Document oDRq54erDneZ92QZ4RojggO3o
AR226-2812
DuPont-12944
TRADE SECRET
Study Title Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures
and Plasma PFOA Concentration in the Rat
Author: Paul M. Hinderliter, Ph.D.
Study Completed on: November 5,2003
P erforming 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 aboratory Project ID: DuPont-12944
Work Request Number:'
Service Code Number:
Sponsor: Association o f Plastics Manufacturers o f Europe (APME) Fluoropolymers Committee Avenue E. Van Nieuwenhuyse 4 Box3,B-1160 Brussels Belgium
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GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles o f Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17 and MAFF Japan Good Laboratory Practice Standards (59 NohSan Number 3850) except for the item documented below. The item listed does not impact the validity o f the study.
The test substance is commercially available and was characterized by the supplier prior to the initiation o f this study. A certificate o f analysis was provided. Although the characterization was not performed under Good Laboratory Practice Standards, based on our monitoring, we have no reason to doubt the validity o f the analysis.
Research Toxicologist E.L du Pont de Nemours and Company
Date
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
QUALITY ASSURANCE STATEMENT
HaskeH Sample Number(s): 25811
Dates o f Inspections: Protocol: June 10, 2003 Conduct: June 13, 17, 20, 2003
Records, Reports: September 16-18, 25, 28, 2003
Dates Findings Reported to: Study Director: September 29, 2003 Management: September 29, 2003; October 6, 2003
DuPont-12944
Reported by:
Joseph C. Hflmnl Staff Quality Assurance Auditor
0 5 ' M l / - 2<x>3 Date
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CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation o f data obtained from this study.
Inhalation Data Evaluation by: r r / c
Michael P. DeLorihe, Ph.D. Research Toxicologist
3* o c f ars
Date
Approved by:
<-
Gary W. Jepson, Ph.D. Principal Research Toxicologist and Manager
Date
Approved by:
Matthew S. Bogdahrfy, PhD , t p s y
Research Manager and
&3-A/ov~
Date
Issued by Study Director:
-J M l
aul M. Hmderliter, PhD. Research Toxicologist
O S - h h n / - 7J>o3 Date
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TABLE OF CONTENTS
Page
GOOD LABORATORY PRACTICE COMPLIANCE STA TEM EN T................................... 2
QUALITY ASSURANCE STATEM ENT..............................................................
3
C ER TIFIC A TIO N .....................................................
4
LIST O F TA B L E S.............................................................................................................................. 6
LIST O F FIG U R E S ............................................................................................................................ 7
LIST O F APPENDICES............................................................................................................. 7
STUDY INFORM ATION.............................................................................................-.................... 8
STUDY PERSONNEL........................................................................................................................9
S U M M A R Y ......................................................................................................................................... 10
IN TRO D U CTIO N ............................................................................................................................. 11
M ATERIALS AND M ETH O D S.................................................................................................... 11
A. Test Substance.........................................................................................................................11
B. Test System ............................................................................................................................. 11
C. Animal Husbandry..................................................................................................................12
1., Animal Housing................................................................................................................12
2. Environmental Conditions................................................................................................12
3. Feed and Water..................................................................................................................12
4. Animal Health and Environmental Monitoring Program..,,.......................................... 12
D. Inhalation Exposure System....................... ..........................................................................13
1. Atmosphere Generation.................................................................................................... 13
2. Chamber Construction and D esign..................;............................................................ 13
3. Exposure M ode.................................................................................................................13
E. Characterization o f Chamber Atmosphere............................................................................ 14
1. Test Substance Sampling and Analysis.......................................................
14
2. Preliminary Air Sampling Studies.................................................................................. 14
3. Particle Size Determination..............................................................................................14
4. Environmental Monitoring...............................................................................................14
F. Inhalation Exposure.................................................................................................................15
1. Phase I (Single Exposure).:.............................................................................................. 15
2. Phase II (Repeated Exposure).........................
15
G. Analytical M ethods.................................................................................................................15
1. Extraction o f PFOA from Plasma for LC/MS Analysis................................................. 15
2. Instrumentation.................................................................................................................. 16
3. Chromatographic Methods............................................................................................... 17
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H. Statistical Analysis......................................... RESULTS AND DISCUSSION...................................
A. Phase I (Single Exposure)..................................
1. Chamber Concentrations o f Test Substance. 2. Chamber Environmental Conditions........... 3. Blood Collection....................................... 4. Pharmacokinetics.......................................... B. Phase II (Repeated Exposure)............................
1. Chamber Concentrations o f Test Substance. 2. Chamber Environmental Condition^............. 3. Blood Collection........................................ 4. Pharmacokinetics........................................... C O N C L U S IO N S ..................................................... RECORDS AND SAM PLE ST O R A G E..................... REFEREN CES................ ;.............................................. T A B L E S ................................................................ FIG U R ES......................................................... ................ A PPEN D ICES..................
...17 ...17 ..17 ..17 ..18 ..18 ..18 .19 .19 .19 .19 .19 .20 ,20 20 21 31 42
LIST OF TABLES
1. PHASE I (SINGLE EXPOSURE) CHAMBER CONCENTRATIONS OF PFOA...............
2. PHASE II (REPEATED EXPOSURE) CHAMBER CONCENTRATIONS OF PFOA....... 3. PHASE II (SINGLE EXPOSURE) PARTICLE SIZE DISTRIBUTION OF PFOA.................. 4. PHASE I (SINGLE EXPOSURE) CHAMBER ENVIRONMENTAL CONDITIONS.................... 5. PHASE II (REPEATED EXPOSURE) CHAMBER ENVIRONMENTAL CONDITIONS............. 6. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION DATA IN MALE R A TS.......... 7. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION DATA IN FEMALE RATS....... 8. PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION DATA IN MALE RATS.... 9. PHASE II (REPEATED EXPOSURE) PLASMA CONCENTRATION DATA IN FEMALE RATS
Page
.... 23 .... 23 .... 24 .... 25 .... 26 ....27 ....28 ....29 ....30
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Perfluorooctanoic Acid: Relationship Between Repeated
LIST OF FIGURES Page
1. SCHEMATIC OF EXPOSURE SYSTEM............................................................................................................. 32 2. PHASE H (SINGLE EXPOSURE) MEAN DAILY CHAMBER CONCENTRATIONS....................................33 3. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION ON A LINEAR SCALE........................... 34 4. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION ON A LOGARITHMIC SCALE...............35 5. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION IN MALE RATS WITH
' STANDARD DEVIATION BARS........................................................................................................................36 6. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS WITH
STANDARD DEVIATION BARS......................................................................................................................... 37 7. PHASE B (REPEATED EXPOSURE) PLASMA CONCENTRATION IN MALE RATS............................... 38 8. PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION IN MALE RATS WITH
STANDARD DEVIATION BARS......................................................................................................................... 39 9. PHASE B (REPEATED EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS........................... 40 10. PHASE II (REPEATED EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS WITH
STANDARD DEVIATION BARS......................................................................................................................... 41
LIST OF APPENDICES Page
A. CERTIFICATE OF ANALYSIS............................................................................................................................. 44 B. PHASE II (REPEATED EXPOSURE) DAILY CHAMBER CONCENTRATIONS..........................................46 C. PHASE n (REPEATED EXPOSURE) DAILY CHAMBER ENVIRONMENTAL CONDITIONS..................48 D. PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION DATA......................................................... 52 E. PHASE B (REPEATED EXPOSURE) PLASMA CONCENTRATION DATA..................................................54
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STUDY INFORMATION
DuPont-12944
PFOA
Haskell Number: 25811 CAS Registry Number:
Physical Characteristics: White powder Stability: The test substance appeared to be stable under the conditions o f the study; no evidence o f instability was observed. Sponsor: Association o f Plastics Manufacturers o f Europe (APME) Fluoropolymers Committee Avenue E. Van Nieuwenhuyse 4 Box 3, B-l 160 Brussels Belgium
Study Initiated/Completed: April 22,2003 / (see report cover page)
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STUDY PERSONNEL
Study Director: Paul M. Hinderliter, Ph.D. Primary Technicians: Shawn A. Gannon, B.S.
Brian P. Shertz, A.A. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T.
Gary W. Jepson, Ph.D.
Inhalation Toxicologist: Michael P. DeLorme, Ph.D. Management: Arthur J. O'Neill, B.S.
Toxicology Report Preparation: Lisa G. Burchfield, A.A. Maryanne M. Wilford, B.A.
