Document XO1OvBOYOkpjvoov2ZkXkzXby
AR226-3211
DuPont-2923 Supplement No. 1
TRADE SECRET Study Title
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1
Laboratory Project ID: DuPont-2923
AUTHOR: Carol Finlay, B.A.
Study Completed on: July 27,2000
Supplement No. 1 Completed on: December 13,2001
Performing Laboratory: E.L 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
3
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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. Hinderliter, Ph.D. Postdoctoral Fellow
Reviewed by:
/ / Judith C. Stadler, PfiJD., D.A.B.T. * Director
Issued by Study Director:
f < L A .U . i a / l U u r ' Carol FijUay, B.A. Q
Staff Scientist
tL -jb e -t--' Date
0 6 -s C - 2 0 o f Date
Date
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
TABLE OF CONTENTS
Page
CERTIFICATION................................................................................................................................. 2
LIST OF TABLES................................................................................................................................. 4
LIST OF FIGURES............................................................................................................................... 4
LIST OF APPENDICES.......................................................................................................................4
STUDY INFORM ATION.....................................................................................................................5
STUDY PERSONNEL...........................................................................................................................7
REASON FOR SUPPLEMENT NO. 1 ..............................................................................................8
SUM M ARY........................
9
MATERIALS AND M ETHODS...................................................................................................... 10
RESULTS AND DISCUSSION.........................................................................................................10
A. Liver Weights............................................................................................................................ ^
1. Test Substance.........................................................
^
2. Positive Controls..........................................................................................................................................
B. Liver Fluorine D ata....................................................................................................................^
1. Positive Controls......................................................
^
2. Test Substance................................................................................... ....................................................... . ^*
C O N C L U S IO N S ...................................................................................................................................11
TABLES....................................................................................................................
12
FIGURES............................................
16
APPENDICES.......................................................................................................................................22
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H-23961: Biopersistence Screening
DuPont-2923
10-Dose Oral Gavage Study in Rats______________________________ _____________________ Supplement No. 1
LIST OF TABLES
Page
1. MEAN BODY AND LIVER WEIGHTS..................................................................................................................13 2. MEAN LIVER FLUORINE LEVELS........................................................................................................................ 15 3. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE.....................................................15
LIST OF FIGURES
Page
1. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROLS..........................
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-23961 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 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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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE:
Substance Tested: Svnonvms/Codes:
Haskell Number: 23691
DuPont-2923 Supplement No. 1
Haskell Number: i^NfRT
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION (Continued)
DuPont-2923 Supplement No. 1
POSITIVE CONTROL:
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: May 30, 1999 / August 30, 1999
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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-23961), 2 positive controls (H-24019 and H-24020), and 2 negative controls (com oil and com oil/acetone).
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-23961, 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 1000 mg/kg/day of H-23961. 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 10,13, and 94 were analyzed for total fluorine. This supplement includes liver weight data and the results of total fluorine analyses in livers. 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-23961.
The mean relative liver weights (liver/body weight) of rats dosed with the test substance, H-23961, were similar to the negative controls during the dosing and recovery periods. 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 at day 10 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-23961, was
18.43 fiMequivalents on day 10 and 3.50 fiMequivalents on day 94. On day 10, mean /xM
equivalent concentrations of fluorine in the livers from rats dosed with the positive control materials were approximately 275-fold (H-24019) and 60-fold (H-24020) greater than the fluorine concentration in livers from rats treated with the test substance. By day 94, the concentrations were approximately 340x and 3x the fluorine concentration in rats treated with H-23961.
The fiMequivalents of fluorine in the livers from rats dosed with the test substance were higher
than levels in the blood.
Under the conditions of this study, there was some absorption and retention of fluorine in the liver from rats dosed with H-23961. However, fluorine levels in the liver were significantly lower than levels in rats dosed with the positive control materials, H-24019 and H-24020. Liver weights were not affected in rats dosed with the test substance.
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
MATERIALS AND METHODS
Blood and livers were collected on days 5 ,1 0 ,1 3 ,2 4 ,5 2 , and 94. The livers were weighed. Only the test day 10,13, 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 body weights, comparison of absolute liver weights was complicated by the fact that there was a difference in age on test day 1 between rats dosed with the test substance and those dosed with the positive or negative controls. The rats dosed with the test substance, H-23961, were older and heavier in weight than the com oil negative control and H-24020 positive control rats, but younger and lighter in weight than the com oil/acetone negative control and H-24019 positive control rats. Therefore, liver weights relative to body weight are presented for comparison.
