Document v198wRB7DwNLj1EJZBmm1wx3Y
AR226-3209
TRADE SECRET
Study Title H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1 Laboratory Project ID: DuPont-2920
AUTHOR: Carol Finlay, B.A. STUDY COMPLETED ON: August 29,2000
SUPPLEMENT No. 1 COMPLETED ON: December 13,2001
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
L 1I WORK REQUEST NUMBER:
^r (--> ^j
r ^ i SERVICE CODE NUMBER: i -- i
Page 1 of 40
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained
from this study.
Reviewed by;
Paul M. Hiluieriiter, PhJ).
Postdoctoral Fellow
Reviewed b^:
CL^W J^^/. ^ HJudith C. Stadler/PhJ)., D.A.B.T.
^
Director
JJL Issned by Study Director: ____<f ^M.K-
h^lAu^
Carc/FmIay.B.A.fl
Staff Scientist
/3'P^-^' Date
^-h^-^OO I Date
13_l^^_^0f Date
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
TABLE OF CONTENTS
Page
CERTIFICATION.......................................................................................................................^
LIST OF TABLES........................................................................................................................4 LIST OF FIGURES......................................................................................................................4
LISTOFAPPENDICES...............................................................................................................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 Weights.................................................................................................................... 10
1. Test Substance........................................................................................................................................ 10 2. Positive Controls....................................................................................................................................10
B. Liver Fluorine Data...........................................................................................................II
1. Positive Controls ....................................................................................................................................11 2. Test Substance........................................................................................................................................11
11 CONCLUSIONS.........................................................................................................................
12 TABLES....................................................................................................................................... FIGURES..................................................................................................................................... 16
APPENDICES.............................................................................................................................22
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 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-23926 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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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE:
Synonyms/Codes: H-23926 Haskell Number: 23926
Composition: Known Impurities: None
POSITIVE CONTROL:
DuPont-2920 Supplement No. 1
Known Impurities: Unknown
5-
cowy sanM^. Does "ot eortata TSCA CBI
STUDY INFORMATION (Continued) POSITIVE CONTROL;
Substance Test
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 16, 1999 / August 17, 1999
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H-23926: Biopersistence Screening ^ 10-Dose Oral Gavage Study in
Rats____________________________
DuPont-2920 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. 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-23926: Biopersistence Screening
DuPont-2920
10-Dose Oral Gavage Study in Rats_________________________________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-23926), 2 positive controls (H-24019 and H-24020),
and 2 negative controls (corn oil and corn oil/acetone).
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
SUMMARY
The objective of this study was to evaluate the potential for H-23926, 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-23926. 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, 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-23926.
The mean relative liver weights (liver/body weight) of rats dosed with the test substance, H-23926, were similar to the negative controls throughout 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. On 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-23926, was 8.68 (JtM equivalents on day 10 and 5.36 ^M equivalents on day 94. On day 10, mean ^M equivalent concentrations of fluorine in the livers from rats dosed with the positive control materials were approximately 580-fold (H-24019) and 130-fold (H-24020) greater than the ' fluorine concentration in livers from rats treated with the test substance. By day 94, the concentrations were approximately 220x and 2x the fluorine concentration in rats treated with H-23926.
The fiM equivalents of fluorine in the livers from animals 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-23926. 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, H-23926.
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ffiniipair8aayiRffi2<ES.Bs Rfi eesuSaEtiiTSCA C5
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 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 10,13, 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 1,2, and 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 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-23926, 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 total body weight are presented for
comparison.
1.
Test Substance
The mean relative liver weights of rats dosed with the test substance, H-23926, were similar to
the negative controls throughout 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 24% higher on day 10 than the liver weight of rats dosed with the test substance, H-23926. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24019 were 42 or 45% higher than the liver weights of rats dosed with H-23926. 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-23926. The mean relative liver weight of rats dosed with H-24020, the other positive control, was 71% higher on day 10 than the liver weight of rats dosed with H-23926. The mean relative liver weights of rats dosed with H-24020 began to decrease during the recovery period and were similar by days 52 and 94 to the liver weights of rats dosed with
H-23926.