Management: Nancy S. Selzer, M.S.
Laboratory Veterinarian: Thomas W. Mayer, D.V.M., Diplomate A.C.L.A.M. Management: Janice L. Connell, M.S., B.A., C.I.H
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SUMMARY
A large pharmacokinetic database exists describing the behavior o f perfluorooctanoic acid (PFOA) following oral exposure. In rat studies, whole body elimination o f PFOA was found to be much more rapid in female rats compared with male rats following oral dosing. The objective o f this study was to quantify plasma PFOA concentrations in rats, following single and repeated inhalation exposures at three airborne concentrations, for the purpose o f bridging the oral and inhalation exposure data sets.
The study was comprised o f two separate experiments: Phase I consisted o f a single 6-hour nose-only exposure while Phase II consisted o f repeated exposures (6 hours per day, 5 days per week for 3 weeks). In both experiments, male and female rats were exposed nose only to an aerosol o f 0,1, 10, or 25 mg/m3PFOA. Levels were selected to produce plasma concentrations similar to those observed in previous oral gavage studies. In Phase I, blood was drawn via the tail vein pre-exposure, during exposure at 0.5,1, 3 and 6 hours, and post-exposure at 1, 3, 6,12, 18 and 24 hours. Rats were not removed from the exposure chamber during the exposure period and blood was taken from the tail vein while the animals remained in the nose-only restrainers attached to the exposure chamber. For Phase n , blood was collected immediately before and after the daily inhalation exposure period three days per week. Plasma derived from the whole blood samples was analyzed by liquid chromatography-mass spectrometry (LC-MS).
PFOA appears rapidly in the blood o f both male and female rats exposed via the inhalation route. PFOA elimination is sex-dependent, with female rats eliminating PFOA from the plasma much more efficiently than male rats. PFOA plasma concentrations are proportional to the inhalation exposure concentrations from 1 to 25 mg/m3. Repeated daily inhalation exposures produce little plasma carryover in female rats, but significant carryover in male rats. Male rats reach a steady state plasma concentration by three weeks with plasma concentrations of 8, 21, and 36 /g/mL respectively for the 1,10, and 25 mg/m3 exposures. Female rats reached post-exposure plasma concentrations o f 1,2, and 4 /ig/mL respectively for the 1,10, and 25 mg/m3 exposures, but returned to baseline levels for the pre-exposure time points.
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INTRODUCTION
A large pharmacokinetic database exists describing the behavior of perfluorooctanoic acid (PFOA) following oral exposure. In rat studies, whole body elimination o f PFOA was found to be much more rapid in female rats compared with male rats following oral dosing. The objective o f this study was to quantify plasma PFOA concentrations in rats, following single and repeated inhalation exposures at three airborne concentrations, for the purpose of bridging the oral and inhalation exposure data sets.
MATERIALS AND METHODS
A. Test Substance
r*FOA was obtained from Aldrich Chemicals (Milwaukee, Wisconsin) and assigned Haskell Laboratory Number 25811 upon receipt. Available information on the purity, composition, and contaminants were provided by the vendor and documented in the study records and report.
Since this study utilized the inhalation route o f exposure, no attempt was made to establish the actual dose each rat received. All results were therefore reported as a function o f the group exposure concentration(s) rather than a function o f dose.
Molecular Weight: Molecular Formula: Structure:
414.1
Purity:
B. Test System
Male and female Crl:CD(SD)IGS BR rats were obtained from Charles River Laboratories, Inc., Raleigh, North Carolina. The Sprague-Dawley rat was chosen for this study because o f the extensive experience with this strain and its suitability with respect to longevity, sensitivity, and low incidence o f spontaneous diseases. Furthermore, the Sprague-Dawley rat has been used previously for toxicokinetic testing of PFOA and other fluorinated test m aterials/1,2,3)
Upon arrival at Haskell Laboratory, all rats were housed singly, sexes separate, in quarantine. The rats were:
quarantined for at least 5 days.
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identified temporarily by cage identification.
weighed twice during the quarantine procedure.
observed with respect to weight gain and any gross signs o f disease or injury.
The rats were released from quarantine by the laboratory animal veterinarian or designee on the basis o f body weights and clinical signs.
At the time of exposure, rats were approximately 6-8 weeks o f age and the weight variation did not exceed 20% o f the mean weight by exposure group. Each animal was assigned an identification number that was used throughout the study. The last 3 digits o f the animal identification number was marked on the tail o f each animal in indelible ink.
C. Animal Husbandry
1. Animal Housing
Except during exposure, rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Each cage rack contained only rats of one sex.
2. Environmental Conditions
Rats were housed in proximity to the inhalation chambers. Animal room(s) were maintained at a temperature of 18-26C (targeted to 22-24C) and a relative humidity o f 30-70% (targeted to 40-60%). Animal rooms were artificially illuminated (fluorescent light) on an approximate 12-hour light/dark cycle, except on blood collection days where lights were turned on as needed up to one hour extra per day. The relative humidity and temperature ranges in the housing rooms were recorded but were not included in this report.
3. Feed and Water
Except during exposure, PMI Nutrition International, LLC Certified Rodent LabDiet 5002 and tap water was available ad libitum.
4. Animal Health and Environmental Monitoring Program
As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity o f the study:
Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants.
Feed samples are analyzed for total bacterial, spore, and fungal counts.
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Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers.
Certified anim al feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity o f the study.
The animal health and environmental monitoring program is administered by the attending
laboratory animal veterinarian. Evaluation o f these data did not indicate any conditions that
affected the validity of the study.
D. Inhalation Exposure System (Figure 1)
1. Atmosphere Generation
For this study, a 5% (weight/weight) solution was prepared by diluting the powdered test substance in deionized water. Concentrated ammonium hydroxide solution was added to achieve a test substance solution pH o f approximately 6.0 to 8.0. Chamber atmospheres were generated by aerosolization o f the 5% test substance solution in air with a Spraying Systems nebulizer. The test substance was metered into the nebulizer with a Harvard Apparatus model 22 syringe infusion pump. Filtered, high-pressure air, metered into the nebulizer by a Brooks model 5850E mass flow controller, carried the resulting atmosphere into the exposure chamber. The pump and flow controller were controlled and monitored by the Camile Inhalation Toxicology Automated Data System (CITADS). Chamber concentrations of test substance were controlled by varying the syringe infusion rate to the nebulizer except for the 1 mg/m3 chamber where dilutional air was also used to achieve the desired atmosphere concentration. See Figure 1 for a schematic of the inhalation exposure setup.
Test atmospheres were exhausted through an MSA charcoal/HEPA filter cartridge prior to discharge into the fume hood. Air from the control chamber was exhausted directly into the fume hood.
2. Chamber Construction and Design
All exposure chambers were constructed o f stainless steel and glass (NYU style) with a nominal internal volume of 150 L. A dispersion plate inside the chamber promoted uniform chamber distribution o f the test atmosphere.
3. Exposure Mode
During exposure, animals were individually restrained in polycarbonate (Phase I) or perforated stainless steel cylinders (Phase II) with conical nose pieces. The restrainers were inserted into a polymethylmethacrylate faceplate which was attached to the exposure chamber so that the nose o f each animal extended into the exposure chamber. Before the start of the exposure phase,
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animals were placed in restrainers on 2 separate days for approximately 15 minutes each day to acclimate the animals to the restrainers. During exposure, the animals from all exposure levels were kept warm with a heat lamp placed behind the animals (see Figure 1).
E. Characterization of Chamber Atmosphere
1. Test Substance Sampling and Analysis
The atmospheric concentration o f PFOA was determined by gravimetric analysis at approximately 60-minute intervals during each exposure. Known volumes of chamber atmosphere were drawn from the sampling port through a 25 mm filter cassette containing a pre weighed Gelman glass fiber (Type A/E) filter. The filters were weighed on a Cahn model C-31 Microbalance. The filter weights were automatically transferred to CITADS, which calculated the chamber concentrations based on the difference in pre- and post-sampling filter weights divided by the volume of chamber atmosphere sampled. Gravimetric sample start- and stoptimes for each sample were controlled and recorded by CITADS.
