Document ppjKVoYxzqLrXNjO1gb1gaEnw

AR226-2799 i Study Title Repeated ** Dose ... .. Oral iAz mToxij ciuty1:Q7HA14-4nDayMalFeeedRaitnsg Study Author John V. Sarver S*rdy Ctnpleted On May 15, 1995 Performing Laboratory E. I. du Pont de Nemours and Company kell Laboratory for Toxicology and Industrial Medicine Elkton Road, P. 0. Box 50 Laboratory Project ID Haskell Laboratory Report No. 326-95 C o inpm y Ooe* noi contain TSCACBI Page 1 o f 47 '"^=-5!-- ,_T Substance Tested: Synonyas/Codes : DuPont HLR 326-95 GENERAL INFORMATION FOR H-19683 Physical Form: Contaminants: Purity: CAS Registry No. : Substance Tested: Synonyms/Codes: Octanoic acid, pentadecafluoro-. ammonium salt H-19704 C-8 Sponsor: Study Initiated - Completed: In Life Phase Initiated - Completed: DuPont Fibers and DuPont Speciality Chemicals E. I. du Pont de Nemours and Cospany Wilmington, Delaware 8/28/92 - 5/15/95 9/16/92 - 11/25/92 Company Sanitized. Does not contain TSCA CBl -2- DuPont HLR 326-95 REPEATED DOSB ORAL TOXICITY 14-DAY FEEDING STUDY WITH 8-19683 AND H-19704 IN HALE RATS SUMMARY The purpose of this study was to evaluate the repeated oral dose toxicity and bioretentivity of H-19683 and H-19704 vhen incorporated into nutritionally adequate chov and fed to male rats for 14 consecutive days. Groups of 20 sale rats each were fed diets containing either 30 or 300 ppe of H-19683 or 30 or 300 ppm of H-19704. Rats vere sacrificed at the end of the 14-day feeding period and on recovery days 7, 28, and 56 and livers removed and weighed. Blood samples /ere taken for fluoride concentration analysis from rats sacrificed at the end of the feeding period and on recovery day 7. No mortalities were observed during the study. No clinical signs of toxicity were observed in rats*fed H-19683. Clinical signs of toxicity noted in rats from the 30 and 300 <pm dose groups of H-19704 during the feeding period included irregular respiration, rapid breathing, red nasal discharge and hunched posture. Significant decreases in mean body weights vere observed in rats from the 300 ppm dose group of H-19704 on days 7 and 14 of the feeding period and on recovery day 7 compared to controls. Mean body weight gains of rats from this same group were significantly depressed during the first week of feeding. Significant increases in mean relative liver weights were observed in rats from the 30 and 300 ppm dose groups of H-19683 sacrificed at the end of the feeding period. No other liver weight effects were observed in these rats during the study. Significant increases in mean absolute liver veights vere observed in rats from the 30 and 300 ppm dose groups of H-19704 sacrificed at the end of the feeding period and or recovery days 7 and 28. Significantly increased mean relative liver veights vere observed in rats from the 30 and 300 ppm dose groups of H-19704 sacrificed at the end of the feeding period and on recovery day 7, and in the 300 ppm dose group rats sacrificed on recovery day 28. Mean blood fluoride concentrations of rats sacrificed on recovery day 0 were 0.30 ppm in control rats, 5.30 ppm in group III rats (30 ppm of H-19683), 8.19 ppm in group V rats (300 ppm of H-19683), 33.23 ppa in group VII rats (30 ppm of H-19704), and 71.52 ppm in group IX rats (300 ppm of H-19704). On recovery day 7, mean blood fluoride concentrations vere 0.94 ppm for controls, 0.58 for group III, 0.56 ppm for group V, 19.26 ppm for group VII, and 22.20 ppm for group IX. No other blood was analyzed for fluoride concentration. Company Sanitized, Does not contain TSCA CBI - 3- DuPont HLK 326-95 RBPEATBD DOSE ORAL TOXICITY: 14-DAY PBBPIHG STUDY WITH H-19683 AND 8-19704 IN HALB RATS Vor* by: Reviewed and Approved for sue: CL.[J Tracy A. Filliben Toxicology Technician John V. Sarver Toxicologist Study Director o /* s> /Q>~ JVS/alv Company Sanitized. Does oof contain TSCA CBI - 4- DuPont BLR 326-95 REPEATED DOSE ORAL : CXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IH HALB RATS INTRODUCTION The purpose of this study vas to evaluate the repeated oral dose toxicity and bioretentivity of H-19683 or H-19704 when incorporated into nutritionally adequate chov and fed to male Crl:CDBR rats for 14 consecutive days. The diet concentrations of H-19683 (3n. or 300 ppa) and H-19704 (30, or 300 ppm) were specified by the sponsor. The dietary route of administration vas selected because it is a potential route of human exposure. MATERIALS AND METHODS A. Test Substance The test substances vere supplied by DuPont Fibers and DuPont Speciality Chemicals, E. I. du Pont de Nemours and Company, Wilmington, Delavare. Available information about the identity, purity, composition, stability, and toxicity of H-19683 and H-19704 vas provided by the sponsor. B. Test Species On 9/8/92, 109 male Crl:CD*BR rats, approximately 6 weeks old, vere received from Charles River Laboratories, Inc., Kingston, New York. At study start, the body veights ranged from 196.0 to 240.1 grams. The Crl:CD*BR rat vas selected on the bases of extensive experience with this strain and its suitability with respect to hardiness, longevity, sensitivity, and low incidence of spontaneous diseases. C. Quarantine Upon arrival at Haskell Laboratory, all rats vere removed from shipping cartons and housed singly in stainless steel, wire-mesh cages suspended above cage Board (DACB) or R-2 Reemay-backed cage boards. The rats vere fed Ground Purina Certified Rodent Chov #5002 and vater vas available ad libitum. Bach