 243 F 194 207 232 236 244 264 278 286 290 297 298 310 310 320 298 F 168 168 190 136 207 212 222 224 230 236 233 234 242 243 224 F 197 205 236 234 242 252 260 274 280 293 286 296 300 310 285
30 oon:
73896 73897 73898 73899 73900
X 216 232 282 300 325 343 344 382 394 408 425 424 434 444 417 X 227 265 328 332 360 387 392 420 440 448 455 458 476 466 464 X 217 240 306 316 344 366 368 410 420 420 431 444 446 454 438 X 208 229 280 292 318 346 350 372 394 401 413 420 434 436 428 X 206 227 272 274 303 311 328 360 370 376 386 399 410 418 408
73901 73902 73903 73904
73905
F 172 180 208 204 213 220 232 238 238 234 236 238 248 241 228 F 199 208 240 242 254 262 264 274 280 285 278 274 290 284 262 F 195 191 210 216 216 216 236 250 244 245 244 243 260 253 235 F 193 201 238 244 255 255 264 276 276 273 272 265 276 280 259 F 172 181 206 212 215 221 232 244 240 235 240 240 244 240 231
100 som:
73906 73907 73908 73910 73946
X 213 200 270 292 292 309 Died X 224 252 306 330 350 359 362 363 390 415 439 424 Died X 212 224 272 300 - 319 305 284 335 382 420 442 457 476 480 466 X 221 245 284 290 284 302 Died X 213 208 246 244 258 262 278 275 280 284 282 292 320 344 320
73911 73912 73913 73914 73915
F 206 217 232 224 210 211 222 234 234 235 245 241 244 230 238
F 205 222 234 226 214 235 Died r 170 182 190 138 196 195 208 212 212 217 218 217 230 228 206 c 181 135 2C4 200 192 204 Died
F 173 136 198 182 200 206 220 220 216 221 217 216 234 225 219
137-085
002111
r Fluorochcmical Surfactant
tart,g 2. c,
Croup,
Precast
Rat So. Sex -1
0
Page 16
BEST COPY AVAILABLE
Hlnaty Day Subacuta Rat toxicity Study
Individual Weekly Body Weights, Grama.
______________________________________ Week of Study -_____________________ ____________ I 2 3 4 3 6 7 3 9 10 U 12 13
300 oon:
73916 73917 73918 73919 73920
M 198 210 212 200 183 Died M 200 213 200 Died H 196 212 210 204 192 Died M 203 230 220 200 200 Died M 214 250 244 224 Died
73921 73922 73923 73924 73923
F 190 200 188 174 165 Died F 183 192 168 162 168 Died F 202 215 178 182 178 Died F 194 202 184 164 152 Died F 165 175 164 150 Died
1.000 oca:
73926 73927 73928 73929 73930
M 207 212 164 Died M 207 212 170 Died M 220 230 190 Died M 232 251 202 Died M 217 248 204 Died
73931 73932 73933 73934 73935
F 188 180 150 Died F 175 180 120 Died 7 176 181 148 Died F 180 180 150 Died F 172 179 142 Died
3.000 Dota:
73936 73937 73938 73939 23940
M 213 242 164 Died
M 217 237 158 Died
M 223 252 Died
-
M 216 245 Died
M 223 248 156 Died
73941 73942 73943 73944 73945
F 187 197 140 Died
F 169 178 Died T 192 198 140 Died
F 177 183 126 Died F 170 177 Died
ji
137-085
002112
l-
, Fluorochemical
Surfactant
Ninety Day Subacute Rat Toxicity Study.
TABLE 3.
T-test Comparison Between Average Food Consumption of Control and Treated Groups.
Week of
Study
Sex
Control
30 ppm
1-13
M F
27.4 19.7
26.0* 19.0
" --o -
ioo ppm 23.9** 15.8**
137-085
Significantly different than Control group mean, p<0.05. Significantly different than Control group mean, p<0.01.
002113
'TIZOO
!'Iii.)riiilirmliMI Suri arian i
TAIII.K 6.
Wook ni
Stmly
Culli rii1
R/ i-al/
Jay
11/ k)./ lay
HAI.I.S:
1 2 .i ii 5 6 7 8 9 IO 11 12 n
l'KHAI.KS:
1 2 1 li 5 6 7 8 9 10 11 12 n
27.0 'li. 9 26.7 26.7 28.7 28.5 29.5 26.9 28.0 28.5 28.3 26.5 28.2
19.9 16.9 20.3 18.7 20.3 20.5 21.0 20.3 21.) 21.1 20.1 17.2 18.3
89.6 77.0 78.1 67.0 75.6 68.5 67.9 60.6 62.0 61.5 59.5 56.6 59.7
90.8 77.2 87.3 77.5 80.7 78.1 79.1 76.7 78.9 76. 7 71.7 56.1 69.2
30 JE2___
r/ b/
rat/
kR/
day day
N liuity Day Siili.irulL' Rat T u x l r l l y S lm ly .
Miiaii Kooil ConsumiliIun.
100 PI'"
11/ 11/
rat/
k|',/
day day
300 ri'__ 11/ R/ nit kR/
day day
27.6 23.0 25.6 23.9 25.2 27.5 27.6 26.0 27.9 26.1 25.5 23.8 27.8
21.2 16.9 19.1 16.9 17.9 19.6 20.5 19.9 20.0 18.6 19.8 17.1 20.3
91.9 75.8 77.7 68.1 70.8 70.7 68.3 63.3 66.1 60.9 58.1 53.6 66.6
96.6 75.5 82.9 71.7 72.9 75.7 80.1 78.5 78.9 73.0 75.1 65.8 83.5
25.5 21.2 21.0 16.9 19.2 21.1 26.0 27.5 26.2 26.1 28.1 25.9 26.5
18.9 13.9 15.7 13.2 16.9 17.1 16.9 15.9 15.9 16.3 16.0 16.7 15.6
92.3 72.9 69.7 56.9 62.5 65.1 76.1 73.7 47.5 66.9 70.7 62.8 67.6
,
88.9 68.3 77.9 62.9 68.5 77.2 76.3 71.0 70.1 72.6 67.8 62.9 70.6
18.2 7.9
12.2
86.0 38.0 63.7
11.0 7.0 9.8
62.7 62.3 59.2
__Iti000 Iin r/ r/
rat kll/ day day
7.5 60.6
6.6 66.3
I
3,000 |i|>M 11/ R/ ral kj*/ day day 5.0 11.
6.2 31.1
Bar cs}
*age itt
_
Surfactant TABLE 5.
Hematology
Erythrocytes, 10 / c m
Hematocrit,
*tm
Hemoglobin, g/100 ml
Leucqcytas, 10J /cmm
Neutrophils, Z
Lymphocytes, Z
Eosinophils,
*fm
Monocytes, Z
Basophils, Z
Reticumtolocytes,
0.& C 17
r copy j h i u h e
Ninety Day Subacute Rac Toxicity Study.
MALES: Means and Significance3 of Hematological Values.
Study Month
Control
30 ppm
100 ppm
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1
3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3 ..
Pretest 1 3
;
Pretest 1 3
5.96 6.50 7.57
45 45 50
15.5 16.0 16.6
11.32 13.14 12.50
7 11 14
93 88 84
0 1 1
0 0 1
0 0 0
5.3 3.9 2.8
6.42 6.28 7.43
47 48 46"
15.5 14.9 15.6
10.60 12.69
9.63
11 12 15
88 86 83
1 2 2
0 0 0
0 0 0
5.2 3.2 2.9
6.40 6.30 5.52"
48 45 3?"
15.9 15.3 12.1"
10.76 9.87 6.21"
17 17 30
82 81 69*
1 1 0
0 1 0
0 0 0
5 .4
2.7 3.2
137-085
*Significantly different than Control group mean, p<0.05.
" Significantly different than Control group mean, p<0.01. Statistical analyses were not conclude-! on the pretest values.
002115
Fluorochemical Suetactant
tas; 3. I
Hematology
ErytgrocytftS, 10 /emm
Hematocrit, ArS
Hemoglobin, g/100 ml
Leucocytes, 10 /earn
Meutrophils, Z
Lymphocytes, **
Eosinophils, *
Monocytes,
tr
am
Basophils,
Reticulocytes,
*
BEST COPY AVAILABLE
ninety Day Subacute Rat Toxicity Study.
FEMALES: Means and Significance8 of Sematologica! Values.
Scudy Month
Control
30 ppm
101 ?;
Pr etest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
6.74 6.54 6.59
48 47 45
16.2 15.9 15.4
9.23 7.23 7.29
17 15 21
82 81 76
1 3 2
0 1 1
0 0 0
4.4 3.1 3.2
6.69 6.58 7.28**
48 47 47
16.0 15.7 16.0
9.77 7.07 5.68
8 8* 19
91 91** 80
t l **
X
0 0 0
0 0 0
4.1 2.3*
2.3
6.3c 6.69 6.03
45 48 41
15.0 16.1 13.8*
9.39 10.25
6.26
11 8*
25
88 91** 75
1 1** 0
0 0
0 0 0
4.4 2.4 1.3*
137-085
Significantly different than Control group mean, p<0.05.
*?Significantly different than Control group mean, p<0.01"Statistical analyses were not performed on the pretest value.
002116
iI
FI unu'llt'lll I r n I Kurlnr I mil
TAIll.R 6.
Crimp.
Krythro-
Rat c y te a
Nuiulicr Sex 1(l^/cima
IlfinuLoc r 11 2
N in e ty liny S u b a c u te Rat T o x i c i t y S tu d y .
Individual Hem atological Vuliien - I'rc lim l.
lleiNOglobln g / 1 0 0 ml
r ytea lOVcimn
N e u t r o p h i l it
Sog.
Non-Seg.
22
l.ymphocyteH 2
Soulnoplills 2
MonocyteH
2
('out n i l :
73886 73887 - 73888 77889 73H90
Mean
7 1891 77892 7)893 7789 73895
M M M M M
F F F F F
30 jipm:
77896 77897 73898 73899 7 1900
M M M M M
Moan
77901 73902 77907 7 190 7790
F F F F F
Moan
Mill j>pm:
77906 7790/ 73908 73910 779 6
O Mom
M M M M M
Sr j 7/'W191"2
r * 77917 7791 7791
F F F F F
Mom
..... . . . ...
6.2
7
16.5
10.20
5.95
4
15.2
12.38
5.77
7
14.9
11.55
5.58
5
15.4
11.01
6.26
8
15.7
11.45
5.96
5
15.5
11.32
6.2
50
16.4
8.65
6.76
41
15.5
7.83
6.67
8
15.5
10.05
7.36
51
17.4
9.52
6.89
9
16.3
10.08
6.7
8
16.2
9.23
6.77
9
16.4
10.15
5.89
14.7
9.05
6.57
7
15.1
12.52
6.41
8
15.4
12.68
6.8
8
15.7
8.61
6.2
7
15.5
10.60
7. 16
50
16.9
9.49
6.28
44
15.5
9.17
7.05
50
16.2
9.57
6.27
7
15.4
6.81
6. 77
8
16.1
13.80
6.69
8
16.0
9.77
6.68 5.99 6.25 6.57 6.52*
9 5 7 50 9
15.9 15.2 15.6 16.4 16.2
10.19 14.71 8.00 17.42 7.88
6. 0
8
15.9 .
