Document oDVK41DX3kJ6JmX5bBe7248JE
TRADE SECRET Study Title
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1
Laboratory Project ID: DuPont-4182
DuPont-4182 Supplement No. 1
AR226-3217
A u t h o r : Carol Finlay, B.A.
Study Completed on: September 5,2000
Supplement No. 1 Completed on: January 11,2002
P e r f o r m in g L a b o r a t o r y : E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
W ork Request Num ber:
Ser v ic e C o de N um ber:
Page 1 of 40
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by:
Paul M . H inderliter, Ph.D. Postdoctoral Fellow
R ev iew ed
a& LJ.
Judith C. Stadler, P h D .. D A B .T . D irector
Issued by Study D ire c to r:_
t LA 8^ - %CfbL/lt* _ Carol Finlay, B-AQ Staff Scientist
D ate
j_3_ai\LM2D ate
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
TABLE OF CONTENTS
Page
C E R T IFIC A T IO N .................................................................................................................................. 2
LIST O F TA B LE S..................................................................................................................................4
LIST O F F IG U R E S ................................................................................................................................4
LIST O F A PP E N D IC E S....................................................................................................................... 4
STUDY IN FO R M A T IO N .....................................................................................................................5
STUDY PER SO N N EL........................................................................................................................... 7
REASON F O R SU PPLEM EN T NO. 1 .............................................................................................. 8
SU M M A RY .......................
9
M ATERIALS AND M E T H O D S....................................................................................................... 10
RESULTS AND DISCUSSION. A. Liver Weights...................
1. Test Substance..................... 2. Positive Controls................
B. Liver Fluorine D ata...........
1. Positive Controls................. 2. Test Substance.....................
10 10
.10 .10
11
.11 .11
C O N C LU SIO N S.......................
11
TABLES.................................................................................................................................................. 12
FIG U R ES................................................................................................................................................16
A PPEN D IC ES....................................................................................................................................... 22
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
LIST OF TABLES
Page
1. MEAN BODY AND LIVER WEIGHTS ( g ) ................................................................................................................. 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..........................!............................................................................................................................................. 17
2. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND POSITIVE CONTROLS......................................................................................................................................................................... 18
3. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24159 AND NEGATIVE CONTROLS.......................................................................19
4. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE.......................................................20 5. COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION
NORMALIZED TO D O S E ............................................................................................................................................... 21
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
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE:
Substance Tested: Svnonvms/Codes :
H-24159 Haskell Number: 24159
C om positional
DuPont-4182 Supplement No. 1
Known Impurities: 0
POSITIVE CONTROL: Substance Tested: Potassium perfluoroalkyl sulfonate Svnonvms/Codes: H-24019
Haskell Number: 24019
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORM ATION (Continued)
DuPont-4182 Supplement No. 1
POSITIVE CONTROL: Substance Tested: Octanoic acid, pentadecafluoro-, ammonium salt Synonvms/Codes: H-24020
Perfluorooctanoate, ammonium salt APFO Ammonium perfluorooctanoate Haskell Number: 24020
Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A.
Study Initiated/Completed: April 30, 1999 / (see report cover page) In-Life Initiated/Completed: July 11, 1999 / October 12,1999
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DuPont-4182 Supplement No. 1
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 Data Analysis: Paul M. Hinderliter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T.
Toxicology Report Preparation: Wanda F. Dinbokowitz
Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M.
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 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-24159), 2 positive controls (H-24019 and H-24020), and 2 negative controls (com oil and com oil/acetone).
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-24159, 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 35 mg/kg/day of H-24159. 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 , 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 for total fluorine. This supplement includes liver weight data and the results of 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-24159.
The mean relative liver weights (liver/body weight) of rats dosed with the test substance, H-24159, were 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-24159, was 1617.20 xM equivalents on day 10 and 91.00 fiM equivalents on day 94. The liver concentrations for the positive control H-24019 were approximately 3x higher (day 10) and approximately 13x higher (end of study) than H-24159. The liver concentrations for the test substance, H-24159, were approximately 1.4x higher (day 10) and approximately 8x higher (end of study) than the positive control H-24020.
