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T.,, tiu-msStudy No. T-7098.1: DT35 Title: Pharmacokinetic Study of Perfluorooctanesulfonyl Fluoride (POSF) Following a Single Oral Gavage Dose In Rats
3M Strategic Toxicology Laboratory Corporate Toxicology
3M Medical Department 3M Center, Building 270-SB-314
St. Paul, M N 55144
Final Report January 31, 2004
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Study Director: Andrew M. Seacat, Ph.D., DABT, Toxicology Specialist
Study Toxicologist: Deanna J. Luebker, M.S., Advanced Research Toxicologist
Sponsor: 3M Specialty Chemicals Division 3M Center Bldg 236 St. Paul, MN 55144
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^-7098.1; ST35 Final Report
Summary
Rats received a single oral dose of 5 mg/Kg perfluorooctanesulfonyl fluoride. Necropsies were performed on days 1, 4, and 29 post dose. POSF was metabolized to PFOS which was maximum in the liver on day 4 post-dose at approximately 11 ppm, or ~ 10% of the dose. PFOS was present in sera at approximately one tenth of the level found in the liver. Thus, perfluorooctanesulfonyl fluoride (POSF) was absorbed and metabolized to perfluorooctanesulfonate (PFOS) by rats following and oral dose.
Study Objective
The objective of this study was to assess the potential for oral absorption, urinary and fecal clearance, and biological persistence of perfluorooctanesulfonyl fluoride (POSF) in male Sprague Dawley rats after a single oral dose. POSF is the starting material for the synthesis of a variety of perfluorooctane sulfonate (PFOS) based materials. Data gathered in this study help define the rate of metabolism of POSF to PFOS by the liver and provide data for proper risk characterization of POSF.
Method Summary
This study was performed in the 3M Strategic Toxicology Laboratory under a defined protocol (1) and classified as a "Class B Study" as explained in TOX SOP 0950, Strategic Toxicology Lab GLP Program Procedure (2).
Briefly, the procedure was as follows. Thirty male Sprague Dawley rats (obtained from Harlan Laboratories), 6-8 weeks in age and approximately 150-250g, were divided into the following dose groups:
Group 1 2 3 4 5 6
Dose POSF 0 mg/kg 0 mg/kg 0 mg/kg 5 mg/kg 5 mg/kg 5 mg/kg
N 5 5 5 5 5 5
Euthanasia day 1 post dose day 4 post dose day 29 post dose day 1 post dose day 4 post dose day 29 post dose
Rats received either a 5 ml/Kg dose of vehicle control (2% Tween 80), or a 5 mL/Kg dose of a 1 mg/mL POSF suspension in 2% Tween 80 (final dose = 5 mg/Kg) via oral gavage on day zero of the study. Three specified rats from groups 3 and 6 were housed individually in metabolism cages for portions of the study. Urine and feces were collected on days 1, 2, 4, 14, and 29-post dose. Necropsies were performed on days 1, 4, and 29 post dose. At necropsy, liver and sera were collected from each animal. For metabolite analysis, these specimens were packed in dry ice and shipped to Kris Hansen, 3M Environmental Technology and Safety Services for FC
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T-7098.1; ST35 Final Report
analysis. Liver and sera were analyzed and the raw data was reported (3). Urine and feces analysis was not performed and was canceled. Results Treatment with PFOS at 5 mg/Kg had no effect on body weight or liver weight (Table 1A, B). Extraction and analysis of the tissues showed that PFOS was detected in the livers of all POSF dosed animals at all time points and was maximum in the liver on day 4 post-dose at approximately 11 ppm (Table 2). Trace amounts of perfluorooctanesulfonamidoacetate (PFOSAA, M556) were also reported for liver samples from POSF treated animals on days one and 4 post-dose (Table 2). The origin of the M556 in the liver samples is unknown, and all samples were near the practical quantitation limit for PFOSAA of 0.06 pg/g. Approximately 10 % of the dose was present in the liver as PFOS on day 4 post dose as calculated from the sum of the liver PFOS and liver PFOS equivalents from PFOSAA (Table 3). The PFOS levels in the sera of the rats were approximately one tenth of the level found in the liver sample extracts and were maximal on day one post dose (Table 4). No other metabolites were detected in the sera. Approximately 0.1 % of the dose was present in the sera as PFOS on day 1 post-dose (Table 4).
