& : "x ,. Pacific Northwest 4 ., t i$&*, ,s& a:, National Laboratory q&$ &@ r, fc, Operated by Battelle for the . ,! Ji. f" f: I' !.. : G ;!?<.. I, y.~,`;^, L * /,..:. ,. ' 7 6 i *vii ?I, U. S. Department of Energy Chemical Dosimetry Group FINAL REPORT Battelle Project, No. 41608 October 18,200l Pharmacokinetics of 1,1,2 Trichloroethane in Rats and Mice Battelle Project No. 41608 T. S. PoetI, T. L. Curti, T. M. Luders', H. Wu', K. G. Studniski', K. K. Weitzl, and R. A. Corleyl `Chemical Dosimetry 2Small Animal Sciences group Molecular Biosciences Department 902 Battelle Boulevard P. O. Box 999, MSIN P7 59 Richland, WA 99352 FOR Dr. Michael L. Gargas, Representing the HAP Task Force The Sapphire Group 4027 Col. Glenn Hwy 4* Floor Beavercreek, OH 45431 Corresponding Author: Torka S. Poet, Ph. D. ph: 509 376 7740 fax: 509 376 9064 e mail: torka. poet@ onl. aov 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 Page 2 of 69 ABSTRACT This report summarizes the pharmacokinetic analyses of 1,1,2 trichloroethane in female F344 rats and B6C3Fl mice. Studies were conducted in support of PBPK modeling efforts by The Sapphire Group. In life studies were conducted at either WIL Laboratories or at Battelle. Blood samples from the subchronic inhalation studies performed at WIL Laboratories were sent to Battelle, Pacific Northwest Division for analysis. In mice, maximal blood concentrations after 4 weeks of inhalation exposure to target concentrations of 100 ppm were approximately 2.1 ug/ ml. In rats, maximal measured blood concentrations following the 4 week inhalation studies were approximately 2.2 ug/ ml. All other studies described in this report were conducted at Battelle, Pacific Northwest Division. Female rats and mice were gavaged with 1,1,2 TCE in corn oil at target doses of 92 or 390 mg/ kg/ day for 5 days, respectively, or in water at target doses of 1.7 or 10 mg/ kg/ day, respectively. Following exposures to the higher concentrations in corn oil, in mice the lowest blood levels were observed at day one and in rats, the highest blood levels were obtained on day one. This observation is consistent with results from the inhalation exposures conducted at WIL Laboratories,

The off gassing of 1,1,2 TCE was followed using an MS/ MS real time breath analysis system following inhalation exposures of female mice to 1000, 500, or 250 ppm for 4 to 6 hr. Overt toxicity was observed during 1000 ppm exposures. Following exposures all 5 exposed animals were placed in a 2.2 L off gassing chamber, maximal chamber concentrations were approximately 6 and 17 ppm for mice exposed to 250 or 500 ppm,

respectively. In addition, partition coefficients were measured in mouse blood and rat brain and spleen. Partition coefficients for 1,1,2 TCE for mouse blood: air, rat spleen: air,

and rat brain: air were 71, 43, and 56, respectively.

This report was submitted in fulfillment of Agreement No. 41608, by Battele Memorial Institute. This report covers a period from December, 2000 to August, 2001 and work was completed as of &Iv, 2001. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 3 of 69 INTRODUCTION 1,1,2 Trichloroethane (1,1,2 TCE) is used as an intermediate in the production of vinylidene chloride, as a solvent, in adhesives and lacquers, and in the production of <EMAIL_ADDRESS>In long term carcinogenicity studies, 1,1,2 TCE administered by gavage resulted in hepatic carcinomas and adrenal gland tumors in both male and female l36C3Fl mice. No incidences of neoplasms were detected in Osborn Mendel rats (NTP,

1978). Under section 4 of the Toxic Substances Control Act (TSCA), the USEPA issued a testing consent order incorporating an enforceable consent agreement with the HAP Task Force to perform toxicity testing and mechanistic and pharmacokinetic studies to satisfy EPA's data needs for 1,1,2 TCE (Federal Register 65( 116), June 15, 2000,

Notices, ~~ 37550 37553). A PBPK model will be used to perform route to route, high

to low dose, and species to species extrapolations in the characterization of certain potential health hazards resulting from inhalation exposures based upon toxicity studies in rats and mice.

Purpose of study Studies described herein were designed to support the development and validation of a physiologically based pharmacokinetic (PBPK) model for 1,1,2 TCE under development by The Sapphire Group. The information in this report is restricted to kinetic and solubility data that may be better interpreted following the PBPK modeling efforts. Therefore, this report is meant to principally describe the concentration data with little discussion or interpretation of results. This report describes the blood concentration results from kinetic studies conducted at either Battelle, or WIL Laboratories. Oral gavage kinetic studies in female B6C3Fl mice and female F344 rats using either a corn oil or water vehicle, partition coefficient determinations, and inhalation studies were conducted by the Chemical Dosimetry Group at Battelle Northwest. A subchronic inhalation study was conducted by WIL .

Laboratories (Ashland, Ohio), and samples collected at times on days 1, 3, and 5 of the 4t" week, The partition coefficient determinations and the single inhalation studies were performed to determine tissue solubility and to provide data that will be used to 1,1,23richlorethane: PK in rats and mice Project No. 41608 Page 4 of 69 estimate metabolic rate constants for the mouse PBPK model. In all, 5 separate studies were conducted and are described:

Study 1. Demonstration of Periodicity Following Repeated Inhalation Exposures.

(exposures conducted at WIL Research Laboratories)

Study 2. Demonstration of Periodicity Following Repeated Corn Oil Oral Gavage Administrations.

Study 3. Demonstration of Periodic& y Following Repeated Aqueous Oral Gavage Administrations.

Study 4. Determination of Metabolic Parameters.

Study 5. Determination of Partition Coefficients.

MATERIALS AND METHODS Test Mat& a/ s and Chemicak 1,1,2 Trichloroethane was obtained from Dow Chemical Co. (Midland, MI). Test material was 99.5% pure as reported by the supplier.

All other compounds and solvents were reagent grade or better.

Test Animak For studies conducted at Battelle (studies #2 5), adult (8 week old)

female F344 rats or B6C3Fl mice were purchased from Charles River Laboratories,

Raleigh, NC. The animals were housed in suspended plastic cages with chipped bedding and acclimated to the laboratory for at least 5 days prior to dosing with 1,1,2 TCE. The rooms in which the animals were housed were on a 12 hr light cycle (7 am  7 pm) and designed to maintain adequate temperatures, relative humidity, and airflows for the species under study. Deionized water (reverse osmosis) and Purina Certified Rodent Chow #5002 (Purina Mills, Inc., St. Louis, MO) were provided ad hiturn. During the acclimation period, animals were uniquely marked with a tail tattoo, weighed, and randomly assigned to subgroups based upon targeted sacrifice times. Animal weights were recorded on each day of exposure. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 5 of 69 Blood Analysis. Samples of heparinized whole blood were analyzed for 1,1,2 TCE by headspace gas chromatography. Chloroform was used as an internal standard. Blood was collected from control {untreated) female rats or mice and standard curves were generated in a blood matrix. The standard curve was linear up to 58.9 pg/ ml and the limit of detection was 0.01 ug/ ml. Aliquots of each blood sample ( O. lg) were added to a 20ml headspace vial. The 20 ml headspace vials were incubated in a 100° C oven for 5 minutes before GC analysis.

GC/ ECD analyses were performed on a Hewlett Packard 6890 Series gas chromatograph equipped with an electron capture detector (ECD). Separations were achieved with a J& W (cat.# 125 1334) DB 624 fused silica capillary column (30 m x 0.53 mmid, 3 urn film thickness; J& W, Folsom, CA). Injections were splitless using a 4 mmid Carbo Frit liner.

Study 1. Demonstration of Periodicity Following Repeated Inhalation Exposures.

Study Design. Under a separate contract, WI1 Laboratories conducted a subchronic inhalation study with 1,1,2 TCE in rats and mice, which included subgroups of animals for pharmacokinetic determinations. Groups of 3 female F344 rats or 3 female B6C3Fl mice per sample time (36 animals/ species) were sacrificed and blood collected by WIL laboratories at target times of 4, 6, 6.25 and 8 hr after the start of the 6 hr exposures to a target concentration of 100 ppm TCE on exposures days 1, 3 and 5 of the 4th week of the study. On day 1, target exposure time and blood sample collection were all delayed 1 hr such that target times were 5, 7, 7.25, and 9 hr. Aliquots of 100 ul of blood were placed in headspace vials which were tightly sealed and the weight of the blood recorded. Analyses were limited to the determination of 1,1,2 TCE in blood samples under this statement of work. However, other tissue samples (brain, lung,

liver, spleen and kidney) were collected and stored frozen for potential future analyses.

Travel and storage quality control spikes containing known amounts of 1,1,2 TCE in 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 6 of 69 each sample matrix were prepared by WIL Laboratories to be included in the analysis,

Individual animal blood 1,1,2 TCE exposure conditions and concentration data are given in Appendix A.

Study 2 and 3. Demonstration of Periodicity Following Repeated Oral Gavage Administrations in either Corn Oil or Water.

Study Design. A total of 4 gavage studies were conducted. Group 1 mice (animal #s MOOl M038) were administered 1,1,2 TCE for 1 to 5 days by gavage at a target dose of 390 mg/ kg/ day in corn oil. Group 2 mice (animal #s MlOl M138) were administered 1,1,2 TCE for 1 to 5 days by gavage at a target dose of 9.5 mg/ kg/ day in water. Group 1 rats (animal #s ROOl R038) were administered 1,1,2 TCE for 1 to 5 days by gavage at a target dose of 92 mg/ kg/ day in corn oil. Group 2 rats (animal #s RlOl R138) were administered 1,1,2 TCE for 1 to 5 days by gavage at target dose of 1.7 mg/ kg/ day in water. Two extra animals/ study were administered 1,1,2 TCE as potential replacements in the event that any problems were encountered during dosing or sacrifice.

Dose Solutions and Administration. Corn oil solutions of 1,1,2 TCE were prepared late on the Friday for administration on the following Monday, and stored at 80° C. Aliquots of dosing solution were stored for GC concentration check analysis, For the 390 mg/ kg/ day target dose (mice), a target concentration of 39 mg/ ml was prepared. For the 92 mg/ ml/ day dose (rats), a target concentration of 46 mg/ ml was prepared, These target doses were chosen to match the highest dose administered in the NTP chronic bioassay (NTP, 1978).

Due to the low solubility of 1,1,2 TCE, water target concentrations were less than 1 mg/ ml. The stated water solubility for 1,1,2 TCE is 0.45%, a sotubility check confirmed this as the maximum, but in repeated checks of homogeneity, it was determined that 1 mg/ ml was the maximum concentration of 1,1,2 TCE that was consistently homogenous. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 7 of 69 Samples of each dose solution were taken for analysis on the day of dosing to confirm targeted concentrations. Each mouse was weighed and administered dose solutions by gavage at a rate of 10 ml/ kg body weight to achieve the targeted dose levels. Each rat was weighed and administered dose solutions by gavage at a rate of 2 ml/ kg body weight to achieve the target dose levels. The dosing syringe was weighed before and after dosing to determine the actual volume delivered to each animal.

Specimen Collection. Scheduled sacrifice times were 0.5, 1, 2, and 8 hr for the corn oil gavage studies and 0.1, 0.25, 0.5, and 1 hr for the water gavage studies. At each scheduled sacrifice time, animals were anesthetized in an 80% CO2 atmosphere and blood samples were collected by closed chest cardiac puncture. To avoid volatilization loss of 1,1,2 TCE, blood samples were quickly aliquoted into duplicate samples of 100 ul each into headspace vials which were immediately sealed. The headspace vials were weighed and immediately frozen on dry ice. In some cases for mice, only a single 100 pl sample was available. Any remaining blood was placed into chilled heparinized VacutainersB in the event that additional sample might be needed. The time of death was recorded at blood draw and all animals were rapidly dissected to remove, trim extraneous tissues, and weigh the kidneys, spleen, liver, lung, and brain. The time at which the final tissue (brain) was removed was also recorded. The tissues were flash

frozen and stored along with the blood samples at 8O'C.

Study 4. Determination of Metabolic Parameters.

Study Resign. To provide data to be used in the PBPK model to determine metabolic rate constants, five female B6C3Fl mice were exposed by whole body inhalation for 4 to 6 hr to three separate exposure concentrations (1000, 500, and 250 ppm).

Immediately following exposure, all 5 mice were placed in an off gassing chamber and 1,1,2 TCE measured by direct sampling of the chamber air using an ion trap mass spectrometer (MS/ MS)

Vapor Generation System. High purity breathing air was regulated through a Kin Tek Laboratories 670 C Precision Gas Standards Generator at a flow rate of approximately 2.0 L/ min. The standard generator was loaded with three 15 ml diffusion tubes filled at 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 8 of 69 half capacity with 1,1,2 TCE. The exposure atmosphere was delivered through a stainless steel circular tube located at the bottom of the glass exposure chamber.

Chamber pressurization was avoided by using an unobstructed %" exhaust port located on the top chamber lid. Target concentrations were obtained by varying the diffusion cell temperature.

Whole Body Exposure Chamber. A dynamic flow through inhalation chamber was designed to allow for rapid changeover between the closed, recirculating chamber and a dynamic, fiow through operation, Each mouse was weighed and 5 animals were exposed to target concentrations of either 250, 500 or 1000 ppm 1,1,2 TCE for up to 6 hr in an 8.59 L glass and stainless steel closed inhalation chamber. After the completion of each exposure, the animals were placed in off gassing system described below.

Chamber Monitoring. Exposure concentrations of 1,1,2 TCE were determined by gas chromatographic analysis of atmosphere from the exposure chamber using a Hewlett Packard 5890 Series II capillary gas chromatograph with flame ionization detection (GC/ FID; Hewlett Packard, Palo Alto, CA). A 30 m x 0.32 mm ID DB 624 with 3 pm film thickness capillary column was used to separate each test chemical from the air (J& W Scientific, Folsom, CA). The chemical concentration during each exposure was monitored approximately every 8 min via automatic injections of 1 mL of chamber air through a Valco gas sampling valve. The GC/ FID was calibrated with a standard curve consisting of 6 standards prepared in 3 L TedlarD bags (SKC, Fullerton, CA) prior to each exposure.

