Document 5yYQ6ZELQJ54Q8JBzXbeBZ10

ARAttachments to Letter to C. Auer dated May 4, 2000 i % - o g s 'i f Perfluoroctane Sulfonate Studies gtm -0800- 373 Acute Toxicity 1) An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat, Bio/dynamics, Inc., Project No. 78-7185, December 31, 1979. (FC-95, Perfluorooctane Sulfonate potassium salt) 2^A cute Oral Toxicity (LD50) Study in Rats with Fluorad Fluorochemical Surfactant FC-95, International Research and Development Corporation, Project No. 137-083, May 31, 1978. (Note: 3M files indicate samples taken during the study were not analyzed.) ^ 3) Eye and Skin Irritation Studies Report on Sample T-l 166 (FC-98, Potassium ^ Perfluoroethylcyclohexyl Sulfonate, presumed 100 %), Warf Institute Inc., Projeiy1 ~Oopmo No. 5011023, January 28, 1975. -~J --hrn a) Combined Eye and Skin Irritation Studies Report b) Eye Irritation Study (with washout procedure) Report PO o Cm M (j'dl ^^aA ^c j /*yry M ' ~ 7'<f-- J "f'C# C 000811791R DOOfillTTlR 001730 /n ~ ~ / Bio/ciynamics Inc. Division of Biology and Safety Evaluation PROJECT NO. 78-7185 AN ACUTE INHALATION TOXICITY STUDY OF T-2306 CoC IN THE RAT Submitted to: 3M Company Attention: Dr. William C. McCormick Date: December 31, 1979 001731 Bio/ T /dynamics Inc. I. GENERAL 78-7185 A series of one-hour inhalation exposures was performed on rats to determine the median lethal concentration (LC50) of T-2306 CoC dust. The test material, a fine white powder, received from the 3M Company was labeled "3M Company; T-2306 CoC". These studies were initiated on January 24, 1979 and completed on April 6, 1979. II. EXPERIMENTAL A. Test Material Delivery For each exposure, the test material was sieved through a 60- mesh sieve and packed into the large-diameter cylinder of a Wright dust-feed mechanism. Dry air, at flow rates ranging from 12 to 16 liters per minute, was passed through the dust-feed mechanism. The resultant dust-laden air- stream was directed into a 32.2-liter glass exposure chamber housing the test animals. Desired concentrations were achieved by varying the air flow rates and the gear ratios on the dust feed mechanisms. The test material exposures lasted for one hour each. The packed cylinder, cutting blade, and nozzle were weighed before and after each exposure. The difference in weight represented the amount of material delivered during the exposure. The nominal concentration was determined by dividing the amount of material delivered by the total air flow through the chamber during the exposure. B. Test Animals The test animals used in this experiment consisted of groups of five male and five female Sprague-Dawley rats obtained from Charles River Breeding Laboratories, Wilmington, Massachusetts. Pre-exposure weights ranged from 201 to 299 grams. Observations for abnormal signs were recorded 001732 2- - bio/ / dynami cs Inc. 78-7185 II. EXPERIMENTAL (Cont.) B. Test Animals (cont.) prior to the exposure, at 15-minute intervals during the exposure, upon removal from the exposure chamber, hourly for four hours post-exposure, and daily thereafter for 14 days. Individual body weights were recorded prior to exposure (Day 0), and on Day 1, Day 2, Day 4, Day 7, and Day 14 (terminus). All animals dying spontaneously were necropsied as soon as possible after death. On Day 14, all survivors were sacrificed (ethyl ether) and gross necropsy examinations were performed. Blood samples were collected at terminus on all animals surviving through Day 14 of each group. The blood samples were drawn aortically, pooled by group and by sex and were sent to the sponsor for analysis. C. Control Animals In order to provide control data for this study, a group of five male and five female Sprague-Dawley rats, weighing from 203 to 263 grams were exposed to dry air at a flow rate of 12 liters per minute. All other exposure conditions, observation procedures, necropsy procedures, and blood sampling procedures were performed the same as for the test material exposed animals. D. LC50 Determination The median lethal concentration and 95% confidence limits were calculated according to the method of Litchfield and WilcoxonJ ^Litchfield, J.T., and F. Wilcoxon J_. Pharma. Exp. Therapy 96: 99-115 (1949). 001733 Bio/ 3- / dynami cs Inc. 78-7185 III. RESULTS AND DISCUSSION A. Exposure Concentrations During the test material exposures, totals of 44.13, 23.13, 6.77, 13.38, 2.06, 4.67, 0.0, 1.81 and 4.10 grams of the test material were delivered, yielding equivalent nominal exposure concentrations of 45.97, 24.09, 7.05, 13.9, 2.86, 6.49, 0.0, 1.89 and 4.88 milligrams per liter (Groups I-IX, respectively). A summary of exposure conditions and mortality results is given in Table 1. Results of the Group I exposure (45.97 milligrams per liter) were not easily comparable to the 18.6 milligrams per liter group of Bio/ dynamics project 78-7184. A second exposure (Group II) was performed at approximately 20 milligrams per liter. Group I was terminated on Day 2 to allow for collection of blood samples from survivors (see C. High Level