Conclusions These data support the conclusion that perfluorooctanesulfonyl fluoride (POSF) can be absorbed by rats following a single oral gavage dose, and metabolized to perfluorooctanesulfonate (PFOS).
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S_ T-7098.1; ST35 Final Report
List of Tables
1. Table 1: Biological Parameters 1A: Control Group IB: POSF Dose Group.
2. Table 2: Liver PFOS and PFOSAA (M556)
3. Table 3: Liver PFOS equivalents and Percent Dose in Liver
4. Table 4: Serum PFOS and Percent Dose in serum
s
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S.,, T-7098.1; ST35 Final Report
Table 1A: Biological Parameters. Control Group
Time Point
Dose
animal # Initial Terminal Kidney Liver wt 9R00-xxx BW (g) BW (g) Weight (g) (g)
Day 1 Day 1 Day 1
Omg/kg Omg/kg 0 mg/kg
001 202 002 204 003 188
207 213 196
1.7 8.7 1.7 9.3 1.6 8.4
Day 1 Omg/kg Day 1 Omg/kg
004 203 005 200
207 207
1.7 9.5 1.6 9
Avg
199 206
1.7 9.0
SD 6 6 0.1 0.4
Range Min
188 196
1.6 8
Max
204 213
1.7 10
N
55
5
55
Day 4 Omg/kg
006 193
206
1.6 8.2
Day 4 Omg/kg
007 198
215
1.7 8.6
Day 4 Omg/kg Day 4 Omg/kg
008 204 009 204
228 220
1.8 9.5 1.7 9.1
Day 4 Omg/kg
010 191
209
1.7 9.1
Avg 198 215 1.7 9
SD 6 9 0.1 1
Range Min
191 206
1.6 8
Max
204 228
1.8 10
N
55
5
55
Day 29 Omg/kg
Oil 196 275
2.1 11.9
Day 29 Omg/kg
012 203
302
2.2 11.8
Day 29 Omg/kg
013 202
297
2.3 11.8
Day 29 Omg/kg
014 201
277
1.9 10.3
Day 29 Omg/kg
015 199
275
1.9 11.1
Avg
200 285
2.1 11
SD 3 13 0.2 1
Range Min
196 275
1.9 10
Max
203 302
2.3 12
N
55
5
55
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T-7098.1; ST35 Final Report
Table 1:
Table IB: Biological Parameters. POSF Dose Group
Time Point
Dose
animal # Initial Terminal Kidney
Liver wt
9R00-xxx BW (g) BW (g) Weight (g) (g)
Day 1 5 mg/kg
031 211
215
1.6 10.0
Day 1 5 mg/kg
032 199
203
1.6 8.7
Day 1 5 mg/kg Day 1 5 mg/kg
033 204 034 197
213 205
1.9 9.8 1.5 8.7
Day 1 5 mg/kg
035 212
216
1.7 8.6
Avg
205 210
1.7 9
SD
76
0.2 1
Range Min
197 203
1.5 9
Max
212 216
1.9 10
N
55
5
55
Day 4 5 mg/kg
036 215
240
1.9 10.2
Day 4 5 mg/kg
037 195
216
1.7 9.0
Day 4 5 mg/kg
038 200
221
1.7 9.3
Day 4 5 mg/kg
039 203
229
1.9 9.8
Day 4 5 mg/kg
040 199
224
1.7 9.3
Avg
202 226
1.8 10
SD
79
0.1 0
Range Min
195 216
1.7 9
Max
215 240
1.9 10
N
55
5
55
Day 29 5 mg/kg
041 202
310
2.3 13.0
Day 29 5 mg/kg
042 205
301
2.2 11.4
Day 29 5 mg/kg
043 196 306
2.2 11.7
Day 29 5 mg/kg
044 202
295
2.1 11.0
Day 29 5 mg/kg
045 203
288
2.0 10.6
Avg
202 300
2.2 12
SD
39
0.1 1
Range Min
196 288
2.0 11
Max
205 310
2.3 13
N
55
5
55
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T-7098.1; ST35 Final Report
