Document jmkamrMNdoL3xaMr0rm4e6w32

AR226-2799 Study Title Repeated Dose Oral Toxicity: 14-Day Feeding Study vith H-19683 and B-19704 in Hale Rats Author John V. Sarver g-'^dy r:np3eted On May 15, 1995 Performing Laboratory Haskell E. I. du Font de Nemours and Company Laboratory for Toxicology and Industrial Elkton Road, P. 0. Box 50 Newark, Delaware 19714 Medicine Laboratory Project ID Baskell Laboratory Report No. 326-95 cmw'l""?eA^-'"..^CB, Page 1 of 47 Substance Tested: Synonyms/Codes: GENERAL INFORMATION FOR H-19683 DuPont HLR 326-95 Physical Form: Contaminants: Purityi CAS Registry No.; Substance Tested: Synonyms/Codes; Octanoic acid, pentadecafluoro-. ammonium salt H-19704 C-8 , Ammonium per fluorooctanoate Physical Form: Purity: CAS Registry No.: Sponsor: Study Initiated - Completed; In Life Phase Initiated - Completed; DuPont Fibers and DuPont Speciality Chemicals E. I, du Font de Nemours and Vilmington, Delaware C&apany 8/28/92 - 5/15/95 9/16/92 - 11/25/92 Company Sanitized. Does not contain TSCA CBI 2 - - DuPont BLR 326-95 REPEATED DOSE ORAL TOXICITY; 14-DAY FEEDING STUDY ----------WITH H-1966J AND H-1970A 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 when incorporated into nutritionally adequate chow and fed to male rats for 14 consecutive days. Groups of 20 Bale rats each were fed diets containing either 30 or 300 pp of H-19683 or 30 or 300 ppm of H-19704. Rats vcre sacrificed at the end of the 14-day feeding period and on recovery days 7, 28, and 56 and livers reaoved and weighed. Blood samples -/ere taken for fluorlde 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, rd 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 weights were observed in rats from the 30 and 300 ppm dose groups of H-19704 sacrificed at the end of the feeding period and OP recovery days 7 and 28. Significantly increased mean relative liver weights 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. III Mean blood fluoride concentrations of rats sacrificed on recovery were 0.30 ppo in control rats, 5.30 ppm in group rats (30 ppn of H-19683), 8.19 ppm in group V rats (300 ppm of H-19683), 33.23 ppc in VII rats (30 ppm of H-19704), and 71.52 ppn in group IX rats (300 ppm H-19704). On recovery day 7, mean blood fluorlde concentrations vere day 0 group of III, 0.94 ppm for controls, 0.58 for group 0.56 ppffl for group V, 19.26 ppa for group VII, and 22.20 ppm for group IX. No other blood was analyzed for fluoride concentration. Company Sanitized. Does not contain TSCA CB1 DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY; 14-DAY FEEDING STUDY ----------WITH 8-1968J AND H-l^ IN MALE HATS-------- vor< by: ^Q^L4/ CL. ^^7] ^JiMj^-^ TracyA. Filliben---- VJ qTi^o--xJic_o_1lo^g__y. TT^e^cLhknJi^cJi^a--n --~John v^ Reviewed and Approved for :5<?ue: i jCTQ'----^ ^ ^<'' ^J QctTW^-^ y.Sarver Toxicologist Study Director ^^_t^l^'s JVS/alv Company Sanmied. D""oews nont. contain TSCACBJ - 4 DuPont BLR 326-95 REPEATED DOSE ORAL :CXICITY! 14-DAY FEEDING STUDY ----------WITH H-19683 AMD H-1970A IN MALE RATS-------- INTRODUCTION The purpose of this study was to evaluate the repeated oral dose toxicity and bioretentivity of H-19683 or H-1970A when incorporated into nutritionally adequate chow and fed to male Crl:CD*BR rats for 14 consecutive days. The diet concentrations of H-19683 (3", or 300 ppm) and H-1970A (30, or 300 ppa) were specified by the sponsor. The dietary route of administration was selected because it is a potential route of human exposure. MATERIALS AND HETHODS A. Test Substance The test substances -.ere supplied by DuPont Fibers and DuPont Speciality Chemicals, E. I. du Font de Nemours and Company, Vilmington, Delaware. Available information about the identity, purity, composition, stability, and toxicity of H-19683 and H-1970A vas provided by the sponsor. B. Test Species On 9/8/92, 109 male Cr^CD^R rats, approximately 6 weeks old, were received from Charles River Laboratories, Inc., Kingston, New York. At study start, the body weights ranged from 196.0 to 240.1 grams. The Crl!CD*BB rat was selected on the bases of extensive experience with this strain and its suitability vith respect ;o hardiness, longevity, sensitl->'i'y, and low incidence of spontaneous diseases. C. Quarantine Upon arrival at Haskell Laboratory, all rats were removed from shipping cartons and housed singly in stainless steel, vire-mesh cages suspended above cage Board (DACB) or R-2 Reemay-backed cage boards. The rats were fed Ground Purina* Certified Rodent Chov #5002 and vater was available ad libitun. Each rat was assigned a temporary identification number which was recorded on a card affixed to the cage. The animals were weighed 3 times during the quarantine period and were observed daily for any gross signs of disease or injury. On the basis of body weights and clinical observations, all rats were released from quarantine on 9/16/92 by the laboratory veterinarian. Company Sanitized. Does not contain TSCA CBI DuPont BLR 326-95 D. Assignnent to Groups After release from quarantine, 100 rats selected on the basis of