Off Gassing, Immediately following the inhalation exposures, all 5 mice were placed in a 2.2 L off gassing chamber. Breathing air was continually supplied to the mice through the lid of the off gassing chamber at a measured rate (179 183 ml/ min). Airflow rates were measured using flow meters from Sierra Instruments (Carmel Valley, CA) and were calibrated prior to use. A Teledyne Discovery II MS/ MS equipped with an atmospheric sampling glow discharge ionization (ASGDI) source sampled from the off

gassing chamber (representing exhalation from the animal) approximately every 5 set for up to 9 hr following the inhalation exposure. The ASGDI source derived reagent ions 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 9 of 69 directly from the volatile chemicals in the sampled air. An electric potential was established by applying 400 V between two plates. Ions were then focused onto the MS/ MS trap. Helium was used as a buffer and collision gas. The intensity data from the MS/ MS was converted to concentration (ppb) through the use of external standards prepared in Tedlar@ bags. A standard curve was generated each day of experimentation 1,1,2 TCE was quantified by selective ion monitoring of the m l (m/ z 83) and m+ l (m/ z 85) ions of the daughter produced.

Study 5. Determination of Partition Coefficients,

Liquid: air and tissue: air partition coefficients were determined for mouse blood and rat brain and spleen using the vial equilibration technique of Gargas et a/. (1989). Tissues were obtained from 5 individual rats and 6 individml mice, and blood was pooled from 4 additional mice. Tissues were collected from the rats, rinsed in phosphate buffered saline, and homogenized in 3 x v/ w PBS. Blood was collected in heparinized syringes.

1.0 ml of tissue homogenate was incubated with shaking for 1 hr and the headspace sampled for 1,1,2 TCE. Due to the low volume of mouse blood obtained, 0.5 ml of whole blood was incubated for 1 hr. Headspace 1,1,2 TCE concentrations were compared to vials containing 1,1,2 TCE vapor only for blood or vials containing 0.75 ml saline for the tissues. A pilot study with rat blood was used to verify that 1 hr incubations with 0.5 ml of blood were sufficient to reach steady state,

RESULTS Study 1. Demonstration of Periodicity Following Repeated Inhalation Exposures.

Samples of blood (~ 100 ul) from inhalation studies in rats and mice were supplied by .

WIL Laboratories in headspace vials with recorded gravimetric weights, In addition, WIL Laboratories provided control blood for the generation of standard curves and storage 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 Page 10 of 69 spikes with known quantities of 1,1,2 TCE. The 1,1,2 TCE concentrations in the storage spikes were quantified using GC headspace analysis. To calculate the expected concentrations, the supplied gravimetric data was used for volumes of blood and spiking solution added and the stock solution concentration as analyzed using GC headspace analysis. Recoveries of 1,1,2 TCE in storage spikes averaged 98.2 and 99.9% for mouse and rat blood, respectively, verifying that the sample collection,

shipping, and storage methods for this study were adequate (Table 1).

Blood concentrations in female B6C3Fl mice on days 1, 3, and 5 of week 4 were analyzed using GC headspace methods. The blood concentrations during and after the inhalation exposures show the typical uptake and elimination profile for this type of exposure (Fig 1). For mice, the blood concentration peaked at the 6 hr target timepoint on day 5 at 2.2 + 0.37 ug/ g blood. The peak concentration achieved in rat blood on day 1 at the 7 hr target timepoint was 2.3 t 0.35 ug/ g blood.

Study 2 and 3. Demonstration of Periodic& y Following Repeated Oral Gavage Administrations in either Corn Oil or Water,

1,1,2 TCE was administered to female B6C3Fl mice or rats in either a corn oil vehicle or water vehicle. Due to the limited solubility of 1,1,2 TCE in water, the target doses in water were IO mg/ kg for mice and 1.7 mg/ kg in rats. Animals were sacrificed at times following administration on days 1, 3, or 5 of the 5 day dosing schedule and blood and tissues collected. Blood was analyzed for 1,1,2 TCE concentrations. Individual animal body weight, sacrifice time, dose administered, and blood 1,1,2 TCE concentration data are given in Appendix B.

Dose Sohtions and Adminstration. Actual concentrations of 1,1,2 TCE in the dose solutions were within 10% of target by gravimetric and GCjECD analyses and were considered homogeneous (Tables 2 and 3). The final GC/ ECD analyzed concentrations were used in determinations of actual doses of 1,1,2 TCE in subsequent analyses,

The dosing syringes were weighed immediately prior to and immediately after dosing and the actual volume dosed determined gravimetrically. The density of corn oil (0.92 1,1,2 trichiorethane: PK in rats and mice Project No. 41608 Page 11 of 69 g/ ml) was included in the dosing concentration calculations. The average actual time of sacrifice, body weights, and 1,1,2 TCE concentrations administered on the day of sacrifice are given in Tables 4 7 for animals administered 1,1,2 TCE by gavage either in corn oil or water. Body weights were determined immediately before dosing on each day. The. daily body weights of the animals from the group administered 1,1,2 ICE for all 5 days are shown in Figure 2.

Blood Concentrations following Corn Oil Gavage. In mice, the peak blood concentration after corn oil gavage was observed at day 5 at the first timepoint, 0.5 hr following dosing. The blood concentrations from day 1 dropped more rapidly than on days 3 and 5 of dosing (Fig. 3). In rats, peak blood concentrations were observed at the first timepoint on day 1 of dosing (Fig. 4).

Blood Concentrations fallowing Water Gavage. In both rats and mice, peak 1,1,2 TCE blood concentrations were observed at the first timepoint (6 min) on the first day of dosing following administration of 1,1,2 TCE in a water vehicle (Fig. 5 and 6).

Terminal Body and Tissue Weights. Lungs, liver, kidneys, spleen and brain were collected from each animal immediately after blood collection upon sacrifice. Tissue weights are given in Appendix C. 1,1,2 trichlorethane: PK in rats and mice Project No, 41608 Page 12 of 69 Study 4. Determination of Metabolic Parameters.

Prefiminarygavage study. A preliminary study was conducted to determine the utility of the real time MS/ MS breath analysis system to detect 1,1,2 TCE in mice following a gavage exposure. For the preliminary study, 5 mice weighing from 22 24 g were gavaged with 26.6 mg/ kg 1,1,2 TCE in a corn oil vehicle and placed in the 2.2 L off

gassing chamber. Dosing and animal weight information is given in Table 8. It took an average of 10 minutes following dosing to begin off gassing analysis. Chamber air was monitored for 3.5 hr post dosing, peak exhaled l, l, 2 TCE concentrations were achieved by 30 min and were no longer detectable by 1.5 hr post dosing (Fig 7).

Inhalatiun Exposures. Female B6C3Fl mice were exposed to 1,1,2 TCE by inhalation at concentrations of 250, 500, or 1000 ppm for 4 to 6 hr (Fig. 8). Immediately after the exposure, all 5 animals were placed in an off gassing chamber and chamber 1,1,2 TCE concentrations monitored for up to 9 hr. The exposure to 1000 ppm resulted in extreme lethargy. About 4 hr post exposure 1 animal died, at 6 hr post exposure all remaining animals were still lethargic or unconscious. The exhaled breath profile from these animals was not typical (Fig 9). Body weights, exposure and off gassing conditions, and comments are given in Appendix D.

Due to indications of developing solvent type anesthesia, the exposure to 500 ppm was stopped after 4 hr. In the subchronic inhalation studies conducted by Wil Laboratories,

equilibrium was reached by 4 hr. Animals showed no overt effects following 250 ppm exposures for 6 hr. Exhaled breath profiles are shown in Fig 9.

Study 5. Determination of Partition Coefficients.

A pilot study using frozen blood from male F344 rats was performed to assess the length of incubation time and validate the use of less than 1 ml of blood. Results and volumes are given in Appendix E. Based on the results from this study, incubations containing 0.5 ml of female B6C3Fl mouse blood or 1 ml of female F344 rat tissue were 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 Page 13 of 69 carried out for 1 hr. Tissue: air partition coefficients are shown in Table 9. Individual incubation data are given in Appendix E. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 14 of 69 DISCUSSION Target corn oil gavage doses of 390 mg/ kg/ day in mice and 92 mg/ kg/ day in rats were chosen based on the high dose from the NTP chronic bioassay (NTP, 1978). The doses for the gavage exposures in water were based on limit of solubility. Blood elimination profiles indicate that periodicity was reached over 5 consecutive days of dosing. This is consistent with blood analysis from rats and mice exposed via inhalation for 4 weeks.

The 4 6 hr inhalation exposures indicated a more pronounced effect of 1,1,2 TCE in mice than expected. Exposure to the highest concentration (1000 ppm) resulted in severe sedation and mortality in one animal, thus the off gassing data from this high concentration is not viable for use in a pharmacokinetic study. No anesthesia or adverse affects were observed during or following exposures to 250 ppm.

Based on a comparison of partition coefficients, 1,1,2 TCE may be slightly more soluble in blood from female B6C3Fl mice than from male F344 rats. Partition coefficients in female F344 rat brain and spleen were 56 and 43, respectively. l&& trichlorethane: PK in rats and mice Project No. 41608 Page 15 of 69 Reference List Gargas, M. L., Burgess, R. J., Voisard, D. E., Cason, G. H. and Andersen, M. E. (1989). Partition coefficients of low molecular weight volatile chemicsl in various liquids and tissues. ToxicoL Apple Pbarmacol. 98, 87 99.

Gargas, M. L. (1990). An exhaled breath chamber system for assessing rates of metabolism and rates of gastrointestinal absorption with volatile compounds. Journal of the American College of Toxicology 9, 447 453.

NTP. 1,1,2 Trichloroethane: bioassay for possible carcinogenicity. 074. 1978, National Toxicology Program. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 16 of 69 Mouse 1 ,I ,2 TCE Blood Cont.  Inhalation Exposures m Day 1 rDay3 *Day5 0.01 1 i / I 0 1 2 3 4 5 6 7 8 9 Time (hr)

Rat 1 ,1,2 TCE Blood Cont.  Inhalation Exposures 0.01 I , ,

0 1 2 3 4 5 6 7 a 9 Time (hr)

Figure 1. Blood 1,1,2 TCE Concentrations in female B6C3Fl Mice (top) and F344 Rats (bottom) following inhalation exposures. Female rats and mice were exposed to target concentrations of 100 ppm 1,1,2 TCE for 6 hr /day for 4 weeks. Blood was collected on exposure days 1, 3 and 5 of the 4' week of the study. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 17 of 69 21  A) Mouse /

.19 I : 6 i J 5 181 2 j 17 j 16 I 1 + 9.5 mg/ kg 1, l ,P TCE in Water I R 390 mglkg 1 ,I ,2 TCE in Corn Oil 15 1 2 3 4 5 Day of Treatment + 1.5 mglkg 1 ,1,2 TCE in Water B 92 mg/ kg 1 ,I ,2 TCE in Corn Oil 125 ! 1 1 2 3 4 5 Day of Treatment Figure 2. Rat and mouse body weights over the five days of treatment with 1,1,2 ICE in either corn oil or water. Body weights were measured for each animal immediately . prior to dosing on each day. These data are from the animals treated for all 5 days only (n= l2). 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 10 i; j h =

=! s 1 8 0 m 0.1 1 ,I ,2 TCE in Blood: Mouse 390 mglkg in Corn Oil i f f: i I Page 18 of 69 r'

1.0 2.0 3.0 4.0 Time (hr) 5.0 6.0 7.0 8.0 Figure 3. Blood 1,1,2 TCE concentrations in female 66C3Fl mice following corn oil gavage with a target of 390 mg/ kg/ day for 5 days. Mice were sacrificed and blood taken at time points on days 1, 3, and 5. 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 1 ,I ,2 TCE in Blood: Rat 92 mglkg in Corn Oil 1 j A Day 3 l* Day5 i Page 19 of 69 I 0.01 !

0.0 2.0 4.0 6.0 8.0 Time (hr)

Figure 4. Blood 1,1,2 TCE concentrations in female F344 rats following corn oil gavage with a target of 92 mg/ kg/ day for 5 days. Rats were sacrificed and blood taken at time points on days 1, 3, and 5. 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 I ,I ,2 TCE in Blood: Mouse 9 mg/ kg in Water n Day 1 rDay3 *_ Dav Page 20 of 69 0.0 0.2 0.4 0.6 0.8 1.0 Time (hr)

Figure 5. Blood 1,1,2 TCE concentrations in female B6C3Fl mice following water gavage with a target of 10 mg/ kg/ day for 5 days. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 1 ,I ,2 TCE in Blood: Rat 1.5 mg/ kg in Water t $ / iDDay j I& Day3 /* Day5 ) Page 21 of 69 f t 0.001 i /_ 0.0 0.2 0.4 0.6 0.8 1 .o Time (hr)

Figure 6. Blood 1,1,2 JCE concentrations in female F344 rats following water gavage with a target of 1.7 mg/ kg/ day for 5 days. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 22 of 69 8o01 700  l * l * l a^ 600  l * l 4+ l l 2 +* **

 500  l * l +*+

E l l l s 400

k +*

f 300  + l *

03 6 l p+% + **

200  l * * l * l *, l 100  l 0 0 0.25 0.5 0.75 1 1.25 1.5 Time (hr)

Figure 7. Chamber concentrations of 1,1,2 TCE following corn oil gavage WITH 26.6 mg/ kg in 5 female B6C3Fl mice. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 23 of 69 ChamberConcentration: 1,1,2 Trichloroethane 248.3 +b a. 54 ppm L~~~; r rt UrlUA~~ AAbA~ A~~ A~~~ A~~~~~.