1. Test Substance
The mean relative liver weights of rats dosed with the test substance, H-23961, were similar to the negative controls during the dosing and recovery periods.
2. Positive Controls
The mean relative liver weight of rats dosed with one of the positive controls, H-24019, was 17% higher on day 10 than the liver weight of rats dosed with the test substance, H-23961. On days 13, 24, and 52 (recovery), the mean relative liver weights of rats dosed with H-24019 were 13-36% higher than the liver weights of rats dosed with H-23961. By test day 94 (end of recovery), the mean relative liver weight of rats dosed with H-24019 was 21% higher than the liver weight of rats dosed with H-23961. The mean relative liver weight of rats dosed with H-24020, the other positive control, was 60% higher on day 10 than the liver weight of rats dosed with H-23961. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24020 were 60 and 33% higher than the liver weights of rats dosed with H-23961. 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
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
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-23961, were not affected.
B. Liver Fluorine Data (Tables 2-3, 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. At day 13, the liver concentrations were
4135.69 and 334.49 xMequivalents. By day 94, the concentrations were 1190.15 and 10.72 /M
equivalents.
2. Test Substance
.
Levels of total fluorine in livers from rats dosed with the test substance, H-23961, were lower than the levels in livers from rats dosed with the positive control materials. The total fluorine
concentration in th liver from rats dosed with H-23961 was 18.43 xMequivalents at day 10, 11.89 ixM equivalent at day 13, and 3.50 pM equivalents at day 94. For the positive control
H-24019, the liver concentrations were approximately 275x higher (day 10) and approximately 340x higher (end of study) than H-23961. For H-24020, the liver concentration was approximately 60x higher (day 10) and approximately 3x higher (end of study).
The xMequivalents of fluorine in the livers from rats dosed with the test substance were higher
than levels in the blood.
CONCLUSIONS
Under the conditions of this study, there was some absorption and retention of fluorine in the
liver from rats dosed with H-23961. However, fluorine levels in the liver were significantly
lower than levels in rats dosed with the positive control materials, H-24019 and H-24020. Liver
weights were not affe'cted in rats dosed with the test substanc.
'
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
TABLES
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 259.3 311.1 322.9 391.2 464.7 557.8
Liver Weight 12.620 15.861 14.906 16.635 17.240 20.118
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-23961: Biopersistence Screening 10-Dose Oral Gavage.Study in Rats
DuPont-2923 Supplement No. 1
TABLE 1 (Continued)
MEAN BODY AND LIVER WEIGHTS (g)
H-24020 (POSITIVE CONTROL)
______________Absolute_____________
Mean Relative
Test Days_____Body Weight______ Liver Weight_____ Liver Weight(% of Body Weight)
5 244.8 10 284.4 13 289.1 24 370.3 52 456.7 94 538.7
17.052 21.944 21.780 20.619 17.713 18.205
0.070 0.077 0.075 0.056 0.039 0.034
Test Days 5 10 13 24 52 94
H-23961 (TEST SUBSTANCE)
Absolute
Body Weight
Liver Weight
264.9
11.821
306.4
14.729
336.7
15.488
381.7
15.991
502.0
19.891
561.7
18.957
Mean Relative Liver Weight(% of Body Weight)
0.045 0.048 0.046 0.042 0.040 0.034
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
TABLE 2 MEAN LIVER FLUORINE LEVELS
Test Days
10 13 94
Negative Controls
Com Oil (ppm) <0.2
Com Oil: Acetone
(ppm) <0.5
--
0.6a l a
Positive Controls
H-24019 (ppm)
328.18 (19.3) 269.02 (10.1) 77.56 (10.1)
H-24020 (ppm)
155.76 (29.2) 46.36 (10.7)
1.68 (0.3)
a One value. Four of the values were below the level of detection (LOD). b Standard deviation is in parentheses. - Indicates no value for this day.
Test Substance
H-23961 (ppm)
20.84 (2.7) 13.52 (1.5) 4.12 (4.0)
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 13 94
Positive Controls
H-24019
H-24020
fiM.F Equivalents jtiM F Equivalents
5045.85 (296.91)3 1127.25 (211.37)
4135.69 (155.38) 334.49 (77.70)
1190.15 (156.05)
10.72 (2.14)
a Standard deviation is in parentheses.
