Document J7bKxQyX4B6D2jd49KjJLekX
AR226-3206
D uP on t-2931 Supplement N o. 1
TRADESECRET Study TUle
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1
Laboratory Project ID: DuPont-2931
Author: Carol Finlay, B.A.
Study Completed on: August 29, 2001
Supplement No. 1 Completed on: December 12,2001
Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences
Hw iElkton Road, P.O. Box 50 Newark, Delaware 19714-0050
Work Request Number:
Service Code Number:!
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by: Reviewed by:
Postdoctoral Fellow
Issued by Study D irector:
A M t ' l 'M j u ,.
Carol Fiipay, B.A. Q
Staff Scientist
Date
o x-& & -zo a / Date
1*1 Date
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H -24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D u P on t-2931 Supplement N o. 1
TABLE OF CONTENTS
Page
CERTIFICA TIO N ______________________________________________________________ 2
LIST OF TABLES
LIST OF FIGURES
LIST O F A PPEN D ICES------------------------------------------------------------------------------------- 4 STUDY INFORM ATION *********"******"***B***********"*"**"*"********"^ STUDY PER SO N N EL...............................................--.....--*.....----
REASON FOR SUPPLEMENT NO. 1
8
SUMMARY
M ATERIALS AND M ETHODS
RESULTS AND DISCUSSION A. Liver W eights.......................................................................................................................
1. T est Substance..........................................................................................................................................................
1 2. Positive C ontrols..................................................................................................................................................... B. Liver Fluorine D ata............................................................................................................... ^ 1. Positive C ontrols......................................................................................................................................................^ 2. Test Substance..............................................................................................................................
CONCLUSIONS
TABLES FIGURES ***************"""***"****************************" *
A P P E N D IC E S
22
**
')
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H -24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
LIST OF TABLES
Page
1. M EAN BODY AND LIVER W EIGHTS............................. 2. M EAN LIVER FLUORINE LEVELS............................................................................ 3. M EAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE............................................
13 15 15
LIST OF FIGURES
Page
1. COMPARISON OF M EAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE C O N T R O L S...........................
17
2. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE A N D POSITIVE CONTROLS.............................................................................................................................................................................. 18
3. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H -24042 AND NEGATIVE CONTROLS.......................................................................................................... .....19
4. M EAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE.........................................................20
5. COMPARISON OF M EAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO D O SE ................................................................................
21
LIST OF APPENDICES
Page
A. INDIVIDUAL FINAL BODY WEIGHTS, LIVER WEIGHTS, AND RELATIVE LIVER TO BODY W EIGHT....................................................................................................................................................................................23
B. INDIVIDUAL FLUORINE LEVELS................................................................................................................................. 34
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STUDY INFORM ATION TEST SUBSTANCE:
Haskell Number: 24042
D uP on t-2931 Supplement N o. 1
Known Impurities: Poly(difluoromethylene), alpha-fluoro-omega-(2-iodoethyl) (2-3%)
Physical Characteristics: Pale yellow to amber brown waxy solid
POSITIVE CONTROL:
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H-24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
D u P on t-2931 Supplement N o. 1
Known Impurities: Unknown POSITIVE CONTROL:
Composition
Known Impurities: Unknown Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A.
Study Initiated/Comoleted: April 30,1999 / (see report cover page) In-Life Initiated/Completed: June 13,1999 / September 14,1999
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H-24042: Biopersistence Screening 10-D ose Oral Gavage Stndy in Rats
DuPont-2931 Supplement N o. 1
STUDY PERSONNEL Study Director: Carol Finlay, B.A.
Management: Judith C. Stadler, Ph.D., D.A.B.T. Primary Technician: Richard P. Mathena
liv e r Fluorine Data Analysis: Paul M. Hinderliter, PhD . Management: Matthew S. Bogdanffy, PhD ., D.A.B.T.
Toxicology Report Preparation: Wanda F. Dinbokowitz
Laboratory Veterinarian: Wanda L. W est, D.V.M., A.C.L.A.M.
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H -24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
D u P on t-2931 Supplement N o. 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-24042), 2 positive controls (H-24019 and H-24020), and 2 negative controls (com oil and com oil/acetone).