Table 2: Table 2: Liver PFOS and M556 in the POSF dose Group Time Point Dose POSF animal # 9R00-xxx Liver [PFOS] ppm Liver [M556]ppm Liver M556 PFOS eq (ppm) 1
Day 1 Day 1
5 mg/kg 5 mg/kg
031 2.35 0.125 032 3.41 0.0957
0.11 0.09
Day 1
5 mg/kg
033
13.80
0.0815
0.07
Day 1 Day 1
5 mg/kg 5 mg/kg
034 3.73 0.114
035 11.20
SE
0.10
Avg
6.90 0.10
0.09
SD
5.22 0.02
0.02
Day 4
5 mg/kg
036 6.76 0.0166
0.01
Day 4 Day 4
5 mg/kg 5 mg/kg
037 6.79 0.0331
038 8.22
SE
0.03
Day 4 Day 4
5 mg/kg 5 mg/kg
039
12.50
0.0125
040 19.70
SE
0.01
Avg
10.79
0.02
0.02
SD
5.50 0.01
0.01
Day 29 5 mg/kg
041 2.55 <PQL
Day 29 5 mg/kg
042 3.30 <PQL
Day 29 5 mg/kg
043 7.54 <PQL
Day 29 5 mg/kg
044 5.47 <PQL
Day 29 5 mg/kg
045 2.57 <PQL
Avg 4.29
SD 2.17
1. Liver M556 PFOS equivalents = Liver M556 concentration * ( MW PFOS/MW M556) = Liver M556 * ( 499/556)
PQL = practical quantitation limit in liver for M556 = 0.060 ug/g SE = sample evaporated, no sample remaining
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T-7098.1; ST35 Final Report
Table 3:
Table 3: Liver PFOS equivalents and Percent Dose in Liver
Time Point Dose POSF Animal# PFOS eq in Total PFOS eq in PFOS eq. In % PFOS eq dosed
mg/Kg
9R00xxx liver (ppm)1 liver (ug)2
dose (ug)3 in liver (%) 4
Day 1 Day 1 Day 1 Day 1 Day 1
5 5 5 5 5
031 2.5 032 3.5 033 13.9 034 3.8 035 11.2
24.6 30.4 136.0 33.3 96.3
1047.2 988.1 1014.9 978.1 1055.7
2.4 3.1 13.4 3.4 9.1
Avg
6.97
64.1 1016.8
6.3
Day 4 Day 4 Day 4 Day 4 Day 4
SD 5 5 5 5 5
5.19 036 6.8 037 6.8 038 8.2 039 12.5 040 19.7
49.6 69.1 61.4 76.4 122.6 183.2
34.5 1066.1 968.2 992.5 1009.4 989.6
4.8 6.5 6.3 7.7 12.1 18.5
Avg
10.81
102.5
1005.2
10.2
Day 29 Day 29 Day 29 Day 29 Day 29
SD 5 5 5 5 5
5.50 041 2.6 042 3.3 043 7.5 044 5.5 045 2.6
51.0 37.1 33.2 1004.0 37.6 1020.4 88.2 975.6 60.2 1002.5 27.2 1009.4
5.2 3.3 3.7 9.0 6.0 2.7
Avg SD
4.29 2.17
49.3 1002.4 25.1 16.5
4.9 2.6
1. PFOS equivalents in liver (ppm) = Liver PFOS (ppm) + Liver M556 PFOS equivalents (ppm) __________
2. Total PFOS equivalents in whole liver (ug) = PFOS equivalent concentration in liver (ppm) * liver weight (g)
3. PFOS equivalents in dose (ug) = Initial BW (g) * dose (mg/kg)*MW PFOS/MW M556 = BW*5 *(499/556)
4. % PFOS eq dosed as M556 in liver = PFOS equivalents in whole liver (ug)/ PFOS equivalents in dose______
T-7098.1; ST35 Final Report
i
Table 4:
T able4: Percent!Dose: Serum PFOS equivalents in POSF Group
Time Dose animal # Sera [PFOS] Serum volume Total PFOS Eq in
Point POSF 9R00-XXX ppm
(m l)1
Serum (ug)
POSF PFOS equivalents % PFOS eq dosed in
in dose (ug)3
serum (%)4
Day 1 5 mg/kg
031 0.0291
7.0
0.2
1047.2
Day 1 5 mg/kg
032 0.0297
6.6
0.2
988.1
Day 1 5 mg/kg
033 0.564
6.9
3.9
1014.9
Day 1 5 mg/kg
034 0.0484
6.6
0.3
978.1
Day 1 5 mg/kg
035 0.177
7.0
1.2 .
