Document 2NNOYry7yQ8XdEgwa8wkmD93a
received
DOW CHEMICAL U.S.A. SEP 12 1977
1825 Connecticut Avenue, N.W. Washington, D.C. 20009
cc: W. V. Andresen, American Cyanamid Company Z. G. Bell, Jr., PPG Industries, Inc. H. A. Cantor, A. E. Staley Manufacturing Co. J. Yamada, Asahi-Dow Limited A. Konishi, Kureha Chemical Industry Co., Ltd. W. A. Patterson, W. R. Grace & Co. P. J. Vanderhorst, duPont L. Rapoport, Olin Corporation J. M. Smith, Rohm and Haas Company J. R. McDonough, Tennessee Eastman Company R. B. Jaeder, BASF Wyandotte Corporation R. J. Turner, Morton Chemical Company P. L. Wright, Monsanto Company M. N. Johnson, B. F. Goodrich Chemical Company
Enclosed you each will find the report entitled, "Results of a 97-Day Toxicity Study in Male and Female Beagle Dogs Orally Administered Vinylidene Chloride in Peanut Oil Via Gelatin Capsules".
Sincerely,
J. M. Norris Associate Scientist Government Registration Health and Environmental Research
Lucille Henschel:
We will send 10 additional copies of the above report to total 25 copies as agreed upon in the contract.
JMN
AN OPERATING UNIT OF THE DOW CHEMICAL COMPANY
SL 083970
1
A
RESULTS OF A 97-DAY TOXICITY STUDY IN MALE AND FEMALE BEAGLE DOGS ORALLY ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL VIA GELATIN CAPSULES
By : W. H. Braun, J. F. Quast, C. G. Humiston,
J. E. LeBeau, and C. E. Wade
Reviewed by: B. A. Schwetz
Toxicology Research Laboratory Health and Environmental Research
1803 Building Dow Chemical U.S.A. Midland, Michigan 48640
SL 083971
RESULTS OF A 97-DAY TOXICITY STUDY IN MALE AND FEMALE BEAGLE DOGS ORALLY ADMINISTERED VTNYLIDENE CHLORIDE IN PEANUT OIL VIA GELATIN CAPSULES By: W. H. Braun, J. F. Quast, C. G. Humiston, j. E. LeBeau,
and C. E. Wade
SUMMARY
The toxicological properties of vinylidene chloride were evaluated in beagle dogs. Groups of four dogs of each sex were given vinylidene chloride in peanut oil solution via gelatin capsules at concentrations which provided 0, 6.5, 12.5, and 25 mg vinylidene chloride/kg of body weight/day for 97 days. Parameters which were unaffected by dosage with these dose levels of vinylidene chloride included demeanor and appearance of animals, mean body weight, food consumption, hematologic measures, clinical chemistry determination urinalyses, organ weights, and organ to body weight ratios as well as gross and microscopic examination of tissues at the termination of the study. The experimental no-detectableadverse-effect dose level of vinylidene chloride was found to be >25 mg/kg/day for both male and female beagle dogs.
SL 083972
INTRODUCTION
The 97-Day study on vinylidene chloride orally administered to beagle dogs, reported herein, was one of a series of toxicological investigations being conducted to aid in the safety evaluation of vinylidene chloride. To adequately help assess the safety of vinylidene chloride, the dose levels of 25, 12.5, and 6.25 mg/kg body weight/day were chosen for this study to administer 25,000, 12,500, and 6,250 times the amount of vinylidene chloride that would be ingested by a 75 kg person on a 1500 gram daily diet, assuming that the food was contained in food packages containing the compound and migration was 50 ppb in the food, Vinylidene chloride was administered orally as a peanut oil solution in gelatin capsules to allow an accurate determination of the dogs' vinylidene chloride exposure. An interim report giving the preliminary results of this 97-day study* of vinylidene chloride has been reported by Humiston and Schwetz (1975) .
*This study was complete in September of 1975.
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EXPERIMENTAL PROCEDURES
Test Material. The test material used in this study was described as follows:
chemical name: vinylidene chloride
synonym: 1,1-dichloroethylene, VDC
molecular formula: structural formula:
molecular weight:
c2h2ci 2
Hxc=c/Cl
Cl
96.95
description: clear, colorless liquid having a characteristic sweet smell
The vinylidene chloride samples were aliquots of production material, minimum purity 99.5%, obtained from The Dow Chemical Company, Freeport, Texas. The specifications of this production material were as follows: acetylenes, 25 ppm maximum; acidity as HC1, 15 ppm maximum; water, 75 ppm maximum; peroxides, 25 ppm maximum; color APHA, 30 maximum; iron, 0.5 ppm maximum; specific gravity at 25/25C, 1.202-1.212; polymer content, free, clear; inhibitor MEHQ (monomethylether of hydroquinone), 180-220 ppm; di-N-propylamine, 0.1 ppm maximum. Since the vinylidene chloride used to prepare various copolymers for food packaging applications is distilled to remove the inhibitor MEHQ, this study was conducted on distilled vinylidene chloride having residual MEHQ in the range of 1-5 ppm.
SL 083974
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Four of the samples were analyzed for impurities , using a gas chromatographic method. Results are as follows:
Impurity
Concentration (ppm) in Sample: I 3 4 Mean
Vinyl bromide
4
NDa ND
ND
<1
Vinyl chloride
50 4 3 ND <14
trans 1,2-dichloroethene 1700 169 162 138 542
cis 1,2-dichloroethene
680
53
52
24 202
1,1,1-trichloroethane
60
2
2 ND <16
1,1,2-trichloroethane 48 ND ND ND <12
MEHQ
2 ND ND ND <1
aND = not detected.
The stability of the vinylidene chloride in peanut oil was verified before the initiation of the study (Madrid, 1976), and the concentration of the vinylidene chloride in the peanut oil was determined periodically during the study (Reigler, 1975a; Reigler, 1975b; Hermann, 1975) . The sample was kept at -15 to -20C at all times except during preparation of the test capsules.
Design. Sixteen male and sixteen female purebred beagle dogs, eight months of age, obtained from Marshall Research Animals, Inc., (North Rose, New York) and acclimated to the kennels of the Toxicology Research Laboratory were randomly selected for one of the following treatment groups;
083975 SL
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Dose Level (mg/kg/day)
25 12.5
6.25
0
Number of Dogs
Males
Females
44 44 44 44
The dogs were housed 4 dogs/pen according to the treatment groups, and supplied commercial laboratory feed (PURINA LABORATORY CHOW) fortified with 1% peanut oil, and water ad libitum.
The capsules for administration of the test material were prepared weekly using the required amount of a 50% solution of vinylidene chloride in peanut oil per capsule to provide the designated dosages on a mg/kg of body weight basis. The prepared capsules were kept refrigerated until used. One capsule was given to each dog each day throughout the 97day test period. The control dogs were also given gelatin capsules containing the same amount of peanut oil as the dogs at the 25 mg/kg of body weight dose level.
Observations and Records. Body weights were recorded weekly during the entire study. Food consumption per pen was recorded twice each week and the average amount consumed/dog/day was calculated. Clinical observations were made daily to discern any changes in general appearance and demeanor, and to detect signs of toxicity.
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Clinical Studies. Hematological studies involving packed cell volume, erythrocyte count, hemoglobin concentration, total and differential leukocyte counts were conducted on all dogs prior to starting on the test as well as after 33 and 84 days on test.
Urinalysis involving pH, specific gravity, sugar, protein, ketones, occult blood, bilirubin, and microscopic examination of sediment were conducted on all dogs on day 83, and males on day 97 and females on day 98 of the study.