Exposures). Group IV (13.9 milligrams per liter) was also terminated (Day 1) as a result of a cylinder blowout during the exposure. Groups I and IV are not used in calculation of the LC50 value and Group IV results are not discussed in this report. B. Control Exposure No abnormalities were observed in the control animals (Group VII) during the sham exposure or upon removal from the exposure chamber. Dry rales was observed in one of ten animals at three hours post exposure. The most significant observation recorded during the 14-day in life period was dry rales (seven of ten rats) which was scattered in oc currence. Exposure, post-exposure, and in-life physical observations are presented in Tables 7 and 15. Body weights, presented along with necropsy observations in Table 23, are considered normal. The most significant abnormal observation upon necropsy was lung discoloration. 001*734 Bio/ / d y n a m i c s Inc. 78-7185 III. RESULTS AND DISCUSSION (Cont.) C. High Level Exposures During the Group I (45.97 milligrams per liter) exposure, a dense cloud of test material was visible in the exposure chamber making animal observation difficult. Labored breathing and/or gasping followed by closing of the eyes and reduction of activity were observed in all animals. Excessive salivation and lacrimation and mucoid nasal discharge were ob served in some animals. Upon removal from the exposure chamber and during the four hour post-exposure period, red and mucoid nasal discharge, dry rales, and yellow-staining of the ano-genital fur were most frequently observed. These observations are presented in Table 2. By Day 2, three of five males and two of five females had died spontaneously. It was decided to terminate Group I on Day 2 in order to collect blood samples from the surviving animals. Samples are retained by the sponsor. Prior to their termination, survivors exhibited reduced activity, red nasal discharge, excessive lacrimation, yellow staining of the ano-genital fur and general poor condition. A full list of individual physical observations are given in Table 10. Body weights, presented along with necropsy observations in Table 18, were depressed in all animals prior to death. Abnormal necropsy observations were of lung discoloration and liver discoloration. In Group II (24.09 milligrams per liter), there was 100% mortality with the last spontaneous death occurring on Day 6. In-chamber observations were similar to those described for Group I. However, the onset was delayed. Post-exposure observations, also similar to those described for Group I, were mainly of red nasal discharge, dry rales, and yellow staining of the ano-genital fur. These observations are presented i 001 -5- Bio/ / d y n a mi c s Inc. 78-7185 III. RESULTS AND DISCUSSION (Cont.) C. High Level Exposures (cont.) Table 3. Observations recorded during the in-life period, presented in Table 11, were mainly of yellow staining of the ano-genital fur, dried red material around the nose, and general poor condition. Weight loss was steady prior to the death of the animals. Individual body weights are presented along with necropsy observations in Table 19. Abnormal necropsy observations include lung, liver, spleen, and kidney discoloration. D. LC50 Exposures A series of five additional one-hour exposures were used along with the Group II exposure in calculating the LC50 value. In both Groups III and VI (7.05 and 6.49 milligrams per liter, respectively) there was 80% mortality. Observations recorded during each exposure period were similar to those described for the higher level ex posure groups. Observations immediately following the exposures were also similar to those described for the higher level groups but were less severe. These observations are presented in Table 4 (Group III) and Table 6 (Group VI). In both Groups III and VI the last spontaneous deaths occurred on Day 10. Observations of yellow or orange staining of the ano-genital fur, dried red material on the face, and general poor condition were re corded during the in-life periods in both the survivors and those animals dying spontaneously. These observations were more frequent in Group III (7.05 mg/1), the higher level group. Other noteworthy observations recorded during this period were body tremors, convulsions, and breathing described as rapid, labored, or irregular. Other observations recorded during the 001736 -6- bo/ / d y n a mi c s Inc. III. RESULTS AND DISCUSSION (Cont.) D. LC50 Exposures (cont.) in-life periods were scattered in occurrence. 