Document 6Rw4wKokwxRq8ZXLndEmwQj21
AR226-3205
DuPont-2927 Supplement No. 1
TRADE SECRET
Study Title H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1
Laboratory Project ED: DuPont-2927
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AUTHOR: Carol Finlay, B.A.
STUDY COMPLETED ON: August 3,2000
SUPPLEMENT No. 1 COMPLETED ON: December 12,2001
PERFORMING LABORATORY:
E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences
EUrton Road, P.O. Box 50 Newark, Delaware 19714-0050
WORK REQUEST NUMBER: [j^^I^B^--.j
SERVICE CODE NUMBER: y m
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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. Ifindertter, Ph-D. Postdoctoral Fellow
C^g^gC Reviewed by;
<'. ^^g^g-^-
/fJudith C. Sladfer. Fh.D-. D.A.B.T.
^/
Director
Issued by Study Director;
QL^f^ ( ^UifrC Carol fvday.B.A. Q Staff Scientist
it-J^e-^
Date
Q^-^e.c'^Q/
Date
n^M. Date ^\
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TABLE OF CONTENTS
Page
CERTIFICATION ........................................................................................................................2 LIST OFTABLES........................................................................................................................ 4 LIST OFFIGURES...................................................................................................................... 4 LIST OF APPENDICES..............................................................................................................^
STUDYINFORMATION.............................................................................................................5
STUDY PERSONNEL..................................................................................................................? REASON FOR SUPPLEMENT NO. 1....................................................................................... 8
SUMMARY....................................................................................................................................9
MATERIALS AND METHODS ............................................................................................... 10 RESULTS AND DISCUSSION................................................................................................. 10
A. Liver Weights................................................................................................................... 10
1. TestSubstance.....................................................................................,..................................................10 2. Positive Controls....................................................................................................................................10
B. Liver Fluorine Data.......................................................................................................... 11
1. Positive Controls....................................................................................................................................11 2. Test Substance........................................................................................................................................ 11
CONCLUSIONS......................................................................................................................... 11 TABLES....................................................................................................................................... 12 FIGURES..................................................................................................................................... 16 APPENDICES............................................................................................................................. 22
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
LIST OF TABLES
Page
1. MEAN BODY AND LIVER WEIGHTS............................................................................................................. 13
2. MEANLIVERFLUORINELEVELS..................................................................................................................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-24018 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
WEIGHT.............................................................................................................................................................^
B. INDIVIDUAL FLUORINE LEVELS..................................................................................................................34
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STUDY INFORMATION TEST SUBSTANCE;
Substance Tested: Synonyms/Codes: H-24018
Haskell Number: 24018
DuPont-2927 Supplement No. 1
Known Impurities:
POSITIVE CONTROL;
Substance Tested: Potassium perfluoroalkyi sulfonate Synonyms/Codes: H-24019
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STUDY INFORMATION (Continued) POSITIVE CONTROL:
Substance Tested: Octanoic acid, pentadecafluoro-, ammonium salt Synonyms/Codes: H-24020
Perfluorooctanoate, ammonium salt APFO Ammonium perfluorooctanoate
Haskell Number: 24020
Composition
Sponsor:
E. I. du Font de Nemours and Company Wilmington, Delaware 19898
U.S.A.
Study Initiated/Completed: April 30,1999 / (see report cover page)
m-Life Initiated/Completed: June 13,1999 / September 14,1999
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
STUDY PERSONNEL
Study Director:
Management: Primary Technician:
Carol Finlay, B.A. Judith C. Stadler, Ph.D., D.A.B.T. Richard P. Mathena
Liver Fluorine Data Analysis: Paul M. Hmderliter, 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-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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-24018), 2 positive controls (H-24019 and H-24020),
and 2 negative controls (corn oil and corn oil/acetone).
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-24018, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male Crl:CD(SD)IGSBR rats each were given 1000 mg/kg/day of H-24018. 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, corn oil and corn 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-24018.
The mean relative liver weight (liver/body weight) of rats dosed with the test substance, H-24018, was up to approximately 27% higher than negative controls on day 10. On day 94, the weights were similar. 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-24018, was 77.12 iiM equivalents on day 10 and 8.59 ^.M equivalents on day 94. On day 10, the mean ^M. equivalent concentrations of fluorine in the livers from rats dosed with the positive control materials were approximately 65-fold (H-24019) and 15-fold (H-24020) greater than the fluorine concentration in livers from rats treated with the test substance. By day 94, the concentration for H-24019 was approximately 140x the fluorine concentration in rats treated with H-24018. The concentrations were similar for H-24018 and H-24020 at day 94.