rat vas assigned a temporary identification number which vas recorded on a card affixed to the cage. The animals vere veighed 3 times during the quarantine period and vere observed daily for any gross signs of disease or injury. On the basis of body veights and clinical observations, all rats vere released from quarantine on 9/16/92 by the laboratory veterinarian. Company Sanitized. Does not contain TSCA CBI -5- D. Assignment to Groups After release from quarantine, 100 rats selected on the basis of body weight gain and freedom from any clinical signs of disease or injury, vere distributed by coaputerized-stratified randomization into five experimental groups of 20 rats each. No statistically significant differences in group body weight means existed. Rats not assigned to a test group were killed by carbon dioxide asphyxiation and discarded without pathological evaluation. E. Animal Husbandry After assignment to treatment groups, each rat vas individually identified by a 3-digit identification number marked an the tail with vater insoluble ink. Additionally, each rat vas assigned a unique 6-digit Haskell animal number. All rats vere individually housed in stainless steel, wire-mesh cages suspended above Upjohn DACB cage boards. GROUP NO. IDENTIFICATION NUMBER*__ TEST SUBSTANCE (ppm) I 101 - 120 III 301 - 320 V 501 - 520 VII 701 - 720 IX 901 - 905 0 (Control) 30 of H-19683 300 of H-19683 30 of H-19704 300 of H-19704 * Each rat vas also assigned a unique 6-digit Haskell Number Animal rooms vere maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the room vere targeted for a temperature of 23 2C and relative humidity of 50Z 10Z. Excursions outside these ranges vere of small magnitude and/or brief duration and did not adversely affect the validity of the study. F. Diet Preparation and Sampling During the test period, rats in each group were fed GPCRC (Ground Purina* Certified Rodent Chow9 #5002) diet that contained 0, 30, or 300 ppm of F-19683 or 30 or 300 ppm of H-19704 (not adjusted for purity). - 6- The study design vas as follows Group Numbers Dietary Concentrations ____ifiEEi___ I 0 (Control) III 30 ppn of H-19683 V 300 ppm of H-19683 VII 30 ppm of H-19704 IX 300 ppm of H-19704 For both diet concentrations prepared vith H-19704, the appropriate amount of H-19704 vas added to GPCRC and thoroughly mixed for 3 minutes in a Hobart high speed mixer. For each diet concentration prepared vith H-19683, the appropriate amount of H-19683 vas first added to a small amount of ground chov and mixed by hand until it appeared homogenous. The hand mixed portion vas then added to the remainder of the ground chov weighed out for that diet in a Hobart high speed mixer and vas mixed for approximately 3 minutes. After mixing, the diet vas visually inspected to ensure it vas free of clumps. The control diet vas also mixed for the same period of time. Diets vere prepared once for the two week feeding period and vere stored refrigerated until used. Samples for concentration, homogeneity, and stability vere taken for analysis at a later date if deemed necessary by the study director. G. Body Weights All rats vere weighed and observed .or clinical signs of toxicity on test days 0, 7, and 14 of the feeding period. Rats not sacrificed at the end of the feeding period vere weighed and observed on recovery days 7, 14, 21, 28, 35, 42, 49, and 56. Cageside examinations to detect moribund or dead rats vere conducted twice daily. H. Food Consumption Food consumption was not determined during this study. I. Necropsy On test day 14 of the feeding period and on recovery day 7, five rats from each group vere anesthetized by chloroform anesthesia and blood vas collected for fluoride concentration analysis. After blood collection, the rats vere euthanatized by chloroform anesthesia and exanguination. The livers vere collected and vere veighed for liver veight/final body veight ratios. Additionally, 5 rats from each group vere sacrificed on recovery days 28 and 56 and the livers vere collected and veighed. r Company Sanitized. Does not contain TSCA CBI - 7- % DuPont HLA 326-95 J* Fluoride Concentration Analysis Blood collected from rats sacrificed at the end of the 14-day feeding period and on day 7 of the recovery period were analyzed for flourled concentration by personnel from Jackson Laboratory, Chambers Works. STATISTICAL ANALYSES Body weights, body weight gains, and organ veights were analyzed by a 0f rari!?ce- Vhen the test for differences among test group means (F test) was significant, pairwise comparisons between test and control groups were made with the Dunnett's test. Bartlett's test for homogeneity of variances was performed on the organ weight data. Significance vas judged at alpha s 0.05. BECQBDS AND SAMPLB RETENTION t w A11 orl8lnal records and the final report were retained at Haskell Laboratory or at the Records Management Center, E. I. du Pont de Nemours and Company, Wilmington, Delaware. A. Diet Sample Analysis RESULTS AND PISCPSSIOH All diets prepared appeared to be thoioughly mixed. No dumps or other signs of non-uniform mixing were observed. Therefore, diet samples taken at the time of diet preparation were discarded without analysis. B * Body Weights and Body Weight Gains (Tables 1-2; Appendix I) Statistically significant decreases in mean body veights were observed in rats from the 300 ppm dose group of H-19704 on days 7 and 14 of the feeding period and on recovery day 7. Mean