Document 3epw49waK850JNM9rZw6X52n3

DOW CONFIDENTIAL INFORMATION R & D REPORT HEALTH & ENVIRONMENTAL SCIENCES THE DOW CHEMICAL COMPANY OFFICE CQP^W<Ld*Wftraftyft Vvl 1 PFI -*HET T2.02-194-000-002 OEPAffTMBT Date laaued MAMMALIAN AND ENVIRONMENTAL TOXICOLOGY RESEARCH LABORATORY June 12, 1989 Title 20 Comparison of the Acute Lethality of Selected Hydrocarbons Via Intratracheal and Oral Routes PAGES IN FULL REPORT Author(s)/Mastsr Numbsr(s) Leslie P. McCarty (056952), Donal C. Flannagan, Scot A. Randall, and Keith A. Johnson Author(s) Signalure(s) Reviewer's, Signature J f^atts'/ RIPTIVE SUMMARY /tiipythn CONCLUSIONS i). Cl A. //r/# A C3L/?]) 8s j/fjgj' Thla report la: INTERIM 0 FINAL and mainly: El SBV j~[ REVIEW The approximate lethal dose (ALD) of six halogenated hydrocarbons via the intratracheal route has been determined in rats and compared with published oral LD50 values. The compounds tested in this study were dichloromethane, perchloroethylene, trichloroethylene, carbon tetrachloride, chloroform and ethylene dichloride. A method of administering the materials intratracheally to unanesthetized animals was developed. The intratracheal ALD of the halogenated hydrocarbons ranged between 3.13 and 17.5 percent of the oral LD50. Thus, aspiration of halogenated hydrocarbons may present more of a hazard than oral toxicity and should be considered when rendering first aid or emergency medical treatment. PHOTO: K-1712-(44) Pi' K-2521-(58) pv1 K=IiS8=(SSJ pt' K-2511 -(25) p y, K-1985-(16) - / DO 1.36593 CONFTDFNTT At, ARE MATERIALS DESCRIBED IN THIS REPORT ON TSCA INVENTORY? IF NO. LIST MATERIALS ON REVERSE SIDE OF THIS PAGE THAT WE WILL USE OR PRODUCE COMMERCIALLY THAT WILL REQUIRE A PMN. YE5 [Xj DISTRIBUTION: SEE ATTACHED LIST - FIFRA REGULATED THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 1 OF 20 Study Title Comparison of Acute Lethality of Selected Hydrocarbons via Intratracheal and Oral Routes Authors Leslie P. McCarty, Donal C. Flannagan, Scot A. Randall and Keith A. Johnson Final Report June 12, 1989 Performing__ Laboratory Mammalian and Environmental Toxicology Research Laboratory Health and Environmental Sciences The Dow Chemical Company Midland, Michigan 48674 Laboratory Project Study ID T2.02-194-000-002 - DOW CONFIDENTIAL - DO C.Ci^ THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 2 Page Two is reserved for the inclusion of a Statement of Data Confidentiality Claims as required by the United States Environmental Protection Agency (EPA) under the Provisions of PR NOTICE 86-5 issued July 29, 1986. - DOW CONFIDENTIAL - OO 136595 CONFI DENT T AL THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 3 COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS To the best of my knowledge and belief the study described in this report was conducted in compliance with the following Good Laboratory Practice Standards United States Environmental Protection Agency, Title 40 Code of Federal Regulations Part 792, Federal Register, 29 November 1983 Japan Ministry of Agriculture, Forestry and Fisheries, 59 Nohsan, Notification No. 3850, Agricultural Production Bureau, 10 August 1984 Organization for Economic Co-Operation and Development ISBN 92-64-12367-9, Paris 1982 Director Mammalian & Environmental Toxicology Research Laboratory - DOW CONFIDENTIAL - DO 1.36596 CONFIDENTIAL THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 4 QUALITY ASSURANCE STATEMENT STUDY TITLE: Comparison of the Acute Lethality of Selected Hydrocarbons Via Intratracheal and Oral Routes This study was examined for conformance with Good Laboratory Practices as published by the U.S. Environmental Protection Agency, and the Food and Drug Administration. The final report was determined to be an accurate reflection of the data obtained. The dates of Quality Assurance activities on this study are listed below. Study Start Date: 8/23/88 Date of Final Report: 6/12/89 TYPE OF AUDIT: ! Preliminary protocol Final protocol Study conduct Draft report DATE OF AUDIT: 8/09/88 9/26/88 9/26/88 4/28/89 DATE FINDINGS REPORTED TO STUDY DIRECTOR/MANAGEMENT: 8/09/88 9/26/88 9/28/88 4/28/89 ARCHIVING: Raw data and a copy of the final report are filed in the . testing facility archives. )T. S. Gushow, B.S. /) Quality Assurance Health and Environmental Sciences The Dow Chemical Company 1803 Building Midland, Michigan 48674 - DOW CONFIDENTIAL - DO 136597 CONFIDENTIAL THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 5 TABLE OF CONTENTS PAGE SUMMARY................................................................................................ 