The juM equivalents of fluorine in the livers from rats dosed with the test substance, H-24159, 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-24159. Fluorine levels in the liver were lower than levels in rats dosed with the positive control H-24019. However, fluorine levels in the livers from rats dosed with the test substance were higher than levels in rats dosed with the positive control H-24020. Liver weights were not affected in rats dosed with the test substance.
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DuPont-4182 Supplement No. 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 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. 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 the 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 weights of rats dosed with the test substance, H-24159, were similar to the negative controls.
2. Positive Controls
The mean relative liver weight of rats dosed with one of the positive controls, H-24019, was 14% higher on day 10 than the liver weight of rats dosed with the test substance, H-24159. The liver weights of rats dosed with H-24019 were 11-36% higher during 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 57% higher on day 10 than the liver weight of rats dosed with H-24159. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24020 were 60 or 24% higher than the liver weights of rats dosed with H-24159. 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 groups. 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.
Therefore, liver weights of rats dosed with the test substance, H-24159, were not affected.
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DuPont-4182 Supplement No. 1
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 /xM 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-24159, were lower than the levels in livers from rats dosed with the positive control H-24019 but higher than the levels in livers from rats dosed with the positive control H-24020. The total fluorine concentration in the liver from rats dosed with H-24159 was 1617.20 ptM equivalents at day 10 and 91.00 [iM. equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 3x higher (day 10) and approximately 13x higher (end of study) than H-24159. The liver concentration was approximately 1.4x higher on day 10 in rats dosed with the test substance than in rats dosed with the positive control H-24020. On day 94, the concentration was approximately 8x higher in rats dosed with H-24159 than in rats dosed with
H-24020.
The iM equivalents of fluorine in the liver 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-24159. Fluorine levels in the liver were lower than levels in rats dosed with the positive control H-24019. However, fluorine levels in the livers from rats dosed with the test substance were higher than levels in rats dosed with the positive control H-24020. Liver weights were not affected in rats dosed with the test substance.
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
TABLES
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DuPont-4182 Supplement No. 1
Test Days 5 10 13 24 52 94
TABLE 1
MEAN BODY AND LIVER WEIGHTS (g)
CORN OIL (NEGATIVE CONTROL)
Absolute
Body Weight
Liver 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
Body Weight
Liver Weight
306.6
15.456
310.1
17.336
344.8
22.049
387.9
21.313
438.1
19.826
597.9
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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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
Test Days 5 10 13 24 52 94
TABLE 1 (Continued)
MEAN BODY AND LIVER WEIGHTS (g)
H-24020 (POSITIVE CONTROL)
Absolute
Body Weight
Liver Weight
244.8
17.052
284.4
21.944
289.1
21.780
370.3
20.619
456.7
17.713
538.7
18.205
Mean Relative Liver Weight(% of Body Weight)
0.070 0.077 0.075 0.056 0.039 0.034
Test Days 5 10 13 24 52 94
H-24159 (TEST SUBSTANCE)
Absolute
Body Weight
Liver Weight
265.0 303.3
13.327 14.764
323.0
15.184
402.6
18.144
488.3
17.842
576.4
21.086
Mean Relative Liver Weight(% of Body Weight)
0.050 0.049 0.047 0.045 0.037 0.037
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
TABLE 2 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) 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-24159 (PPm)
90.5 (8.45) 5.3 (1.10)
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 94
Positive Controls
Test Substance
H-24019
H-24020
H-24159
/tM F Equivalents /M F Equivalents______ /M F Equivalents
5045.85 (296.91)a 1127.25 (211.37)
1617.20 (151.34)
1190.15 (156.05)
10.72 (2.14)_________ 91.00 (19.76)
a Standard deviation is in parentheses.