body weight gains of rats from this same group were significantly depressed during the interval 0-7 days on test compared to controls. The mean body veight gain of rats from the H-196B3 30 ppm dose group vas significantly increased during the interval 14-21 days on test compared to controls. c * Clinical Observations (Appendix II) No mortalities were observed during the study. Filoerection and brown nasal discharge were observed in all groups, including controls. These observations are not considered to be compound-related. The reason for the Company Sanitized. Does not contain TSCA CBI - 8I DuPont BLR 326-95 presence of the din::al signs is unknown. Clinical signs of toxicity noted in test rats exposed :o 30 or 300 ppm H-19704 included irregular respiration, rapid breathing, red =asal discharge, and hunched posture. No clinical signs of toxicity were observed in rats treated with H-19683. D. Mean Pinal Body ar.d Organ Weights (Table 3, Appendix III) Statistically significant increases in mean relative liver weights were observed in rats froi the 30 and 300 ppm dose groups of H-19683 sacrificed at the end of the 14-day feeding period. No other liver weight effects were observed in these rats during the study. Statistically significant increases in mean absolute liver weights were observed in rats iron the 30 and 300 ppm dose groups of H-19704 sacrificed at the end of the feed:r.i period and on recovery days 7 and 28. Significantly increased mean relat.'e liver weights vere observed in rats fro the 30 and 300 ppm dose groups :: H-19704 sacrificed at the end of the feeding period and on recovery day ' Additionally, the 300 ppm dose group rats sacrificed on recovery day 28 ha: significantly increased mean relative liver weight. E. Mean Fluoride Ccr :antrations Found in t e Blood of Rats (Table 4, Append:- IV) Mean blood flue: 0.30 ppm in control 8.19 ppm in Group V (30 ppm of H-19704) recovery day 7, mea1 0.58 ppm for group 22.20 ppm for group concentration. s concentrations observed on recovery day 0 were 's, 5.30 ppm in Group III rats (30 ppm of H-19683), 's (300 ppm of H-19683), 33.23 ppm in Group VII rats nd 71.52 ppm in Group IX rats (300 ppm of H-19704). On lood fluoride concentrations were 0.94 ppm for group I, .0.56 ppm for group V, 19.26 ppm for group VII, and . No other blood was analyzed for fluoride CmpanY Sanitized. D e s not contain T sCA C8 / - 9- DuPont HLB 326-95 REPEATED nnSE ORAL TOXICITY: 14-DAY PBBOING STUDY ----------- WITH H-19683 AND H-19704 IN MALE RATS TABLES GROUP ARE DEFINED a :-: Group I - 0 ppm - Controls Group II - 30 ppit :f H-19683 Group V - 300 ppc of H-19683 Gro'io VII - 30 ppit - f H-19704 G IV - 300 ppr of H-19704 - 10 - not contain ^SCA CBl DuPont HLR 326-95 1 ponpany Sanitized. Does not contain TSCA REPEATED DOSE ORAL TOXICITY: l4-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS TABLE 1 ucam nnnv UETCHTS OF HALE RATS GROUP: CONC. (PPM): I 0 III V 30 300 VII 30 IX 300 DAYS DAYS ON ON TEST RECOVER' 0 ___ 7-- 14 -- 21 7 28 14 35 21 42 28 49 35 56 42 63 49 70 56 212.3( 9.5)* 278.3(13.5) 329.7(20.7) 375.5(24.1) 408.9(30.2) 448.0(35.9) 489.6(41.2) 537.3(37.3) 562.6(40.7) 586.4(43.1) 621.6(42.9) 211.1( 8 .2) 278.7(14.5) 324.1(25.1) 373.8(26.4) 401.3(35.1) 432.4(39.5) 471.1(44.8) 496.8(43.4) 517.5(43.6) 536.0(46.5) 562.1(51.6) 214.2(10.0) 272.4(15.0) 320.1(21.5) 370.1(29.0) 413.8(32.5) 447.0(36.1) 484.7(39.0) 508.2(44.5) 528.4(47.1) 551.6(47.3) 577.6(44.5) 211.9(10.2) 285.2(14.4) 341.3(20.2) 385.0(22.5) 414.4(27.7) 455.7(30.2) 498.4(37.1) 507.1(40.1) 523.6(34.4) 544.7(38.1) 578.8(39.6) 213.3( 9.0) 235.5(19.8)* 287.4(16.5)* 338.9(26.0)* 380.1(28.5) 411.3(30.6) 447.7(33.1) 461.2(42.3) 481.9(48.4) 503.6(53.4) 527.1(54.1) Standard deviation is reported in parentheses Statistical methods: One-way AOV and Dunnett's tests were performed on weekly interval data. (See Statistical Analyses) * Statistically significant difference from control at alpha = 0.05. o CO # REPEATED DOSE ORAL T M B C t n . M - ' STY WITH H-19683 AND H-19704 IN MALE RAlb TABLE 2 MEAN BODY WEIGHT GAINS OF MALE RATS Durcnt HLR 326-95 Company Sanitized. Does not contain GROUP: CONC. (PPM): I 0 III 30 V 300 VII 30 IX 300 DAYS DAYS ON ON TEST RECOVERY 0- 7 -- 7-14 I 14-21 21-28 PO 28-35 0-7 7-14 14-21 35-42 21-28 42-49 28-35 49-56 35-42 56-63 42-49 63-70 49-56 0-70 66.0(13.1)* 51.4(11.8) 44.0(14.1) 33.6( 9.2) 39.1( 9.6) 41.6( 8.0) 22.3( 1.6) 25.3( 4.8) 23.8( 5.4) 35.2( 9.3) 406.8(49.7) 67.7( 8.9) 45.4(11.8) 54.6( 7.7)* 24.9( 7.0) 31.K 6 - D 38.7( 7.4) 21.1( 1-9) 20.7( 3.3) 18.6( 6.9) 26.1( 6.7) 351.0(46.2) 58.3(12.2) 47.6( 9.3) 51.7( 8.9) 3b.K 9.5) 33.2( 6.7) 37.6( 5.0) 15.9( 7.9) 20.2( 5.4) 23.2( 1.3) 26.0( 8.6) 363.7(54.0) 73.3(11.1) 56.1( 8.2) 44.9(11.6) 32.5( 9.7) 41.3( 6.4) 42.7(10.3) 20.5( 6.7) 16.5(19.9) 21.1( 8.5) 34.1( 5.3) 363.2(38.8) 22.1(19.8)* 52.0(13.7) 52.5(12.7) 37.5(14.4) 31.2( 6.5) 36.4( 4.4) 16.8( 6.4) 20.6( 9.2) 21.8( 7.1) 23.5(12.0) 313-4(47.6) Standard deviation is reported in parentheses Statistical ,,ethCst One-.,, AOV anO both weekly and summary interval data. ( * Statistically significant difference from control at alpha = 0.05. tn o> DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS H-19683 TEST DAY 14 RECOVERY DAY 0 MEAN FINAL BODY AND LIVER WEIGHTS FROM MALE RATS MEAN FINAL BODY WEIGHTS (grams) GROUP I III V CONCENTRATION (PPM) 0 30 300 FINAL BODY 324.3 ( 31.0) 339.1 ( 34.3) 325.0 ( 23.4) MEAN ABSOLUTE LIVER WEIGHTS (grams) GROUP x HI V