Document 5km9oLKjOwQyjN3V2EVr0dqmR
AR226-3204 DuPont-2925 Supplement No. 1
TRADE SECRET
Study Title
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1 Laboratory Project ID: DuPont-2925
Author: Carol Finlay, B.A. Study Completed on: September 1,2000 Supplement No. 1 Completed on: December 12,2001 Performing Laboratory: EH.aI.skdeullPLoanbtodreatNoreymfoourrHs eaanldthCaonmdpEannvyironmental Sciences
Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
Work Request Number: Service Code Numbei
Page 1of 40 Company Sanitized. Does net contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by:
'PauPloMst.dHocmtodrearllFiteerll,oPwh.D.
Reviewed by:
Director
Issued by Study Director:_ f hAJbCiaSr,otal/fjFfiSinc'laiMeyn,tBistUA. ryt
i2 ~X)ec--2-0"/
Date
OK-J)E'ZOf
Date
n - rDdatjeL -/lt>bt
-2Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
TABLE OF CONTENTS
Page
CERTIFICATION
. . . . . . a* .....****.<
LIST OF TABLES ...................................................................................... .
LIST OF FIGURES a*#.......********'
,.2
.4 4
LIST OF APPENDICES
aa* . . . . . . . *
STUDY IN FO R M A TIO N ..a...*.......*.**..*.**************************"**1 STUDY PERSONNEL....a**.*.*****.***************************************"*"***
^ ..a....*.*..**.*********************>*n1iS
.............................. .
7
REASON FOR SUPPLEMENT NO* 1 ..............................**<
MSUAMTME RAIRAYL*S. AND M E T H O D S ----- .a.*...........*<.....t..*.l....*l***Mt*MI*********H***1Q0...................... .................................................................................................*............... .
RESULTS AND DISCUSSION...
10
A. Liver Weights........................
21.. PToessittSivuebCstoanntcreo..l.s...........
,,,,.111000
B. Liver Fluorine Data..
.11
21.. TPoessittSivuebCstoanntcreo..l.s..........
,,,,1111
C O N C LU SIO N S ........... 11,c#aa. ................* * * * * * * * * * * * * * aa. . ...**.****************************
TA B LES. >***.....a** 12a. . . a. a. . . * . . ......****************** 'a. . . . . . . .....*.***.************
F IG U R E S ........ 16a. . . . a. . . . . . . ..*.********'
aa* *.*****.*.** ** **********""**
APPENDICES 22...aa. .***.*.******'
. . a. . . a. a... .*** a.. a. . . a. ****.************',a. a. . .*.**********
- 3 - Company Somtlaod. Doss soi contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
LIST OF TABLES
Page
1. MEAN BODY AND LIVER WEIGHTS..................................................................................................................13
2. MEAN LIVER FLUORINE LEVELS.......................................................................................................................15 3. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE....................................................15
LIST OF FIGURES
Page
1. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROLS...............................................................................................................................................................
2. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND POSITIVE CONTROLS...............................................................................................................................................................
3. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24000 AND NEGATIVE CONTROLS.....................................................................................................
4. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE.................................................
5. COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE......................................................................................................................................
LIST OF APPENDICES
Page
A. INDIVIDUAL FINAL BODY WEIGHTS, LIVER WEIGHTS, AND RELATIVE LIVER TO BODY W E IG H T .....................................................................................................................................................................23
B. INDIVIDUAL FLUORINE LEVELS...................................................................................................................... 34
4 Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE:
Substance Tested: Svnonvms/Codes
H-24000 Haskell Number: 24000
DuPont-2925 Supplement No. 1
Known Impurities: Not supplied by the sponsor
Known Impurities: Unknown
- 5 - Gompany Sanitized. Does not contain TSCA CBi
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION (Continued)
DuPont-2925 Supplement No. 1
Haskell Number: 24020 Compositi'
Known Impurities: Unknown
Sponsor: EW.iIl.mdiungPtoonnt, dDeeNlaewmaroeur1s9a8n9d8 Company U.S.A.
Study Initiated/Completed: April 30,1999 / (see report cover page) Tn-Life Initiated/Completed: June 13,1999 / September 14, 1999
- 6 - Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Judith C. Stadler, Ph.D., D.A.B.T. ' Primary Technician: Richard P. Mathena Liver Fluorine DMataanAagneamlyesnist:: PMaautlthMew. HSi.nBdeorglidteanr,ffPyh,.DPh..D., D.A.B.T. Toxicology Report Preparation: Wanda F. Dinbokowitz Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M.