The pM equivalents of fluorine in livers from rats dosed with the test substance, H-24018, 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-24018. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control, H-24019. Fluorine levels in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. Liver weights were elevated in rats dosed with the test substance, H-24018, at the end of the dosing period, but not at the end of the recovery period.
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
MATERIALS AND METHODS
Blood and livers were collected on days 5,10,13,24, 52, and 94. The livers were weighed.
Only the test day 10 and 94 livers were analyzed for total fluorine. These time points provided sufficient data to determine the accumulation and persistence of fluorine in the liver. See the original report for details of the analysis.
RESULTS AND DISCUSSION
A. 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-24018, were older and heavier in weight than the corn oil negative control and H-24020 positive control rats, but younger and lighter in weight than the corn 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 weight of rats dosed with the test substance, H-24018, was up to approximately 27% higher than negative controls on day 10. On day 13, the weight was up to approximately 26% higher than the negative controls. The weights were similar throughout the
remainder of the recovery period.
2.
Positive Controls
The mean relative liver weight of rats dosed with one of the positive controls, H-24019, was similar on day 10 to the liver weight of rats dosed with the test substance, H-24018. On days 13, 24, and 52 (recovery), the mean relative liver weights of rats dosed with H-24019 were 10 or 20% higher than the liver weights of rats dosed with H-24018. By test day 94 (end of recovery), the mean relative liver weight of rats dosed with H-24019 was 17% higher than the liver weight of rats dosed with H-24018. The mean relative liver weight of rats dosed with H-24020, the other positive control, was 38% higher on day 10 than the liver weight of rats dosed with H-24018. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24020 were 29 and 22% higher than the liver weights of rats dosed with H-24018. 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
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
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-24018, were elevated at the end of the 10-day dosing period. The mean relative liver weight by the end of recovery in rats dosed with the test substance was higher than in rats dosed with the positive control H-24019 but similar to rats dosed with the positive control H-24020.
B.
Liver Fluorine Data
(Tables 2 and 3, Figures 3 through 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 fJiM equivalents.
2.
Test Substance
Levels of total fluorine in livers from rats dosed with the test substance, H-24018, were generally
lower than the levels in livers from rats dosed with the positive control materials. The total
fluorine concentration in the liver from rats dosed with H-24018 was 77.12 juM equivalents at
day 10 and 8.59 pM equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 65x higher (day 10) and approximately 140x higher (end of
study) than H-24018. For H-24020, the liver concentration was approximately 14x higher at the end of dosing. The concentrations were similar by the end of the study.
The jtiM equivalents of fluorine in the livers from rats dosed with the test substance, H-24018,
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-24018. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control, H-24019. Fluorine levels in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. Liver weights were elevated in rats dosed with the test substance, H-24018, at the end of the dosing period, but not at the end of the recovery period.
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TABLES
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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 ODLACETONE (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-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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
BodyWei^ght
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-24018 (TEST SUBSTANCE)
Absolute
BodyWei^sht
Liver Weight
265.5
14.828
296.5
16.650
333.8
19.479
406.6
18.642
488.9
20.056
596.5
20.595
Mean Relative
Liver Weight(% of Body Weight)
0.056 0.056 0.058 0.046 0.041 0.035
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rate
DuPont-2927 Supplement No. 1
TABLE 2 MEAN LIVER FLUORINE LEVELS
Negative Controls
Positive Controls
Test Substance
Test Corn Oil
Corn OihAcetone
H-24019
H-24020
H-24018
K)0.2<0.5328.18 Days 94
(ppm)_____(ppm)______(ppm) ____(ppm)______(ppm) (19.3)"155.76 (29.2)131.3 (30.1)
0.6"______I3______77.56 (10.1)
1.68 (0.3)
14.8 (7.9)
a One value. Four of the values were below the level of detection (LOD).
b Standard deviation is in parentheses.
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 94
Positive Controls
Test Substance
H-24019
H-24020
H-24018
fiM F Equivalents
5045.85 (296.91)'
fiM F Equivalents___juM F Equivalents
1127.25 (211.37)
77.12 (17.7)
1190.15 (156.05)
10.72 (2.14)______8.59 (4.7)
a Standard deviation is in parentheses.
