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DuPont-2932 Supplement No. 1
TRADE SECRET Study Title
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1
Laboratory Project ID: DuPont-2932
Author: Carol Finlay, B.A Study Completed on: August 29,2000 Supplement No. 1 Completed on: February 7, 2002 Performing Laboratory: 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 Work Request Number: Service Code Number:
SCKCBt ,, o ic o n ^ San*i1ttend Do* Con>PanY
Page 1 of 40
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by:
Reviewed by:
C. sz& oU ltJu
% Judith C. Stadler. PbJD., D.A.B.T. Director
Issued by Study D irector:
Staff Scientist
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
TABLE OF CONTENTS
Page
CERTIFICATION......................................................................................................................... 2
LIST OF TABLES.......................
4
LIST OF FIGURES....................................................................................................................... 4
LIST OF APPENDICES............................................................................................................... 4
STUDY INFORMATION............................................................................................................. 5
STUDY PERSONNEL................................................................................................................... 7
REASON FOR SUPPLEMENT NO. 1 ........................................................................................ 8
SUMMARY.................................................................................................................................... 9
MATERIALS AND METHODS................................................................................................ 10
RESULTS AND DISCUSSION.................................................................................................. 10 A. Liver W eights............................................................................................................................... 10 B. Liver Fluorine D ata...................................................................................................................... 11
CONCLUSIONS...........................................................................................................................11
TABLES.........................................................................................................................................12
FIGURES.......................................................................................................................................16
APPENDICES.............................................................................................................................. 22
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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-24043 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 DOSE................................................................................................................................... 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-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORM ATION TEST SUBSTANCE:
Substance Tested: Svnonvms/Codes: H-24043
Haskell Number: 24043 Composition:
DuPont-2932 Supplement No. 1
Known Impurities: Not supplied by the sponsor POSITIVE CONTROL:
Substance Tested! C-
Synonvms/Codes : H-24019
Haskell Number: 24019 Compositio:
Known Impurities: Unknown
Company Sani**. D oe. not co n tain T S C A CB1
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORM ATION (Continued) POSITIVE CONTROL:
Substance Tested!
DuPont-2932 Supplement No. 1
Known Impurities: Unknown
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
Company Sanitized. Dorn contain TSCA CBJ
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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.
Company Sanitized. D oes not contain TSCA CB(
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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-24043), 2 positive controls (H-24019 and H-24020), and 2 negative controls (com oil and com oil/acetone).
C"* anr S a n i c i
Doe* not contain TSCACBt
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-24043, 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-24043. 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 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 and analyzed as described for H-24043.
The mean relative liver weight (liver/body weight) of rats dosed with the test substance, H-24043, was up to 30% higher than the negative controls on day 10. The weights were similar by day 94. 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-24043, was 1306.27 [iM equivalents on day 10 and 80.27 (iM equivalents on day 94. The liver concentrations for the positive control H-24019 were approximately 4x higher (day 10) and approximately 15x higher (end o f study) than H-24043. The liver concentration for the test substance, H-24043, was slightly higher on day 10 and approximately 7x higher at the end of the study than the positive control H-24020.
The fiM equivalents of fluorine in the livers from rats dosed with the test substance, H-24043, were higher than levels in the blood.
Under the conditions of this study, there was some absorption and retention of fluorine in the livers from rats dosed with H-24043. Fluorine levels in the liver were lower than levels in rats dosed with the positive control material, 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 elevated at the end of the 10-day dosing period.
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
MATERIALS AND MET HODS
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. 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. Therefore, liver weights relative to total body weight are presented for comparison for all rats.
1. Test Substance
The mean relative liver weight (liver/body weight) of rats dosed with the test substance, H-24043, was up to 30% higher than the negative controls on day 10. On days 13 and 24 (recovery), the weights were 37 or 27% higher than the negative controls. The weights were similar to the negative controls on days 52 and 94.