DuPont-2925 Supplement No. 1
-7Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
REASON FOR SUPPLEMENT NO. 1 The purpose of this supplement is to present the results from analysis of selected liver samples from rats treated with the test substance (H-24000), 2 positive controls (H-24019 and H-24020), and 2 negative controls (com oil and com oil/acetone).
- 8 - company Sanitized. Does not contain TSCA CBi
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-24000, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male Crl:CD(SD)IGS BR rats each were given 300 mg/kg/day of H-24000. The test substance was administered to one group of 5 rats for 5 consecutive days and to 5 groups for 10 days. On selected days (5,10, 13, 24, 52,94) 5 rats per group were euthanized and the blood and livers were collected. Livers were weighed and those collected on study days 10 and 94 were analyzed faonraltyostaelsfilnuolirvineres.. TAhdisdistuiopnpallelmy,e2ntniengcalutidveescloivnetrrowlse,icgohmt doaitlaaannddctohme reosilu/latcseotofntoeta(8l 0fl:2u0o)r,inaend 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-24000. THh-2e4m00ea0n, wrealsatuivpetoliv3e6r%wheiigghhter(laivt edra/ybo1d0ytwhaenigthhte) moferaantsredloastievdewliivthertwheeitgehsttssuobfstthaencnee,gative control groups. By day 94, the mean relative liver weight of rats dosed with the test substance was similar to the negative controls. On day 10, the mean relative liver weight of rats dosed with the positive control H-24019 was up to 27% higher than the negative controls. By day 94, the Hm-e2a4n0r2e0la, ttihvee mliveaenr wreeliagtihvtewlaivseurpwteoig2h8t%whasiguhpertoth7a5n%thheingehgearttihvaenctohnetrnoelsg.atIinveractosngtirvoelsn. By day 94, the weights were similar. The concentration of fluorine in the livers from rats dosed with the test substance, H-24000, was e6q4u8i.v1a6lepnMt ceoqnucievnatlreantitosnosnodfafylu1o0riannedin4.t6h9e pliMveresqfuriovmaleranttss doonsdeadyw9i4th. tOhen pdoasyit1iv0e, mcoenatnroplM materials were approximately 8-fold (H-24019) and 2-fold (H-24020) greater than the fluorine concentration in livers from rats treated with the test substance. By day 94, the concentrations were approximately 250x and 2x the fluorine concentration in rats treated with H-24000. The pM equivalents of fluorine in the livers from rats dosed with the test substance were higher than levels in the blood. Under the conditions of this study, there was some absorption and retention of fluorine in the liver from rats dosed with H-24000. However, fluorine levels in the liver were lower than levels in rats dosed with the positive control materials, H-24019 and H-24020. Liver weights were elevated in rats dosed with H-24000, at the end of the dosing period, but not at the end of the recovery period.
-9Company Sanitized. Does not contain TSCA OBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
MATERIALS AND METHODS Blood and livers were collected on days 5,10,13,24,52, and 94. The livers were weighed. Only the test day 10 and 94 livers were analyzed for total fluorine. These time points provided sufficient data to determine the accumulation and persistence of fluorine in the liver. See the original report for details of the analysis.
RESULTS AND DISCUSSION
A. L(TiavbelreW1;eFigighutsres 3-5; Appendix A) As with the body weights, comparison of absolute liver weights was complicated by the fact that there was a difference in age on test day 1 between rats dosed with the test substance and those wdoesreedowldiethr athned phoesaivtiivereionrwneegigahtitvtehacnonthtreolcso. mThoeilrnaetsgadtoivseedcownittrhotlhaentdesHt-s2u4b0s2ta0npcoe,siHti-v2e4c0o0n0t,rol rats, but younger and lighter in weight than the com oil/acetone negative control and H-24019 positive control rats. Therefore, liver weights relative to total body weight are presented for comparison.
1. Test Substance The mean relative liver weight of rats dosed with the test substance, H-24042, was up to 36% higher than the negative controls on day 10. On days 13,24, and 52 (recovery), the mean relative liver weights of rats dosed with the test substance were up to 11-37% higher than the negative controls. The weights were similar by day 94.