6 INTRODUCTION........................................................................................ 7 METHODS.................................................................................................. 8 RESULTS.................................................................................................... 1 0 DISCUSSION.............................................................................................. 1 1 REFERENCES............................................................................................. 1 4 TABLE 1...................................................................................................... 15 APPENDIX 1................................................................................................ 1 7 - DOW CONFIDENTIAL OO 1.36598 CONFIDENTIAL. THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 6 SUMMARY The approximate lethal dose (ALD) of six halogenated hydrocarbons via the intratracheal route has been determined in rats and com pared with published oral LD50 values. The compounds tested in this study were dichloromethane, perchloroethylene, trichloroethy lene, carbon tetrachloride, chloroform and ethylene dichloride. A method of administering the materials intratracheally to unanes thetized animals was developed. The intratracheal ALD of the halo genated hydrocarbons ranged between 3.13 and 17.5 percent of the oral LD50. Thus, aspiration of halogenated hydrocarbons may pre sent more of a hazard than oral toxicity and should be considered when rendering first aid or emergency medical treatment. - DOW CONFIDENTIAL - DO 136599 CONFTDFNTTAL INTRODUCTION THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 7 The chemical pneumonitis associated with the ingestion of hy drocarbons has long been recognized. Deichmann1 showed that hydrocarbons, administered via the oral or intraperitoneal routes to experimental animals, could produce pneumonitis. Gerard2 showed that intratracheal administration of kerosene to rats also produced a pneumonitis; the amounts required being 140 times less than by the oral route. Beamon3 reviewed 116 cases of children who had ingested various hydrocarbons and who were treated in various ways. There was a suggestion of increased incidence of pulmonary complications when emesis was induced although the difference was not statistically significant. Rumak4 reviewed the literature and came to an opposite conclusion that induction of emesis was the best course of action; the exception being mineral seal oil (which is used in furniture polish). Halogenated hydrocarbons are used infrequently in household materials. However, they can be found in dry cleaning fluids, some pesticide formulations, paint and varnish removers and metal cleaners such that accidental ingestion can occur. The information on the toxicity of aliphatic hydrocarbons has been gathered from clinical information in addition to animal experiments. There is data on the oral and inhalation toxicity of halogenated hydrocarbons in experimental animals but little or no human clinical data related to the effects of these materials via the intratracheal route. This lack of information on either humans or experimental animals via the intratracheal route prompted this study. - DOW CONFIDENTIAL - DO CONF lOF-N1 T. AD METHODS THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 8 Animals: Sprague-Dawley rats (200-250 g) obtained from Charles River Breeding Laboratory, Portage, MI, were used in this study. Surgery: The animals were sedated with methoxyflurane and then anesthetized with isoflurane (2.5% at a rate of 0.2 1/min) via a glass nose cone. A 2 cm incision was made on the ventral midline of the neck, caudal to the larynx. Adipose tissue and regional muscles were bluntly dissected to expose the trachea. Using a 17 gauge needle as a trochar, a Silastic cannula (0.02 in id x 0.037 in od) was inserted 7 