6 100 :

01 0: OO 0: 30 I: 00 1: 30 2: 00 2: 30 3: 00 3: 30 4: 00 4: 30 300 5: 30 6: 00 Elapsed Time (hr)

Figure 8, Mice were exposed to 1,1,2 TCE by inhalation exposure for 4 6 hr at target concentrations of 1000, 500, and 250 ppm. Exposure chamber concentrations were measured approximately every 8 minutes over the time of exposure. The average exposure concentration rt SD. is given above the data from each exposure concentration. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 24 of 69 ( L 250 ppm A A * ,`,

* A 4 , I I I 0.0 1 .o 2.0 3.0 4.0 5.0 Time (hr)

Figure 9. Off gassing of 1,1,2 TCE following 4 6 hr inhalation exposures (points averaged every one minute interval). Five mice were exposed to target concentrations of 1000, 500, or 250 ppm of 1,1,2 TCE via inhalation and off gassing of 1,1,2 TCE measured using a real time MS/ MS system. 1,1,2 trichlorethane: PK in rats and mice Project No, 41608 Page 25 of 69 Table 1. Inhalation Study Storage Spikes Average GC/ FID % Gravimetric Cont. of Target @g/ ml) _+ SD Mouse Blood Samples 173.6 98.2 f 8.5 Rat Blood Samples 135.9 99.9 f 11.8 Storage spikes were provided by WIL Laboratories. The gravimetric concentration was calculated using weights of each component (blood and spike solution) supplied by WIL Laboratories and the concentration of the spike solution. The spike solutions were also supplied by WIL Laboratories and analyzed using GC headspace analysis to determine the accurate concentration. Four storage spikes/ species/ day (total of 12 for mice and 12 for rats) were provided. 1,1,2+ richlorethane: PK in rats and mice Project No. 41608 Page 26 of 69 Table 2. Oral Gavage in Corn Oil: 1,1,2 TCE Dose Solutions. Study Target Cont. &a vimetric GC/ FID Cont. GC/ FID 96 (mg/ mg Cont. (mg/ ml) (mg/ mf) of Target Mouse: 390 mg/ kg 39 39.0 35.0 89.7 target dose Rat: 92 r w/ kg target dose 46 46.2 46.5 101.1 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 27 of 69 Table 3. Oral Gavage in Water: 1,1,2 TCE Dose Solutions. Study Target Cont. Gravimetric GC/ fID Cont. GC/ FID % (mg/ mo Cont. (mg/ m~ (mq/ ml) of Target Mouse: 10 mg/ kg 0.9 0.895 0.891 99.0 target dose Rat: 1.7 mg/ kg 0.9 0.882 0.854 94.9 target dose 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 28 of 69 Table 4, Oral Gavage in Corn Oil: Body Weights, Sacrifice Times and Amounts of 1,1,2 TCE. Mouse: 390 mg/ kg target dose Scheduled Sacrifice 77me Actual Sacrifice Body Wt. at Actual Dose Actual Dose (hr: min) Time (bf: min) Dosing (kqy (mdkd % of Target 0: 30 1: oo 2: oo 8: 00 0: 30 1: oo 2: oo 8: 00 0: 30 1: oo 2: oo 8: 00 Day1 0: 31 I 0: Ol 0: 58 rt 0: Ol 1: 57 + 0: 03 8: 00 k 0: 02 Day3 0: 32 III 0: 02 0: 59 IL 0: Ol 2: Ol If: 0: Ol 7: 56 + 0: Ol Day5 0: 31 i 0: Ol 0: 58 f 0: OO 2: Ol i 0: oo 8: 01 I 0: Ol 0.019 zk 0.001 0.020 rt 0.001 0.020 i 0.001 0.020 F 0.001 354.3 + 12.5 90.8 352.2 c 8.5 90.3 350.1 i: 7.1 89.7 351.7 k 6.4 90.2 0.020 zk 0.001 0.019 i: 0.001 0.020 + 0.001 0.019 rt 0.000 354.2 k 10.9 391.1 i 42.6 360.2 1 32.0 371.7 zk 8.7 90.1 100.3 92.4 95.3 0.019 z! z 0.001 365.3 z! z 16.2 93.7 0.019 i 0.001 399.2 + 31.3 102.3 0.019 z! z 0.001 378.3 + 48.2 97.0 0.018 i 0.001 358.1 f 18.1 91.8 Study Averages I 0,019 + 0.001 365.5 + 25.8 93.7 `Animals were dosed on a 5 day schedule, Body Weight and Actual Dose are for the day of sacrifice. The dose administered was calculated from the pre and post dosing syringe weights and the GC analysis of the dosing solution. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 29of69 Table 5. Oral Gavage Study: Body Weights, Sacrifice Times and Amounts of 1,1,2 TCE.

Rat: 92 mg/ kg ta Scheduled Sacrifice Time (br: min)

0: 30 l: oo 2: oo 8: 00 0: 30 l: oo 2: oo 8: 00 r T 0: 30 l: oo 2: oo 8: 00 let dose Actual SacrRe Body Wt. at Actual Dose Actual Dose % Time (hr: min) Dosing (kgy h W&? 1 ' of Target Day 1 0: 33 5 0: 03 0.145 i: 0.004 97.5 ?c 0.9 106.0 0: 57 I 0: 06 0.144 k 0.003 95.7 + 1.6 104.0 2: Ol f 0: Ol 0.145 k 0.005 96.1 t 2.6 104.5 7: 59 rt 0: oo 0.149 i 0.003 97.0 k 3.2 105.3 Day 3 0: 30 +_ 0: 02 0.148 I! C 0.005 96.3 + 5.0 104.6 l: oo k 0: Ol 0.148 + 0.006 92.8 + 4.1 100.9 2: Ol i 0: Ol 0.147 T! z 0.003 93.4 Lk 2.2 101.5 8: Ol + 0: Ol 0.147 i 0.001 95.1 1: 5.4 103.4 Day 5 0: 30 ri: 0: Ol 0.149 s_ 0.004 93.0 i 1.8 101.1 1: 03 i 0: Ol 0.147 I 0.008 93.0 c_ 4.3 101.1 2: oo IL 0: 02 0.150 k 0.006 91.3 k 2.6 99.2 8: 02 rt 0: Ol 0.150 i 0.006 89.7 F 4.6 97.5 Study Aberages I 0.147 IO. 0043 94.2 zk 3.7 102.4 `Animals were dosed on a 5 day schedule, Body Weight and Actual Dose are for the day of sacrifice. Zrhe dose administered was calculated using the pre and post dosing syringe weights and the GC analysis of the dosing solution. 1,1,2 trichforethane: PK in rats and mice Project No, 41608 Page3Oof69 Table 6. Oral Gavage in Water: Body Weights, Sacrifice Times and Amounts of 1,1,2 ICE,

Mouse: 10.0 r Scheduled Sacrifice 77me (hr: min)

0: 06 0: 15 0: 30 1: oo O: O6 0: 15 0: 30 l: oo 0: 06 0: 15 0: 30 1: oo Stud Day 1 0: 06: 05 k 0: 00: 09 0.019 s 0.001 9.9 ; 0.8 99.0 0: 14: 20 ic 0: 00: 17 0.019 k 0.001 10.0 I 0.9 100.0 0: 30: 10 i 0: 00: 23 0.019 r 0.001 9.5 rt 0.7 95.0 0: 59: 40 t 0: 00: 31 0.019 F 0,001 9.6 +_ 0.3 96.0 Day 3 0: 07: 00 5 0: 01: 09 0.019 k 0.000 9.6 k 0.3 96.0 0: 14: 40 z! T 0: 00: 31 0.019 F 0.001 10.6 A 2.2 106.0 0: 30: 55 + 0: 00: 46 0.019 I 0.000 10.7 zk 2.0 107.0 0: 59: 45 +_ 0: 00: 15 0.019 Ik 0.000 9.5 t_ 1.5 95.0 Day5 0: 06: 30 + 0: 00: 30 0.020 i 0.001 9.61 0.2 96.0 0: 15: 45 z! z 0: 00: 15 0.020 I 0.000 9.5 k 041 95.0 0: 30: 10 + 0: 00: 23 0.019 + 0.001 9.3 t 0.8 93.0 0: 59: 40 z! z 0: 00: 31 0.018 ?I 0.001 9.3 k 0.6 93.0 Averages I 0.019 1. 0.001 9.7 rt 1.1 97.0 'Animals were dosed on a 5 day schedule, Body Weight and Actual Dose are for the day g/ kg target dose Actual Sacritce 7ime (hr: min: sec) Body Wt. at Actual Dose Actual Dose Dosing (kg) ' bWW ' % of Target of sacrifice. r The dose administered was calculated from the pre and post dosing syringe weights and the GC analysis of the dosing solution. 1,1,2 trichlorethane: PKin rats and mice Project No. 41608 Page31of69 Table 7. Oral Gavage In Water: Body Weights, Sacrifice Times and Amounts of 1,1,2 TCE.

Rat: 1.7 mg/ kg target dose Scheduled Actual Sacrifice Body Wt. at Actual Dose Actual Dose Sacrifice Time Time (hcmin) Dosing (kgy hW~ sU 2 % of Target' (hr: min) Day 1 0: 06 0: 06: 10 i 0: 00: 09 0.148 it 0,001 1.7 in 0.01 100.0 0: 15 0: 14: 50 + 0: 00: 31 0.147 * 0.002 1.7 i 0.09 100.0 0: 30 0: 30: 55 + 0: 00: 38 0.149 ~fr 0.002 1.7 Ii 0.04 100.0 l: oo 0: 59: 50 ic 0: 00: 31 0.148 rt 0.003 1.7 rt 0.06 100.0 Day3 0: 06 0: 06: 50 i 0: 00: 35 0.154 I 0.004 1.6 I 0.08 94.1 0: 15 0: 14: 45 Ik o: oo: oo 0.151 c 0.004 1.6 + 0.11 94.1 0: 30 0: 30: 00 i: 0: 01: 31 0.152 AZ 0.002 1.6 I 0.03 94.1 l: oo 0: 59: 45 i 0: 00: 15 0.150 i: 0.003 1.9 + 0.28 111.8 Day5 0: 06 0: 06: 10 I 0: 00: 23 0.155 + 0.002 1.7 t 0.03 100.0 0: 15 0: 15: 20 I 0: 00: 31 0.154 of: 0.005 1.4 I! 0.07 82.4 0: 30 0: 30: 20 AZ 0: 01: 02 0.153 ?I 0.005 1.6 i: 0.02 94.1 l: oo 1: 00: 00 rt 0: 00: 26 0.154 + 0.001 1.5 rt: 0.18 88.2 Stud Averages 0.152 i 0.004 1.7 i 0.15 97.6 `Animals were dosed on a 5 day schedule, Body Weight and Actual Dose are for the day of sacrifice. The dose administered was calculated using the pre and post dosing syringe weights and the GC analysis of the dosing solution. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 32 of 69 Table 8. Corn Oil Gavage: Preliminary study to determine the utility of MS/ MS system. Body Weights, Amounts of 1,1,2 TCE.

target vol syringe syringe lnj Dose Inj Mouse BW (g) (I4 pre weight post weighi (ml) mg/ kg 1 22 220 5.199 4.944 0.254 28.91 2 23 230 5.156 4.905 0.251 27.25 3 23 230 5.140 4.915 0.225 24.42 4 24 240 Syringe weights not recorded 5 23 230 5.132 4.896 0.236 25.67 Aw 23.0 26.6 SD 0.707 1.94 mg/ kg Note: The administered dose is averaged from animals l 3 and 5. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 33 of 69 Table 9. Female BK3Fl Blood: Air and Female F344 Rat Brain: air and Spleen: air Partition Coefficients Tissue Partition Coefficients (mean ir S. D) Mouse Blood 71.1 + 8.03 Rat Spleen 43.0 i 8.16 Rat Brain 56.1 + 4.94 Saline 11.7 + 2.07 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 34 of 69 APPENDIX A. Subchronic inhalation exposures to 100 ppm for 6 hr/ day conducted at WIL Laboratories Table A l Oral Gavage: Female BK3Fl Mouse 390 mg/ kg target dose in corn oil Table A 2 Oral Gavage: Female F344 Rat 92 mg/ kg target dose in corn oil Table A 3 Oral Gavage: Female B6C3Fl Mouse 10 mg/ kg target dose in water Table A 4 Blood concentrations following inhalation exposures in mice Table A 5 Blood concentrations following inhalation exposures in rats B. Individual animal data for gavage studies Table B l Oral Gavage: Female B6C3Fl Mouse 390 mg/ kg target dose in corn oil Table B 2 Oral Gavage: Female F344 Rat 92 mg/ kg target dose in corn oil Table B 3 Oral Gavage: Female B6C3Fl Mouse 10 mg/ kg target dose in water Table B 4 Oral Gavage: Female F344 Rat 1.7 mg/ kg target dose in water C. Terminal Tissue Weights.

Table C l. Oral Gavage: Female B6C3Fl Mouse 390 mg/ kg target dose in corn oil Table C 2. Oral Gavage: Female F344 rat 92 mg/ kg target dose in corn oil Table C 3. Oral Gavage: Female B6C3Fl Mouse 10 mg/ kg target dose in water Table C 4. Oral Gavage: Female F344 rat 1.7 mg/ kg target dose in water D. Off Gassing Study Table D l Pilot off gassing study: 5 mice were treated with 25 mg/ kg 1,1,2 TCE via gavage in corn oil.

