Document rBpX2xJ1ZrMyYv7eBYaMvb5Z0

479 /"N TRADE SECRET DuPont-11671 fiK S L ifi-W Study Title H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats Laboratory Project ID: DuPont-11671 A u t h o r : Linda A. Malley, Ph.D., D.A.B.T. S t u d y C o m p l e t e d o n : September 4, 2003 P e r f o r m in g L a b o r a t o r y : E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 W ork Request Num ber Service C ode N u m ber : Page 1 o f 49 H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Anatomic Pathology Evaluations by: / h --S _ ____________ Steven R. Fram e, D.V.M., Ph.D. Diplomate .C.V.P. Principal Research Pathologist and Research M anager D ate Approved by: Scott E. Loveless, Ph-D. Research M anager and D irector b~ Z o o j Date Issued by Study D irector Linda A. M alley, P!t.D.,d5.A.B.T. Senior Research Toxicologist O - J * * / - # at??. D ate -2ossmipawiy iguraigedL @@n@8oesMIato HT / H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ TABLE OF CONTENTS CERTIFICATION............................................. LIST OF TABLES............................................. LIST OF APPENDICES................................... STUDY INFORMATION................................ S U M M A R Y ....................................................... IN T R O D U C T IO N ............................................. O B J E C T IV E ...................................................... MATERIALS AND METHODS..................... A. Test Substances..................................... B. Test Species........................................... C. Animal Husbandry................................ 1. Housing.............................................. 2. Feed and W ater................................. 3. Identification..................................... 4. Health Monitoring Program............. D. Quarantine and Pretest Period.............. E. Study Design.......................................... F. Assignment to Groups and Study Start G. Administration o f Test Substances..... H. Body Weights......................................... I. Clinical Observations and Mortality.... J. Pathology Evaluations......................... RESULTS AND DISCUSSION....................... RECORDS AND SAMPLE STORAGE........ REFERENCE...................................................... T A B L E S ............................................................. A P P E N D IC E S .................................................... DuPont-11671 Page .......2 ..... 4 ..... 4 ..... 5 ......6 .... .7 ..... 7 ..... 7 .... 7 ..... 8 .....8 .8 ..8 ..8 ..9 ..9 ..9 10 10 10 10.11 .12 ,12 .13 ,24 -3 - Como"* M r**.'* * * ' H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 LIST OF TABLES Page TABLE 1 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET ONE........................................ 15 TABLE 2 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET TWO.......................................16 TABLE 3 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET THREE...................................17 TABLE 4 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET O N E ...........................................................................18 TABLE 5 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET TWO...........................................................................19 TABLE 6 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET THREE.......................................................................20 TABLE 7 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET O NE................................................................................................................. 21 TABLE 8 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET TW O................................................................................................................ 22 TABLE 9 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET THREE............................................................................................................. 23 LIST OF APPENDICES Page APPENDIX A INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS....................................26 APPENDIX B INDIVIDUAL ANIMAL MICROSCOPIC OBSERVATIONS LISTING INDIVIDUAL ANIMALS AFFECTED................................................................................................................................................................................46' -4 - Compamf SanWwKl. Dom not plain TCA cm H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 STUDY INFORMATION Test Substance 1 Substance Tested Svnonvms/Codes: H-25499 H-24616 Haskell Number: 25499/24616 Purity Physical Characteristics: Opaque tan liquid Stability: The test substance appeared to be stable under the conditions o f the study; no evidence o f instability was observed. Test Substance 2 Haskell Number: 25500 Purity: Physical Characteristics: Clear liquid Stability: The test substance appeared to be stable under the conditions o f the study; no evidence o f instability was observed. Sponsor: E.l. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: November 5, 2002 / (see report cover page) -5 - Conrnamr SartWwd. Does not contain T8CA CBl H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 SUMMARY A 90-day oral study in rats was conducted to evaluate the potential nasal toxicity o f H-25499a H-25500f i H H f l P V in Crl:CD(SD)BR rats. Groups o f 15 male rats were administered daily dosages by oral gavage o f the vehicle, 70 mg/kg H-25500, or 1000 mg/kg o f H-25499 for 14, 28, or 91 days. Body weight was measured twice weekly. Clinical observations were evaluated throughout the study. After 14, 28, and 91 days of treatment, 5 rats per group per time point were sacrificed for evaluation of nasal histopathology. Nasal lesions were produced in rats administered H-25499 and H-25500. The nasal lesions in rats administered H-25499 were characterized by degeneration/atrophy o f the olfactory epithelium and degeneration/regeneration of the respiratory epithelium. The incidence of affected rats was low for animals sacrificed after 14 or 28 days o f treatment, however; all the rats treated with H-25499 were affected after 91 days of treatment. The nasal lesions in rats administered H-25500 were similar to those observed in rats treated with H-25499, with the additional finding that rats treated with H-25500 had adhesions in the nasal turbinates. The lesions observed in this study were similar to those observed in a previous 90-day study with H- 2461 6 Bas ed on the results o f this study, the nasal lesions observed in the previous study with organofluoride urethane polymer with a surfactant can be attributed to the surfactant component o f the material. aDuring the course o f the study, a second lot (H-24616) o f the same test substance was used due to an insufficient supply o f H-25499. -6Comnanv O m T8CA CBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 INTRODUCTION The test substance contains and is used as a carpet protectant. "En a previous 90-day oral study, rats were administered daily dosages o f 0, 50, 250, nr 1000 mg/kg/day (based on active ingredient) o f this same product by gavage.(!:> Nasal olfactory epithelium degeneration/necrosis was observed in maleUnd female rats at all dosages, and inflammation o f the olfactory epithelium was observed in male rats administered 250 or 1000 mg/kg/day. It was hypothesized that the surfactant in the product may have contributed to the nasal lesions. In order to test this hypothesis, in the current study, male rats were administered daily dosages o f the vein (deionized water), 1000 mg/kg/day o: formulation (H-25499), or 70 mg/kg/day of the surfactant alone (H-25500). The dosage for the surfactant was based on the concentration o f surfactant in theH B H M form ulation. The study was originally initiated using test substance lot identified as H-25499. However, during the course o f the study, the amount of H-25499 was determined to be insufficient for the remainder o f the study. Therefore, H-24616 (a second lot o f the test substance) was used to complete the 90-day treatment period. All references to the test substance in this report will use H-25499. OBJECTIVE The objective o f this study is to compare the potential nasal toxicity o f H-25499 and surfactant, H-25500, when administered by gavage to male rats. The oral route o f administration was selected because it was the route o f exposure in the previous studies. MATERIALS AND METHODS A. Test Substances The test substance, H -25499gpH M |f lw a s supplied byjfae sponsor as a opaque tan liquid. On test day 52, the quantity o f H-25499 H H P f l H I I H g f w a s determined to be insufficient for the remainder o f the study. Therefore, a second lot of the same test substance m M 0 H w a s used until study termination. The su rfactantJpH H H H H H V J was supplied by sponsor a clear liquid. The surfactant was assigned Haskell Laboratory Number H-255CK The test substances appeared to be stable under the conditions o f the study. No evidence of instability, such as a change in color or physical state, was observed. -7 - i e* "** ew"8alwTSC H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 B. Test Species Male Crl:CD(SD)IGS BR rats received from Charles River Laboratories, Inc., Raleigh, North Carolina were used on study. The rat was selected for this study because it is the recommended species specified in the guidelines. The Crl:CD(SD)IGS BR strain was chosen because extensive background information is available from the literature, the supplier and previous studies at Haskell Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, sensitivity to the test substance, and low incidence o f spontaneous diseases. C. Animal Husbandry 1. Housing All rats were housed in stainless steel, wire-mesh cages suspended above cage boards. Rats were housed one per cage. Cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature o f 22 3C and a relative humidity of 50 20%. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, LLC Certified Rodent LabDiet 5002 ad libitum. During the test (exposure) period, test substance was incorporated into the food at concentrations specified by study design. 3. Identification Prior to assignment to groups, each rat was temporarily identified by cage identification. After assignment to groups, an individual identification number was tattooed on the tail o f each rat. The information on the cage labels included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity o f the study: Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. -8wsipwtf D@s not wrialffi TSCA CB H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 Certified animal feed was used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence o f these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity o f the study. The animal health and environmental monitoring program was administered by the attending laboratory animal veterinarian. Evaluation o f these data did not indicate any conditions that affected the validity of the study. D. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for at least 5 days. The rats were observed daily for any clinically apparent signs of disease or injury and weighed 3 times. On the bases of acceptable body weight gains and clinical observations, all rats were released from quarantine by the laboratory animal veterinarian. E. Study Design Male Number o f Males Daily Dosage Dose Volume (mL/kg) I 15 0 (Control)a 4.08 III 15 70 mg/kg Surfactant H-25500 1.00 V 15 1000 mg /kg H-25499b 4.08 a Deionized water b Group V received a second lot (H-24616) of the same test substance beginning on test day 52. Study animals consisted of three subgroups: Subset 1 was sacrificed on test day 14 (5 rats/group), Subset 2 was sacrificed on test day 28 (5 rats/group), and Subset 3 was sacrificed on test day 91 (5 rats/group). F. Assignment to Groups and Study Start The rats were selected for study use on the bases o f adequate body weight gain, freedom from any clinical signs of disease or injury, and a body weight within 20% o f the mean. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means. Administration of test substances began on test day 0. The rats were between 6 and 8 weeks of age on test day 0. -9 - Company Ssnftfzed, Does not contain TSCA CBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 G. Administration of Test Substances H-25499 was administered undiluted, once daily by gavage to the study animals. Starting on test day 52, H-24616 replaced H-25499 and was administered daily to the study animals. H-25500 was diluted with deionized water and administered once daily by gavage. Animals designated for Subset 1 were dosed for 14 days. Animals designated for Subset 2 were dosed for 28 days. Animals designated for Subset 3 were dosed for 91 days. The volume o f the test substances given to each rat daily was based on the most recently recorded weight. Control animals were similarly treated at the same dose volume o f deionized water as the 1000 mg/kg H-25499 group. H. Body Weights All rats were weighed twice per week. I. Clinical Observations and Mortality Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least twice daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. J. Pathology Evaluations Five animals from each group were sacrificed on test days 14, 28, and 91. Noses from all sacrificed animals were processed and microscopically evaluated. -10Osmpany Sanitized. Does not contain TSCA C8I H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 RESULTS AND DISCUSSION Nasal lesions were produced in rats administered! t ^ l H i i d in rats administered H-25500 (surfactant only). These lesions are summarized in *Text Table 1. TEXT TABLE 1 INCIDENCES OF COMPOUND-RELATED MICROSCOPIC LESIONS IN THE NOSE OF MALE RATSa 14 Days No abnormality detected Degeneration/atrophy, olfactory mucosa Degeneration/regeneration, respiratory mucosa. Adhesion, turbinates. Exudate, nasal cavity Vehicle Control 3 1 1 - - H-25500 H-25499 70 mg/kg/day 1000 mg/kg/day 31 13 12 111 28 Days No abnormality detected Degeneration/atrophy, olfactory mucosa Degeneration/regeneration, respiratory mucosa Adhesions, turbinates Exudate, nasal cavity 4 1 - - - 2 1 - - - 2 2 1 - 1 91 Days No abnormality detected Degeneration/atrophy, olfactory mucosa Degeneration/regeneration, respiratory mucosa. Adhesion, turbinates. Exudate, nasal cavity a 5 rats/group/time point 4 1 - - 5 1 5 - 5 - - 1 The primary finding in the nose o f male rats administered 1000 mg/kg/day H-25499 by gavage was degeneration and atrophy o f olfactory epithelium. Degeneration or regeneration of respiratory epithelium and exudates within the nasal cavity (composed o f proteinaceous material and neutrophils) were also present in a few affected animals. Olfactory lesions were present in low incidences at 14 and 28 days, but all animals were affected