10.76
6.08
2
14.8
11.85
6.51
6
15.3
10.77
6.1
5
14.8
5.67
6.19
3
14.2
10.74
6.61
7
15.9
II.36
6.76
5
15.0
9.79
...... .. __ _______ ... ..... ....
*11 1\ I v r liroiunslu
8 0 92 9 0 91 C 0 94 6 0 94 6 0 94
7 0 93
9 0 91 11 0 89 12 0 86 34 0 66 17 0 82
17 0 82
0 1) 00 00 00 00
00
00 00 20 00 10
10
12 0 87 10 0 89 17 0 82 6 0 94 8 0 91
11 0 88
6 0 93 11 0 89 11 0 89 6 0 94
5 0 93
8 0 91
10 10 10 00 10
10
10 00 00 00 20
10
15 0 83 10 0 89 18 0 81 17 0 87 30 1 69
20 l0 10 00 00
17 0 82
10
17 0 87 11 0 87 II 0 87 9 0 91 12 0 88
00 20 20 00 00
11 0 88
10
......... ..... ..... ... ____ _____ _ .
llanopill 1ft
2
Hot I c iilo cytea 2
0 4. ft 0 3.4 0 7.3 0 4.6 0 6.7
0 5.3
0 2.5 0 4.4 0 6.2 0 3.5 0 5.4
0 4.4
0 6.9 0 10.7 0 5.8 0 2.7 0 0.3
0 5.2
0 3.8 0 5.8 0 2.0 0 5.9 0 3.1
0 4.1
0 0 0 0 0
0
0 0 0 0 0
0 ......
6.4 6.8 6.4 7.5 4.1
5.4
2.7 5.1 2.6 5.9 6.0
. 4.4
BEST COPYAVAILABLE
002117
III
1
rl liurm luuili'.l 1 Surf .ui.iut TAIII.K 6. 1
HrythroKaL ry tea Nmntirr Sex 1<r'/cma
llcmato*:r11 z
Ninety Day Subacute Itat Toxicity Study.
Individual Hematological Values - 1`releNl.
llemogloliln g/100 Ml
l.eiicocyLcB llP/cim
Neutrophils Seg. Non-Seg ZZ
I.ynpliueytes
Z
Koslnopill la
Z
-- ......-----
Monocytea
Z
flah o phi la
Z
Met leulocylen Z
BEST COPY AVAILABLE
002118
MV lii H 7 .1 0
50
15.8
10.11
16
0
83
7Til 7
M 6 . IH
42
14.5
8.85
6
0
93
71918
M 6.61
49
16.1
11.93
10
0
90
73*11*1
M 5.96
41
14.9
10.12
7
0
92
im u
H 6.11
47
15.1
13.36
10
0
90
Mean
6.47
46
15.1
10.91
10
0
89
73*121
F 6.69
49
15.8
7.76
14
0
85
7 3**22 F 7 .1 2
49
17.0
11.18
71
0
93
71921 P 6.66
48
15.9
9.30
10
0
90
71924
F 6.48
48
16.5
11.49
12
0
88
71925
F 6.45
48
16.2
10.78
5
0
95
Mean
6.68
48
16.3
10.10
10
0
90
1j 000
71926
M 7.08
49
16.5
12.76
9
0
91
71927
M 6.14
48
16.1
13.67
12
0
88
7 1928
M 6.09
49
16.0
9.75
17
0
83
71929
M 6.84
49
16.4
13.02
8
0
91
71910
H 6.51
47
15.1
15.59
8
0
91
Mean
b.54
48
16.0
12.96
11
0
89
71911
F 6.66
50
16.7
10.50
17
0
82
71912
F 7.60
51
17.8
12.79
15
0
84
71911 F 7.11
49
17.6
14.12
17
0
83
71914 F 7.12
47
16.8
11.74
15
0
83
71915 F 6.16
46
15.4
17.48
7
0
92
Mean
7.01
49
16.9
13.33
14
0
85
IJIOO ppm:
71916
M 7.12
49
16.4
13.52
9
0
91
71917
M 7.11
47
15.5
17.97
8
0
92
71918
M 6.15
44
15.0
14.79
9
0
91
71919
H 6.12
46
15.1
17.2H
6
0
94
71940
H 6.48
49
16.4
15.29
14
0
H6
Hcan
6.68
47
15.7
15.77
9
0
91
71941
F 6.00
44
15.5
13.11
13
0
85
71942 F 7.15
49
17.1
12.25
14
0
85
71941
F 6.51
49
17.4
9.49
14
0
85
71944
F 6.59
4H
16.2
11.87
16
0
81
71945
F 6.57
46
15.6
11.72
10
0
90
Mean
6.56
47
16.4
11.69
13
0
86
I17-HHS
1 0 0 4.5 1 0 0 1.9 0 0 0 4.1 1 0 0 8.1 0 0 0 6.4
1
00
5.5
1
00
1.6
0 0 0 2.3
0 0 0 2.7
0
00
3.0
0 0 0 3.7
0 0 0 2.7
0 0 0 2.0 0 0 0 6.7 0 0 0 6.7 1 0 0 8.0 1 0 0 5.4
0 0 0 5.8
1 0 0 2.0 1 0 0 l.l 0 0 0 4.0 2 0 0 3.5
1 0 0 1.8
1 0 0 2.9
0 0 0 5.8 0 0 0 6.9 0 0 0 6.0 0 0 0 5.7 0 0 0 5.1
0 0 0 5.9
2 0 0 4.8 l 0 0 5.0
1 0 0 2.4
3 0 0 2.5 0 0 0 1.6
1 0 0 3.7
N> N>
e n z oo
l;iiiiinirlii'nili'.iI
S iilla ila i.t
lAlll.i; /.
Crimp, Kill NiiuIum
111 yl l i r a i:yl:an
Coat nil :
73886 73887 7JHHB 7 3889 73890
Haim
73891 73892 71891 7 3894 73895
Mean
30 | ijim:
73896 73897 73898 73899 73900
Mean
73901 77902 7 1903 73904 7 1904
lluaii
J 00 jipm:
73906 73907 73908 7 1910 71946
Mean
7391 1 73912 73913 73914 7391 `i
Mean
H M M M M
V r
M H H H H
H, H N M N
1'
6.76 6. 15 6.45 6.48 6.46
6.50
6.51 6.68 6.66 6.68 6.19
6.54
6.87 6.46 6.59 6.44 5.04*
6.28
6.64 6.50 6.58 6.55 6.61
6.58
7.08 6.38 5.71 5.96 6 . 19
6.30
6.68 7.08 6.71 6.50 6.48 6.69
IIimiiiI o IT It w
47
-
42 46 45
45
44 50 46 47 46
47
51 46 49 46 49
4B
49 51 48 45 44
47
50 48 43 78 46
45 48 48 47 47 48
48
Niin*ty Day S n liar.urr Hat T a x li*I y Sillily.
Imllvltliial lli>niar.i)lii|>Ji:al Valuai: - I Hamit.
lli*nmI' 1oil 1II r./HH) ml
l.pin:n10-*/fiimi
____ NimiI ro i'lil I s
Mon-S*!',.
l,y|i|io-
ryl pr
Z
16.9 14.8 15.9 16.2 16.2
16.0
16.2 16.6 16.0 15.8 15.1
15.9
16.5 15.3 15.4 15.0 12.5
14.9
16.2 17.0 15.2 16.3 13.9
15.7
16.7 16.1 13.7 14.6 15.4
15.3 15.7 16.4 16.1 15.9 16.5
16.1
13.63 9.95
16.14 12.44 13.52
13.14
7.89 7.37 9.50 6.15 5.22
7.23
9.11 11.15 12.12 15.74 15.31
12.69
5.22 6.36 7.30 7.92 8.56
7.07
10.42 8.96 9.05 13.32 7.60
9.87
12.65 13.08
7.26 9.82 8.45 10.25
6 9 11 12 17
11
23 17 8 11 15
15
16 12 16
8 6
12
7 8 13 9 5
8
21 13 29 8 16
17 10 8
5 8 8 8
0 93 0 89 0 88 0 87 0 81
0 88
0 73 0 81 0 89 0 83 0 79
0 81
0 83 0 84 0 82 0 90 0 94
0 86
0 92 0 92 0 86 0 90 0 93
0 91
0 77 0 85 0 70 0 92 0 79
0 81 0 88 0 92 0 95 0 90 0 92
0 91
Ijifllnophi la
Z
1 2 0 1 1
1
3 2 3 3 3
3
1 4 2 2 0
2
1 0 1 l 1
1
1 2 1 0 2
1 2 0 0 l 0
1
......... ...............
ft 1t I'u 1yrlir''Mian 1a
I I :t I 'a . . . . I . . . . . . 1 1 -.1. I . .
--
----------------------------- --
. . . . . . . '*" ..--------*1"*
Ilium-
*
0 0 1 0 1
0
1 0 0 3 3
1
0 0 0 0 0
0 0 0 0 0 1 0
1 0 0 0 1 1 0 0 0 1 0
0
IIiihhplil Im
z
0 0 0 0 0
0
0 0 0 0 0
0
0 0 0 0 0
0
0 0 0 0 0
0
0 0 0 0 0 0 0 0 0 0 0
0
lti-r I r i i l u -
ryli'S
Z
1.8 1.5 3.0 3.3 5.9
1.9
3.0 1.4 2.8 3.3 3.1
3.1
2.6 3.5 3.1 2.0 4.8
3.2 (30
3.1
1.8 S3
2.4 2.2
1.9 S
2.3
2.8 1.9 3.5 1.0 2.4 2.7 5 2 2.6 m 3.7 l.l 2.9 1.7
2.4 ns P> OQ (B N> U>
Fliioi'oclicmlciil S n rfm lan l
TABI.K / . ( u n i .
Croup,
Krylliro-
Kill cyioH
Niiiubur Sox IOf`/ cmm
300 ppm:
73916 73917 7 3 9 1B 73919 73920
73921 73922 73923 7392 73925
1,000 ppm:
73926 73927 73928 73929 73930
73931 73932 73933 7393 73935
3.000 ppm:
73936 73937 73938 73939 7390
739 1 73942 739 3 7394 73945
H H M H M
F Y F F F
H H H M H
F F F F F
H M H H H
F F F <F F
1)1Oil Died 1)1oil Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
llomntocrlt Z
N inety Day Suhm'iite Hat Toxic II v Si inly.
liu llv litu a l lleiimlo l o g i c a l Vuliieu - l HonIII.