Clinical chemistry determinations (Technicon Autoanalyzer System) of blood urea nitrogen, serum glutamic pyruvic transaminase activity, alkaline phosphatase activity, and serum glutamic oxaloacetic transaminase activity were made on serum samples from all dogs prior to starting the study as well as on day 85 and males on day 97 and females on day 98 of the study. The dogs were fasted overnight before collecting the blood samples for these determinations. The non-protein free sulfhydryl content of a portion of liver and kidney was determined for each dog at the time of necropsy by the Sedlak and Lindsay method (1968).
Pathology. At the termination of the study, the dogs were fasted overnight, weighed, anesthetized by intravenous admini stration of pentobarbital sodium and killed by exsanguination.
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A complete gross pathological examination was made by a veterinary pathologist at necropsy. The heart, brain, liver, kidneys, and testes (males) were removed and weighed. Representative portions of the following tissues were excised and preserved in buffered 10% formalin: adrenal glands, aorta (thoracic), bone, bone marrow (sternum), brain (cerebrum, cerebellum, brain stem), cecum, colon, epididymis (males), esophagus, gall bladder, heart, kidneys, larynx, liver, lungs, lymph nodes (cervical, mediastinal, mesenteric), mesenteric adipose tissue, muscle (skeletal), parathyroid gland, pancreas, peripheral nerve (sciatic and brachial plexus), pituitary gland, prostate gland (males), salivary gland (submaxillary), small intestine (duodenum, jejunum, ileum), spinal cord, spleen, skin, mammary tissue (females), stomach (cardia, fundus, pylorus), testes or ovaries, thymus, thyroid gland, tonsil, trachea, uterus (female) and urinary bladder. The right sciatic nerve and the left brachial Dlexus were removed and pinned to a nonflexible surface before fixation in buffered formalin. Microscopic examination of hematoxylin and eosin stained tissues from all dogs in the control and top dose group was performed by a veterinary pathologist.
Ophthalmologic Examination. Ophthalmological examinations (slit lamp and ophthalmoscope) were conducted by a veterinarian on all animals prior to starting and at the termination of
SL 083978
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the study. At necropsy, both eyes were examined grossly and fixed in Zenker's solution. The eyes from the dogs on the control and top dose were prepared by routine histological procedures and examined by light microscopy.
Statistical Analysis. Statistical evaluation of body weights, organ weights, organ and body weight ratios, hematology, and clinical chemistry data were made using an analysis of variance and Dunnett's test (Steel and Torrie, 1960) . Food consumption was not tested by an analysis of variance since the 4 dogs/ group were housed together (n=l) but trends were tested for by regression analysis. The level of significance in all cases was p<0,05.
RESULTS
Appearance and Demeanor. Mo treatment related alterations in appearance or demeanor or significant clinical signs were observed in any of the male or female dogs at any dose level of vinylidene chloride or in the control groups.
Body Weight. The mean body weights of male and female dogs administered vinylidene chloride in gelatin capsules for 97 days are summarized in Table 1. Except for a slight loss of weight by the control males, all groups of dogs maintained
SL 083979
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their weight or showed a slight increase in body weight during the study. There was no deleterious effect associated with the ingestion of vinylidene chloride on the rate of weight gain by dogs.
Food Consumption. The food consumption by dogs administered vinylidene chloride is summarized in Table 2. Vinylidene chloride had no significant effect on food consumption of any group of dogs at any time during the study.
Hematology. The hematologic values for the dogs are indicated in Table 3. There were no hematologic measures that were considered to be altered to a toxicologically significant extent by ingestion of vinylidene chloride in the diet. The mean white blood cell counts of the dogs at 6.25 and 25 mg/kg/day were significantly lower than the concurrent control values on day 84 of the study. Since the values for these groups of dogs were not different from their own pre-exposure white blood cell counts, these differences were not considered to be of toxicological significance.
Clinical Chemistry. The clinical chemistry values for the dogs are indicated in Table 4. No alterations in BUN levels, AP activity, SGOT activity, SGPT activity, or non-protein free sulfhydryl levels in either sex of dogs at any
SL 083980
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dose level were present which were considered treatment related. The statistically significant differences found in SGPT, SGOT, and BUN for the dogs receiving the low dose of vinylidene chloride were not found in dogs on the higher doses and are within the range of normal values observed in this laboratory. The blood samples from one male dog at the high dose level had an elevated SGPT activity on day 85 of the study but not on day 97.
Urinalysis. The results of the urinalyses conducted on the male and female dogs are presented in Table 5. There were no alterations considered related to treatment in any of the parameters examined, including the specific gravity and the microscopic examination of urinary sediment.
Pathology. The terminal organ weights and body weights of dogs administered vinylidene chloride are summarized in Table 6. No treatment related changes were observed in organ weights or organ to body weight ratios at any dose level.
The gross and histopathologic changes in beagle dogs administered vinylidene chloride in peanut oil in gelatin capsules are presented in Tables 7 through 10. No treatment related gross or histopathologic changes were present in either male or female dogs at any dose level.
087,9^
-10-
The pathologic changes present were interpreted to be spontaneous in occurrence and comparable in treated and control dogs, A single male dog receiving 12.5 mg/kg/day of vinylidene chloride had kidneys which grossly appeared increased in size; however, no significant histopathologic alterations were recognized in this animal. Evaluation of hematologic, clinical chemistry, and urinalysis values of this dog did not reveal abnormalities. In view of these negative findings and the lack of other effects at the high dose level, the grossly observed large kidneys in this one dog at the intermediate dose level was considered normal and not treatment-related.
Ophthalmologic Examination. Examination of the eyes of dogs by direct and slit-lamp ophthalmoscopy during the pretest period and just prior to termination of the study revealed no significant alterations of the conjunctiva, cornea, iris, retina, and lens among the dogs that could be considered to be related to dosage with vinylidene chloride.
CONCLUSION
Based upon the parameters evaluated in this study, no detectable signs of toxicity were observed in dogs given up to 25 mg/kg/day of vinylidene chloride in peanut oil for a period of 97 days. The dosages administered approximated 25,000,
083^82
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12,500, and 6,250 times the amount of vinylidene chloride that would be ingested by a 75 kg person on a daily diet of 1,500 grams, assuming that the food was contained in food packages containing the compound and migration was 50 ppb into the food.
WRITTEN BY:
APPROVED BY:
W. H. Braun Senior Research Chemist 1803 Building July 19, 1977
Diplomate, American College of Veterinary Pathologists
Research Specialist 1803 Building July 19, 1977
C^K.t.
C. G, Humiston, Ph.D. Research Specialist 1803 Building July 19, 1977
Toxicology Research Laboratory Health and Environmental Research
1803 Building Dow Chemical Company Midland, Michigan 48640 U.S.A.
j. E. LeBeau, D.V.M., m.s. Research Manager Health and Consumer Products Zionsville, Indiana
Research Biologist 1803 Building July 19, 1977
sL 083983
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REFERENCES
1. Hermann, E. A. 1975 Analysis of vinylidene chloride concentration in peanut oil, letter to C. E. Wade.
2. Humiston, C. G. and Schwetz, B. A. 1975 Interim Report: A two-year toxicological study of vinylidene chloride incorporated in the drinking water of rats and a 96-day study of vinylidene chloride given orally to beagle dogs.
3. Madrid, E. 0. 1976 Stability study of 50% vinylidene chloride in peanut oil (in capsules), Report #AL-75-30530.
4. Reigler, P. F. 1975a Vinylidene chloride in peanut oil. Report #AL-75-30685 .
5. Reigler, P. F. 1975b The determination of vinylidene chloride in peanut oil, Report #AL-75-30819.
6. Sedlak, J. and Lindsay, R. H. 1968 Analytical Biochemistry, 25, 192-205.
7. Steel, R.G.D. and Torrie, H. H. 1960 Principles and Procedures of Statistics. McGraw-Hill Book Company, Inc., New York, New York, pp. 101-105 and 111-112.