2. Positive Controls
The mean relative liver weights of rats dosed with one of the positive controls, H-24019, were similar to the liver weights of rats dosed with the test substance, H-24043. The mean relative liver weight of rats dosed with the other positive control, H-24020, was 35% higher on day 10 than the liver weight of rats dosed with H-24043. On day 13 (recovery), the mean relative liver weight of rats dosed with H-24020 was 19% higher than the liver weight of rats dosed with H-24043. On days 24, 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 were elevated in rats dosed with the test substance. The relative liver
weight by the end of recovery in rats dosed with the test substance was similar to the liver
weights of rats dosed with the positive controls, H-24019 and H-24020.
not contain TSCA CBf
Company S an.'1- " "
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 /M equivalents for H-24019 and H-24020, respectively. By day 94, the concentrations were 1190.15 and 10.72 juM equivalents.
2. Test Substance
Levels of total fluorine in livers from rats dosed with the test substance, H-24043, were lower than the levels in livers from rats dosed with the positive control material H-24019 but higher than the levels in livers from rats dosed with the positive control material H-24020. The total fluorine concentration in the liver from rats dosed with H-24043 was 1306.27 p.M equivalents at day 10 and 80.27 juM equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 4x higher (day 10) and approximately 15x higher (end of study) than H-24043. The liver concentration was slightly 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 7x higher in rats dosed with H-24043 than in rats dosed with H-24020.
The xM 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 following dosing with H-24043. Fluorine levels in the liver were lower than levels in rats dosed with the positive control material H-24019. However, fluorine levels in the liver were higher than the levels in livers from rats dosed with the positive control H-24020. Liver weights were elevated at the end of the 10-day dosing period.
Company Santtzed .Does boi contain TSCA CBI
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
TABLES
C om paq Sanitized.
not conta, TSCA CBl
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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
Company
Does not co^a.;, `
CBI
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
TABLE 1 (Continued) MEAN BODY AND LIVER WEIGHTS (g)
Test Days 5 10 13 24 52 94
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-24043 (TEST SUBSTANCE)
Absolute
Body Weight
Liver Weight
253.8
14.049
298.0
17.077
321.3
20.332
379.1
19.642
486.5
19.101
606.7
22.411
Mean Relative Liver Weight(% of Body Weight)
0.055 0.057 0.063 0.052 0.039 0.037
Company Sanitized. Doeess not <>
TSCa
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
TABLE 2 . MEAN LIVER FLUORINE LEVELS
Test Days
10 94
Negative Controls
Positive Controls
Test Substance
Com
C om O il Oil:Acetone
H-24019
H-24020
H-24043
(ppm)________ (PPm)__________(ppm)__________(ppm)_________ (ppm)
<0.2 <0.5 328.18 (19.3)a 155.76 (29.2) 196.1 (16.13)
0.6b__________ 1^___________77.56 (10.1) 1.68 (0.3)
12.2 (1.64)
a Standard deviation is in parentheses. b One value. Four of the values were below the level of detection (LOD) or level of quantification (LOQ).
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Pays
10 94
Positive Controls
Test Substance
H-24019
H-24020
H-24043
/ttM F Equivalents /M F Equivalents______ M F Equivalents
5045.85 (296.9l) a 1127.25 (211.37)
1306.27 (107.50)
1190.15 (156.05)
10.72 (2.14)__________ 80.27 (10,94)
a Standard deviation is in parentheses.
Company Sanitized. Does not contain TSCA CBl
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
FIGURES
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H-24043: Biopersistence Screening
DuPont-2932
10-Dose Oral Gavage Study in Rats____________________________________ _________________________________________________ Supplement No. 1
0.07
0.06
0.05
5 0.04
jg
Kaav
<T0OOH23
0.03
0.02
0.01
0.00
FIGURE 1 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND NEGATIVE CONTROLS HCorn Oil (Negative Control) Corn OihAcetone (Negative Control) OH-24043 (Test Substance)
Test Day
Sanifizecf, Does nof o n la in TSCA CBI
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
DuPont-2932 Supplement No. 1
Mean Relative Liver W t
TO;3>
o
T est Day
94
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
FIGURE 3
COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24043 AND NEGATIVE CONTROLS
Mean Relative Liver Wt. (OrganrBody Wt.)