1055.7
Avg
0.17 6.8
1.2
1016.8
SD
0.23 0.2
1.6
34.5
Day 4 5 mg/kg
036 0.1008
7.7
0.8
1066.1
Day 4 5 mg/kg
037 0.094
7.0
0.7
968.2
Day 4 5 mg/kg
038 0.0712
7.1
0.5
992.5
Day 4 5 mg/kg
039 0.121
7.4
0.9
1009.4
Day 4 5 mg/kg
040 0.119
7.2
0.9
989.6
Ayg
0.10 7.3
0.7
1005.2
SD
0.02 0.3
0.2
37.1
Day 29 5 mg/kg
041 0.0523
10.0
0.5
1004.0
Day 29 5 mg/kg
042 0.0928
9.7
0.9
1020.4
Day 29 5 mg/kg
043 0.21
9.9
2.1
975.6
Day 29 5 mg/kg
044 0.152
9.5
1.4
1002.5
Day 29 5 mg/kg
045 0.0671
9.3
0.6
1009.4
Avg
0.11 9.7
1.1
1002.4
SD
0.07 0.3
0.6
16.5
1. There are 32.3 mL Plasma per Kg of rat.
2. Total PFOS equivalents in sera (ug) = PFOS equivalent concentration in sera (ppm) * serum volume (ml)
3. PFOS equivalents in dose (ug) = Initial BW (g) * dose (mg/kg) * MW PFOS/ MW M556 = BW*5*(499/556)
4. % PFOS equivalents dosed in serum = (PFOS equivalents in sera (ug)/ PFOS equivalents in dose (ug)) *100
0.02 0.02 0.38 0.03 0.12 0.11 0.16 0.07 0.07 0.05 0.09 0.09 0.07 0.02 0.05 0.09 0.21 0.14 0.06 0.11 0.07
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DT 35; T-7098.1 Final Report
Signatures:
Prepared By:
Deanna Luebker, NS Advanced Research Toxicologist Study Toxicologist
Date
Andrew Seacat, Ph.D. Toxicology Specialist Study Director
y } ' / _________ O ! / ? / / o Date
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DT 35; T-7098.1 Final Report
References 1. 3M Medical Department, Study No. T-7098.1. 3M Strategic Toxicology Protocol Number: DT35. Title: PHARMACOKINETIC STUDY OF POSF IN RATS. 2. 3M Medical Department, Corporate Toxicology Strategic Toxicology Laboratory Standard Operating Procedure (TOX SOP) No. 0950 - GLP Program Procedure, 1999. 3. Hansen K. Laboratory Report Final Report of Data for POSF (T-7098.1) Pharmacokinetic Study in Rats. Laboratory Report No. FACT-TOX-116. 3M Testing Laboratory 3M Environmental Technology & Safety Services 3M Environmental Laboratory Fluorine Analytical Chemistry Team (FACT) 2-3E-09 935 Bush Avenue, St. Paul, MN 55106.
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