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H -24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
D u P on t-2931 Supplement N o. 1
SUMMARY
The objective of this study was to evaluate the potential for H-24042, 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 100 mg/kg/day of H-24042. 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 ,1 0 ,1 3 ,2 4 ,5 2 ,9 4 ) 5 rats per group were euthanized and the blood and livers were collected. liv e rs were weighed and those collected on study days 10 and 94 were analyzed for total fluorine. This supplement includes liver weight data and the results o f total fluorine analyses in liver. Additionally, 2 negative controls, com oil and com oil/acetone (80:20), and 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-24042.
The mean relative liver weight (liver/body weight) of rats dosed with the test substance, H-24042, was up to 39% higher at day 10 than the mean relative liver weights of the negative 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 mean relative liver weight was up to 28% higher than the negative controls. In rats given H-24020, the mean relative liver weight was up to 75% higher than the negative controls. By day 94, the weights were similar.
The concentration of fluorine in the livers from rats dosed with the test substance, H-24042, was 271.39 fiM equivalents on day 10 and 15.15 xM equivalents on day 94. On day 10, mean jtiM equivalent concentrations of fluorine in the livers from rats dosed with the positive control materials were approximately 18-fold (H-24019) and 4-fold (H-24020) greater than the fluorine concentration in livers from rats treated with the test substance. By day 94, the fluorine concentration in rats dosed with the positive control H-24019 was approximately 80x the fluorine concentration in rats treated with H-24042. The fluorine concentration in rats dosed with the positive control H-24020 and test substance H-24042 was similar by day 94.
The iM equivalents of fluorine in the livers from rats dosed with the test substance, H-24042, were higher than levels in the blood.
Under the conditions o f this study, there was some absorption and retention o f fluorine in the liver from rats dosed with H-24042. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control H-24019. Fluorine levels in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. Liver weights were elevated in rats dosed with the test substance, H-24042, at the end of the dosing period, but not at the end o f the recovery period.
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DuPont-2931 Supplement N o. 1
MATERIALS AND METHODS
Blood and livers were collected on days 5 ,1 0 ,1 3 ,2 4 , 52, and 94. The livers were weighed. Only the test day 10 and 94 livers were analyzed for total fluorine. These tim e 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. Liver Weights (Table 1, Figures 1-3, Appendix A)
As with the body weights, comparison of absolute liver weights was complicated by the fact that there was a difference in age between rats dosed with the test substance and those dosed with the H-24019 positive control and com oil:acetone negative control. Therefore, liver weights relative to total body weight are presented for comparison for all rats.
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 day 13, the mean relative liver weight of rats dosed with the test substance was up to 48% higher than the negative controls. The weights were similar throughout the remainder of the recovery period.
2. Positive Controls
The mean relative liver weights of rats dosed with one of the positive controls, H-24019, were slightly lower on days 10 and 13 than the liver weights of rats dosed with the test substance, H-24042. The liver weights of rats dosed with H-24019 were 13-21% higher during the remainder of the recovery period than the liver weights of rats dosed with the test substance. The mean relative liver weight of rats dosed with H-24020, the other positive control, was 26% higher on day 10 than the liver weight of rats dosed with H-24042. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24020 were 10 or 40% higher than the liver weights o f rats dosed with H-24042. On days 52 and 94, the weights were similar.
The mean relative liver weight of rats dosed with H-24019 was up to 27% higher at day 10 than the negative control group. By day 94, the mean relative liver weight of rats dosed with H-24019 was up to 28% higher than the negative controls. The mean relative liver weight of rats dosed with H-24020 was up to 75% higher at day 10 than the negative controls. The mean relative liver weights of rats dosed with H-24020 began to decrease during the recovery period and were similar by test day 94 to the negative controls.
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H-24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
Therefore, liver weights of rats dosed with the test substance, H-24042, were elevated at the end of the 10-day dosing period. The relative liver weight by the end of recovery in rats dosed with the test substance was lower than in rats dosed with the positive control material H-24019 and similar to rats dosed with the positive control material H-24020.
B. Liver Fluorine Data (Tables 2 and 3, Figures 3 - 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 juM equivalents for H-24019 and H-24020, respectively. By day 94, the concentrations were 1190.15 and 10.72 xM equivalents.
2. Test Substance
Levels of total fluorine in livers from rats dosed with the test substance, H-24042, were generally lower than the levels in livers from rats dosed with the positive control materials. The total fluorine concentration in the liver from rats dosed with H-24042 was 271.39 /iM equivalents at day 10 and 15.15 iM equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 18x higher (day 10) and approximately 80x higher (end of study) than H-24042. For H-24020, the liver concentration was approximately 4x higher by day 10. The fluorine concentration in rats dosed with the positive control H-24020 and test substance H-24042 was similar by day 94.