2. Positive Controls The mean relative liver weights of rats dosed with the positive control H-24019 was 7% lower on day 10 than the mean relative liver weight of rats dosed with the test substance. At the end of the recovery period, the mean relative liver weight of rats dosed with H-24019 was 11% higher than the mean relative liver weight of rats dosed with the test substance. The mean relative liver weight of rats dosed with the positive control H-24020 was 28% higher on day 10 than the mean relative liver weight of rats dosed with the test substance. The mean relative liver weights of rats dosed with H-24020 began to decrease during the recovery period and were similar on test days 52 and 94 to the mean relative liver weights of rats dosed with the test substance. The mean relative liver weights (% of body weight) of rats dosed with H-24019 were up to 27% higher during the dosing period than the negative controls. The mean relative liver weights of rats dosed with H-24019 were 13-39% higher than the negative controls on test days 13, 24, and
- 10Company Sanitized. Does not contain TSCA CB
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
52 (recovery). At test day 94 (end of recovery), mean relative liver weights of rats dosed with H-24019 were 14 or 28% higher than controls.
The mean relative liver weights (% of body weight) of rats dosed with H-24020 were 43-75% higher during the dosing period than the mean relative liver weights of the negative controls. The mean relative liver weights were 30-63% higher than controls. On test days 52 and 94, the mean relative liver weights of the positive controls were similar to the negative controls.
Therefore, liver weights of rats dosed with the test substance, H-24000, were elevated at the end of the 10-day dosing period but not at the end of the recovery period.
B. L(TiavbelreFs l2u-o3,riFnieguDreasta3-5, Appendix B) 1. Positive Controls
The positive controls were H-24019 and H-24020. The concentrations of fluorine in the livers on day 10 from rats dosed with the positive control materials were 5045.85 and 1127.25 /M
eaqnudiv1a0l.e7n2tsfiMforeHqu-2iv4a0l1e9ntas.nd H-24020, respectively. By day 94, the concentrations were 1190.15
2. Test Substance Levels of total fluorine in livers from rats dosed with the test substance, H-24000, were lower than the levels in livers from rats dosed with the positive control materials. The total fluorine
wcaonendrce4e.an6pt9rparftoiiMoxnimeiqnautteihvlyeall8eixvnethsrigafrthodemray(rda9at4sy. d1Fo0os)eradtnhwdeiaptphopsHriot-ix2vi4em0c0aot0neltwyroa2ls5H604-x284h.10ig61h9/ei,Mrth(eeenqlduiviovefar slcetounndtscye)anttthdraaantyio1n0s
H-24000. For H-24020, the liver concentrations were approximately 2x higher (end of dosing) and 2x higher (end of study) than H-24000.
The ixM equivalents of fluorine in the livers from rats dosed with the test substance were higher
than levels in the blood.
CONCLUSIONS Under the conditions of this study, there was some absorption and retention of fluorine in the liver from rats dosed with H-24000. However, fluorine levels in the liver were lower than levels in rats dosed with the positive control materials, H-24019 and H-24020. Liver weights were elevated in rats dosed with H-24000, at the end of the dosing period, but not at the end of the recovery period.
-11 - Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
TABLES
- 12Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
TABLE 1
MEAN BODY AND LIVER WEIGHTS (g)
' CORN OIL (NEGATIVE CONTROL)
____________ Absolute______________
Mean Relative
Test Days 5 10 13 24 52 94
Body Weight 259.3 311.1 322.9 391.2 464.7 557.8
Liver Weight 12.620 15.861 14.906 16.635 17.240 20.118
Liver Weight(%0.0o4f9Body Weight) 0.051 00..004436 0.037 0.036
Test Days 5 10 13 24 52 94
CORN OILACETONE (NEGATIVE CONTROL)
Absolute
Body Weight 313.4 356.5 377.6 423.5 527.6 567.8
liver Weight 13.632 15.597 1177..711752 21.275 18.447
Mean Relative Liver Weight(% of Body Weight)
0.043 0.044 0.047 0.041 0.040 0.032
Test Days 5 10 13 24 52 94
H-24019 (POSITIVE CONTROL)
Absolute
Bodv Weight Liver Weight
306.6 310.1 344.8 387.9 438.1 597.9
1157..435366 22.049 21.313 19.826 24.455
Mean Relative Liver Weight(0%.0o5f0Body Weight)
0.056 0.064 0.055 0.045 0.041
-n- _ ^
Company Sanitized. Does not contain fSCACBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
Test Days 5 10 13 24 52 94
TABLE 2 (Continued)
MEAN BODY AND LIVER WEIGHTS (g)
H-24020 (POSITIVE CONTROL)
Absolute______________
Mean Relative
Body Weight 244.8 284.4 289.1 370.3 456.7 538.7
liv e1r7.W05e2ight 21.944 21.780 20.619 17.713 18.205
Liver Weight(% of Body Weight) 0.070 0.077 00..007556 0.039 0.034
Test Days 5 10 13 24 52 94
H-24000 (TEST SUBSTANCE)
Absolute
Body Weight
236.6
279.6
304.3
'
378.7 512.8
608.6
Liver Weight 12.090 16.710 1189..118436 21.158 22.816
Mean Relative Liver Weight(% of Body Weight)
00..005610 0.063 0.048 0.041 0.037
- 14Company Sanitized. Does not contain 3CA CB1
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
TABUE 2 MEAN OVER FLUORINE LEVELS
Negative Controls
Test Com Oil Days (ppm)
Oil:CAocmetone (ppm)
10 <0.2 94 0.6a
<0.5 la
Positive Controls
H-24019 (ppm) 328.18 (19.3)6 77.56 (10.1)
H-24020 (ppm) 155.76 (29.2) 1.68 (0.3)
a One value. Four of the values were below the level of detection (LOD). b Standard deviation is in parentheses.