after 91 days exposure. These lesions were characterized by disorganization and thinning of the olfactory epithelium especially along the ventral one-half o f the nasal septum in the posterior nasal sections. Other areas more commonly affected included the medial extents o f the ethmoturbonates. Minimal focal olfactory degeneration was noted in some controls; however, these lesions were randomly distributed and -11 mttpamj? Sanitized. Does not contain TSCA CBf H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 thus distinguishable from the compound-induced lesions.a The compound-related lesions _ observed in the current study following exposure to 1000 mg/kg/day o f t h e J j ^ H H H M D i s^m^ar to those produced in a previous study with this material.1 1 } ^ In animals administered 70 mg/kg/day surfactant alone (H-25500), olfactory changes similar to those observed with H-25499 were observed in the nose. However, in the surfactant only group, olfactory changes were also associated with fibrous adhesions between individual turbinates and between turbinates and the nasal septum. These adhesions were likely a sequela o f focally more severe olfactory epithelial necrosis and ulceration. Thus, microscopic changes in the nose o f rats in the surfactant-only group were qualitatively similar to those o f rats in the polymer/surfactant group, although lesions in the surfactant-only group appear somewhat more severe based on the consistent presence o f turbinate adhesions. The mechanism underlying this apparently greater severity is not known. No studies have been conducted with the, lone, and thus its potential for nasal toxicity has not been determined. Neve: eiess, on the results o f this study, th en asal lesions observed in a previous study wit] 9 H i j p ; a n be largely, if not completely, attributed to the surfactant component o f the material. RECORDS AND SAMPLE STORAGE All data and records for analytical characterizations conducted by the sponsor will be retained by the sponsor. Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. A sample o f the test substance will be collected for archive purposes and retained at Haskell Laboratory, Newark, Delaware. Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware or at Iron Mountain Records Management, Wilmington, Delaware. REFERENCE 1. DuFont Haskell Laboratory (2001). H-24616: Subchronic Toxicity 90-Da Rats with One-Generation Reproduction Evaluations. Unpublished report. aFocal minimal degeneration o f olfactory epithelium in one animal administered 1000 mg/kg/day H-25499 for 28 days (animal #665965) was similar to that seen in controls and thus may represent a spontaneous occurrence o f this lesion. In addition, artifactual disruption o f the olfactory mucosa precluded critical evaluation o f the olfactory epithelium in this animal. - 12CosupaRf Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLES - 13- Company Sanitized. Does no! contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLES EXPLANATORY NOTES STUDY DESIGN Male Number of Males Daily Dosage Dose Volume (mL/kg) I 15 0 (Control)3 4.08 III 15 70 mg/kg Surfactant H-25500 1.00 V 15 1000 m g/kg H-25499b 4.08 a Deionized water b Group V received a second lot (H-24616) o f the same test substance beginning on test day 52. Study animals consisted o f three subgroups: Subset 1 was sacrificed on test day 14 (5 rats/group), Subset 2 was sacrificed on test day 28 (5 rats/group), and Subset 3 was sacrificed on test day 91 (5 rats/group). - 14- Conmany ganftfced. Does net contain T8CA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats TABLE 1 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET ONE (DAY 14) DuPont-11671 |LESION INCIDENCE (#)| !i 1 1 1 Males | LESIONS j | | TREATMENT 1 ! 1 o 1 70 | 1000 j | mg/kg|mg/kga |mg/kgb | 1 I 1 III j V I 11 | NOSE | NO ABNORMALITY DETECTED 11 1 (5) j (5) | (5) J I 1 { 1 I 1 I1 1 5j 5j 5! Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified a 70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 - 15- Canspanif Sanitized. Does not contain TSCACBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLE 2 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET TWO (DAY 28) 1 |LESION INCIDENCE (#)| Males | LESIONS 1 | NOSE I1 | NO ABNORMALITY DETECTED 1 | TREATMENT | 1 o | 70 | 1000 | | mg/kg|mg/kga |mg/kgb | 1 I 1 III i v | 1111 ____ |1 11 (5) ! (5) 1 (5) | [I j1 1 51 51 5| 1111 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified a 70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 - 16- CMMpanySanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLE 3 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET THREE (DAY 91) |LESION INCIDENCE (#)| | LESIONS | Males 1 | TREATMENT ! i 1 0 I 70 I 1000 j | mg/kg|mg/kga |mg/kgb | | I j III | V | 1111 | NOSE 11 | NO ABNORMALITY DETECTED 1 \ (5) ! (5) i (5) j | 1 j 5j 5j 5I 1 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified a70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 - 17- Company Sanitized. Does not contain TSCA CSI H-25499 and H-25500: Subchronic Toxicity 90-Day Oavage Study in Male Rats DuPont-11671 TABLE 4 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET ONE (DAY 14) LESIONS LESION INCIDENCE (#) | TREATMENT 1 1 1 Males __ I1 1 o 1 70 1 1000 I 1 mg/kg 1mg/kga |mg/kg" | | i 1 HI 1 V I RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. EXUDATE, NASAL CAVITY. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. ADHESION, TURBINATES. | (5) ! (5) | (5) I |1 I1 1 31 3| 11 1 11 1I 1 1 11 11 1 11 11 2| 1 11 11 3j j j1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified a70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 -18- Company San ded. Does not contain TSC CBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 TABLE 5 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET TWO (DAY 28) LESION INCIDENCE (#) Males LESIONS | TREATMENT | 1 | 0 70 1 1000 | mg/kg|mg/kga Irng/kg1 1 I | III 1 v RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, TOOTH. INFLAMMATION, SUBACUTE/CHRONIC. EXUDATE, NASAL CAVITY. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. 11 11 I (5) | (5) | (5) | 11 14 21 2 1 11 1 i 11 1 1 11 1 |1 11 11 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified a 70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 -19- ComPny Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 TABLE 6 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET THREE (DAY 91) 1 |LESION INCIDENCE (#)| I Males | LESIONS 1 j 1 | RESPIRATORY SYSTEM j NOSE II | NO ABNORMALITY DETECTED | INFLAMMATION, SUBACUTE/CHRONIC. j EXUDATE, NASAL CAVITY. j DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. j DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. j ADHESION, TURBINATES. | TREATMENT 1 1 1 o | 70 I 1000 1 | mg/kg|mg/kga |mg/kgb | 1 I 1 III 1 V 1 1 11 1 111 | (5) 1 (5) I (5) | 1j ! 4| 1 | 1 1 1i 1 1 | | 1 1 11 1 1 11 1 1 1i 5 I 5 | 1 i1 5 | 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified a 70 mg/kg Surfactant H-25500 b 1000 mg/kg H-25499 -20- H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLE 7 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET ONE (DAY 14) |LESION INCIDENCE (#)| |---------------------------------- | | Males | LESIONS | TREATMENT I 1 | 0 | 70 | 1000 | I mg/kg|mg/kga |mg/kgb | | ! 1 III | V | RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion EXUDATE, NASAL CAVITY. minimal total observations per lesion DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. minimal mild total observations per lesion DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. minimal moderate total observations per lesion ADHESION, TURBINATES. mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 1 | (5) 13 1 11 |1 1 1 1 1 11 1 11 1 11 1 11 1 1 1 1 (5) | 31 1 1| 1| 1 11 11 1 1 11 11 1 1 1| 11 1 1| 11 (5) | 1j 1| 1| 2| j 2| 3! 31 70 mg/kg SurfactantH-25500 b 1000 mg/kg H-25499 -21 - ompaisf S an ifted . Does nol contain TSC CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLE 8 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET TWO (DAY 28) 1 | LESIONS | | RESPIRATORY SYSTEM | NOSE | NO ABNORMALITY DETECTED | INFLAMMATION, SUBACUTE/CHRONIC, TOOTH. j mild | total observations per lesion j INFLAMMATION, SUBACUTE/CHRONIC. | minimal | total observations per lesion j EXUDATE, NASAL CAVITY. | moderate | total observations per lesion | DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. | minimal | total observations per lesion | DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. | minimal | mild | moderate | total observations per lesion |LESION INCIDENCE {#)| |--------------------- | | Males | -----------------------| | TREATMENT | 0 | 70 | 1000 | j | mg/kg|mg/kga |mg/kgb | | I | III | V | |11i j (5) | (5) 1 (5) | 1 4I 21 2| 11 | 11 1 1 1 11 1 1111 1 11 11 1 1 11 11 1 11 1 1 41 j 1 1 11 1111 1 1 1 11 ! i1 1111 11 1 i1 1 11 1 1 1 1 11 1| 11 2| Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 70 mg/kg SurfactantH-25500 b1000 mg/kg H-25499 - 22- Company Sanftfzed. Does not contain TSCA GBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 TABLE 9 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS SUBSET THREE (DAY 91) |LESION INCIDENCE (#)| |--------------------- | | Males | | LESIONS | TREATMENT 1 | RESPIRATORY SYSTEM 1 NOSE j NO ABNORMALITY DETECTED | INFLAMMATION, SUBACUTE/CHRONIC. | minimal | total observations per lesion | EXUDATE, NASAL CAVITY. | mild | total observations per lesion j DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. | mild | total observations per lesion j DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. | minimal j mild | total observations per lesion j ADHESION, TURBINATES. | minimal | mild | total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified | 0 | 70 | 1000 | | mg/kg|mg/kga |mg/kgb | 1 1 | HI | v | j1! | (5) | (5) 1 (5) | 1 4I 1 11! 1| 11 j 1| 1 1 1 1 1 1 11 | 1 11 |111 11 1 11 1 1 1 11 1 1 ! 