Hemo
globin g /1 0 0 ml
l.enrocyteu ltM/cmm
____ NnutropJilJ s Seg. Non-Seg.
XX
Lympho cyte* Z
P.OHlno-
phlle Z
M iiiio-
cytea Z
IlilHIlplit Ih
z
Hoi lenliicyl mi Z
BEST COPY AVAILABLE
02T2J00
I37-OH5
0p0) 0) K F
I
I'liiDiDilu-nili'iil Surlnrlnut
TAIH.I! 1.
(!roii|i,
Kryllirn-
Kill nylon
NiiuiIh !r
Sex
lOO/nuu*
Hewnto-
nr It X
Homo-
gloliln g/100 ml
Ninety liny Snbucute Knt Toxlolly Study.
hull vlilunl Ilematnlnglnnl Values - 1 Moiitlm.
l.eticocyteu 1 0 l/cmu1
Ncutroplil In
So b .
Non-SeR
XX
l.ymptio-- cytes Z
KiihIiiiipillIs Z
Monocyten
Z
Husopit11H
Z
KulIrulocytus Z
Control:
7)886 71887 7 1888 738H9 -71890
73891 7 1892 71891 71894 71895
Menu
10 ]i|im:
71896 73R97 71898 71899 7.1900
Menu
7 1901 7 1902 71901 71904 71905
H inn
100 jijiiu:
71906 73907 71908 71910 7 1946
Menu
71911 71912 73911 71914 71915
Menu
H H M H M
e
H H H H H
K Y
H H H M H
V V V
I 17-llH'V
8. 10 7.19 7.16 7.62 7.59
7.57
6.88 6.85 6. 77 5.96 6.47
6.59
7.58 7.18 11.21 7.00 7.18
7.41
7.70 7.15 7.36 7.10 6.91
7.28
01 oil Died 5.04 01 til 6.00
5.52
6.14 1)1ml 5.91 OIl-iI 6.04
6.01
52 50 47 50 50 50 48 47 47 44 40 45
46 48 46 46 45 46 49 44 48 48 47 47
III
39 39 40
43
19 41
17.3 16.4 15.7 170 16.4
16.6
16.1 15.5 15.5 16.0 13.6
15.4
16.1 15.2 15.7 15.2 15.7
15.6
16.5 15.6 15.8 16.3 16.0
16.0
10.35 11.89 16.20 10.25 11.80
12.50
7.02 4.95 8.71 9.68 6.07
7.29
8.60 10.65
9.90 10.35
8.66
9.63
4.80 6. 11 5.37 5.16 6.77
5.68
14 17
8 12 20
14
17 12 15 36 23
21
11 11 22 8 20
15
23 11 22 27 11
19
0 82 0 81 0 91 0 85 1 77
0 84
0 81 0 86 0 83 0 56 0 75
0 76
0 88 0 85 0 77 0 90 0 77
0 83
0 75 0 87 0 78 1 70 0 86
0 80
2 2 0 2.1 1 | (1 1.0
l 00
1.0
2 1 0 2.7
0 20
1.1
1 1 0 2.8
2 00 1 10 1 l0 6 20 2 00
3.1 2.9 2.7 1.4 1.5
2 l 0 1.2
1 00 2 00 1 00 1 10 3 00
2 00
1 10 1 10 0 00 2 00 3 00
1 00
2.5 2.6 1.1 1.0 1.1
2.9
1.2 l.li 2.5 2.5 2.1
2.8
11.0
13.2 12.1 14.1
11.8 11.6 13.8
5.70 6.71 6.21 7.58 6. 17 4.H4 6.26
...
24 0 76
00
17 0 62 31 0 68 2H 1 71
10 10 00
26 0 74
00
21 0 79 25 0 75
00 00
......... ... ...-- --------......--- - --- --------- --- ----
0 0 0 0 0 0 0
......
3.5
2.9 3.2 2.4
2.1 1.0 1.8
TZTZOO
BEST COPY AVAILABLE
N; l/i
!
Fluorocliemlcal Surfactant
TAIII.h H. . .n r .
Croii|it Rat Ninniler
Bryllirocytea
Sex 10^/cmm
300 ppm:
71916 73917 739IR 71919 7)920
71921 73922 7)923 73924 73925
ljOOO^jiiim;
73926 71927 73928 73929 7)930
73931 73932 73933 739)4 73935
3,00(1 ppm:
73936 73917 7)938 7 1939 73940
73941 73942 73943 73944 73945
H H H M M
F F
f
F F
M M M H H
F F F F F
M M M M M
r F F vF F
Died 11led Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Menatocrlt Z
Ninety liny Subacute Rat Toxicity Study,
lui]Ividimi Hematological Vulueu - 1 Hontlia.
liemoglobln g/100 ml
l.eucocytea 10^/cmm
Neutrophils
Seg.
Nou-Seg.
ZZ
Lynpliocytes Z
CosinopiiU s Z
!
Monocytes
Z
Basopill Is
Z
RetIculocytes Z
BESTCOPYAVAILABLE
002122
T pi OQ 0> N
O'
Fluorochemical Surfactant TABLE 9.
Hiochemistry
Glucose, mg/100 ml
a.ti.s., mg/100 ml
'( -G.T.P. Sigma units/ml
Creatinine Phoepholcinase, Sigma units/ml
P.G.Q.T., int'l units/1
P.G.P.T., int'l units/1
Calcium, meq/1
Altea!ine Phosphatase, int'l units/1
SEST COPY AVAILABLE
Ninety Day Subacute Rat Toxicity Study.
HALES: Means and Significance9 of Biochemical Values.
Study Heath
Control
30 ppm
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest1* 1 3
84 120 112
11.2 IS.4 13.3
2 1 1
13 13 12
95 112 101
93 47 33
9.5 8.4 10.4
166 89
120 111 UO
13.4 13.2 28.9
1 1 3
15 10 11
112 106
88*
47 54 43
8.4 8.5 10.2
190 127
i^age 27
100 ppm
112 158* 112
15.3 29.5* 23.9
1 1 2 12 44 10 101 539 90 33 485 37 10.4 7.6 10.1
229 103
137-035
Significantly different chan Control group mean, p 0<05. Significantly different chan Control group naan, p 0<0l. ^Statistical analyses were not conducted on the pretest values.
Sot determined in pratest period because of anticoagulant interference.
002123
BEST COPY AVAILABLE '8' 28
Fluorocheaical Surfactant
TABLE 9. ----
Biochemistry
Glucose, ag/100 al
B.U.N., ag/100 al
>-G.T.P. Sigma units/ml
Creatinine Phosphokinase, Sigma units/al
P.G.O.T., lnt'l units/I
P.G.P.T., iac'l units/l
Calcium, aeq/1
Alkaline Phosphatase, inc'l units/l
Ninety Day Subacute Rat Toxicity Study.
FOALES: Means and Significance3 of Biochemical Values.
Study Month
Concrol
30 ppm
Pretest 1 3
Precesc 1 3
Precesc 1 3
Pretest 1 3
Precesc 1 3
Pretest 1 3
Precesc 1 3
Pretest6 1
103 119 112
11.3 17.0 14.6
2 2 0
10 8 9
82 103 203
79 36 136
10.3 10.1 10.2
99 47
119 123 110
17.0 20.0 20.2
2 1 1
8 11
9
103 107
91
36 61 34
10.1 8.1
10.4
125 75
100 ppm
112 149 107
14.6 40.0* 20.6*
0 1 1
9 32* 25
203 290 397
136 179 504
10.2 8.7
10.4
182** 142
137-085
Significantly different than Concrol group mean, p 0<05. `Significantly differenc chan Concrol group aean, p 0<0l. ^Statistical analyses were not conducted on the precesc values,
l.'cc determined in precesc period because of anticoagulant tncerference.
002124
Fluorochemlcal Surfactanc
TABLE 10.
Croup, Sac Glucose Number Sex mg/100 ml
Control:
73886 73887 73888 73889 73890
Mean
73891 73892 73893 73894 73895
Mean
30 pom:
73896 73897 73898 73899 73900
Mean
73901 73902 73903 73904 73905
Mean
100 oom:
73906 73907 73908 73910 73946
Mean
73911 73912 73913 73914 73*13
Mean
M M M M M
F F F F F
M M M M X
F F F F F
M M M M M
F F F F F
96 93 69 81 81
34
75 87 132 111 111
103
84 93 87 75 66
81
99 90 102 81 93
93
96 93 81 93 5*i
83
90 81 87 72 78
82
O9EST copy AVAILABLE Page 29
Ninety Day Subacute Sac Toxicity Study. Individual Biochemical Values - Pretest.
B..N. ag/100 ml
y -c .t .p . Sigma unics/ml
C.P.K.* Sigma
unics/ml
P.C.O.T. inc'l unics/1
P.G.P.T. inc'l
units/I
Calcium meq/1
11.7 9.9
10.5 11.7 12.0
11.2
11.1 12.0 11.7 10.2 11.7
11.3
12.9 8.7
11.4 10.8
9.0
10.6
15.3 9.0
12.0 11.7
6.6 -
10.9
9.0 12.3
9.0 9.9 12.0
10.4
10.5 11.7
6.6 6.9 9.3
9.0
'
1 2 2 2 2
2
2 2 2 2 2
2
2 2 1 1 1
1
1 1 1 1 1
1
1 1 1 1 1
1
1 .1 1 2 i
i
12 96 13 108 15 87 12 96 14 90
13 95
14 87 13 93 12 66
8 78 5 87
10 82
23 84 42 96 38 93 15 90 12 93
26 91
13 81 5 81
12 102 24 87
9 78
13 86
9 1128 10 114 11 90 10 81 37 96
15 302
11 75 20 114 10 78 23 132 24 66
18 93
102 105
84 84 90
93
96 66 72 69 90
79
84 81 78 78 69
78
99 93 117 96 90
99
1104 120 111 87 150 314
31 96 72 90 66
81
9.5 9.6 9.0 9.4 9.9
9.5
9.5 9.8 9.4 10.2 12.8
10.3
9.7 9.5 8.5 8.9 9.0
9.1
9.7 9.8 9.2 9.5 9.1
9.5
9.1 9.7 9.9 10.1 9.8
9.7
10.4 10.5 10.6 10.8 10.8
10.6
137-085
*Creacinine phosphoitioase.
002125
Fluorochemical Surfactant
TABLE 10. Cvu
Group, Rat Glucose umber Sex mg/100 ml
300 o d d :
73916 73917 73918 73919 73920
M M M M M
Mean
73921 73922 73923 73924 73925
F F F F F
Mean
1.000 nom:
73926 73927 73928 73929 73930
M M M M M
Mean
73931 73932 73933 73931 73935
F F F F F
Mean
3.0Q0 o v a :
73936 73937 7393 73939 73510
M M M M M
Mean
73911 73912 73913 73911 73915
F F F F F
Mean
84 102 105
87 93
94
U1 90
108 93
108
102
108 108
96 105
90
101
111 90 81 96 99
95
87 93 78 75 l
83
102 37
102 96 96
97
Sinecy Day Subacuta Elat Toxicity Study
30B E S T C O P Y A V A I L S
Individual Biochemical Values - Pretest.