mm into the trachea. The cannula was affixed to the tissue surrounding the trachea with cyanoacrylate adhesive. A 1 cm incision was made on the dorsal aspect of the animals' neck at the same level as the cannula implantation. The cannula was tunneled subcutaneously from the implantation site to the incision on the back of the neck. Excess tubing was left subcutaneously to allow for displacement due to movement. Externally, the end of the cannula was knotted and sutured to the skin on the back of the neck. Inci sions were closed with sutures. The following day, the animals had recovered fully from anesthesia and surgery. Approximate Lethal Dose (ALD): To minimize the use of animals, the ALD of the test compounds was determined as described by Deichmann5. Thus, a single animal was used for each dose of the test materials and the controls. The doses were calculated on a logarithmic scale as described by Kennedy6. The ALD method derived the maximum amount of information using the minimum number of animals. Dosing: The material was administered by cutting of the knot from the end of the cannula, inserting a blunt needle and injecting the - DOW CONFIDENTIAL - DO 136601 CONFIDENTIAL THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 9 calculated dose from a syringe. Air was used to force the test material from the cannula into the trachea. An initial test dose of 10% of the oral LD507 was administered intratracheally. If the animal survived for the three day post-dosing observation period, the dose for the next test animal was increased by one-fourth log unit. This dosing regimen was repeated until the rat died within the three-day interval which was defined as the ALD. If the rat died following the initial dose of 10% of the oral LD50, the next dose level was decreased one log unit (1% of the oral LD50). As all rats survived the 1% dose level, intermediate dose levels on a one-fourth log basis were then used to determine the ALD. Control animals were pre pared by implanting cannulas in the trachea. The effects of introducing fluid into the trachea were tested by injecting physiological saline at zero, one and two times the maximal volume of the test compounds. Materials'. The test compounds were as follows: methylene chloride and ethylene dichloride, (Fischer Scientific, Pittsburgh, PA, ACS grade); trichloroethylene, perchloroethylene, chloroform and carbon tetrachloride, (Aldrich Chemical Co., Milwaukee, WI, Spectrophotometric Grade). Necropsy. All rats surviving the three-day observation period were euthanized via CO2 anesthesia. A complete necropsy examination was conducted by a veterinary pathologist. Specific attention was paid to the surgical site and determination as to whether the cannula remained in the trachea. Rats dying spontaneously were similarly necropsied. Lung changes at necropsy were summarized into three categories based on the nature of change and the extent of pulmonary parenchyma involved. These were as follows: - DOW CONFIDENTIAL - DO 13660? CONFIDENTIAL. THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 10 Minor--Changes involved less than one-fourth of the tissue and were generally rose to dark-red foci or areas. Discolored areas were usually depressed and most likely atelectatic foci. Occasionally these foci were raised and contained fluid. As such, these most likely represented a more active inflammatory response. Moderate--Changes involved one-fourth to one-half of the parenchyma, and were usually rose to dark-red areas. Slight pulmonary edema and fluid or froth in the trachea were frequently noted, particularly for those dying spontaneously. Marked--Changes involved more than one-half of the parenchyma and were bright red to dark-red and frequently swollen. Pulmonary edema and tracheal fluid or froth, often pink, were usually present. I II In a few cases (6), the cannula was found not to be in the trachea at necropsy; these animals were not tabulated in the study and the dose was repeated in another animal. RESULTS The results of this study are summarized in Table I. The ALD via the intratracheal route ranged between 3% and 17.5% of the published oral LD507. The results were analyzed statistically by the binomial probability method8. Since all 