body weight gain and freedom froa any clinical signs of disease or injury, were distributed by coBputerized-stratified randomization into five experlwntal groups of 20 rats each. No stati-tically significant differences in group body weight Beans 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 was individually identified by a 3-digit identification number harked an the tail with water insoluble ink. Additionally, each rat was assigned a unique 6-digit Raskell animal number. All rats were individually housed in stainless steel, vire-aesh cages suspended above UpJohn DACB cage boards. GROUP NO. IDENTIFICATION NUMBERS__ 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 was also assigned a unique 6-digit Haskell Number Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the room were targeted for a temperature of 23 2"C and relative humidity of 50Z 10X. 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 GFCRC (Ground Purina Certified Rodent Chow 15002) diet that contained 0, 30, or 300 ppm of F-19683 or 30 or 300 ppm of H-19704 (not adjusted for purity). ^Paoy'. s'^0-^ 6 - DuPont BLR 326-95 The study design vas as follows: Group Numbers Dietary Concentrations (ppm) IIII 0 (Control) 30 ppo of H-19683 V 300 ppo of H-19683 VII 30 ppm of H-19704 IX 300 ppo of H-19704 For both diet concentrations prepared vith B-19704, the appropriate amount of H-19704 was added to GPCRC and thoroughly mixed for 3 minutes in a Hobart high speed oixer. For each diet concentration prepared with H-19683, the appropriate amount of H-19683 was first added to a small amount of ground chow and mixed by hand until it appeared homogenous. The hand mixed portion was then added to the remainder of the ground chov weighed out for thc diet in a Hobart high speed mixer and vas mixed for approximately 3 minutes. After mixing, the diet was visually inspected to ensure it was free of clumps. The control diet was also mixed for the same period of time. Diets were prepared once for the two week feeding period and were stored refrigerated until used. Samples for concentration, homogeneity, and stability were taken for analysis at a later date if deemed necessary by the study director. G. Body Weights All rats were 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 vas 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 were anesthetized by chloroform anesthesia and blood vas collected for fluoride concentration analysis. After blood collection, the rats vere euthanatized by chloroform anesthesia and exangulnation. The livers vere collected and vere veighed for liver weight/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. Company Sanitized. Does not contain TSCA CBI 7 - DuPont BLR 326-95 J. Pluoride Concentration Analysis Blood collected frou rats sacrificed at the end of the 14-day feeding period and on day 7 of the recovery period were analyzed for flouried concentration by personnel from Jackson Laboratory, Chambers Works. STATISTICAL ANALYSES Body weights, body weight gains, and organ weights were analyzed by a one-way analysis of variance. When the test for differences aaong test group cans (F test) was significant, palrwise comparisons between test and control groups were made with the Dunnett's test. Bartlett's test for hosogeneity of variances was performed on the organ weight data. Significance was Judged at alpha =0.05. RECORDS AND SAMPLE aBTEHTIOH All original records and the final report were retained at Haskell Laboratory or at the Records Management Center. E. I. du Font de Nemours and Company, Wilmington, Delaware. RESULTS AND DISCUSSION A. Diet Sanple Analysis All diets prepared appeared to be thoioughly mixed. No cluops 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 alight Gains (Tables 1-2; Appendix I) Statistically significant decreases in mean body weights were observed in rats froa the 300 ppn 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 weight gain of rats from the H-19683 30 ppa dose group was significantly increased during the interval 14-21 days on test compared to controls. C. Clinical Observations (Appendix II) No oortalities were observed during the study. Piloerection 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 DuPont HLB 326-95 presence of the clini:al signs is unknown. Clinical signs of toxicity noted in test rats exposed -o 30 or 300 ppa H-19704 included irregular respiration, rapid breathing, red nasal discharge, and hunched posture. of toxicity vere observed in rats treated with H-19683. No clinical signs D. Mean Final Body a--.d Organ Weights (Table 3, Appendix III) \ Statistically sif-.ificant increases in mean relative liver weights vere observed in rats froir 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 vere observed in these ra'; during the study. Statistically si^-.ificant increases in oean absolute liver weights were observed in rats fron r.he 30 and 300 ppo dose groups of H-1970A sacrificed at the end of the feed.