B.O.M. mg/100 ml
r-G.T.P. Sigma unita/ml
C.P.K.* Sigma
units/ml
P.G.O.T. int'l
units/1
P.G.P.T int'l
units/l
Calcium meq/1
8.7 7.5 9.3 9.0 9.3
8.8
U.7 9.6 9.0
12.0 12.0
10.9
14.1 11.4
9.3 11.1
8.7
10.9
12.6 10.8
8.7 9.3 10.8
10.4
9.3 14.4 11.7 12.6 23.7
14.3
11.4 11.4 11.7 17.7 12.3
12.9
2 2 1 1 2
2
1 1 1 2 1
1
1 2 2 2 2
2
1 1 2 2 2
2
2 2 2 2 22
6
2 2 1 2 1
2
19 37 21 84 10 34 27 72 11 69
18 79
6 60. 10 87 13 72 11 63 10 60
10 68
14 84 8 60
18 87 9 75
41 129
18 87
16 117 13 87 12 72 12 90 12 93
13 92
11 84 14 84 12 81 10 108 14 105
12 92
32 93 16 78
9 72 21 90 11 90
18 85
102 11.3 87 11.3 93 11.5 84 11.1 87 11.7
91 11.5
78 11.4 90 11.4 84 12.1 96 11.0 87 10.3
87 11.2
84 11.7 90 11.6 66 11.3 66 10.2 90 11.6
79 11.3
129 10.7 75 10.9 60 11.3 96 12.0 90 11.4
90 11.3
108 11.2 132 11.6
99 11.1 126 11.5
93 11.6
112 11.4
99 10.9 108 11.1 117 10.8 102 11.3 126 9.2
110 10.7
137-085
`Creatinine ahosahoicinase.
002126
'Fluorochemical Surfactant
TABLE U
Group, Rar Glucose Bumber Sex mg/100 ml
Control:
73886 73887 73888 73889 73890
Mean
73891 73892 73893 73894 73895
Mean
30 own:
73896 73897 73898 73899 73900
Mean
73901 73902 73903 73904 73905
Mean
100 own:
73906 73907 73908 73910 73946
Mean
73911 73912 73913 73914 73915
Mean
M M M M M
F F F F F
M M M M M
F F F F F
M M M M M
F F P F ?
138 108 117 120 117
120
120 126 123 117 108
119
108 117 108 111 111
111
120 147 120 123 114
125
135 171 183 171 129
153
153 225 120 123 126
149
" w w w !* p e 31
Binary Day Subacute Hat Toxicity Study
Individual Biochemical Values - 1 Month.
3.U.B. mg/100 ml
y-C.T.P. Sigma units/ml
C.P.K.*
Sigma units/ml
P .G.O.T. int'l
units/1
P.G.P.T. int'l
unlts/1
Aik. Phos.
Calcium int'l
meq/1
units/i
17.4 14.4 14.7 15.3 15.0
15.4
18.0 16.5 15.3 15.3 19.8
17.0
13.5 15.0 18.6 15.3 13.5
15.2
22.2 16.3 22.5 17.7 21.0
20.0
29.7 30.0 30.0 34.5 23.4
29.5
29.7 42.0 38.4 60.3 29.7
40.0
3 16 108 54 8.1 . 201 1 8 93 39 3.0 147 1 8 90 33 7.7 147 1 30 150 66 9.3 138 0 11 117 45 8.7 198
1 15 112 47 8.4 166
2 6 117 60 8.3 93
2 10 108 60 8.3 120
2 6 93 51 9.3 105
1
8
105
54
10.8
87
1
12
93
54
13.4
90
2
8
103
56
10.1
99
1 9 93 54 7.7 207 1 10 90 42 8.4 267 1 15 123 75 8.7 162 1 6 99 48 8.8 168 0 8 123 51 8.9 147
1 10 106 54 8.5 190
0 6 102 45 7.5 132 2 9 111 72 8.0 144 1 a 93 51 8.2 90 1 9 120 66 8.1 120 1 23 108 72 8.3 138
1 11 107 61 8 .1 125
1 36 363 345 8.0 219
1 29 243 180 8.0 198
2
96
1527
1248
7,0 180
2 44 396 480 7.2 258
1 16 163 171 7 .6 2SS
1
44
539 485
7.6 229
0 42 432 282 8.3 162 2 56 657 393 8.2 132 1 24 123 75 9.0 ISO 1 19 120 78 8.8 231 1 17 117 69 9.2 204
1 32 290 179 8.7 182
.37-085
Creatinine onosphokiaase.
002127
Fluorochemical Surfactant
TABLE 11
Group, Rat Glucose Number Sex mg/100 ml
300 oom:
73916 73917 73918 73919 73920
X X X X X
73921 73922 73923 73924 73925
F F F F F
1.000 ppm:
73926 73927 73928 73929 73930
X X X X X
73931 73932 73933 73934 73935
F F F F F
3,000 oom:
73936 73937 73938 73939 73940
73941 73942 73943 73944 74945
X X X X X
F F ? F ?
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Ninety Day Subacuta Rae Toxicity Study.
Individual Biochaoical Falas - 1 Month.
B.O.N. mg/100 ml
y-G.T.P. Sigma units/ml
C.P.K.* Sigma
unics/al
P.G.Q.T. int'l
units/1
P.G.P.T. inc'l Calcium
units/l maq/1
Aik. Phos. int'l
units/l
137- 085
Creatinine phosphokinase.
002128
'fluorochemical Surfactant
TABLE 12.
Group, Sac Number
Sex
Glucose og/100 ml
mumbest copy
Page 3J
Ninety Day Subacuta tot Toxicity Study.
Individual Biochemical Values - 3 Months.
3.U.M. mg/100 ml
y -c .t .p . Sigma units/ml
C.P.K.* Sigma
units/ml
P.G.O.T. inc'l
units/l
P.G.P.T. int'l
units/l
Calcium meq/l
Aik. Phos i n t 'l
units/l
Control:
73386 73387 73888 73889 73890
Mean
73891 73892 73893 73894 73895
Mean
30 oom:
73896 73897 73898 73899 73900
Mean
73901 73902 73903 73904 73905
Mean
100 nnm:
73906 73907 73908 73910 73946
Mean
73911 73912 73913 73914 73915
Mean
M M M M M
F F F F F
M M M M M
F F F F F
M M M M M
F F F F r
116 105 110 111 118
112
105 102 128 111 112
112
145 91
116 94
105
110
105 125 121 103
95
110
Died Died 100 Died 123
112
117 Died 121 Died
34
107
14.1 14.2 15.7 17.6 14.9 15.3 16.0 14.0 13.9 12.0 17.0 14.6
74.4 16.5 19.1 18.3 16.1 23.9 23.6 17.6 22.1 17.4 20.1 20.2
21.4
26.3 23.9 19.0
19.0
23.8 20.6
0 1 1 1 0 1 1 1 0 0 0 0
13 1 0 1 0 3 0 0 1 1 1 1
1
2 2 0
1
1 1
11 109 13 97 12 95
8 102 14 102 12 101
8 87 9 86 9 88 9 663 11 100 9 205
11 86 10 86 12 100 13 79
8 90 11 88
6 71 9 90 8 90 9 106 U 96 9 91
7 87
13 93 10 90
7 95
42 786
27 309 25 397
42 10.4 120
31 10.0
79
30 10.8
99
32 10.3
59
30 10.3
86
33 10.4
39
29 11.0 27 10.3 24 9.7 560 9.8 41 10.2
46 43 47 47 53
136 10.2
47
39 10.5 175 48 10.1 139 38 9.9 107 42 9.8 105 49 10.5 111
43 10.2 127
19 10.5 23 10.5 38 10.3 53 10.4 35 10.5
70 95 49 60 99
34 10.4
75
46 27 37 60 1344
108 504
10.3 9.9
10.1 10.8
10.0 10.4 10.4
79 127 103 95
176 154 142
137-035
Creatinine phosphokinase.
002129
Fluorochemlcal Surfactant
TABLE 12
Group, Bat Glucose Number Sex ag/100 ml
300 oom:
73916 73917 73918 73919 73920
M M M M M
73921 73922 73923 73924 73925
F F F F F
1.000 Pi:
73926 73927 73928 73929 73930
Si M M M M
73931 73932 73933 73934 73935
F F F F F
3.000 som:
73936 73937 73938 73939 73940
M M M M M
73941 73942 73943 73944 73943
F F
F
F ?
Oled Oled Died Oled Died
Died Oled Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
BEST COPY AVAILABLE - 34
Ninety Day Subacute Bat Toxicity Study.
Individual Biochemical Values - 3 Months.
B.U.M. mg/100 ml
y -G.T.P. Sigma units/ml
C.P.K.* Sigma
unita/ml
P.G.O.T. lnc'l
unlts/1
P.G.P.T. lnt'l Calcium
units/1 meq/1
Aik. Phos. lnt'l
units/l
137-083
*Creatlnine phosphokinase.
002130
Fluorochemical Surfactant TABLE 13.
Urinalysis MALES: Volume,
ml PH,
Specific Gravity,
FEMALES: Volume,
PH,
Specific Gravity,
BEST COPY AVAILABLEpa!e 35
Kinety Day Subacute Rat Toxicity Study.
Seans and Significance3 of Urinalysis Values.
Study Month
Control
30 ppm
100 ppm
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
Pretest 1 3
2.1 2.8 3.1
7.6 7.4 7.2
1.050 1.067 1.068
1.3 1.8 0.8
6.8 7.0 6.7
1.079 1.038 1.071
3.5 3.1 2.3
7.0 6.5 6.3
1.054 1.057 1.067
1.7 2.1 2.1
7.0 7.3 7.2
1.063 1.048 1.055
3.2 3.3 3.5
7.0 6.8 7.4
1.047 1.042 1.042
1.6 2.9 0.0
6.8 6.7 QNS
1.069 1.054 QNS
137-085
OKS - Quanity not sufficient `Statistical analyses were not conducted on pretest values.
002131
1un roehciiiIr.iI Kurfiic inni
TAIII,li 14.
Croup,
Hui
Number
Sl*K
ViliHUH! Ul)
Coniol:
738B6 n 2.5
718B7 H 0.5
7 1888 II 3.5
73BB9
II 2.5
73890
II 1.5
73891 73892 73893 73894 73895
H 0.5 K 1.0 H 1.0 H <0.5 H 2.0
30 jijiw:
73896 73897
73898
73899
73;>0
H M M H H
2.5 5.5 5.0 3.5 1.0
73901 73902 73903 73904 7 3905
100 jijini:
F H
H F H
4.0 1.0 1.5 1.5 0.5
73906 H 3.5
73907 H 4.0
73908 H 2.5
73910
H 4.0
73946 M 2.0
73911 73912 73913 7 1914 73915
F . 2.0 F ' 2.5 F 1.0 F 1.0 F ' 1.5
Color ami
Appetir.