SL 083984
TABLE 1
MEAN BODY WEIGHTS3 FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOR 97 DAYS
Days on
Test
-------- 0
Males ------ 5715------ 12.5
Dose Level, mg/kg/day
-------- 23
-------- o-------
Females 5725 ------- T775
0 11.6+0.9 10.2+1.1 10.1+0.6 10.4+0.9 5 11.3+0.9 10.2+1.2 10.0+0.5 10.210.8 12 11.2+1.0 10.1+1.1 10.2+0.8 10.2+0.8 19 10.910.6 10.2+1.4 10.210.6 10.410.8 25 11.4+1.0 10.5+1.0 10.210.4 10.2+0.8 32 11.4+1.0 10.3+1.0 10.1+0.7 10.410.8 39 11.4+1.0 10.2+1.0 10.1+0.6 10.410.9 46 11.4+1.1 10.2+0.9 10.010.6 10.5+1.1 53 11.5+1.1 10.4+0.8 10.1+0.6 10.5+0.9 60 11.6+1.2 10.7+0.8 10.0+0.5 10.7+0.8 67 11.5 + 1.0 10.410.9 10.1+0.6 10.6+0.9 74 11.0+0.8 10.4+0.6 10.310.6 10.611.0 81 11.2+0.8 10.6+0.9 10.5 + 0.8 10.4+0.8 90 11.4+0.9 10.5+1.0 10.4+0.6 10.8+0.9 95 11.2+0.7 10.6+1.1 10.510.6 10.7+0.8
8.110.7 8.2 + 0.8 8.210.8 8.410.7 8.210.8 8.210.7 8.210.7 8.2 + 0.6 8.4 + 0.8 8.610.7 8.5+1.0 8.410.9 8.511.0 8.511.0 8.710.9
8.710.5 8.5 + 0.5 8.710.4 8.810.3 8.9+0.4 8.810.5 9.0 + 0.4 8.810.4 9.210.4 9.110.4 9.2 + 0.4 9.410.3 9.210.4 9.2+0.5 9.4+0.7
8.210.4 8.4+0.4 8.2+0.5 8.1+0.6 8.210.5 8.210.6 8.610.6 8.4 + 0.7 8.610.6 8.610.8 8.810.9 8.6+0.7 8.6 + 0.7 8.810.6 8.6+0.6
25
8.5+1.0 8.6+1.1 9.0 + 1 .2 8.911.2 8.6 + 1 .0 9.1 + 1 . 0 8.6 11 . 2 8.511.1 8.7 + 1 . 2 8.611.1 8.8+1 . 3 9.3+1.3 9.1 + 1 .4 9.0+1 .4 9.0 + 1 . 3
SL 083985
aAll values are the mean one SD of 4 dogs per group.
^Females were maintained on test for 98 days.
See Table A-l for individual data. There were no significant differences between treated and control groups by Dunnett's test, p<0.05.
TABLE 2
MEAN FOOD CONSUMPTION3 FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOR 97 DAYS*3
Days on Test
1-4 5-11 12-18 19-24 25-31 32-39 40-45 46-52 53-58 59-66 67-73 74-80 81-89 90-94 Average
0
281 298 317 369 350 319 300 352 408 284 259 318 361 320 324
Males
<TT5
12.5
259 269 311 277 330 303 304 333 314 293 316 275 296 267 336 311 412 338 275 261 346 312 371 307 322 283 350 300 324 295
Dose Level, mg/kg/day
25 0
300 331 262 271 341 292 298 279 325 286 294 264 296 269 341 277 379 362 278 245 307 254 259 268 339 278 300 320 308 285
aAll values are the mean grams/dog/day for 4 dogs per group. ^Females were maintained on test for 98 days.
Females
6.25
12.5
266 256 289 275 270 272 279 290 296 311 281 309 262 288 309 325 319 348 272 278 321 286 293 293 253 2 56 350 300 290 291
25
294 307 269 260 307 228 246 296 350 250 304 311 303 320 289
SL 083986
TABLE 3
HEAN HEMATOLOGIC VALUES* FOE HALE AND FEMALE BEAGLE DOCS GIVEN V1MYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOB 9? DAYS0
Dose Level mg/kg/day
pev Percent
Days on Test: -48 13 84
HALES
0 51*3 51*1 50*2
6.25
50*2 47*2 47*2
12.5
32*4 6Gil 49*2
25 50*2 46*2 47*2
Rod Blood Cells lid6/*.3
-48 33
84
6.9310.28 7.02*0.30 6.9110.33 6.6910.31 6.6710.58 6.6H0.52 6.8910.49 6.7410.28 6.80*0.11 6,9310.14 6.90*0.11 6.60*0.33
Hemoglobln r/100 ml
-48 33
84
White Blood Ceils K1UJ/ML3 M.utrulll.tia
-48 31
84
Ly^l-h^t^
,-48 -3.-3i *8w4.
Differential White Cell Hunoc^tea
________. <v-Basophils
-4j.8a 1i*1 a84t _-44H8 3133 8844 --4488 3333 8844 "-4488 3133 8844
17.6*1.1 17.710.5 17.2*0.9 13.0*2.2 16.8^10. 7 16.310.9 16.4*0.8 10.4 iJ ,9 17.711.0 17.110.8 17.1*0.7 9.8*i.O 17.2*1.0 16.9*1.1 16.7*0.8 10.8*1.7
13.511.5 11.1*1.3 12.0*1.9 11.9*1.2
12.9*1.2 10.7*0.6* 10.8*0.8 I0.5H.6*
61 56 55 57 62 tu 51 57 61 52 57 56
25 31 32 33 26 26 34 26 28 33 30 29
5 75 4 45 8 75 5 56
9 58 6 77 6 10 5 9 79
0 00 0 12 1 01 1 10
FEMALES 0 6.25 12.5
25
50tl 49*1 48*1 50i4 48*1 47*4 48 *4 47*1 48*4 50*6 45tl 48i6
6.5310.12 6.9310.61
6.72*0.42 6.6510.52
6.62*0.31
4 6.60*0.64
17.2*0.6 17.311.1 17.2*0.5 9.7 iO. 5 17.1*1.4 16.6 to.8 16.3*1.7 10.5*2.0
6.60*0.52 6.62*0.21 6.7610.50 16.711.5 16.510.5 17 .Oil.4 U.213.7
6.52i0.53 6.18*0.26 6,6710.66 17.0*1.6 15.6U.1 16.8*1.6 11.7*2.2
10.1+1.4 10.9*1.8 ll.Bil.O 11.712.1
10,6+0.6 10.7+3.2 11.1*3.6 11.5*2.1
50 55 56 64 61 59 63 64 59 66 60 61
17 29 30 27 28 29 29 27 29 21 29 24
5 56 6 64 3 46 8 55
7 10 7 3 57 5 46 5 5 10
1 11 0 01 0 10 0 10
aValues are means 1 standard deviation for tour dogs/group. ^FeBrilee were maintained on test for 98 days.
CDays on teat. See Table A-2 for individual data. The differential white cell counts were not analyzed statistically. *Signiflcantly different from control mean by Dunnett's test, p<0,05.
