Document aOL2RxDrr95MEkqGOmkxyqra
AR226-1896
T-7483.1 ST-45
CONFIDENTIAL BUSINESS INFORMATION SUBJECT TO PROTECTION UNDER THE TOXIC SUBSTANCES CONTROL ACT AND OTHER LAWS HAS BEEN REDACTED FROM THIS DOCUMENT
Title: Toxicokinetic Screen of FC Methyl Carboxamide (T-7483) In Rats.
Final Report Date: January 15, 2004
3M Medical Department Study Number: T-7483.1 3M Strategic Toxicology Lab Study Number: ST-45
Author:
Andrew M. Seacat Ph.D.1 3M Medical Department, Corporate Toxicology, Strategic Toxicology Laboratory. 3M Center 220-2E-02. Saint Paul MN. 55133
Study Toxicologist: Deanna J. Luebker, M.S. Study Director: Andrew M Seacat Ph.D, DABT
CONFIDENTIAL BUSINESS
INFORMATION SUBJECT TO
PROTECTION UNDER THE
T-7483-1
TOXIC SUBSTANCES CONTROL ACT
S'1"-45 AND OTHER LAWS HAS BEEN
Introduction
REDACTED FROM THIS PAGE
Perfluoroalkylcarboxamides have been found as low level residuals in fluorochemical
compounds used as paper protectors. The structure of the carboxamides suggest that they could
be either hydrolyzed and/or metabolized to their corresponding carboxylate moiety.
Study Objective: This study is designed to determine if the FC methyl carboxamide
(feCm7Fa1lseCrOatNs (aHn)dMbee,m"etabolized
to
"}T-7483.1) can be absorbed orally by perfluorooctanoate (PFOA) acid, as measured
male and by excretion
o
f
PFOA in the urine.
Methods 4 Male and 4 Female, Harlan Sprague-Dawley rats, 150-250 g each, received a single oral dose of 1200 ug MePFOAA The averaged residual PFOA in dose = 1.3 ug PFOA /rat.. 2 Male and 2 Female, Harlan Sprague-Dawley rats, 150-250 g each, received a single oral dose of the vehicle control. (In deviation from the protocol, no animals were dosed intravenously due to solubility problems with the compound).
Sample Collection: Urine was collected pre-dose to provide matrix for extraction method
development and to verify the absence of background FC. Urine was be collected from all rats in
each dose and control group asphyxiation and necropsied
on on
days day
1,2,3,4 and-7 post 7 post-dose. Liver
dose. All rats and sera were
wbeerceoelluetchtaendizfreodmbyeaCcOh 2rat.
Sample Analysis: Unrine samples were extracted and analyzed for the quantity o f PFOA by LCMS in the 3M Environmental Laboratory (FACT TOX 158).
RTheseurletssults of the analyses showed that MePFOAA is metabolized to PFOA following an oral dose. The highest percentage of dose excreted as PFOA was excreted within the first 24 hours by both male and female rats, with female rats exhibiting higher percentages than males (Figures 1 and 2 respectively). The cumulative amount of excretion o f PFOA by day 7 post dose (Figure 3) accounted for 25 % of the MePFOAA dosed in female rats and for 7% of the MePFOAA dosed in male rats (Figure 4). The residual PFOA in dose did not contribute to PFOA in urine (Appendix 1). A summary of the results from the Analytical report (FACT TOX 158) from the 3M Environmental Lab is shown in Appendix 2. The certificate of Analysis o f the starting material showing a low background of APFO is shown in Appendix 3.
MCoenPcFluOsAioAn:can be metabolized to PFOA following an oral dose in both male and female rats.