-.; period and on recovery days 7 and 28. Significantly increased mean relari-s liver weights were observed in rats froa the 30 and 300 ppn dose groups :: H-19704 sacrificed at the end of the feeding period and on recovery day * Additionally, the 300 ppffl dose group rats sacrificed on recovery day 26 'r.s.: significantly increased mean relative liver weight. E. Mean Fluoride Cc-ientrations Found in r e Blood of Rats (Table 4, Append:. IV) III Mean blood luc--'-:9 concentrations observed on recovery day 0 were 0.30 ppm in control :i'.s, 5.30 ppm in Group rats (30 ppm of H-19683), 8.19 ppm in Gnup V :i'.s (300 ppm of H-19683), 33.23 ppm in Group VII rats (30 ppm of H-19704). ind 71.52 ppm in Group IX rats (300 ppa of H-19704). On recovery day 7, mea- :lood fluoride concentrations vere 0.94 ppa for group I, 0.58 ppm for group ::'. 0.56 ppn for group V, 19.26 ppm for group VII, and 22.20 ppm for group :'.'. No other blood was analyzed for fluoride concentration. cotttp^s^^^. ^co^nTSc^ 9 - DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY --------WITH H-J96B3 AND H-J^04 IN MAU-RATS-------- TABLES GROUP ARE DEFINED -.:: Group I - I I G r o u p - Group V - Gr"-'o VII - G IV - 0 ppm - Controls 30 ppf :f H-19683 300 ppc of H-19683 30 ppit :f H-19704 300 ppc of H-19704 ^~i^wD~^,,, 10 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS TABLE 1 MEAN BODY WEIGHTS OF MALE RATS MEAN BiODY WEIGHT;S ( S) GROUP: I CONC. (PPM): 0 III V VII IX 30 300 30 300 DAY!S ON TlBST DAYS ON RECOVERY 0 7 ' 14 T 21 fi 28 g 35 42 *< CA 49 56 gs 63 N (O 70 p. 212.3( 9.5)' 211 .!( 8.2) 214.2(10. 0) 211.9(10. ?.) 213 3( 9.0) 278.3(13.5) 278 .7(14.5) 272.4(15. 0) 285.2(14. 4) 235 .5(19.8)" -- 329.7(20.7) 324 .1(25.1) 320.1(21. 5) 341.3(20. 2) 287 .4(16.5)" 7 375.5(24.1) 373 .8(26.4) 370.1(29. 0) 385.0(22. 5) 338 .9(26.0)' 14 408.9(30.2) 401 .3(35.1) 413.8(32. 5) 414.4(27. 7) 380.1(28.5) 21 448.0(35.9) 432 .4(39.5) 447.0(36. 1) 455.7(30.2) 411 .3(30.6) 28 489.6(41.2) 471 .1(44.8) 484.7(39.0) 498.4(37. 1) 447 .7(33.1) 35 537.3(37.3) 496.8(43.4) 508.2(44. 5) 507.1(40.1) 461 .2(42.3) 42 562.6(40.7) 517 .5(43.6) 528.4(47. 1) 523.6(34. 4) 481 .9(48.4) 49 586.4(43.1) 536 .0(46.5) 551.6(47. 3) 544.7(38. 1) 503 .6(53.4) 56 621.6(42.9) 562 .1(51.6) 577.6(44. 5) 578.8(39. 6) 527 .1(54.1) | a Standard deviation is reported in pai-eritheses Statistical methods: One-way AOV and Dunnett's tests were performed on sr 5" weekly interval data. (See Statistical Analyses) CO P Statistically significant difference from control at alpha =0.05 > 0 0; REPEATED DOSE URAL TOXICITY: 14-DAY FEEDING STUDY VITH H-19683 AND H-19704 IN MALE RATS TABLE 2 MEAN BODY WEIGHT GAINS OF MALE RATS MEAN E10DY WEI G1IT G<MNS (g) GROUP: I 01C. (PPM): 0 DAYS ON TEST DAYS ON RECOVERY II II I V V IX 3 0 300 3 0 300 0- 7 7-14 14-21 21-28 28-35 35-42 42-49 49-56 56-63 63-70 0-70 -- 0-7 7-14 14-21 21-28 28-35 35-42 42-49 49-56 66.0(13.1)51.4(11.8) 44.0(14.1) .33.6( 9.2) 39.!( 9.6) 41.6( 8.0) 22.3( 1.6) 25.3( 4.8) 23.8( 5.4) 35.2( 9.3) 67. 7( 8.9) 45. 4(111.8) 54. 6( 7.7)* 24. 9( 7.0) 31. 1( 6.1) 38. 7( 7.4) 21. 1( 1.9) 20. 7( 3.3) 18. 6( 6.9) 26. 1< 6.7) 58.3(1.2 .2) 47.6( 9 .3) 51.7( 8 .9) 36.1( 33.2( 37.6( 15.9( 20.2( 23.2( 26.0( 9.5) 6 .7) 5 .0) 7 .9) 5 .4) 1 .3) 8 .6) 406.8(49.7) 351.0(.'6.2) 363.7(54 .0) 73. 3(11.1) 56. K 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. K 8.5) 34. K 5.3) 363. 2(38.8) 22.K19.P) 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 paLeiiiliusus Statistical methods: One-way AOV and Dunnett's tests were performed on both weekly and summary interval data. (See Statistical Analyses) Statistically significant difference from control at alpha = 0.05. DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN HALE RATS TABLE 3 H-19683 TEST DAY 14 RECOVERY DAY 0 MEAN FINAL BODY AND LIVER WEIGHTS PROM 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) NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grams) GROUP I III V CONCENTRATION LIVER (PPH) 0 12.755 (2.044) 30 15.098 (1.768) 300 14.057 (1.358) MEAN RELATIVE LIVER WEIGHTS (% of body weight) GROUP I III V CONCENTRATION (PPM) 0 30 300 LIVER 3.916 (0.295) 4.448 (0.126)# 4.325 (0.275)# STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) t - SI3NIFICAKTLY DIFFERENT (P<0.05) DlINNETT'S TEST. FROM CONTROL GROUP BY LSD FROM CONTROL GROUP BY LSD AND Company Sanitized. Does not contain TSCA CBI 13 - DuPoot BUt 3)6-99 REPEATED DOSE ORAL TOXICTTYl 14-DAY FEEDING STUDT | VITH H-19683 AND B-19704 IN MALE RATS TABU; 3 (CWTINUBD) H-1^683 TEST DAT 21 RECOVERY DAT 7 MEAN FINAL BOOT AND LIVER WEIGHTS PROM MALE RATS MEAN FINAL BOOT WEIGHTS (grams) GROUP I III V CONCENTRATIO'; (FPM) 0 30 300 FINAL BOOT 376.0 ( 18.1) 368.5 ( 18.8) 355.1 ( 29.4) NUMBER OF ANIMAL;; 5 5 5 MEAN ABSOLUTE LIVER --EIGHTS (grams) GROUP I III V CONCENTRATION LIVER (PPM) 0 16.261 (1.771) 30 15.212 (1.880) 300 15.545 (2.371) MEAN RELATIVE LIVER EIGHTS (X of body weight) GROUP I III V CONCENTRATIOS (PPM) 0 30 300 LIVER 4.317 (0.281) 4.120 (0.342) 4.362 (0.316) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BT LSD - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST. 14 - Company Sanitized. Does not contain TSCA CBI REPEATED DOSE ORAL