TABLE 4
MEAN CLINICAL CHEMISTRY VALUES3 FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOR 97 DAYS*3
Dose Level mg/kg/day Days on Test:
MALES 0
6.25
12.5
25
BUN mg %
-7 85
97
21 + 6 17+4 18 + 2 21 + 4 20 + 10 18+4 18 + 2 15 + 3 15 + 2 17 + 1 18+4 20 + 3
SGPT mU/ml
-7 85
97
AP mU/ml
-7 85 97
42 + 6 34 + 1 40+4
7 2 18 69 21 82 39
46 + 6 42 + 11 70+20* 8 5 21 94 + 24 106 + 7
51+6 32 + 11 49 + 7
69 + 25 7129 7 5 2 5
4 6 5 122+162 54+10 62 12 71 21 78 19
SGOT mU/ml
-7 85
97
30 + 5 34+2 31 3 4 0 1 0i 4 2 8 68+21* 3 0 6 36 + 9 39 8 34 5 41 5 4 2 8
FEMALES 0 6.25
12.5 25
22 + 2 17 + 3 17 + 2* 19+5 18 + 3 18 + 3 222 22 + 2
18 + 3 21 2 20 + 4 21+1
42+8 38 + 7 49 8 39+10 50 + 6* 54 10 38 7 4 25 50 + 4 388 40 + 6 48 11
61 15 64 17 6514 8623 78 20 7 7 21 92 36 94 6 10114 67 23 99 41 98 45
34 5 4 0 7 44 8 34 6 34 2 3 7 6 3 6 8 38 4 36 5 29 6 38+7 40 7
aValues are mean standard deviation for four dogs/group. u ^Females were maintained on test for 98 days.
See Table A-3 for individual data.
*Significantly different from control mean by Dunnett's test, p<0.05.
SL 083988
TABLE 5
SUMMARY OF URINALYSES FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOR 97 DAYS*3
Dose Level mg/kg/day
pHC Specific0
(Range) Gravity
Sugar0
Protein c (Range)
Ketones0
Occult Blood
MALES, Test day 83
0 6.25 12.5 25
5.5-6.0 7.5-9.0 6 .5-8 .5 6.0-7 .5
1.042 1.038 1.024 1.030
neg.(4)a neq.(4) neg . (4) neg.(4)
0-10 mg % 0-30 mg QO. 0-50 mg % 5-400 mg %
neg. (4 ) neg . (4) neg . (4) neg . (4)
neg. (4) neg . (4 ) neg. (4) sm.(1), neg.(4)
Bilirubin
neg . (4) neg. (4) neg . (4) neg . (4)
Test day 97
0 6.25
12.5 25
6.0-7.0 8.0
6.5-8.0 7.0-8.0
1.030 1.042 1.035 1.032
neg.(4) neg.(4) neg.(4) neg.(4)
0 mg % 5-10 mg % 0-10 mg % 0-10 mg %
neg. (4) neg.{4) neg.{4) neg. (4)
neg. (4) neg . (4) neg. (4) neg . (4)
neg . (4) neg. (4) neq . ( 4) neg . (4)
FEMALES, Test day 83
0 6.25 12.5 25
6.0-9.0 6.0-9.0 6.5-7 .5 5.5-6.0
Test day 98
0 6.25
12.5 25
6.0-7.5 6.5-7.5 7.0-8.5 6.5-7.0
1.026 1.023 1.015 1.031
1.034 1.044 1.032 1.031
neg.(4) neg.(4) neg.(3) neg.(4)
neg.(4) neg. (4) neg. (4) neg.(4)
0 mg % 0 mg % 0 mg % 0 mg %
neg . (4} neg . (4) neg. (3) neg. (4 )
neg. (3) , sm. (1) neg. (4) neg. (3}
neg. (3) , tr . (1)
neg . (4) neg . (4) neg . (3) neg.(4)
0-10 mg % 0-5 mg % 0-5 mg %
0 mg %
neg.(4) neg . (4) neg . (4) neg . (4)
neg. (3) , sm. (1) neg. (4) neg . (4) neg. (4)
neg.(4) neg . (4) neg . (4) neg . (4)
Sij 083989
3( } - number of dogs; neg. = negative; sm. ;= small; tr. = trace; mod . - moderate. ^Females were maintained on test for 98 days cSee Table A-5 for individual animal data.
'iAINAS 6
MEAN ORGAN WEIGHTS*1 OK HALE AND FEMALE BEAGLE ]>OGS GIVEN VJNYLiDEhE GIILOKlb!: WITH PEANUT Oil. ORALLY IN GAPSJJLF.S FOR 97 l>AYSb
Dose Level dav
HAI.ES 0
S Lai V ud Hody
Wal^hl 1^
ju.b to. 5
ii.2^
Jo.Nil . 1
12.5
y. 920.7
lb 16.210.7
Hi a In _ . il____ 8/100 e
yj. J4i4.24 0.7/10.01 8/.1 Ufa.42 u.88+0.l4 77.96*2.67 0.79*0.05 H2.14*4.89 0.8J +0.08
Organ WclKliti (k and k/100 K Body Weight)
Hear t
L tver
Kidneys
8 /100
6/100 K E h/um k _
84.91ifa.75 0.79iO.07 83.3119.97 0.8410. (Vi 74 . 38+6.15 0. 7510.09 84.9511 1.00 0.8310.08
294.72146.54 2.7510.53 267.54iifa. il 2.69+0,21 252.80117.89 2.5710.33 298.51112.47 2.9310.29
50.79*5.74 0.47iO.U7 48.9415.11 0.49i0.0b 48.1 >il i .80 0.50 + U. lt> 45.00(5.77 0.44+O.Oi
T Lbt e b K &/ 1 110 L;
14.4-1 + 2 , id 0.1 5(0.02 U .2(+tl .94 0,]iiO.01 1J.5H.MJ./4 0 . 1 4 0 . o L 12.10+1.41 0.12 +0.02
FEMALLS 0 b.ib
12.5 2S
U.2+U .8 a.7io. 5 a . 2(0.fa 8,7 il .1
76.15*1.18 0.94*0.10 74.8715.12 U.iJOiU. Q9 72.57i2.S7 0.89*0.04 80.421i.72 0.9110.OS
64.2hl8.7fa 0.7910.(It) fa2.3U2.Jl 0.7210.04 fa5.4319.01 0.8010.07 66.6314.26 0. 78+0.10
221.49115.72 2.7310.34 228,86132.84 2.6Ji(J.39 221.90120.78 2.7110. 14 236.41115.76 2.7410.27
37 .8015.32 0.46+0.04 38 ,82 + s. 52 0.45*0.06 37.8915.19 0.4faiO.04 37.4413.67 0.4310.05
Values are means I standard deviation tor four dogs/group. ^Females were maintained on d it*t ter 97 days.
See fable A-4 tor individual data. ihere were no signit leant ditlereures between treated and control groups by Dunnettrs test
l><0.05.
SL 083990
TABLE 7
GROSS PATHOLOGIC FINDINGS OF MALE BEAGLE DOGS ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL
IN GELATIN CAPSULES FOR 97 DAYS
Gross Pathologic Findings
Focal areas of pulmonary consolida tion less than 1 cm in diameter
White subcapsular foci in the liver
Nematode parasites in the small intestine - ascarids
Both kidneys appear to be increased in size
Dosage Level (mg/kg/day)
0 6.25
12.5
25
2/4 4/4 1/4 0/4 1/4 1/4 0/4 0/4
3/4 3/4 1/4 0/4 0/4 0/4 1/4 0/4
Data listed as number affected/number examined.