B Corn Oil (Negative Control)
I Corn OU:Acetone (Negative Control)
H-24043 (Test Substance)
I
I
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
__________________________________________
)
DuPont-2932 Supplement No. 1
6000
5000
4000
B3 w'O3' 3000 o to ssc
I 2000
FIGURE 4 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
SIH-24019 (Positive Control) H-24020 (Positive Control) H-24043 (Test Substance)
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1000
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3
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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DuPont-2932 Supplement No. 1
FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Company Sanitteed. Does rt confa;n TSCA CBI
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
APPENDICES
Company Si*n*0r#<f frrsK?
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CRI
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
Company Sanitized. Doe* not contain TSCA CBI - 23 -
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
dirt*.
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 W t . 11.428 12.216 14.081 13.395 11.981
Relative Liver to Body W t . 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 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 W t .
322.7
320.3
305.2
336.2
330.2
GROUP III
Liver W t . 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
Company Sanitized. Does not contain TSCA CBI
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t .
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
Company Smamernd. Does confafn TSCA CBf
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t . 16.800 11.236 13.845 13.253 13.026
Relative Liver to Body W t . 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 W t . 14.409 14.363 16.139 17.745 15.328
Relative Liver to Body W t . 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 W t . 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
Company Sanitized. Does not contain TSCA CBI
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t .
396.1
459.6 447.3
432.9 381.8
GROUP IV
Liver W t . 16.383 18.313 17.859 19.168 14.135
Relative Liver to Body W t . 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 W t . 20.498 22.901 23.312 21.287 18.378
Relative Liver to Body W t . 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 W t . 18.655 17.379 20.073 18.869 17.261
Relative Liver to Body W t . 0.033
0.034 0.030
0.032
0.035
Test Day 94 94 94 94 94
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t . 16.409 14.830 16.545 13.809 15.685
Relative Liver to Body W t . 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 W t . 0.060
0.063
0.064
0.072
0.061
Test Day 13 13 13 13 13
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DuPont-2932 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 W t . 21.479 22.100 18.018 23.131 21.835
Relative Liver to Body W t . 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 W t . 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 W t .
577.5
579.5
556.9
638.9
636.8
GROUP VI
Liver W t . 23.749 21.548 23.945 27.416 25.615
Relative Liver to Body W t . 0.041
0.037
0.043
0.043
0.040
Test Day 94 94 94 94 94
nalcontain T s c j
cBt -29-
H-24043: Biopersistenee Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t . 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 W t . 0.084
0.077
0.070
0.070
0.073
Test Day 13 13 13 13 13
C0mpany S a n ft b r ^
-30-
TSCA CBf
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 W t . 22.707 19.579 19.540 24.858 16.410
Relative Liver to Body W t . 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 W t . 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 Wt. 17.732 19.324 17.296 15.628 21.044
Relative Liver to Body W t . 0.034
0.032
0.031
0.035
0.038
Test Day 94 94 94 94 94
COmp*ny S |">*feed. Doe Snotco^ r s CA CBl
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
H-24043 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 628254
628266
628267
628270
628279
Final Body W t .
244.7
240.2
260.3
281.0
242.9
GROUP I
Liver W t . 14.432 12.948 14.289 15.256 13.318
Relative Liver to Body W t . 0.059
0.054
0.055
0.054
0.055
Test Day 5 5 5 5 5
Animal Number 628253
628256
628258
628276
628278
Final Body W t .
