Document RMvBKqazd05pBJKv0r7X3B6V

Bio/dynamics Inc. Divisionof Biology and Safety Evaluation PROJECT NO. 78-7185 AN ACUTE INHALATION TOXICITY STUDY OF T-2306 CoC IN THE RAT Submittedto: 3M Company Attention: Dr. William C. McCormick Date: December 31, 1979 Bi '/dN-nan-iies Inc. 78-7185 GENERAL A seriesof one-hourinhalatioenxposureswas performedon rats to determinethe medianlethalconcentratio(nLC50)of T-2306CoC dust. The test material,a finewhitepowder,receivedfromthe 3M Companywas labeled"3MCompany;T-2306CoC". Thesestudieswere initiatedon January 24, 1979and completedon April6, 1979. ii. EXPERIMENTAL A. TestMaterialDelivery For eachexposure,the test materialwas sievedthrougha 60- mesh sieveand packedintothe large-diametecrylinderof a Wrightdust-feed mechanism.Dry air,at flow ratesrangingfrom12 to 16 litersper minute, was passedthroughthe dust-feedmechanism.The resultantdust-ladenairstreamwas directedintoa 32.2-literglassexposurechamberhousingthe test animals. Desiredconcentrationwsere achievedby varyingthe air flow ratesand the gearratioson the dust feedmechanisms.The test material exposureslastedfor one hour each. The packedcylinder,cuttingblade,and nozzlewere weighed beforeand aftereach exposure.The differencein weightrepresentetdhe amountof materialdeliveredduringthe exposure.The nominalconcentration was determinedby dividingthe amountof materialdeliveredby the totalair flow throughthe chamberduringthe exposure. B. TestAnimals The testanimalsusedin thisexperimentconsistedof groupsof five maleand five femaleSprague-DawleryatsobtainedfromCharlesRiver BreedingLaboratoriesW,ilmington,Massachusetts.Pre-exposurweeights rangedfrom 201 to 299 grams. Observationfsor abnormalsignswere recorded -2- 0 /dynarnies 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 thereafterfor 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 spontaneouslywere necropsied as soon as possible after death. On Day 14, all survivorswere 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 providecontrol 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 Wilcoxon.1 ILitchfield,J.T., and F. Wilcoxon J. Pharma. fH. Therapy L6: 99-115 (1949). Bi '/d,.%@namics Inc. 78-7185 III. RESULTS AND DISCUSSION A. Exposure Concentrations During the test materialexposures,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 materialwere delivered,yielding equivalentnominal exposureconcentrationsof 45.97, 24.09,7.05, 13.9, 2.86, 6.49, 0.0, 1.89 and 4.88 milligramsper liter (GroupsI-IX, respectively). A summaryof exposureconditionsand mortality resultsis given in Table 1. Results of the Group I exposure(45.97milligramsper liter) were not easily comparableto the 18.6 milligramsper liter group of Bio/ dynamics project78-7184. A second exposure (Group II) was performed at approximately20 milligramsper liter. Group I was terminatedon Day 2 to allow for collectionof blood samplesfrom survivors(see C. High Level Exposures). Group IV (13.9milligramsper liter)was also terminated (Day 1) as a result of a cylinderblowoutduringthe exposure. Groups I and IV are not used in calculationof the LC50 value and Group IV results are not discussedin this report. B. Control Exposure No abnormalitieswere observed in the control animals (GroupVII) during the sham exposure or upon removal from the exposure chamber. Dry rales was observed in one of ten animals at three hours postexposure. The most significantobservationrecordedduringthe 14-day inlife periodwas dry rales (sevenof ten rats)which was scatteredin occurrence. Exposure, post-exposure,and in-lifephysicalobservationsare presentedin Tables 7 and 15. Body weights, presentedalong with necropsy observationsin Table 23, are considerednormal. The most significant abnormal obse@vation upon necropsy was lung discoloration. B0 /d,.%,namics Inc. 78-7185 III. RESULTS AND DISCUSSION (Cont.) C. High Level Exposures During the Group 1 (45.97milligramsper liter) exposure,a dense cloud of test material was visible in the exposurechamber making animal observationdifficult. Laboredbreathingand/or gaspingfollowedby closingof the eyes and reductionof activitywere observed in all animals. Excessive salivationand lacrimation and mucoid nasal dischargewere observed in some animals. Upon removal from the exposure chamber and during the four hour post-exposureperiod,red and mucoid nasal discharge,dry rales, and yellow-stainingof the ano-genitalfur were most frequently observed. These observationsare presented in Table 2. By Day 2, three of five males and two of five females had died spontaneously. It was decided to terminateGroup I on Day 2 in order to collect blood samplesfrom the survivinganimals. Samples are retainedby the sponsor. Prior to their termination,survivorsexhibitedreduced activity,red nasal discharge,excessivelacrimation,yellow stainingof the ano-genitalfur and generalpoor condition. A full list of individual physicalobservationsare given in Table 10. Body weights, presentedalong with necropsyobservationsin Table 18, were depressedin all animals prior to death. Abnormal necropsy observationswere of lung discolorationand liver discoloration. In Group 11 (24-09milligramsper liter),there was 100% mortalitywith the last spontaneousdeath occurringon Day 6. In-chamber observationswere similar to those describedfor Group I. However,the onset was delayed. Post-exposureobservations,also similarto those describedfor Group I, were mainly of red nasal discharge,dry rales, and yellow stainingof the ano-genitalfur. These observationsare presentedin -5- B0 1 /d-.