SL 083991
TABLE 8
HISTOPATHOLOGIC FINDINGS OF MALE BEAGLE DOGS ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL
IN GELATIN CAPSULES FOR 97 DAYS
Histopathologic Findings
Dosage Level (mg/kg/day)
0
6.25*
12.5*
25
Focal eosinophilic granulomatous
inflammation in the liver
3/4 2/4
1/4 0/4
Focal mononuclear inflammatory cell infiltrate in the liver
4/4 3/4
4/4 4/4
Focal eosinophilic granulomatous inflammation in the mesenteric lymph nodes
1/4
0/4
Focal chronic interstitial nephritis - minimal
1/4 0/4
1/4 1/4
Granular casts within the renal papillae
3/4
3/4
4/4 4/4
Focal chronic urocystitis minimal
1/4
-
- 0/4
Focal chronic prostatitis minimal
2/4
-
- 2/4
Focal mononuclear cell infiltrate in the epididymides
1/4
-
- 0/4
Focal peribronchial lymphoid cellular infiltrate
3/4 3/4
3/4 4/4
Focal pyogranulomatous pneumonia suggestive of parasitic infestation 2/4
2/4
2/4 2/4
Subepithelial mononuclear cell infil
trate in the tongue - minimal
3/4
-
- 1/4
Focal lymphoid cellular infiltrate in the gallbladder mucosa
2/4
--
--
*In these dogs only liver, kidneys and lungs were examined for histopathologic changes.
Data listed as number affeeted/number examined.
3/4
SL 083992
TABLE 8 (Continued)
HISTOPATHOLOGIC FINDINGS OF MALE BEAGLE DOGS ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL
IN GELATIN CAPSULES FOR 97 DAYS
Histopathologic Findings
Focal eosinophilic granulomatous inf lamination in the mucosa of the small intestine
Focal mononuclear cell infiltrate in the tracheal mucosa
Multifocal chronic lymphocytic thyroiditis
Dosage Level (mg/kg/day)
0
6.25*
12.5*
25
1/4 -
1/4
-
1/4
- 0/4 - 1/4
0/4
*In these dogs only liver, kidneys and lungs were examined for histopathologic changes.
Data listed as number affected/number examined.
SL 083993
TABLE 9
GROSS PATHOLOGIC FINDINGS OF FEMALE BEAGLE DOGS ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL
IN GELATIN CAPSULES FOR 98 DAYS
Gross Pathologic Findings
Focal areas of pulmonary consolida tion less than 1 cm in diameter
Nematode parasites in the small intestine - ascarids
Focal petechial hemorrhage in the urinary bladder mucosa
Dosage Level (mg/kg/day)
0
6.25
12.5
25
1/4 2/4 3/4 0/4 1/4 0/4
3/4 0/4 2/4 1/4 0/4 0/4
Data listed as number affected/number examined.
SL 083994
TABLE 10
HISTOPATHOLOCIC FINDINGS OF FEMALE BEAGLE DOGS ADMINISTERED VINYLIDENE CHLORIDE IN PEANUT OIL
IN GELATIN CAPSULES FOR 98 DAYS
Histopathologic Findings
Focal eosinophilic granulomatous inflammation in the liver
Dosage Level (mg/kg/day)
0
6.25*
12.5*
25
1/4 0/4
1/4 0/4
Focal mononuclear inflammatory cell infiltrate in the liver
3/4
3/4
3/4 3/4
Focal chronic interstitial nephritis - minimal
1/4 0/4
0/4 0/4
Granular cast within the renal papillae
4/4 4/4
4/4 4/4
A dilated renal tubule containing an eosinophilic staining cast
1/4
0/4
0/4 0/4
Focal chronic urocystitis - minimal
1/4
-
- 0/4
Focal peribronchial lymphoid cellular infiltrate
3/4 2/4
3/4 2/4
Focal pyogranulomatous pneumonia suggestive of parasitic infestation 1/4
1/4
2/4 1/4
Focal lymphoid cellular infiltrate in the gallbladder mucosa
2/4
-
- 2/4
Subepithelial mononuclear cell infiltrate in the tongue - minimal
2/4
-
- 0/4
Focal mononuclear inflammatory cell infiltrate in the parotid salivary gland
0/4
1/4
*In these dogs only liver, kidneys, and lung were examined for histopathologic change.
Data listed as number affected/number examined.
083995
Sh
APPENDIX
SL 083996
TABLE A--1
INO 1Vi DUAL AND MEAN 1SODY WEIGHTS IN KILOGRAMS FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIOFNL itHORIDE WITK PEANUT OIL ORALLY IN CAPSULES FOR 9? DAYS3
Days on Test
Animal Numbers
75-2077 ,
-78,
0 -79,
Mean!SO
-80
Duse LcVel mg/kg/day
J
W'l
] 2.5
Mran+SD
75-2089, -90, -91, -92
Mean +SD 75-2085, -86, -87, -88
25 McanlSD
75-2Gdi, -82, -8 j, -84
MALES
0 5
12
19
25
32 39 46 53 60 67 74 81 90
95
10.6, 12.6, 11.9, 11.3 10.4, 12.5, 11.2, 11.2 10.1, 12.4, 11.4, 10.8 10.4, 11.8, 10.9, 10.6 10.3, 12.6, 11.6, 11 .0 10.2, 12.7, 11.4, 11.3 10.5, 12.7, 11.6, L0.9 10.4, 12.9, 11.3, 10.9 10.1, 12.9, 11.5, 11.4 10.2, 13.2, 11.6, 11 6 10.4, 12.7, 11.8, n.o 10.3, 12.0, 11-4, 10.5 10.3, 12.Q, 11,6, 10.7 10.2, 12.5, 11.5, 11.2 10.3, 11.7 , 11.8, 11.0
11.6+0.9 1L.3+0.9 11.2+1.0 10.9+0.6 11.4+ 1,0 11.4+1.0 11.411.0
11.4U.1
11.5+1.1 11.6H .2 11.5+1.0 11.010.8 11.2+0.8 11.4+0.9 U. 2+0. 7
8.8, 11.1, 11.2, 9.9 8.5, 10.9, 11.0, 10.3 8.5, 10.6, 10.9, 10.4 8.3, 11.4, 10.9, 10.3 9. 1, 11.2, 11.2, 10.4 9.0, 11.1, U.l, 9.9 8.8, 10.9, 10.9, 10.1 8.9, 10.9, 10,8, 10.0 9.3, 10.9, 11.2, 10.3 9.4, 11.1, 11.0, 11.2 9.0, jo.a, n.o, 10.6 9. 5, 11.0, 10.5, 10.6 9.4, U.l, V0.5, n.5 9.0, 11.0, 10.9, 11.2 9.0, U.3, 10.8, U.3
10.2*1.1 10.2*1.2
10.1 + 1. 1
10.2+1.4 10.5+1.0 10.3+J.0 10.2+1.0 10.2+0.9 10,4+0.8 10.7+0.8 10.4+0.9 10.4+0.6 10.610.9 10.511.0 10.6+1.1
10.6, 9,6, 9.6, 10.5 10.1+0.6 10.4, 9.6, 9.5, 10.5 10.0+0.5 10.4, 9,6, 9.5, 11.1 10.2+0.8 10.6, 9.9, 9.5, 10.8 10.2+0.6 10.4, 10,2, 9.5, 10.5 10.2+0.4 10,6, 9.4, 9.7, 10.8 10.1+0.7 10.3, 9-7, 9.5, 10.8 10.1+0.6 10.2, 9.4, 9.6, 10.6 10.0+0.6 10.3, 9-7, 9.6, 10.8 10.1+0.6 10.1, 9.7, 9.6, 10.8 10.0+0.5 10.4, 9.8, 9.4, 10.7 10.1+0.6 10.2, 10.0, 9.8, U.l 10.3+0.6 10.6, 10.0, 9.8, 11.5 10.5+0.8 10.5, 10.0, 9.8, 11.1 10.4+0.6 10.6, 10.0, 10.0, 11.3 10.5+0.6
10.9, 10.7, 10.7, 10.8, 10.6, 10.8, 11 .2, 11 .7, 11 .3, 10.9,
vo.a.