78-7185 Individual physical observations are presented in Table 12 (Group III) and Table 14 (Group VI). All animals dying spontaneously experienced weight losses prior to death. Those animals surviving the 14-day in-life period (62F and 63F Group III, 120F and 122F - Group VI) had not regained their original Day 0 body weight by Day 14. Individual body weights and necropsy observations are presented in Table 20 (Group III) and Table 22 (Group VI). Abnormal necropsy observations for those animals dying spontaneously included lung, liver, and small intestine discoloration and gaseous distention of the small intestines. Surviving animals sacrificed at terminus had lung discoloration (two of four rats) and absence of abdominal body fat (one of four rats). Groups IX, V, and VIII (4.88, 2.86, and 1.89 milligrams per liter, respectively) had 20%, 10%, and 0% mortality, respectively. In chamber observations were again similar to those described for the higher level exposure groups but no mucoid nasal discharge was observed. Observa tions recorded immediately following the exposures were most frequently of excessive salivation, mucoid nasal discharge, and yellow staining of the ano-genital fur. Exposure and post-exposure observations are presented in Table 9 (Group IX), Table 5 (Group V), and Table 8 (Group VIII). Spontaneous deaths occurred on Days 7 and 10 in Group IX and on Day 12 in Group V. In-life observations common to these groups were mucoid nasal discharge, dry rales, and yellow staining of the ano-genital fur. Other noteworthy signs were soft stool, hypersensitivity to touch, 001737 Bio/ ---------------------------------------------------------------------------------=7"=----------------------------------------------------------- / d y n a mi c s Inc. 78-7185 III. RESULTS AND DISCUSSION (Cont.) D. LC50 Exposures (cont.) dried red material on the face, and rapid breathing. Abnormal in-life observations were less frequent in the lower level exposure groups. Individual physical observations are presented in Table 17 (Group IX), Table 13 (Group V) and Table 16 (Group VIII). Animals dying spontaneously in Group IX (170M, 180F) and Group V (103F) lost weight steadily prior to death. Weight gain in the surviving animals was slower than is normally observed. In Group IX one of eight surviving rats did not regain its Day 0 body weight; in Group V four of nine and in Group VIII four of ten. When weight gain was observed in Groups IX and V it usually did not occur before Day 7. In Group VIII weight gain usually did not occur before Day 4. Individual body weights are presented along with necropsy observations in Table 25 (Group IX), Table 21 (Group V) and Table 24 (Group VIII). The most frequent abnormal necropsy observa tion was lung discoloration. E. LC50 Determination According to the method of Litchfield and Wilcoxon, the estimated LC50 value for a one-hour exposure to T-2306 CoC was determined to be 5.2 milligrams per liter with approximate 95% confidence limits of 4.4 milligrams per liter and 6.4 milligrams per liter. 001738 78-7185 IV. CONCLUSION A series of one-hour inhalation exposures to a dust of T-2306 CoC was performed on Sprague-Dawley rats. The nominal exposure concentra tions of Groups II, III, V, VI, VII, VIII and IX were 24.09, 7.05, 2.86, 6.49, 0.0, 1.89 and 4.88 milligrams per liter, respectively. Total mortality was produced at the nominal exposure concentration of 24.09 milli grams per liter. Partial mortality was produced at nominal exposure concen trations of 7.05 (80%), 6.49 (80%), 4.88 (20%) and 2.86 (10%) milligrams per 1iter. Predominate physical abnormalities observed during the exposure and post-exposure periods were labored breathing, reduced activity, exces sive salivation and lacrimation, mucoid and red nasal discharge, yellow staining of the ano-genital fur, dried red material on the facial area, and general poor condition. The most frequent abnormal necropsy observations were of lung and liver discoloration. Lung discoloration was also observed in a high number of control rats and thus may not be treatment-related. The nominally determined median lethal concentration (LC50) for a one-hour exposure to T-2306 CoC was determined to be 5.2 milligrams per liter with approximate 95% confidence limits of 4.4 milligrams per liter and 6.4 milligrams per liter. 001739 -fl* Bio/ / d y n ami cs Inc. 78-7185 A f , ___Gorge Mi' Rusch, Ph.D Directtsrt Inhalation Technology William E. Rinehart, Sc.D. Vice President, Science Report Preparation: Cecelia A. Bozak, B.A. Study Monitor 001740 -10- 78-7185 Table 1 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Summary of Exposure Conditions and Mortality Results Group Date Exposed Nominal Exposure Test Day of Last Concen Material Chamber Length of Spontaneous tration Delivered Flow Rate Exposure Mortality Death mg/1 9 1pm min. I* 1-24-79 45.97 44.13 16 60 5/10 2 II 1-25-79 24.09 23.13 16 60 10/10 6 III 3-1-79 IVb 3-8-79 7.05 13.9 6.77 13.38 16 16 60 60 8/10 0/10 10 - V 3-9-79 2.86 2.06 12 60 1/10 12 VI 3-12-79 6.49 4.67 12 60 8/10 10 VI Ic 3-13-79 0.0 0.0 12 60 0/10 - VIII 3-22-79 1.89 1.81 16 60 0/10 - IX 3-23-79 4.88 4.10 14 60 2/10 10 jJGroup I terminated Day 2, not used in calculation of LCso* "Group IV terminated Day 1, not used in calculation of LC50. cControl group. 