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-23926: Biopersistence Screening
-
DuPont-2920
10-Dose Oral Gavage Study in Rats_______T________________________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-23926, 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 ^M equivalents for H-24019 and H-24020, respectively. At day 13, the liver concentrations were 4135.69 and 334.49 [JM equivalents. By day 94, the concentrations were 1190.15 and 10.72 fiM
equivalents.
2.
Test Substance
Levels of total fluorine in livers from rats dosed with the test substance, H-23926, were 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-23926 was 8.68 /xM equivalents at day 10,
11.70 {iM at day 13, and 5.36 ^M equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 580x higher (day 10) and approximately 220x higher (end of study) than H-23926. For H-24020, the liver concentrations were approximately 130x higher (end of dosing) and 2x higher (end of study) than H-23926.
The ^M equivalents of fluorine in the livers from animals 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 following dosing with H-23926. However, fluorine levels in the liver in rats dosed with H-23926 were significantly lower than the 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-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
TABLES
12S. Does noB eanSmIn
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
Test Days 5 10 13 24 52 94
TABLE 1
MEAN BODY AND LIVER WEIGHTS (g)
CORN OIL (NEGATIVE CONTROL)
Absc>lute
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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Cteipaisy ganEBbed. DO ng QQ^^ TSCA
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
TABLE 1 (Continued)
DuPont-2920 Supplement No. 1
MEAN BODY AND LIVER WEIGHTS (g)
Test Days
5 10 13 24 52
94
H-24020 (POSITIVE CONTROL)
Abs olute
Body Weight
Lh^er 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
H-23926 (TEST SUBSTANCE)
Test Days 5 10 13 24 52 94
__B_o_d_y_W_e_igAhbt_s_o_l_uLtivee_r_W_e_ig_h_t __
304.4
13.704
329.8
14.832
349.4
15.748
401.4
15.395
509.8
19.756
574.9
19.587
Mean R.elativs
Liver Weight(% of Body Weight)
0.045 0.045 0.045 0.038 0.039 0.034
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Company SanRIzed. Does not contain TSCA CBI
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
TABLE 2 MEAN LIVER FLUORINE LEVELS
Negative Controls
Positive Controls
Test Substance
Test Corn Oil
Corn OiLAcetone
H-24019
H-24020
H-23926
K)<02OJ328.18 Days 13
(ppm)_____(ppm)_______(ppm)
(ppm)_______(ppm)
(19.3)"155.76 (29.2)8.88 (1.3)
-
-
269.02 (10.1)
46.36 (10.7)
11.70 (1.4)
94
0.63_____1^_____77.56 (10.1)
1.68 (0.3)
5.56 (2.1)
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.
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 13 94
Positive Controls
Test Substance
H-24019.
H-24020
H-23926
iiM F Equivalents 5045.85 (296.91)3
jttM F Equivalents___fiM F Equivalents
1127.25 (211.37)
8.68 (1.27)
4135.69 (155.38)
334.49 (77.70)
11.50 (1.42)
1190.15 (156.05)
10.72 (2.14)______5.36 (2.13)
a Standard deviation is in parentheses.
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Compsmy Sanftfzed. Does not contain TSCA CBt
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in
Rats___________'__________
DuPont-2920 Supplement No. 1
FIGURES
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
0.060
FIGURE 1
COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROLS
0.0504
0.040
^SIS ^
<s
^ ^
S S
0.030 0.020
0.010
0.000
Test Day
17CCTgnpatey^anretewd. D
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 2
COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND POSITIVE CONTROLS
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURES COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTR
FOR H-23926 AND NEGATIVE CONTROLS
Day 10
Day 94
E3 Corn Oil (Negative Control) H Corn Oil:Acetone (Negative Control) D H-23926 (Test Substance)
19Coinnipany Sainitteed. Does not co
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
6000
5000
4000
.2;
a
er
M
to
s 2000
1000
Day 10
D a y. .1 3
Day 94
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURES COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION NORMALI
6000
5000
4000
3000
u te.