CONCENTRATION LIVER (PPM) o 12.755 (2.044) 30 15.098 (1.768) 300 14.057 (1.358) NUMBER OF ANIMALS 5 5 5 MEAN RELATIVE LIVER WEIGHTS (% of body weight) GROUP X XXI V CONCENTRATION (PPM) 0 30 300 LIVER 3.916 (0.295) 4.448 (0.126)# 4.325 (0.275)1 STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD # - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DlINNETT'S TEST. Company Sanitized. D oes not contain TSC A CBI - 13 - D uPont 8LR 326-9$ repeated dos e o b a l Tonern ia-day pbbding studt tfITH H-19683 AND B-1970A IN MALE BATS TABLE 3 (CONTINUED) H-19683 TEST DAT 21 RECOVERY DAY 7 MEAN FINAL BODY AND LIVER WEIGHTS FROH HALB RATS MEAN FINAL BODY WEIGHTS (grans) GROUP I III V CONCENTRATION (PPM) 0 30 300 FINAL BODY 376.0 ( 18.1) 368.5 ( 18.8) 355.1 ( 29.A) NUMBER OP ANIMALS 5 5 5 MEAN ABSOLUTE LIVER VEIGHTS (grains) GROUP I III V CONCENTRATION LIVER (PPM) 0 30 300 16.261 (1.771) 15.212 (1.880) 15.545 (2.371) MEAN RELATIVE LIVER VEIGHTS (X of body veight) GROUP I III V CONCENTRATION; LIVER (PPM) 0 30 300 4.317 (0.281) 4.120 (0.342) 4.362 (0.316) STANDARD DEVIATION IN PARHITHBSES __ __ + - SIGNIFICANTLY DIFFERENT (P<0.05) PROM CONTROL GROUP BY LSD # - SIGNIFICANTLY DIFFERENT (P<0.05) PROM CONTROL GROUP BY LSD AND DUNNETT'S TEST. Company Sanitized. Does not contain TSCA CBI - 1A - DuPont BUI 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY PBBDIRS STUDY H T k H-19683 AND H-19704 IN BALE RATS TABLE 3 (CONTINUED) H-19683 TEST DAY 42 RECOVERY DAY 28 MEAN FINAL BODY AND LIVER WEIGHTS PROM MALE RATS mea n FINAL BODY WEIGHTS (grans) GROUP I III V CONCENTRATION (PPM) 0 30 300 FINAL BODY 464.2 ( 28.1) 466.5 ( 50.0) 476." ( 41.7) NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grans) GROUP CONCENTRATION LIVER (PPM) 0 !o III 30 V 300 17.737(0.398) 18.787 (4.102) 18.555 (2.743) MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP TH I v CONCENTRATION (PPM) 0 30 300 LIVER 3.834 (0.290) 3.994 (0.457) 3.881 (0.355) f ? S ^ A 3 ? j S | > 25S E SS 5 - - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROU DUNNETT'S TEST. Company Sanitized. Does noi contain TSCA CBI - 15 - DuPont B * 326-95 RBPEATBD DOSE ORAL urn n.14U3 AND B-19704 IN HALE RATS TABLE 3 (CONTINUED) H-19683 TEST DAT 70 RECOVERY DAT 56 KEAN FINAL BODY AND LIVER WEIGHTS FROM MALE RATS MEAN FINAL BODY WEIGHTS (grau) GROUP I III V CONCENTRATION (PPM) 0 30 300 FINAL BODY 621.6 ( 42.9) 562.1 ( 51.6) 577.6 ( 44.5) NUMBER OF ANIMALS MEAN ABSOLUTE LIVER WEIGHTS (grans) GROUP T III V CONCENTRATION LIVER (PPM) 0 30 22.466 (3.865) 20.322 (1.607) 300 22.858 (3.504) MEAN RELATIVE LIVEP WEIGHTS ( of body weight) GROUP I III V CONCENTRATION LIVER (PPM) 0 30 3.596 (0.405) 3-628 (0.296) 300 3.949 (0.400) ; : S S d Ipf^ DUNNETT'S t e s t . T O W COHTROL GROUP BT LSD t (P<0.05) froh c o h t r o l g r o u p r t LSD AND Company Sanitized. Does not contain TSCA CBI - 16 - VITB H-19683 AMD H-19704 IH MALE RATS TABLE 3 (CONTINUED) H-19704 TEST DAY 14 RECOVERY DAY 0 HBAN PINAL BODY AND LIVER WEIGHTS FROM HALE RATS MEAN FINAL BODY WEIGHTS (graas) GROUP CONCENTRATION (PPM) FINAL BODY 10 VII 30 IX 300 324.3 ( 31.0) 345.0 ( 15.8) 290.7 ( 10.9)t NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grans) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 12.755 (2.044) 30 20.698 (0.972)* 300 23.674 (1.752)# MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 3.916 (0.295) 30 6.003 (0.243)* 300 8.139 (0.417)# hu DuPont BU 326-95 r b p b a t b d d o s b o r a l T o n e r n ia-d a y fee ding studi tin R-14704 Di HALB RATS TAULE 3 (CONTINUED) H-19704 TEST DAT 21 RECOVERY DAT 7 m e a n f i n a l b o d y AND LIVER VBIGHTS fr o n male rat s KRAN FINAL BODY WEIGHTS (grau) GROUP CONCENTRATION (PPM) FINAL BODY T X 0 VII 30 IX 300 376.0 (18.1) 391.3 ( 25.8) 331.5 ( 27.3)# NUMBER < animals 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grau) GROUP I VII IX CONCENTRATION LIVER (PPH) 0 30 300 16.261 (1.771) 22.711 (1.998)1 22.034 (0.617)1 MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 30 300 4.317 (0.281) 5.811 (0.490)1 6.673 (0.396)# dS fS S ^ ' o s ) from c o n trol c r o w LSD J I f S j E K S S S r dif fS S t (P<o .o s ) from corirol gro up ri LSD AND DUNNETT'S TEST. 1 I DuPpnt P t! 326-95 REPEATED DOSE ORAL TOXICITYt 14-DAT FEEDING STUDY WITH H-19683 AND H-19704 IN KALI RATS TABLB 3 (CONTINUED) 3-19704 TEST DAT 42 RECOVERY DAT 28 MEAN final b od y a n d l iv er w e i g h t s f r o m h a l e r a t s MEAN FINAL BODY WEIGHTS (grans) GROUP I VII IX CONCENTRATI: (PPM) 0 30 300 FINAL BODY 464.2 ( 28.1) 510.1 ( 40.4) 450.9 ( 32.4) MEAN ABSOLUTE LIVE? WEIGHTS (grans) GROUP I VII IX CONCENTRATI: LIVER (PPM) 0 17.737 (0.398) 30 21.111 (1.844)# 300 21.234 (1.852)# NUMBER OF ANIMALS 5 5 5 MEAN RELATIVE LIVE? WEIGHTS (Z of body veight) GROUP I VII IX CONCENTRATI (PPM) 0 30 300 LIVER 3.834 (0.290) 4.148 (0.353) 4.714 (0.310)# STANDARD DEVIATION IN PARENTHESES - SIGNIFXCANTLY DIFFERENT (P<0.05) PROM CONTROL GROUP BY LSD # - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST. Company Sanitized. Does not contain TSCA CBI - 19 - DuPont 8Ut 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 ADD H-19704 IN HALE HATS TABLE 3 (CONTINUED) H-19704 TEST DAY 70 RECOVERY DAY 56 mean final body and liver weights from male rats MEAN FINAL BODY WEIGHTS (grans) GROUP I VII IX CONCENTRATION (PPM) 0 30 300 FINAL BODY 621.6 ( 42.9) 578.8 ( 39.6) 527.1 ( 54.1)# NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grans) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 