TOXICITT: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN HALE RATS TABLE 3 (CONTINUED) H-19683 TEST DAT 42 RECOVERY DAT 28 NBAN FINAL BODY AND LIVER WEIGHTS FROM HALE RATS MEAN FINAL BODY WEIGHTS (grass) GROUP I III V CONCENTRATION (PPH) 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 I III V CONCENTRATION LIVER (PPH) 0 17.737 (0.398) 30 IB.787 (4.102) 300 18.555 (2.743) MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I III V CONCENTRATION (PPM) 0 30 300 LIVER 3.834 (0.290) 3.994 (0.457) 3.881 (0.355) 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. Company Sanitized. Does not contain TSCA CBI 15 - DuPoot RJt 326-99) REPEATED DOSE ORAL TOnCITT: 14-DAY FBBnNG STUDT WITH B-19683 AND H-19704 IN MALE RATS TABLE 3 (COOTINUED) H-19683 TEST DAT 70 RECOVERY DAY 56 MEAN FINAL BODY AND LIVER VEIGBTS FROM HALE RATS MEAN FINAL BODY VEIGBTS (gram) GROUP I III V CONCENTRATION (PFM) 0 30 300 FINAL BODY 621.6 ( 42.9) 562.1 ( 51.6) 577.6 ( 44.5) NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (graas) GROUP T III V CONCENTRATION LIVER (PPM) 0 22.466 (3.865) 30 20.322 (1.607) 300 22.858 (3.504) MEAN RELATIVE LIVEP VEIGBTS (X of body weight) GROUP I III V CONCENTRATION (PPM) 0 30 300 LIVER 3.596 (0.405) 3.628 (0.296) 3.949 (0.400) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP B7 LSD AND DUNNBTT'S TEST. Company Sanitized. Does not contain TSCA CBI 16 - DuPont % BUI 326-95 REPEATED DOSE ORAL TOXICITT: U-DAT FEEDING STUDY WITH H-19683 AMD H-19704 IH MALE RATS TABLE 3 (CONTINUED) H-19704 TEST DAT 14 RECOVERY DA? 0 MEAN FINAL BODY AND LIVER WEIGHTS FROM HALE RATS MEAN FINAL BODY WEIGHTS (grass) GROUP CONCENTRATION (PPM) FINAL BODY 1 0 VII 30 IX 300 324.3 ( 31.0) 345.0 ( 15.8) 290.7 ( 10.9) NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVER WEIGHTS (grams) GROUP I VII IX CONCENTRATION LIVER (FPM) 0 12.755 (2.044) 30 20.698 (0.972)* 300 23.674 (1.752)# HEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I VII IX CONCENTRATION (PWO 0 30 300 LIVER 3.916 (0.295) 6.003 (0.243)t 8.139 (0.4l7)# STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) - SIGNIFICANTLY DIFFERENT (P<0.05) DUNMETT'S TEST. FROM FROM CONTROL GROUP BY LSD CONTROL GROUP BY LSD AND Company SanWzed. Does not contain TSCACBI 17 - REPEATED DOSE ORAL TOnCTTTt U-DAT FEEDING STUDY tfITH H-19683 AID B-1970A HALE RATS TABLE 3 (COOTINUED) H-19704 TEST DAT 21 RECOVERY DAY 7 MEAN FINAL BODY AND LIVER WEIGHTS FROM HALE RATS MEAN FINAL BODY VBIGHTS (grass) GROUP CONCENTRATION (PPM) FINAL BODY I 0 VII 30 IX 300 376.0 ( 18.1) 391.3 < 25.8) 331.5 ( 27.3) NUMBER OF ANIMALS HEAN ABSOLUTE LIVER WEIGHTS (grus) GROUP I VII IX CONCENTRATION LIVER (PPN) 0 16.261 (1.771) 30 22.711 (1.998) 300 22.034 (0.617) MEAN RELATIVE LIVER WEIGHTS (X of body weight) GROUP I VII IX CONCENTRATION (PPM) 0 30 300 LIVER 4.317 (0.281) 5.811 (0.490)* 6.673 (0.396X STANDARD DEVIATION IN PARENTHESES 4 - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST. Company Sanitized. Does not contain TSCA CBf 18 - Dufoot HUl 326-95 REPEATH) DOSE ORAL TOXICITTi 14-DAY FEEDING 51001 ITH H-19683 AND H-19704 IN HALE BATS TABLE 3 (CWTWJSD) 3-19704 TEST DAT 42 RECOVERY DAT 28 MEAN FINAL BOOT AND LIVER VEIGBTTS PROM HALE RATS HEAN FINAL BOOT WEIGHTS (graas) GROUP I VII IX CONCENTRATION (PPM) 0 30 300 FINAL BODY 464.2 ( 28.1) 510.1 ( 40.4) 450.9 ( 32.4) NUMBER OF ANIMALS 5 5 5 MEAN ABSOLUTE LIVE? WEIGHTS (grans) GROUP I VII IX CONCENTRATICN LIVER (PPM) 0 17.737 (0.398) 30 21.111 (1.844) 300 21.234 (1.852)* MEAN RELATIVE LIVE;. /EIGHTS (Z of body weight) 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 + - SIGNIFICANTLY DIFFERENT (P<0.05) t - SIGNIFICANTLY DIFFERENT (P<0.05) DUNNETT'S TEST. PROM CONTROL GROUP BT FROM CONTROL GROUP BT LSD LSD AND Company Sanitized. Does not contain TSCA CBl 19 - .._..........^......^-. ....-^ ..,.,..^^....^^^.^.0^^^^ . .,J DuPont BLR 326-95 REPEATED DOSE ORAL TOXICTTYt 14-DAY FEEDING 51(10? WITH H-19683 AND H-19704 IN MALE RATS TABLE 3 (CWTINUED) H-19704 TEST DAT 70 RECOVERY DAT 56 MEAN FINAL BOD? AND LIVER WEIGHTS FROM MALE RATS MEAN FINAL BODY WEIGHTS (grass) 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 (grass) GROUP I VII IX CONCENTRATION LIVER (PPM) 0 22.466 (3.865) 30 21.402 (2.558) 300 19.835 (3.326) MEAN RELATIVE LIVER WEIGHTS (Z of body weight) GROUP I VII IX CONCENTRATION (PPM) 0 30 300 LIVER 3.596 (0.405) 3.696 (0.317) 3.767 (0.508) STANDARD DEVIATION IN PARENTHESES * - SIGNIFICANTLY DIFFERENT (P<0.05) * - SIGNIFICANTLY DIFFERENT (P<0.05) DUNNETT'S TEST. FROM CONTROL GROUP BY FROM CONTROL GROUP BY LSD LSD AND Company Sanitized. Does not contain TSCA CBl DuPont BLR 326-99 REPEATED DOSE ORAL TOXICITTi 14-DAY FEEDING STUDY Vrra H-19683 AND H-1970A IN MALE BATS TABLE MEAN FLUOBIDE CONCENTRATIONS (PPM) FOUND IN THE BLOOD OF MALE BATS TREATED WITH H-19683 08 H-19704 GROUP _____ I III V VII IX CONCENTRATION OF TEST SUBSTANCE 0 PPM (CONTROLS) 30 PPM OF H-19683 300 PPM OF H-196B3 30 PPM OF H-19704 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-1970A IX 300 PPM OF H-1970A RECOVERY DAYS _________ 7 7 7 7 7 MEAN FLUORIDE CONCENTRATION ________(PPM)_______ 0.30 5.30 8.19 33.23 71.52 0.94 0.58 0.56 19.26 22.20 Company Sanitized. Does not contain TSCA CB1 - 21 - OuPoat OR 326-95 H-i^j REPEATED DOSE ORAL TOPCITYt U-DAT TOPING STTOT iiTH Ato H-iy^ tt* NgrBEK APPENDIX I INDIVIDUAL BODY WEIGHTS SD* = Sacrifice by Design Company Sanitized. Does not contain TSCA CBI 22 - ----"-----^8i!a REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN HALE RATS APPENDIX I INDIVIDUAL BODY WEIGHTS (g) OP HALE RATS GROUP: I CONCENTRATION: 0 PPH DlITS ON TEST; 0 RECOVERY DAYS - 7 14 21 28 35 42 49 56 7 14 21 28 35 42 ANIMAL i 524405 212.5 265.7 297.8 SD (DAY 14) A SnD (<D^A.wY 14) ^ 5..2.4..4.0^6 221.5E 29-6/ .7-. 