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
FIGURES
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 1 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND NEGATIVE CONTROLS
_i
S
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
Test Day
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURES COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRA
FOR H-24018 AND NEGATIVE CONTROLS
Day 10
DayW
Day 10
D
H Corn Oil (Negative Control) Corn OiLAcetone (Negative Control) D H-24018 (Test Substance)
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
6000
5000
4000
ss
B" 3000
a |X|
S 2000
1000
Day 10
Day 94
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALIZE
6000
5000
4000
Sg. 3000
a.
2000
1000
Blood / Liver
Blood / Liver
Blood / Liver
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DuPont-2927 Supplement No. 1
APPENDICES
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H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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H-24018: Biopersistaice Screening 10-Dose Oral Gavage!Study in Rats
DuPont-2927 Supplement No. 1
CORKr OIL (NEGATIVE CONTROL)
INDI^iTDUAL FINAL BCIDY WEIGHTS (g), LIVER WEIGHTS (cr), AND RELATIVE LFi/ER TO BODY WEI GHT OF MALE RATS
Animal Number 627789 627801 627805 627810 627818
Final
Body Wt. 247.7
240.1
283.7
265.0
260.2
GROUP I
Liver Wt.
11.428 12.216 14.081 13.395 11.981
Relative Liver to Body Wt.
0.046
0.051
0.050
0.051
0.046
Test Day
5 5 5 5 5
Animal
Number 627793
627797
627799
627800 627808
Final
Body Wt. 283.5
324.2
294.7
331.3
321.8
GROUP II
Liver Wt. 15.292 15.803 14.285 16.344 17.580
Relative Liver to Body Wt. 0.054
0.049
0.048
0.049
0.055
Test Day
10 10
10 10
10
Animal Number 627796
627806 627807
627809
627816
Final
Body Wt. 322.7
320.3
305.2
336.2
330.2
GROUP III
Liver Wt. 13.404 15.413 14.935 14.967 15.811
Relative Liver to Body Wt. 0.042
0.048
0.049
0.045
0.048
Test Day
13 13 13 13 13
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CORN" OIL (NEGATIVE CONTROL)
INDI^TDUAL FINAL BO'DY WEIGHTS (g) ,, LIVER WEIGHTS (cr), AND RELATIVE LBrER TO BODY WEI:GHT OF MALE RATS
-
Animal
Number 627791 627794 627804 627812 627817
Final
Body Wt. 365.6
416.7
378.1
388.4
407.3
GROUP IV
Liver Wt.
15.371 19.105 15.326 16.775 16.600
Relative Liver to Body Wt.
0.042
0.046
0.041
0.043
0.041
Test Day
24 24 24
24
24
Animal Number 627792
627798
627813
627814
627815
Final
Body Wt. 496.8
517.3
416.8
386.9
505.9
GROUP V
Liver Wt. 16.359 19.293 15.234 14.358 20.958
Relative Liver to Body Wt. 0.033
0.037
0.037
0.037
0.041
Test Day
52 52 52 52 52
Animal
Number 627795
627811
627819
627820
627821
Final
Body Wt.
485.0
511.6
653.1
618.0
521.5
GROUP VI
Liver Wt. 16.649 17.405 21.828 26.766 17.943
Relative Liver to Body Wt. 0.034 0.034 0.033
0.043 0.034
Test Day
94 94 94 94 94
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CORN OIL.:ACETONE (NEGA1IVE CONTROL)
INDI\riDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g]1 , AND
RELATIVE LI^/ER TO BODY WEK3HT OF MALE RATS
.
Animal
Number 625361 625363 625364 625380 625383
Final
Body Wt. 349.7
286.7
312.0
305.5
313.1
GROUP I
Liver Wt. 16.800 11.236 .13.845 13.253 13.026
Relative Liver to Body Wt.
0.048 0.039 0.044 0.043 0.042
Test Day
5
5 5 5
5
Animal
Number 625355
625362
625367
625368
625378
Final
Body Wt. 333.6
332.9
363.8
386.7
365.4
GROUP II
Liver Wt. 14.409 14.363 16.139 17.745 15.328
Relative Liver to Body Wt.