S
a.
2000
1000
Blood / Liver
Blood / Liver
Blood / L
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H-23926: ^BiopersistenceScreening
DuPont-2920
10-Dose
Oral
Gavage
Study in
Rats_________________________________Supplement
No.
1
APPENDICES
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CiassspissSvafnSfzwS. Qwss noS eoniato TSCA CBI
H-23926: Biopersistence Screening
, DuPont-2920
10-Dose Oral Gavage Study in Rats________________________________Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 t
Supplement No. 1
CORKI OIL (NEGATIVE CONTROL)
INDI\?IDUAL FINAL BC)DY WEIGHTS (g), LIVER WEIGHTS (gf), AND RELATIVE LI'VER TO BODY WEHGHT 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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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study'in Rats
DuPont-2920 Supplement No. 1
CORKF OIL (NEGATIVE CONTROL)
INDF/IDUAL FINAL BC>DY WEIGHTS (g),, LIVER WEIGHTS (cr), AND ,RELATIVE LF/ER TO BODY WE I 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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H-23926; Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
CORN OH,: ACETONE (NEGA1IVE CONTROL)
INDI\riDUKL FINAL BCDY WEIGHTS (g), LIVER WEIGHTS (cI), AND
RELATIVE LF/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
16.1-39 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-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
CORN 01 L:ACETONE (NEGA'TIVE CONTROL)
INDP/IDUAL FINAL B.ODY WEIGHTS (g) , LIVER WEIGHTS (gr), AND
RELATIVE L:EVER TO BODY WEI:GHT OF MALE RATS
Animal Number 625354 625365
625371
625376
625381
Final
Body Wt. 396.1
459.6
447.3
432.9 381.8
GROUP IV
Liver Wt. 16.383 18.313 17.859 19.168 14.135
Relative Liver to Body Wt. 0.041
0.040
0.040
0.044
0.037
Test Day
24
24 24 24 24
Animal
Number 625356
625359
625360
625372
625374
Final
'Body Wt.
533.7
530.3
555.4
506.2
512.3
GROUP V
Liver Wt. 20.498 22.901 23.312 21.287 18.378
Relative Liver
to Body Wt. 0.038
0.043
0.042
0.042
0.036
Test Day
52 52
52 52 52
Animal Number 625353
625369
625373
625375
625377
Final
Body Wt. 565.3
514.8
673.7
588.8
496.6
GROUP VI
Liver Wt. 18.655
17.379 20.073 18.869 17.261
Relative Liver
to Body Wt. 0.033
0.034
0.030
0.032
0.035
Test Day
94 94 94 94 94
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H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
H-24'019 (POSITIVE (CONTROL) IND IVIDUAL FINAL BOH)Y WEIGHTS (g), LIVER WEIGHTS (g ) , AND
RELATIVE LIV.1ER TO BODY WEK3HT 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
-28-
Company Sanitized. Does not contain TSCA CB1
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
H-2^1019 (POSITIVE (CONTROL)
IVSD1\^DUAL FINAL BOCY WEIGHTS (g), LIVER WEIGHTS (g'), AND
RELATIVE m /ER TO BODY WEK3HT 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
Number625326
625335
625346
626347
625351
Final
Body Wt.
577.5
579.5
556.9
638.9
636.8
GROUP VI
Liver Wt. 23.749 21.548 23.945 27.416 25.615
Relative Liver
to Body Wt. 0.041
0.037
0.043
0.043
0.040
Test Day
94 94 94
94 94
-29-
Compeny Sanitized. Does not contain TSCA CB1
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
; DuPont-2920 Supplement No. 1
H-24'020 (POSITIVE iCONTROL)
IND3:VIDUAL FINAL BOE)Y WEIGHTS (g). LIVER WEIGHTS ( g), AND
RELATIVE LIV:ER TO BODY WEIl3HT OF MALE RATS
Animal
Number 627756
627767
627771
627773
627777
Final
Body Wt.