3e51.2 SD (DAY 14) U 524407 199.2 254.2 295.5 SD (DAY 14) 524408 206.4 265.3 314.1 SD (DAY 14) 524409 524410 214.5 217.8 298.5 294.1 273.2 362.B 340.8 311.8 382.8 !SD (DAY 21) 357.3 SO (DAY 21) SD (DAY 21) 524411 524412 228.3 203.3 272.6 327.0 376.2 SD (DAY 21) 524413 1 524414 208.5 208.1 286.7 271.7 344.1 318.3 325.6 402.3 361.2 SD (DAY 365.5 390.7 21) 417.1 5 524415 (0 524416 215.5 216.4 282.2 288.9 334.4 392.5 348.0 421.7 375.6 462.1 410.4 1 524417 N' 524418 199.7 201.4 267.0 262.1 307.5 302.9 343.8 369.7 391.3 <B & 524419 218.8 286.3 332.5 362.2 427.3 408.8 466.1 456.3 501.9 0 0 524420 524421 217.5 233.1 300.6 264.5 369.5 342.2 344.6 390.6 434.9 (B (0 524422 198.1 271.4 340.9 393.2 399.3 434.3 434.6 487.1 480.6 0 8 524423 524424 209.3 216.0 287.: 277.6 345.1 329.8 375.7 396.4 438.0 3 S 5' -(ni P ^ 0 m 454.3 496.0 453.0 428.3 489.6 558.8 SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 581.5 480.0 535.6 529.2 471.3 501.4 555.6 552.6 495.4 42) 42) 42) 42) 42) 612.5 528.6 582.0 576.3 513.4 63 70 49 56 639.1 558.5 606.4 599.0 528.8 661.4 599. 648. 641. 557. .. . . .... REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN HALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OP HALE RATS CHOUl': 111 CDNCKNTKATIUN: 10 1'1'M UK II DOIIl DAYS ON TEST: 0 ) RECOVERY DAYS - ANIMAL * 524425 524426 524427 524428 524429 524430 524431 524432 524433 524434 524435 524436 524437 524438 524439 524440 524441 524442 524443 524444 211. 222. 198. 203. 212. 210. (B 228.'7 204.44 208.<9 205.:5 223.'7 216.<9 202.;k 205. 4 210.^4 214. 6 222. 3 202. 6 206. 1 209. 9 7 287.0) 310.9) 267.11 270.S1 290. S) 273.71 296. 260. 268. 276. 294. 279. 259. 263.E1 283.!5 272.-7 298.!5 257..3 280.:3 282. 3 14 21 28 35 - 7 14 21 346.3 384.3 304.6 305.1 355.2 307.2 339.3 293.4 309.7 319.6 355.6 329.1 289.1 307.8 329.0 310.9 354.3 295.7 317.6 329.0 SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 354.9 396.6 349.5 365.0 376.6 418.7 378.1 333.6 348.8 389.0 358.8 421.9 346.2 374.7 394.0 14) 14) 14) 14) 14) SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 451.7 403.3 351.2 370.1 419.3 389.2 455.9 362.3 400.6 409.2 21) 21) 21) 21) 21) 491.1 426.1 374.9 394.4 448.0 419.4 494.4 395.2 435.0 445.0 42 49 56 28 35 42 535.8 459.0 409.8 433.1 494.8 450.7 543.6 424.9 481.4 477.8 SD (DAY SD (DAT SO (DAT SO (DAT SD (DAT 469.6 563.4 448.7 502.3 499.8 42) 42) 42) 42) 42) 488.0 581.8 467.5 524.3 525.7 63 49 509.0 601.1 478.0 538.1 554.0 70 56 527.6 637.1 502.1 567.1 576.  REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OP HALE RATS GROUP: V CONCENTRATION: 300 PPH OF H-19683 OATS ON TEST: 0 RECOVERY CAYS - ANIMAL 524445 524446 524447 524448 524449 524450 0 524451 3 524452 S 524453 ) 524454 f 524455 & 524456 F 524457 [ 524458 l 524459 524460 524461 524462 524463 524464 216.8 227.8 204.8 204.3 213.5 218.9 224.7 205.7 219.8 209.8 218.5 225.9 199.9 205.3 218.2 219.7 236.0 201.3 203.0 209.2 7 271.7 308.6 266.3 259.1 277.5 266.2 280.9 243.3 259.9 259.2 273.4 286.3 256.9 269.3 283.5 278.2 288.9 275.3 289.0 255.2 14 21 28 35 7 14 21 314.6 362.4 314.3 302.0 331.6 307.9 341.2 282.6 297.4 309.8 315.2 336.5 303.7 310.8 349.1 315.9 329.4 335.5 352.4 289.1 SD (DAY SO (DA" SD (DAY SO (DAY SD (DAY 353.8 403.4 326.7 337.1 354.3 365.7 399.6 348.4 360.3 411.6 362.9 373.5 401.6 414.5 338.8 14) 14) 14) 14) 14) SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 393.9 433.6 382.6 381.1 456.2 400.5 400.1 440.6 467.0 382.7 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 42 49 56 28 35 42 459.5 503.4 439.2 446.0 536.6 464.1 473.9 532.8 536.5 454.5 SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 477.1 480.9 561.5 551.8 469.8 42) 42) 42) 42) 42) 489.0 501.5 587.9 570.7 492.9 63 49 513.5 525.1 611.8 593.7 514.0 70 56 534.1 565.5 635.0 612.6 540.7 REEPEATED DOSE OORUAVL TOXIICCII"TTYY: 1144--DDAAYY FEEDDIINNGG STUDY WVIITHB H-1968(E313 AND Ha--119704 INN MALE RAfTfSS APPENDIX I (CONT .) INI)IVIDUAL BODY VSIGHTS (g) OP HALE RATS II GROUP: V] CONCEKITRATIOt(: 30 PPH OF H-19 704 | DAYS ON TEST: 0 REOOVERY DA^YS - 7 14 21 28 35 42 49 56 63 70 7 U 21 28 35 42 49 56 ANIHAL >24465 213.1 294.8 360.1 SD (DAY 14) 358.3 SD (DAY 14) M 0> i 24466 &24467 240.1 206.5 307.0 273.0 331.7 SD (DAY 14) 1 >24468 200.5 271.7 332459..27 SSDD ((DDAAY: 1144)) SD (DAY 21) 124469 )24470 211.8 212.3 283.6 295.5 353.0 357.7 411.1 412.5 SD (DAY 21) 24471 r524472 220.9 197.8 297.1 270.7 328.4 368.5 SD (DAY 21) 524473 r524474 201.9 204.5 287.3 272.8 303.2 352.6 319.1 368.6 406.2 SD (DAY 358.4 SD (DAY 422.4 468.2 21) 21) 518.7 576.4 SD (DAY 42) (DAY 42) 524475 0 524476 207.3 220.8 302.2 358.1 385.2 430.8 462.5 433.4 494.9 SO 473.4 SD (DAY 42) ? 