IlS-cl OS-el OS-el OS-C OS-el
OS-C s-c s-c s-c S-c 1
S-C OS-cl OS-C
S-C DS-cl
S-C OS-C OS-c 1
S-C l'S-cl
S-C S-C S-C OS-el I.S-C
S-C OS-el I.S-C OS-cl
S-c 1
N in e ty liny S u b a cu te Hut T o x i c i t y S t u d y . Individuili U rinalysis Vulucs - I'reteHt.
Spec. I'" Orav.
Albumin
lucime
Billruhln
Occult Hloud
Ko- Krythrotoiien cytes
7.5 1.070
2+
NN
1+
2+ ncc
7.6 1.010
1+
NN
2+
tr 1-3
8.2 1.035
N
N N 1+ N
6.9 1.065
N
NN
1+ N occ
7.9 1.070
N
N N 3+ N 1-3
7.9 1.075
N
NN
4+
II 1-3
6.3 1.080
N
N N 1+ N
6.0 1.095
N
NN
N
N
6.0 1.090
tr
NN
N
N
8.0 1.055
N
N N 3+ tr
6.8 1.065
tr
NN
N
1+
6.9 1.050
N
N N 1+ tr
7.2 1.040
N
N N tr N
6.9 1.050
N
NN
N
2+
7.1 1.065
tr
NN
31
N OCC
7.0 1.037
N
NN
N
N
6.1 1.090
tr
NN
tr
1+ occ
8.4 1.039
N
N N 2+ tr occ
6.0 1.080
tr
NN
N
N
7.5 1.070
tr
NN
4+
2+
7.0 1.045 6.9 1.050 6.0 1.065
8.3 1.038 6.9 1.036
N N N N N
N N 1+ tr
NN
N
N
NN
N
tr 1-3
N N 3t N
NN
N
N
5.9 1.065
N
NN
N
N
7.8 1.070
N
N N 4+ N
6.0 1.075
N
NN
N
N
6.2 1.085
tr
NN
2+
N occ
7.9 1.050
N
N N tr N
Epi. Cells
OCC occ occ
occ occ
occ
Amor. Ilrnles
T rip le Pluiepules
Cn 1e . Ox.
lineter In
HN OCC occ
HH occ occ
HH
H occ occ H occ H occ H occ H
occ F HF
occ H occ F occ occ
occ occ FF
occ F occ F occ H
occ F occ F occ F
rF F FF
occ F F M occ
occ nee F
occ M
M M H H H
H M H M H
H N M H M
N H M F H
M M M H F
F H F H H
"1
002132
137-085
Code:
Ir - Trnce I t - Trnce In nll|;lil 21 - SI Iplit t o m o d e r a t e It - Hiillunito 4 1 - M.liked
S - St row I.S - l .l p h t S trnw l)S - b a r k S trn w I.Ain - 1.1((lit Amber DAin - Dnrk Author cl - Cloudy
0 - Cl onr
N - Ney.ntiv
F - How
I. - I.untied
M - Many
K - Hari:
nee - OueiiHlimili
(U
00
(0
U>
ai
FI llorncllcmlca 1 Sitrfm l ,ml
TAIII.F 14. ..>1 .
Group,
Uni Volume
Number Sox
uil
Color nini
Apponi.
100 ppm:
7)9 Hi 7 111 7 7)918
73919 73920
M H M II M
7)921 73922 7)923 7)924 7)92'
F F F F F
) .000 ppm:
7)926
7J927 73928 73929 73930
H
II H H II
7393) 73932 739)3 73934 739)5
F F F F F
3,000 ppm:
7)9)6 7)9)7
7)9)8
739)9 7)940
M M II 11 H
7)941' 7)942 7)943 7)944 7)945
F F F F' F
l)NS 1.5 <0.5 4.0 7.0
2,0 3.5 4.0 2.0 2.0
8.0 4.5 5.5 5.0 4.0
<0.5 1.5
<0.5 5.0 (JNS
2.5 4.5 5.0 3.5 6.0
4.0 4.0 2.4 1.0 3.5
IIS-: 1 s-t:
DS-c 1 IIS--1
S-C. IIS-.: 1
S-C S-C S-C
S-el I.S-:I I.S-el
S-C S-c 1
DS-c I IlS-C IIS-C I.S-C
IIS-:l S-c.t S-c 1 S-C S-cl
IIS--*l IIS-C IIS-c 1 IIS-c 1 IIS-c 1
N i n e t y Day S u b a c u t e Kill T o x i c i t y S t u d y . I n d i v i d u a l U r l u u l y a l s V alu es - I'r e l u H l .
Spec. Grsv.
Albumin
til 1-- B i l l C06U r u b l n
Occult Bluoil
Ke- F.rytbrotunes cytes
F.p 1. Celia
8.0 1.045 8.2 1.070 5.3 1.042 8.0 1.036
7.9 1.085 5.9 1.040 7.8 1.045 6.9 1.065 6.1 1.070
8.9 1.032 8.0 1.036 7.9 1.0)6 6.3 1.042 8.1 1.040
6.5 1.090 7.0 1.080 8.9 1.070 7.1 1.036
N tr N N
N N N N N
N N N N N
tr N tr N
8.2 1.050 8.4 1.038 8.4 1.037 6.1 1.045 6.4 1.048
8.1 1.035 8.4 1.036 8.6 1.042 6.7 1.070 7.0 1.038
tr N N N N
N lr i+ N N
NN NN NN NN
NN NN NN NN NN
NN NN NN NN NN
NN NN NN NN
NN NN NN NN NN
NN NN NN NN NN
4+ N 1+ tr
N 4+ N N' N
tr N N N N
1+ 2+ 4+ N
H 1+ tr N N
4+ 4+ 4+ 4+ 3b
N N N N
N occ N N N occ N
N occ N N N N
N t r 1-3 N OCC N
t r 1-3 N occ N N N
N occ N N 1-3 N N
OCC occ
OCC
OCC occ occ occ
Amur. Unites
Triple Fliospates
Cn 1:. tlx.
occ OCC occ F
KM FH
occ F occ M
FF occ F occ F
occ F occ H occ ore occ M occ F
occ F FM
occ F occ II
MH FM occ occ occ H occ II
FH occ F
FF occ F occ F
Uni-L u r i d
H II II H H' II H II II
II H H II H F II H H
II H II M II
II M II II II
I
HSICOPVAMIUBIE
002133
Omit* ;
l r - Tra:: II - Trnr.u t> a l l Kilt 21 - SI l|>lil l u m m le r n te it - Iliiilernte
4 I - Ibirkeil
S - Straw I.S - l.ln lil St raw IIS - Dark S t r a w I.Am - l.ip jit Amber IIAm - Dark Amber c l - Cloudy
N - Neipilive F - Few 1. - bonded II - Many R - Ibi r e
occ - <)rrn.sloiiul
<|NS - t y i n n l t y n o t s i l f i l r l e n t
I
I I iiiiKU'lieHi I r a l Surfactant
TAIII.K 15.
Croup,
Hat Vo 1timo
Niiiulier Sox
ml
Color uiul
Appear.
Spec. pit Crnv.
N i n e t y Day S u b a c u t e Rat T o x i c i t y S t u d y . Itkdivldtini U rin a ly s is V alues - 1 Month.
Albu min
Clucose
Bili rubin
Occult Blood
Ke Erythro tonen cytes
Epl. Celia
Amor. Uratea
Triple 1`tlOBpntes
Cute. Ox.
lliiclrr In
Control :
73886
73HH7 73888 7 18119 73890
73891 73892 73893 73894 73895
30 ppm:
73896 7 1897 73898 73899 73900
73901 73902 73903 73904 73905
100 ppm :
73906 73907 73908 73910 73946
7391 1 73912 73913 73914 73915
M H M H M
V
M II M H H
K F
M M H M M
F F K K F
3.5 0.5 5.0 4.5 0.5
2.0 ONS 1.0 1.0 3.0
5.5 5.0 1.5 1.5 2 .0
2.5 1.0 3.5 2.5 1.0
2.5 2.5 7.5 2 .0 2 .0
. 3.5 1.5 ()NS 3.5 1 .0
S-rl S-C S-rl im cl lS-rl
OS-c 1
IlS-c.1 S-C
LS-C
6.9 6.8 6.8 8.1 8.2
8.0
7.6 6.2 6.0
1.040 1.045 1.080 1.080 1.090
1.045
1.045 1.040 1.020
N N H N N
N
H N N
I.S-C IIS-c 1 OS-c l
S-C S-C
S-rl S-rl S-cl IlS-c 1 OS-c 1
6.3 6.2 8.0 6.2 5.8
6.9 7.0 6.8 8.0 8.0
1.040 1.045 1.040 1.070 1.090
1.050 1.040 1.055 1.045 1.050
N N N N N
N N N N N
S-C S-C S-C S-C S-cl
6.8 1.045 7.0 1.045 7.0 1.035 6.5 1.050 6.5 1.037
S-C 5.9 1.040 OS-cl 7.9 1.050
S-cl 6.5 1.045 S-cl 6.3 1.080
N N N N N
N N
N N
NN NN NN NN NN
NN
tr tr N 1 13
23
HN
13
NN
tr'-
N N .N
NN NN NN NN NN
NN NN NN NN NN
NN NN NN NN NN
NN NN
NN NN
N N tr N N
N N N 13 13
N N N N N
N 13
tr N
H occ N N ir 1-1 tr
N occ
N N 1-3 N
N 1-3 N 1-3 N N occ N occ
N N 1-3 N 1-3 N occ N
13 1-3 13 tr 13 13 occ
N N
N N
OCC
occ
F
occ r H
occ F
(ICC occ M
occ occ
occ F M F
occ 1-3
H F occ H
OCC
F
OCC occ H occ occ F occ occ F occ occ H occ occ F F
OCC occ F FN
occ occ F occ occ F F F occ F H
occ occ H occ F
occ F H occ occ F
occ F
occ F F
p occ
H
occ
FF
H
occ F M occ
M M H M F
M
It H H
H M II M H
II II M M H
H II II M M
II H
H H
BEST COPY AVAILABLE
002134
Code:
tr - Trace II - T race to h I Iglit 23 - SI Ip,lit to m o d era te
13 - M o d e rate 41 - H arked
S - Straw I.S - 1.1ftlit S tra w OS - Dark Si raw I.Am - l.t|;lit Arnlier DA - D ark Andier
e l - Cloudy C - C lear
N - N egative F - Few 1. - l.oaileil M - Many Il - Ita re
nee - Drena Iona 1
()NS - (Jn n n lty n o t n n f f l c l e n l
Kluiirui'luunlr-ill Snrl actant
TAIIIK I*). ....
(loop,
Hal Volume
Uumlier Sex
ml
Color anil
Appeal.
Spec. pll firav.