Test Substance H-24000
486.32(PP(m3>8_.2__) 3.72 (0.9)
TABLE3 MEAN LIVER FLUORINE CONCENTRATION
NORMALIZED TO DOSE
Positive Controls
Test Substance
Test Pays
H-24019 /M F Equivalents
xM FHE-2q4u0i2v0alents______
fiM
H-24000 F Equivalents
10 5045.85 (296.91)a 1127.25 (211.37) 648.16 (50.9)
94 1190.15 (156.05) 10.72 (2.14)___________ 4.69 (1.1)
a Standard deviation is in parentheses.
- 15Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
FIGURES
Company Sanitized. Does not on tan i 3CA CBI
H10-2-D40o0se0:OBrailoGpearvsaisgteenScteudSycrineeRnaintsg
SuppDleumPeonntt-N29o2. 51
FIGURE 1 COMTEPSATRSISUOBNSTOAFNMCEEAANNRDENLEAGTAIVTEIVLEIVCEORNWTREOIGLHSTS:
0.07
El Corn Oil (Negative Control)
0.06
Corn OihAcetone (Negative Control) H-24000 (Test Substance)________
0.05
0.04
0.03
Mean Relative Liver Wt. (% ofBody Wt.)
0.02
0.01
0.00
Test Day
- 17Company Sanitized. Does not contain TSCA CBI
H10-2-D40o0se0:OBrailoGpearvsaisgteenSctuedSycrieneRnaintsg
FIGURE 2 CONTPEASRTISSUOBNSOTFAMNCEEANANRDELPAOTSIIVTIEVLEIVCEORNTWREOIGLSHTS:
SuppDleumPeonntt-N29o2. 51
Mean Relative Liver Wt. (% of Body Wt)
-18Company Sanitized. Does not contain TSCA CBI
H10-2-D40o0se0:OBrailoGpearvsaisgteenScteudSycrineeRnaintsg_______________________________________________________________________
SuppDleumPeonntt-N29o2. 51
FIGURE 3 COMPARISON OF RELATIVFEORLIHV-E2R40W00EAIGNHDTNAENGDAMTIEVAENCLOINVTERROFLLSUORINE CONCENTRATION
H CCHoo-rm2n40OO0ii0ll:(A(NTceeegstoatntSievueb(NsCteaognnactterio)vle) Control) - 19-
' ^ n iz e a . Does not contain T sr*
H10-2-D40o0se0:OrBailoGpearvsaisgteenSctuedSycrineeRnaintsg
FIGURE 4 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
SuppDleumPeonntt-N29o2. 51
/tM F Equivalents
6000 1H-24019 (Positive Control) H-24020 (Positive Control)
5000 H-24000 (Test Substance) 4000 3000
2000
1000
Day 10
Day 94
- 20-
Company Sanitized. Does not contain TSCA CBi
H10-2-D40o0se0:OBrailoGpearvsaisgteenSctuedSycrieneRniantsg
SuppDleumPeonntt-N29o2. 51
FIGURES COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
liM F Equivalents
-21 Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
APPENDICES
- 2 2 - Company Sanitized. Does noi contain TSCA CB!
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
- 2 3 - Company Sanitized. Does not contain TSCA CBi
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627789
627801 627805
627810
627818
Final Body Wt.