237.5
248.6
239.6
262.3
236.0
GROUP I
Liver Wt. 15.360 19.033 16.968 17.629 16.268
Relative Liver
to Body Wt. 0.065
0.077
0.071
0.067
0.069
Test Day
5 5 5 5 5
Animal Number 627768
627774
627776
627782
627785
Final
Body Wt. 293.5
338.2
254.4
268.2
267.9
GROUP II
Liver Wt.
22.536 27.332 18.821 20.172 20.857
Relative Liver
to Body Wt. 0.077
0.081
0.074
0.075
0.078
Test Day
10 10 10 10 10
Animal
Number 627758
. 627763
627764
627787
627788
Final
Body Wt. 308.7
285.8
306.7
234.9
309.4
GROUP III
Liver 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-
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
H-240 20 (POSITIVE CONTROL)
INDI VIDUAL FINAL BOD1!' WEIGHTS (g), LIVER WEIGHTS (gr), AND RELATIVE LIVE,R TO BODY WEI GHT OF MALE RATS
Animal Nuinber 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
-31-
H-23926: Biopersistence Screening f 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
H-:23926 (TEST SUB;STANCE)
INDIV^IDUAL FINAL BOIDY WEIGHTS (g), LIVER WEIGHTS (g ) , AND RELATIVE LP/ER TO BODY WEK3HT OF MALE RATS
Animal Number 626448 626450
626453
626457
- 626460
Final
Body Wt.
318.6
285.7
311.4
283.4
323.1
GROUP I
Liver Wt. 13.999 12.368 14.869 11.552
15.734
Relative Liver to Body Wt. 0.044
0.043
0.048
0.041
0.049
Test Day
5
5 5 5 5
Animal Number 626430
626433
626444
626449
626452
Final
Body Wt. 320.7
344.4
307.8
356.6
319.7
GROUP II
Liver Wt. 14.500 15.356 13.668 16.219 14.419
Relative Liver
to Body Wt. 0.045 0.045 0.044 0.045 0.045
Test Day
10 10
10 10 10
Animal
Number 626435
626436
626445
626459
626472
Final
Body Wt. 301.4
348.4
392.4
358.0
346.7
GROUP III
Liver Wt. 12.439 14.497 20.528 15.015
16.261
Relative Liver to Body Wt. 0.041
0.042
0.052
0.042
0.047
Test Day
13 13 13 13 13
32-
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
H-:23926 (TEST SUB.STANCE)
INDIV]:DUAL FINAL BCIDY WEIGHTS (g) ,, LIVER WEIGHTS (c?), AND RELATIVE LI17ER TO BODY WEI GHT OF MALE RATS
Animal Number 626437
626438
626443
626456
626458 -
Final
Body Wt. 366.5
410.1
399.5
445.2
385.9
GROUP IV
Liver Wt.
15.057 15.879 15.002 15.075 15.963
Relative Liver to Body Wt.