Test Substance H-23961
jtiM F Equivalents 18.43 (2.4) 11.89 (1.4) 3.50 (3.6)
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
FIGURES
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
0.06
0.05
0.04
3
J>2
0o3
0.03
s w *
<u
0.02
FIGURE 1 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND NEGATIVE CONTROLS
m C o rn Oil (Negative Control) ISICorn Oi hAc et on e (Negative Control) H-23961 (Test Substance)
0.01
0.00
Test Day
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#
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats______________________________________________________________
#
DuPont-2923 Supplement No. 1
0.08
0.07
u 0.06-
0>oa3. 0.05-
u
> 0.04<>au
2 0.03-
103
acs
0.02-
0.01
0.00-
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
H-24019 (Positive Control) G0H-24O2O (Positive Control) H-23961 (Test Substance)
Test Day
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3961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
0
DuPont-2923 Supplement No. 1
FIGURE 3
COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-23961 AND NEGATIVE CONTROLS
@1 Corn Oil (Negative Control) I Com Oil:Acetone (Negative Control) H-23961 (Test Substance)
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i -23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN UVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
#
DuPont-2923 Supplement No. 1
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^ ^ 3 9 6 1 : Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
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m
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
APPENDICES
n
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627789
627801
627805
627810
627818
Final Body Wt.
247.7
240.1 283.7
265.0
260.2
GROUP I
Liver 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 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 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 Wt. 0.042 0.048
0.049 0.045
0.048
Test ] 13 13 13 13 13
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 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 W t . 16.359 19.293 15.234 14.358 20.958
Relative Liver to Body Wt. 0.033
0.037
0.037
0.037
0.041
Test Day 52 52 52 52 52
Animal Number 627795
627811
627819
627820
627821
Final Body 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 Wt. 0.034
0.034
0.033 0.043
0.034
Test Day 94 94 94 94 94
1
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 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 W t . 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 W t . 0.050
0.038
0.053
0.046
0.046
Test Day 13 13 13 13 13
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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 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 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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DuPont-2923 Supplement No. 1
H-24019 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 625322
625323
625336
625343
625349
Final Body Wt.
329.0
298.0
318.1 294.0
293.7
GROUP I
Liver 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
Filial 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 Wt. 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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H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 Wt. 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 Wt. 0.041
0.037
0.043 0.043
0.040
Test I 94 94 94 94 94
- 29Company Sanitized. Does not contain TSCA CBI
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
H-24020 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 627756
627767
627771
627773
627777
Final Body Wt.
237.5 248.6
239.6
262.3
236.0
GROUP I
Liver Wt. 15.360 19.033 16.968 17.629 16.268
Relative Liver to Body Wt. 0.065 0.077
0.071
0.067
0.069
Test Day 5 5 5 5 5
Animal Number 627768
627774 627776
627782
627785
Final Body 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 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 W t .
308.7
285.8
306.7
234.9
309.4
GROUP III
Liver Wt. 26.021 22.123 21.526 16.498 22.730
Relative Liver to Body Wt. 0.084 0.077
0.070 0.070
0.073
Test Day 13 13 13 13 13
Company Sanitized. Does not contain TSCA CB1
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 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 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
-31 CoiHpEny Sanfirzerf. D oes nofaxsifeita! TSC&CS8
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
H-23961 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 626876 626877
626885
626889
626890
Final Body Wt.
262.6
278.2
245.9
268.9
268.9
GROUP I
Liver W t . 12.535 12.834 10.960 11.468 11.306
Relative Liver to Body Wt. 0.048
0.046
0.045 0.043
0.042
Test Day 5 5 5 5 5
Animal Number 626871
626872 626875
626882
626888
Final Body Wt.
309.0
318.1 315.1
325.1
264.8
GROUP II
Liver W t . 16.809 15.772 15.102 14.461 11.499
Relative Liver to Body W t . 0.054
0.050
0.048
0.044
0.043
Test Day 10 10 10 10 10
Animal Number 626868 626879
626886
626887
626891
Final Body Wt.
366.9
320.6
319.9
329.9 346.3
GROUP III
Liver W t . 16.841 15.748 14.966 13.393 17.845
Relative Liver to Body W t . 0.046
0.049 0.047
0.041 0.052
Test I 13 13 13 13 13
- 32Compsny Sanitized. Does not contain TSCA CB1
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
H-23961 (TEST SUBSTANCE)
INDIVIDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LIVER TO BODY WEIGHT OF MALE RATS
Animal Number 626864
626865
626873
626894
626895
Final Body W t .