247.7
240.1 283.7
265.0
260.2
GROUP I
Liver Wt. 11.428 12.216 14.081 13.395 11.981
Relative Liver to Body Wt. 0.046
0.051
0.050
0.051
0.046
Test Day 5 5 5 5 5
Animal Number 627793
627797
627799
627800
627808
Final Body Wt.
283.5
324.2
294.7
331.3
321.8
GROUP II
Liver Wt. 15.292 15.803 14.285 16.344 17.580
Relative Liver to Body W t . 0.054
0.049
0.048
0.049
0.055
Test Day 10 10 10 10 10
Animal Number 627796
627806
627807
627809
627816
Final Body Wt.
322.7
320.3
305.2
336.2
330.2
GROUP III
Liver Wt. 13.404 15.413 14.935 14.967 15.811
Relative Liver to Body Wt. 0.042
0.048
0.049
0.045
0.048
Test Day 13 13 13 13 13
- 24- Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627791
627794
627804
627812
627817
Final Body Wt.
365.6
416.7
378.1
388.4
407.3
GROUP IV
Liver Wt. 15.371 19.105 15.326 16.775 16.600
Relative Liver to Body Wt. 0.042
0.046
0.041
0.043
0.041
Test Day 24 24 24 24 24
Animal Number 627792
627798
627813
627814
627815
Final Body Wt.
496.8
517.3
416.8
386.9
505.9
GROUP V
Liver W t . 16.359 19.293 15.234 14.358 20.958
Relative Liver to Body Wt. 0.033
0.037
0.037
0.037
0.041
Test Day 52 52 52 52 52
Animal Number 627795
627811
627819
627820
627821
Final Body Wt.
485.0
511.6
653.1
618.0
521.5
GROUP VI
Liver Wt. 16.649 17.405 21.828 26.766 17.943
Relative Liver to Body Wt. 0.034
0.034
0.033
0.043
0.034
Test Day 94 94 94 94 94
.
- 2 5 - Company Sanitized. Does not contain TSCA CS!
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 625361
625363
625364
625380
625383
F inai Body Wt.
349.7
286.7
312.0
305.5
313.1
GROUP I
Liver Wt. 16.800 11.236 13.845 13.253 13.026
Relative Liver to Body Wt. 0.048
0.039 0.044
0.043
0.042
Test Day 5 5 5 5 5
Animal Number 625355
625362
625367
625368
625378
Final Body Wt.
333.6
332.9
363.8
386.7
365.4
GROUP II
Liver Wt. 14.409 14.363 16.139 17.745 15.328
Relative Liver to Body Wt. 0.043
0.043
0.044
0.046
0.042
Test Day 10 10 10 10 10
Animal Number 625357
625358
625370
625384
625385
Final Body Wt.
405.6
340.7
407.0
357.1
377.6
GROUP III
Liver Wt. 20.091 12.954 21.654 16.520 17.355
Relative Liver to Body W t . 0.050
0.038
0.053
0.046
0.046
Test Day 13 13 13 13 13
26 Company Sanitized. Doss not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 625354
625365
625371
625376
625381
Final Body Wt.
396.1
459.6
447.3
432.9
381.8
GROUP IV
Liver Wt. 16.383 18.313 17.859 19.168 14.135
Relative Liver to Body Wt. 0.041
0.040
0.040
0.044
0.037
Test Day 24 24 24 24 24
Animal Number 625356
625359
625360
625372
625374
Final Body Wt.
533.7
530.3
555.4
506.2
512.3
GROUP V
Liver Wt. 20.498 22.901 23.312 21.287 18.378
Relative Liver to Body Wt. 0.038
0.043
0.042
0.042
0.036
Test Day 52 52 52 52 52
Animal Number 625353
625369
625373
625375
625377
Final Body Wt.
565.3
514.8
673.7
588.8
496.6
GROUP VI
Liver Wt. 18.655 17.379 20.073 18.869 17.261
Relative Liver to Body Wt. 0.033
0.034
0.030
0.032
0.035
Test Day 94 94 94 94 94
.
- 2 7 - Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24019 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 625322
625323
625336
625343
625349
Final Body Wt.
329.0
298.0
318.1 294.0
293.7
GROUP I
Liver Wt. 16.409 14.830 16.545 13.809 15.685
Relative Liver to Body Wt. 0.050
0.050
0.052 0.047
0.053
Test Day 5 5 5 5 5
Animal Number 625320
625330
625332
625341
625350
Final Body Wt.