0.041
0.039
0.038
0.034
0.041
Test Day
24 24 24 24 24
Animal Number 626429
626432
626439
626442
626461
Final
Body Wt. 513.4
522.8
547.9
459.7
505.0
GROUP V
Liver Wt. 18.960 19.234 22.369 18.616 19.603
Relative Liver
to Body Wt. 0.037
0.037
0.041
0.040
0.039
Test Day
52 52 52 52 52
Animal Number 626434
626441
626446
626447
626455
Final
Body Wt. 601.3
532.3
571.8
575.3
593.6
GROUP VI
Liver Wt. 19.471 17.986 19.983 20.851 19.643
Relative Liver to Body Wt. 0.032
0.034
0.035
0.036
0.033
Test Day
94
94 94
94 94
33-
Cosnpany Sanitized. Does not contain TSCA CBt
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 Supplement No. 1
APPENDIX B Individual Fluorine Levels
-34-
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920
Supplement No. 1
Terms: Active % Active
Mol Wt Active Formulation Dose % Fin 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-
CoCTiparBySanifiteesS. Does not contain TSCA CBI
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920 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)
jiimolar equivalents of active in liver
The /zmolar [/xmol/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
36-
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2920
'
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 offluorinated 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 component(s) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation
-37-
CoBiBpany Sanitized. Does not contain TSCA CBl
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24019
DuPont-2920 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
497
Formulation Dose (mg/kg):
10
% Active (F Containing) in Formulation: 100
%F in A.ctive:
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^_
Rat Number
Test Day Sample
ppmF
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
13
625327
13
625342
13
625345
13
625348
13
255.9 275.3 277.9 260.4 275.6
Group VI
625326
94
625335
94
625346
94
625347
94
625351
94
79.8 89.6 73.8 62.5 82.1
ppm F in Liver
Minus Bkg 0.2 ppm
319.2 355.2 338.2 304.8 322.5
255.7 275.1 277.7 260.2 275.4
79.6 89.4 73.6 62.3 81.9
ppm F in Liver Normalized to
0.1 mmoles/kg Dose
/imolar Equivalents of Active in
Liver
1586.42 1765.34 1680.85 1514.86 1602.83
4910.77 5464.62 5203.08 4689.23 4961.54
1270.83 1367.25 1380.17 1293.19 1368.74
3933.85 4232.31 4272.31 4003.08 4236.92
395.61 444.32 365.79 309.63 407.04
1224.62 1375.38 1132.31 958.46 1260.00
.38- ffiiiipareByanSBBzed, BI(S>@n8 eonfialit TSCA CBP
H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24020
DuPont-2920 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
426
% F in Active:
69
.
Formulation Dose (mg/kg):
20
Mol Wt. F (g/mol):
19
% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
20 0.047 42.6
Dose F (mmol/kg):
0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):_____13.8
Rat Number
Test Day Sample
ppmF
in
Liver
Group II
627768
10
627774
10
627776
10
627782
10
627785
10
182.5 109.0 174.0 147.5 165.8
Group III
627758
13
627764
13
627787
13
627763
13
627788
13
61.5 40.5 33.3 51.3 45.2
Group VI
627778
94
1.9
627783 . 94 1.2
627762
94
1.9
627775
94
1.6
627769
94
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
/zmolar 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
130.57 85.84 70.50
108.84 95.85
444.20 292.03 239.86 370.29 326.09
3.62 2.13 3.62 2.98 3.41
12.32 7.25
12.32 10.14 11.59
.39-
Cofflipany Sanitized. Qees nof contain TSCA CBI
H-23926: Biopersistence Screening, 10-Dose Oral Gavage Study in Rats
Data for H-23926
DuPont-2920 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
2500
% F in Active:
40
Formulation Dose (mg/kg):
1000
Mol Wt. F (g/mol):
19
% Active (F Containing) in Formulation: 25
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
250 0.100 1000.0
Dose F (mmol/kg):
5.263
Molar Ratio (Active/F): 0.019
Dose F (mg/kg):_____100
Rat Number
Test Day Sample
ppmF
in
Liver
Group II
626430
10
8.6
626433
10
10.3
626444
10
6.9
626449
10
9.1
626452
10
9.5
Group III
626435
13
11.3
626436
13
10.8
626445
13
10.2
626459
13
13.8
626572
13
12.4
Group VI
626434
94
8.4
626441
94
7.3
626446
94
3.8
626447
94
4.0
626455
94
4.3
ppm F in Liver
Minus Bkg 0.2 ppm
8.4
10.1
6.7 8.9 9.3
11.1 10.6 10.0 13.6 12.2
8.2 7.1 3.6 3.8 4.1
ppm F in Liver Normalized to
0.1 mmoles/kg Dose
8.40 10.10
6.70 8.90 9.30
11.10 10.60 10.00 13.60 12.20
8.20 7.10 3.60 3.80 4.10
/imolar Equivalents of Active in
Liver
8.40 10.10
6.70 8.90 9.30
11.10 10.60 10.00 13.60 12.20
8.20 7.10 3.60 3.80 4.10
.40-