0.043
0.043
0.044
0.046
0.042
Test Day
10 10
10 10
10
Animal Number 625357
625358
625370
625384
625385
Final
Body Wt. 405.6
340.7
407.0
357.1
377.6
GROUP III
Liver Wt. 20.091 12.954 21.654 16.520 17.355
Relative Liver to Body Wt. 0.050
0.038 0.053 0.046 0.046
Test Day
13 13 13 13 13
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H-24018: Biopersistelice Screening 10-Dose Oral Gavage!Study in Rats
DuPont-2927 Supplement No. 1
CORN OIL,:ACETONE (NEGA'riVE CONTROL)
INDIVTDUAL FINAL BCIDY WEIGHTS (g) ,, LIVER WEIGHTS (gr), AND RELATIVE LIii7ER 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
Animal
Number 625353 625369 625373 625375 625377
Final
Body Wt. 533.7 530.3 555.4 506.2 512.3
Final
Body Wt. 565.3 514.8 673.7 588.8
496.6
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
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
52 52 52 52 52
Test Day
94 94 94 94 94
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H-2.4019 (POSITIVE CONTROL)
1NDI\TDUAL FINAL BC)DY WEIGHTS (g), LIVER WEIGHTS (gr), AND RELATIVE LFi/ER TO BODY WEI GHT OF MALE RATS
Animal Number 625322
625323 625336
625343
625349
Final
Body Wt. 329.0
298.0
318.1
294.0
293.7
GROUP I
Liver Wt. 16.409
14.830 16.545 13.809 15.685
Relative Liver to Body Wt.
0.050 0.050
0.052 0.047
0.053
Test Day
5
5 5
5 5
Animal Number 625320 625330
625332
625341
625350
Final
Body Wt. 312.1
310.1
318.3
325.6
284.3
GROUP II
Liver Wt. 18.845 16.343 17.528 18.254
15.709
Relative Liver
to Body Wt. 0.060 0.053 0.055 0.056 0.055
Test Day
10 10 10 10 10
Animal
Number 625321
625327
625342
625345
625348
Final
Body Wt. 371.2
355.3
324.4
336.9
336.4
GROUP III
Liver Wt. 22.322 22.259
20.718 24.403 20.541
Relative Liver to Body Wt. 0.060 0.063 0.064
0.072
0.061
Test Day
13
13 13
13 13
-28Company Sanitized. Does not contain TSCA CBI
H-24018: Biopersistelice Screening 10-Dose Oral Gavage;Study in Rats
DuPont-2927 Supplement No. 1
H-2.4019 (POSITIVE CONTROL)
INDUi'TDUAL FINAL BCIDY WEIGHTS (g) , LIVER WEIGHTS (gf), AND RELATIVE LFi/ER TO BODY WE:IGHT OF MALE RATS
Animal
Number 625325
625328
625338 625340
625352
Final
Body Wt. 381.3
423.9
339.9
419.0
375.3
GROUP IV
Liver Wt. 21.479 22.100 18.018 23.131 21.835
Relative Liver to Body Wt. 0.056 0.052 0.053 0.055 0.058
Test Day
24 24 24
24
24
Animal Number 625324
625329
625333
625334
625344
Final
Body Wt. 447.4
498.1
427.4
426.5
391.0
GROUP V
Liver Wt. 20.900 20.911 20.508 19.144 17.666
Relative Liver to Body Wt. 0.047
0.042
0.048 0.045 0.045
Test Day
52 52
52
52 52
Animal Number 625326
625335
625346
626347
625351
Final
Body Wt. 577.5
579.5
556.9
638.9
636.8
GROUP VI .