N i n e t y l>;iy S n l m c u t u Hut T o x i c i t y S t u d y . lmllvliliiiil Urinalysis Values - 1 Huulli.
Mbitmin
Clucose
HillruliJn
Occult Mood
Ke- Kryttirotonei cytes
Epl. Cells
Amor. Urates
Triple I'liuspates
Calc. Ox.
H.-icterlu
300 ppm:
71916 7J917 7391H 73919 73920
M H M M U
73921 73922 73923 73924 73925
K K V 1V
J ,0U0_ ppm:
73926 7 1927 73928 73929 73930
H M M H M
73931 73932 73933 73914 73935
K 1*' K K K
3,000 ppm:
73936 73917 739311 73939 739411
M H H H M
73941 73942 73943 73944 7 1945
1K K K V
Died Died Died Died llleil
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
Died Died Died Died Died
'llleil Died
4 Died Died Died
KST COPYAVAILABLE
002135
t r - liaci*
H - Tran* lu stlK lii
ik - SM j'.lil l imulcrnU*
Jl - Modrl .lt t*
- Markml
S - Straw
I.S - 1.1i;ltl S tra w
US - Dark S tra w
1.Am -
Autln*!'
1)Am - Dark Author
v 1 - Cloudy
C - Cl o ar
N - N o|;nllvt
K - Ki'W 1. - t,o;uli`d
H - Many H - Hart* )<*? - lUtraHliiii
I
Flunrneliem lrnl Surlnelnnt
TARI.K |h.
(;roii|i,
Knt Volume
Number Sex
ml
(`.out nil :
73886 73BH7 7IHHH 7 IHH*I 7 1890
73891 71892 71893 73B94 7urn
10 ppm:
73896 7 1897 73H9B 73899 7 1900
7 1901 73902 71901 73904 73905
lOOjipm:
73906 71907 71908 73910 71946
71911 71912 7191 1 73914 71915
M II II II II
F l` F F K
M II M 11 II
F F F F F
H 11 M H M
F F F I'1 F
0.5 1.5 4.0 4.0 3.0
2.5 <0.5 (/NS
0.7 (/NS
1.0
5.0 3.5 2.5 2.0
2.0 0.7 2.0 5.0 0.8
Died Died 5.0 Died 2.0
(/NS Died (/NS Died t/NS
Color und
Appear.
S-e 1 OS-.I
S-e 1 S-el S-e 1 I.S-C IIH-cl
I.S-cl
I.S-C1 I.S-ci
S-el S-el S-e 1 S-el S-cl S-el I.S-c1 1)8-1
LS-0
IIS--e 1
Ninety Day Subacute Rut Toxicity Study. Individual Urinalysis Value - 3 Mouths.
Spec. pll Cray.
Albumin
('.Incose
Rillrubln
Occult lllood
Ke- Rrythrotone cytes
7.0 1.110
tr
N
N
2+
N
8.0 1.070
N
N
N
1+
N 1-3
7.2 1.059
N
N
N
It
N oec
6.8 1.045
N
N
N
N
N
7.(1 1.057
N
N
N
2+
N
6.2 1.042
N
N
N
N
N
H.O 1.060
N
N
N
4t
N 1-1
6.0 1.110
N
N
N
N,
N
1-3
6.0 1.080
N
N
N
N
6.2 1.042
N
N
N
N
6.0 1.062
N
N
N
N
6.3 1.080
N
N
N
N
7.2 1.070
N
N
N
N
N N N 1-3 It 1-3 N
7.8 1.022
tr
N
N
3t
N occ
5.0 1.120
tr
N
N
N
N
8.2 1.030
N
N
N
It
N
6.8 1.040
N
N
N
N
N ut:c
8.0 1.062
N
N
N
It
N 1-3
6.0 1.042
N
N
N
N
N
8.8 1.042
N
NN
It
N
Kpl, Cells
(ICC
occ occ
OCC
occ
occ
Amor. Urates
Triple 1`lioupates
Cu Ie . Ox.
Ilurtcrlu
H F OCC FM FF VF VF
M M M M M
FF
F
M F occ M
MK
F
ucc
F ICC
occ occ
FF
FF
F F ucc
M FH F II FN HF F II occ
F F F 11 M
M 11 M 11 H
F occ M M occ
F 11
t
BEST COPY AVAILABLE
002136
Code:
tr - Truro I t * Truce to nli^ht 21 - Sll^lil Lu moderate It - Mm)c*rule 4 l - Marked
S - Straw I.S - l.l|>6( Straw OS - Hark St raw (Ain - Uj;lit Anther DAin - Dark Anther cl - Cloudy
C - Cle.tr
N - NennLIve F - Few 1 - Loaded II - Many K - Hare occ - OectiHlnnnl
(/NS - (funnily not stiffleieat
bd I OQ
ID
CO
I
!'1iio ro c b c m lc n l Sur lit*-1ni(
TAlil.K ........ .
Croni),
Kai Volumi*
Ninnili1r Sox
ini
Color mid
Appear.
JUO pj>w:
71916 73917 7391B 73919 73920
M H H 11 N
73921 73922 71923 73924 73925
E E E E E
1.000 ppm:
73926 73927 73928 73929 71930
H H M H II
73931 73932 73933 73934 73935
E E E E E
3.000 ppm:
73936 73937 73938 73939 73940
H M H M M
73941 73942 73943 73944 73945
E E E E
E
Died led led led led
led led led Died led
led led led led Died
led led led led led
led led led led led
.led led led . 1ed led
Spec. |ill Craw-
Ninety Day Subacute Rat Toxicity Study. Individual Urinalysis Values - 3 Hunt Its.
Albu min
Clucnse
Billrubn
Occult Blood
He- Krytlirotunen cytes
Epl. Cells
Amur. Urates
Triple 1'lioapotea
Calc. Ox.
Hucter In
BEST COPYAVAILABLE
002137
tr - Trace
S - Straw
1+ - T r a c e t o s l i g h t
l.S - M u h l S tra w
21 - S i t u i l i t o m o d e r a te I)S - Dark S tr a w
31 - M o d e rate
1Am - 1.1t'lil Amber
41- - Marked
Ain - a r k Amber i` I - C ltunly
C - Clt*ar
N - Netta l i v e
E - Kew
1. - bnuded
M - Many It - R are o t:r - 0tr*iHloii;il
BEST COPY AVAILABLE
002138
'1
FI mirochemical Surfactant
N i n e t y Day S u b lim ile Hut T o x i c i t y S i l l i l y .
TAIII.K 17.
Summary of Cross Necropsy Obscrv.it lunu.
Control MF
30 ppm MF
Terminal Sucriflee ________________ __
100 ppm 100 ppm 1.00(1 ppm 3 , 0 0 0 ppm
h H II H
M
MF
1^
Number u c c r o p s le d No g r o s s l e s i o n s
55 43
5523 2
KxLcrnuI punirIut 1oli luilr loss, forelimb reddisli lunterlul iiround mout li/iinse/ ture lliuti yel lituiHli/rcd iiiutcrlui, uiingcultal re);Imi
11
____________ Deaths. Unscheduled Sacrlf lee
Control 30 ppn 100 ppm too ppm 1,(100 ppm
H F H F (I F N F
Hr
I.U00 ppm II F
32 12
55
55
55 1
2I
Ili L 11
1
liyuH corneal opacity
I
luniks congest Ion ulilte/ilm k lirown/red/yellow foci n te le c la s ls
t 2
12 11
11
|
l.ympli Nudes red discoloration - cervical red/dnrk black discoloration mesenteric
1 1/
Stnmacli h y p erem la/cniigestlon dark brown/red fo c i - gl nudili nr mucoso l in e a r hemorrhage - g la n d u la r mucosa
I
112 2343425
1
Small Intestine durk red - greenish contents seminili Id, dark .brown, tun contents htuck, mucoid mater Ini
1.1 v e r
t
enlarged
congouI Inn
a c c e n tu a l eil l o b u l a t i o n
yelloulsli/browu/wblte foci
irregular areas
greenish - yellow exudate
adhesion to rig h t kidney
hrowu In c o lo r
22 22 2 111
223
1
3
2 1
23
1 1 1
2
Kidneys hydronephrosis congestion
I
I I
I17-OH
I
(hUi OQ (D iPo-
riiioioiiu'ihiiwii Surfactant TAIII.K I 7. Ci.......
U terus en larged/liydrom etrn
Ml s e e l I annona scanty abdominal fut
N i n e t y Uny S u b a c u t e Rat T o x i c i t y S t u d y .
Summary o f C ro s s N ecropsy O b serv a t i o n s .
_____________________ `I 'e r m ln a l S a c r i f i c e______________________
C o n t r o l 30 ppm 100 ppm 300 ppm 1 , 0 0 0 ppm 3 , 0 0 0 ppm
MF
H P H F MP
HP
MP
_______________ D e n t il s , Un s c h e d u l e d S a c r i f i c e _____ ________
C o n t r o l 30 ppm 100 ppm 300 ppm 1 , 0 0 0 ppm 3 , 0 0 0 ppm
HFMPHFHF
MK
HP
12
I1
i
BEST COPy AVAILABLE
002139
137-085
P)
OnQ>
-P-
u>
I'l uiirnrlicin Ica I Kuffact anl
TABI.K. IH.
Croup, Sex
Body lit. g
__ Spleen___ gZ
Control: H K
30 ppuit M K
101) j|pm: H K
ASA 253
AIA 211
373 206
0 .7 / 0. AB
0.17 0. 19
0.61 0 . AS
0. IS 0.19
0. 56 0. 3H
0. IA 0.18
I
N in e ty Day Su bacu te Kat T o x i c i t y S tu d y . Absolute (Crums) mid Kclatlvc (Z body Uelglit) Organ Weights.
_____ Liver ____ g "Z
___KIdneya gZ
Brain _ gT
Adrenals___ , g ZxlO
Thyroid/ Karatliyrotil,
g ZxlO
1`ltultiiry g Zxllr
13.80 7.7A
1.05 3.07
17.19 9.69*
A .lb A . 17**
2 9 .SI 1 3 .5A**
7.88* 6.57**
A .01 2.21
0.89 0.88
3.60 2.05
0.87 0.88
3.73 2.09
1.00* 1.01*
2.27 2.06
0.50 0.82
2.30 2.13
0.56 0.92
2.28 1.98
0.6A 0.96
7A 1.6A 76 2.9 9
55** 82
1.3A* 3.56
70 1.9 6 79 3.82
A1 0 .9 0 36 1.A6
32* 0 .7 8 35 1.50
36 0 .9 8 26 1.25
22 0.A 9 20 0 .7 9
15* 20
0.36 0.B9
IA .A0 19 0 .9 2
BEST COPY AVAILABLE
002140
137-085
(roup mean relative organ welglitB aliowu In this table were calculated by averaging the Individually calculated relative organ welgliLs.
*Slgnl flrmit ly different from control group wean, p<0.05. **Slgnl flcnntly different from control gruup menu, p<0.0l.