The /iM 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 o f fluorine in the liver from rats dosed with H-24042. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control H-24019. Fluorine levels in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. Liver weights were elevated in rats dosed with the test substance, H-24042, at the end of the dosing period, but not at the end of the recovery period.
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TABLES
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D u P on t-2931 Supplement N o. 1
Test Days
5 10 13 24 52 94
TABLE 1
MEAN BODY AND LIVER WEIGHTS (g)
CORN OIL (NEGATIVE CONTROL)
Absolute
Body Weight
liv e r Weight
259.3
12.620
311.1
15.861
322.9
14.906
391.2
16.635
464.7
17.240
557.8
20.118
Mean Relative
Liver Weight(% of Body Weight) 0.049 0.051 0.046 0.043 0.037 0.036
Test Days 5 10 13 24 52 94
CORN OIL:ACETONE (NEGATIVE CONTROL)
Absolute
Body Weight
Liver Weight
313.4
13.632
356.5
15.597
377.6
17.715
423.5
17.172
527.6
21.275
567.8
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 W eight
Liver Weight
306.6
15.456
310.1
17.336
344.8 387.9 438.1 597.9
22.049 21.313 19.826 24.455
, Mean Relative Liver Weight(% of Body Weight)
0.050 0.056 0.064 0.055 0.045 0.041
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D u P on t-2931 Supplement N o. 1
TABLE 1 (Continued)
MEAN BODY AND OVER WEIGHTS (g)
H-24020 (POSITIVE CONTROL)
Test Days
5 10 13 24 52 94
_____________ Absolute_____________
Mean Relative
Body W eight______ Liver Weight Liver Weight(% of Body Weight)
244.8
17.052
0.070
284.4
21.944
0.077
289.1
21.780
0.075
370.3
20.619
0.056
456.7
17.713
0.039
538.7
18.205
0.034
Test Days 5 10 13 24 52 94
H-24042 (TEST SUBSTANCE)
Absolute
Body W eight
Liver Weight
258.9
16.273
286.3
17.575
317.7
21.447
385.2
17.580
480.1
19.048
592.0
20.150
Mean Relative Liver Weight(% of Body Weight)
0.063 0.061 0.068 0.046 0.040 0.034
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H -24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
TABLE2 MEAN LIVER FLUORINE LEVELS
Test Days
10 94
Negative Controls
Com
Com Oil Oil:Acetone
(PPm)
(ppm)
<0.2 <0.5
0.6a l a
Positive Controls
H-24019 (ppm)
328.18 (19.3)b 77.56 (10.1)
H-24020 (PPm)
155.76 (29.2) 1.68 (0.3)
a One value. Four o f the values were below the level o f detection (LOD). b Standard deviation is in parentheses.
Test Substance
H-24042 (ppm)
203.74 (20.45) 11.56 (2.22)
TABLE3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 94
Positive Controls
H-24019
H-24020
ixM F Equivalents jlM F Equivalents
5045.85 (296.9l)a 1127.25 (211.37)
1190.15 (156.05)
10.72 (2.14)
a Standard deviation is in parentheses.
Test Substance H-24042
jttM F Equivalents 271.39 (27.26) 15.15 (2.96)
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
FIGURES
I
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H -24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
FIGURE 1 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND NEGATIVE CONTROLS
D u P on t-2931 Supplement N o. 1
Test Days
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H-24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
D uP on t-2931 Supplement N o. 1
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H -24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
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FIGURE 3
COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24042 AND NEGATIVE CONTROLS
B Com O il (Negative Control)
Com O il:Acetone (Negative Control)
ID H -24042 (Test Substance)
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H-24042: Biopersistence Screening, 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN UVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
D uP on t-2931 Supplement N o. 1
6000-
5000
4000
1 ? 'W3er 3000
fct
2000
1000
D ay 10
S H -2 4 0 1 9 (Positive Control) H-24020 (Positive Control) H-24042 (Test Substance)
D ay 94
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FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN OVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
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APPENDICES
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APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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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 Wt. 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
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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 TV
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 W t .
496.8
517.3
416.8
386.9
505.9
GROUP V
Liver Wt. 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
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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
Final 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 W t .