001741 -11- 78-7185 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Key to Tables 2-9 aKey: NOA A-G T No Observable Abnormalities Ano-Genital Removal from Chamber 001*742 Table 2 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group I - 45.97 mg/1 Time Interval (min. Into exposure) N0Aa Reduced Activity Eyes Closed Excessive Excessive Labored Lacrimation Salivation Breathing Gasping Mucoid Red Nasal Nasal Discharge Discharge Pretest 5 10 15 30 45 60 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 some some some some some some 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 some some some Yellow A-G Fura 78-7185 TOE3 Material Peri- Ocular Dry Rales Moist Soft Rales Stool Ta PostExposure Period 120 180 240 300 2 of 10 4 of 10 3 of 10 4 of 10 1 of 10 6 of 10 4 of 10 2 of 10 8 of 10 9 of 10 2 of 10 5 of 10 7 of 10 4 of 10 6 of 10 2 of 10 5 of 10 1 of 10 6 of 10 9 of 10 9 of 10 6 of 10 8 of 10 1 of 10 6 of 10 5 of 10 4 of 10 2 of 10 1 of 10 1 of 10 4 of 10 1 of 10 O O h* vj CO Table 3 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat 78-7185 Exposure and Post-Exposure Observations Group II - 24.09 mg/1 T ime Inteval (min. into exposure) N0Aa Mucoid Labored Excessive Excessive Eyes Nasal Reduced Dry Breathing Lacrimati on Salivation Closed Discharge Activity Rales Moist Rales Red Yel1ow Nasal A-G Fura Discharge Pretest 10 of 10 15 most 30 10 of 10 45 10 of 10 60 10 of 10 Ta PostExposure Period most 4 of 10 most some 10 of 10 10 of 10 10 of 10 most 10 of 10 10 of 10 10 of 10 most some 10 of 10 10 of 10 10 of 10 10 of 10 3 of 10 3 of 10 5 of 10 i C1O 120 2 of 10 6 of 10 6 of 10 8 of 10 180 1 of 10 1 of 10 4 of 10 5 of 10 10 of 10 8 of 10 240 1 of 10 1 of 10 3 of 10 2 of 10 10 of 10 8 of 10 300 4 of 10 10 of 10 9 of 10 001744 Table 4 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat 78-7185 Exposure and Post-Exposure Observations Group III - 7.05 mg/1 Time Interval (min. into exposure) NOAa Reduced Activity Eyes Closed Excessive Excessive Lacrimati on Salivation Mucoid Labored Nasal Breathing Discharge Reef Yel1ow Dry Nasal A-G Fura Rales Discharge Pretest 10 of 10 5 15 30 45 60 Ta PostExposure Period 120 180 240 2 of 10 300 5 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 some most 10 of 10 10 of 10 10 of 10 2 of 10 some most 10 of 10 10 of 10 10 of 10 5 of 10 5 of 10 1 of 10 most some some some some 6 of 10 8 of 10 4 of 10 1 of 10 7 of 10 5 of 10 10 of 10 7 of 10 3 of 10 4 of 10 2 of 10 3 of 10 3 of 10 1 of 10 I 4I 001745 Table 5 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group V - 2.86 mg/1 Time Interval (min. Into exposure) N0Aa Reduced Activity Eyes Cl osed Excessive Excessive Lacrimation Salivation Mucoid Labored Nasal Breathing Discharge Yellow A-G Fura Dry Rales Soft Stool Pretest 10 of 10 5 10 15 30 45 60 Ta 1 of 10 Post- Exposure Period 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 1 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 9 of 10 some some some some some 6 of 10 4 of 10 3 of 10 1 of 10 120 3 of 10 180 5 of 10 240 8 of 10 300 5 of 10 2 of 10 1 of 10 1 of 10 2 of 10 1 of 10 3 of 10 5 of 10 1 of 10 2 of 10 1 of 10 1 of 10 1 of 10 2 of 10 2 of 10 78-7185 Brown A-G Fur 1 of 10. O O Table 6 An Acute Inhalation Toxicity Study of T-2306 CoC In the Rat Exposure and Post-Exposure Observations Group VI - 6.49 mg/1 Time Interval (min. Into exposure) NOAa * Reduced Activity Eyes Closed Excessive Excessive Lacrimation Salivation Mucoid Labored Nasal Breathing Di scharge Yellow A-G Fura Pretest 10 of 10 5 15 30 45 60 Ta PostExposure Period 120 min 4 of 10 180 m1n 3 of 10 240 min 3 of 10 300 min 2 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 most 10 of 10 10 of 10 10 of 10 10 of 10 some most most most 4 of 10 2 of 10 3 of 10 most most some some 8 of 10 2 of 10 1 of 10 2 of 10 most most most most some some most most most 1 of 10 2 of 10 5 of 10 7 of 10 6 of 10 3 of 10 2 of 10 1 of 10 Dry Rales 1 of 10 3 of 10 2 of 10 Moist Rales 4 of 10 1 of 10 78-7185 m Nasal Discharge 1 of 10 O <1 17- Table 7 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group VII - 0 mg/1 (Control) Time Interval (min. into exposure) N0Aa Pretest 15 30 45 60 Ta 120 180 240 300 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 9 of 10 10 of 10 Dry Rales 1 of 10 78-7185 001748 Table 8 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat 78-7185 Exposure and Post-Exposure Observations Group VIII - 1.89 mg/1 Time Interval (min. into Exposure) N0Aa Reduced Activity Eyes Closed Excessive Excessive Lacrimation Salivation Mucoi d Labored Nasal Yel1ow Breathing Discharge A-G Fura Dried Red Dry Material Rales on Face Pretest 10 of 10 5 15 30 45 60 Ta PostExposure Peri od 120 1 of 10 180 7 of 10 240 5 of 10 300 6 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 most 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 most 10 of 10 10 of 10 4 of 10 3 of 10 2 of 10 3 of 10 most most 10 10 of 10 10 of 10 10 of 10 8 of 10 9 of 10 1 of 10 I 00 2 of 10 3 of 10 3 of 10 2 of 10 6 of 10 1 of 10 2 of 10 2 of 10 2 of 10 1 of 10 001749 001750 Time Interval (min. into Exposure) N0Aa Reduced Activity Eyes Closed Table 9 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group IX - 4.88 mg/1 Excessive Excessive Lacrimation Salivation Mucoid Labored Nasal Breathing