2. Preliminary Air Sampling Studies
For this study, the test substance, PFOA, was diluted to 5% (w/w) in deionized water and subsequently aerosolized into the exposure chambers. In order to determine if the gravimetric analytical method used to quantitate the airborne test substance concentration indicated the mass o fjust the test substance or test substance plus water, a preliminary desiccation study was performed. In this study, air samples were taken from chamber atmospheres that ranged from 1 to 25 mg/m3test substance as described in Materials and Methods Section E l. Following the determination of the filter weight immediately post-sampling, the filters were placed in a desiccation chamber for 24 hours to remove any water that was on the filter. After desiccation, the filters were re-weighed, the mass recorded and compared to the values obtained immediately following air sampling. Results demonstrated that the filters lost <0.03% o f their mass following 24 hours o f desiccation, indicating that the material collected on the filter reflected the total mass o f suspended aerosol in the exposure chambers.
3. Particle Size Determination
A sample to determine particle size distribution (mass median aerodynamic diameter and percent particles less than 1,3, and 10 fim diameter) was taken from each test exposure chamber at least once per week during the Phase II study with a Sierra Series 210 cyclone preseparator/Cascade impactor and Sierra series 110 constant flow air sampler.(5)
4. Environmental Monitoring
Chamber airflow was set at the beginning o f each exposure to achieve at least 10 air changes per hour and was monitored continually with a calibrated Brooks model 5850E mass flow controller. Chamber temperature was targeted at 22 3C. Chamber relative humidity was targeted at 40 to 60%. Airflow, temperature, and relative humidity were monitored continuously with a CAMILE Inhalation Toxicology Automated Data System (CITADS) and recorded at approximately 15minute intervals during each exposure. Chamber oxygen concentration was targeted to at least
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19%. Chamber oxygen concentration was measured with a Biosystems model 3100R oxygen analyzer and was recorded twice during each exposure
F. Inhalation Exposure
1. Phase I (Single Exposure)
To determine the proper exposure concentrations for Phase n , four groups of 3 male and 3 female rats each were exposed nose only for a single, 6-hour period to an aerosol o f the test substance. The test groups were exposed to an atmospheric concentration o f 1 mg/m3, 10 mg/m3, or25m g/m 3. A control group o f rats was exposed to air only. Blood was collected via the tail vein and was drawn pre-exposure, during exposure at 0.5,1, 3 and 6 hours, and post-exposure at 1 ,3 ,6 , 12, 18 and 24 horn's. Individual animal exposure times were staggered by five minutes to allow time for blood collection. Rats were not removed from the exposure chamber during the exposure time. Blood was taken from the tail vein while the animals remained in the nose-only restrainers in the exposure chamber. Blood was collected in heparinized tubes and stored on wet ice. Plasma was separated by centrifugation. Rats were sacrificed following the final blood collection. Plasma derived from the whole blood samples was analyzed by LC-MS as described in Section H.
The exposure concentrations selected for Phase II were levels that produced plasma concentrations similar to plasma concentrations observed in a previous study o f oral gavage dosing in rats.^4)
2. Phase II (Repeated Exposure)
After the dose levels were selected, four groups o f 5 male and 5 female rats each were exposed (nose only) for a 6-hour period, 5 days per week (weekends excluded), for 3 weeks to an aerosol o f the test substance. The starting time of the exposure is defined as the time when the nose only restrainers containing the animals are loaded into the exposure chamber. The exposure end time is defined as the time when the nose only restrainers are removed from the chamber. After each exposure, rats were returned to their cages. The control group o f rats was exposed to air only. Exposure start times were staggered by 10-30 minutes by exposure concentration group to allow time for blood collection. As in Phase I, blood was collected via the tail vein. Blood was collected before and after the daily inhalation exposure period three days per week. Rats were sacrificed following the final blood collection.
G. Analytical Methods
1. Extraction of PFOA from Plasma for LC/MS Analysis
Plasma samples were processed by protein precipitation (PPT) using Isolute Array protein precipitation columns (Argonaut Technologies, Foster City, CA). A 0.5 /rg/ml solution of
tidrich Chemicals, Milwaukee, WI) in ACN was used as an internal standard. Plasma samples were thawed, and a 20 fiL aliquot o f each sample was applied to the PPT array. The plasma samples were precipitated by adding appropriate dilution rate volumes of
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ACN/intemal standard solution. Dilution rates, ranging from 1:4 (60 /tL o f internal standard solution) to 1:50 (980 fiL of internal standard solution), were utilized in order to capture the sample concentrations within the range o f the standard curve concentrations. The array was slowly eluted under vacuum into a 96-well receiver plate, centrifuged at -3000 rpm for 5 minutes, and the extracts were analyzed by LC/MS.
2. Instrumentation
System:
Detector: Mode: Source:
LM 1 resolution: HM 1 resolution Ion energy 1: Entrance: Collision: Exit: LM 2 resolution: HM 2 resolution: Ion energy 2: Multiplier (V): Capillary (kV): Cone (V): Extractor (V): RF lens (V): Source temperature: Desolvation temperature: MS Method: Mode: Time: Chi:
Ch2:
Limit of Quantitation:
Waters 2790 Liquid Chromatograp heater, and autosampler
Quattro Micro Mass Spectrometer Multiple Reaction Monitoring (MR Negative Electrospray ' 10.0 10.0 1.0 5 2 5 14 14 2.0 650 2.0 15 0 0 130C 350C
MRM, 2 transitions 0-11.0 min
413.00 - 369.00 Dwell: Collision energy: 469.00 -- 419.00 Dwell: Collision energy: 0.1 /ig/mL - Phase I 0.05 /ig/mL - Phase II
0.25 sec 15 eV
0.25 sec 15 eV
t
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
3. Chromatographic Methods
Method: Column: Column temperature: Mobile phases:
Gradient:
Plasma concentration analysis Waters Xterra MS C l8 ,2.1x30mm, 2.5 fim Ambient A: 50 mM Ammonium Acetate B: Acetonitrile
Time (min) 0.0 0.5 10.0 10.9 11.0
%B 10 10 100 100 10
Flow rate: Stop time: Injection volume:
0.25 mL/min 11.0 min 5/iL
DuPont-12944
H. Statistical Analysis
Parameter Exposure Concentration
Data Environmental Data Plasma Concentration
Preliminary Test None
Method of Statistical Analysis
If preliminary test is not If preliminary test is
significant
significant
Descriptive statistics (e.g., mean, standard deviation)
RESULTS AND DISCUSSION
A. Phase I (Single Exposure) (Tables 1, 3-4, and 6-7, Figures 3-6, Appendix D)
1. Chamber Concentrations of Test Substance
The mean chamber atmosphere concentrations for the three levels were all within 20% of the targeted concentrations (Table 1). Due to the logistics o f performing venipunctures on the animals during the exposure, aerosol size analysis could not be performed during Phase I . However, aerosol size data obtained during the preliminary rangefinding work demonstrated aerosol sizes were 1.8-2.0 fim mass median aerodynamic diameter (MMAD) with geometric standard deviations that ranged from 1.9-2.1 fim for atmosphere concentrations that were similar to those used in the Phase I study. Aerosols were also shown to be respirable under identical generation conditions used in the Phase II studies (Table 3). Therefore, the test substance aerosols were considered to be respirable in Phase I.
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2. Chamber Environmental Conditions
The mean temperature in all the exposure chambers ranged from 24-25C except for the control
chamber, where the mean temperature was 26 C, which is outside o f the targeted range o f 22
3C (Table 4). This temperature was out o f range due to heat lamps that were utilized to keep
the animals warm to facilitate the tail venipuncture procedure during the exposures. This
temperature deviation (control only) is not expected to adversely affect the results of this study.
The mean relative humidity in all the exposure chambers during the single 6 hour exposure
ranged from 34-40%, which was within the targeted range o f 50 20%. The airflow into the
chambers ranged from 27-70 L/min, which was adequate to achieve at least 10 air changes per
hour. The mean oxygen concentration in all the exposure chambers was 21% which was within
the targeted oxygen concentration of >19%.
'
Overall, the environmental conditions in the Phase I study were within acceptable comfort ranges for the animals and was considered adequate for the conduct of the study.
3. Blood Collection
Almost all blood collections occurred within five minutes o f the described sample time; the maximum difference was seven minutes which occurred on only two samples. This difference was not judged to impact the quality o f the data since the animals were not removed from the exposure chamber during blood sampling.
4. Pharmacokinetics
For both sexes, PFOA plasma concentrations rose during the 6 hour inhalation exposure (Tables 6-7). A proportional relationship was produced in both the male and female rat maximum plasma concentrations (Cmax) between 1 and 25 mg/m3 (Figure 3). The male Cmax values were approximately 2-3 times higher than the female Cmax- The female Cmax occurred at the end o f the exposure period or 1 hour post exposure while the male Cmax occurred at the end o f
the exposure period up to 6 hours post exposure.