Liver Wt. 23.749
21.548
23.945 27.416
25.615
Relative Liver to Body Wt. 0.041
0.037
0.043 0.043
0.040
Test Day
94
94 94 94
94
-29Company Sanitized. Does not contain TSCAGBI
H-24018: Biopersistelace Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
H-2.4020 (POSITIVE 'CONTROL)
iironODUAL FINAL BCIDY WEIGHTS (g), LIVER WEIGHTS (ar), AMD
RELATIVE LPi^ER TO BODY WEFGHT OF MALE RATS
Aniinal Number 627756
627767
627771
627773
627777
Final
Body Wt. 237.5
248.6
239.6
262.3
236.0
GROUP I
Liver Wt. 15.360 19.033 16.968 17.629 16.268
Relative Liver to Body Wt. 0.065
0.077 0.071 0.067 0.069
Test Day
5 5 5
5
5
Animal Number 627768
627774
627776
627782
627785
Final
Body Wt. 293.5
338.2
254.4
268.2
267.9
GROUP II
Liver Wt. 22.536 27.332 18.821 20.172 20.857
Relative Liver
to Body Wt. 0.077 0.081 0.074 0.075 0.078
Test Day
10 10
10
10 10
Animal
Number 627758
627763
627764
627787
627788
Final
Body Wt. 308.7
285.8
306.7
234.9
309.4
GROUP III
Liver Wt. 26.021 22.123 21.526 16.498 22.730
Relative Liver to Body Wt. 0.084
0.077 0.070 0.070 0.073
Test Day
13 13 13
13 13
-30-
Company Sanitized. Does not contain TSCACB1
H-24018: Biopersiste:ace Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
H-2-4020 (POSITIVE CONTROL)
iND:nTTOUAL FINAL BCIDY WEIGHTS (g) , LIVER WEIGHTS (g ) , AND
RELATIVE LFi/ER TO BODY WE!:GHT OP MALE RATS
Ariimal Number 627759
627761
627770
627779
627786
Final
Body Wt. 380.1
359.4
379.8
406.2
326.1
GROUP IV
Liver Wt.
22.707 19.579 19.540 24.858 16.410
Relative Liver to Body Wt.
0.060
0.054 0.051
0.061 0.050
Test Day
24 24 24
24 24
Animal Number 627757
627760
627765
627772
627781
Final
Body Wt. 436.7
456.5
455.6
513.5
421.0
GROUP V
Liver Wt. 16.899 18.240
16.505 20.225 16.695
Relative Liver to Body Wt. 0.039
0.040
0.036
0.039
0.040
Test Day
52 52
52
52
52
Animal Number 627762
627769
627775
627778
627783
Final
Body Wt. 528.6
609.6
552.8
445.3
557.2
GROUP VI
Liver Wt.
17.732 19.324 17.296 15.628 21.044
Relative Liver to Body Wt. 0.034
0.032
0.031
0.035
0.038
Test Day
94 94 94 94 94
-31Company Sanitized. Does not contain TSCA CBI
H-24018: Biopersist<ince Screening 10-Dose Oral Gavage; Study in Rats
DuPont-2927 Supplement No. 1
H-:24018 (TEST SUB STANCE)
INDI VIDUAL FINAL BC>DY WEIGHTS (g), LIVER WEIGHTS (gr), AND RELATIVE LFi/ER TO BODY WEI GHT OF MALE RATS
-
Animal
Number 627252 627253 627260 627273 627274
Final
Body Wt. 247.9
271.4
265.0
293.7
249.3
GROUP I
Liver Wt. 14.099 15.371 15.086 16.354 13.228
Relative Liver to Body Wt.
0.057 0.057 0.057 0.056 0.053
Test Day
5 5 5 5 5
Animal
Number 627246
627258
627261 627268
627269
Final
Body Wt. 283.0
272.7
314.3
338.6
273.7
GROUP II
Liver Wt. 14.068 15.101 17.363 20.561 16.156
Relative Liver
to Body Wt. 0.050 0.055
0.055 0.061 0.059
Test Day
10
10
10 10 10
Animal Number 627249
627262
627265
627266
627277
Final
Body Wt. 357.2
322.7
312.7
309.1
367.3
GROUP III
Liver Wt. 22.366 19.749 17.171 17.390 20.717
Relative Liver to Body Wt.
0.063
0.061 0.055 0.056 0.056
Test Day
13 13 13 13 13
-32-Companif Sanifaed. Does not contain TSCA CBS
H-24018: Biopersistelice Screening 10-Dose Oral Gavage!Study in Rats
DuPont-2927 Supplement No. 1
H-;24018 (TEST SUE1STANCE)
INDIVTDUAL FINAL BC1DY WEIGHTS (g) , LIVER WEIGHTS (cr), AND RELATIVE DPi/ER TO BODY WEI:GHT OP MALE RATS
-
Animal
Nuinber 627247 627250 627255 627257 627259
Final
Body Wt. 397.3 419.9 430.7
378.3
--
GROUP IV
Liver Wt. 17.316 21.643 20.139 15.468
--
Relative Liver to Body Wt. 0.044
0.052 0.047 0.041
--
Test Day 24 24
24 24 24
Animal
Number 627256 627264 627271 627275 627278
Animal Number 627248 627251 627254 627263 627270
Final
Body Wt. 468.5 489.0 495.9 455.6 535.5
Final
Body Wt.