Discharge 78-7185 Yellow A-G Fura Dry Rales Pretest 10 of 10 5 10 15 30 45 60 Ta 1 of 10 PostExposure Period 120 1 of 10 180 4 of 10 240 5 of 10 300 6 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 most 10 of 10 10 of 10 10 of 10 10 of 10 10 of 10 some 10 of 10 most most most 1 of 10 most most most most most most 6 of 10 4 of 10 4 of 10 4 of 10 2 of 10 some most 10 of 10 most most most 3 of 10 4 of 10 4 of 10 3 of 10 2 of 10 8 of 10 3 of 10 1 of 10 2 of 10 2 of 10 1 of 10 t -20- An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Physical Observations Key to Tables 10-17 78-7185 N.O.A. Agr. (+)Act. (-)Act. Exc.Lacr. Exc.Sal. A-G Poor Cond No Observed Abnormalities. Agressive Behavior Increased Activity Reduced Activity Excessive Lacrimati on Excessive Salivation Ano-Genital Poor condition 001751 78-7185 Table 10 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Physical Observations^ Group I - 45.97 mg/1 Behavior Respiration Ocular Appearance Digest Other Dried Red Total Nasal Material Yellow Number An. No. Sex (-) Act. Discharge Rales Exc. Around Red orx Lacr. Nose Eye(s) Stains Poor Soft Body of Days Closed A-G Area Cond. Stool Convulsions Tremors Observed 10 M 11 M 12 M 13 M 14 M 1 1 1 1 1 2 1 11 1 11 0, 21 1 12 1 1 2' 12 20 F 21 F 22 F 23 F 24 F 1 1 1 1 11 11 1 11 1 11 2 11 1 2 11 2 2 1 1 2 1 2 2 1A total of 2 observations were reported during the study. Group was terminated on Day 2. Total number of ab normalities observed may exceed 2 since an animal may have been observed with more than one abnormality during any given observation period. Total number of observations may also be less than 2 due to the spontaneous death of an animal. 001752 78-7185 Table 11 An Acute Inhalation Toxicity Study of T-2306 CoC 1n the Rat Physical Observations^ Group II - 24.09 mg/1 Behavior Respiration Ocular Appearance Digestion Other Loss of Fur Total Nasal Red and/or Brown Stains A-G Area Con- Right- Wet Number An. (-) D1 scharge Rales Labored Exc. Mat'l. Nasal Area Yellow Yellow Poor Exc. vul- 1ng Nasal of Days No. Sex NOA Act. Red Hue Dry Moist Breathing Lacr. Dry Mo1 st Red Orange Yellow Cond. Sal. Ataxia slons Reflex Area Observed 30 N 31 N 32 M 33 N 1 34 M 40 F 41 F 42 F 43 F 44 F 1 1 1 3 2 1 11 11 11 11 1 1 1 2 11 1 11 1 1 12 1 1 21 1 3 3 2 3 11 2 2 1 2 12 3 4 12 1 2 2 11 2 1 11 1 2 3 3 5 4 2 4 12 1 14 1 2 2 3 2 4 3 1 1 115 iTotal number of observations may exceed total number of days observed (usually 14, unless there were spontaneous deaths) since an animal may have ob served with more than one abnormality during an observation period. 001753 An. No. Sex N.O.A. 78-7185 Table 12 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Physical Observations^ Group III - 7.05 mg/1 Nasal Discharge Mucoid Respiration Appearance Dry Red Rales Breathlnc| Material Pllo- Stained A-G Dry Moist Labored Rapid ][rreg. Nasal Area Erectloni Orange Yellow Poor Cond. Digest Soft Convul Stool sions Other Total Number Body of Days Tremors Slezure Observed 50 N 51 H 52 M 53 M 54 M 11 1 1 1 1 3 1 1 1 1 1 60 F 1 1 2 61 F 11 1 2 62 F 3 1 22 63 F 1 1 2 64 F 1 21 1 12 i 43 11 31 1 7 122 2 4 2 91 5 95 12 10 2 1 11 1 13 14 1 1 1 21 3 5 2 3 8 9 10 14 14 8 1Total number of observations may exceed total number of days observed (14, except when there were spontaneous deaths) since an animal may have been observed with more than one abnormality during an observation period. O Q P 78-7185 Table 13 An Acute Inhalation Toxicity Study of T-2306 CoC In the Rat Physical Observations^ Group V - 2.86 mg/1 Behavior An. () No. Sex N.O.A. Agr Act. Respiration Ocul ar Nasal Film Discharge Rales Breathing Exc. Covering Mucoid Dry 1Moist Labored Rapiir Lacr. Eye(s) Appearance Dried Red Yellow Material Sta1ns Poor Nasal Area Hair loss A-G Area Cond. Digestion Other Total Cold Number Soft Exc. Sensitive to: Extre- of Days Stool Sal. Touch Movement mltles Observed 90 M 91 N 92 M 93 M 94 M 100 F 11 8 10 9 5 4 1 1 21 31 31 21 2 12 1 101 F 102 F 12 2 1 6 1 103 F 1 32 2 11 104 F 7 51 1 1 1 1 2 4 2 8-abdomen 5-L.hind leg 1 8 1-B.h1nd 7 legs 2 71 2 2 11 11 1 2 3 11 14 14 14 14 14 14 14 14 14 14 1Total number of observations may exceed total number of days observed since an animal may have been observed with more than one abnormality during an observation period. O O P <1 ic/ni 78-7185 Table 14 An Acute Inhalation Toxicity Stud(y of T-2306 CoC In the Rat Physical Observations^ Group VI - 6.49 mg/1 Behavior Respiration Ocular Appearance 1)1gestion Uther ' Total Nasal Film Dried Red/Brown Stainea A-6 Con- Body Cold Sensitive Number An. (-) Discharge Rales Breathing Covering Exc. Material: Area Poor Exc. Soft vul- Tre- Extre- to: of Days No. Sex N.O.A. Agr Act. Red Hue Dry Labored Rapid Eye(s) Lacr. Nose Mouth Forepaws Orange Yellow Cond. Sal. Stool slons mors miti es Touch Sound Observed 110 N 111 N 112 M 113 M 114 M 1 1 1 1 1 1 1 1 1 1 1 120 F 121 F 122 F 123 F 124 F 2 1 1 62 21 12 1 2 2 11 1/0 1/0 2/0 2/0 0/1 1 2/0 1/0 21 21 1 2 21 1 111 11 1 2 21 2 5 4 4 3 5/0 9/0 7/0 6/0 3/0 1/0 1/0 2/0 2/0 1/0 1/0 3 11 36 11 1 2 3 