Elimination of PFOA from female rat plasma was rapid and complete at all exposure levels in Phase I. Plasma concentrations dropped below the analytical limit o f quantification (0.1 /ig/mL) by 12 hours post exposure (Figure 4). Plasma elimination was much slower in male rats than female rats. After 24 hours of post exposure recovery, the plasma concentrations were approximately 90% o f the peak concentrations at all tested exposure levels. The male and female elimination kinetics are consistent with the previously reported elimination kinetics of PFOA following oral dosing/4* In addition, there did not appear to be a concentration dependence of the elimination rate in either male.or female rats as the plasma curves are parallel on a log scale. Figures 5 and 6 also show the Phase I plasma concentrations with standard deviation bars indicating the significant differences between exposure groups.
For the setting of exposure levels for Phase II o f the study, male and female Cmax values were compared to plasma Cmax from an oral gavage study o f PFOA.(4) This study examined single oral gavage doses from 0.1 to 25 mg PFOA/kg body weight. The Cmax values for this study ranged from 0.598 to 160.00 pg/mL (male) and 0.67 to 132.65 (female). Because the CmaX
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values from Phase I fell within the middle o f the existing range and oral gavage data, the inhalation exposure concentrations were not changed for Phase II.
B. Phase II (Repeated Exposure) (Tables 2-3, 5, and 8-9, Figures 2 and 7-10, Appendices B-C and E)
1. Chamber Concentrations o f Test Substance
The mean chamber atmosphere concentrations for the three levels were all within 10% o f the targeted concentrations (Table 2, Figure 2). Aerosol size analysis o f all three exposure levels indicated an aerosol size distribution of 1.3-1.9 xm MMAD with geometric standard deviations o f 1.5-2.1, which is considered to be respirable to rats (Table 3). Therefore, these exposure methods were considered acceptable for the purpose o f this study.
2. Chamber Environmental Conditions
The mean temperature in all the exposure chambers ranged from 24-25C, which was within the targeted range of 22 3 C (Table 5). The mean relative humidity in all the exposure chambers during the 3 week exposure period ranged from 33 -39% , which was within the targeted range of 50 20%. The airflow into the chambers ranged from 28-70 L/min, which was sufficient to achieve at least 10 air changes per hour. The mean oxygen concentration in all the exposure chambers was 21% which was within the targeted oxygen concentration o f >19%.
Overall, the environmental conditions in the Phase II study were within acceptable comfort ranges for the animals and considered adequate for the conduct o f the study.
3. Blood Collection
No clinical signs were noted among rats during Phase II. Blood collections occurred within thirty minutes of the described sample time, samples were taken before and after the 6 hour exposure periods. Blood was collected on the first, third, and fifth exposure day for all three weeks.
4. Pharmacokinetics
Phase II plasma concentrations are shown in Tables 8-9 and in Figures 5-8. Exposures were conducted five days per week, with plasma samples taken before and after exposure on the first, third and fifth exposure day per week. The male (Figure 7) and female (Figure 9) concentration curves demonstrate the effects o f the differing elimination kinetics oft plasma levels following repeated exposure. In the female rats, there was little day-to-day carryover of PFOA in the plasma. There is no significant difference between the peak heights o f the sampled exposure days. For the male rats, there is carryover between test days as expected from Phase I. Steady state was not achieved until week 3. This steady state value is approximately 2-3 times as high as the mean single dose Cmax- Figures 8 and 10 show the mean plasma concentrations with standard deviation bars to demonstrate the differences by exposure level. As in Phase I, repeated exposures demonstrate a proportional relationship between exposure concentration and plasma concentrations in male and female rats. Male rats reach a steady state plasma concentration by
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three weeks with plasma concentrations of 8, 21, and 36 ig/mL respectively for the 1,10, and 25 mg/m3 exposures. Female rats reached post-exposure plasma concentrations o f 1,2, and 4 /xg/mL respectively for the 1,10, and 25 mg/m3 exposures, but returned to baseline levels for the pre-exposure time points.
CONCLUSIONS
PFOA appears rapidly in the blood o f both male and female rats exposed via the inhalation route. PFOA elimination is sex-dependent, with female rats eliminating PFOA from the plasma much more efficiently than male rats. At the tested concentrations from 1 to 25 mg/m3, PFOA plasma concentrations relate proportionally to the inhalation exposure concentration. Repeated daily inhalation exposures produce little plasma carryover in female rats, but significant carryover in male rats. Male rats reach a steady state plasma concentration by three weeks with plasma concentrations o f 8, 21, and 36 /xg/mL respectively for the 1,10, and 25 mg/m3 exposures. Female rats reached post-exposure plasma concentrations o f 1, 2, and 4 /xg/mL respectively for the 1,10, and 25 mg/m3 exposures, but returned to baseline levels for the pre-exposure time points.
RECORDS AND SAMPLE STORAGE
Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware.
REFERENCES
1. Vanden Heuvel, J.P., Kuslikis, B.I., Van Rafelghem, MJ . and Peterson, R.E. (1991) Tissue Distribution, Metabolism, and Elimination of Perfluorooctanoic Acid in Male and Female Rats. J. Biochem. Toxicol. 6(2): 83-92.
2. Biegel, L.B. (1997) Hazard Characterization for Human Health C8 Exposure. DuPont Haskell Laboratory.
3. Vanden Heuvel, J.P., Davis, J.W., Sommers, R., and Peterson, R.E. (1992). Renal Excretion
o f Perfluorooctanoic Acid in Male Rats: Inhibitory Effect o f Testpsterone. J Biochem
Toxicology, 7(1): 31-36.
,
4. DuPont Haskell Laboratory (2003). Perfluorooctanoic Acid: Toxicokinetics in the Rat. Unpublished r e p o r ^ | ^ | ^ ^ ^ p ^
5. Calculation described in Sierra Instruments, Inc., Bulletin 7-79-219IM, Instruction Manual: Series 210 Ambient Cascade Impactors and Cyclone Preseparators.
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PerfluorooctanoicAcidrRelationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
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TABLES
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
TABLES
ABBREVIATIONS:
EXPLANATORY NOTES
n S.D. S.E.M.
number of samples standard deviation . standard error of the mean
NOTES:
Tables 1-5: Values are reported to 2 significant figures. Calculations were performed prior to rounding values.
DuPont-12944
#
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TABLE 1
PHASE I (SINGLE EXPOSURE) CHAMBER CONCENTRATIONS OF PFOA
Design Concentration
(mg/m3) 1 10 25
Mean 1.2 9.8 27
Measured Concentration
(mg/m3) S.D. Range 0.38 0 .6 6 -1 .7 . 0.58 9.0 -1 1 3.1 2 4 -3 2
n 6 6 6
a Values represent the mean, standard deviation (S.D.), and range of the values obtained from 1 exposure.
TABLE 2
PHASE II (REPEATED EXPOSURE) CHAMBER CONCENTRATIONS OF PFOA
Design Concentration
(mg/m3) 1 10 25
Mean 1.1 10 25
Measured Concentration
(mg/m3)
S.E.M.
Range
0.04 0.81 - 1.3
0.11 9.4-11
0.43 2 1 -2 7
n 15 15 15
a Values represent the mean, standard error of the mean (S.E.M.), and range of the daily mean values obtained from n exposures.
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TABLE 3
PHASE E (SINGLE EXPOSURE) PARTICLE SIZE DISTRIBUTION OF PFOA
Design Concentration
(mg/m3) 1
10
25
Exposure 2 4 7 12 3 8 13 5 9 14
Mass Median Aerodynamic Diameter (pm)
1.7 1.7 1.8 1.3 1.3 1.5 1.8 1.7 1.8 1.9
Geometric Standard Deviation
1.6 1.6 1.6 1.9 1.9 2.1 1.5 2.0 1.8 1.5
% Particle
by Mass
<1 pm <3 pm <10 pm
12 90
100
13 90 100
14 85 100
33 87 100
30 92 100
29 84 100
10 84 100
24 80 100
15 85 100
6 84 100
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* Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
#
DuPont-12944
TABLE 4
PHASE I (SINGLE EXPOSURE) CHAMBER ENVIRONMENTAL CONDITIONS
Design
T em perature
Relative Humidity
Airflow
Concentration
(C)a
(% )a
(L/min)a
(mg/m3) M ean S.D. Range n M ean S.D. Range n M ean S.D. Range n
0 26 0.62 24 - 27 27 37 1.1 3 6 -4 0 27 28 0.025 28 27
1 ' 25 1.2 2 2 -2 7 28 34 4.5 3 1 -4 8 16 70 0.050 70 28
10 25 1.5 2 2 -2 6 30 40 1.7 3 8 -4 5 30 28 0.040 28 30
25 24 0.93 21 -25 32 34 2.5 3 0 -3 8 32 27 0.60 2 6 - 2 8 32
a Values represent the mean, standard deviation (S.D.), and range of the values obtained from 1 exposure.