51 5I 11 51 51 1111 21 1 1 1 31 1 51 1 70 mg/kg SurfactantH-25500 b 1000 mg/kg H-25499 -23 - Company Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 APPENDICES -24Company Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 APPENDICES EXPLANATORY NOTES STUDY DESIGN Male Number o f Males Daily Dosage Dose Volume (mL/kg) I 15 0 (Control)3 4.08 III 15 70 mg/kg Surfactant H-25500 1.00 V 15 1000 mg /kg H-25499b 4.08 a Deionized water b Group V received a second lot (H-24616) o f the same test substance beginning on test day 52. Study animals consisted of three subgroups: Subset 1 was sacrificed on test day 14 (5 rats/group), Subset 2 was sacrificed on test day 28 (5 rats/group), and Subset 3 was sacrificed on test day 91 (5 rats/group). -25- Company Sanitized. Does not contain TSCA CBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 APPENDIX A INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS -26Company Sanitized. Doe* not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS EXPLANATORY NOTES Lesion Grading Histopathological changes are described according to their morphologic character, distribution and severity. The distribution (extent of tissue involvement) is indicated, where appropriate, by modifiers such as focal, multifocal, diffuse, unilateral, bilateral, etc.; A severity score, if appropriate, is also assigned as follows: Minimal: the amount of change present barely exceeds that which is considered to be within normal limits. Mild: in general, the lesion is easily identified but o f limited severity. The lesion probably does not produce any functional impairment. Moderate: the lesion is prominent but there is significant potential for increased severity. Limited tissue or organ dysfunction is possible. Severe: the degree of change is either as complete as considered possible or great enough in intensity or extent to expect significant tissue or organ dysfunction. Comment: grades minimal through severe represent progressive involvement/severity along a continuum with minimal lesions being the least severe and severe lesions being the most severe. While the grades refer to the morphological characteristics o f lesions, they also indicate their relative biological significance. Gross observations listing multiple masses for a tissue are distinguished with letters (i.e., a, b, c, d, etc.) Neoplasm Designations *B: Benign neoplasm, primary site *M: Malignant neoplasm, primary site -27Company Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 STUDY Dose Group Individual Animal Listing howing animal data for individual animals ale (* APPROVED PROTOCOL *) 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665927 Terminal Sacrifice Killed on Day 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665928 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 665929 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE -28Companr Sanitized. D o not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 Individual Animal Listing f lowing animal data for individual animals STUDY % f l H H B B n a l e (* APPROVED PROTOCOL *) Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665930 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset X Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665931 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : INFLAMMATION, SUBACUTE/CHRONIC, minimal. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, minimal. -29Mttpatif SanRfzed Does not contain TSCA C if H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 Individual Animal Listing animal data for individual animals STUDY I J H H H H H m a l e (* APPROVED PROTOCOL *) Dose Group : III 70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665942 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665943 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665944 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, moderate. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, mild. ADHESION, TURBINATES, mild. EXUDATE, NASAL CAVITY, minimal. -30- Cempanf Sanitized. Does not'contain TSCA CBi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ STUDY M B Dose Group Individual Animal Listing ^Sho w i n g animal data for individual animals B B > a l e (* APPROVED PROTOCOL *) : III 70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665945 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : INFLAMMATION, SUBACUTE/CHRONIC, minimal. 665946 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE DuPont-11671 -31 - Company Sanitized. Does not contain T3CA CSi H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats__________________ DuPont-11671 Individual Animal Listing <BKhowing animal data for individual animals STUDY M f e l ^ ^ n a l e (* APPROVED PROTOCOL *) Dose Group : V 1000 mg/kg H-25499 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665957 Terminal Sacrifice Killed on Day : 14 Exposure Group ; Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 665958 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, minimal. DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. EXUDATE, NASAL CAVITY, minimal. 