390.7
351.8
424.7
380.8
360.6
GROUP IV
Liver Wt. 16.059 14.379 18.570 15.501 15.449
Relative Liver to Body W t . 0.041
0.041
0.044 0.041
0.043
Test Day 24 24 24 24 24
Animal Number 626867
626880 626881
626884
626892
Filial Body Wt.
478.7
470.8 533.9
507.8 ,,
518.8
GROUP V
Liver Wt. 17.371 19.473 21.007 21.287 20.319
Relative Liver to Body W t . 0.036
0.041 0.039
0.042
0.039
Test Day 52 52 52 52 52
Animal Number 626866
626869
626874
626893
626896
. Final Body W t . 565.5 507.0
654.5 539.5
541.8
GROUP VI
Liver Wt. 19.198 17.216 22.444 16.143 19.786
Relative Liver to Body Wt. 0.034
0.034
0.034
0.030
0.037
Test : 94 94 94 94 94
-33C oiiipsisy S an itized -
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 Supplement No. 1
APPENDIX B Individual Fluorine Levels
-34Company Sanitized. Does R3 contain 7SCA CEI
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Terms: Active
% Active
TERMS AND CALCULATIONS
DuPont-2923 Supplement No. 1
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 W t 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 Ccnpany Sanitized. Does notcoritain TSCA GBl
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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 Wt F [mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /mol/mmol
-36Company Sanitized. Does not c a s t T S C A CBf
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2923 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
- 37Cespaai Sanitized. Does not eantain TSCACBj
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-2923 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 Day Sample
ppm F in
Liver
Group II
625320
10 319.4
625330
10 355.4
625332
10 338.4
625341
10 305.0
625350
10 322.7
Group III 625321 625327 625342 625345 625348
13 13 13 13 13
255.9 275.3 277.9 260.4 275.6
Group VI 625326 625335 625346 625347 625351
94 94 94 94 94
79.8 89.6 73.8 62.5 82.1
ppm F in Liver
Minus Bkg 0.2 ppm
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
319.2 355.2 338.2 304.8 322.5
1586.42 1765.34 1680.85 1514.86 1602.83
255.7 275.1 277.7 260.2 275.4
1270.83 1367.25 1380.17 1293.19 1368.74
79.6 89.4 ' 73.6 62.3 81.9 '
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
3933.85 4232.31 4272.31 4003.08 4236.92
1224.62 1375.38 1132.31 958.46 1260.00
- 38-
Company Sanitized. Does not contain TSCA CBI
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24020
DuPont-2923 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
ppm F in
Liver
Group II
627768
10 182.5
627774
10 109.0
627776
10 174.0
627782
10 147.5
627785
10 165.8
Group III 627758 627764 627787 627763 627788
13 13 13 13 13
61.5 40.5 33.3 51.3 45.2
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
61.3 40.3 33.1 51.1 45.0
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
130.57 85.84 70.50 108.84 95.85
3.62 2.13 3.62 2.98 3.41
/molar Equivalents of Active in
Liver
1321.01 788.41 1259.42 1067.39 1200.00
444.20 292.03 239.86 370.29 326.09
12.32 ' 7.25
12.32 10.14 11.59
- 39-
Company SaniSzecL D oes not c o sia in is g a
H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-23961
DuPont-2923 Supplement No. 1
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
27500 1000 28
% F in Active: Mol Wt. F (g/mol):
40 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
280 0.010 9821.4
Dose F (mmol/kg):
5.895
Molar Ratio (Active/F): 0.002
Dose F (mg/kg):
112
Rat Number
Test Day Sample
ppm F in
Liver
Group II 626871 626872 626875 626882 626888
10 10 10 10 10
19.6 22.8 20.8 17.1 23.9
Group III 626868 626879 626886 626887 626891
13 13 13 13 13
15.7 13.4 12.4 14.3 11.8
Group VI 626866 626869 626874 626893 626896
94 94 94 94 94
11.3 2.5 1.6 2.4 2.8
ppm F in Liver
Minus Bkg 0.2 ppm
19.4 22.6 20.6 16.9 23.7
15.5 13.2 12.2 14.1 11.6
11.1 2.3 1.4 2.2 2.6 '
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
190.54 221.96 202.32 165.98 232.77
152.23 129.64 119.82 138.48 113.93
109.02 * 22.59
13.75 21.61 25.54
/molar Equivalents of Active in
Liver
17.32 20.18 18.39 15.09 21.16
13.84 11.79 10.89 12.59 10.36
9.91 2.05 1.25 1.96 2.32
-40Coispsny SamBsacL Dees net cantain T3G C6I