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
WJ
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TABLE 5
PHASE E (REPEATED EXPOSURE) CHAMBER ENVIRONMENTAL CONDITIONS
Design Concentration
(m g /m 3) 0 1 10 25
T em perature
Relative Humidity
(C)a
_________ i% ______
Mean S.E.M. Range Mean S.E.M. Range
25 0.070 2 5 - 2 6 39
0.39 3 6 - 4 2
25 0.16 2 4 - 2 6 35
1.6 2 7 - 4 7
25 0.090 2 4 - 2 6 38
0.57 3 3-4 1
24 0.080 2 3 - 2 4 33
0.58 2 9 - 3 7
Mean 28 70 28 28
Airflow
(L/min)a
S.E.M. Range
0.066
28
0.014
70
0.031
28
0.090 2 7 - 2 9
n 15 15 15 15
a Values represent the mean, standard error of the mean (S.E.M.), and range of the daily mean values obtained from n exposures.
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat______________________________________________________________ _____DuPont-12944
TABLE
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION DATA IN MALE RATS
Hours
0
# Mean S.D. >LOQ
Mean
Cham ber Concentration (mg/mJ)
1 10
#
S.D. >LOQ
Mean S.D.
Exposure Predose 0.5 1 3 6
<LOQ <LOQ <LOQ <LOQ <LOQ
* *
*
0 0 0 0 0
<LOQ <LOQ <LOQ
1.05 2.41
* * *
0.32 0.91
0 0 0 3
3
<LOQ <LOQ 0.98 3.04
5.85
* *
0.53 1.09
Post-Exposure 1 3 6 12 18 24
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
* * * * * * \
0 0 0 0 0 0
2.16 2.37 1.81 2.25 2.03 2.09
Data expressed as /ig/mL. *Standard deviation not calculated for 2 or fewer samples >LOQ.
0.42 *
0.92 1.13 0.77 0.57
3 2 3 3 3 3
7.39 1.29 7.89 0.97 8.57 * 7.43 1.32 6.97 1.19 6.63 1.33
# >LOQ
0 0 2 3 3
3 3 2 3 3 3
25 #
Mean S.D. >LOQ
0.64 1.18 2.55 5.89 12.87
* *
1.69 2.31
1 2 2 3 3
15.31 17.78 17.58 16.74 16.1 15.34
3.95 4.79 4.72 4.17 3.56 3.14
3 3 3 3 3 3
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TABLE 7
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION DATA IN FEMALE RATS
Hours
0
# Mean S.D. >LOQ
Mean
Cham ber Concentration (mg/m3)
1 10
#
S.D. >LOQ
Mean S.D.
Exposure Predose 0.5 1 3 6
<LOQ <LOQ <LOQ <LOQ <LOQ
* * *
0 0 0 0 0
<LOQ <LOQ <LOQ 0.83 0.88
# * * *
0.14
0 0 0 2 3
<LOQ 0.43 1.2 2.62
3.68
* *
0.18 *
0.53
Post-Exposure 1 3 6 12 18 24
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
* * *
0 0 0 0 0 0
0.75 0.67 <LOQ <LOQ <LOQ <LOQ
0.14 0.21
* * * *
3 3 0 0 0 0
3.69 2.54 0.54 <LOQ <LOQ <LOQ
0.66 *
0.07 * * *
Data expressed as /xg/mL. *Standard deviation not calculated for 2 or fewer samples >LOQ.
# >LOQ
0 2 3 2 3
3 1 3 0 0 0
25 #
Mean S.D. >LOQ
<LOQ 1.33 2.74 5.91 6.87
* *
0.96 0.53 2.18
0 2 3 3 3
7.15 6.35 3.12 <LOQ <LOQ <LOQ
1.44 0.50 0.44
*
*
3 3 3 0 0 0
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TABLE 8
PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION DATA IN MALE RATS
0
# Hours Mean S.D. >LOQ
Mean
Chamber Concentration (mg/m3) 1 10 ##
S.D. >LOQ Mean S.D. >LOQ
0 <LOQ a 6 <LOQ a 48 <LOQ a 54 <LOQ a
96 <LOQ a 102 <LOQ a
168 0.83 a 174 0.49 a 216 <LOQ a 222 <LOQ a 264 <LOQ a 270 <LOQ a 336 <L0Q a 342 <LOQ a 384 <LOQ a 390 <LOQ a 432 <LOQ a 438 <LOQ a
0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0
0.58 a 1.35 0.51 2.20 0.86 4.38 1.62 4.65 1.33 6.18 1.58 4.90 1.36 6.29 1.64 6.58 1.40 7.32 1.90 7.58 1.81 8.15 2.14 6.82 2.06 7.65 1.78 7.35 1.48 8.11 1.84 8.33 1.84 9.25 2.07
1 5 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
<LOQ 3.69 7.39 11.22 13.73 15.81 13.97 16.70 18.81 19.50 20.33 21.73 20.86 19.43 20.16 21.48 21.87 24.13
a 1.32 2.78 5.10 6.19 6.24
5.23 5.55 6.31 6.42 7.73 8.17 7.76 6.85 7.18 7.85 6.89 6.90
0 5 5 5 5 5 5 5 5 5 5 5. 5 5 5 5 5 5
Steady State"
0
8 21
Data expressed as fig/mL.
"Standard deviation not calculated for 2 or fewer samples >LOQ. bSteady state values calculated as the mean of 336-438 hour samples.
25 #
Mean S.D. >LOQ
<LOQ 7.73 17.68 29.26 30.04 40.33 30.10 35.06 32.09 35.67 36.36 39.58 30.88 32.64 31.89 34.79 39.58 46.32
a 3.08 5.25 7.04 5.65 9.97 5.26 6.83 11.10 6.54 10.42 11.63 10.29 10.88 9.19 10.89 17.78 23.74
0 5 5 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5
36
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TABLE 9
PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION DATA IN FEMALE RATS
0
# Hours Mean S.D. >LOQ
0! 1.71 a 6 <LOQ a
48 <LOQ a 54 <LOQ a 96 0.74 a
102 <LOQ a
168 <LOQ a 174 <LOQ a
216 <LOQ a
222 <LOQ a
264 <LOQ a 270 <LOQ a 336 <LOQ a 342 <LOQ a 384 <LOQ a 390 <LOQ a 432 <LOQ a
438 <LOQ a
1 0 0
0 1
0 0 0
0 0
0 0 0 0 0 0 0 0
Mean
Chamber Concentration (mg/m3)
1 10
## SJ). >LOQ Mean SJ). >LOQ
<LOQ
0.86
<LOQ 0.72 <LOQ 0.84 1.18 0.77 <LOQ 0.73 <LOQ 0.60 <LOQ 0.75 <LOQ
0.66
<LOQ 0.81
a 0.41
a
0.20
a
0.11
a 0.28
a
0.22
a 0.17
a 0.15
a 0.14
a 0.17
0
4
0
5
0
5
1
5
0
5
0
5
0
5
0
5
0
5
<LOQ
2.12
0.33
2.46 0.27
1.51 <LOQ 2.14
<LOQ 2.03 <LOQ 2.41 <LOQ
1.01
<LOQ 1.73
<LOQ
2.02
a 1.07
a
0.68
a 0.99
a 1.18
a 0.24
a 0.85
a a a 0.61 a 1.29
0
5
1
5
2
3
0
4
0
4
0
4
0 2 0
4
0
4
25 #
Mean S.D. >LOQ
<LOQ 2.97 0.62 3.53 0.45 4.18 <LOQ 3.30 0.38 5.71 0.38 3.95 <LOQ 3.45 0.37 4.15 0.41 6.47
a
1.00
0.27
1.75
0.20
2.38 a
2.28 a
1.34
0.21
2.78 a
1.37 0.13 4.32
a 3.94
0
5 4
5 4 5
0
5
2
5 3 5
0
5 3 5
2
5
Steady
State6 0 1 2 4
Data expressed as jig/mL. "Standard deviation not calculated for 2 or fewer samples >LOQ. bSteady state values calculated as the mean of all post-exposure samples.