14 21 1 10 11 3 14 3 23 iTotal number of observations may exceed total number of days observed (usually 14, except when an animal died spontaneously) since an animal may have been observed with more than one abnormality during an observation period. oo p in ft -26- 78-7185 Table 15 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Physical Observations1 Group VII - 0 mg/1 Respiration Appearance Other Total Nasal Dried Material Hyper- Number An. Discharge Rales Around Nose sensitive of Days No. Sex N.O.A. Mucoid Dry Moist Red Brown to Touch Observed 130 M 131 M 132 M 133 M 134 M 8 14 11 12 12 3 12 2 11 2 1 1 14 14 14 14 14 140 F 141 F 142 F 143 F 144 F 12 13 10 14 10 11 3 4 1 1 14 14 14 14 14 !a total of 14 observations were reported during the study. Total number of abnormalities observed may exceed 14 since an animal may have been observed with than one abnormality during any given observation period. 001757 Table 16 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Physical Observations^ Group VIII - 1.89 mg/1 Respiration Appearance Digest Nasal Dried Red Stained A-G An. Di scharge Raies Breathing Material Area Soft Exc. No. Sex N.O.A. Mucoid Dry Moist Rapid Nose Mouth Yellow Brown Stool Sal. 78-7185 Other Sensitive to Touch Total Number of Days Observed 150 M 151 M 152 M 153 M 154 H 160 F 161 F 162 F 163 F 164 F 7 9 8 13 6 1 8 7 8 4 32 21 11 41 47 21 31 4 15 1 1 1 11 1 21 2 4 1 11 5 1 3 2 2 1 2 4 5 1 1 3 14 14 14 14 14 14 14 14 14 14 iTotal number of observations may exceed total number of days observed since an animal may have been observed with more than one abnormality during an observation period. P cn0 00 78-7185 Table 17 Acute Inhalation Toxicity Study of T-2306 CoC In the Rat Physical Observations^ Group IX - 4.88 mg/1 Respiration Appearance Digest Other Dried Red Nasal Material Stained Total Number An. Discharge Rales Breathing Nose/ A-G Area Soft Convul- Body Sensitive Fur Stained of Days No. Sex N.O.A. Mucoid . t o Rapid Labored Mouth Head Halrloss Yellow Orange Stool sions Tremors to Touch Red Observed 170 M 171 M 172 M 173 M 174 M 180 F 181 F 182 F 183 F 184 F 1 5 8 5 4 6 6 7 12 25 2 2 3/0 1 2/1 2 13 2 15 4-B.fore- 1 6 paws 3 11 8 1 2 1 11 2 23 5 5/0 6 3/0 1 1-abdomen 3 3 1 9 5 1 4 6 6 14 14 14 14 9 14 1 14 14 14 ^Total number of observations may exceed total number of days observed (usually 14, except when an animal died spontaneously) s1nee an animal may have been observed with more than one abnormality during an observation period. 001759 JOo 001760 78-7185 Table 18 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group I - 45.97 mg/1* Animal Body Weiihts (g) Number Sex day 0 day 1 Day 2d iJay 4 Day / Day 14 Necropsy Observations 10 M 214 177 11 M 229 198b 12 M 251 203 195b 13 M 240 197 182 14 M 221 171 172 B. lungs mottled pink and dark red. Liver mottled purple and brown. B. lungs mottled dark red, pink, and red. B. lungs mottled pink and dark red. Liver mottled dark purple and brown with brown area (1 cm x 1 cm) on visceral surface of L. lobe. Liver has white areas (approx. 1 cm diameter) on all lobes. B. lungs mottled pink and white. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. aGroup I terminated on Day 2. ^Spontaneous death. KrfIOo 78-7185 Table 18 (cont.) An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group I - 45.97 mg/1* Animal Body Weights fg)---- Number Sex Day 0 T a y T Day 2d Day 4 Day 7 Day 14 Necropsy Observations* 20 F 202 169 162b 21 F 201 172 162 22 F 211 176 167b 23 F 204 180 169 24 F 201 172 164 B. lungs mottled pink and purple. B. lungs mottled white, orange, and pink. B. lungs mottled red and dark red. Liver mottled purple and brown. B. lungs mottled oange and red with white foci. Liver mottled dark red and purple with brown area (1 cm x 4 cm) on visceral surface of medial lobe. B. lungs mottled pink and orange. Entire surface of liver light brown in color. * N.O.A. - No observed abnormalities. Key: R = right; L left; B = bilateral. aGroup I terminated on Day 2. ^Spontaneous death. 001761 U) o ,1 78-7185 Table 19 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group II - 24.09 mg/1 Animal Body Weights (g) Number Sex Day 0 Day 1 Day 2 Day 4 Day 7 30 M 266 221 193a 31 M 243 212 1903 32 M 230 199 1333 33 M 278 148 227 310a 34 M 227 192 175 157a ______________ Necropsy Observations*_______ _________ 8. lungs mottled dark red and red. Liver mottled dark red and tan. Upper half of spleen light red, lower half dark red. Small intestines distended with gas. B. lungs mottled red and dark red. Liver mottled dark brown, black, and purple. B. kidneys mottled brown and purple. Spleen mottled black and purple. Small intestines yellow and pink in color. 8. lungs mottled red and dark red. Liver mottled dark brown, purple, and tan. Small intestines yellow and pink in color. B. lungs mottled orange, red, and dark red. Liver mottled purple, black, and brown on anterior surfaces of all lobes; visceral surfaces mottled tan, red, and brown. Small intestine distended with gas. Absence of abdominal fat around adrenal glands and kidneys. B. lungs mottled orange and red. Liver mottled brown, purple, and black; white area on visceral surfaces of L. lobe (approx. .5 cm x 2 cm), white area on visceral surface of medial lobe (approx. .2 cm x .7 cm). Absei of abdominal fat around adrenal glands and kidneys. 