2
T-7483.J ST-45
Signature:
Jy^cc^Jr_____ f f / >y
Andrew M. Seacat, Ph.D. DABT Study Director
Date
T-7483.1 ST-45
Figure 1
N-Methyl Carboxamide PK in Rats. % of Dose in Urine Vs time. Female rats (n=4)
782 F 783 F 0784 F 0 785F
Time (days)
4
T-7483.1 ST-45
Figure 2
N-Methyl Carboxamide PK in Rats. % of Dose in Urine Vs time. Male rats (n=4)
S773M 774 M 775 M 776 M
Time (days)
T-7483.1 ST-45
Figure 3
6
T-7483.1 ST-45
Figure 4
Methyl Carboxamide Study in Rats. % of MePFOAA Dosed Excreted in Urine as PFOA by Day 7. (n=4)
________________ Day 7_____________________
mMale Avg % in Urine
Female Avg % in Urine
T-7483.1 ST-45
Appendix 1 Individual Results
Perftuorooctanoate (PFOA) in the urine of Methylcarboxyamide dosed rats.
Day Animal
Dose Body Dose Volume Dilution POAA
# Sex Group weight (ug r Urine Factor Reported
(ORxxx)
(g) collected (ug/mL)
(ml)
0
771 M
Control
250
1
771 M
Control
258
8 4.38 <LOQ
2
771 M
Control
261
6 5.83 <LOQ
3
771 M
Control
271
6 5.83 <LOQ
4
771 M
Control
276
5 7.00 <LOQ
7
771 M
Control
295
20 1.75 <LOQ
0
772 M
Control
236
1
772 M
Control
239
7 5.00 <LOQ
2
772 M
Control
252
9 3.89 <LOQ
3
772 M
Control
249
12 2.92 <LOQ
4
772 M
Control
259
7 5.00 <LOQ
7
772 M
Control
261
14 2.50 <LOQ
0
773 M
5 mg/kg
249 1245
1
773 M
5 mg/kg
251 1255
8 4.38 0.291
2
773 M
5 mg/kg
257 1245
8 4.38 0.579
3
773 M
5 mg/kg
263 1245
12 2.92 0.520
4
773 M
5 mg/kg
267 1245
10 3.50 0.383
7
773 M
5 mg/kg
285 1245
15 2.33 0.834
0
774 M
5 mg/kg
235 1175
1
774 M
5 mg/kg
231 1155
5 7.00 0.313
2
774 M
5 mg/kg
239 1175
6 5.83 0.468
3
774 M
5 mg/kg
242 1175
5 7.00 0.394
4
774 M
5 mg/kg
248 1175
2 17.50 0.213
7
774 M
5 mg/kg
263 1175
5 7.00 0.275
0
775 M
5 mg/kg
231 1155
1
775 M
5 mg/kg
251 1255
9 3.89 0.438
2
775 M
5 mg/kg
256 1155
7 5.00 0.527
3
775 M
5 mg/kg
259 1155
6 5.83 0.495
4
775 M
5 mg/kg
268 1155
6 5.83 0.338
7
775 M
5 mg/kg
286 1155
7 5.00 0.272
0
776 M
5 mg/kg
229 1145
1
776 M
5 mg/kg
240 1200
8 4.38 0.477
2
776 M
5 mg/kg
246 1145
8 4.38 0.842
3
776 M
5 mg/kg
250 1145
8 4.38 0.639
4
776 M
5 mg/kg
255 1145
6 5.83 0.268
7
776 M
5 mg/kg
238 1145
19 1.84 1.29
0
780 F
Control
195
1
780 F
Control
191
8 4.38 <LOQ
2
780 F
Control
192
6 5.83 <LOQ
3
780 F
Control
200
9 3.89 <LOQ
4
780 F
Control
201
12 2.92 <LOQ
7
780 F
Control
208
16 2.19 <LOQ
Cone, in Urine (ug/mL)
1.27 2.53 1.52 1.34 1.95
2.19 2.73 2.75 3.74 1.93
1.70 2.64 2.89 1.97 1.36
2.09 3.68 2.79 1.56 2.37
Amount in
Urine (ug)
10.193 20.251 18.214 13.397 29.188
10.967 16.385 13.773 7.470 9.639
15.333 18.461 17.322 11.827 9.533
16.696 29.466 22.356 9.379 45.111