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Perfluorooctanoic Acid:' 'Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
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FIGURES
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
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FIGURE 1: SCHEMATIC OF EXPOSURE SYSTEM
Spraying Systems Nebulizer
Dilution Air (Low Level Only)
Houseline Air
=D i
Syringe Drive (Low, Intermediate & High only)
Nose-Only Restrainers
Exposure Chamber
MSA Filter
Heat Lamp exhaust
- 32Compapy Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
FIGURE 2: PHASE E (SINGLE EXPOSURE) MEAN DAILY CHAMBER CONCENTRATIONS
DuPont-12944
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
FIGURE 3:
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION ON A LINEAR SCALE
end of exposure
O -25 mg/m* male
-2 5 mg/m* female O * 10 mg/m* male
M 10 mg/m* female
A * 1 mg/m* male
- A --1 mg/m* female
** *0 mg/m* male K 0 mg/m* female
- 34-
Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
FIGURE 4:
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION ON A LOGARITHMIC SCALE
end of exposure
O *25 mg/m* male -- -- 25 mg/m* female - O *10 mg/nP male
10 mg/m* female A *1 mg/m* male
1 mg/m* female - *0 mg/m* male
- 0 mg/m* female
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FIGURE 5:
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION IN MALE RATS WITH STANDARD DEVIATION BARS
- - O **25 mg/m* male O ' *10 mg/m* male & 1mg/m* male " " 0 mg/m* mate
0
5
10 15 20 25
30
Study Hours
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
FIGURE 6:
PHASE I (SINGLE EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS WITH STANDARD DEVIATION BARS
'25 m0/m* female --* --10 mg/m* female -A --1 mg/m* female
--K--Omg/m* female
-37Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
FIGURE 7: PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION IN MALE RATS
DuPont-12944
-38Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
FIGURE 8:
PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION IN MALE RATS WITH STANDARD DEVIATION BARS
25 mgfrn* male 10mgfm*male 1 mg/m* male
mg/m* male
0 50 100 150 200 250 300 350 400 450 Study Hours
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Perfluorooctanoic-Acid:- Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
FIGURE 9: PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS
DuPont-12944
25 mg/rn* female 10 mg/m* female - A 1 mgIn f female -- 0 mg/m* female
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
FIGURE 10:
PHASE H (REPEATED EXPOSURE) PLASMA CONCENTRATION IN FEMALE RATS WITH STANDARD DEVIATION BARS
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APPENDICES
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
APPENDICES
EXPLANATORY NOTES
ABBREVIATIONS:
LOQ n NS S.D.
limit of quantitation number of samples no sample standard deviation
NOTES:
Appendices A-B: Values are reported to 2 significant figures. Calculations were performed prior to rounding values.
DuPont-12944
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
APPENDIX A Certificate of Analysis
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Perfluorooctanoic Acid; .Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
S IG M A -A L D R IC H
3050 Spruce Street Saint Louis, Missouri 63105 USA Telephone (800) 521-8956 (3 i4 ) 771-5765 Fax (800) 325-5052 (314) 77-5757 Visit Us At w*w^gma-aidrictixixn
Certificate of Analysis
APPEARANCE
INFRARED SPECTRUM
T IT R A T IO N
GAS L IQ U ID CHROMATOGRAPHY
T IT R A T IO N
QUALITY CONTROL ACCEPTANCE DATE
WHITE POWDER CONFORMS TO STRUCTURE AND STANDARD
A PRIL, 2003
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ALDRICH CHEMICAL COMPANY RONNIE MARTIN A PRIL 2 4 , 2003
We are Committed to Ike success of our Customers, Employees and Shareholders through leadership in Life Science, High Technology and Service.
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m
DuPont-12944
APPENDIX B
Phase II (Repeated Exposure) Daily Chamber Concentrations
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DuPont-12944
P hase I I D a i l y Chamber C o n c e n t r a t i o n s (mg/m3)
1 mg/m3
Exposure Mean S.D.
Range
10 mg/m3
25 mg/m3
n Mean S.D. Range n Mean S .D . Range n
1 1 . 0 0.44 0 .3 9 1 .4 6 10 1 .5 9 .1 - 13 6 26 2 . 0 23 - 29 6 2 1 . 0 0.31 0 .5 1 - 1 .4 6 9 .4 1 .2 7 .2 - 10 6 24 5 . 0 20 - 33 6 3 1 . 1 0 .4 6 0 .2 5 - 1 .5 6 9 .8 0.7 3 8 .6 - 10 6 27 3 .3 21 - 31 6
4 1 .1 0.29 0 .6 7 - 1 .5 6 11 1 . 1 8 .6 - 12 6 26 18 8 . 9 - 68 9
5 1 . 2 0 .3 5 0 .6 0 - 1 .6 6 9 .9 0 .5 8 9 .1 - 11 6 27 6 .1 21 - 36 6 6 1 .2 0 .3 2 0.7 7 - 1 .7 6 11 0 .9 8 9 .2 - 12 6 24 2 .9 21 - 27 6
7 1 .2 0.092 1 .1 - 1.3 6 11 1 .7 8 .3 - 13 6 26 2 . 5 23 - 30 6
8 1 . 1 0 .4 8 0 .3 6 - 1 .7 6 9 .6 0 .7 2 8 .6 - 11 6 27 1 . 7 24 - 29 6
9 1 .3 0.2 2 1 .1 - 1 .6 6 10 0 .7 7 8 .9 - 11 6 26 7 . 1 22 - 42 7 10 1 . 0 0.2 4 0 .6 5 - 1 .3 6 11 0 .4 1 10 - 11 6 24 5 .4 15 - 32 6
11 1 .2 0.5 5 0 .8 3 - 2 .2 5 10 2 . 2 8 .7 - 14 6 26 2 .4 23 - 29 6
12 0 .9 5 0 .4 6 0 .5 6 - 1 .7 6 9 .4 0 .7 9 8 .0 - 10 6 23 5 .6 18 - 34 6 13 1 .1 0 .6 0 0 .3 8 - 2 .1 6 10 0 .9 2 9 .1 - 11 6 21 3 . 1 18 - 26 7
14 0 .8 1 0 .3 4 0 .2 5 - 1 .2 6 9 .8 1 .3 8 .4 - 12 6 25 2 . 5 21 - 28 6
15 0 .8 2 0 .5 0 0 .3 3 " 1 .6 6 10 2 .0 7 9 .0 - 15 6 24 3 . 2 18 - 27 6
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APPENDIX C
Phase II (Repeated Exposure) Daily Cham ber Environmental Conditions
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Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
P h a se I I D a i l y Chamber E n v ir o n m e n ta l C o n d i t i o n s - T e m p e r a tu re <c)
0 mg/m3 E x p o su re Mean S . D. Range
1 mg/m3 n Mean S . D. Range
10 mg/m3
25 mg/m3
n Mean D. Range n Mean S . D. Range n
1 2 3 4
5 6 7 8 9 10 11 12 13 14
15
25 25 25
25 25 25
25 25 25 25 25 26 25 25 26