591.0 651.5 628.7 531.5 579.6
GROUP V
Liver Wt. 18.735 20.115 19.999 18.417 23.014
Relative Liver to Body Wt. 0.040 0.041 0.040 0.040 0.043
Test Day
52 52 52 52 52
GROUP VI
Liver Wt. 19.084 23.777 20.844
18.753 20.515
Relative Liver to Body Wt.
0.032 0.036 0.033 0.035 0.035
Test Day
94 94
94 94
94
Rat found dead on test day 9
-33-Company Sanitized. Does not contain TSCA CBl
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 Supplement No. 1
APPENDIX B Individual Fluorine Levels
-34-
TSCA CBS
Company Sanifeed. Does not contain
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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/I 00) 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/I 00) 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-
Company Sanitized. Does not contain TSCA CB1
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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
ppm F in Liver normalized to 0.1 mmol/kg Dose
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.
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)
/imolar equivalents of
active in liver
The ^imolar [/nnol/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 -
Img/L = (Normalized ppm [mg/L] fluorine in liver / Mol Wt F
[mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /miol/mmol
-36Company Sanitized. Does not contain TSCA CBI
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2927 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 be justified 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 components) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation
-37Corepany Sanitized. Does not contain TSCACBI
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-2927 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
497
Formulation Dose (mg/kg):
10
% Active (F Containing) in Formulation: 100
%F in Adive:
65
Mol Wt.F (g/mol):
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
ppm Fin
Liver Minus Bkg
0.2 ppm
319.2 355.2 338.2 304.8 322.5
Group VI
625326
94
625335
94
625346
94
625347
94
625351
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
jxmolar 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
.38Company Sanitized. Does not contain TSCACBI
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24020
DuPont-2927 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
426
Formulation Dose (mg/kg):
20
% Active (F Containing) in Formulation: 100
%Fin Active:
69
MolW't. F (g/mol):
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/P): 0.065
Dose F (mg/kg):_____13.8
Rat Number
Test Day Sample
ppmF
in
Liver
Group 11
627768
10
627774
10
627776
10
627782
10
627785
10
182.5 109.0 174.0 147.5 165.8
ppmF in
Liver Minus Bkg
0.2 ppm
182.3 108.8 173.8 147.3 165.6
Group VI
627778
94
1.9
1.7
627783
94
1.2
1.0
627762
94
1.9
1.7
627775
94
1.6
1.4
627769
94
1.8
1.6
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
ptmolar Equivalents
of Active in Liver
388.30 231.74 370.19 313.75 352.73
1321.01 788.41
1259.42 1067.39 1200.00
3.62 2.13 3.62 2.98 3.41
12.32 7.25
12.32 10.14 11.59
-39Compansf Sanitized. Does nol contain TSCACBI
H-24018: Biopersistence Screening 10-Dose Oral Gavage Study m Rats
Data for H-24018
DuPont-2927 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
845
% Fin Active:
50
Formulation Dose (mg/kg):
1000
MolWt.F(g/mol):
19
% Active (F Containing) in Formulation: 34
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg):
Formulation Dose Normalization Factor:
340 0.402 248.5
Dose F (mmol/kg):
8.947
Molar Ratio (Active/F): 0.045
Dose F (mg/kg):_____170
Rat Number
Test Day Sample
ppmF
in
Liver
Group II
627246
10
126.4
627258
10
130.6
627261
10
169.4
627268
10
86.6
627269
10
143.5
ppmF in
Liver Minus Bkg
0.2 ppm
126.2 130.4 169.2
86.4 143.3
Group VI
627248
94
627251
94
627254
94
627263
94
627270
94
10.7 8.9
27.6 17.4
9.4
10.5 8.7
27.4 17.2
9.2
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
^tmolar Equivalents of Active in
Liver
31.36 32.41 42.05 21.47 35.61
74.24 76.71 99.53 50.82 84.29
2.61 2.16 6.81 4.27 2.29
6.18 5.12 16,12 10.12 5.41
-40Cwpaa^ Sanitized. Does not eonSain TSCA CBI