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 Wt. 0.050
0.038
0.053
0.046
0.046
Test Day 13 13 13 13 13
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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
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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
- 2 8 - Company Sanitized. Does net contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D uP on t-2931 Supplement N o. 1
H-24019 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 625325
625328
625338
625340
625352
Final Body Wt.
381.3
423.9
339.9
419.0
375.3
GROUP IV
Liver Wt. 21.479 22.100 18.018 23.131 21.835
Relative Liver to Body Wt. 0.056
0.052
0.053
0.055
0.058
Test Day 24 24 24 24 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
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D uP on t-2931 Supplement N o. 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 W t . 26.021 22.123 21.526 16.498 22.730
Relative Liver to Body Wt. 0.084 0.077
0.070 0.070
0.073
Test Day 13 13 13 13 13
Company Sanitized. Does not contain TSCACBI
H-24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 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
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
H-24042 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627295
627298
627300
627302
627311
Final Body Wt.
278.0
241.9
259.6
257.0
257.9
GROUP I
Liver Wt. 18.201 13.763 16.695 16.611 16.097
Relative Liver to Body Wt. 0.065
0.057
0.064
0.065
0.062
Test Day 5 5 5 5 5
Animal Number 627283
627289 627292
627293
627309
Final Body Wt.
264.4
277.6
308.6
274.2
306.6
GROUP II
Liver Wt. 15.437 16.911 19.006 16.548 19.975
Relative Liver to Body Wt. 0.058
0.061
0.062
0.060
0.065
Test Day 10 10 10 10 10
Animal Number 627285
627288 627294
627301
627304
Final Body Wt.
314.3
316.5
292.6
343.6
321.4
GROUP III
Liver W t . 20.897 20.220 19.927 23.344 22.845
Relative Liver to Body Wt. 0.066
0.064
0.068 0.068
0.071
Test Day 13 13 13 13 13
-32-
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D u P on t-2931 Supplement N o. 1
H-24042 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627279
627282
627286
627287
627299
Final Body Wt.
368.4
346.2
411.4
396.6
403.6
GROUP IV
Liver Wt. 17.672 13.799 19.798 17.616 19.014
Relative Liver to Body Wt. 0.048
0.040
0.048
0.044
0.047
Test Day 24 24 24 24 24
Animal Number 627290
627296 627306
627307
627310
Final Body Wt.
438.4
411.4
497.7
527.6
525.6
GROUP V
Liver Wt. 19.563 15.623 17.617 21.739 20.699
Relative Liver to Body Wt. 0.045 0.038
0.035 0.041
0.039
Test Day 52 52 52 52 52
Animal Number 627281
627297
627303
627305
627308
Final Body Wt.
574.3
531.5
512.5 743.2
598.6
GROUP VI
Liver Wt. 18.730 18.196 16.634 27.873 19.317
Relative Liver to Body Wt. 0.033
0.034
0.032
0.038
0.032
Test Day 94 94 94 94 94
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
APPENDIX B Individual Fluorine Levels
-34-
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement N o. 1
Ternis: Active % Active
TERMS AND CALCULATIONS
Mol W t Active Formulation Dose % F in Active
Mol W t F
Compound C alculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of animal body weight.
= ( % active/lOO) x Formulation Dose
Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of animal body weight = dose [mg/kg] / Mol Wt Active [mg/mmol]
Dose F (mg/kg)
The mg Fluorine administered per kg of animal body weight = (% F in active/100) x Dose Active [mg/kg]
Dose F (mmol/kg)
The mmole of fluorine administered per kg of animal body weight
= Dose F [mg/kg] / Mol W t F [mg/mmol]
'
Molar Ratio (Active/F) The moles of fluorine containing compound per mole of fluorine = Dose Active [mmol/kg] / Dose F [mmol/kg]
Formulation Dose Normalization Factor
The formulation dose that would be required to administer the amount of active needed to achieve the normalized dose
= (Normalized dose of Active [mmol/kg] / Dose Active [mmol/kg]) x Formulation Dose
- 35-
Company Sanitized. Does not contain TSCACB1
H -24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D uP on t-2931 Supplement N o. 1
TERMS AND CALCULATIONS
Individual Animal M easurem ent:
ppm F in liver
The ppm fluoride measured in liver
Individual Animal C alculations:
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.
ppm F in Liver normalized to 0.1 mmol/kg Dose
The ppm fluoride minus background that would be expected if the aetive 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 liver 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 active dose. This assumes that all liver fluorine is derived from the fluorine-containing component in the formulation. Note: 1 ppm 1 mg/L
= (Normalized 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
Does not contain "ESCA.CBS
H -24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D uP on t-2931 Supplement No. 1
FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
Considerations:
- The data used for kinetic analysis was from a limited screen and extrapolation should be done cautiously.