Table D 2 Exposure and Animal information: 1000 ppm Table D 3 Exposure and Animal information: 500 ppm Table D 4 Exposure and Animal information: 250 ppm Table D 5 Off gassing of 1,1,2 TCE following exposure to 1000 ppm by inhalation Table D 6 Off gassing of 1,1,2 TCE following exposure to 500 ppm by inhalation Table D 7 Off gassing of 1,1,2 TCE following exposure to 250 ppm by inhalation E. Partition Coefficients Table E l Time and volume determination using rat blood Table E 2 Blood: Air Partition Coefficient: Female B6C3Fl Mouse Blood 1,1,2 trichlorethane: PK in rats and mice Page 35 of 69 Project No. 11GO8 Appendix A. Subchronic inhalation exposures to 100 ppm for 6 hr/ day conducted at VVIL Laboratories Table A l. Exposure and blood collection information in mice and rats Day 1   _~._ I_  Exposure Start Exposure End Time Animal Removed Blood Collection Time Mean Cont. Dody Weight .~__

Animal If Group # /HH: MM) __ fHH: MM) /HH: MM) JHH: MM) .. Study Davof BW Dateof EtW @pm) (g)

69365 5 O& 16 15: 16 l3: 16 13: lQ 99 156 OG125/ 01 25 _._..  . ~____ ______ __._ . l_ . 69372 5 0B: lG 15: lG 13: lG 13: 2G 99  159 0G/ 25101 25 _I_.  69374 5 OR: 16 15: 16 . __ I 13: 16 13: 21 99 166 06/ 25/ 01 25 _.. ____ . ____________._. 69367 5 00~ 16 15: lG 1i: lG 1520 99 `56 _____ ._ .I_ 25 OG/ 25/ 01 ____.. . ____  69397 5 0616 15: lG 15: 16 15: 20 99 IGD 06/ 25/ 01 25  _~  _I ~.. ...__ . G9400 5 0D: lG 1516 15: 16 15: 20 99 171 OG/ 25/ 01 25 ____ ... ~ ______ _.._.". 69407 5 O& 16 _____  _______ II_^ __ .. .__ 1516 15: 31 1535 99 155 OG/ 25/ 01 ._. ___ __ 25 . G9410 _..  ._..._ __..__ 5 O& 16 15: lG 1531 1536 99 156 OGl25lOl 25 _ ... .___ _."  ...____ 69420 5 08: 16 15: 16 15: 31 1535 99 I& OG125/ 01 25 ~___  __ 69429 5 O& 16 15: 16 1533 17: 16 99  K 06/ 25/ 01 25 _  ___ G9430 5 0616 15: 16 1533 163 OF/ 25/ 01 25 ___.___   ~ I~..___~_ __ .._ __ . . GE) 434 5 __ Of%: 16 15: lG 15: 33 17: 18 99 170 06/ 25/ 01 25 ~_. .._ I.__ ~. ____  .  . ._____.. ...   5207 G 07: 45 13: 45 II: 50 ll: 5G 100  2? 5    .._ __^  OGf25l01 25 __ __ .  .  5212 G 07: 45 13: 45 II: 50 1154 100 24.1 OF/ 25/ 01 25 ..  . __ . __ . __ 5214 G 07: 45 13: 45 Ii: 50 II: 53 `00 .__ 22.2 OG/ 25/ 01 25 _. . ___ 5221 G 07145 13: 45 13: 4G 13: 50 100 22.5 OF/ 25/ 01 25   _..._ 5224 ___~. ____._ __ ___....... . ___. ___ G 07: 45 13: 45 13: 46 13: 52 100 22.3 OF/ 25/ 01 25 .__ I_  ~. _ I __ __ _____ I_.  . . .._ . 5225 6 07: 45 13: 45 13: 46 13: 55 100 21.7 OGf25fOl 25 .  ... ______ ..___. ____ _.. __.. 5231 6 07: 45 13: 45 14: 03 14: 06 fQQ _____  .. . .._ __ 21.9 06f25lOl 25 _._ . I__.____ 5236 G 07: 45 13: 45 14: 03 14:& i 100 22.1 OG/ 25/ 01 25 _   __ 5238 6 07: 45 ._____ ..._ . .._ 13: 45 14: 03 14: 07 100 23.3 OGf2VOl 25 _ . 5239 6 07: 45 13: 45 14: 06 15: 45 100 23.3 06f25fOl 25  5245 F 07: 45 25 5249 G  . ... __ I_ .. 07: 45 13: 45 25 . __

* tt should bo noted that 2 minutes were subtracted from blood collection times as recorded on form T5 091 5 for this study !O nCCOUnlfO1 a discrepancy of 1 minute 40 seconds between the clock used for exposure time and that used in necropsy.

l It should also be noted that exposure was extended for 1 hour on Group 5 to account for problems with the generation system for that group that occurred near the beginning of exposure. Concentrations for this group are reported as a lime weighted average over the entire exposure. 1,1,2 trichlorethane: PK in rats and mice Project No. 11GOU Page 36 of 69 (Table A l Continued)

1 69425 1 5 ! Of351 12: 51   I 13: 06 I 13: 11 I 100 12: 51 13: 06 13: ll 100 _____

1320 13: 35 13: 39 `00 21.9  I ~___ II_~~~ 13: 20 13: 46 15: 21 100 23.8 ~ 13: 20 13: 46 15: 20  .. 100 23.6 _  __. 13: 20 1 X46 1520 100 ~ %?~_~__ I)~!~!~!

l It should be noted that 2 minutes were subtracted from blood collection times as recorded on form T5 091 5 for this study to account for a discrepancy of 1 minute 40 seconds between the clock used for exposure time and that used in necropsy. 1,1,2 trichlczthane: PK in rats and mice Project No. llCO8 (Table A l. Continued)

___

__ I

69414 ) 5 1 06: 54 __..  __

07: 21 __ 0721  07~ 21 5227 1 ."_ 6 ! 0721 "_ __ __

__ __

__

_.

.

_.

__ Page 37 of 69 ExposureEnd Time Animal Removed Blood Collection Time Mean Cont. Body Weight !B! M! a iHH: MM) JHt kJMM_ I f! lEEL. Is). ._%.* Study DayofBJ Date of BW 1254 IO: 54 10: 59 101 174 OtY25lOl 25 __ . ~ _______ I 12: 54 10: 54 IO: 59 101 178 06125101 25 . ___. 12: 54 1054 1059 101 164 06/ 25101 25 12: 54 12: 54 i2: 5a 101 158 06/ 25/ 01 25 ~.

 1254 I?: 54 12157 101 152 06/ 25/ 01 25  _______ . 12: 54 12; 54 12: 5a 101 164 OG125/ 01 25 . ___. 12: 54 13: 09 13: f2 101 137 06/ 25/ 01 25 . 12: 54 13: 09 13: 12 101 170 OG/ 25/ 01 25 __.. . __ ~ 12: 54 13: 09 13: 12 101  150 ___ OG125fOl 25 1254 13: ll 14157 101 161 OGl25fOl 25 . . ___ ...

14% ~ .

_ll 13: 21  13: 21 L 13: 22 13: 25  _ I I '00 ______ c 22.6 4 OBf25f01 25 _ .._ I 13: 21 13: 22 ____.., __ ... 13: 21 IX22 __. ____ I_ ___~ 13: 21 13: 36 ___._ II __.._ .______

13: 21 13: 3G ~~~  _I_.._  13: 21 13: 36 . 13: 21 13: 41 ____.. 13: 21 13: 41 13: 21 13: 41 1,1,2 trichiorethane: PK in rats and mice Project No. 41608 Page 38 of 69 Table A 2. Blood concentrations following inhalation exposures Samples from Wil Labs Limit of detection 0.013 pglg B6C3Fl Mouse Inhalation Exposures, Data collected June 2529,290l Collection _~ ~..~ . .____,___ ~. ._ . . ..... . Date Sample Duplicates 1 25Jun Time blood cone (ug/ g) Average for Timepoint An# hr a b avg AVG SD j 5207 5.00 : 0.639 0.57 0.6045 0.608 0.014 j 5212 0.572 0.621 0.5965 j 5214 0.623 0.623 / 5221 7.00 ! 1.121 0.97 1.0455 0.951 0.083 i 5224 0.852 0.979 0.9155 I / 5225 0.859 0.922 0.8905 5231 7.25 1.174 1.289 1.2315 0.960 0.243 5236 0.807 0.722 0.7645 ; 5238 0.783 0.984 0.8835 I 5239 9.00 0.047 0.015 0.031 0.022 0.009 / 5245 0.012 0.014 0.013 i 5249 0.024 0.022 0.023 ._._  ..__  _.... ..__ Collection  Date Sample Duplicates 27 Jun Time 1 blood cone &g/ g) verage for Timepoint An# hr ' a b avg 1 AVG SD 5209 4.0 : 2.08 2.02 2.05 j 1.838 0.277 5215 5216 5217 5218 5220 5222 5226 5229 5234 5247 5248 1.5 1.55 1.525 1.84 2.04 1.94 6.0 1.89 2.18 2.035 1.728 0.368 1.8 1.86 1.83 1.11 1.53 1.32 6.25 ; 0.53 0.58 0.555 0.433 0.107 I 0.39 0.39 0.39 0.41 0.3 0.355 8.0 ND #DIV/ O! #DIV/ O! #DIV/ O!

8.00 ND $DIV/ O!

8.00 0 0 _____  .  . . 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 39 of 69 (Table A 2 Continued)

Collection ____~_______ _ Date 29Jun Time! Sample Duplicates An# hr / blood cone (pg/ g) Average for Timepoint a b j avg AVG SD 5204 4.0 j 1.98 2.29 2.135 1.983 0.167 5205 I 1.78 1.83 1.805 1.77 2.25 2.01 2.33 2.74 j 2.535 ' 2.162 0.368 2.15 2.15 2.15 0.67 0.705 0.592 0.098 1 5232 ' 0.54 0.53 0.535 /

5235 a. 0 i 0.04 0.04 : 0.04 0.055 0.015 5240 8.00 ; 0.07 0.07 j 0.07 5242 a. 00 i 0.06 0.05 0.055 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 40 of 69 Table A 3. Blood concentrations following inhalation exposures in rats F344 RAT inhalation Exposures, Data collected June 25 29, 2001 Collection r . . . ... .._ .._. ___. . . . . . Date Sample Duplicates 25Jun Time, blood cone (pglg) Average for Timepoint An# hr : a b avg AVG SD 69365 5.00' 1.87 2.29 2.08 1.997 0.101 69372 2.01 1.76 i 1.885 j 69374 1 2.03 2.02 ! 2.025 1 69387 2.6 2.63 2.615 2.337 0.345 j 69397 7.00;

! 2.33 2.56 2.445 i 69400 : 2 1.9 1.95 1 7.25 / j 69407 1.016 0.964 0.936 0.047 69410 I 0.89 0.923 0.9065 0.99 1 69420 $ 0.927 0.893 0.91 1 69429 9.00; 0.122 / 69430 j 0.168 i 69434 I 0.105 Collection Date /

27 Jun Time/ Sample Duplicates Anf: hrj blood cone @g/ g) duplicate Average for Timepoint a b : avg AVG SD j 69357 4.0 j 1.84 I. 8 1.82 1.777 0.051 j 69358 i 1.74 1.7 ; 1.72 j 69360 : 1.9 1.68 1.79 i 69399 6.0 j 1.79 2.38 2.085 1.738 0.355 / 69403 I 1.77 1.74 1.755 i 69411 1.41 1.34 1.375 ! 69418 j 69421 6.25; 0.64 0.55 ! 0.33 0.42 0.595 0.375 0.533 0.138 I 69422 0.53 0.73 0.63 j 69423 8.0 j 0.13 E5 L 0.108 0.058 I 69424 b425 1 0.05 i 0.12 ._. ____ _.. ___ ... 0.;. 1 1 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 41 of 69 (Table A 3 Continued)

Collection 1,1,2 trichL, ethane: PK in rats and mice Project No. 41608 Page 42 of 69 Appendix B. Individual Animal Data from Demonstration of Periodicity Following Repeated Gavage Administrations.

B l. Mouse Corn Oil Gavage Day 1 1 .I ,2TCE cont.

Sample Duplicates 1 ,I ,2 TCE AVG AVG BNW MO01 19.2 15.350 19.5 0.57 354.3 12.48 BNW MO02 20.2 341.4 31 BNW MO03 19.2 366.3 33 .._. ___.. BNW MO04 19.3 343.1 60 BNW MO05 19.7 359.7 58 BNW MOO6 20.5 353.9 58 12.430 _ ..__. BNW MO07 19.5 BNW MO08 19.7 2.820 BNW MOO9 20.7 BNW MO10 19.5 BNW MO11 20.6 BNW MO12 20.5 ______.____

lay 3 `&& V M013 19.1 364.9 30 BNW MO14 20.2 343.2 32 BNW MO15 20.4 354.4 35 __~ BNW MO1 G 18.9 428.6 Ei8 BNW MO17 18.2 399.8 58 BNW MO18 20.2 344.8 61 BNW MO19 20.0 327.1 120 BNW MO20 19.1 391 .o 120 BNW MO21 20.3 362.5 123 __~~ BNW MO22 18.4 375.8 478 BNW MO23 18.5 377.5 477 BNW MO24 19.2 361.7 475 Table B l Continued 0.50 17.005 17.077

0.53 21.599 20.153 0 58 14.168  A  13.032 0.97 11.560 14.450 0.97 26.040 26.020 1.02 22.110 21.660 2.00 18.300 16.440 2.00 20.990 19.120 2.05 18.450 21.330 7.97 7.210 8.120 7.95 10.990 7.92 7.010 6.680 C _~ AVG BW (9) SD  .~ 17.041 13.9 0.70 20.876 13.600 13.005 19.1 1.02 26.030 21.885 17.370 19.8 0.63 20.055 19.890  7.665 18.7 0.44 10.990 6.845 AVG AVG `0~ Q%$ kgl_ S_ D E!! z.( hi   . 354.2 10.85 0.54 .___ 391.1 42.58 0.98 __ 3G0.2 32.01 2.02  371.7 8.67 7.94 AVG AVG AVG timepoint AVG Time (hr) AVG (pg/ g) SD 0.52 11.132 4.577 . 0.98 7.837 3.991 8.00 0.154 I 1 .I ,2TCE cont.

imepoint AVG `VG (Kl! cL2L  17.172 3.640 20.307 6.654 ____ 19.105 1.505 8.500 2.195 1 ,I .2TCE cont.

AVG timepoint AVG 1,1,2 trichlorcthane: PK in rats and mice Project No. 11608 Page 13 of 69 Day 5 _. . BEls). sD~~~[ n_ g& Q)> P~ Tim_ e_ LUAVG( Clg~~ BNW MO25 17.7 372.9 30 19.2 1.45 365.3 16.16 0.52 25.013 10.805 BNW M02F 19.3 376.2 30 23.430 24.090 23.760 .__. _ 19.0 0.57 399.2 31.30 0.98 18.020 4.876 BNW MO29 19.5 363.2 59 16.500 BNW M03u 19.2 BNW MO31 18.2 19.0 0.71 378.3 48.19 2.02 23.462 2.136 BNW MO32 19.1 BNW MO33 19.6 . __ _I____ BNW MO34 18.1 17.8 0.64 358.1 18.13 8.03 12.022 2.577 BNW MO35 17.1 BNW MO36 18.3 NJ 19.3 365.5 SD 0.91 25.8 ] 93.72% 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 44 of 69 B 2. Rat Corn Oil Gavage Day 1 An ft __ BW &L . BNW ROOI 148.2 BNW R002 140.9 BNW R003 146 6 .._~_ BNW R004 146.8 BNW R005 141 .O BNW ROO6 145.5 _I_  BNW R007 147.6 BNW ROCEI 139.1 Dose Time iE! J! kL~~ 97.6 34 98.3 33 96.6 33 94.3 50 _

97.4 60 95.4 61 96.0 122 98.8 122 BNW R009 148.4 93.6 120 ..__ BNW ROIO 152.0 93.5 479 BNW ROI 1 146.5 99.6 482 BNW R012 149.8 98.0 482

klv 3 BNW R013 145.5 91.3 29 BNW R014 153.1 101.3 28 BNW ROf 5 144.3 96 2   2 34 BNW ROI G 146.6 94.6 59 BNW ROI 7 154.5 88.1 61 BNW R018 142.9 95.7 62   ._____ BNW RO19 145.2 94.5 120 BNW R020 150.2 90.9 121 BNW R02 1 144.0 94.8 123 . .__" _.._ ~__.._. BNW R022 147.2 91.1 479 BNW R023 146.0 92.9 482 BNW R024 148.6 101.3 482  ___ Table B 2 Continued ^.^... Tirnc Sample Duplicate.