524477 196.0 267.6 272.2 317.5 308.3 363.1 363.1 395.8 393.4 438.6 487.7 SD (DAY 42) (DAY 42) 524478 524479 211.4 215. 286.3 346.2 398. J. 439.9 430.3 479.2 469.5 518.0 SD 509.0 535.8 558.7 577.0 61 59 I 524480 222. 290.0 343.9 381.3 395.6 397.2 416.1 465.0 523.9 549.6 491.0 531.2 518.0 565.9 541.2 58 3s"r 552244448812 221088.. 321727..59 328.7 337503..85 339709..61 443131..74 447117..79 447.8 468.2 480.7 5519 ^ 524483 s 524484 216. 211. 267.6 271.5 313.5 324.5 369.4 399.6 444.6 490.6 511.2 541.9 558.7 sff . mj -B- REPEATED DOSE ORAL TOXICITY: 14-DAY FEEDING STUDY VITH H-19683 AND H-19704 IN MALE RATS APPENDIX I (CONT.) INDIVIDUAL BODY WEIGHTS (g) OP HALE RATS GROUP: IX CONCENTRATION: 300 PPM OF H-19704 D A1S on TEST: 0 RECOVERY DAYS - 7 14 21 28 35 - - 7 14 n ANIMAL t 524485 524486 524487 524488 00 524489 524490 "2 524491 S 524492 w 524493 & 524494 I 524495 524496 524497 524498 524499 524500 n 524501 1 524502 524503 3 -< 524504 8 > 0 OS 215.1 230.6 201.4 208.6 216.9 215.2 224.1 197.0 21?.1 211.3 219.9 224.6 203.4 207.0 210.6 215.1 229.3 204.2 209.5 210.5 221.8 239.6 23.2.0 222.5 236.7 248.9 260.9 225.2 22*). (, 2W.') 227.5 286.7 254.5 210.8 249.9 206.6 220.6 241.0 248.8 204.7 279.0 293.0 284.2 289.7 307.7 279.3 303.3 262.2 ?7*). 11 .(. 280.2 333.4 301.8 272.5 291.8 276.2 298.7 274.7 297.4 270.4 SD (DAY SD (DAY SD (DAY SD (DAY SD (DAY 348.7 366.5 298.5 Til. 2 '.\7.'i 338.5 380.6 357.7 307.8 358.6 308.7 366.8 321.7 362.1 323.2 U) U) 1*) 14) 14) SD (DAY SD (DAY SD (DAY SD (DAY :;D (DAY 378.0 416.8 381.9 335.8 400.7 381.0 412.1 347.3 399.8 347.6 21) 21) 21) 21) ^1) 40:3.6 439.3 418.6 367.6 434.0 423.0 448.1 369.4 433.4 373.9 42 49 56 28 35 42 439.1 474.7 458.9 400.7 480.9 460.4 484.1 401.3 468.1 408.4 SU (DAY SD (DAY SD (DAY SD (DAY SD (DAY 481.1 500.9 413.7 493.1 417.4 42) 42) 42) 42) 42) 513.9 524.8 421.2 511.5 437.9 63 49 533.6 548.0 436.8 544.8 454.9 70 56 572. <. 575.1 460.5 549.9 477.9 DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY; 14-DAY FEEDING STUDY WITH H-19683 AND H-19704 IN MALE RATS APPENDIX II INDIVIDUAL CLINICAL OBSERVATIONS NR = Not resolved - 28 - Company Sanitized. Does not contain TSCA CBJ ANIMAL NUMBER OBSERVATION 524410 524411 524412 524413 524414 524415 524416 524417 524418 524419 524420 524421 52442? PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTIOM PILOERECTION PILOERECTION - - - , , PILOERECTION COLORED DISCHARGE PILOERECTIOM PILOERBCTION PILOERECTION NOSE BROWN FIRST DAT OBSERVED LAST DAT 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 CompanySanitized. Does not contain TSCACBl 29 - MlltfiiiHilftHUilMiWlll ANIMAL NUMBER OBSERVATION 524425 524426 524427 524428 524429 524430 524431 524432 524433 524435 52A436 524437 524438 524439 524440 524441 524442 524443 524444 PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION COLORED DISCHARGE PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTICN COLORED DISCHARGE PILOERECTION NOSE NOSE BROWN BROVN FIRST DAT OBSERVED LAST DAT OBSERVED 14 14 NR 14 14 NR 7 14 NR 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 7 7 42 70 NR 7 21 7 21 42 70 NR 7 21 28 35 7 21 Co/atpanys<^^ 30 - ^eowaw T'.SCAc^ DuPont BUt 326-95 REPEATED DOSE ORAL TOgCITYt 14-DAY FEEDING STUM ------UtTH d-i96fl3 AM> tt-i9yoA 1H NAU Ms------ APPENDIX II (COOT.) INDIVIDUAL CLINICAL OBSERVATIONS IN HALE RATS GROUP: V CONCENTRATION: 300 PPH OF H-19683 kNIHAL NUMBER OBSERVATION FIRST DAY OBSERVED LAST I)AY OBSER^TED 524445 524447 524448 524449 524450 524451 524452 524453 524454 524455 524456 524457 524458 524460 524461 524462 524463 PILOERECTION PILOERECTION PILOERECTION COLORED DISCHARGE PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION NOSE BROWN 7 14 NR 7 14 NR 7 7 7 7 7 7 7 21 NR 7 14 7 21 NR 7 21 NR 7 14 7 7 7 21 14 21 7 21 14 14 7 21 14 21 14 21 42 70 NR ^^,, ^ 31 - ^.Ooe,'snot ^aw ^ Cfi/ ^ ANIMAL NUMBER OBSERVATION 524465 524466 524467 524468 524469 524470 524471 524472 524473 524474 524475 524478 524479 524480 524481 524482 524484 t'TLOERECTION COLORED DISCHARGE NOSE PILOERECTION COLORED DISCHARGE NOSE IRREGULAR RESPIRATION PILOERECTION RAPID BREATHING PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILGERBCTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION *COLORED DISCHARGE LEFT *COLORED DISCHARGE BOTH *TOP rEETH CROOKED *BOTTON TEETH TOO LONG *COLORED DISCHARGE NOSE PILOERECTION PILOERECTION PILOERECTION RED BROVN ETE(S) ETE(S) BROVN BROWN BROVN * Attributed to oalocclusion of the teeth FIRST DAT OBSERVED LAST DA? OBSERVED 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 7 7 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 ^"^ysw^ ^""""""rsc.cs, 32 - APPENDIX II (CWT.) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE BATS GROUP: IX CONCENTRATION! 