6 test materials were more toxic by the intratracheal route than the oral route, it was calculated that p=0.0156 which is statistically significant. Those compounds which are the most toxic orally were not necessarily most toxic by the in tratracheal route. - DOW CONFIDENTIAL - 00 t3f>603 confi^nTTAI- THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 11 The findings at necropsy were variable. Control animals with no fluid injected into the cannula had no lesions or minor lung changes which indicate that the surgical procedure produces few changes. A dose of 0.89 ml/kg of saline (equivalent to the maximum volume of test compound) caused the animal to show some spontaneous move ment for about 10 seconds, after which, it appeared normal. A dose of 1.77 ml/kg of saline (twice the maximum volume of test compound) produced the same reaction. Minor to moderate lesions were seen in the anteroventral lobes of saline controls. Rats dying spontaneously generally had moderate to marked pul monary lesions. The variability was partly due to the interval be tween dosing and death with rats dying peracutely generally having moderate lesions and those surviving longer having marked lesions. Most of the animals receiving lethal doses of the test compounds died in less than ten seconds. One animal receiving carbon tetrachloride and one receiving trichloroethylene died overnight. DISCUSSION The results clearly indicate that halogenated hydrocarbons are much more toxic via the intratracheal route of administration than when given orally as are aliphatic hydrocarbons. Death in the case of aspi rated aliphatic hydrocarbons is due to pneumonitis and is delayed. The rapidity with which the animals expired in this study indicates that the cause of death was absorption of the materials by the pul monary route leading to anesthesia which rapidly progresses to Stage IV and death. When administered by inhalation, the lethal doses are anesthetic followed by respiratory arrest and circulatory collapse. Pathological changes were seen in all the animals but the most se- - DOW CONFIDENTIAL - ccfVo^*' THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 12 vere changes were not always seen in animals receiving the highest doses. This can be interpreted that a significant hazard from halogenated hydrocarbons is pulmonary absorption rather than the en suing pneumonitis associated with aliphatic hydrocarbons. Some first aid procedures have suggested that ingested halogenated hydrocarbons are so toxic that emesis should be induced to remove them as quickly as possible. The toxic manifestations are usually liver and kidney damage when these materials are given by the oral route. Other toxic materials may be dissolved in the halogenated hy drocarbons, such as pesticides, which have to be considered. Because of this toxicity, these materials should be removed from the stomach but not at the risk of aspiration into the pulmonary tract. One also must consider that all the halogenated hydrocarbons have anesthetic properties and are capable of depressing the central ner vous system. This being the case, the gag reflex may be obtunded which will increase the risk of aspiration during emesis. As pointed out by Thompson9 "because the onset of sedation may be rapid with some poisons, the patient who is alert when emesis or lavage is be gun may be stuporous and aspirating 20 minutes later, before emesis or lavage is completed. Never use emesis or lavage unless the air way is secure; aspiration is more deadly than absorption of most poi sons". The administration of milk or other fluids has been suggested in the case of halogenated hydrocarbons for the alleged purpose of dilution. Since hydrocarbons, halogenated or aliphatic, are not miscible with water or milk it is difficult to see how dilution could occur. The drinking of large quantities of fluids may promote spontaneous eme sis with the risk of aspiration. - DOW CONFIDENTIAL - DO 136605 OONFTOFNTTAl THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 13 When presented with a patient who has ingested hydrocarbons, halogenated or aliphatic, the attending medical personnel are faced with an unpleasant choice of options. If the quantity is known to be very small, the