% of Dose in Urine
0.812 1.627 1.463 1.076 2.344
0.950 1.394 1.172 0.636 0,820
1.222 1.598 1.500 1.024 0.825
1.391 2.573 1.952 0.819 3.940
TST-7-44853.1
0
781 F
Control
204
1
781 F
Control
200
1 35.00 <LOQ
2
781 F
Control
206
8 4.38 <LOQ
3
781 F
Control
209
6 5.83 <LOQ
4
781 F
Control
211
4 8.75 <LOQ
7
781 F
Control
219
6 5.83 <LOQ
0
782 F
5 mg/kg
189 945
1
782 F
5 mg/kg
190 950
4 8.75 3.93
2
782 F
5 mg/kg
196 945
8 4.38 1.07
3
782 F
5 mg/kg
198 945
6 5.83 0.579
4
782 F
5 mg/kg
201 945
2 17.50 0.278
7
782 F
5 mg/kg
214 945
11 3.18 0.206
0
783 F
5 mg/kg
192 960
1
783 F
5 mg/kg
195 975
4 8.75 3.44
2
783 F
5 mg/kg
198 960
4 8.75 0.922
3
783 F
5 mg/kg
203 960
4 8.75 0.308
4
783 F
5 mg/kg
207 960
2 17.50 0.235
7
783 F
5 mg/kg
216 960
5 7.00 0.259
0
784 F
5 mg/kg
188 940
1
784 F
5 mg/kg
186 930
8 4.38 6.65
2
784 F
5 mg/kg
189 940
7 5.00 1.07
3
784 F
5 mg/kg
194 940
6 5.83 0.420
4
784 F
5 mg/kg
195 940
5 7.00 0.173
7
784 F
5 mg/kg
204 940
14 2.50 0.281
0
785 F
5 mg/kg
183 915
1
785 F
5 mg/kg
183 915
9 3.89 6.09
2
785 F
5 mg/kg
185 915
10 3.50 1.53
3
785 F
5 mg/kg
187 915
9 3.89 0.750
4
785 F
5 mg/kg
190 915
9 3.89 0.361
7
785 F
5 mg/kg
202 915
21 1.67 0.264
* Dose = (1 mg/ml)(5 ml/kg)(BW (g)){1 Kg/1000g)(1000 ug/mg)
34.37 4.69 3.38 4.86 0.65
30.12 8.07 2.69 4.11 1.81
29.11 5.37 2.45 1.21 0.70
23.70 5.34 2.92 1.40 0.44
137.470 37.549 20.250 9.725 7.194
120.486 32.286 10.775 8.221 9.061
232.885 37.612 14.684 6.047 9.827
213.320 53.418 26.267 12.634 9.226
14.471 3.973 2.143 1.029 0.761
12.358 3.363 1.122 0.856 0.944
25.041 4.001 1.562 0.643 1.045
23.314 5.838 2.871 1.381 1.008
1. Study Director: Andrew M Seacat Ph.D. Study Toxicologist: Deanna J. Luebker, M.S.
9
HAZLETON LABORATORIES AMERICA, INC.
__________________________________
A p p e n c f^ ^ ' ^ ff^ P R s fifis
W S ? N . W l 53707 (608)241-4471 T LX 703956 H A Z R A L M D S UD
Study: TOX-158 PR0T0 C0L Ju^omer protocol: T-7483, ST-45
Product Number(Test
MSuabtsrtixa:nce):
A c ^ i f l ^ W I P t ^ u d y in Rabbits
Rat (1 9 8 2 EPA G u id e li^ g ^ ester; 3M Toxicology
Method/Revision:
UErTiSne-8-96.0 S sE f^ ^ .O 5 0603940
A. Seacat
Analytical Equipment System Number:
Instrument Software/Version: Masslynx 3.3
FRi-lSenqaumaree:d Value:
See listing to the right See Attachments
Slope: See Attachments
YIntercept:
See Attachments fo r
Dates of Extraction/Analyst: Dates of Analysis/Analyst:
3/27/00sal
The 3M Company
Date of Data
Reduction/Analyst:
Non-QA'd Sample Data
RAT URINE day 1-7
Group Dose
Sample #
Filename PROuepgA/omArtLed
APvOerAaAge ug/mL
StdR.SDDev.