(hrJ A B  I I_____~ 0.567 0.550 0 550 . L 0.833 1 .ooo 1.017 2.033 2.033 2.000 7.983 8.033 a 033  L_"__

0.483 0.467 0.567  0.983 1.017 1.033 __ I. 2.000 2.017 2.050  7.983 8.033 8.033

 15.73 18.09 16.33 16.51 J 6.52 16.19 9.06 9.00 11.52 12.72 9.97 9.70 5.20 5.44 5.56 5.10 5.98 6.73 0.23 0.20 0.15 0.15 0.11 0.12 6.42 5.92 9.74 10.79 12.82 12.36 5.62 5.30 6.92 2.56 8.56 9 10 .

2.53 2.58 1.77 1.87 2.11 2.32 0.05 0.05 0.04 0.04 0.04 0.08

l

_

 1 ,I ,2TCE cont.

,I ,2 TCE AVG AVG AVG timepoint AVG BW (9) SD Dose (mglkg) SD Time (hr) AVG &g/ g) Avg SD 16.910 145.2 3.84 97.5 0.85 0.56 16.562 0.303 16.420 106.0%

%&/% i?(,, 0.95 10.328 1.603 9.835 1 5.320 1 145.0 5.35 1~ 1?%?/ 5.668 0.595 5.330 104.5%

6.355 0.211 149.2~ 2.77 97.0 3.16 8.02 0.158 0.050 0.150 105.5%

0.113  ___

AVG AVG AVG 6.170 BW (91.. 14% SD DoseJmg/ kg) SD Time (hr 4.77 96.3 5.00 0.51 10.265 104.6%

12.590  __  . . 5.460 14a. o 5.93 92.8 4.11 1 .Ol 4.740 100.9% 8.830 ___ 2.555 146.5 3.29 93.4 2.17 2.02 1.820 101 .5% 2.215 6.050 __. 147.3 1.30 95.1 5.44 8.02 0.040 103.4%

0.063 1 2;

1 ,I ,2TCE cont. `mepoint AVG \LG (i& d  ._ SD 8.478 3.250 8.122 2.183 2.197 0.368 0.051 0.012 ,I ,2TCE cont. 1,1,2 trichlorethane: PK in rats and mice Project No. 11608 !z!! 5 .. BNW R025 150.9 91.1 29 BNW R02G 144.8 94.6 31 BNW R027 151 0 93.4 32 __ . L  BNW R028 155.7 88.4 63 BNW R029 142.5 93.9 62 BNW R030 142.9 96.8 65 BNW R031 155.0 88.6 118 BNW R032 143.6 93.9 120 BNW R033 150.6 91.3 122 BNW R034 143.9 92.3 482 BNW R035 149.1 93.3 479 BNW R036 156.7 84.4 482 Av9 147.422 94.244 I 0.483 0.517 0.533  1.050 1.033 1.083 1.967 2.000 2.033 8.033 7.983 8.033 ~ 12.89 13.97 10.54 10.53 6.28 6.66 7.56 7.94 8.84 9.48 7.96 10.25 4.17 4.17 3.16 3.01 4.46 6.47 0.17 0.15 0.05 0.05 0.68 0.60 SD 4.342 3.719 /102.44% 1 I 13.430 10.535 6.470 7.750 9.160 9.105  4.170 3.085 5.465 0.160 0.048 0.640 Page 45 of 69 AVG AVG BW (4 SD Dose mglkg) SD ._  148.9  l  3.55 93.0 1.78 101. l%

.. 147.0 7.51 93.0 4.27 101.1%

149.7 5.75 91.3 2.65 99.2%

 149.9 6.44 89.7 4.56 97.5% 1 _

_

 1.192 8.02  I 0.283 0.315 I 1,1,2 trichlorethane: PK in rats and mice Page 46 of 69 Project No. 11608 B 3. Mouse Water Gavage Day 1 r

f Dose Time \n # fE!!~ Um_ sLks~~~ E~ BNW Ml01 19.4 9.0 6.0 BNW Ml02 17.9 10.1 6.0 BNW Ml03 18.1 10.3 6.3 BNW Ml04 18.2 10.3 14.5 BNW MI05 18.3 10.7 14.0 BNW Ml06 20.3 8.9 14.5 . BNW Ml07 20.1 8.8 30.5 BNW Ml08 20.0 9.6 29.8 BNW Ml09 18.8 102 30 3 *.^ A BNW Ml10 20.4 9.4 59.3 BNW Ml11 19.8 9.4 60.3 BNW Ml12 18.1 9.9 59.5

33 BNW MI 13 18.8 9.9 6.0 BNW Ml14 19.4 9.4 6.8 BNW Ml15 18.8 9.6 8.2 BNW Ml16 18.1 11.5 14.5 BNW MI 17 18.5 8.1 14.3 BNW Ml18 19.2 12.1 15.3 ~.. __ BNW Ml19 18.4 13.0 31.8 BNW Ml20 18.9 10.2 30.3 BNW Ml21 19.1 9.1 30.8 %W Ml22 __ 19.2 8.7 59.5 BNW Ml;; 19.0 8.6 59.8 BNW Ml24 18.9 11.2 60.0 l%& e B 3 Continued _.__ Time Sample Duplicates 1 ,I ,2 TCE AVG BW (9) SD 18.5 0.81 0.104 0.306 0.296 0.301 0.242 b. 270 0.270 18.9 1.18 0.233 0.201 0.198 0.200 0.242 0.182 0.182 0.508 0.130 0.090 0.110 19.6 0.72 0.496 0.168 Oll68 0.504 0.182 0.182  A_ ._ 0.988 0.064 0.064 19.4 1.19 1.004 0.034 0.026 0.030 0.992 0.030 0.027 0.029 AVG BW @> SD 0.310 0.290 0.300 19.0 0.35 0.086 0.103 0.095 0.110 0.090 0.100 0.033 0.037 18.6 0.56 0.030 0.031 0.062 0.047   0.016 0.016 18.8 0.36 0.054 0.063 0.020 0.018 0.017 0.016 19.0 0.15 0.026 nd C c _ AVG lose (mglkg) SD 9.8 0.70 10.0 0.92 9.5 0.73 9.6 0.29 AVG lose (mglkg) SD 9.6 0.26 10.6 2.18 10.7 2.03 9.5 1.45 0.99 0.041 0.020  1 ,I .2TCE cont. AVG timepoint AVG E~~.~! O AVGP~~ SD 0.12 0.165 0.117  0.24 0.038 0.008 0.52 0.032 0.026 ___. 1 .oo 0.02 1 0.007 1 .I .2TCE cont. 1,1,2 trichlnwthane: PK in rats and mice Project No. 11608 Page 47 of 69 `35  BNW Ml25 20.8 9.6 6.5 BNW Ml26 20.2 9.4 7.0 BNW Ml27 18.8 9.8 6.0 BNW Ml28 20.4 9.4 16.0 BNW Ml29 20.1 9.6 15.5 BNW Ml30 20.3 6.5 158 . L BNW Ml31 21.5 8.7 30.3 BNW Ml32 19.7 10.1 31.3 BNW M 133 20.4 9.1 30.3 BNW Ml34 20.9 8.7 60.3 BNW M135, 20.1 9.7 60.3 BNW Ml36 19.2 9.6 61.0 Avg 19.4 9.7 SD 0.9 1.1  0.108 0.117 0.100 0.267 0.258 0.263 ... 0.504 0.521 0.504 1.004 1.004 1.017 0.290 0.210 0.130 0.110 0 270 L. 0.280 0.049 0.044 0.039 0.032 0.040 0.100  0.089 0.093 0.065 0.034 0.030 0.025 0.024 0.040 0 027 2 0.026 0.250 0.120 0 275 . L 0.047 0.036 0.070 0.089 0.079 0.032 0.025 0.040 2.027 AVG AVG BW_! g) SD Dose (mg/ kq) SD . a 5. 19.9 1.03 9.6 0.20 20.3 0.15 8.5 1.74 2o. F 0.91 9.3 0.75 20.1 0.85 9.3 0.55 0.26 0.051 0.018 0.51 0.067 0.030 1.01 0.030 0.008 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 B 4. Rat Water Gavage Day 1 Dose Time A!! ff BW ~~@~~~~~~ BNW RI01 147.8 1.69 6.3 BNW RI02 146.9 1.70 6.0 BNW RI03 148.4 1.70 6.3 . BNW RI 04 144.6 1.73 ~ 15.3 BNW RI05 146.3 1.84 14.3 BNW RIO6 148 8 1 67  A 15.0 .BNW RI 07 150.2 1.70 30.3 BNW RI 08 146.9 1.71 31.0 BNW RI 09 150.3 1.65 31.5 ___ BNW RI10 151.6 1.60 60.3 BNW RI 11 148.3 1.72 59.3 BNW RI12 151.4 1.68 GO. 0 ~~._. .~ ____

33 BNW RI 13 150.7 1.69 7.5 BNW RI 14 158.4 1.54 6.5 BNW RI 15 151.8 1.68 6.5  BNW RI 16 146.6 1.75 14.8 BNW RI 17 153.4 1 55 14.8 BNW RI 18 152.6 1: 59 14.8 BNW RI 19 150.1 1.61 28.3 BNW RI20 154.2 1.66 31 .o BNW RI21 151.6 1.64 30.8 BNW RI22 151.5 1.80 59.8 BNW R123 146.3 1.68 60.3 BNW RI24 151.2 2.22 , 60.0 Table B 4 Continued Time @! L 0.104 0.100 0 104 L 0.254 0.238 0.250 ___ 0.504 0.517 0 525 . L_ 1.004 0.988 1 000 L.. 2amplc Duplicates 1 ,I ,2 TCE A B Avg _ 0.047 0.030 0.039 0.038 0.037 0.038 JO32 0.039 0.036 _ l_ 0.020 0.020 0.020 0.015 0.014 0.015 0.030 0.060 0.045  . 0.020 0.020 0.020 0.041 0.021 0.031 0.022 0.017 0.020 ~_. ~  0.014 0.014 0.014 0.020 0.010 0.015 0.029 0.020 0 025 L

0.125 0.043 0.047 0.045 0.108 0.028 0.031 0.030 0.108 0.037 0.040 0.039 0.246 0.014 0.014 0.246 0.018 0.018 0.246 0.050 0.030 0.040 0.471 0.020 0.010 0.015 0.517 0.015 0.015 0.513 0.041 0.053 0.047 0.996 0.052 0.037 0.045 1.004 0.027 0.027 0.027 1 .ooo 0.014 0.013 0.014 PXJC 48 of 69 AVG AVG SD BW (g) lose (mglkg) SD 147.7 0.75 1.7 0.01 146.6 2.11 149.1 1.93 150.4 1.85 1.7 0.06 AVG AVG sw((?) so~ lose (mg/ kg) SD 153.6 4.16 1.6 0.08 150.9 3.72 1 .G 0.11 152.0 2.07 l. G 0.03 149.7 2.92 1.9 0.28  1.7 0.09 1.7 0.03 I

.

_

" I  1 ,I ,2TCE cont.

AVG timepoint AVG Time (hr) AVG (pglg) SD 0.10 0.037 0.00;

0.25 0.027 0.01 E 0.52 0.024 0.006 ~ 1 .oo 0.018 0.006 1 ,I ,2TCE cont.

AVG timepoint AVG Time (hr) AVG &g/ g) SD 0.11 0.038 0.008 .__. __ 0.25 0.024 0.014 0.50 0.026 0.018 1 .oo 0.028 0.01 G 1 ,I ,2TCE cont. 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 3ay 5 ._ ___ .._ BNW RI25 153.7 BNW RI26 154.0 1.76 6.3 1.71 5.8 BNW R127 157.6 1.73 G. 5  BNW RI 28 150.3 1.49 15.5 BNW RI29 159.1 1.34 15.8 BNW RI30 151 6 1 45 14.8 __^___  .____ _........ A :. .. BNW RI 31 156.3 1.63 29.5 BNW R132 156.7 1.65 31.5 BNW RI33 147 1 _ L 1.67 30.0 BNW RI 34 163.9 1.54 59.8 BNW RI 35 152.0 1.33 60.5 BNW RI36 154 2 __ p... 2 1.68 59.8 AxI 151.6 1.66 SD 4.2 0.15 0.104 0.068 0.079 0.096 0.074 0.079 0.108 0.047 0.041 0.258 0.028 0,024 0.263 0.027 0.038 OmL 3027 __ 0.492 0.013 0.013 0.525 0.038 0.016 0.500 0.014 0.046  0.996 0.016 0.046 1.008 0.014 2. 0 996 . I 0 031 0.074 0.077 0.044 0.026 0.033 0.027 ._____ 0.013 0.027 0.030 0.031 0.014 0.031 __ Page 49 of 69 AVG AVG BW (n) _. .._ SD Dose (mglkq) SD . 5 . 155.1 2.17 1.7 0.03 153.7 4.75 1.4 0.08 153.4 5.43 1.7 0.02 156.7 6.33 1.5 0.18 AVG timepoint AVG Time (hr) AVG @g/ g) .. SD 0.10 0.065 0.018 0.26 0.029 0.004 0.51 0.023 0.009 7.00 0.025 0.010 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 50 of 69 Appendix C. Terminal Tissue Weights.