11.0,
n.o,
11.3, 11.0,
9.1, 10.8, 10 8 9.0, 10.6, 10.7 9.1, 10.6, 10.5 9.2, 10.6, 11.0 9.0. 10.5, 10.6 9.1, 30,8, 30.7 9.1, 10.6, 10.6 9.0, 10.6, 10.7 9.2, 10.6, 11.0 9.5, 10.8, 11.5 9.3, 10.7, 11.4 9.2, 10.6, 11.4 9.1. 10.2, J1.0 9.4, 11.0, 11.3 9.6, 10.9, 11.4
10.410.9 10 2+0.8 10,2+0.8 10.4+0.B 10.2+0.8 10.4+0.8 10.4+0,9 10.5+1.1 10.5+0.9 1 0.710.8 10.6*0.9 10.6+1.0 10.4+0.8
io.e+o.9
10.7+0.8
FEMALES
Animal
HeantSD
Kean+SD
Meau+SD
Mean+Sp
Numbera 75-2093, -94, -95, -96
75-2105, -06, -07, -08
75-2101, -02, -03, -04
75-2097, -98, -99, -2100
0
7.8, 7.6, 7,8, 9.2 8.1+0.7
8.0, 9.2, 8.6, a.9 8.7+0.5
a.o, 8.5, 7.8, 8.6 8.2+0.4
8.8, 7.5, 7-9, 9.8 8.5+1.0
5
8.0, 7.7, 7.6, 9.4 8.2+0.8
7.9, 9.0, 8.4, 8.7 8.5+0.5
8.2, 8.5, 7.9, 8.9 8.4+0.4
8.6, 7.6, 7.9, 10.1 8.6+1.1
12
8.0, 7.8, 7.6, 9.3 8.2+0.8
8. 1, 8.9, 8.8, 9.1 8.7+0.4
8.1, 8.6, 7.6, 8.6 8.2*0.5
9.1, 8.2, 6.2, 10.7 9.0+1.2
19
8.2, 8.0, 7.9, 9.4 8.4+0.7
8.4, 8.9, 9.2, 8.9 8.8+0.3
8.3, 8.1, 7.3, 8.8 8.1+0.6
9.2, 8.0, 8.0, 10.5 8.9+1.2
25
8.1, 7.9, 7.6, 9.4 8.2+0.8
8.4, 8.8, 9.1, 9.2 8.90.4
8.3, 8.3, 7.4, 8.6 8.2+0.5
9.0, 7.8, 7.8, 9.9 8.6*1.0
32
7.8, 7.8, 7.9, 9.3 8,2+0.7
8. 1, 8.9, 9.0, 9.2 8.8 + 0.5
8.4, 8.3, 7.4, 0.7 8.2+0.6
9.2, 8.6, 8.2, 10.4 9. 1 + 1.0
39
7.9, 7.9, 7.6, 9.2 8.210.7
8.4, 9,3, 9.2, 9.2 9.0+0.4
8.9, 8.4, 7.9, 9.3 8.6+0.6
8.4, 7.8, 7.8, 10.4 8.6+1.2
46
8.1, 8.0, 7.8, 9.1 8. 2+0.6
8.3, 9.1, 8.9, 9.0 8.810.4
8.6, 8.3, 7.4, 9.1 8.4+0.7
8.4, 7.8, 7.7, 10.1 8.5+1.1
53
8.2, 8.0, 7.8, 9.5 8.4 + 0.8
8.7, 9.3, 9.4, 9 6 9.2+0.4
9.0, 8.8, 7.7, 9.1 8.6+0.6
8.5, 8.0, 7.8, 10.5 8.7+1. 2
60
8.3, 8.5, 8.1, 9.7 8.6+0.7
8.5, 9.1, 9.5, 9.4 9.1+0.4
8.9, 8.6, 7.6, 9.4 B.6+0.8
8.4, 8.1, 7,8, 10.2 8.6+1. 1
67
8.1, 8.0, 8.0, 10.0 8.5+1.0
8.7, 9.0, 9.5, 9.7 9.2+0.4
9.1, 8.7, 7.7, 9.9 8.8+0.9
8.5, 8.1, 7.9, 10.8 8.8+1. i
74
7 .9, 8.1, 8.0, 9,8 8.4+0.9
9.0, 9.5, 9.4, 9.6 9.4+0.3
9.0, 8.5, 7,7, 9.3 8.610.7
9.0, 8.9, 8-1, 11 ,1 9.3 + 1. 1
81
8.0, 8.0, 8.0, 10.1 8.511.0
8.8, 9.2, 9.2, 9.7 9.2+0.4
8.8, 8.7, 7.6, 9.2 8.610.7
9.0, 8. i, 6,0, U.l 9 l?1.4
90
8.1, 7.9, 8.1, 10.0 8.5+1,0
8.4, 9.2, 9.5, 9.5 9.2+0.5
9.0, 8.7, 8.0, 9.5 8.8+0.6
9.0, 8. j, 7 9, ! t 0 9 lit J . 4
95
8.3, 8.2, 8.3, 10.0 8.7*0.9
B. 4, 9,5, 10.0, 9.5 9.4+U.7
8.9, 8.6, 7.8, 9.2 8.6+0.6
4.0, a. j. t. 9, 10.9
1 U'1. i
3Femaleai were inaintdincd on lest for 98 days. See Table l for summary data.
L'b ^re wtre nu s ignlf Kant d if fereni-es f rom com rol il,l n3i by Duuiu-U's tc-st. |><0.05.