J 09 fD
P-
Kl uururlieiulcal Sur faci ml
TAHI.li 19.
Croup Kat Nu.
Cunt r l :
7J i m 73887 7 1888 73889 ,7'18*1(1
71H01 718*72 73891 73894 71895
30 ppm;
73896 73897 73898 73899 71900
'/.1901 7 1902 71901 71904 73905
100 ppm:
73908 71946
71911 71911 71915
Kux
N H M H H
K K F pr K
H H H H H F F F F F
M H
F F F
Unity Ul . g
450 419 500 423 457
262 212 284 211 273
404 442 423 416 387 216 251 224 251 221
446 100
221 192 206
Spleen 8
Ninety Day Subacute Kat T o x ic i t y Study. Individual Organ Weights - Terminal S a c r i f i c e .
1.1ver 8
Kidneys 8
llruln 8
Adrenals mg
0.77 0.63 0.76 0.84 0.H5
0.40 0.42 0.54 0.60 0.45
0.58 0.77 0.59 0.40 0.69
0.40 0.51 0.45 0.48 0.39
0.77 0.35
0.38 0.35 0.40
13.44 15.24 13.92 12.83 13.58
7.02 7.05 7.97 7.05 9.59
18.48 19. 75 19.63 9.46 18.65
9.46 10.55
8.98 .98 9.50
35.75 23.26
13.83 12.45 14.34
3.95 4.10 4.14 3. 74 4.12
2.28 1.92 2.32 2.10 2.44
3.70 4.75 3.96 1.80 3.80
1.80 2.22 2.13 2.16 1.93
4.50 2.96
2.38 1.78 2.111
2.31 2.19 2.47 2.23 2,13
2.19 1.87 1.87 2.11 2.27
2.35 2.34 2.01 1.89 2.90
1.89 2.19 2.30 2.13 2.14
2.10 2.45
2.15 1.75 2.04
73 74 89 66 70
88 31 79 72 112
62 54 55 49 56
64 70 96 63 116
65 74
70 70 96
I
Thyroid/ Parathyroid
"8
42 40 48 40 34
32 30 30 52 35
29 28 38 33 33
23 36 38 34 43
40 32
36 20 22
I'ltulLary 8
30 19 22 20 19
22 16 20 21 20
12 17 18 13 14
18 14 32 18 20
12 16
24 17 16
BEST COPy AVAILABLE
002141
i '7_ nun
*0 tu OQ Pu>
002142
Kl iioroi'lioailrn I Sur fi' t .in I
YAIII.K 20.
N i n e t y Duy S u h n c i i t e Rat T o x i c i t y S t ml y . illstomorplmlogic Observations. Control
30 ppw
100 ppm_____
73886 73887 i 73888 73889 1 73891 73892 73895 73896 73897 73898 73899 73900 73901 73902 73903 73905 1 i 73906 73907 73908 j 73910 | 73913 73914
Tisane I.u h I oii
S S cJ O MS
y, T\ y. > y. o0ni0'03.
m t*. tu tu PO)' CD CmD - iv
y. y. y. y, y. u.
h h lu noon*> I'm
IIrnlii (With C ervical Cord)
S p i n a l Curd ........ heir)
P eripheral Nerve
P itu ita ry foc-al cytoplaB iulc vac-uolntlon o f b a s o p h i ls 1.11 <>11yin.1 c y s t
----- . ... -------------------------------------------------------------------------------- -- Thyroid
remnant o f ultlm ohrnnchial re s t focal I n t e r s t i t i a l lymphoid i n f i l t r a t e s
l1 11 i 11l i 1
111I 111111
11 1 1 i 1 l i i -
11l 1111111
1 1 1 i 1 1 l i 1
11l 111111 1
1 1. i i 1 22 2 2 3
1- l 11 1 1 222
-- 11 1
11 X
-- --- --
--
XX --
----
XXXX 2
11
1
X XX
--
1 X
1
1
P sralh y ru Id
1
11
11l
1l
111
1
Adrenal focal cytoplasmic: vucuolat Ion o f c o r t i c a l c e l l s diffuse congestion
l1
1
1
22
2
32 2
2
1
22
34
22
2 2 2323
l.ung focal pe rib ro n c h ia l lymphoid hyperplasia focal p e riv a s c u la r 1ymphoid I n f i l t r a t e s focal aggregates of a lv e o lar macrophages congestion (agonal) focal I n te r s tltiu l Inflammatory c e ll I n f iltr a te s a l v e o l a r edema
22 2 2 2 2 2 3 3 2
2 22
2
22 2
23
23
1
32 2 32223
2
22222
22
2
222
3
2
2
22
2
2
Kye
Henri
'
focal myocardial dcgennrnllun/iiilnerallzution
fo c a l I n t e r s t i t i a l lyiii|iliolil I n f i l t r t e s i n aiyocurdliim
focal myocardial fllirosls
focal uec-rosls w ith mononuclear c e ll i n f i l t r a t e s lu
m yor.irdl mu
Aorta
:P l***u atrophy d e p l e t i o n lu iiniulier ami sire- o f lymphoid f o l l i c l e s iiicruiiKoil h e m o s id e rin pigment In rod p u lp
1l 1 1 1 1 1 1 1 l
11
111
1
1I 1 I I 1 I I1
1II
2 I -2 2 I /.
11l 1l 11l 11 1 1 1 11 11 1
2
1111
111 II
II
II1
1
2 I2
Code: x - coiiill I Ion p r o s o n l 4 . iiHulor.it o
Z Z y. Si Jfl
|* U t M |M
!ssOmOi*'
r1~-1i CIOnO'
nrH ma * rs
O OrHS
1 l l 1 1 >1 1 - - - - l 1- - 1
1 1i 11
22 2
2
11 1
11
XX
X
2
11 i
1
1l
l
322
2
23
2
32 22 2 2 32 2
222
22
2
3
25
24
2
2
1 11 l 1 1111
71 1 . 1 1 1
I1
III II I III II I I
'O I 0d a>
*> o-
BEST COPYAVAILABLE
1 SZ6L I
002143
FI iiorocheiulcn I Surfactant
TAIII.K 211.
N in e ty Day Suhiicute Rat T o x i c i t y S tu d y . Illstom orpholngtc Oliser vat Inna. 300 ppm
1 ,0 00 ppw
___________3 , 0 0 0 ppm_________ _
*. h
t. & 1 t t t. L i:
% t. t t t t
Tissue Cesin
Urnlu (Willi C crvlc.il Curd)
S p i ita I Cim i (I,ululili i')
l'o r Iplu'i'u I ilfi'vu
I'11 III1.11v 1oii' ii I ey l iiplanml I' Viiruullll lull ul h a s u p h l I H I .1.*Ic'11 in11
Thyroid remnant n f ul r I muli r i u n i i I il I r e s t I ui'ii I I m o r s l 11 In I I vmul it 1 1! I n f i l t r a t e s
BOU UM o
P 7 .
co ot o
lilil
73923 73924 1 ! 73926 1 73927 ! 73928 73929 73930 73931 73932 73933 73935 73936 73937 73938 73939
1 11 l 11 I 1) 1- -
<o4\0 nr> 11 1111 1 i 1 1- 11l 1l -- 1 l - 11111 1 i 1 1 1 1 11 1 1- - 1
o OStoj*)
r*On~4t' i'*
C<44 IOcSn'
tOmn4' 1'
-*O1' m
1 1 111 i 1i i
li - 1- i 1- i
1 1111i 1i i
1111i 1i i '
1I1
--
1 1 1 11 XX
--
1 1I X
11t
----
1l XX
1i X
1i
X
l'a r a I liy ru l li
1l
11
A'lrcita I f in a l ry ln p ln s m lc vintili lilt lull o f c o r t i c a l c e l l s d ii fuse co lineai Ion
I.UIII'. f o c a l p o r i tin n irli III 1 lym phoid h y p e r p l a s i a focal p e rlv a sc u lu r lymphoid I n f i l t r a t e s local aggregates of a lv e o la r macrophages congestion (agonal) f o c a l I n l e r s t 11 l u i In f lamina f u r y c e l l I n f i l t r a t e s rttvt'uliit' o ile ma
111 22
l1 2
22
2222
22222
2 22 3222
322 3
222
3
22
liye 1 1 1 1 1 l 1 l 1 1
llcort
1111
l 1 111
fin al I n t e r s t i t i a l lymphoid I n f i l t r a t e s In nynenrdlurn fucili iiiynia rii I il I f i b r o s i s f i n a l n e c r o s i s w i t h inolinone I e a r c e l l I n f i l t r a t e s 1it
uiyinaiil I nm
11 11
11
t 1l 1
2
2 32
23
, 2
22222
23222
24
33
2
2 3
l - 11111111
111111
11 1
1 11
i
l
1\
1
2
2 2 332
2223222222
3 4 3
2 2
22
3 23
I 1111l 1111 , 111111
Aor t a
Spl een at ro| ihy iloplol (on 1I H X '.ISfii
lit iiiiiiihcr ami a l z o o 1yiitplio 11 fallirle* 1d*rIn | i i fimi*ot In roil |*ulp
i i I 1111111 111111111l
11I l 111111
X X X X X XXX X X 4 3544 344 33
XX XXXXXXXX 4 34 5444 334
X X X X X X XXX X 5444 3354 55
n7-tw >
Cinie :
x - condition present 1 - not remnrknlite 2 - very slig h t
A - moderate 5 - marked fi - e x t r e m e
t 0Q a>
BEST COPY AVAILABLE
002144
--i
Pliioruclieiulral Surfni I..lit
TAHI.h -II. (.in ,
Sex
T I hhiiu I.i' h I oii
f9t
OPH
^ M4
o JS
M e s e n t e r i c 1.yti>li Nude d e p le tio n In a lz e and number o f f o l l i c l e s
Thymus d e p le tio n In Blze and numlier u f lymphoid fo lllc le B
Hone Harrow (SLerniim) hypocetlular o u te o c ln stlc re so rp tio n o f bone
S a l 1v a r y 111and
focal mucosal erosion lu glandular p o rtio n focal mucosal liemorrliage In g la n d u la r p o rtio n mucosal liypurkeraLosls In furestomacli (nonglandular)
Small Inival lav (Duodenum, .lc|imiim. Ileum) atrophy (decrease In s iz e o f muconal v i l l i )
l.argo In lv H lIiif (Ciiliio)
I'ancrens focal I n t e r s t i t i a l lymphoid I n f i lt r a t e s focal cytoplasm ic vacuo IulIon of a cin ar c e lls focal atrophy of acinar c e lls
l.lviT focal pcrlporfal/M lm iH nldal lymphoid I n f i l t r a t e s capsular llh ro sls (lift use, s Iniiso Ida I congest Ion focal p n rla l'/s iiu iB o id a l ext r/imedol la r y h e m a to p o ie sis focal hepatocellular necrosis focal cytoplasmic vacuolatIon of hepalocytes focal hcp.iloccl lo la r hypertrophy iiiiilillnc.il, h ep ato cellu lar hypertruphy I n c re a s e d yet low lull-brown pigment In c y to p la sm o f licpalocytcs
N i n e t y Day S u b a c u t e Rat T o x i c i t y S t u d y .
lllatoiuurphologlc O bservatlona.