665959 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, minimal. - 32Cempm^ SanKfzed. Dorn notcontain TSCA crii H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 STUDY Dose Group Individual Animal Listing howing animal data for individual animals ale (* APPROVED PROTOCOL *) V 1000 mg/kg H-25499 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665960 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 665961 Terminal Sacrifice Killed on Day : 14 Exposure Group : Subset 1 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE -33Company Sanitized. Does not contain TSCACBf H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 Individual Animal Listing ^^Ghowing animal data for individual animals STUDY i M M i p i a l e (* APPROVED PROTOCOL *) Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665932 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665933 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 665934 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE -34Company Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ Individual Animal Listing r ___ _____ IBphowing animal data for individual animals STUDY H H H w i a l e (* APPROVED PROTOCOL *) Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665935 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665936 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE DuPont-11671 - 35- SwUfeeA, Dow rwt contain TSCA CBl H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats Individual Animal Listing ^S h o w i n g animal data for individual animals STUDY M R ( m a l e (* APPROVED PROTOCOL *) Dose Group : III 70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665947 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : INFLAMMATION, SUBACUTE/CHRONIC, minimal. 665948 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology NOSE : INFLAMMATION, SUBACUTE/CHRONIC, TOOTH, mild. 665949 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. DuPont-11671 -36- ewpanf S ! feed. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ STUDY Dose Group Individual Animal Listing howing animal data for individual animals _ ale (* APPROVED PROTOCOL *) III 70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665950 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665951 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE DuPont-11671 -37Campany Santtbed. D m not contain TSCA CBl /'***'*% H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 Individual Animal Listing a^Showing animal data for individual animals STUDY B ^ H j j p n a l e (* APPROVED PROTOCOL *) Dose Group : V 1000 mg/kg H-25499 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665962 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, moderate. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, minimal. EXUDATE, NASAL CAVITY, moderate. 665963 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology No Microscopic Abnormality Observed : NOSE 665964 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : INFLAMMATION, SUBACUTE/CHRONIC, minimal. - 38- Company San5fized*Does not contain TSCA CBl H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 Individual Animal Listing S h o w i n g animal data for individual animals STUDY I j m Q P n a l e (* APPROVED PROTOCOL *) Dose Group : V 1000 mg/kg H-25499 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665965 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 665966 Terminal Sacrifice Killed on Day : 28 Exposure Group : Subset 2 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE - 39- Compwj Sanitized. Doe* not contain TSCA CBf H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ Dose Group Individual Animal Listing howing animal data for individual animals ale (* APPROVED PROTOCOL *) : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665937 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665938 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665939 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : No Microscopic Abnormality Observed : NOSE DuPont-11671 -40- Company Sanitized. Does not contain TSCA CSI /!**"*\ H-25499 andH-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats DuPont-11671 STUDY Dose Group Individual Animal Listing S h o w i n g animal data for individual animals m p m A n a l e (* APPROVED PROTOCOL *) : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665940 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : No Microscopic Abnormality Observed : NOSE 665941 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. INFLAMMATION, SUBACUTE/CHRONIC, minimal. -41 - Company Sanitized. Does not contain TSCA CBI /"N H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ Individual Animal Listing Kho w i n g animal data for individual animals STUDY : I M | H H H H m a l e (* APPROVED PROTOCOL *) Dose Group : III 70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665952 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, minimal. 