0 .6 5 23 - 26 24 0 .5 2 24 - 26 24 0.63 23 - 26 24 0 .3 4 24 - 25 24
0 .9 6 22 - 26 24 0 .7 9 22 - 26 24
0 .6 9 23 - 26 24 0 .6 9 23 - 26 24 0 .7 8 24 - 26 24 0 .4 8 24 - 26 24 0 .7 0 23 - 26 24 0 .5 6 24 - 27 24 0 .6 9 23 - 26 24 0 .3 5 24 - 25 24
0.70 23 - 27 24
24 25 24
24 24 24
25 25 25 24 25 26 26 26 25
0 .4 9 23 - 25 24
0 .5 1 23 - 26 24 0 .4 6 23 - 25 24
0 .4 5 23 - 25 24
0 .4 8 23 - 24 24 0 .4 5 22 - 24 24
0 .4 8 23 - 25 24 0 .4 5 23 - 25 24 0 .5 5 23 - 25 24 0 .5 1 23 - 25 24 0 .7 6 23 - 26 24 0.71 24 - 27 24 0 .4 0 25 - 26 24 0.53 24 - 26 24
0 .3 9 24 - 26 24
25 25 25 25
25 25
25 25 25 25 24
26 25 25 25
0 .5 6 23 - 25 24 0.91 23 - 25 24
1.0 22 - 26 24
0 .8 7 23 - 26 24 0 .7 7 23 - 26 24 0 . 8 8 22 - 26 24
0 .72 23 - 26 24 0 . 6 6 22 - 25 24
0 .7 0 23 - 26 24
1.0 22 - 26 24
0 . 6 6 23 - 25 24
0 . 8 8 23 - 27 24 0 .7 6 22 - 26 24
0.73 23 - 26 24 0 .7 4 23 - 26 24
24 24 24 23
23 23 23 24
23 24 24
24 24 24 24
0 .3 8 23 - 24 24 0 .6 7 22 - 25 24 0 .5 2 22 - 24 24 0 .4 5 22 - 24 24 0 .3 6 22 - 24 24 0 .3 1 22 - 24 24 0 .3 7 22 - 23 24 0 .3 6 23 - 24 24
0.53 22 - 24 24 0.20 23 - 24 24 0 .5 4 22 - 24 24 0 .5 2 22 - 24 24 0 .3 9 23 - 25 24
0 .4 3 22 - 24 24 0.32 23 - 24 24
Com pany Sanitized. Does not contain TSCA CBI
- 49-
'erfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
P h ase I I D a i l y Chamber E n v i r o n m e n t a l C o n d i t i o n s - R e l a t i v e H u m id ity (%)
0 mg/m } E x p o su re Mean S.D. Range
1 mg/m 1 . n Mean S.D. Range
10 mg/m3 n Mean S.D. Range
25 mg/m3 n Mean S.D. Range
n
1 2 3 4
5 6 7 8 9 10 11 12 13 14
36 38 37 40 38 38 40 40 39 40 42 40 38 40
1.2 1.1 0.89 0.89 1.4 1.3 1.4 1.0 1.3 0.91 0.59 1.0 0.82 1.1
34 - 40 36 42 36 40
38 42 36 - 42 37 - 43
38 - 43 38 41 37 - 42 38 - 42 41 - 43 38 - 44 36 - 39 38 " 43
24 24 24
24 24 24
24 24 24 24 24 24 24 24
28 27 28
31 32 35 34 32 30 35 47 37 43 42
0.82 0.99 1.6 1.2
0.94 1.4
1.1 1.5 0.93 1.2 4.2 3.3 3.3 4.5
26 _ 30
25 - 29 26 - 31
29 - 33
30 - 34 31 - 38
32 - 36 30 - 37 29 - 32 32 - 37 40 - 53
32 - 42 40 - 51 24 - 45
24 24 24 24 24 24
24 24 24 24 24 24 24 24
38 38 36 39 37 39 41 40 39 40 40 41 39 33
1.6 1.6 1.4
1.4 1.6 1.2
1.4 1.1 0.93 1.2 2.0 1.7 1.1 4.1
36 - 43 35 - 43 33 - 41 37 - 44 36 - 44 37 - 42
39 - 45 38 - 42 38 - 42 38 - 42 38 - 48 39 - 46 37 - 42 18 - 36
24 24 24 24 24 24
24 24
24 24 24 24 24 24
32 33 31 30 30 33 35 35 33 37 36 32 29 32
1.6 2.4 2.6 3.1 1.6 2.2 2.0 0.95 1.9 0.87 1.5 2.2 0.68 1.6
30 37 30 _ 39 29 _ 40
26 27
_
37 34
29 32
_
_
40 41
33 32 35 34 29
_
_ _ _ _
37
40 39 41 39
28 _ 30
30 _ 38
24 24 24 24 24 24 24 24 24 24 24 24 24 24
15 37 1 .3 35 41 24 44 1 .5 40 47 24 36 2 .4 34 - 47 24 30 1 .7 28 - 34 24
f.
Com pany Sanitized. Does not contain TSCA CBI
- 50-
luorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
Phase I I D aily Chamber Environmental C onditions - A irflow (L/min)
0 mg/m 1 E x p o su re Mean S . D. Range
1 mg/m*
10 mg/m3
25 mg/m3
n Mean S . D . Range n Mean S.D. Range n Mean S . D .
R ana
n
1 2 3 4 5 6 7
8 9 10 11 12
13 14
15
28 0 .1 5 27 - 28 24 70 0 .0 4 2
28 . Ulb 28 24 70 0 .0 4 4
28 0 .1 1 27 - 28 24 70 0 .0 5 2
28 0.023 28 24 70 0.027
28 0 .14 27 28 24 70 0.052
28 0 .1 5 27 28 24 70 0 .0 5 2
28 0.022 28 24 70 0.036
28 0 .1 1 27 - 28 24 70 0 .0 4 9
28 0 .0 24 28 24 70 0 .0 5 8
28 0 .11 27 28 24 70 0 .0 5 2
28 0 .11 27 28 24 70 0 .0 6 7
23 0.022 28 24 70 0.047
28 0 .15 27 28 24 70 0 .0 3 6
28 0 .027 28 24 70 0 .0 3 6
28 0.10
28 24 70 0 .0 3 5
70 70 70 70 70 70 70 70 70 70 70 70 70 70 70
24 28 0.050 24 28 0.028 24 28 0.067
24 28 0.021 24 28 0.063 24 28 0.063 24 28 0.023 24 28 0.0 6 4 24 28 0.024 24 28 0.055 24 28 0.053 24 28 0.043 24 28 0.072 24 28 0.032
24 28 0 .0 5 9
28 28 28 28 28 28 28 28 28 28 28 28 28 28 28
24 28 0 .4 2 28 - 30 24
24 27 0 .3 9 26 - 7R 74
24 29 0 .4 4 28 - 29 24
24 28 0 .0 1 6 28 74
24 28 0 .0 2 2 28 74
24 28 0 .0 2 1 28 74
24 28 0 .0 2 7 28 ?4
24 28 0 .0 2 0
28
24 28 0 .0 2 7
78
24 28 0.023
78
24 28 0 .0 3 2 28 74
24 28 0 .0 2 9 28 24
24 28 0 .0 2 0
28
24 28 0.023 28 74
24 28 0 .0 3 6 28 24
Com pany Sanitized. Does not contain TSCA CBI
51
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
APPENDIX D
Phase I (Single Exposure) Plasma Concentration Data
- 52Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
Predose
Hours During Exposure___________________Hours Post-Exposure
0.5 1 3 6
1 3 6 12 18
24
Males, 0 mg/m3
101 <LOQ 102 <LOQ
103 <LOQ
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
Females, 0 mg/m3
201 <LOQ
202 <LOQ
. 203
<LOQ
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ NS NS NS NS <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
Males, 1 mg/m3 301 <LOQ 302 <LOQ 303 <LOQ
<LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
0.92 1.42 0.82
2.07 3.45 1.72
-
2.03 1.87 1.69 1.61 1.94 1.94 2.63 2.87 2.79 3.55 2.84 2.72 1.81 NS 0.96 1.58 1.31 1.60
Females, 1 mg/m3 401 <LOQ 402 <LOQ 403 <LOQ
<LOQ <LOQ 1.01
<LOQ <LOQ 0.64 <LOQ <LOQ <LOQ
0.94 0.99 0.72
0.83 0.72 <LOQ <LOQ <LOQ <LOQ 0.83 0.84 <LOQ <LOQ <LOQ <LOQ 0.59 0.44 <LOQ <LOQ <LOQ <LOQ
Males, 10 mg/m3 501 <LOQ 502 <LOQ 503 <LOQ
<LOQ 1.18 <LOQ <LOQ <LOQ 0.77
3.50 2.46 3.15
6.70
4.62
6.22
8.29 8.86 9.91 8.26 7.97 7.82
5.91 6.92 NS 5.91 5.65 5.20
7.98 7.88 7.23 8.12 7.30 6.88
Females, 10 mg/m3
601 <LOQ 0.46 1.16 NS 4.01
602 <LOQ 0.40 1.40 2.69 3.97
2001
<LOQ <LOQ 1.05 2.55 3.07
3.81 <LOQ 0.52 <LOQ <LOQ <LOQ 4.28 2.54 0.48 <LOQ <LOQ <LOQ 2.97 <LOQ 0.61 <LOQ <LOQ <LOQ
Males, 25 mg/m3 701 0.64 702 <LOQ 703 <LOQ
1.51 2.86 7.36 12.84
<LOQ NS 4.04 10.58 0.84 2.24 6.27 15.20
15.26 11.39 19.29
17.68 13.04 22.61
17.24 13.04 22.47
16.25 12.84 21.13
15.75 12.72 19.82
15.42 12.17 18.44
Females, 25 mg/m3 801 <LOQ 802 <LOQ 803 <LOQ
1.14 1.52 <LOQ
3.73 - 6.48 2.65 5.83 1.83 5.42
8.23 8.03 4.36
7.87 6.63 3.33 <LOQ <LOQ <LOQ 8.07 6.65 2.61 <LOQ <LOQ <LOQ 5.49 5.78 3.42 <LOQ <LOQ <LOQ
Data expressed as /xg/mL.