Control
30 ppa
100 pin
JR 51 r. S T. u* Ua K 1*4 1*4
SCCOOO
fs 0000
is
0C0O 00
0o000s
l>
oOs mf0s0
rOOHCsOOs
cOts N0n0
0nO0s ICsO
IO0Cs"0s)
Os 00 Is
55 JR T. T. S3 In 1*4 1*4 1*4 1*4
ISoOr*sOo3s
Is Os nNCO
tOos
00 Iros
OOss nIs0
ooOs mIS.
fOnOSs
OMOs nIS
noOs |nS
SOost trns
nIOAss
1: t : r. *3 S3 1*4 !* 1*4
smfoOOss
rs oOs nfs
C0 ffoOsOs-
o mrOss
Os rs
H nrs
ro nOs InOss IS
IO
11 111i i l 1l
1 11i 11i 1i ,
111i i I , 11l
1111111111
11111 1111 1
1 1 1 1 1 1 1 111
1 1 1 1 1 1 ,1 1
,
22 111 1 111 11 1
Jlllltllll
2 llllllllll
11
1 11 1111 1 11111 1111
2
1111111111 1111111111
1111111111
1 1 llllll 2
3
1111111111
llllllllll
llllllllll
1 111
1
22
22
11I 22222 2 3
3 2
22 2 3 22
llllllllll
l1
l 111
22
2
3
llllllllll 1 I11111 I1
2
2 2222222
3
22
32
22 144 2
22 22
2 2
2
2 22
22
2 2
S2 342
22
2 2 3
2 222
2 2222
2
1 14
1 37-OM'i
x - condition prenent 1 - not remarkable 2 ve ry n i l p.li 1
4 - mi 5 - iii/i rk cmI 1. - f*Xl 1*1till*
d P>
0tQo
S'
00
i
Kluurochemlrnl Surfactant
TAIll.K 2.
.
Ninety Day Subacute Hat T o x ic i ty Study. lUslotnorphologlc Observations.
300 ppm
1 , 0 0 0 ppm
3 , 0 0 0 ppm
Tissue l.esiou
K J t/i
o.
3
u
p$i
o S5
% % i : S: 5: t & i . &
s0 r- fOO' h*
r> H O' fO f>
CO Ok HH o* Ok
r> h.
o fOO' h*
H N O' CO h*
M COJ' CO r-
fO IS O' CO
<* OM'
*ISo O'
CO CO
h*
lb S: Si fc t
l
kO (S O' m i**
fs IM O' Cr>O
CO M OCO' N
O' N O' ICnO
o CO O' o
H O COO' h*.
IS CO Oco' N
CO CO O' CO r-
CO O' CO In
<o COO' NCO
Si f. t f . fc f .
VO IN 00 CO CO co
O' CO
o 4
H 4
rsc)
CO <4
s| 4
*vVo
OCO'
O' CO
cOo'
f s IN h .
COO' fN
O' ICnO
O' CO r-
O' CO IN
OCO'
O' CInO
O' CINO
Mesenteric- Lymph Node d e p le t io n in s i z e and uiuulier o f f u l t i c l e s
Thymus d e p le t io n In s i z e and uiuulier u f lymphoid f o l l i c l e s
Rune Marrow (Sternum) hypnrullular o s t e o c l a s t i c resorption o f hone
S a liv a r y i'.land
Stomach focal mucosal erosion in glandular portion focal mucosal hemorrhage in glandular portion mucosal h y p erk era to sis in foruHtomach (nonglandulur)
Small lu lcH lIu e (Duodenum, .le|unum. Ileum) atrophy (decrease in s i z e u f mucosa] v i l l i )
IsirKi1 1til i*Hl 1no (Colun)
Pancreas focal i n t e r s t i t i a l lymphoid in f i l t r a t e s focal cytoplasmic vscuolallon of acinar c e lls focal utrophy of acinar c e ll s
Liver focal perIp ortal/sin u soid al lymphoid i n f i l t r a t e s cupsular fibrosis diffuse, sinusoidal congestion focal portnl/ainusoldul extramedullary hematopoiesis focul hepatocellular necrosis focal cytnplusnlc vacuolatlim of bcpatocytes focul lieputocelJular hypertrophy Mult I f o c a l , b c p n lo c e l1ulur hypertrophy Increased yellowlsh-brown pigment in cytoplasM o f liepatocytes
2 3 3 AAA 3 AAA
_
2 3A
AAA 3 3
11 2 2 3 3 2 3 A3
3 3 3 5 AAA3 A
__
A A5 5 AAA A
3 A3 A3 3 3 3 3 3
A3 AAAAA 3 A 3
5 5 5 AA
AA3 5
A3 3 3 A3 3 AA 3
1111111111
11
1
222
22
32
2
1 3 33232333
1 1 1 11 1 1 11 1
11
1111
2 32
2
1 1 1 11 1 l 1 1 1
1
3 3 32
2 2 22 3
2
322
32
3 2 2 3 3 3 AA 3 3 1 11 1 1 1 11 1 1 1 11111111
2
1111111l 11
1 1 1A
3 233
2A
31
2
A
2 3 3A
3 3A3 3
1i 1 1A11 11 1
11
1A1A1 1 1
2
3 2 332
AA
3 A3
22
2 32
3A 3
1
23
2 23
35
3 3 A3 2
22
1
A 3A 33 12
: 2
i
23
rn
aSS
002145
I 17-011*1
Code
x - condition present 1 - not remarkable 2 - very sligh t
A - moderate "> - marked b - ext renie
fb 00 It P vc
i
' l'l uorouhemlriil Surfart aul
N in e ly Day Su b a cu te Knt T o x i c i t y S t u d y .
TAIll.f: 20. i .mil .
lllutumorplioloRlc (llisurval Ihiih. Control
30 PPM
100 lip m
Sex
Tissue I.eu foil
xX
s: Xi M Ui M* fu tu
88$
o
O 2 !54
vO GO CroO
r0s0 CmO
oo 0Cm0O
O00n00l
oOomox
HOv GO rt
cOocnokl
tOn' CcnO
cCcnnO
*c0CnnO0
r- I-* rs fs
N h i- |N N
X X X X X fu 1 Ml
Me
S<oOon cINn
ICccNnnO
Cc0nD0 nI'N
OO00ss fns
s
CrDt I'N
HOncn rN
Nocn CO n
cfoccNnnn.
Omc4n |N*
in fOcOn r-
Si Si
is
M t Me t M
n8cn I'N
I'N fOOcNn'
C<conOn N
O IccHnnn
043 cIcnnn
Hr-i ccnn N
M cIHcnn-
cn IcH0nn3
|*cHcNnn9
*n mHcn r*.
Kidney hydronephrosis
` fucili I il t ti rut 11 In I lymphoid l u l l I trat oh t tiltiilnr m-plii'oHln liyullnu drop Iel In cytoplasm o f proxlmnl convoluted
t lltlU IO B l nini Inr iie e ro sls with m in e ra lIza tlu u pnrenchymul c y s l prnlelim ceoiiB lu liiiln r cantH atrophy (decrease In s iz e )
U r i n a r y It I a d d e r
T este s
Ovaries
Prostate tucul l i i t u r s t l t i n i lymphoid I n f i l t r a t e s
Uterus liyd romei ra
SkcloLal Muscle atrophy
Skin focal epidermal acanthosis diffuse epidermal hyperkeratosis
2
32
2
2 2233222 2 2 332222222 2 2 2 4 2 2 2
22
2
3
4
22
1-11111111
11111
1ll11
111 23
111 42
1111111111
1111111111 11111
11111 1111
11 1 44 1111111111
111 11 111II
11111
1 11 11
111
1 3
111 1I
11111)1111
l111l111 1
1111111111
111)111
22
i 09
002146
I 37-08*1
Code! x - cond I ion present 1 - not remarkable
2 - very slig h t
4 - moderate 3 - marked
fi - extreme
.I .. .1
P> OQ ID
l/l O
^T?roo Sex
i
Kl notoeheiulcol Surfactant TAlll.li 20. I.IHU.
TlHSiie l.eal on
N in e ty Day Su b a cu te Rat T o x i c i t y S t u d y .
Illstnm orpholoplc OliuervntIoiih.
300 ppm__________________________ 1,0 0 0 ppw _______ _____________3,000 ppm
S;
Jb
X
X
*
fc
u*
c. S: Si $1 5: 2. t 2. 2. 2. S; % Si Si Si 2. 2. 2. t
ad.
n
zo
vOrfr--ONov4
IOCHsOv
I0OnrHs0V
HOv
|Onss
IOraSosx
|<corssox||
MNOnIsx
c|nMOoSx
fNOnsX
IwCOcso4x
sMOcrOsox
fs
NCfOsOx
N0OcIS0ox
fOIOnSsxx
foOn*s>x
CCfrOHsOOx
MCOCfOsOx
CO CfCOOsOX
*CfOsOx
tCOCfoOOsx
fCCxOOsOOx
IOiCCssOXO
COCIOS0Ox
CfOfOOsOxx
CIoO*sOx
OCIi*Hs4Ox
*OCI4SOsx
cCI<OsoOrx
iaC4xO
n
IC<OTsOx
Kidney liydrnnupliroHla focu l I n t e r s t i t i a l lymphoid i n f i l l r u le s tubular nephrosis liyallna dro p lets In cytuplanw of proximal convoluted tubuluH tu b u lar n e c ro sis wllli mlnernIIzal Ion parenchymal cyst proteinaceous tubular casts atr upby (de c re a s e lit s i z e )
U r i n a r y II l a d d e r
Testefl
Ovaries
Prostate focul I n t e r s t i t i a l lymphoid I n f i l t r a t e s
llterun liydrntuot ra
Skeletal atrophy
Skin focal epidermal acanthosis diffuse epidermal hyperkeratosis
t 2
2
222
2 3222
' x
X
XX
XXX
11 1 1l11 1 1 1
1 11 l 1
11111 11 ' 22
11111
XXXX XXXXXX
] 111111111
1111 1 111 1 1
11 11 1
1111
x
XXX XXXXXXX
1 1 1 1 A1 1 1 1 1
l 1111 1111 1
11111
1111 1
11
1
l
2 23 333
1_ 2 3332 3 33A 322 2
32 3AA3 33 33
l 2
11
2
3332
22
A A32A2 3 33A
11 22 A2223 2 22
Il_ilU A
(lode: x - condition prcHcnt
1 - not it*nuirkal1<* > - w..r,, oil . , Id
A - modi;rate
S - Marked r. _ nvl-ri.lma
hfl
pi 0Q Ui I--