30 300 22.466 (3.865) 21.402 (2.558) 19.835 (3.326) MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 30 300 3.596 (0.405) 3.696 (0.317) 3.767 (0.508) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD # - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST. - 20 - Company Sanitized. Does not contain TSCA CBi DuPont BUI 326-95 RBPBATED DOSE ORAL TOXICITY: 14-DAY FBBDING STUDY WITH H-19683 AND H-19704 IN HAU RATS TABLE 4 MEAN FLUORIDE CONCENTRATIONS (PPM) FOUND IN THE BLOOD OF maiji hats TREATED WITH H-19683 OR H-19704 GROUP t CONCENTRATION OF TEST SUBSTANCE I 0 PPM (CONTROLS) III 30 PPM OF H-19683 V 300 PPM OF H-19683 VII 30 PPM OF H-19704 IX 300 PPM OF H-19704 I 0 PPM (CONTROLS) III 30 PPM OF H-19683 V 300 PPM OF H-19683 VII 30 PPM OF H-19704 IX 300 PPM OF H-19704 RECOVERY DAYS ____________ 0 0 0 0 0 7 7 7 7 7 MEAN FLUORIDE CONCENTRATION __________ (ppi---------- 0.30 5.30 8.19 33.23 71.52 0.94 0.58 0.56 19.26 22.20 Company Sanitized. D oes not contain TSC A CBI - 21 - DuPont ELI 326-95 RBPBATBD DOSE ORAL TOXICITYt 14-DAY FBEDIHG STUDY gifH H - i M M aBp h Ii m m a m i hAta----- APPENDIX I INDIVIDUAL BODY VBIGBTS SD* = Sacrifice by Design # Company Sanitized. Does not contain TSCA CBI - 22 - 1lf>t Si djiittai! itti wy repbatbd dose oral Tottcm; w b OTDI APPENDIX I INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP: I CONCENTRATION: 0 PPM DATS ON TEST: RECOVERY DAYS 14 21 28 35 42 49 56 63 70 7 14 21 28 35 42 49 56 ANIMAL I 524405 524406 524407 524408 524409 524410 524411 524412 524413 524414 524415 524416 524417 524418 524419 524420 524421 524422 524423 524424 212.5 221.5 199.2 206.4 214.5 217.8 228.3 203.3 208.5 208.1 215.5 216.4 199.7 201.4 218.8 217.5 233.1 198.1 209.3 216.0 265.7 296.7 254.2 265.3 298.5 294.1 273.2 272.6 286.7 271-7 282.2 288.9 267.0 262.1 286.3 300.6 264.5 271.4 287.1 277.6 297.8 SD (DAY 14) 351.2 SD (DAY 14) 295.5 SD (DAY 14) 314.1 SD (DAY 14) 362.8 SD (DAY 14) 340.8 382.8 SD (DAY 21) 311.8 357.3 SD (DAY 21) 327.0 376.2 SD (DAY 21) 344.1 318.3 325.6 334.4 307.5 302.9 402.3 SD (DAY 361.2 SD (DAY 365.5 390.7 392.5 421.7 348.0 375.6 343.8 369.7 21) 21) 417.1 462.1 410.4 391.3 332.5 362.2 408.8 456.3 369.5 427.3 466.1 501.9 342.2 344.6 390.6 434.9 340.9 345.1 329.8 393.2 399.3 375.7 434.3 434.6 396.4 487.1 480.6 438.0 454.3 SD (DAY 42) 496.0 SD (DAY 42) 453.0 SD (DAY 42) 428.3 SD (DAY 42) 489.6 SD (DAY 558.8 581.5 480.0 501.4 535.6 555.6 529.2 552.6 471.3 495.4 42) 612.5 528.6 582.0 576.3 513.4 639.1 558.5 606.4 599.0 528.8 661.4 SD* 599.4 SD* 648.5 SD* 641.6 SD* 557.1 SD* DuPont HLR 326-95 Company Sanitized. Does not contain TSCA CBI REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-1%83 AND H-19704 IN HALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS CROUP: 111 CONCENTRATION: 10 I'l'H OK II I'Xjlll DuPont HLR 326-95 Company Sanitized. Does not contain TSCA CBI HIS ON TEST: 0 7 14 21 28 35 42 49 56 63 70 RBCOVBRY DAYS - - - 7 14 21 28 35 42 49 56 ANIMAL 1 524425 524426 524427 524428 524429 524430 524431 524432 524433 524434 524435 524436 524437 524438 524439 524440 524441 524442 524443 524444 211.5 222.3 198.6 203.9 212.3 210.8 228.7 204.4 208.9 205.5 223.7 216.9 202.4 205.4 210.4 214.6 222.3 202.6 206.1 209.9 287.0 310.9 267.1 270.8 290.9 273.7 296.6 260.6 268.9 276.3 294.8 279.3 259.5 263.8 283.5 272.7 298.5 257.3 280.3 282.3 346.3 SD (DAY 14) 384.3 SD (DAY 14) 304.6 SD (DAY 14) 305.1 SD (DAY 14) 355.2 SD (DAY 14) 307.2 354.9 SD (DAY 21) 339.3 396.6 SD (DAY 21) 293.4 349.5 SD (DAY 21) 309.7 365.0 SD (DAY 21) 319.6 376.6 SD (DAY 21) 355.6 418.7 451.7 491.1 329.1 378.1 403.3 426.1 289.1 333.6 351.2 374.9 307.8 348.8 370.1 394.4 329.0 389.0 419.3 448.0 310.9 358.8 389.2 419.4 354.3 421.9 455.9 494.4 295.7 346.2 362.3 395.2 317.6 374.7 400.6 435.0 329.0 394.0 409.2 445.0 535.8 SD (DAY 42) 459.0 SD (DAY 42) 409.8 SD (DAY 42) 433.1 SD (DAY 42) 494.8 SD (DAY 42) 450.7 469.6 488.0 543.6 563.4 581.8 424.9 448.7 467.5 481.4 502.3 524.3 477.8 499.8 525.7 509.0 601.1 478.0 538.1 554.0 527.6 SD* 637.1 SD* 502.1 SD* 567.1 SD* 576.8 SD* 9 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP: V CONCENTRATION: 300 PPM OF H-19683 DATS ON TEST: 0 lYS - 7 14 21 28 35 42 49 56 63 70 - - 7 14 21 28 35 42 49 56 ANIMAL I 524445 216.8 524446 227.8 524447 204.8 524448 204.3 524449 213.5 J9 524450 524451 3 524452 524453 218.9 224.7 205.7 219.8 524454 209.8 524455 218.5 524456 225.9 524457 199.9 524458 205.3 ? 524459 524460 218.2 219.7 a 524461 236.0 524462 201.3 5 524463 203.0 I 524464 209.2 271.7 308.6 266.3 259.1 277.5 266.2 280.9 243.3 259.9 259.2 273.4 286.3 256.9 269.3 283.5 278.2 288.9 275.3 289.0 255.2 314.6 SD (DAY 14) 362.4 SD (DA7 14) 314.3 SD (DAY 14) 302.0 SD (DAY 14) 331.6 SD (DAY 14) 307.9 353.8 SD (DAY 341.2 282.6 297.4 403.4 SD (DAY 326.7 SD (DAY 337.1 SD (DAY 309.8 354.3 SD (DAY 315.2 365.7 393.9 336.5 399.6 433.6 303.7 348.4 382.6 310.8 360.3 381.1 349.1 411.6 456.2 315.9 362.9 400.5 329.4 335.5 352.4 289.1 373.5 401.6 414.5 338.8 400.1 440.6 467.0 382.7 21) 21) 21) 21) 21) 419.0 467.9 411.1 411.6 497.5 430.3 430.7 487.9 495.6 418.6 459.5 SD (DAY 503.4 SD (DAY 439.2 SD (DAY 446.0 SD (DAY 536.6 SD (DAY 464.1 477.1 473.9 480.9 532.8 561.5 536.5 551.8 454.5 469.8 42) 42) 42) 42) 42) 489.0 501.5 587.9 570.7 492.9 513.5 525.1 611.8 593.7 514.0 534.1 SD* 565.5 SD* 635.0 SD* 612.6 SD* 540.7 SD* DuPont HLR 326-95 repeated dose oral p o m i TM v APPENDIX I (CONT.j INDIVIDUAL BODY WEIGHTS (g) OP HALE RATS GROUP: VII