300 PPM OF H-19704 ANIMAL NUMBER OBSERVATION FIRST DAY OBSERVED LAST DA? OBSER7BD 524485 524486 524487 524488 524491 524492 524493 524494 524495 524496 524498 524499 524500 524501 524502 524504 PILOERECTION PILOERECTION PILOERBCTION RAPID BREATHING PILOERECTION PILOERBCTION ALOPECIA LEFT HIND PILOERECTION PILOERECTION PILOERECTION PILOERECTION PILOERECTION HUNCHED OVER PILOERECTION PILOERBCTION HUNCHED OVER PILOERECTION PILOERECTION PILOERECTION QUARTERS 7 14 NR 7 7 7 7 14 14 NR 14 14 7 7 7 21 NR 7 7 7 14 14 21 7 21 7 4J1Z.4 UNRR 7 7 7 14 7 21 7 7 14 7 70 NR 7 70 NR flBII(p^nfu^.i 33 - con^y Sanity. Doe^ot contain TSCACBI 34 - &.'8ia REPEATED DOSE ORAL TOnCITTt 14-DAY nODING STUDY WITH H-19683 AND H-19704 IN HALE RATS INDIVIDUAL FINAL BODY AMD ABSOLUTE LIVER VEICTTS (grau) FKOM HALE BATS GROUP I - 0 PPM TEST DAY 14 ANIMAL NUMBER RECOVERY DAY 0 FINAL BODY BT LIVER WT 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. TEST DAY 21 524410 524411 524412 524413 524414 GROUP MEAN STD. DEV. TEST DAY 42 524415 524416 524417 524418 524419 GROUP MEAN STD. DEV. TEST DAY 70 524420 524421 524422 524423 524424 GROUP MEAN STD. DliV. 324.3 31.0 12.755 2.044 RECOVERY 382.8 357.3 376.2 402.3 361.2 DAY 7 16.752 14.358 15.408 19.036 15.753 376.0 18.1 16.261 1.771 RECOVERY 454.3 496.0 453.0 428.3 489.6 DAY 28 17.501 17.432 18.374 17.882 17.495 464.2 28.1 17.737 0.398 RECOVERY 661.4 599.4 648.5 641.6 557.1 DAY 56 26.406 19.284 26.333 22.212 18.097 621.6 42.9 22.466 3.865 CQtttatn ^CAI 35 - DuTont BUt 326-95 INDIVIDUAL REPEATED DOSE ORAL TOXZCZTTi 14-DAY FIXDIMG STUDY VITH H-19683 AND B-19704 IN HALE BATS III FIFU BOOT AND ABSOLUTE LIVER WEIGHTS (frau) FROM GROUP - 30 PEN KALE RATS TEST DAY 14 RECOVERY DAT 0 ANIMAL NUMBER FINAL BOOT VT LIVER VT 524425 524426 524427 524428 524429 346.3 384.3 304.6 305.1 355.2 15.729 17.457 12.963 13.771 15.572 GROUP MEAN STD. DBV. 339.1 34.3 15.098 1.768 TEST DAY 21 RECOVERY DAY 7 524430 354.9 14.495 524431 396.6 18.471 524432 349.5 13.976 524433 365.0 15.116 524434 376.6 14.003 i GROUP MEAN STD. DEV, 368.5 18.8 15.212 1.880 TEST DAY 42 524435 524436 524437 524438 524439 RECOVERY 535.8 459.0 409.8 433.1 494.8 DAY 28 24.960 16.385 15.757 15.773 21.060 GROUP MEAN STD. DEV. TEST DAY 70 524440 524441 524442 524443 524444 466.5 50.0 18.787 4.102 RECOVERY 527.6 637.1 502.1 567.1 576.8 DAY 56 20.851 22.618 19.299 20.447 18.393 GROUP MEAN STD. DEV. 562.1 51.6 20.322 1.607 ^^y^^,^^,,^, n T s c ^ - 36 - INDIVIDUAL FINAL BODY AND AGBRSOOULPUTVE UV3B0B0 WPPEMIGHTS (grass) FROM HALE RATS - TEST DAT 14 ANIMAL NUMBER 524645 524446 524447 524448 524449 GROUP MEAN STD. DEV. TEST DAT 21 524450 524451 524452 524453 524454 GROUP MEAN STD. DEV. TEST DAT 42 524455 524456 524457 524458 524459 GROUP MEAN STD. DEV. TEST DAT 70 524460 524461 524462 524463 524464 GROUP MEAN STD. DEV. RECOVERY DAT 0 FINAL BOOT WT LIVER VT 314.6 362.4 314.3 302.0 331.6 15.040 15.836 12.844 12.747 13.820 325.0 23.4 14.057 1.358 RECOVERY 353.8 403.4 326.7 337.1 354.3 I)AT 7 14.631 19.682 13.636 15.003 14.772 355.1 29.4 15.545 2.371 RECOVERY 459.5 503.4 439.2 446.0 536.6 DAY 28 19.545 19.180 17.045 14.867 22.140 476.9 41.7 18.555 2.743 RECOVERY 534.1 565.5 635.0 612.6 540.7 DAT 56 20.478 23.355 28.756 21.269 20.430 577.6 44.5 22.858 3.504 ^"'^sanfHrd.j DuPont Bit 326-95 REPEATED DOSE ORAL TOXICITTt 14-DAY FEEDING STUDY UITB H-19683 AND H-19704 IN HALE RATS INDIVIDUAL FINAL BOOT AND ABSOLUTE LIVER WEIGHTS (gruu) FROM HALE BATS GROUP VII - 30 PPM TEST DAT 14 RECOVERY DAY 0 ANIMAL NUMBER PIKAL BODY UT LIVER VT 524465 524466 524467 524468 524469 360.1 358.3 331.7 325.2 349.7 21.718 21.003 19.086 2C.790 20.892 GROUP MEAN STD. DEV. TEST DAY 21 524470 524471 524472 524473 524474 345.0 15.8 20.698 0.972 RECOVERY 411.1 412.5 368.5 406.2 358.4 DAY 7 23.372 24.361 24.350 21.810 19.661 GROUP MEAN STD. DEV. TEST DAY 42 524475 524476 524477 524478 524479 391.3 25.8 22.711 1.998 RECOVERY 576.4 494.9 473.4 487.7 518.0 DAY 28 23.014 22.983 20.776 18.919 19.864 GROUP MEAN STD. DEV. TEST DAY 70 524480 524481 524482 524483 524484 510.1 40.4 21.111 1.844 RECOVERY 616.8 593.5 530.4 512.1 591.2 DAY 56 25.762 20.008 20.143 19.507 21.592 GROUP MEAN STD. DEV. 578.8 39.6 21.402 2.558 ^ i n Cft^Pan, >ysa^ e^ 0,'oes nof 38 INDIVIDUAL REPEATED DOSE ORAL TOXICITYi 14-DAY FEEDING STUDY VrrH B-19683 AND H-19704 111 HALE RATS FINAL BODY AND ABSOLUTE LIVER WEIGHTS (grau) FIOM GROUP IX - 300 PPN MALE RATS TEST DAY 1A RECOVERY DAY 0 ANIMAL NUMBER FINAL BODY VT LIVER WT 524485 524486 524487 524488 524489 GROUP MEAN STD. DEV. TEST DAY 21 524490 524491 524492 524493 52449A 279.0 293.0 784.2 289.7 307.7 23.269 22.664 21.723 24.453 26.260 290.7 10.9 23.674 1.752 RECOVERY 348.7 366.5 298.5 331.2 312.5 DAY 7 22.845 22.413 21.230 21.836 21.845 GROUP MEAN STD. DEV. TEST DAY 42 524495 524496 524497 524498 524499 GROUP MEAN STD. DEV. TEST DAY 70 524500 524501 524502 524503 524504 331.5 27.3 22.034 0.617 RECOVERY 439.1 474.7 458.9 400.7 480.9 DAY 28 21.474 22.941 19.103 19.567 23.084 450.9 32.4 21.234 1.852 RECOVERY 572.2 575.1 460.5 549.9 477.9 DAY 56 20.888 24.770 16.900 16.648 19.969 GROUP MEAN STD. DEV. 527.1 54.1 19.835 3.326 ""'""^r^^ ^ftpflflyg ^Wfced. 