665953 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, mild. 665954 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, mild. DuPont-11671 -42- Company Sanitized. Does not contain TSC CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 STUDY Dose Group Individual Animal Listing howing animal data for individual animals ale (* APPROVED PROTOCOL *) III "70 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665955 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, mild. 665956 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : INFLAMMATION, SUBACUTE/CHRONIC, minimal. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, minimal. mild. - 43- Company Sanitized. Does not contain TSCA CBI H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats Individual Animal Listing _ ^ phowing animal data for individual animals STUDY (* APPROVED PROTOCOL *) Dose G r O T i p T v i O O O mg/kg H-25499 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665967 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. 665968 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. 665969 Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. DuPont-11671 - 44- Company Sanitized. Does not contain TSCA CBS H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats Individual Animal Listing (Showing animal data for individual animals STUDY I j I H H M B ^ p m a l e (* APPROVED PROTOCOL *) Dose Group : V 1000 mg/kg H-25499 Sex: Males Animal Ref 665970 Microscopic & Macroscopic Findings Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : 665971 NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. Terminal Sacrifice Killed on Day : 91 Exposure Group : Subset 3 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : NOSE Histopathology : NOSE : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. EXUDATE, NASAL CAVITY, mild. DuPont-11671 -45Company Sanitized. Does not contain TSCA CBf H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats________ DuPont-11671 APPENDIX B INDIVIDUAL ANIMAL MICROSCOPIC OBSERVATIONS LISTING INDIVIDUAL ANIMALS AFFECTED - 46- Company Sanitized. Does not contain TSCA CBS H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET 1 (DAY 14) DuPont-11671 111 1 1! | LESIONS 1 1 l 11 _- ----------- 1 | RESPIRATORY SYSTEM 1 | NOSE |! | NO ABNORMALITY DETECTED 1 1 | INFLAMMATION, SUBACUTE/CHRONIC. | EXUDATE, NASAL CAVITY. j DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. 1 | DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. 1 ! | ADHESION, TURBINATES. | TREATMENT 1 1 1 |LESION INCIDENCE (#) j i1 1 1 Males 1 11 1 0 1 70 I 1000 1 1 mg/kg |mg/kga|mg/kgb| 1 I 1 III |1 V 1 1 1i i1 1 -- 11 1 !1 1 ! 1 111 1111 1 111 1 (5) |1 (5) 1 (5) I j! iI1 1I jI |665927|6659421|6659611 |665929 j665943 l 1 665930 665946 1 l 665931! 665945 1 1 1 1665944 |665958| |665931j665944 j665958 j 1 1 j665959 |665928|665944 j665957| 1 1 j665958| 1 1 j665960| 1 |665944 1 1 !!11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 70 mg/kg SurfactantH-25500 b1000 mg/kg H-25499 - 47- Censpanf Sanitised. Dees netentain TSCA CBt ) H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats >) ____________________________________ DuPont-11671 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET 2 (DAY 28) LESIONS |LESION INCIDENCE (An 11 1 Males | TREATMENT j 1 1 | 0 1 70 1 1000 | mg/kg jmg/kga|mg/kgt>| 1 I | III 1 v 1 RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, TOOTH. INFLAMMATION, SUBACUTE/CHRONIC. EXUDATE, NASAL CAVITY. DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. 1 1 i 1 | (5) | (5) | (5) i1 |665932 j665950 |665963 |665934 5665951 665966 j6S5935 665936 1 |665948 1 1 |665947 |665964 1 665962 1 |665962 |665933 j665949 665962 1 1 665965 111 Figure in parentheses is number ot animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 70 mg/kg SurfactantH-25500 b1000 mg/kg H-25499 -48- o m p a n y S a n i t i z e d . P o e s n o t c o n t a i n tscacb! H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS SUBSET 3 (DAY 91) DuPont-11671 1 1I 1 11 | LESIONS 1 | TREATMENT 1 |LESION INCIDENCE (An | 11 - II | Males __ | _ I1 1 0 I 70 | 1000 I i mg/kg |mg/kga|mg/kgb| 1 RESPIRATORY SYSTEM 1 1 | NOSE I1 | NO ABNORMALITY DETECTED | 1 1 | INFLAMMATION, SUBACUTE/CHRONIC. | EXUDATE, NASAL CAVITY. | DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA. | DEGENERATION/ATROPHY, OLFACTORY, MUCOSA. 1 1 1 | i ADHESION, TURBINATES. | 1 1 1 1111 1111 1111 1 (5) | (5) 1 (5) | 1 11 j j |665937 1 1 1 j665938 1 1 1 665939 1 1 1 |665940 1 1 1 j665941 |665956 1 ! 1 I |665971| |665956 1 1 j665941 |665952 |665967| 1 665953 j665968 j 1 665954 j665969 j 1 j665955 j665970 j ! 665956 665971j ! 665952 1 1 1 665953 1 1 1 665954 1 1 1 |665955'1 1 1 665956 ! 1 1 1 i1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 370 mg/kg SurfactantH-25500 b1000 mg/kg H-25499 - 4 9 - Company Sanitized. Does not oniain TSCA CBf