312.1
310.1
318.3
325.6
284.3
GROUP II
Liver Wt. 18.845 16.343 17.528 18.254 15.709
Relative Liver to Body Wt. 0.060
0.053
0.055
0.056
0.055
Test Day 10 10 10 10 10
Animal Number 625321
625327
625342
625345
625348
Final Body Wt.
371.2
355.3
324.4
336.9
336.4
GROUP III
Liver Wt. 22.322 22.259 20.718 24.403 20.541
Relative Liver to Body Wt. 0.060
0.063
0.064
0.072
0.061
Test Day 13 13 13 13 13
V
"- -- -
i
TyT
Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24019 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
GROUP IV
Animal
Final
Relative Liver
Number______ Body Wt.______ Liver Wt._____ to Body Wt._____ Test Day
625325
381.3
21.479
0.056
24
625328
423.9
22.100
0.052
24
625338
339.9
18.018
0.053
24
625340
419.0
23.131
0.055
24
625352
375.3
21.835
0.058
24
Animal Number 625324
625329
625333
625334
625344
Final Body Wt.
447.4
498.1
427.4
426.5
391.0
GROUP V
Liver Wt. 20.900 20.911 20.508 19.144 17.666
Relative Liver to Body Wt. 0.047
0.042
0.048
0.045
0.045
Test Day 52 52 52 52 52
Animal Number 625326
625335
625346
626347
625351
Final Body Wt.
577.5
579.5
556.9
638.9
636.8
GROUP VI
Liver Wt. 23.749 21.548 23.945 27.416 25.615
Relative Liver to Body Wt. 0.041
0.037
0.043
0.043
0.040
Test Day 94 94 94 94 94
' 29 ~ company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24020 {POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627756
627767
627771
627773
627777
Final Body Wt.
237.5
248.6
239.6
262.3
236.0
GROUP I
Liver Wt. 15.360 19.033 16.968 17.629 16.268
Relative Liver to Body Wt. 0.065
0.077
0.071 0.067
0.069
Test Day 5 5 5 5 5
Animal Number 627768
627774
627776
627782
627785
Final Body Wt.
293.5
338.2
254.4
268.2
267.9
GROUP II
Liver Wt. 22.536 27.332 18.821 20.172 20.857
Relative Liver to Body Wt. 0.077
0.081
0.074
0.075
0.078
Test Day 10 10 10 10 10
Animal Number 627758
627763
627764
627787
627788
Final Body Wt.
308.7
285.8
306.7
234.9
309.4
GROUP III
Liver Wt. 26.021 22.123 21.526 16.498 22.730
Relative Liver to Body W t . 0.084
0.077
0.070
0.070
0.073
Test Day 13 13 13 13 13
- 3 0 - Ccmpany Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24020 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g) , LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627759
627761
627770
627779
627786
Final Body Wt.
380.1
359.4
379.8
406.2
326.1
GROUP IV
Liver Wt. 22.707 19.579 19.540 24.858 16.410
Relative Liver to Body Wt. 0.060
0.054
0.051
0.061 0.050
Test Day 24 24 24 24 24
Animal Number 627757
627760
627765
627772
627781
Final Body Wt.
436.7
456.5
455.6
513.5
421.0
GROUP V
Liver Wt. 16.899 18.240 16.505 20.225 16.695
Relative Liver to Body Wt. 0.039
0.040
0.036
0.039
0.040
Test Day 52 52 52 52 52
Animal Number 627762
627769
627775
627778
627783
Final Body Wt.
528.6
609.6
552.8
445.3
557.2
GROUP VI
Liver Wt. 17.732 19.324 17.296 15.628 21.044
Relative Liver to Body Wt. 0.034
0.032
0.031
0.035
0.038
Test Day 94 94 94 94 94
-31 - Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24000 {TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627227
627229
627234
627237
627239
Final Body Wt.
234.5
246.4
221.7
250.9
229.6
GROUP I
Liver Wt. 12.326 11.258 11.419 13.360 12.086
Relative Liver to Body Wt. 0.053
0.046
0.052
0.053
0.053
Test Day 5 5 5 5 5
Animal Number 627213
627219
627231
627243
627244
Final Body Wt.
301.3
262.2
295.1
262.6
276.6
GROUP II
Liver Wt. 18.118 16.329 17.325 ' 14.537 17.241
Relative Liver to Body W t . 0.060
0.062
0.059
0.055
0.062
Test Day 10 10 10 10 10
Animal Number 627216
627235
627238
627240
627242
Final Body Wt.