279.8
274.0
319.9 286.7
329.7
GROUP II
Liver W t . 15.869 14.854 19.664 16.531 18.469
Relative Liver to Body W t . 0.057
0.054
0.061
0.058
0.056
Test Day 10 10 10 10 10
Animal Number 628261
628271
628275
628280
628284
Final Body W t .
335.5
303.2
345.6
271.4
351.0
GROUP III
Liver W t . 19.948 17.968 21.913 17.147 24.682
Relative Liver to Body W t . 0.059
0.059
0.063
0.063
0.070
Test Day 13 13 13 13 13
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
H-24043 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 628255
628259
628265
628274
628282
Final Body W t .
391.8
387.1
414.4
342.3
359.8
GROUP IV
Liver W t . 19.481 18.307 23.561 18.561 18.298
Relative Liver to Body W t . 0.050
0.047
0.057
0.054
0.051
Test Day 24 24 24 24 24
Animal Number 628260
628262
628263
628272
628281
Final Body W t .
490.9
487.6
469.9
505.9 478.4
GROUP V
Liver W t . 18.856 18.601 17.361 21.200 19.485
Relative Liver to Body W t . 0.038
0.038
0.037
0.042 0.041
Test Day 52 52 52 52 52
Animal Number 628257
628264
628268
628269
628285
Final Body W t .
647.6
678.2
560.3 478.1
669.2
GROUP VI
Liver W t . 25.004 26.072 19.742 16.116 25.123
Relative Liver to Body W t . 0.039
0.038
0.035
0.034
0.038
Test Day 94 94 94 94 94
Cl
- 33 -
*ic ^ n r s C4 CBi
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
APPENDIX B Individual Fluorine Levels
Company Sanitized. DO* * n~ ' T S C A C B f
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 o f 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 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
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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 [/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 W t F [mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /mol/mmol
Company Sanitized. Does not contain TSCA CBI -36-
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 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
Company Sanitized. Does not contain TSCA CBI -37 -
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-2932 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
Group I
625320
10 319.4
625330
10 355.4
625332
10 338.4
625341
10 305.0
625350
10 322.7
ppm F in Liver
Minus Bkg 0.2 ppm
319.2 355.2 338.2 304.8 322.5
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
1586.42 1765.34 1680.85 1514.86 1602.83
Hmolar Equivalents of Active in
Liver
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
Sanflaad. Does not contain TSCA CBi Company
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H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2932 Supplement No. 1
Data for H- 24020
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): Molar Ratio (Active/F): Dose F (mg/kg):
0.726 0.065 13.8
Rat Number
Test ppm F Day in Sample Liver
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 Liver
Minus Bkg 0.2 ppm
182.3 108.8 173.8 147.3 165.6
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
388.30 231.74 370.19 313.75 352.73
/molar Equivalents of Active in
Liver
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
Company Sanitized. Does not contain TSCA CBI -39-
H-24043: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24043
DuPont-2932 Supplement No. 1
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
494 100 25
% F in Active: Mol Wt. F (g/mol):
60 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
25 0.051 197.6
Dose F (mmol/kg): Molar Ratio (Active/F): Dose F (mg/kg):
0.789 0.064 15
Rat Number
Test ppm F Day in Sample Liver
Group I
628258
10 178.5
628278
10 193.2
628256
10 214.0
628276
10 211.6
628253
10 183.4
ppm F in Liver
Minus Bkg 0.2 ppm
178.3 193.0 213.8 211.4 183.2
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
352.32 381.37 422.47 417.73 362.00
pmolar Equivalents of Active in
Liver
1188.67 1286.67 1425.33 1409.33 1221.33
Group VI 628269 628268 628257 628285 628264
94 94 94 94 94
12.8 10.1 14.6 11.9 11.8
12.6 9.9 14.4 11.7 11.6
24.90 19.56 28.45 23.12 22.92
84.00 66.00 96.00 78.00 77.33
n af corrfafrt TSCA CBf