- Sample size is low - Analytical data used without validation - Steady-state not reached - Terminal phase may not be reached - Some compounds are mixtures of fluorinated compounds - Different active and formulation doses were used - Different vehicles were used to deliver formulations - Each compound may have very different potency for producing toxicity
Assumptions: (May or may not bejustified in all cases)
- Liver fluorine concentrations are linear with respect to dose - Analytical method is appropriate for all types of compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of
individual components - Background Fluorine is 0.2 ppm - % F data is the % Fluorine of the active (Fluorine containing com ponents) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation
37- - Company SanitizecL D oes notcontain TSGA.CBS
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
D ata for H- 24019
D uP on t-2931 Supplement N o. 1
G iven: Mol 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 alculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
10 0.020 49.7
Dose F (mmol/kg):
0.342
M olar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
R at Number
Test ppm F Day in Sample Liver
G roup II
625320
10 319.4
625330
10 355.4
625332
10 338.4
625341
10 305.0
625350
10 322.7
ppm F in L iv er
M inus Bkg 0.2 ppm
319.2 355.2 338.2 304.8 322.5
ppm F in Liver N orm alized to 0.1 mmoles/kg
Dose
1586.42 1765.34 1680.85 1514.86 1602.83
/tm olar E q u iv ale n ts of Active in
L iv er
4910.77 5464.62 5203.08 4689.23 4961.54
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
395.61 444.32 365.79 309.63 407.04
1224.62 1375.38 1132.31 958.46 1260.00
- 38Cotnpany Sanitized. Does not contain TSCA CBi
H-24042: Biopersistence Screening 10-D ose Oral Gavage Study in Rats
D ata for H- 24020
DuPont-2931 Supplement N o. 1
G iven: 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
C alculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
20 0.047 42.6
Dose F (mmol/kg):
0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):
13.8
R at N um ber
Test ppm F Day in Sam ple L iver
Group II
627768
10 182.5
627774
10 109.0
627776
10 174.0
627782
10 147.5
627785
10 165.8
ppm F in L iv er
M inus Bkg 0.2 ppm
182.3 108.8 173.8 147.3 165.6
ppm F in Liver Norm alized to 0.1 mmoles/kg
Dose
388.30 231.74 370.19 313.75 352.73
pm olar E q u iv ale n ts o f Active in
L iv er
1321.01 788.41 1259.42 1067.39 1200.00
Group VI 627778 627783 627762 627775 627769
94 94 94 94 94
1.9 1.2 1.9 1.6 1.8
1.7 1.0 1.7 1.4 1.6
3.62 12.32 2.13 7.25 3.62 12.32 2.98 10.14 3.41 11.59
- 39-
Company Sanitized. Does not contain TSCA CBI
H -24042: B iopersistence Screening 10-D ose Oral G avage Study in Rats
D ata fo r H-24042
D u P on t-2931 Supplem ent N o. 1
G iven: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
531 100 100
% F in Active: Mol Wt. F (g/mol):
75 19
C alculated V alues: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
100 0.188 53.1
Dose F (mmol/kg):
3.947
M olar Ratio (Active/F): 0.048
Dose F (mg/kg):
75
R at N um ber
Test ppm F Day in Sam ple Liver
G roup II 627283 627289 627292 627293 627309
10 194.9 10 234.0 10 214.1 10 182.1 10 193.6
ppm F in L iv er
M inus Bkg 0.2 ppm
194.7 233.8 213.9 181.9 193.4
ppm F in Liver N orm alized to 0.1 m m oles/kg
Dose
/tm olar E q u iv ale n ts o f Active in
L iv er
103.39 124.15 113.58 96.59 102.70
259.60 311.73 285.20 242.53 257.87
G roup VI
627281 94 10.3
10.1
5.36
13.47
627297 94 11.4
11.2
5.95
14.93
627303 94 12.2
12.0
6.37
16.00
627305 94 14.9
14.7
7.81
19.60
627308
94
9.0
8.8
4.67
11.73
-40-
ram yaofl Sanitized. Does not contain TSCA CBl