wisest course of action is probably to do nothing. In many cases, if not most, the quantity ingested is unknown. The safest course of action is probably gastric lavage after the airway is protected although this procedure is not without some hazard. Written by: Reviewed by: Study Director U Associate Scientist Mammalian & Environmental Toxicology Research Laboratory Donal C. Flannagan Scot A. Randall iff/m Keith A. Johns<C D. V. M., Pft. D Diplomate, American College of Veterinary Pathologists Mammalian & Environmental Toxicology Research Laboratory - DOW CONFIDENTIAL - DO 136606 CONFTDFNTTAL THE DOW CHEMICAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 14 REFERENCES 1. Deichmann WB, Kitzmiller KV, Witherup S, et al: Kerosene intoxication. Ann Internal Med 1944;21:803-823. 2. Gerard HW: Toxicology studies on hydrocarbons V. Kerosine. Tox Appl Pharmacol 1959;1:462-474. 3. Beamon RF, Siegel CJ, Landers G, et al: Hydrocarbon ingestion in children: A six-year retrospective study. JACEP 1976;5:771-775. 4. Rumack BH: Hydrocarbon ingestions in perspective. JACEP 1977;6:172-3. 5. Deichmann WB, LeBlanc TJ: Determination of the approximate lethal dose with about six animals. J Ind Hyg Toxicol 1943;25:415417. 6. Kennedy GL Jr., Ferenz RL, Burgess BA: Estimation of acute oral toxicity in rats by determination of the approximate lethal dose rather than the LD50. / Appl Toxicol 1986;6:145-148. 7. Torkelson TR, Rowe VK: Halogenated aliphatic hydrocarbons containing chlorine bromine and iodine, in Clayton GD, Clayton FE (eds): Patty's Industrial Hygiene and Toxicology, ed 3 New York, NY, John Wiley & Sons, 1981, vol 2B, p 3433-3601. 8. Steel RGD, Tome JH: Principles and Procedures of Statistics, ed 2. New York, McGraw-Hill, 1980, p 43-45. 9. Thompson WL: Recognition, treatment and prevention of poisoning, in Shoemaker WC Thompson WL Holbrook PR (eds): Textbook of Critical Care, ed 1. Philadelphia, Pennsylvania, W. B. Saunders Co. 1984, p801-832. - DOW CONFIDENTIAL - DO CO^F THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 15 TABLE I COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES TEST MATERIAL ORAL LD50 DOSE% IT* ORAL LD50 ALD SURVIVAL2 PATHOLOGY3 CONTROL Saline (vol) Saline (vol) METHYLENE CHLORIDE TRICHLOROETHYLENE PERCHLOROETHYLENE 0 0.89 ml/kg 1.77 ml/kg 2.0 g/kg 1.0 10.0 17.5 31.3 0.35 g/kg 4.92 g/kg 1.0 1.75 3.13 5.6 10.0 0.15 g/kg 2.60 g/kg 5.5 9.6 17.2 55.5 0.45 g/kg + + + + + - + + - - + + - Minor Moderate Minor Minor Marked Moderate Marked Minor Moderate Marked Marked Moderate Moderate Moderate Moderate Moderate 00 13660 gonfiofntt - DOW CONFIDENTIAL - THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 16 ----- TABfcE I (cont.) COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES TEST MATERIAL ORAL LDso DOSE % IT ORAL LD50 ALD SURVIVAL PATHOLOGY ETHYLENE DICHLORIDE 0.68 g/kg 1.0 10.0 17.5 31.3 CHLOROFORM 2.00 g/kg 1.0 1.75 3.13 5.6 10.0 CARBON TETRACHLORIDE 2.92 g/kg 1.0 1.75 3.13 10.0 1 IT/ALD = Intratracheal Approximate Lethal Dose 2 + indicates survival; - indicates died 3 See Appendix 1 for full discussion 0.12 g/kg 0.11 g/kg 0.09 g/kg + + - - + + + - + + - Moderate Moderate Moderate Minor Minor Moderate Minor Minor Moderate Minor Moderate Moderate Marked - DOW CONFIDENTIAL - THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 17 APPENDIX 1 COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES Summary of Gross Pathologic Observations Dose Level Compound Animal ID (% of LD50) Death Status Pertinent Necropsv Observations Control 88A5157 88A5158 88A5159 88A5160 Scheduled*1 Scheduled Saline- xla Scheduled Saline-x2a Scheduled No lesions. Minor lung changes in anteroventral lobes. Moderate lung changes in anteroventral lobes and scattered in other portions. Catheter not present in trachea. Minor changes scattered throughout lungs, primarily right side. Catheter may have been in place at the time of dosing. DO 1,366)10 OONFTOFNTT Methylene chloride 88A5164 88A5163 88A5166 a> 1% Scheduled Minor lung changes in an anteroventral lobe. 10% Scheduled Catheter not present in trachea. Minor lung changes in anteroventral lobes and scattered in other portions. Catheter probably not in trachea at time of dosing based upon both clinical and necropsy observations. 