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
FIG U R E S
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 1 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND NEGATIVE CONTROLS
U TcOe3
o
4>) 3 >a QS
DuPonPTl82 Supplement No. 1
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
oa ua>> 3 S C0>Q
DuPont-4182 Supplement No. 1
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
#
DuPPOoi!PP44188:2
Supplement No. 1
FIGURE 3
COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LTVER FLUORINE CONCENTRATION FOR H-24159 AND NEGATIVE CONTROLS
Day 10
Day 13
Day 94
Day 10
01 Com Oil (Negative Control) Com Oil:Acetone (Negative Control) H-24159 (Test Substance)
Day 94
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159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Supplement No. 1
6000
5000
4000
aa0) a> EO3d' 30 0 0 ta
2000
G3H-24019 (Positive Control) H-24020 (Positive Control) H-24159 (Test Substance)
1000
0
D ay 10
D ay 94
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^^14159: Biopersistence Screening
10-Dose Oral Gavage Study in Rats
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D u P3ooin!PR4il88:2
Supplement No. 1
FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
6000
H-24019 (Positive Control)
H-24020 (Positive Control)
H-24159 (Test Substance)
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H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
APPENDICES
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DuPont-4182 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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DuPont-4182 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 W t .
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 W t .
283.5 324.2
294.7
331.3
321.8
GROUP II
Liver W t . 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 W t . 0.042
0.048
0.049
0.045
0.048
Test Day 13 13 13 13 13
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DuPont-4182 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 W t .
365.6
416.7
378.1
388.4
407.3
GROUP IV
Liver W t . 15.371 19.105 15.326 16.775 16.600
Relative Liver to Body W t . 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 W t . 16.359 19.293 15.234 14.358 20.958
Relative Liver to Body W t . 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 W t . 16.649 17.405 21.828 26.766 17.943
Relative Liver to Body W t . 0.034
0.034 0.033
0.043
0.034
Test Day 94 94 94 94 94
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DuPont-4182 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
Final Body W t .
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 W t .
405.6 340.7
407.0
357.1
377.6
GROUP III
Liver W t . 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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DuPont-4182 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 W t .
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 W t .
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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DuPont-4182 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 W t .
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 W t .
312.1
310.1
318.3
325.6 .
284.3
GROUP II
Liver W t . 18.845 16.343 17.528 18.254 15.709
Relative Liver to Body W t . 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 W t .
371.2
355.3 324.4
336.9 336.4
GROUP III
Liver W t . 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
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Company Sanitized. Does not contain TSCA CB1
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 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 625325
625328
625338
625340 625352
Final Body W t .
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 W t .
447.4
498.1
427.4
426.5
391.0
GROUP V
Liver W t . 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 no? contain TSCA CB1
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 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 W t .
237.5
248.6
239.6
262.3 236.0
GROUP I
Liver W t . 15.360 19.033 16.968 17.629 16.268
Relative Liver to Body W t . 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 W t .
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 W t . 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 W t .
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
- 30-
Company Sanitized. Does not contain TSCA CBI
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 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 W t .
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 W t .
436.7
456.5
455.6
513.5
421.0
GROUP V
Liver W t . 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 W t .
528.6
609.6 552.8
445.3
557.2
GROUP VI
Liver W t . 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-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
H-24159 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 628162
628173
628176
628183
628186
Final Body Wt.
271.8
269.1
254.2
298.4 231.5
GROUP I
Liver W t . 12.989 14.117 12.659 15.958 10.912
Relative Liver to Body W t . 0.048
0.052
0.050
0.053 0.047
Test Day 5 5 5 5 5
Animal Number 628159
628165
628168 628172
628177
Final Body W t .
299.3
300.1
313.0
281.8
322.5
GROUP II
Liver W t . 14.843 15.557 13.711 13.779 15.930
Relative Liver to Body W t . 0.050
0.052
0.044
0.049
0.049
Test Day 10 10 10 10 10
Animal Number 628154
628158 628171
628175
628185
' GROUP III
Final Body Wt.
338.9
332.7
320.6
326.5
296.1
Liver Wt. 16.428 16.667 14.018 14.365 14.443
Relative Liver to Body Wt. 0.048 0.050
0.044
0.044
0.049
Test Day 13 13 13 13 13
- 32-
Company Sanitized. Does not contain TSCA CBI
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
H-24159 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 628155
628164
628166
628170 628184
Final Body W t .