Table C l. Oral Gavage: Female B6C3Fl Mouse 390 mg/ kg target dose in corn oil Scheduled Sacrifice( hr) Lung W( g) Liver wt. (q) Kidney wt. (q) Spleen wt. (g) Brain wt. (q)

Day1 0.5 0.177 I 0.008 1.05 ~fr 0.061 0.282 10.005 0.079 5 0.003 0.464 i 0.014 1 0.180 2 0.021 1.03 ?I 0.089 ,0.290 e 0.031 0.076 f 0.005 0.468 zk 0.011 2 0.178 + 0.001 0.99 + 0.065 0.300+ 0.013 0.070 i 0.002 0.475 5 0.002 8 0.163 i 0.013 0.94 i 0.082 0.270 i 0.003 0.068 I 0.001 0.466 i 0.014 Day 3 0.5 0.170 5 0.031 1.17 i 0.115 0.276 k 0.005 0.083 t 0.003 0.474 + 0.013 1 0.165 f 0.014 1.00 f 0.111 0.275 f 0.009 0.069 k 0.002 0.471 f 0.005 2 0.167 i 0.002 1.09 i 0.061 0.284 Z! I 0.019 0.064 it 0.004 0.469 I! Z 0.014 8 0.163 + 0.013 0.94 f 0.082 0.270 i 0.003 0.068 i: 0.001 0.466 + 0.014 Day 5 0.5 0.184 i 0.046 1.34 i 0.155 0.283 i 0.015 0.066 k 0.015 0.467 2 0.004 1 0.154 f 0.017 1.38 + 0.015 0.273 i 0.002 0.068 2 0.003 0.455 i 0.006 2 0.154 f 0.012 1.26 i 0.081 0.284 i 0.004 0.071& 0.013 0.460 f 0.001 8 0.151+ 0.008 1.22 i: 0.078 0.255 i 0.056 0.073 c 0.01 0.449 f 0.010 1,1,2 trichlorethane: PKin rats and mice Page 51of69 Project No. 41608 Table C 2. Oral Gavage: Female F344 Rat 92 mg/ kg target dose in corn oil Scheduled Sacrifice (hr) Lunq wt( g) Liverwt. (q) Kidney wt.( q) Spleen wt. (q) Brain wt.( q) Day1 0.5 0.731 5 0.047 4.89 i 0.385 1.11 f 0.034 0.3912 0.017 1.67 4 0.047 1 0.678 2 0.019 5.04 i 0.155 1.12 I 0.068 0.370 5 0.030 1.66 I 0.037 2 0.715 10.035 4.92 ?I 0.307 1.09 10.078 0,367 2 0.014 1.65 t 0.042 8 0.737 I 0.032 4.71 iz 0.317 1.10 F 0.054 0,352 i 0.018 1.62 k 0.033 Day3 0.5 0.698 t 0.023 5.21 f 0.131 1.11 t 0,054 0,377 + 0.015 lo62 k 0.050 1 0.7312 0.070 5.16 zk 0.293 1.18 I 0.016 0.365 + 0.038 1.67 k 0.046 '2 0.721 f 0.018 5.04 f 0.081 1.18 rt 0.038 0.355 ?c 0.012 1.67 f 0.047 8 0.739 + 0.052 4.70 k 0.211 1.15 + 0.059 0.340 f 0.008 1.63 I 0.051 Day 5 0.5 0.723 i 0.010 5.19 + 0.217 1.17 i 0.059 0.345 k 0.009 1.63 1. 0.011 1 0.726 i 0.031 5.16 1. 0.345 1.19 k 0.029 0.360 i 0.016 1.62 f 0.041 2 0.715 f 0.009 5.13 + 0.218 1.15 i 0,014 0.349 k 0.008 1.68 + 0.032 8 O 741? 0.037 5.00 10.113 1.19 IO. 075 0.348 I 0.027 1.62 f 0.019 1,1,2+ richlorethane: PK in rats and mice Page 52 of 69 Project No. 41608 Table C 3. Oral Gavage: Female 66C3Fl Mouse 10 mg/ kg target dose in water Scheduled Sacrifice (hr) Lunq wt @) Liver wt. (q) Kidneywt, (g) Spleen wt. (g) Brain wt. (g) Day 1 0.1 0.137 rt 0.028 0.929 It 0.049 0.249 rt 0,002 0.059 IO. 006 0.437 i 0.034 0.25 0.138 i 0.010 0.909 i 0.097 0.243 I 0.007 0.063 I 0.006 0.440 rt 0.011 0.5 0.134 k 0.010 1.008 i 0.040 0,251~ 0.015 0.062 i 0.002 0.436 + 0.005 1 O. l31_ t 0.012 0.940 5 0.054 0.239 F 0.015 0.058 + 0.009 0.429 + 0.017 Day3 0.1 0.149 k 0.023 0.976 5 0.075 0.266 rt 0.016 0.059 2 0.003 0.457 F 0.006 0.25 0.165 k 0.041 1.098 2 0.359 0.244 k 0.014 0.057 i 0.003 0.433 f 0.005 0.5 0.137 ?r: 0.014 0.946 i 0.076 0.245 i: 0.006 0.063 + 0.009 0.437 + 0.008 1 0,157 k 0.027 0.888 rt 0.093 0.244i 0.012 0.059 i. 0.000 0.431_+ 0.031 Day5 0.1 0.141 f 0.017 1.024 I 00088 0.250 k 0.009 0.057 + 0.009 0.451 + 0.018 0.25 0.134 t 0.016 0.931 ri: 0.051 0.264 i 0.006 0.057 i: 0.005 0.440 5 0.004 0.5 0.134 f 0.018 0.9911 0.060 0.277 2 0.005 0.063 F 0.009 0.447 I 0.012 1 0.181 i 0.049 0.940 i 0.029 0.255 + 0.009 0.062 I 0.010 0.444 f 0.012 1,1,2 trichlorethane: PKin rats and mice Page 53 of69 Project No. 41608 Table C 4. Oral Gavage: Female F344 Rat 1.7 mg/ kg target dose in water Scheduled Sacrifice (hr) Lung wt( q) Liverwt. (g) Kidneywt. (q) Spleen wt.( g) Brain wt.( q) Day 1 0.1 0.685 5 0.024 5.29 k 0.046 1.23 f 0.19 0.362 t 0.008 1.63 2 0.031 0.25 0.744 4 0.044 5.27 i 0.041 1.14 i 0.037 0.376 I 0.006 1.61 I 0.019 0.5 0.793 k 0.060 5.59 i 0.267 1.17 t 0.11 0.365 2 0.026 1.59 + 0.071 1 0.741 + 0.019 5.23 i 0.052 1.17 + 0.044 0.364 rt 0.009 1.61 f: 0.023 Day3 0.1 0.811 k 0.065 5.64 i. 0.318 1.23 t 0.070 0.373 z! z 0.021 1.67 % 0.022 0.25 0.879 zk 0.080 5.31 i 0.296 1.26 t 0.035 0.380 i 0.016 1.69 5 0.024 0.5 0.804 zk 0.119 5.33 + 0.061 1.20 k 0.063 0,357 5 0,030 1.66 f 0.007 1 0.825 + 0.001 5.43 f 0.423 1.16 k 0.07 0.363 i 0.013 1.69 2 0.014 Day 5 0.1 0.817 zk 0.056 5.60 + 0.375 1.22 + 0.021 0.374 IO. 011 1.71 * 0.010 0.25 0.860 5 0.072 5.75 k 0.159 1.25 i 0.046 0.365 2 0.012 1.66 I 0.058 0.5 0.790 2 0.019 5.45 10.056 1.23 2 0.030 0.379 5 0.013 1.70 i: 0.009 1 0.810 f 0.055 5.75 i 0.454 1.25 i 0.045 0.380 z 0.011 1.68 = 0.005 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Appendix D. Off Gassing Data Table p 1. Pilot study for off gassing of 1,1,2 TCE Time Post Exposure (hr) 0.19 0.20 0.22 0.24 0.25 0.27 0.29 0.30 0.32 0.34 0.35 0.37 0.39 0.40 0.42 0.44 0.45 0.47 0.49 0.50 0.52 0.54 0.55 0.57 0.59 0.60 0.62 0.64 0.65 0.67 0.69 0.70 0.72 0.74 0.76 Chamber Cone, (wb) 315.6 473.9 524.3 563.0 497.1 522.3 548.8 679.0 661.4 687.5 630.7 646.3 622.3 614.1 604.1 595.5 658.5 600.2 567.1 567.1 526.9 582.6 602.9 536.6 528.1 549.0 490.9 374.2 328.3 362.7 325.2 262.8 243.0 228.9 253.5 Time Post Exposure (hr) 0.77 0.79 0.81 0.82 0.84 0.86 0.87 0.89 0.91 0.92 0.94 0.96 0.97 0.99 1.01 1.02 1.04 1.06 1.07 1.09 I, 11 1.12 1.14 1.16 1.17 1.19 1.21 1.22 1.24 1.26 1.27 1,29 1.31 1.32 1.34 Chamber Cont. (wb) 255.1 271.6 253.6 186.4 188.7 243.3 227.3 258.3 212.5 192.1 170.6 176.4 225.9 204.6 73.5 43.9 153.3 126.8 93.7 80.5 44.8 97.3 90.9 57.8 87.1 40.6 1.8 47.4 48.3 72,4 28.1 30.1 12.8 45.0 91.9 Page 54 of 69 Time Post Exposure (hr) 1.36 1.37 1.39 1.41 1.43 1.44 1.46 1.48 1.49 1.51 . 1.53 1.54 1.56 1.58 1.59 1.61 1.63 1.64 1.66 1.68 1.69 1.71 1.73 1.74 1.76 1.78 1.79 1.81 1.83 1.84 1.86 1.88 1.89 1.91 1.93 Chamber Cont. cm&

8.; 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 . 0.0 0.0 0.0 0.0 0.0 Page 55 of 69 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Time Post Exposure (hr) 1.94 1.96 1.98 1.99 2.01 2.03 2.04 2.06 2.08 2.10 2.11 2.13 2.15 2.16 2.18 2.20 2.21 2.23 2.25 2.26 2.28 2.30 2.31 2.33 2.35 2.36 2.38 2.40 2.41 2.43 2.45 2.46 Chamber COIX. (ppb) 0l0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Chamber Time Post Cont. Exposure (hr) (ppb) 2.48 2.50 2.51 2.53 2.55 2.56 2.58 2.60 2.61 2.63 2.65 2.66 2.68 2.70 2.71 2.73 2.75 2.77 2.78 2.80 2.82 2.83 2.85 2.87 2.88 2.90 2.92 2.93 2,95 2.97 2.98 3.00 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Time Post Exposure (hr) 3.02 3.03 3.05 3.07 3.08 3.10 3.12 3.13 3.15 3.17 3.18 3.20 3.22 3.23 3.25 3.27 3.28 3.30 3.32 3.33 3.35 3.37 3.38 3.40 3.42 3.44 3.45 3.47 3.49 3.50 Chamber Cont.

(; P;)

0: o 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 56 of 69 Table D 2. Exposure and Animal information: 1000 ppm A% SD Mouse 8 $ 17.8 1 19.36 2.02 Start Time r 4/ 12/ 01 IO: 04 AM End exposure 4/ 12101 4104 PM MS Start Time MS End Time Total 9.02 hr GC Conditions/ Comments Flow  2.5 Llmin Generator Temperature 69 C 2 hr into exposure animals let

3 hr extremely lethargic, no coordination.

4 hr  2 laying on side, shallow, labored breathing 6 hr  all animals slow, shallow, labored breathing, completely unconscious MS/ MS Conditions/ Comments Flow 183mVmin 1 hr post exposure  animals still unconscious 2 3 hr post exposure  animals beginning to become active, still lethargic and uncoordinated 4.5 hr post eposure  1 animal dead, 1 still unconscious 6 hr post exposure  all living animals lethargic and uncoordinated 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Table D 3. Exposure and Animaf information: 500 ppm +$$/ I s,, r&/

AQ 20.48 SD I .44 Page 57 of 69 Start Time 4116/ 01 9: 20 AM End exposure 4116101 I: 20 PM Time between Exposureend and MS Start MS Start Time 0: 03: 45 min MS End Time MS run hr GC Conditions/ Comments Flow  2.5 Llmin IO: 40 am animals OK 1120 am  animals lethargic I: 00 pm  3 lethargic, 2 anesthetized MS/ MS Conditions/ Comments Flow 181 mHmin All animals awake, 2 very slightly uncoordinated 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Table D 4. Exposure and Animal information: Page 58 of 69 250 ppm Avg 19.62 SD 1.09 Start Time 1 4/ 18/ 01 9: 07 AM 1 End exposure 3: 07 PM MS Start Time MS End Time MS run Time between Exposure end and MS Start 02: 30 min hr GC Conditions/ Comments Flow  2.5 L/ min MS/ MS Conditions/ Comments Flow 179 mllmin 1,1,23richlorethane: PK in rats and mice Page 59 of 69 Project No. 41608 Table D 5. Off Gassing: 6 hr inhalation to 1000 ppm 1,1,2 TCE Time Post Exposure (hr) 0.05 0.07 0.08 0.09 0.11 0.12 0.13 0.15 0.16 0.17 0.18 0.20 0.21 0.22 0.24 0.25 0.25 0.26 0.27 0.27 0.28 0.28 0.29 0.31 0.33 0.36 0.38 0.41 0.43 0.46 0.48 0.51 0.54 0.56 0.59 0.61 0.64 0.66 0.69 Chamber Cont. `P$ yl 40: 1 30.3 31.6 34.7 34.9 33.3 32.2 32.1 31.6 32.0 31.5 32.9 32.9 31.9 30.3 31.1 30.0 32.5 33.4 33.7 33.5 34.2 32.3 30.9 31.5 34,4 37.1 38.1 37.9 38.7 37.1 41.1 45.5 43.4 41.5 40.4 37.8 38.8 Time Post Exposure (hr) 0.71 0.74 0.75 0.77 0.78 0.80 0.82 0.84 0.85 0.87 0.88 0.90 0.92 0.93 0.94 0.95 0.97 0.99 1.02 1.05 1.08 1.12 1.15 1.18 1.22 1.25 1.28 1.31 1.35 1.38 1.41 1.44 1.48 1.51 1.54 1.58 1.61 1.64 1.67 Chamber Cont.