10% Scheduled Marked and extensive lung involvement. l a Saline xl and saline x2 indicate an intratracheal saline volume equal to or double, respectively, the largest volume of solvent given any animal. * Scheduled indicats the animal survived the 3-day observation period. DOW CONFIDENTIAL Compound THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 18 APPENDIX 1 (continued) COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES Summary of Gross Pathologic Observations Dose Level Animal ID (% of LD50) Death Status Pertinent Necropsy Observations 88A5167 88A5168 88A5170 Chloroform 88A5673 88A5675 88A5676 88A5677 o 88A5674 o O' O' 17.5% 17.5% 31.3% Scheduled Spontaneous Spontaneous Catheter not present in trachea. Minor lung changes, primarily in the anteroventral portions. Catheter assumed not to have been in trachea at time of dosing based upon clinical and necropsy observations. Moderate changes throughout lungs; primarily in the anteroventral lobes. Marked lung changes involved most of the lung parenchyma. 1% 1.75% 3.13% 5.56% 10% Scheduled Scheduled Scheduled Spontaneous Spontaneous Minor lung changes, primarily in the anteroventral portions. Moderate lung changes involved primarily the anteroventral portions. Minor lung changes, primarily the caudal portions. Minor lung changes primarily involved the left lung lobe. Moderate changes throughout all lung lobes. DOW CONFIDENTIAL y ilN 3 G lJ N 0 J THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 19 APPENDIX 1 (continued) COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES Summary of Gross Pathologic Observations Dose Level Compound Animal ID (% of LD5Q) Death Status ________Pertinent Necropsy Observations Carbon tetrachloride 88A5665 88A5667 88A5670 88A5668 88A5666 1% 1.75% 1.75% 3.13% 10% Scheduled Scheduled Scheduled Spontaneous Spontaneous Minor lung changes, primarily of the right anteroventral lobes. Moderate changes involved most of the lung parenchyma. Moderate changes involved most of the lung parenchyma. Subcutaneous and muscular hemorrhages at surgical site but the catheter was in place. Moderate changes throughout the lungs. Marked and extensive lung involvement. 00 106612 CO NFIDENTIAL Ethylene dichloride 88A5681 88A5682 88A5683 88A5684 1% 10% 17.5% 31.3% Scheduled Scheduled Spontaneous Spontaneous Catheter not present either externally or internally. Moderate lung changes involved primarily the anteroventral lobes. Based on the lung changes, the catheter was assumed to be in place at the time the rat was dosed. Moderate lung changes present, primarily at the hilus of the lung lobes. Moderate lung changes involved primarily the areas near the hilus of the lobes. Minor lung changes throughout all lobes. DOW CONFIDENTIAL THE DOW CHEMCAL COMPANY STUDY ID: T2.02-194-000-002 PAGE 20 APPENDIX 1 (continued) Compound COMPARISON OF THE ACUTE LETHALITY OF SELECTED HYDROCARBONS VIA INTRATRACHEAL AND ORAL ROUTES Summary of Gross Pathologic Observations Dose Level Animal ID (% of LD50) Death Status _______ Pertinent Necropsy Observations Trichloroethylene 88A5177 88A5183 88A5184 88A5185 88A5180 88A5182 Perchloroethylene 88A5172 88A5173 Sz-^noo-1 ow O' r-*1 \ 88A5174 88A5171 1% 1.75% 3.13% 5.6% 10% 10% 1% 1.75% 3.13% 10% Scheduled Scheduled Spontaneous Spontaneous Scheduled Spontaneous Catheter not present either externally or internally. Minor lung changes, primarily in the anteroventral portions. Catheter may have been in place at time of dosing. Moderate lung changes involved the entire left lobe and the anteroventral portions of the right lobes. Marked changes throughout the entire lungs. Marked changes involved much of the lungs, particularly near the hilus. Catheter not in place. No lung lesions were noted. It is assumed that the catheter was not in place when the animal was dosed. Moderate changes involved all lung lobes, particularly near the hilus. Scheduled Scheduled Spontaneous Spontaneous Moderate lung changes in all lobes, particularly the anteroventral portions. Moderate lung changes present throughout the lungs, particularly the anteroventral portions. Moderate lung changes in all lung lobes. Moderate lung changes in all lung lobes, especially near the hilus. DOW CONFIDENTIAL