'Do 39 - DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITYt 14-DAY FEEDING STUDY UITH H-19683 AND B-1970A IN MALE RATS APPENDIX III (COOT.) INDIVIDUAL ANIHAL FINAL BODY AND LIVER WEIGHTS RELATIVE LIVER WEIGHTS (X of body weight) FROM HALE RATS GROUP I - 0 PPM SACRIFICED (DAYS OF RECOVERY) ANIMAL NUMBER 5244U5 524406 524407 524408 524409 LIVER 3.7928 4.3158 3.5096 3.9640 3.9964 GROUP MEAN STD. DEV. 524410 524411 524412 524413 524414 3.916 0.295 4.3762 4.0185 4.0957 4.7318 4.3613 GROUP MEAN STD. DEV. 4.317 0.281 2F 524415 3.8523 28 524416 3.5145 28 524417 4.0561 28 524418 4.1751 2 524419 3.5733 GROUP MEAN STD. DEV. 3.843 0.290 56 524420 3.9924 56 . 524421 3.2172 56 524422 4.0606 56 524423 3.4620 56 524424 3.2484 GROUP MEAN STD. DEV. 3.596 0.405 ^PanySanrtucAooes "ot contain rsCACBl - 40 - APPENDIX in (con.) INDIVIDUAL ANIHAL FINAL BOD? AND LIVER WEIGHTS RELATIVE LIVER WEIGHTS (X of body veiq:ht) PROM HALE RATS GROUP III - SACRIFICE (DAYS OF RECOVER.*) 30 PPM OP H-19683 ANIMAL NUMBER LIVER 0 524425 4.5420 0 524426 4.5425 0 524427 4.2557 0 524428 4.5136 0 524429 4.3840 GROUP MEAN STD. DEV. 4.448 0.126 7 524430 4.0842 7 524431 4.6573 7 524432 3.9989 7 524433 4.1414 7 524434 3.7183 GROUP MEAN STD. DEV. 4.120 0.341 28 524435 4.6585 28 524436 3.5697 28 524437 3.8450 28 524438 3.6419 28 524439 4.2563 GROUP MEAN STD. DEV. 3.994 0.457 56 524440 3.9520 56 524441 3.5501 56 524442 3.8437 56 524443 3.6055 56 524444 3.1888 GROUP HEAt1 STD. DEV. 3.928 0.296 CoWjteflyfianHixed. Do- "otconWnTSCACBl 41 - ^&\ | f APPENDIX III (COOT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS RELATIVE LIVER VEIGI3TS ((aC of body weight) FROM MALE RATS GROUP V - 300 PPM OF H-19683 SACRIFICE (DAYS OF RECOVERY) 0 0 0 0 0 5 7 7 28 28 28 28 28 56 56 56 56 56 ANIMAL NUMBER LIVER 524445 524446 524447 524448 524449 4.7807 4.3698 4.0865 4.2209 4.1677 GROUP MEAN STD. DEV. 4.325 0.275 524450 524451 524452 524453 524454 GROUP MEAN STD. DEV. 4.1354 4.8790 4.1739 4.4506 4.1693 4.362 0.316 524455 524456 524457 524458 524459 4.2535 3.8101 3.8809 3.3334 4.1260 GROUP MEAN STD. DEV. 3.881 0.355 524460 524461 524462 524463 524464 3.8341 4.1300 4.5285 3.4719 3.7784 GROUP MEAN STD. D2V. 3.949 0.400 ""'! ^8WI^'^.^^. - 42 - - """'^cai APPENDIX III (COOT.) INDIVIDUAL ANIMAL FINAL BODY AND LIV1BR VEIGBTS RELATIVE LIVER WEIGHTS (X of body weight) FROM MALE RATS GROUP VII - 30 PPM OP H-19704 SACRIFICED (DAYS OF RECOVERY) 0 0 0 0 0 7 7 7 7 7 2.? 28 28 28 28 56 56 56 56 56 ANIMAL NUMBER LIVER 524465 324466 524467 524468 524469 6.0311 5.8618 5.7540 6.3930 5.9743 GROUP MEAN STD. DEV. 524470 524471 524472 524473 524474 6.003 0.243 5.6852 5.9057 6.6079 5.3693 5.4858 GROUP MEAN STD. DEV. 524475 524476 524477 524478 524479 5.811 0.490 3.9927 4.6440 4.3887 3.8792 3.8347 GROUP MEAN STD. DEV. 524480 524481 524482 524483 524484 4.1>8 0.353 4.1767 3.3712 3.4705 3.8092 3.6522 GROUP MEAN STD. DEV. 3.696 0.317 ^Pai]wsw"^^. - 43 - APPENDIX III (COOT.) INDIVIDUAL ANIMAL FINAL BODY AND LIVER WEIGHTS FSLATIVE 1LIVER WEIGHTS (X of body weight) FROM MALE RATS Gaou" is - 300 PPM OF H-19704 & ftCRIFICED (DAYS OF RECOVERY) 0 0 0 0 0 7 7 7 7 ANIMAL NUMBER 524485 524486 524487 524488 524489 GROUP MEAN STD. DEV. 524490 524491 524492 524493 524494 GROUP MEAN STD. DEV. LIVER 8.3401 7.7352 7.6436 8.4408 a.5343 8.139 O.<*1; 6.5515 6.1154 7.1122 6.5930 6.9904 6.6/3 0.396 28 3iWfO V.OOJt. 28 524499 4.8002 GROUP MEAN STD. DEV. 4.714 0.310 56 .524500 3.6505 56 524501 4.3071 56 524502 3.6699 ; 56 524503 3.0275 ;24504 4.1735 1 GROUP MEAN 3.767 STD. DEV. 0.508 - 44 ^Mnyfl^fttteMd oo, esw^^^ DuPont HLR 326-95 REPEATED DOSE ORAL TOXICITY; 14-DAY FERDIHG STUDY --------WITH H-19663 AND U-iW T*' MALE RATS-------- APPENDIX IV INCIVIDUAL FLUORIDE CONCENTRATIONS WITH H-l 9683 AND H-19704 IN MA1LE RATS> APPEiNDIX IV INDIVIDUAL FLUORIDE CONCENT?IATIONS (PPH) 1POUND 1[N THE BLOOD OP HALE RAT S TREATED) WITH H-19683 OR H-l19704 GROUP CONCENTRATION OF TEST SUBSTANCE TEST DAYS RECOVERY DAYS RAT PPM IN BLOOD L 0 PPM (CONTROLS) 14 0 14 0 14 0 14 0 14 0 101 0 (BLANK) 102 0.32 103 0.14 104 0.35 105 0.39 21 7 21 7 21 7 21 7 106 0.45 107 0.37 108 0 (BLANK) 109 0 (BLANK) 21 7 110 1.99 1 30 PPM OF H-19683 14 0 14 0 301 3.91 302 4.85 14 0 303 4.47 14 0 304 5.21 14 0 305 8.04 7 i 7 21 7 21 7 21 7 306 1.30 307 0.34 308 0 (BLANK) 309 0 (BLANK) 310 0.09 V 300 PPM OP B-196B3 14 0 14 0 14 0 14 0 14 0 501 6.87 502 7.26 503 4.76 504 15.09 505 6.99 21 7 21 7 21 7 21 7 21 v 1 506 0 (BLANK) 507 0.25 508 0.63 509 0.70 510 0.68 | ^o,, ^^ "^c. - 46 - INDIVIDUAL FLUORIDE CONCENTRATIONS (PPM) FOUND IN THE BLOOD OP MALE RATS TREATED WITH H-19683 OR H-19704 GROUP # VII CONCENTRATION OF TEST SUBSTANCE > PPH OF H-ly/04 IX 1 PPM OF H-19704 TEST DAYS RECOVERY DAYS RAT PPH IN BLOOD 14 0 14 0 14 0 14 0 14 0 701 38.19 702 27.83 703 33.99 704 33.52 705 32.62 21 7 21 7 21 7 21 7 21 7 706 14.09 707 25.88 708 27.10 709 17..14 710 11.81 14 0 14 0 14 0 14 0 14 0 21 , 21 / 21 7 21 "* 21 -- 901 64.51 902 67.41 903 54.44 904 101.58 905 69.65 906 25.52 907 20.26 908 22.66 909 18.42 910 23.16 ^"Panj ^Saw",t9ft. Ooe, fotcc 47 -