CONCENTRATION: 30 PPM OF H-19704 DAYS ON TEST: A recovery days - 7 1A 21 28 35 42 49 56 7 14 21 28 35 42 ANIMAL I 524465 524466 4467 4468 4469 524470 524471 a>524472 2524473 524474 524475 524476 <f/> 524477 O3 524478 o 524479 3o 524480 5T 524481 5' H Cft 524482 524483 2 524484 213.1 240.1 206.5 200.5 211.8 212.3 220.9 197.8 201.9 204.5 207.3 220.8 196.0 211.4 215.9 222.9 218.6 208.5 216.6 211.6 294.3 307.0 273.0 271.7 283.6 295.5 297.1 270.7 287.3 272.8 303.2 302.2 267.6 272.2 286.3 290.0 312.5 277.9 267.6 271.5 360.1 SD (DAY 14) 358.3 SD (DAY 14) 331.7 SD (DAY 14) 325.2 SD (DAY 14) 349.7 SD (DAY 14) 353.0 411.1 SD (DAY 21) 357.7 412.5 SD (DAY 21) 328.4 368.5 SD (DAY 21) 352.6 406.2 SD (DAY 21) 319.1 358.4 SD (DAY 21) 368.6 422.4 468.2 518.7 358.1 317.5 308.3 346.2 343.9 385.2 363.1 363.1 398.3 395.6 430.8 395.8 393.4 439.9 430.3 462.5 433.4 438.6 479.2 469.5 381.3 328.7 313.5 324.5 397.2 370.8 353.5 369.4 416.1 390.6 379.1 399.6 465.0 433.7 411.4 444.6 576.4 SD (DAY 42) 494.9 SD (DAY 42) 473.4 SD (DAY 42) 487.7 SD (DAY 42) 518.0 SD (DAY 509.0 535.8 523.9 549.6 471.7 491.0 437.9 447.8 490.6 511.2 42) 558.7 531.2 518.0 468.2 541.9 63 70 49 56 577.0 565.9 541.2 480.7 558.7 616.8 SD* 593.5 SD* 580.4 SD* 512.1 SD* 591.2 SD* REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN HALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OF HALE RATS GROUP: IX CONCENTRATION: 300 PPH OF H-19704 DuPont HLR 326-95 Company Sanitized. Does not contain TSCA CBI DAIS ON TEST: 0 RECOVERY DAYS - ANIMAL # 7 14 21 28 35 42 49 56 63 70 - - 7 14 71 28 35 42 49 56 i tvoj 524485 524486 524487 215.1 230.6 201.4 221.8 239.6 232:0 279.0 SD (DAY 14) 293.0 SO (DAY 14) 284.2 SD (DAY 14) I 524488 208.6 222.5 289.7 SD (DAY 14) 524489 216.9 236.7 307.7 SD (DAY 14) 524490 215.2 248.9 279.3 348.7 SD (DAY 21) 524491 224.1 260.9 303.3 366.5 SD (DAY 21) 524492 524493 524494 524495 197.0 212.1 211.3 219.9 225.2 229.6 240.9 227.5 262.2 279.8 2/3.6 280.2 298.5 SD (DAY 331.2 SD (DAY 312.5 SD (DAY 338.5 378.0 21) 21) 71) 405.6 439.1 SD (DAY 42) 524496 224.6 286.7 333.4 380.6 416.8 439.3 474.7 SD (DAY 42) 524497 203.4 254.5 301.8 357.7 381.9 418.6 458.9 SD (DAY 42) 524498 207.0 210.8 272.5 307.8 335.8 367.6 400.7 SD (DAY 42) 524499 210.6 249.9 291.8 358.6 400.7 434.0 480.9 SD (DAY 42) 524500 524501 524502 215.1 229.3 204.2 206.6 220.6 241.0 276.2 298.7 274.7 308.7 366.8 321.7 381.0 412.1 347.3 423.0 448.1 369.4 460.4 484.1 401.3 481.1 500.9 413.7 513.9 524.8 421.2 533.6 548.0 436.8 572. i SD* 575.1 SD* 460.5 SD* 524503 209.5 248.8 297.4 362.1 399.8 433.4 468.1 493.1 511.5 544.8 549.9 SD* 524504 210.5 204.7 270.4 323.2 347.6 373.9 408.4 417.4 437.9 454.9 477.9 SD* DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY UITH H-19683 AND H-19704 IN MALE RATS APPENDIX II INDIVIDUAL CLINICAL OBSERVATIONS NR = Not resolved - 28 - Company Sanitized, Does nol contain TSCA CBJ DuPont m 3Z6>95 REPEATED DOSB ORAL T0KlClTY;14-DAT FBBDIgS STUDY ------ tftTH b -1 M M A*fa 5 - 1 W M ik MALI RAfs APPENDIX II INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP: I CONCENTRATION: 0 PPM ANIMAL NUMBER OBSERVATION 524410 524411 524412 524413 524414 524415 524416 524417 524418 524419 524420 524421 524423 PILOBRECTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION PILOERBCTION COLORED DISCHARGE NOSE BROUN PILOERBCTION PILOBRECTION PILOERBCTION FIRST DAT LAST DAT OBSERVED OBSERVED 14 21 NR 14 21 NR 14 21 NR 14 21 NR 14 14 14 14 7 42 NR 7 14 7 14 7 21 7 21 7 21 28 35 42 70 NR 14 21 42 70 NR APPENDIX II (COW.) INDIVIDUAL CLINICAL OBSERVATIONS IN HALE RATS GROUP: III CONCENTRATION: 30 PPM OP H-19683 ANIMAL NUMBER OBSERVATION FIRST DAT LAST DAT OBSERVED OBSERVBD 524425 524426 524427 524428 524429 524430 524431 524432 524433 524435 524436 524437 524438 524439 524440 524441 524442 524443 524444 PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION COLORED DISCHARGE NOSE BROWN PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION COLORED DISCHARGE NOSE BROWN PILOERECTION 14 14 NR 14 14 NR 7 14 rat 7 14 NR 14 14 NR 7 21 NR 7 21 NR 7 21 NR 7 21 NR 7 21 14 14 14 21 7 14 7 14 77 42 70 NR 7 21 7 21 42 70 NR 7 21 28 35 7 21 APPENDIX II (CONT.) INDIVIDUAL CLINICAL OBSERVATIONS IN HALE RATS GROUP: V CONCENTRATION: 300 PPM OP H-19683 ANIMAL NUMBER OBSERVATION 324445 524447 524448 524449 524450 524451 524452 524453 524454 524455 524456 524457 524458 524460 52441 524462 524463 PILOBRECTION PILOERBCTION PILOERECTION COLORED DISCHARGE NOSE BROUN PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERBCTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION FIRST DAY LAST DAY OBSERVED OBSERVED 7 14 NR 7 14 NR 77 77 77 7 21 NR 7 14 7 21 NR 7 21 NR 7 14 77 7 21 14 21 7 21 14 14 7 21 14 21 14 21 42 70 NR DuPont BLR 326-95 REPEATED POSE ORAL TOXICITY 16-DAY FEEDING STUDY WITH H-19683 AND H-1$7Q4 Pi MALE RATS APPENDIX II (OMIT.) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP: VII CONCENTRATION: 30 PPM OF H-19704 INAL NUMBER OBSERVATION FIRST DAT LAST DAT OBSERVED OBSERVED 524465 524466 524467 524468 524469 524470 524471 524472 524473 524474 524475 524478 524479 524480 524481 524482 524484 iTLOBRECTION COLORED DISCHARGE NOSE RED PILOBRECTION COLORED DISCHARGE NOSE BROWN IRREGULAR RESPIRATION PILOERECTION RAPID BREATHING PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION COLORED DISCHARGE LEFT ETE(S) BROWN COLORED DISCHARGE BOTH ETE(S) BROWN TOP TEETH CROOKED BOTTOM TEETH TOO LONG COLORED DISCHARGE NOSE BROWN PILOERECTION PILOBRECTION PILOBRECTION * Attributed to malocclusion of the teeth 7 14 NR 14 14 NR 7 14 NR 14 14 NR 14 14 NR 14 14 NR 14 14 NR 7 14 NR 7 21 NR 7 21 NR 7 21 NR 77 7 14 7 21 14 14 42 42 NR 7 14 7 14 14 14 21 21 28 70 NR 28 70 NR 28 28 28 28 7 14 28 28 7 70 NR Go,npany S a n ity - 32 - Does not contain tsc A CBl nNitttiilAli DuPont HU 326-95 REPEATED DOSB ORAL TOXICITY: STUPY ------ trtTH H-1MA3 AND H-197M ni HALE BA APPENDIX II (CONI.) INDIVIDUAL CLINICAL OBSERVATIONS IN KALE RATS GROUP: IX CONCENTRATION: 300 PPM OP H-19704 ANIMAL NUMBER OBSERVATION FIRST DAY LAST DAY OBSERVED OBSERVED 524485 524486 524487 524488 524491 524492 524493 524494 524495 524496 524498 524499 524500 524501 524502 524504 PILOERBCTION PILOERECTION PILOERBCTION RAPID BREATHING PILOERBCTION PILOERBCTION ALOPECIA LEFT HIND QUARTERS PILOERBCTION PILOERBCTION PILOERBCTION PILOERECTION PILOERBCTION HUNCHED OVER PILOERECTION PILOERBCTION HUNCHED OVER PILOERECTION PILOERECTION PILOERBCTION 7 14 NR 77 77 14 14 NR 14 14 77 7 21 NR 77 7 14 14 21 7 21 7 42 NR 77 7 14 7 21 7* 7 14 7 70 NR 7 70 NR - 33 0 0 0 3 contain TSCAcai a*t m 3 2 6 - # ;:" REPBATED DOSE ORAI TOZZCITTt 14-DAY FBEDING STUDI VITH H-19683 AND B-19704 IN MALE RATS INDIVIDUAL FINAL BODY AND ASSOLUTE LIVER WBIG8TS (g r U S ) FIMI MALE RATS GROUP I - 0 PPM TEST DAY 14 ANIMAL NUMBER RECOVERY DAY 0 FINAL BODY VT LIVER VT 524405 524406 524407 524408 524409 297.8 351.2 295.5 314.1 362.8 11.295 15.157 10.371 12.451 14.499 GROUP MEAN STD. DEV. 324.3 31.0 12.755 2.044 TEST DAY 21 524410 524411 524412 524413 524414 RECOVERY DAY 7 382.8 16.752 357.3 14.358 376.2 15.408 402.3 19.036 361.2 15.753 GROUP MEAN STD. DBV. 376.0 18.1 16.261 1.771 TEST DAY 42 524415 524416 524417 524418 524419 GROUP MEAN STD. DEV. RECOVERY DAY 28 454.3 17.501 496.0 17.432 453.0 18.374 428.3 17.882 489.6 17.495 464.2 28.1 17.737 0.398 TEST DAY 70 524420 524421 524422 524423 524424 RECOVERY DAY 56 661.4 26.406 599.4 19.284 648.5 26.333 641.6 22.212 557.1 18.097 GROUP MFAN 621.6 22.466 ! STD. DEV. 42.9 3.865 I j f i I - 35 - TsACfi| REPEATED DOSB ORAL ITB R-19683 TOn AND <jIT!i- l H-19704 I^NI .fP HALB Ss ATS INDIVIDUAL FIP1L BOOT AND ABSOLUTE U V E R T O U R I S <fr-- > FROM HALE RATS GROUP III - 30 PPM TEST DAT 14 RECOVERY DAY 0 ANIMAL NUMBER 524425 524426 524427 524428 524429 GROUP MEAN STD. DEV. TEST DAY 21 524430 524431 524432 524433 524434 GROUP MEAN STD. DEV. TEST DAY 42 524435 524436 524437 524438 524439 GROUP MEAN STD. DEV. TEST DAY 70 524440 524441 524442 524443 524444 GROUP MEAN STD. DEV. FINAL BODY VT LIVER VT 346.3 384.3 304.6 305.1 355.2 15.729 17.457 12.963 13.771 15.572 339.1 34.3 15.098 1.768 r e c o v e r y DAY 7 354.9 14.495 396.6 18.471 349.5 13.976 365.0 15.116 376.6 14.003 368.5 18.8 15.212 1.880 RECOVERY DAY 28 535.8 24.960 459.0 16.385 409.8 15.757 433.1 15.773 494.8 21.060 466.5 50.0 18.787 4.102 RECOVERY DAY 56 527.6 20.851 637.1 22.618 502.1 19.299 567.1 20.447 576.8 18.393 562.1 51.6 20.322 1.607 " `""'" ''Wlta*. d 9s rofcontain Tsca CBe 36 - a*TM m 'fz s r s TEST DAY 14 RECOVERY DAY 0 ANIMAL NUMBER FINAL BODY VT LIVER VT S2444S S24446 524447 524448 524449 314.6 362.4 314.3 302.0 331.6 15.040 15.836 12.844 12.747 13.820 GROUP MEAN STD. DEV. 325.0 23.4 14.057 1.358 TEST DAY 21 524450 524451 524452 524453 524454 RECOVERY DAY 7 353.8 403.4 14.631 19.682 326.7 337.1 354.3 13.636 15.003 14.772 GROUP MEAN STD. DEV. 355.1 29.4 15.545 2.371 TEST DAY 42 524455 524456 524457 524458 524459 RECOVERY DAY 28 459.5 503.4 19.50 19.180 439.2 446.0 17.045 14.867 536.6 22.140 GROUP MEAN STD. DEV. 476.9 41.7 18.555 2.743 TEST DAY 70 524460 524461 524462 524463 524464 RECOVERY DAY 56 534.1 20.47B 565.5 635.0 612.6 540.7 23.355 28.756 21.269 20.430 GROUP MEAN STD. DEV. 577.6 44.5 22.85B 3.504 raoM " " - 37 - B* * m **TM a . 0Ms no`contain TSCACBI INDIVIDUAL PINAL BODY AND ABSOLUTE LIVER VEIGBTS (gru) PRON HALE RATS GROUP VII - 30 PPM TEST DAY 14 RECOVERY DAY 0 animal NUMBER 524465 524466 524467 524468 524469 GROUP MEAN STD. DEV. TEST DAY 21 524470 524471 524472 524473 524474 GROUP MEAN STD. DEV. TEST DAY 42 524475 524476 524477 524478 524479 GROUP MEAN STD. DEV. TEST DAY 70 524480 524481 524482 524483 524484 GROUP MEAN STD. DEV. fikal BODY VT LIVER VT 360.1 358.3 331.7 325.2 349.7 345.0 15.8 21.718 21.003 19.086 2C.790 20.892 20.698 0.972 RECOVERY DAY 7 411.1 23.372 412.5 24.361 368.5 24.350 406.2 21.810 358.4 19.661 391.3 25.8 22.711 1.998 RECOVERY DAY 28 576.4 23.014 494.9 22.983 473.4 20.776 487.7 18.919 518.0 19.864 510.1 40.4 21.111 1.844 RECOVERY DAY 56 616.8 25.762 593.5 20.008 580.4 20.143 512.1 19.507 591.2 21.592 578.8 39.6 21.402 2.558 I { DuPont B U 326-95 REPEATED DOSB ORAL **** WITH H-19683 AND H-19704 IN MALE HATS INDIVIDUAL FINAL BODY AND ABSOLUTE LIVER WEIGHTS (grans) P10M MALE RATS GROUP II - 300 PPM TEST DAT U nemvERY DAY 0 ANIMAL NUMBER 524485 524486 524487 524488 524489 GROUP MEAN STD. DEV. TEST DAY 21 524490 524491 524492 524493 524494 GROUP MEAN STD. DEV. TEST DAY 42 524495 524496 524497 524498 524499 GROUP MEAN STD. DEV. FINAL BODY VT LIVER VT 279.0 293.0 284.2 289.7 307.7 23.269 22.664 21.723 24.453 26.260 290.7 10.9 23.674 1.752 RECOVERY DAY 7 348.7 22.845 366.5 22.413 298.5 21.230 331.2 21.836 312.5 21.845 331.5 27.3 22.034 0.617 RECOVERY DAY 28 439.1 21.474 474.7 22.941 458.9 19.103 400.7 19.567 480.9 23.084 450.9 32.4 21.234 1.852 TEST DAY 70 524500 524501 524502 524503 524504 GROUP MEAN STD. DEV. RECOVERY DAY 56 572.2 20.888 575.1 24.770 460.5 16.900 