412.0
386.4
417.1
421.1
376.2
GROUP IV
Liver Wt. 18.626 18.622 18.295 18.890 16.289
Relative Liver to Body Wt. 0.045
0.048
0.044
0.045 0.043
Test Day 24 24 24 24 24
Animal Number 628156
628157
628160 628180
628181
Final Body W t .
475.5 532.7
474.3
508.1
450.8
GROUP V
Liver W t . 18.319 20.768 17.939 17.447 14.735
Relative Liver to Body W t . 0.039
0.039
0.038
0.034
0.033
Test Day 52 52 52 52 52
Animal Number 628161
628167 628174
628178
628179
Final Body W t .
503.0
635.7
571.7
541.9
629.8
GROUP VI
Liver Wt. 18.991 22.640 20.463 19.841 23.497
Relative Liver to Body W t . 0.038
0.036 0.036
0.037
0.037
Test Day 94 94 94 94 94
Company Sanitized. Does not contain TSCA CBI
- 33-
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
APPENDIX B Individual Fluorine Levels
Company Sanitized. Does not contain TSCA CB1 - 34-
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
Terms: Active % Active
Mol Wt Active Formulation Dose % F in Active
Mol Wt F
TERMS AND CALCULATIONS
Fluorine containing compound The % of formulation that is made up of fluorine containing components The molecular weight of the fluorine containing components (g/mole) The mg of formulation given per kg of animal body weight The % fluorine in the fluorine containing components of the formulation (weight basis) The molecular weight of fluorine g/mol
Compound Calculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of animal body weight.
= (% active/100) 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 Wt 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-
impany Sanitized. Does not contain TSCA CB1
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 Supplement No. 1
TERMS AND CALCULATIONS
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.
ppm F in Liver normalized to 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 liver minus background)
/molar equivalents of active in liver
The /molar [/imol/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 W t F [mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /mol/mmol
otnpany Sanitized. Does not contain TSCA CB1
- 36-
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-4182 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 component(s) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation
- 37-
impany Sanitized. Does not contain TSCA CB!
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-4182 Supplement No. 1
Given: 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
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
10 0.020 49.7
Dose F (mmol/kg):
0.342
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
Rat Number
Test ppm F Day in Sample Liver
ppm F in Liver
Minus Bkg 0.2 ppm
Group II
625320
10 319.4
625330
10 355.4 .
625332
10 338.4
625341
10 305.0
625350
10 322.7
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 1132.31 958.46 1260.00
- 38-
wOltloanv Sanitized. Hoes no*
TRPh
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24020
DuPont-4182 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): 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
Rat Number
Test Day Sample
ppmF in
Liver
Group II 627768 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
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
388.30 231.74 370.19 313.75 352.73
3.62 2.13 3.62 2.98 3.41
pmolar 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
Company Sanitized. Does not contain TSCA CB1 - 39-
H-24159: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24159
DuPont-4182 Supplement No. 1
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
450 35 29
% F in Active: Mol Wt. F (g/mol):
55 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
10.15 0.023 155.2
Dose F (mmol/kg):
0.294
Molar Ratio (Active/F): 0.077
Dose F (mg/kg):
5.5825
Rat Number
Test Day Sample
ppm F in
Liver
Group II 628177 628168 628165 628172 628159
10 10 10 10 10
88.4 91.9 81.8 104.1 86.2
Group VI 628178 628167 628161 628179 628174
94 94 94 94 94
3.9 6.6 4.8 4.9 6.2
ppm F in Liver
Minus Bkg 0.2 ppm
88.2 91.7 81.6 103.9 86.0
3.7 6.4 4.6 4.7 6.0
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
391.03 406.55 361.77 460.64 381.28
16.40 28.37 20.39 20.84 26.60
imolar Equivalents of Active in
Liver
1579.94 1642.63 1461.71 1861.17 1540.53
66.28 114.64 82.40 84.19 107.48
:jmpany Sanitized. Does not contain TSCACBT - 40-