SL 083997
TABLE A-2
INDIVIDUAL AND MEIAN HtMATOLOClC VALUES FOR MALE AND FEMALE BEAGLE DOGh GIVEN VI Iff LIDENE CHLORIDE UUH PLAMJT OIL ORALLY IN CAPSULES FOR 9? DAYS3
Dose Level g/kg/day
ays on Teat:
75-2077 2073 2079 2080
HLANtSD
75-2089 2090 2091 2092
KEAKXSD
75-2085 2086 2087 2038
MEAKiSD
7 5-2081 2082 2083 2084
HEAMiSD
-48 33 84
Red Blood Cells
Hemoglobin
-46
___ 33_____ ____84____ ____-48
33____
84
3White blood Cells
-46 33
84
-48 33 64
Differential White Cell CuiniC (.)_ -48 33 8i*_ -48 33 8 A -48 11 84
Basophils -48 Ik !14
52 52 47 54
51*3
50 52 51 52
51*1
50 51 46 51
50*2
7.05 7.14 6.51 7.00
6.93*0.28
6.60 7.27 7.20 7.00
7.02*0.30
6 79 7.28 6.54 7.11
6.93*0.33
50 48 52 48
50*2
43 44 48 49
47*2
49 45 45 48
47*2
7.00 6.22 6.76 6.76
6.6910.33
7.00 5.94 6.50 7.24
6.67*0.56
7.04 6.16 6.14 7.06
6.61*0.52
50 56 48 52
52*4
48 54 48 49
50t3
46 51 47 50
49*2
7.02 7.44 6.27 6.33
6.69*0.49
6.77 7.10 6.44 6.65
6.74*0.26
6.81 7.14 6.39 6.87
6.60r0.31
48 52 52 50
50*2
48 50 50 45
48 tl
46 49 50 45
47*2
6.46 6.99 7.26 6.99
6. 93*U.3`i
6.81 7.08 7.19 6.50
6.90*0.31
6.47 6.80 7.26 6.68
6.80*0.33
16.2 18.1 16.0 18.1
17.6S1.1
17.0 18.3 17.7 17.7
17.7*0.5
17.6 18.0 16.0 17.2
17,2*0,9
15.5 13.4 10.1 12.9
13.0*2.2
17.3 16.1 17.5 16.4
16.8*0.7
16.8 15.1 16.3 17.0
16.3*0.9
17.0 15.6 15.7 17.1
16.4*0.6
6.3 9.5 11.1 12.6
10.4*1.9
1B.1 18.6 16.2 17.9
17.7*1.0
16.6 16.2 16.5 17.0
17.1*0.8
16.8 17.4 16.2 17.9
17.1*0.7
10.3 10.4 10.1
8.2
9.6*1.0
15.8 18.0 17.9 17.1
17.2*1.0
16.4 17.6 17.9 15.6
16.9*1.1
15.9 17.2 17.5 16.0
16.7*0.8
9.6 12.1
9.1 12.5
10.8*1.7
15.6 12.5 12.2 33.6
13,5*1.5
10.9 10.6 10.5 13.3
11.3*1.3
11.1 14.7 11.7 10.4
12.0*1.9
11.4 11.9 10.6 13.5
11.9*1.2
13.5 13,0 13 2 14.0
I2.9tl.2
63 60 60 66 59 69 59 58 48 57 46 44
61 56 55
10.1 10.7 3 1.5 10.3
53 64 55 59 63 65 43 56 52 72 63 68
10.7*0.6* 57 62 60
9.9 11.2 11.7 10.5
10.6*0.8
55 63 58 47 56 66 47 44 56 53 64 60
53 57 61
9.3 12.4
9.0 11.2
49 62 58 49 53 56 51 54 56 57 62 55
10.5*1.6* 52 57 56
21 3 3 27 19 27 20 33 27 42 27 38 39
25 31 32
26 26 30 36 22 28 46 31 30 22 23 17
J3 26 26
29 20 28 30 26 22 44 36 27 32 22 34
34 26 28
40 34 33 27 25 25 35 31 27 28 29 30
33 JO 29
5 5H
11 2 a
7 10 5 a 4 6
56
3
4 7 4 12
7
5 75
9
58
5 4 8 16 a2
5 36 3 35
4 45
6
J * 77
8 57
7 12 6
6 5 4 1 7 13 7
8 64
1 10
9 94
5
8 75
6 10 5
5 33 4 1 6 6 8 6 17 13 9 88 5 7 2 0 6 12
b5 5
9
7y
U 01 0
0 00 0 33
2 0 '2 1 01
1
1 01 2 00
1 10
SL 083998
75-2093 2094 2095 2096
MEANiSD
75-2105 2106 2107 2108
MEANiSD
75-2101 2102 2103 2104
MEANlSD
75-2097 2098 2099 2100
KEANiSD
50 51 50 48
50*1
45 52 50 49
49*3
48 50 47 46
48*1
46 56 49 51
50*4
46 48 46 52
46*3
43 53 47 46
47*4
43 48 53 44
484
47 48 48 46
47S1
44 51 52 45
48*4
56 42 51 50
50*6
44 45 49 42
4 5i3
56 46 47 42
48*6
6 57 6.66 6.42 6.45
fi. 53*0.12
6.12 7.07 6.73 6.94
6.72*0.42
6.57 6. 96 6.23 6.68
6.62*0.31
6.13 7.20 7.56 6.8J
6.9310.61
6.21 6.68 7.42 7.07
6.65*0.52
5.95 7.36 6.87 6.23
6.60t0.64
6.81 6.31 7.22 6.04
6. 60*0.52
6.63 6.33 6.79 6. 74
6.62*0.21
6.35 6.64 7.41 6.42
6.76*0.50
7.05 5.82 6.42 6.79
6.52*0.53
5.96 6.15 6.55 6.07
6.18*0.26
7.59 6.68 6.22 6.18
6,67*0.66
17.4 17.8 16.9 16.5
17.2*0.6
15.7 18.4 17.7 17.3
17.3x1.1
17.3 17.6 16.7 17.1
17.2*0.5
10.3 9.7 9.1 9.5
9.710.5
15.6 13.9 16.4 17.5
17 . 1*1.4
15.4 16.7 16.7 17.4
16.6*0.8
14 .8 18.7 16.1 15.7
16.3*1.7
9.6 11.0 12.9
6.3
10.5*2.0
J 7. 3 17.0 18.0 14.5
16.711.5
15.9 17,0 16.6 16.3
16.510.5
15.6 16.3 18.1 15.7
17,Oil.4
6.3 14.6 14.0
7.6
11.2*3.7
18.7 14,5 17.4 17.5
17.0*1.8
14.9 15.5 17.1 14.7
15.6*1.1
19.4 16.5 16.4 15.0
16.8*1,6
12.1 6.7
12.3 13.8
11.712.2
9.2 11.5
6.7 U.O
10.1*1.4
11.3 9.2
13.2 9.9
10.9*1.8
10.9 12.5 U.O 12.7
11.8il.O
11.7 9.5
11.2 14.5
11.7x2.1
10,4 10.6 10.0 11.5
10.6*0.6
10.2 9.8
15.2 7.5
10.713.2
8.3 16.4
9.7 10.0
11.1x3.6
13.3 B. 5
12.1 11.9
11.5*2.1
42 58 58 47 42 57 59 58
53 62 49 58
50 55 56
51 53 65 60 59 42 71 71 81 65 61 51
64 61 59
64 66 56 70 71 71 65 65 52 53 55 58
63 64 59
55 57 61 66 65 61 68 52 56 72 67 67
66 60 61
Females were uintaliied on test for 93 days. The differential white cell counts were not analyzed stat 1 st IlsIly. See Table 3 for summary data. *Signlficautly different froa control ncan by Dunnett's test, p<(J.Q5,
39 17 29 35 J 2 29 45 34 39 27 33 29
37 29 30
36 34 21 25 34 49 24 20 17 23 2* JO
27 28 29
23 2ti 30 24 23 17 28 23 33 39 34 34
29 27 29
28 25 25 22 26 23 15 36 24 17 29 24
21 29 2h
7 45 3 10 7 6 26 4 35
5 56
10 20 11 4 11 3 5 65 95
7 10 7
9 53 7 55 4 62 4 8b
6 64
7 3b 3 56 2 57 1 33
3 4b
4 2 1 8
3
4 3 5 7
5
7 11 23 30 7 13
57
46 14 58 85
46
8 95
V
10 7 9
2
5 5 3 12
6 04
i
6 55
5
99 27 6 17 3
5 10
2 12 0 00 U 11 i 10
1 11
0 10 0 01 0 00 0 01
0 01
2 12 0 00 0 20 00
0 10
0 00 0 00 0 10
0
0 10
TABLE A-3
INDIVIDUAL AND MEAN CLINICAL CHEMISTRY VALUES FOR MALE AND FEMALE BEAGLE DOGS GIVEN vinylidene chloride with peanut oil orally in capsules for 97 days3
Dose Level mq/kg/day
Animal Number
Days on Test:
MALES
0 75-2077 2078 2079 2080
MEAN+SD
BUN mg %
14 20 18 29
21 + 6
13 14 20 22
17+4
97
15 17 18 20 18 + 2
6.25
75-2089 2090 2091 2092
MEAN+SD
22 25 23 15
21+4
14 35 17 13
20+10
17 23 13 17