`E 42: 7 40.9 43.2 45.0 48.4 49.4 49.6 45.4 47.6 43.4 41.5 41.4 43.1 43.1 42.9 42.0 39.6 37.8 37.5 39.3 40.8 40.5 42.6 43.9 39.1 39.3 37.5 38.5 39.7 37.2 35.5 37.4 36.7 36.1 38.9 42.3 41.7 42.5 Time Post Exposure (hr) 1.71 1.74 1.77 1.80 1.84 1.87 1.90 1.93 1.97 2.01 2.05 2.10 2.15 2.20 2.24 2.29 2.34 2.39 2.43 2.48 2.53 2.58 2.62 2.67 2.72 2.76 2.81 2.86 2.91 2.95 3.00 3.05 3.10 3.14 3.19 3.24 3.29 3.33 3.38 Chamber Cont. `~ W?

47.3 45.5 43.8 45.1 45.6 43.2 42.8 43.0 43.8 47.4 44.8 40.3 41.9 45.4 39.2 40.6 42.1 44.0 51.5 54.7 53.6 57.0 56.4 58.2 60.9 65.9 73.9 63.3 59.1 61.7 60.4 59.4 58,3 : 57.8 58.6 60.7 70.3 72.5 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Time Post Exposure (hr) 3.43 3.47 3.52 3.56 3.60 3.64 3.69 3.73 3.77 3.81 3.85 3.90 3.94 3.98 4.02 4.06 4.11 4.15 4.19 4.23 4.27 4.32 4.36 4.40 4.44 4.48 4.53 4.57 4.61 4.65 4.69 4.74 4.78 4.82 4.86 4.90 4.95 4.99 5.03 5.07 Chamber Cont. '; gy '

68: 4 70.5 75.6 73.4 72.9 75.1 69.9 70.2 63.8 65.3 68.6 71.0 71.4 69.5 67.9 66.0 60.5 59.6 64.1 60.2 59.4 63.0 66.1 63.1 66.5 65,9 57.5 60.4 64.3 59.9 60.9 59.8. 56.1 53.9 49.7 49.2 49.4 47.6 46.8 Time Post Exposure( hr) 5.11 5.16 5.20 5.24 5.28 5.32 5.37 5.41 5.45 5.49 5.53 5.58 5.62 5.66 5.70 5.74 5.79 5.83 5.87 5.91 5.95 6.00 6.04 6.08 6.12 6.16 6.21 6.25 6.29 6.33 6.37 6.42 6.46 6.50 6.54 6.58 6.63 6.67 6.71 6.75 Chamber Cont.

'4psp" 7'

51: o 49.9 50.4 45.2 48.3 47.2 44,3 43.5 41.2 38.3 42.9 43.3 43.2 41.0 39.6 39.9 39.1 38.1 40.0 39.4 38.5 38.0 36.0 35.3 35.3 34.4 33.6 32,4 32.2 33.8 33.5 30.1 32.6 29.9 30.2 31.2 32,2 29.1 28.0 Page 60 of 69 Chamber Time Post Cont. Exposure( hr) @pm> 6.79 ~26.6 6.84 25.4 6.88 25.6 6.92 26.3 6.96 24.9 7.00 26.2 7.05 26.4 7.09 24.6 7.13 25.2 7.17 25.1 7.21 23.6 7.26 23.4 7.30 22.5 7.34 21.8 7.38 20.4 7.42 21.0 7.47 21.4 7.51 21.2 7.55 20.9 7.59 20.0 7.63 18.6 7.68 17.7 7.72 17.0 7.76 16.3 7.80 15.3 7.84 15.1 7.89 14.4 7.93 13,8 7.97 13.3 8.01 12.9 8.05 14.6 8.12 16.8 8.18 15.3 8.24 14.5 8.31 12.7 8.37 10.9 . . 8.44 9.4 8.50 8.2 8.57 7.6 8863 8.1 1,1,2 trichlorethane: PK in rats and mice Page 61 of 69 Project No. 41608 Chamber Chamber Chamber Time Post Cont. Time Post Cont. Time Post Cont. Exposure (hr) Exposure (hr) Exposure (hr) 8.70 8.83 8.96 8.76 8.89 9.02 1,1,2 trichlorethane: PK in rats and mice Page 62 of 69 Project No. 41608 Table D 6. Off Gassing: 4 hr inhalation to 500 ppm 1,1,2 TCE Time Post Exposure( hr) 0.09 0.10 0.12 0.14 0.15 0.17 0.19 0.20 0.22 0.24 0.25 0.27 0.29 0.30 0.32 0.34 0.35 0.37 0.39 0.40 0.42 0.44 0.45 0.47 0.49 0.50 0.52 0.54 0.55 0.57 0.59 0.60 0.62 0.64 0.65 0.67 0.69 0.70 0.72 Chamber Cont.

i" pY: 15: 24 16.78 17.63 17.14 15.11 13.86 13.37 13.03 12.97 12.57 12.23 11.99 11.82 12.03 11.89 11.57 11.61 11.46 11.30 11.00 10.61 10.40 10.36 10.66 10.34 9.88 9,85 9.85 9.48 8.97 9.08 8.90 8.25 8.08 8.39 8.81 8.38 7.56 Time Post Exposure( hr) 0.74 0.75 0.77 0.79 0.80 0.82 0.84 0.85 0.87 0.89 0.90 0.92 0.94 0.95 0.97 0.99 1.00 1.02 1.04 1.05 1.07 1.09 1.10 1.12 1.14 1.15 1.17 1.19 1.20 1.22 1.24 1.25 1.27 1.29 1.30 1.32 1.34 1.35 1.37 Chamber Cont. ';? g 7: 49 7.16 6.84 7.27 7.83 7.83 7.55 6.92 6.82 7.31 7.15 6.91 7.06 7.35 7.02 6.31 6.10 6.38 6.38 5.89 6.10 6.69 6.62 6.45 6.71 7.24 7.29 7.37 7.77 7.47 6.69 6.57 6.07 5.28 5.16 5.07 4.95 5.33 Time Post Exposure( hr) 1.39 1.40 1.42 1.44 1.45 1.47 1.49 1.50 1.52 1.54 1.55 1.57 1.59 1.60 1.62 1.64 1.65 1.67 1.69 1.70 1.72 1.74 1.75 1.77 1.79 1.80 1.82 1.84 1.85 1.87 1.89 1.90 1.92 1.94 1,95 1.97 1.99 2.00 2.02 Chamber Cont.

(~ ps" z'

5: 99 6.03 5.93 5.52 4.93 4.52 4.12 4.10 4.28 4.37 4.64 4.93 5.08 4.94 4.83 5.01 5.02 4.49 4.10 3.99 3.93 3.86 3.97 4.05 3.81 3.46 3.20 3.24 3.35 3.41 3.73 4.01 4.04 4.09 . 4.37 4.51 4.57 4.54 1,1,2 trichlorethane: PK in rats and mice Page 63 of 69 Project No. 41608 Chamber Time Post Cont. Exposure (hr) 0w Q 2.04 2.05 2.07 2.09 2.10 2.12 2.14 2.15 `2.17 2.19 2.20 2.22 2.24 2.25 2.27 2.29 2.30 2.32 2.34 2.35 2.37 2.39 2.40 2.42 2.44 2.45 2.47 2.49 2.50 2.52 2.54 2.55 2.57 2.59 2.60 2.62 2.64 2.65 2.67 2.69 4.27 3.95 3.82 3.71 3.48 3.50 3.70 3.65 3.51 3.62 3.55 3.25 3.17 3,12 3.10 3.04 3.11 3.07 2.87 2.81 2.84 2.95 2.91 2.87 2.85 2.75 2.74 2.78 2.56 2.44 2,61 2.86 2.89 2.79 2.75 2.63 2.45 2.22 1.92 2.03 Time Post Exposure (hr) 2.71 2.72 2.74 2.76 2.77 2.79 2.81 2.82 2.84 2.86 2.87 2.89 2.91 2.92 2.94 2.96 2.97 2.99 3.01 3.02 3.04 3.06 3.07 3.09 3.11 3.12 3.14 3.16 3.17 3.19 3.21 3.22 3.24 3.26 3.27 3.29 3.31 3.32 3.34 3.36 Chamber Cont.

`2pplrl'

2: 04 2.09 2.09 2.08 2.15 2.12 1.92 1.75 1.74 1.66 1.65 1.75 1.92 1.96 1.88 1.76 1.68 1.59 1.65 1.75 1.73 1.77 1.68 1.64 1.67 1.56 1.36 1.35 1.37 1.25 1.18 1.19 1.22 1.22 1.32 1.30 1.21 1.22 1.22 Chamber Time Post Cont. Exposure (hr) (w N 3.37 1.22 3.39 1.16 3.41 1.18 3.42 1.21 3.44 1.18 3.46 1.11 3.47 1.16 3.49 1.23 3.51 1.17 3.52 1.16 3.54 1.16 3.56 1.09 3,57 1.06 3.59 1.00 3.61 0.96 3.62 0.91 3.64 0.87 3.66 0.94 3.67 1.03 3.69 1.00 3.71 0.96 3.72 0.91 3.74 0.84 3.76 0.75 3.77 0.69 3.79 0.68 3.81 0.71 3.82 0.74 3.84 0.72 3.86 0.74 3.87 0.76 3.89 0.77 3.91 0.76 3.92 0.73 3.94 0.73 3.96 0.74 .. 3.97 0.76 3.99 0.71 4.01 0.72 4.02 0.76 1,1,2 trichlorethane: PK in rats and mice iroject No. 41608 Chamber Time Post Cont. Exposure( hr) 4.04 ';;; I 4.06 0: 61 4.07 0.59 4.09 0.61 4.11 0.59 4.12 0.59 4.14 0.59 4.16 0.57 4.17 0.59 4.19 0.60 4.21 0.59 4.22 0.53 4.24 0.53 4.26 0.56 4.27 0.54 4.29 0.52 4.31 0.52 4.32 0.54 4.34 0.52 4.36 0.48 Time Post Exposure( hr) 4.37 4.39 4.41 4.42 4.44 4.46 4.47 4.49 4.51 4.52 4,54 4.56 4.57 4.59 4.61 4.62 4.64 4.66 4.67 4.69 Chamber Cont.

`opP$ '

0: 49 0.49 0.54 0.54 0.52 0.50 0.50 0.48 0.41 0.38 0.42 0.44 0.44 0.40 0.37 0.39 0.39 0.37 0.37 Page 64 of 69 Time Post Exposure( hr) 4.71 4.72 4.74 4.76 4.77 4.79 4.81 4.82 4.84 4.86 4.87 4.89 4.91 4.92 4.94 4.96 4.97 4.99 5.01 Chamber Cont. . '; P$

0: 43 0.41 0.43 0.46 0.45 0.42 0.46 0.47 0.41 0.40 0.42 0.40 0.34 0.31 0.31 0.30 0.30 0.23 1,1,2 trkhlorethane: PK in rats and mice Project No. 41608 Page 65 of 69 Table D 7. Off Gassing: 5 hrinhalationto 250 ppm 1,1,2 TCE Time Post Exposure( hr) 0.06 0.08 0.10 0.11 0.13 0.15 0.16 0.18 0.20 0.21 0.23 0.25 0.26 0.28 0.30 0.31 0.33 0.35 0.36 0.38 0.40 0.41 0.43 0.45 0.47 0.48 0.50 0.52 0.53 0.55 0.57 0.58 0.60 0.62 0.63 0.65 0.67 0.68 0.70 Chamber Cont.

!% 5: 710 5.905 6.067 5.468 4.361 3.835 3.546 3.430 3.292 3.177 3.114 3.042 2.904 2.755 2.653 2.526 2.415 2.396 2.358 2.311 2,262 2.218 2.174 2.055 1.901 1.828 1.788 1.729 1.654 1.627 1.555 1.463 1.415 1.410 1.358 1.326 1.430 1.446 Time Post Exposure( hr) 0.72 0.73 0.75 0.77 0.78 0.80 0.82 0.83 0.85 0.87 0.88 0.90 0.92 0.93 0.95 0.97 0.98 1.00 1.02 1.03 1.05 1.07 1.08 1.10 1.12 1.13 1.15 1.17 1.18 1.20 1.22 1.23 1.25 1.27 1.28 1.30 1.32 1.33 1.35 Chamber Cont.

!!%: 1: 321 1.272 1.258 1.119 1.030 1.017 1.014 1.095 1.102 1.043 0.996 0,924 0,945 0.954 0.957 0.896 0.808 0.822 0.801 0.736 0.718 0.754 0.755 0.740 0.749 0.726 0.662 0.675 0.692 0.613 0.622 0.661 0.700 0.657 0.598 0.553 0.544 0.520 Chamber Time Post Cont. Exposure( hr) (PPm) 1.37 0.499 1.38 0,508 1.40 0.537 1.42 0.521 1.43 0.486 1.45 0.477 1.47 0.459 1.48 0.449 1.50 0.457 1.52 0.449 1.53 0.455 1.55 0.452 1.57 0.446 1.58 0.444 1.60 0.473 1.62 0.470 1.63 0.429 1.65 0.401 1.67 0.388 1.68 0,352 1.70 0.360 1.72 0.375 1.73 0.363 1.75 0.329 1.77 0.339 1.78 0.362 1.80 0.331 1.82 0.343 1.83 0.340 1.85 0.328 1.87 0.323 1.88 0.331 1,90 0.304 1.92 0.295 . . 1.93 0.313 1.95 0.262 1.97 0.259 1.98 0.305 2.00 0.295 1,1,2 trichlorethane: PK in rats and mice Project No. 41608 Page 66 of 69 Time Post Exposure (hr) 2.02 2.03 2.05 2.07 2.08 2.10 2.12 2.13 2.15 2.17 2.18 2.20 2.22 2.23 2.25 2.27 2.28 2.30 2.32 2.33 2.35 2.37 2.38 2.40 2.42 2.43 2.45 2.47 2.48 2.50 2.52 2.53 2.55 2.57 2.58 2.60 2.62 2.63 2.65 2.67 Chamber Cone,

EL2 0: 240 0.295 0.290 0.230 0.223 0.268 0.267 0.228 0.225 0.252 0.276 0.255 0.235 0.242 0.235 0.247 0.285 0.263 0.253 0.252 0.230 0.222 0.217 0.252 0.255 0.242 0.256 0.248 0,216 0,209 0.242 0.237 0.212 0.213 0.214 0.233 0,251 0.238 0.205 Time Post Exposure (hr) 2.69 2.70 2.72 2.74 2.75 2.77 2.79 2.80 2.82 2.84 2.85 2.87 2.89 2.90 2.92 2.94 2.95 2.97 2.99 3.00 3.02 3.04 3.05 3.07 3.09 3.10 3.12 3.14 3.15 3.17 3.19 3.20 3.22 3.24 3.25 3.27 3.29 3.30 3.32 3.34 Chamber Cont.