549.9 16.648 477.9 19.969 527.1 54.1 19.835 3.326 - 39 - Does n* c nt*in TSCA CBl D uPont BLU 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY u t t h H-146113 AND H-19704 IN KALE RATS APPENDIX III (CONT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS RELATIVE LIVER WEIGHTS IX of body weight) FROM MALE RATS GROUP I - 0 PPM SACRIFICED (DAYS OF RECOVERY) 0 0 0 0 'J 1 2F 28 28 28 28 56 56 56 56 56 ANIMAL NUMBER 524405 524406 524407 524408 524409 GROUP MEAN STD. DEV. 524410 524411 524412 524413 524414 GROUP MEAN STD. DEV. 524415 524416 524417 524418 524419 GROUP MEAN STD. DEV. 524420 .524421 524422 524423 524424 group mean STD. DEV. LIVER 3.7928 4.3158 3.5096 3.9640 3.9964 3.916 0.295 4.3762 4.0185 4.0957 4.7318 4.3613 4.317 0.281 3.8523 3.5145 4.0561 4.1751 3.5733 3.843 0.290 3.9924 3.2172 4.0606 3.4620 3.2484 3.596 0.405 Con>panyS a n itiz e - 40 - noi contain TSCA CSf DuPont BU 326-95 REPEATED DOSE ORAL TOXIOTY. 1A-UAY PTOS STUDY Iim AMD H-19704 IN MALE RATS APPENDIX III (COWT.j INDIVIDUAL ANIMAL PINAL BODY AND LIVER WEIGHTS SACRIFICE (DAYS OF RECOVER*) nV . o V AV nV 0 7 7 7 7i 7 o9 ft A9 Ofl A9 fOt 9 0ft 28 56 56 56 56 56 ANIMAL NUMBER 524425 524426 524427 524428 524429 GROUP MEAN STD. DEV. 524430 524431 524432 524433 524434 GROUP MEAN STD. DEV. 524435 524436 524437 524438 524439 GROUP MEAN STD. DEV. LIVER 4.5420 4.5425 4.2557 4.5136 4.3840 4.448 0.126 4.0842 4.6573 3.9989 4.1414 3.7183 4.120 0.341 4.6585 3.5697 3.8450 3 6419 4.2563 3.994 0.457 524440 . 524441 524442 524443 524444 3.9520 3.5501 3.8437 3.6055 31888 GROUP MEAN 3.928 STD. DEV. 0.296 tscacbi DuPont HUt 326-95 REPEATED DOSE ORAL TOXICITYi 14-DAY FEEDING STUDY WITH H-19683 AND B-19704 IN MALE RATS APPENDIX III (CONT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS RELATIVE LIVER WEIGHTS (X of body weight) FROM HALE RATS GROUP V - 300 PPM OF H-19663 SACRIFICE (DAYS OF RECOVERY) 0 0 0 0 0 7 7 7 7 7 28 28 28 28 28 56 56 56 56 56 ANIMAL NUMBER 524445 524446 524447 524448 524449 GROUP MEAN STD. DEV. 524450 524451 524452 524453 524454 GROUP MEAN STD. DEV. 524455 524456 524457 524458 524459 GROUP MEAN STD. DEV. 524460 524461 524462 524463 524464 GROUP MEAN STD. DEV. LIVER 4.7807 4.3698 4.0865 4.2209 4.1677 4.325 0.275 4.1354 4.8790 4.1739 4.4506 4.1693 4.362 0.316 4.2535 3.8101 3.8809 3.3334 4.1260 3.881 0.355 3.8341 4.1300 4.5285 3.4719 3.7784 3.949 0.400 - 42 - tQoiconia/Q Ts A cBi Hit 326-95 REPEATED DOSB ORAL TOXICITY 14-DAY FEEDING STUDY WITH E-19683 AND H-19704 IN HALE RATS APPENDIX III (PONT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS BBI.ATTWR LIVER WEIGHTS CX-of body weight) FROM MALE RATS r.&nilP VII - 30 PPM OF B-19704 IFICED 1RECOVERY) ANIMAL NUMBER LIVER o 524465 6.0311 o 524466 5.8618 o 524467 5.7540 o 524468 6.3930 0 524469 5.9743 GROUP MEAN 6.003 STD. DEV. 0.243 #7 524470 5.6852 7 524471 5.9057 7 524472 6.6079 7 524473 5.3693 7 524474 5.4858 GROUP MBAN STD. DEV. 5.811 0.490 2P 524475 3.9927 28 524476 4.6440 28 524477 4.3887 28 524478 3.8792 28 524479 3.8347 GROUP MEAN STD. DEV. 4.1 >8 0.353 56 524480 4.1767 56 524481 3.3712 56 524482 3.4705 56 524483 3.8092 56 524484 3.6522 GROUP MBAN STD. DEV. 3.696 0.317 `Wilted. I l! DuPont BUI 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS APPENDIX III (CONT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS -ELATIVE LIVER WEIGHTS (X of body weight) FROM MALE RATS t.*OUp IX - 300 PPM OF H-19704 SACRIFICED (DAYS OF RECOVERY) 0 0 0 o 0 7 7 7 7 28 28 28 28 28 56 56 56 56 56 ANIMAL NUMBER 524485 524486 524487 524488 524489 GROUP MEAN STD. DEV. 524490 524491 524492 524493 524494 GROUP MEAN STD. DEV. 524495 524496 524497 524498 524499 GROUP MEAN STD. DEV. .524500 524501 524502 524503 524504 GROUP MEAN STD. DEV. LIVER 8.3401 7.7352 7.6436 8.4408 8.5343 8.139 o.4i ; 6.5515 6.1154 7.1122 6.5930 6.9904 6.673 0.396 4.8905 4.8327 4.1628 4.8832 4.8002 4.714 0.310 3.6505 4.3071 3.6699 3.0275 4.1735 3.767 0.508 - 44 potoPsny Saniti. " *.0oes notcontain TSca Cb i I APPENDIX IV Trirr>tomai P1.II0RIDE CONCENTRATIONS i HLR 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS APPENDIX IV INDIVIDUAL FLUORIDE CONCENTRATIONS (PPM) FOUND IN THE BLOOD OF HALE RATS TREATED WITH H-19683 OR H-19704 GROUP # X CONCENTRATION OF TEST SUBSTANCE 0 PPM (CONTROLS) III 30 PPM OF H-19683 * V 300 PPM OF B-19683 TEST RECOVERY DAYS DAYS 14 0 14 0 14 0 14 0 14 0 21 7 21 7 21 7 21 7 21 7 14 0 14 0 14 0 14 0 14 0 7 t7 21 7 21 7 21 7 14 0 14 0 14 0 14 0 14 0 21 7 21 ' 7 21 7 21 7 21 t RAT * 101 102 103 104 105 106 107 108 109 110 301 302 303 304 305 306 307 308 309 310 501 502 503 504 505 506 507 508 509 510 PPM IN BLOOD 0 (BLANK) 0.32 0.14 0.35 0.39 0.45 0.37 0 (BLANK) 0 (BLANK) 1.99 3.91 4.85 4.47 5.21 8.04 1.30 0.34 0 (BLANK) 0 (BLANK) 0.09 6.87 1.26 4.76 15.09 6.99 0 (BLANK) 0.25 0.63 0.70 0.68 - 46 - 00ft'Shot mco/tfi Tsq*C B , REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY UITB H-19683 AND 1-19704 IN HALE RATS APPENDIX IV (Continued) INDIVIDUAL FLUORIDE CONCENTRATIONS (PPM) POUND IN THE BLOOD OF HALE RATS TREATED WITH H-19683 OR H-19704 GROUP # CONCENTRATION OF TEST SUBSTANCE VII 30 PPM OF H-19/04 IX 300 PPM OF H-19704 TEST RECOVERY DAYS DAYS 14 0 14 0 14 0 14 0 14 0 21 7 21 7 21 7 21 7 21 7 14 0 14 0 14 0 14 0 14 0 21 21 t 21 21 21 RAT * 701 702 703 704 705 706 707 708 709 710 901 902 903 904 905 906 907 908 909 910 PPM IN BLOOD 38.19 27.83 33.99 33.52 32.62 14.09 25.88 27.10 17.44 11.81 64.51 67.41 54.44 101.58 69.65 25.52 20.26 22.66 18.42 23.16 l