Method RTU03270-H20 Blk-1 <LOQ
Blk
RTU03270-H20 A0328000 Blk-2
<L Q
by
Matrix Blk
RRTTUU00BB33ll2k2k77--4300--HH2200 RTU-03270-Blk-3
^m AA' 003321289t0f<M3fej
LaVo?ator: es A m erica, f01^ iKMinsemnacne 3BDoiuvl<e&va$r2dn Lyi^ b Q WLbti< m sin 53704
]nc.
<LOQ <LOQ
22
RTU-03270-Blk-4 HMU-03270-Blk-
3
AA003322223488000000
<LOQ <LOQ
<LOQ
HMU-034270-B 1k-
A0328000 25
<LOQ
<LOQ
<LOQ
QC
OR771-MS50ppb3-l
A032288000 132ftie 18, 1985
OR771-MS- A0328000 136%
50ppb3-2
29
OR771-MS-19 150ppb3-l
30
tiiP'^a'bori to r ie s Americ a , Ittt,TM
OR77I-MS-150ppb3-2* 110% 123% 0.134
HHMMUU0033227700--MMSS--5500ppppbb--33--l2*
129% 122%
125%
3.93% 0.0493
Day 1 OORR777721//MM//ccoonnttrrooll//llDDaayy PPDD <<LLOOQQ <LOQ <<LLOOQQ
Chemical & BioMedical Sciences Division
10
T-7483.1 ST-45
T-7483.1 ST-45
OORR778823//FF//55mmgg//kkgg//77DDaayy PPDD 00..220569
OR784/F/5mg/kg/7Day PD OR785/F/5mg/kg/7Day PD
00..228614
0.252
0.1023.295
* Samples were interchanged during prep. The values reported were interchanged from how they
were listed on the summary report.
Limit of Quantitation (LOQ):0.0075 pg/ml
Date 4/10/00 DEnatteerVede/rBifyi:ed/ 44//1111//0000 mMmEhE, 4/11/00 kjh By:
12
T-7483.1 ST-45
Appendix 3: Carboxamide AnalysisCertificate Of Analysis
[ ]N-MeCarboxamide
March 14,2000
Richard M. Payfer
tThheissestaemstpslsehwowastahneaslaymzepdleustoincgoGntCai,nLtChe/MfoSl,lo'wHi-nNgMwRe,igih9Ft-pNeMrceRn,tFcTom-IRpo, saintidonG:C/MS techniques. The results of
C<iq3C(0)N(H)CH3 C7F 15C (0)N(H )CH3 (CC7F7F,5IO3C)C(0()0N)N(H(H)C)CHH3 3 C7F 14HC(0)N(H)CH3 C7F !SC (0)N(H )CH2CH3 C7F, j.C(0)N(H)CH3 (C7F,,0)C(0)N(H)CH3 C7F,,C(0)N(H)CH3 (C7F,,0)C(O)N(H)CH3
C7Fi5C(0)NH2 c7f i5c o 2h
Unknown MW 360 Unknown MW 380 Unknown MW 400 Unknown MW 312
0.12% 95.85% 0.02 % 0.52 % 1.20% 0.15% 0.32 % 0.36 % 0.04 % 0.04 % 0.20 % 0.13% 0.53 % 0.42 % 0.06 % 0.03 %
Additionally, the isomer distribution of the sample was determined using I9F-NMR techniques and found to contain the following mole percent composition:
(Normal
CchFa3i(nC, wF2h)exr-eCx(0is)
mainly
6)
CF3(CF2)x-CF(CF3)-(CF2)y- C(O)-
(Intemal monomethyl branch,
where x+y is mainly 4, and x 5*0, y * 0)
CxF2x+,-CF(CF3)-C (0 )-
(Alpha branch, where x is mainly 5)
(CF3)2CF-(CF2)X- C (0)-
(Isopropyl branch, where x is mainly 4)
CF3-(CF2)x-C(CF3)2-(CF2)y- C(O)-
(Intemal gem-dimethyl branch, where x+y is
mainly 3, and x + 0)
(CF3)3C-(CF2)X- C(O)-
(t-butyl branch, where x is mainly 3)
70.9 %
11.2% 9.0 % 8.3 %
0.3 % 0.3 %
13