300.3
308.6
319.7
307.5
285.4
GROUP III
Liver Wt. 19.998 19.957 20.224 17.884 17.851
Relative Liver to Body Wt. 0.067
0.065
0.063
0.058
0.063
Test Day 13 13 13 13 13
- 3 2- Sanitized. Does nofcconairt TSCA CB?
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
H-24000 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627220
627222
627223
627228
627232
Final Body Wt.
354.3
379.6
382.0
407.4
370.2
GROUP IV
Liver Wt. 15.193 17.304 18.827 20.462 18.946
Relative Liver to Body Wt. 0.043
0.046
0.049
0.050
0.051
Test Day 24 24 24 24 24
Animal Number 627212
627214
627221
627241
627245
Final Body Wt.
520.5
482.8
447.8
595.7
517.2
GROUP V
Liver Wt. 19.870 18.189 17.604 26.836 23.292
Relative Liver to Body Wt. 0.038
0.038
0.039
0.045
0.045
Test Day 52 52 52 52 52
Animal Number 627218
627224
627230
627233
627236
Final Body Wt.
594.4
594.6
510.1
679.3
664.8
GROUP VI
Liver Wt. 21.496 23.067 17.673 27.844 24.002
Relative Liver to Body Wt. 0.036
0.039
0.035
0.041
0.036
Test Day 94 94 94 94 94
- 33- Company Sanitized. Does not contain TSCA CSf
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
APPENDIXE Individual Fluorine Levels
- 34- Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
Terms: Active % Active
TERMS AND CALCULATIONS
Mol Wt Active Formulation Dose % F in Active
Mol Wt F
Compound Calculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of
anim=a(l%boadcytiwvee/i1g0h0t.) x Formulation Dose
.
Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of anim=adlobsoed[ymwge/kiggh]t/ Mol Wt Active [mg/mmol]
Dose F (mg/kg)
The=m(g%FFluionriancetiavdem/1i0n0i)stxerDedospeerAkcgtivoef a[nmigm/kagl ]body weight
Dose F (mmol/kg)
The mmole of fluorine administered per kg of animal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol]
Molar Ratio (Active/F) The=mDoolesseoAfcftliuvoeri[nmemcoonl/tkagin]i/nDg ocsoemFpo[munmdopl/ekrgm] ole of fluorine
Formulation Dose Normalization Factor
The formulation dose that would be required to administer the amount of a=cti(vNeonremeadleidzetdo daochseieovfeAthcetinvoer[mmamliozel/dkgd]o/seDose Active
[mmol/kg]) x Formulation Dose
Company Sanitized. Does not contain i SCA CB1
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
__________ t e r m s a n d c a l c u l a t io n s
Individual Animal Measurement:
ppm F in liver
The ppm fluoride measured in liver
Individual Animal Calculations:
ppm F in Liver minus Bkg 0.2 ppm
The ppm fluoride measured in liver minus the background fluoride measured in control animal liver. In this case the value was established at 0.2 ppm.
pnpomrmFaliinzeLdivtoer 0.1 mmol/kg Dose
The ppm fluoride minus background that would be expected if the active dose was 0.1 mmol/kg instead of the actual active dose. This assumes linearity between administered dose and liver fluorine levels, but is needed because different doses of active were used in the study.
= ( 0.1 [mmol/kg] / Active dose [mmol/kg]) x (ppm F in blood minus background)
/molar equivalents of active in liver
The /molar [/mol/L] concentration of fluorine containing compound in liver based on the ppm fluorine in liver normalized to 0.1 mmol/kg falcutoivriendeo-csoen. tTaihniisngascsoummpesontheantt ainll tlhiveefrofrlmuourliantieoins. dNeroitvee:d 1frpopmmth-e 1 m=g/(LNormalized ppm [mg/L] fluorine in liver / Mol Wt F
[mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /mol/mmol
Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2925 Supplement No. 1
_________f a c t o r s in f l u e n c in g in t e r p r e t a t io n o f k in e t ic a n a l y s is ________
Considerations:
- The data used for kinetic analysis was from a limited screen and extrapolation should be done
cautiously.
-- SAanmalpylteicsailzedaistalouwsed without validation
- Steady-state not reached
-- TSoermmeincaolmpphoausendmsaayrenmotibxeturreeascohfedfluorinated compounds
.