- 53Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
APPENDIX E
Phase II (Repeated Exposure) Plasma Concentration Data
-54Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
___________________________ ___ _________________ Hours ________________ _______________________________ 6 48 54 96 102 168 174 216 222 264 270 336 342 384 390 432 438
Males, 0 mg/m3 101 <LOQ <LOQ <LOQ <L0Q <LOQ <LOQ <L0Q <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 102 <LOQ <LOQ <LOQ <LOQ <LOQ <IX)Q 0.83 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 103 <LOQ <LOQ <LOQ <L0Q <LOQ <LOQ <L0Q 0.49 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 104 <LOQ <L0Q <LOQ <LOQ <LOQ <LOQ <L0Q <L0Q <LOQ <L0Q <LOQ <L0Q <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 105 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <L0Q <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ
Males, 1 mg/m3 301 0.58 1.87 3.25 5.52 5.16 7.67 6.18 7.27 7.59 8.53 7.58 10.06 8.73 9.60 8.74 10.07 10.00 10.77 302 <LOQ 1.39 2.24 3.49 4.44 4.94 4.10 6.73 5.59 5.95 6.84 6.71 5.40 7.36 6.99 6.95 7.99 8.45 303 <LOQ 1.05 2.15 4.06 4.27 5.83 4.89 5.84 6.82 8.00 8.64 9.41 8.42 8.58 8.11 9.69 8.88 10.57 304 <LOQ 0.64 1.15 2.37 2.87 4.48 3.08 3.69 4.76 4.77 5.02 5.10 3.97 4.84 4.94 5.69 5.31 5.95 305 <LOQ 1.79 NS 6.46 6.50 7.96 6.24 7.93 8.14 9.34 9.80 9.45 7.57 7.89 7.95 8.13 9.46 10.52
Males, 10 mg/m3 501 <LOQ 502 <LOQ 503 <LOQ 504 <LOQ 505 <LOQ
2.15 6.01 8.79 12.23 15.61 13.19 16.76 17.39 17.80 15.39 15.36 29.79 14.91 15.37 16.04 16.12 18.43 3.59 7.90 11.57 15.14 19.88 17.50 18.16 22.58 24.20 25.06 27.48 21.94 23.72 23.79 25.62 24.80 26.50 4.23 8.86 14.92 20.43 13.36 17.52 21.31 9.12 26.01 29.87 31.46 24.84 27.73 28.88 31.35 31.57 33.14
2.87 3.44 3.97 4.01 6.98 5.16 7.27 25.81 9.62 10.29 11.82 9.06 10.54 10.67 11.47 14.54 16.05 5.60 10.72 16.86 16.86 23.24 16.47 20.00 19.16 19.86 21.03 22.51 18.69 20.25 22.10 22.92 22.32 26.53
Males, 25 mg/m3 701 <LOQ 10.44 23.60 NS 37.73 51.07 38.17 45.28 47.69 45.84 40.66 49.34 42.11 45.23 43.12 47.39 54.23 68.00 702 <LOQ 5.67 12.02 27.54 31.80 49.36 30.75 37.27 37.55 38.23 52.07 54.76 40.94 43.18 40.21 45.59 62.72 75.42 703 <LOQ 10.27 22.95 39.31 30.59 38.84 29.79 35.00 18.13 30.19 24.81 29.07 19.19 21.09 22.16 23.64 22.58 22.41 704 <LOQ 3.42 14.93 27.30 27.80 35.11 28.05 29.57 28.51 30.47 31.87 31.72 23.50 25.47 26.83 28.68 27.06 31.26
705 <LOQ 8.87 14.91 22.87 22.28 27.25 23.72 28.19 28.57 33.61 32.38 33.00 28.65 28.24 27.15 28.65 31.30 34.49
Data expressed as pg/mL.
- 55Company Sanitized. Does not contain TSCA CBI
Perfluorooctanoic Acid: Relationship Between Repeated Inhalation Exposures and Plasma PFOA Concentration in the Rat
DuPont-12944
_________________________________________________ Honrs__________________________________________________ 0____ 6 48 54 96 102 168 174 216 222 264 270 336 342 384 390 432 438
Females, 0 mg/m3 201 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 202 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 203 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 204 <LOQ <LOQ <LOQ <LOQ 0.74 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ 205 1.71 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ<LOQ
Females, 1 mg/m3 401 <LOQ 0.48 <LOQ 402 <LOQ 0.60 <LOQ 403 <LOQ 0.96 <LOQ 404 <LOQ <LOQ <LOQ 405 <LOQ 1.39 <LOQ
0.77 <LOQ 0.81 <LOQ 0.46 <LOQ 0.59 <LOQ 0.98 <LOQ
0.93 <LOQ 0.75 1.18 0.89 <LOQ 0.93 <LOQ 0.69 <L0Q
0.95 <LOQ 0.90 <LOQ 0.28 <LOQ 0.94 <LOQ 0.80 <LOQ
0.93 <LOQ 0.51 <LOQ 0.74 <LOQ 0.98 <LOQ 0.51 <LOQ
0.77 <LOQ 0.69 <LOQ 0.37 <LOQ 0.69 <LOQ 0.46 <LOQ
0.64 <LOQ 0.59 <LOQ 0.82 <LOQ 0.74 <LOQ 0.97 <LOQ
0.59 <LOQ 0.79 <LOQ 0.74 <LOQ 0.75 <LOQ 0.45 <LOQ
0.73 1.03 0.90 0.79 0.59
Females, 10 mg/m3 601 <LOQ 602 <LOQ 603 <LOQ 604 <LOQ 605 <LOQ
1.99 <LOQ 1.43 <LOQ 2.90 0.33 0.81 <LOQ 3.46 <LOQ
1.97 0.22 2.60 <LOQ 3.11 NS NS NS 2.87 <LOQ 1.25 <LOQ 1.53 0.32 <LOQ <LOQ 2.82 <LOQ 0.67 <LOQ
2.84 <LOQ NS NS 1.49 <LOQ 0.83 <LOQ 3.38 <LOQ
2.28 <LOQ NS NS 2.19 <LOQ 1.82 <LOQ 1.83 <LOQ
2.24 <LOQ 0.90 <LOQ NS NS NS NS 3.66 <LOQ <LOQ <LOQ 1.91 <LOQ <LOQ <LOQ 1.83 <LOQ 1.11 <LOQ
2.01 <LOQ NS NS 2.38 <LOQ 1.59 <LOQ 0.95 <LOQ
2.73 NS 3.42 1.29 0.62
Females, 25 mg/m3 801 <LOQ 802 <LOQ 803 <LOQ 804 <LOQ 805 <LOQ
2.24 <LOQ 1.59 0.32 3.84 0.74 3.58 0.93 3.61 0.48
2.98 0.74 1.44 <LOQ 3.72 0.29 3.24 0.38 6.27 0.38
7.07 <LOQ 1.74 <L0Q 2.54 <LOQ 3.19 <LOQ 6.36 <LOQ
7.00 0.51 1.67 <LOQ 4.02 <LOQ 1.98 <LOQ 1.81 0.24
7.72 0.62 6.33 0.26 4.34 <LOQ 4.98 <LOQ 5.16 0.25
8.37 <LOQ 2.10 <LOQ 2.11 <LOQ 2.14 <LOQ 5.04 <LOQ
5.42 0.52 4.31 <LOQ 2.26 <LOQ 2.34 0.27 2.92 0.33
11.33 0.58 2.67 <LOQ 0.94 <LOQ 0.96 <LOQ 4.87 0.24
13.03 6.42 5.34 2.52 5.03
Data expressed as fig/mL.
-56Company Sanitized. Does not contain TSCA CBI