001762 * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. "Spontaneous death. 4 78-7185 Table 19 (cont.) An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group II - 24.09 mg/1 Animal Body Weights (g) Number Sex Day 0 Day 1 Day 2 Day 4 Day 7 Day 14 ______________ Necropsy Observations*_________________ 40 F 210 188 172a 41 F 213 195 187 178a 42 F 217 189 185a 43 F 218 196 181a 44 F 224 199 185 168a B. lungs bright red in color with scattered tan areas; all lobes slightly distended. Liver abnormally dark red in color with tan areas on dorsal surfaces. Up per half of spleen light red in color, lower half dark red. B. lungs bright red in color. Liver mottled purple, brown, and black; brown and tan areas on visceral sur faces of medial and left lobes (approx. .3 cm x 1 cm). Absence of abdominal fat around adrenal glands and kidneys. B. lungs mottled pink, red, and dark red. Liver mottled purple, brown and black. Spleen black and purple in color. B. lungs bright dark red. Liver abnormally dark red- brown in color. Ileum, duodenum, and jejunum dis tended with gas. Half of spleen appears black 1n color. Stomach impacted with food. B. lungs mottled orange, red, and dark red. Liver mottled black, brown, and purple. Small intestines green in color and distended with gas. Absence of abdominal fat covering adrenal glands and kidneys on dorsal body wall. N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. Spontaneous death. 001763 78-7185 Table 20 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group III - 7.05 mg/1 Animal Number 50 51 52 53 54 Body Weights (g) Sex TfaylT1 5 a y T Day 2 Day 4 Day 7 Day 14 Necropsy Observations* M 291 251 245a M 286 249 237 212a M 297 262 248a M 233 263 259a M 265 242 237 231 21la B. lungs mottled orange and red. Liver mottled purple and tan. Small intestines yellow-green in color and distended with gas. Thymus dark red in color. B. lungs orange-red in color Both surfaces of L. lateral lobe of liver mottled. B. lungs mottled dark and light red. Liver mottled dark red and tan. Thoracic cavity contains small amount of fluid. Thymus congested. B. lungs mottled red and dark red. Liver congested. B. lungs mottled red and white. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. ^Spontaneous death. 001764 1 CO CIO 78-7185 Table 20 (cont.) An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group III - 7.05 mg/1 Animal Body Weights (g) Number Sex bay 0 D a y " T Day 2 Day 4 Day 7 D a y IT Necropsy Observations* 60 F 220 189 184 174 1553 B. lungs mottled orange and dark tan with light tan foci on L. lobe. Liver mottled brown and dark brown. Small intestines dark green in color. 61 F 213 186 177 165 152a B. lungs mottled pink and red. Liver has brown and green areas (.5 cm x 1 cm) on visceral surfaces of L. and R. lobes. Small intestines green-yellow in color and distended with gas. Posterior half of L. kidney dark brown in color. Distal (caudal) tip of spleen black in color. Stomach distended with gas. 62 F 229 208 205 190 192 216 N.O.A. 63 F 214 197 189 178 165 148 Absence of abdominal adipose tissue. 64 F 221 206 203 190 173a B. lungs mottled dark red and dark pink. Liver spotted brown and tan with some purple mottling. Intestines yellow in color. * N.O.A. - No observed abnormalities. Key: R * right; L = left; B = bilateral. Spontaneous death. 0 I-* I CO <T,) I 01 78-7185 Table 21 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group V - 2.86 mg/1 Animal Boc[y Weights (g) ~ Number Sex bay 0 bay 1 Day 2 Day 4 Day 7 Day 14 ______________ Necropsy Observations* 90 M 250 233 232 231 253 291 B. lungs have purple foci. 91 M 248 234 230 239 255 302 B. lungs have red foci. 92 M 232 208 193 185 211 252 B. lungs have purple foci. 93 M 225 208 208 221 238 268 N.O.A. 94 M 254 230 218 196 182 242 Red focus on diaphragm surface of L. posterior lobe of left lung. 100 F 213 194 192 190 208 227 N.O.A. 101 F 212 198 195 182 175 211 N.O.A. 102 F 209 197 195 190 189 205 N.O.A. 103 F 210 192 194 172 1673 Anterior and middle lobe of R. lung and anterior half of L. lung mottled tan and purple; posterior and post caval lobe of R. lung and posterior (caudal) half of L. lung bright red in color. Liver has brown area (1 cm x .5 cm) on visceral surface of median lobe. Absence of abdominal body fat covering adrenals and kidneys. 104 F 213 198 193 186 190 204 N.O.A. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. Spontaneous death. 