-- DDiiffffeerreenntt avcethiviceleasnwd eforermusueladtitoonddeloisveesrwfoerrmeuulsaetidons
- Each compound may have very different potency for producing toxicity
Assumptions: (May or may not bejustified in all cases) -- LAinvaelryftilcuaolrimneetchoondciesnatrpaptiroonpsriaartee lfionreaalrlwtyipthesreosfpceocmt tpooduonsdes
- Elimination kinetics can be determined based on total fluorine rather than on concentrations of individual components
-- B%aFckdgartoauinsdthFelu%orFinleuoisri0n.e2opfptmhe active (Fluorine containing component(s) in the formulation)
- Molecular weight is the molecular weight of the active component in the formulation
37- - Company Sanitized. Does not contain TSCA CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-2925 Supplement No. 1
GivMeno: l Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
497 10 100
% F in Active: Mol Wt. F (g/mol):
65 19
C a lDc uolsaeteAdcVtiva leu(ems:g/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
10 0.020 49.7
Dose F (mmol/kg): 0.342
Molar Ratio (Active/F): .U59
Dose F (mg/kg):
6.5
ppm F in
Test ppm F
Liver
R at Day in Minus Bkg
Num ber Sample Liver_______ 0.2 ppm
G6r2o5u3p20II 625330 625332 662255334510
10 10 10 10 10
319.4 355.4 338.4 305.0 322.7
319.2 ~ 355.2 338.2 304.8 322.5
Group VI 625326 625335 625346 625347 625351
94 94 94 94 94
79.8 89.6 73.8 62.5 82.1
79.6 89.4 73.6 62.3 81.9
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose 1586.42 1765.34 1680.85 1514.86 1602.83 395.61 444.32 365.79 309.63 407.04
/molar Equivalents of Active in
Liver 4910.77 5464.62 5203.08 4689.23 4961.54 1224.62 1375.38 1132.31 1925680.4.060
- 38-
Corapasy Sanitized. Does not contain TSCA CBf
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H -24020
DuPont-2925 Supplement No. 1
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
426 20 100
% F in Active: Mol Wt. F (g/mol):
69 19
Calculated Values: Dose Active (mg/kg): FDoorsmeuAlacttiiovneD(mosmeoNleo/krmg)a:lization Factor:
20 0.047 42.6
Dose F (mmol/kg): 0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):
13.8
Test ppm F
Rat Number
Day Sample
in Liver
G6r2o7u7p68II 627774 627776 627782 627785
10 10 10 10 10
182.5 109.0 174.0 147.5 165.8
Group VI 627778 627783 627762 627775 627769
94 94 94 94 94
1.9 1.2 1.9 1.6 1.8
ppm F in Liver
Minus Bkg 0.2 ppm
182.3 108.8 173.8 147.3 165.6 1.7 1.0 1.7 1.4 1.6
pNpomrmFailnizLedivteor 0.1 mmoles/kg
Dose 388.30 231.74 370.19 313.75 352.73 3.62 23..1632 2.98 3.41
/tmolar Equivalents of Active in
Liver 1321.01 788.41 1259.42 1067.39 1200.00 12.32
7.25 12.32 10.14 11.59
3 9- Company Sanitized. Does not contain TSC CBI
H-24000: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24000
GivMeno:l Wt. Active (g/mole): F%orAmcutilvaetio(Fn CDoonsteai(nming/gk)gi)n: Formulation:
2500 1000 25
Calculated Values: Dose Active (mg/kg): FDoorsmeuAlacttiiovneD(mosmeoNleo/krmg)a:lization Factor:
250 0.100 1000.0
DuPont-2925 Supplement No. 1
% F in Active: Mol Wt. F (g/mol):
40 19
Dose F (mmol/kg): 5.263
Molar Ratio (Active/F): 0.019
Dose F (mg/kg):
100
Test ppm F
Rat Number
Day Sample
in Liver
Group n 627213 627219 627231 627243 627244
10 10 10 10 10
485.5 511.3 459.1 535.1 440.6
G6r2o7u2p18VI 627224 627230 627233 627236
94 9944 94 94
4.1 3.5 5.0 3.1 2.9
ppm F in Liver
Minus Bkg 0.2 ppm 485.3 455118..19 534.9 440.4
3.9 3.3 4.8 2.9 2.7
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose 194.12 204.44 183.56 213.96 176.16 1.56 1.32 1.92 1.16 1.08
/imolar Equivalents of Active in
Liver 647.07 681.47 611.87 713.20 587.20 5.20 46..4400 33..8670
- 40-
Company Sanitized. Does not contain TSCA CBI