E2 0: 236 0.209 0.192 0.208 0.221 0.228 0.192 0.184 0.203 0.189 0.172 0.181 0.166 0.159 0.152 0.186 0.193 0.173 0.198 0.195 0.177 0.168 0.148 0.139 0.153 0.176 0.187 0.177 0.179 0.196 0.237 0.213 0.162 0.166 0.170 0.146 0.140 0.117 0.093 Time Post Exposure (hr) 3,35 3.37 3.39 3.40 3.42 3.44 3.45 3.47 3.49 3.50 3.52 3.54 3.55 3.57 3.59 3.60 3.62 3.64 3.65 3.67 3.69 3.70 3.72 3.74 3.75 3.77 3,79 3.80 3.82 3.84 3.85 3.87 3.89 3.90 3.92 3.94 3.95 3.97 3.99 4.00 Chamber Cont.

K. 01126 0.126 0.116 0.119 0.140 0.175 0.163 0.135 0.120 0.090 0.113 0.189 0.201 0.183 0.192 0.185 0.130 0.104 0.112 0.124 0.117 0.137 0.143 0.141 0.145 0.149 0.143 0.130 0.137 0.128 0.139 0.165 0.164 0.156 0.127 .' 0.1?. 4 0.099 0.084 0.096 1,1,2 trichlorethane: PK in rats and mice Page 67 of 69 Project No. 41608 Chamber Chamber Time Post Cont. Time Post Cone. Exposure( hr) (PPm) Exposure( hr) (iv r 0 4.02 0,117 4.04 0.159 4.05 0.185 4.07 0.157 4.09 0.105 4.10 0.112 4.12 0.119 4.14 0.127 4.15 0.098 4.17 0.101 4.19 0.124 4.20 0.107 4.22 0.114 4.24 0.140 4.25 0.151 4.27 0.126 4.29 0.133 4.30 0.131 4.32 0.115 4.34 0.094 4.35 0.115 4.37 0.123 4.39 0.138 4.40 0.088 4,42 0.028 4.44 0.067 4.45 0.093 4.47 0.087 4.49 0.053 4.50 0.095 4.52 0.108 4.54 0.092 4.55 0.071 4.57 0.083 4.59 0.096 4.60 0.110 4.62 0.097 4.64 0.077 4.65 0.088 4.67 0.055 4.69 0.031 4.70 0.043 4.72 0.065 4.74 0.072 4.75 0.082 4,77 0.119 4.79 0.096 4.80 0.077 4.82 0.080 4.84 0.070 4.86 0.050 4.87 0.057 4.89 0.@ 72 4.91 0.084 4.92 0.083 4.94 0.052 4.96 0.057 1,1,23richlorethane: PK in rats and mice Project No. 41608 Page 68 of 69 Appendix E: Partition Coefficients Table E l. Time and volume determination using rat blood. Incubation Sample Volume Time (hr) (9) Partition Coefficient Averaqe 1 0.500 58.0 1 0.498 46.1 52.0 1 1.020 57.5 1 1.036 50.1 53.8 1 2.030 47.8 1 2.010 53.9 1 2.010 53.9 51.9 rfI 3.53 3 0.500 54.6 3 0.500 50.3 3 0.497 50.2 51.7 f: 2.52 3 1.02 54.1 3 1.036 61.7 3 1,030 55.1 56.9 t 4.17 Page 69 of 69 Table E 2. Blood: Air Partition Coefficient: Female B6C3Fl Mouse Blood Sample Volume (g) Partition Coefficient Average 1 0.509 82.8 2 0.502 63.1 3 0.509 73.0 4 0.501 76.0 5 0.498 61.5 6 0.502 69.9 71.0 Ik 8.03 Pool A 1.017 65.1 ;:: i : 1.026 1.009 74.3 66.9 68.7 k 4.87 Note: The blood from 4 extra animals was pooled with left over blood from the original 6 animals, and partition coefficients determined in 1 ml volumes of the pooled blood.


[Federal Register Volume 87, Number 68 (Friday, April 8, 2022)]
[Rules and Regulations]
[Pages 20705-20707]
[FR Doc No: 2022-07515]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket Number USCG-2022-0176]
RIN 1625-AA00

Safety Zone; Columbia River, Rufus, OR

AGENCY: Coast Guard, Department of Homeland Security (DHS).

ACTION: Temporary final rule.

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SUMMARY: The Coast Guard is establishing a temporary emergency safety
zone within 200 yards of a power line lying across the Columbia River,
approximately 300 yards west of the John Day Lock and Dam. The safety
zone is needed to protect personnel, vessels, and the marine
environment from potential hazards associated with the repair of the
damaged power line that is 10 ft above the water line. Entry of vessels
or persons into this zone is prohibited unless specifically authorized
by the Captain of the Port Columbia River.

DATES: This rule is effective without actual notice from April 8, 2022,
through April 10, 2022. For the purposes of enforcement, actual notice
will be used from April 4, 2022, until April 8, 2022.

ADDRESSES: To view documents mentioned in this preamble as being
available in the docket, go to https://www.regulations.gov, type USCG-
2022-0176 in the search box and click ``Search.'' Next, in the Document
Type column, select ``Supporting & Related Material.''

FOR FURTHER INFORMATION CONTACT: If you have questions on this rule,
call or email Lieutenant Sean V. Murphy, Waterways Management, Marine
Safety Unit Portland, U.S. Coast Guard, telephone<PHONE_NUMBER>, email
[email protected].

SUPPLEMENTARY INFORMATION:

I. Table of Abbreviations

CFR Code of Federal Regulations
DHS Department of Homeland Security
FR Federal Register
NPRM Notice of proposed rulemaking
Sec.  Section
U.S.C. United States Code

II. Background Information and Regulatory History

    The Coast Guard is issuing this temporary rule without prior notice
and opportunity to comment pursuant to authority under section 4(a) of
the Administrative Procedure Act (APA) (5 U.S.C. 553(b)). This
provision authorizes an agency to issue a rule without prior notice and
opportunity to comment when the agency for good cause finds that those
procedures are ``impracticable, unnecessary, or contrary to the public
interest.'' Under 5 U.S.C. 553(b)(B), the Coast Guard finds that good
cause exists for not publishing a notice of proposed rulemaking (NPRM)
with respect to this rule because a power line is laying across the
Columbia River, 10 feet above the waterline, and immediate action is
needed to protect the public from dangers associated with its existence
and repair. It is impracticable to publish an NPRM because we must
establish this safety zone on April 4, 2022.
    Under 5 U.S.C. 553(d)(3), the Coast Guard finds that good cause
exists for making this rule effective less than 30 days after
publication in the Federal Register. Delaying the effective date of
this rule would be impracticable because immediate action is needed to
respond to the potential safety hazards associated with the damaged
power line laying across the Columbia River.

III. Legal Authority and Need for Rule

    The Coast Guard is issuing this rule under authority in 46 U.S.C.
70034 (previously 33 U.S.C. 1231). The Captain of the Port Columbia
River (COTP) has determined that potential hazards associated with a
damaged power line laying across the Columbia River, approximately 300
yards west of the John Day Lock and Dam, will be a safety concern for
anyone within 200 yards of the power line. This rule is needed to
protect personnel, vessels, and the marine environment in the navigable
waters within the safety zone while the power line is repaired.

IV. Discussion of the Rule

    This rule establishes a safety zone from April 4, 2022, until April
10, 2022. The safety zone will cover all navigable waters within 200
yards of the power line laying across the Columbia River, approximately
300 yards west of the John Day Lock and Dam. The duration of the zone
is intended to protect personnel, vessels, and the marine environment
in these navigable waters while the power line is being repaired. No
vessel or person will be permitted to enter the safety zone without
obtaining permission from the COTP or a designated representative.

V. Regulatory Analyses

    We developed this rule after considering numerous statutes and
Executive orders related to rulemaking. Below we summarize our analyses
based on a number of these statutes and Executive orders, and we
discuss First Amendment rights of protestors.

A. Regulatory Planning and Review

    Executive Orders 12866 and 13563 direct agencies to assess the
costs and benefits of available regulatory alternatives and, if
regulation is necessary, to select regulatory approaches that maximize
net benefits. This rule has not been designated a ``significant
regulatory action,'' under Executive Order 12866. Accordingly, this
rule has not been reviewed by the Office of Management and Budget
(OMB).
    This regulatory action determination is based on the size,
location, and duration of the safety zone.

B. Impact on Small Entities

    The Regulatory Flexibility Act of 1980, 5 U.S.C. 601-612, as
amended, requires Federal agencies to consider the potential impact of
regulations on small entities during rulemaking. The term ``small
entities'' comprises small businesses, not-for-profit organizations
that are independently owned and operated and are not dominant in their
fields, and governmental jurisdictions with populations of less than
50,000. The Coast Guard certifies under 5 U.S.C. 605(b) that this rule
will not have a significant economic impact on a substantial number of
small entities.
    While some owners or operators of vessels intending to transit the
safety zone may be small entities, for the reasons stated in section
V.A above, this rule will not have a significant economic impact on any
vessel owner or operator.
    Under section 213(a) of the Small Business Regulatory Enforcement
Fairness Act of 1996 (Pub. L. 104-121), we want to assist small
entities in understanding this rule. If the rule would affect your
small business, organization, or governmental jurisdiction and you have
questions concerning its provisions or options for compliance, please
call or email the person listed in the FOR FURTHER INFORMATION CONTACT
section.
    Small businesses may send comments on the actions of Federal
employees who enforce, or otherwise determine compliance with, Federal
regulations to the Small Business and Agriculture Regulatory
Enforcement Ombudsman and the Regional Small Business Regulatory
Fairness Boards. The Ombudsman evaluates these actions annually and
rates each agency's responsiveness to small business. If you wish to
comment on actions by employees of the Coast Guard, call 1-888-REG-FAIR
(1-888-734-3247). The Coast Guard will not retaliate against small
entities that question or complain about this rule or any policy or
action of the Coast Guard.

C. Collection of Information

    This rule will not call for a new collection of information under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

D. Federalism and Indian Tribal Governments

    A rule has implications for federalism under Executive Order 13132,
Federalism, if it has a substantial direct effect on the States, on the
relationship between the National Government and the States, or on the
distribution of power and responsibilities among the various levels of
government. We have analyzed this rule under that order and have
determined that it is consistent with the fundamental federalism
principles and preemption requirements described in Executive Order
13132.
    Also, this rule does not have tribal implications under Executive
Order 13175, Consultation and Coordination with Indian Tribal
Governments, because it does not have a substantial direct effect on
one or more Indian tribes, on the relationship between the Federal
Government and Indian tribes, or on the distribution of power and

responsibilities between the Federal Government and Indian tribes.

E. Unfunded Mandates Reform Act

    The Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1531-1538)
requires Federal agencies to assess the effects of their discretionary
regulatory actions. In particular, the Act addresses actions that may
result in the expenditure by a State, local, or tribal government, in
the aggregate, or by the private sector of $100,000,000 (adjusted for
inflation) or more in any one year. Though this rule will not result in
such an expenditure, we do discuss the effects of this rule elsewhere
in this preamble.

F. Environment

    We have analyzed this rule under Department of Homeland Security
Directive 023-01, Rev. 1, associated implementing instructions, and
Environmental Planning COMDTINST 5090.1 (series), which guide the Coast
Guard in complying with the National Environmental Policy Act of 1969
(42 U.S.C. 4321-4370f), and have determined that this action is one of
a category of actions that do not individually or cumulatively have a
significant effect on the human environment. This rule involves a
safety zone that will prohibit entry within 200 yards of a damaged
power cable that is laying across the Columbia River, approximately 300
yards west of the John Day Lock and Dam. It is categorically excluded
from further review under paragraph L 60(c) of Appendix A, Table 1 of
DHS Instruction Manual 023-01-001-01, Rev. 1.

G. Protest Activities

    The Coast Guard respects the First Amendment rights of protesters.
Protesters are asked to call or email the person listed in the FOR
FURTHER INFORMATION CONTACT section to coordinate protest activities so
that your message can be received without jeopardizing the safety or
security of people, places or vessels.

List of Subjects in 33 CFR Part 165

    Harbors, Marine safety, Navigation (water), Reporting and
recordkeeping requirements, Security measures, Waterways.

    For the reasons discussed in the preamble, the Coast Guard amends
33 CFR part 165 as follows:

PART 165--REGULATED NAVIGATION AREAS AND LIMITED ACCESS AREAS

0
1. The authority citation for part 165 continues to read as follows:

    Authority:  46 U.S.C. 70034, 70051; 33 CFR 1.05-1, 6.04-1, 6.04-
6, and 160.5; Department of Homeland Security Delegation No.
00170.1, Revision No. 01.2.

0
2. Add Sec.  165.T13-0176 to read as follows:

Sec.  165.T13-0176  Safety Zone; Safety Zone; Columbia River, Rufus,
OR.

    (a) Location. The following area is a safety zone: All waters of
the Columbia River, from surface to bottom, 200 yards around a line
connecting the following points: 45[deg]42'51'' N, 120[deg]42'39'' W
and 45[deg]42'22.9'' N, 120[deg]42'28.1'' W. These coordinates are
based on the 1984 World Geodetic System.
    (b) Definitions. As used in this section, designated representative
means a Coast Guard Patrol Commander, including a Coast Guard coxswain,
petty officer, or other officer operating a Coast Guard vessel and a
Federal, State, and local officer designated by or assisting the
Captain of the Port Columbia River (COTP) in the enforcement of the
safety zone.
    (c) Regulations. (1) Under the general safety zone regulations in
subpart C of this part, you may not enter the safety zone described in
paragraph (a) of this section unless authorized by the COTP or the
COTP's designated representative.
    (2) To seek permission to enter, contact the COTP or the COTP's
representative by contacting the Sector Columbia River at<PHONE_NUMBER>.
Those in the safety zone must comply with all lawful orders or
directions given to them by the COTP or the COTP's designated
representative.
    (d) Enforcement period. This section will be enforced from April 4,
2022, to April 10, 2022.

    Dated: April 4, 2022.
M. Scott Jackson,
Capt, U.S. Coast Guard, Captain of the Port Columbia River.
[FR Doc. 2022-07515 Filed 4-7-22; 8:45 am]
BILLING CODE 9110-04-P