001766 OfJ U1 1 78-7185 Table 22 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group VI - 6.49 mg/1* Animal Body Weights (gj ~~ ~ Number Sex Day 0 Day 1 Day 2 Day 4 Day 7 bay IT ______________ Necropsy Observations 110 M 274 238 223a 111 M 254 220 202 179a 112 M 237 215 202 170a 113 M 234 205 197 168a 114 M 281 254 236a B. lungs mottled orange and dark red. Liver mottled dark red and brown; light brown areas on visceral surface of R. lobe (approx. .2 cm x .5 cm). Small intestines yellow-green in color and distended with gas. Absence of abdominal fat covering kidneys and adrenal glands. B. lungs mottled dark and light red. Jejunum, ileum, and duodenum yellow in color. L. lateral lobe of liver mottled dark red and tan. Liver mottled dark red and light green. B. lungs mottled red, tan, and pink with numerous red foci. Liver motttled brown and tan. Anterior half of stomach cream colored. Absence of abdominal body fat. B. lungs mottled orange and red. Liver mottled dark red and dark brown. Small intestines yellow-green in color and distended with gas. Absence of ab dominal body fat. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. Spontaneous death. oUI>> 1 001767  78-7185 Table 22 (cont.) An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group VI - 6.49 mg/1* Animal body Weights' Number Sex U 5 7 T T W T Day 2 Bay 4 Day 7 " W I T Necropsy Observations* 120 F 214 193 185 176 168 172 B. lungs mottled pink and red. Absence of abdominal fat. 121 F 227 202 192 178 160a B. lungs bright red in color. Liver has alternating patches of brown and dark red. 122 F 220 199 190 176 162 201 B. lungs mottled pink and white. Absence of fat covering adrenals and kidneys. 123 F 218 192 183a B. lungs mottled dark red and orange. Liver mottled dark red and brown. Small intestines yellow-green in color. Absence of abdominal body fat. 124 F 209 182 171a B. lungs mottled orange and red. Liver mottled brown and dark red. Absence of abdominal body fat. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. Spontaneous death. 001768 I CO vj I 78-7185 Table 23 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group VII - 0 mg/1 (control) Animal Body weights (g) Number Sex Day Day 1 Day 2 Day 4 Day 7 Day 14 Necropsy Observations* 130 M 241 238 242 249 257 280 B. lungs mottled pink and grey. 131 M 256 252 268 274 279 311 B. lungs have small grey foci. 132 M 233 238 248 260 249 306 B. lungs mottled light and dark red; nodular green areas on L. lung. 133 M 263 263 274 281 295 329 B. lungs pink with dark red foci. 134 M 218 215 224 231 244 272 B. lungs mottled red and white. 140 F 205 201 208 208 207 220 B. lungs mottled pink and white. 141 F 203 199 204 214 213 214 3. lungs mottled red and pink with red foci. 142 F 216 213 219 215 226 231 B. lungs pink with dark red foci. L. kidney has dilated pelvis. 143 F 208 210 212 213 205 226 N.O.A. 144 F 203 201 204 209 210 219 B. lungs mottled pink and red. * N.O.A. - No observed abnormalities. Key: R = right; L = left; B = bilateral. O O OtJ o 00 1 78-7185 Table 24 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group VIII - 1.89 mg/1 Animal Body Wei <qhts Number Sex Day 0 T J a y T Day 2 I5i *Q<J "WIT Necropsy Observations* 150 M 264 240 226 208 210 265 B. lungs have numerous red and white foci. 151 M 276 253 248 248 264 314 N.O.A. 152 M 299 280 270 279 280 312 B. lungs mottled pink and tan with many dark foci. 153 M 286 264 264 270 289 318 B. lungs mottled tan and pink with numerous red foci; few white foci of L. lobe. 154 M 274 248 242 240 251 293 B. lungs mottled pink and grey. 160 F 215 198 186 175 200 211 B. lungs mottled pink and orange. 161 F 212 191 184 192 189 219 B. lungs mottled pink and red; posterior lobe of R. lung has two large white foci. 162 F 230 202 190 178 196 226 B. lungs mottled pink and orange. 163 F 228 208 204 199 206 224 B. lungs mottled pink and tan with small dark foci. 164 F 204 188 179 169 166 195 B. lungs have numerous white foci. * N.O.A. - No observed abnormalities. Key: R * right; L = left; B = bilateral. 001770 CK1OD i 78-7185 Table 25 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group IX - 4.88 mg/1 7Animal Number Sex Body Weiiahts (9{ Day 0 "Day T bay 1 I)ay 4 Day . Day 14 ______________ Necropsy Observations*_________________ 170 M 228 206 195 171a B. lungs bright red in color. Liver mottled purple and brown. 171 M 255 230 220 194 191 269 B. lungs pink with dark foci. 172 M 257 242 242 240 249 288 B. lungs mottled pink and beige with numerous red foci. 173 M 239 215 204 197 209 264 B. lungs pinkish-red with dark red mottling. 174 M 240 224 220 211 206 246 B. lungs light tan in color with numerous red foci. 180 F 217 193 185 167 1479 B. lungs mottled pink and red. Liver has brown areas on visceral surfaces of R. and L. lobes. L. kidney has brown area (.5 cm diameter) on ventral surface. Small intestines yellow-green 1n color and distended with gas. Absence of abdominal fat pads. 181 F 207 194 196 181 188 215 B. lungs pink with dark red mottling. 182 F 204 189 186 185 174 205 B. lungs mottled pink and white with few red foci. 183 F 213 189 184 169 174 222 B. lungs mottled pink and tan with dark red foci. 184 F 225 195 190 177 b 213 B. lungs mottled light tan and white with few red foci. * N.O.A. - No observed abnormalities. Key: R * right; L = left; B = bilateral. ^Spontaneous death, tylody weight not recorded. 1 01 001771