18+4
12.5
75-2085 2086 2087 2088
MEAN1SD
17 20 19 16
1812
18 12 16 13
15 + 3
13 18 15 15
1512
25
75-2081
18 23
24
2082
18 14
19
2083
15 16
18
2084
17 18
20
MEAN1SD
17 + 1 1814 20 3
-7 '
SGPT mU/ml
85
97
46 34 46 43
4216
35 34 33 35
3411
43 34 42 40
40 + 4
93 81 56 59
72 + 18
38 46 52 47
4616
31 47 36 56
42111
97 56 53 85 71 100 57 100
70+20* 85121
59 54 46 46
5116
41 41 22 23
32 + 11
54 56 43 43
4917
95 65 37 79
69125
42 50 49 41
46 + 5
37 36 366 51
1221162
47 54 68 45
54+10
68 62 73 46
62 + 12
A? mU/ml
S3
97"
SGOT mU/ml -7 85
100 63 57 55
69121
140 67 60 61
82139
23 34 28 34
30 + 5
35 36 31 35
34 + 2
61 109
95 113
110 97
113 105
94124 10617
29 35 36 43 49 36 48 52
4 0 10 4218
98 60 35 90
71129
96 71 41 93
75125
35 36 27 24
306
40 47 30 28
3619
95 65 78 45
71121
100 75 82 54
78119
41 33 33 30
34 + 5
48 42 35 40
4115
C,
32 27 32 34
31 + 3
91 47 79 54 68 + 21
41 49 35 32
39 + 7
53 40 35 39
42 + 8
FEMALES 0
6.25
12.5
25
75-2093 2094 2095 2096
MEAN1SD
75-2105 2106 2107 2108
MEAN1SD
75-2101 2102 2103 2104
MEANiSD
75-2097 2098 2099 2100
MEAN1SD
21 13 22 35 36 43 57 68 78 33 46 54 23 19 15 49 37 48 66 65 67 27 35 40 24 19 18 35 30 43 43 40 45 34 32 36 20 16 19 48 47 61 78 82 69 40 45 48
2212 1713
16 17 20 20 14 13 17 25
1712* 195
18 14 21 17
18+3
IS 14 20 20
1813
24 21 19 23
2212
24 20 21 21
2212
1813
20 20 20 23
21 2
25 18 19 16
2014
22 19 22 21
21il
4218 3817
51 27 42 36
39110
51 45 47 59
5016*
41 38 28 44
3817
41 38 39 49
4215
41 46 38 28
3818
41 48 40 33
4016
4918 61115
48 53 46 68
54110
113 75 60 94
86123
5Q 47 47 55
5014
144 87 63 72
92136
47 64 42 40
48111
82 90 52 43
67123
64117 65114 3415 40 + 7
62 105
65 80
78120
67 103
54 85
77+21
33 27 35 41
34 + 6
33 32 32 37
3412
90 102
91 92
9416
122 95 98 91
101U4
30 45 29 41
3618
42 40 33 35
3814
150 113
57 75
99141
157 108
56 72
98145
33 34 30 20
2916
45 41 35 30
38+7
44+8
33 34 35 47
37 + 6
29 36 37 41
365
45 45 39 30
4017
aFeroalee were maintained on test for 98 days. See Table 5 for summary data.
*Significantly different from control mean by Dunnett's test, p<0.05.
SL 083999
TABLE A-5
INDIVIDUAL URINALYSES FOR MALE AND FEMALE BEAGLE DOGS GIVEN VINYLIDENE CHLORIDE WITH PEANUT OIL ORALLY IN CAPSULES FOR 97 DAYS3
Dose Level Animal Specific mg/ka/day Number Gravity
MALES, Test: day 83
0 6.25 12.5 25
75-2077 2078 2079 2080
75-2089 2090 2091 2092
75-2085 2086 2087 2088
75-2081 2082 2083 2084
1.048 1.050 1.048 1.021
1.043 1.033 1.037 1.038
1.031 1.024 1.013 1.029
1.033 1.031 1.014 1.043
Test: day 97
0 75-2077 2078 2079 2080
6.25
75-2089 2090 2091 2092
12.5
75-2085 2086 2087 2088
25 75-2081 2082 2083 2084
1.021 1.057 1.032 1.012
1.038 1.042 1.051 1.036
1.033 1.033 1.042 1.033
1.039 1*024 1.025 1.040
FEMALES. Test day 83
0 75-2093 1.010 2094 1.055 2095 1.036
2096 1.004
6.25
75-2105 2106 2107 2108
1.015 1.022 1.038 1.018
12.5
75-2101 2102 2103 2104
1.006 ND
1.023 1.017
25 75-2097 1.027 2098 1.023 2099 1.035 2100 1.039
Test day 98
0 75-2093 1,026 2094 1.049 2095 1.033 2096 1.028
6.25
75-2105 2106 2107 2108
1.045 1.041
1.043 1.048
12.5
75-2101 2102 2103 2104
1.028 1.036 1.031 1.031
25 75-2097 1.028 2098 1.027 2099 1.037 2100 1.031
pH (Range)
5.5 6.0 6.0 5.5
8.0 9,0 7.5 8,0
7.5 8.0 6.5 8.5
6.5 7.0 7.5 6.0
6.0 6.5 7.0 7,0
8,0 8.0 8.0 8.0
6.5 8.0 8.0 8.0
8.0 8.0 8.0 7,0
9.0 6.0 7,0 6.5
9,0 6.0 7.0 8.0
6.5 ND
7.0 7.5
5.5 6.0 6.0 6.0
7.0 6.5 6.0 7.5
7.0 7.5 7.0 6.5
7.0 7.5 8.5 8.5
6.5 7.0 6.5 7.0
Sugar
Protein
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
5 mg 1 5 mg %
LQ mg Z
0 mg %
30 mg % 10 g X
0 mg % 5 mg %
50 mg Z
20 mg % 0 mg X
30 mg Z _
5 mg Z
10 mg Z
400 mg % 50 mg X
neg. neg. neg* neg*
neg. neg. neg. neg.
neg. neg. neg* neg.
neg. neg. neg. neg.
0 mg X
0 mg z 0 mg z 0 mg z
5 mg X 5 mg X
10 mg z 5 mg z
0 mg z
10 mg X
0 mg z
5 mg X
0 mg z
0 mg X
10 mg z 0 mg z
neg. neg* neg. neg.
neg. neg. neg. neg.
neg. ND
neg. neg.
neg* neg. neg. neg.
0 mg z 0 mg z 0 mg z 0 mg z
0 mg z
0 0
mg mg
z z
0 mg X
0 mg X ND
0 mg z 0 mg z 0 mg z 0 mg z 0 mg z 0 mg 1
neg, neg. neg. neg*
nag. neg. neg. neg
neg. neg. neg. neg.
neg. neg. neg. neg.
10 mg z
0 mg X
0 mg z 0 mg z
5 mg X 0 mg X
0 mg z
0 mg X
0 mg X
0 mg z 5 mg z 0 mg z 0 mg z 0 mg z
0 mg X
0 mg z
aFemales were maintained on test for 98 days. ND no data available; neg. 9 negative; mod. moderate, See Table 4 for summary data.
Ketones
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg* neg.
neg. neg. neg* neg.
neg. neg. neg. neg.
neg. ND
negneg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg, neg.
Occult Blood
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. small neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg*
neg* neg. neg* neg.
neg. small
neg. neg.
neg. neg. neg. neg.
neg* ND
neg. neg.
trace neg. neg. neg.
small neg. neg. neg*
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
Bilirubin
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg* neg. neg. neg.
neg. neg. neg. neg*
neg* neg. neg, neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. ND
neg. neg.
neg. neg. neg. neg.
neg. neg. neg. neg.
neg. neg. neg* neg.
neg* neg. neg. neg*
neg* neg. neg. neg*
0840