-namics Inc. 78-7185 III. RESULTS AND DISCUSSION (Cont.) C. High Level Exposures(cont.) Table 3. Observationsrecordedduring the in-lifeperiod,presentedin Table 11, were mainly of yellow stainingof the ano-genitalfur, dried red materialaround the nose, and general poor condition. Weight loss was steady priorto the death of the animals. Individualbody weights are presentedalong with necropsy observationsin Table 19. Abnormal 'necropsy observationsincludelung, liver, spleen,and kidneydiscoloration. D. LC50 Exposures A series of five additionalone-hourexposures were used along with the Group II exposure in calculatingthe LC50 value. In both Groups III and VI (7.05and 6.49 milligramsper liter, respectively)there was 80% mortality. Observationsrecordedduring each exposure periodwere similarto those describedfor the higher level exposure groups. Observationsimmediatelyfollowingthe exposureswere also similarto those describedfor the higher level groups but were less severe. These observationsare presentedin Table 4 (GroupIII) and Table 6 (GroupVI). In both Groups III and VI the last spontaneousdeaths occurred on Day 10. Observationsof yellow or orange stainingof the ano-genital fur, dried red materialon the face, and generalpoor conditionwere recorded duringthe in-lifeperiods in both the survivorsand those animals dying spontaneously. These observationswere more frequent in Group III (7.05 mg/1), the higher level group. Other noteworthyobservationsrecorded during this period were body tremors, convulsions,and breathing described as rapid, labored,or irregular. Other observationsrecordedduring the -6- 0 331 /d.%*namics Inc. III. RESULTS AND DISCUSSION (Cont.) 78-7185 D. LC50 Exposures (cont.) in-lifeperiodswere scattered in occurrence. Individualphysicalobservationsare presentedin Table 12 (Group111) and Table 14 (GroupVI). All animals dying spontaneouslyexperiencedweight losses prior to death. Those animalssurvivingthe 14-day in-lifeperiod (62F and 63F - Group 111, 120F and 122F - Group VI) had not regainedtheir originalDay 0 body weight by Day 14. Individualbody weightsand necropsyobservations are presentedin Table 20 (Group III) and Table 22 (GroupVI). Abnormal necropsy observationsfor those animals dying spontaneouslyincluded lung, liver, and small intestinediscolorationand gaseousdistentionof the small intestines. Survivinganimals sacrificedat terminushad lung discoloration (two of four rats) and absenceof abdominalbody fat (one of four rats). Groups IX, V, and VIII (4.88,2.86, and 1.89 milligramsper liter,respectively)had 20%, 10%, and 0% mortality,respectively. In- chamber observationswere again similarto those described for the higher level exposure groups but no mucoid nasal dischargewas observed. Observa- tions recorded immediatelyfollowing the exposureswere most frequentlyof excessivesalivation,mucoid nasal discharge,and yellow stainingof the ano-genitalfur. Exposure and post-exposureobservationsare presented in Table 9 (GroupIX), Table 5 (GroupV), and Table 8 (GroupVIII). Spontaneous deaths occurred on Days 7 and 10 in Group IX and on Day 12 in Group V. In-life observationscommon to these groups were mucoid nasal discharge,dry rales, and yellow stainingof the ano-genital fur. Other noteworthysigns were soft stool,hypersensitivittyo touch, B0 /dvnamics 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 observationsare 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 survivingrats 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 observation 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 approximate95% confidence limits of 4.4 milligramsper liter and 6.4 milligramsper liter. B0 /d.%'namics Inc. 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 milligramsper 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%) milligramsper liter. 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-genitalfur, dried red material on the facial area, and general poor condition. The most frequent abnormal necropsy observations were of lung and liver discoloration. Lung discolorationwas 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 milligramsper liter. B"/dN-namics Inc. 78-7185 G6orge W Rusch- Ph.D Direc , Inhal;tion Technology @er WilliamE. Rinehart,Sc.D. Vice President,Science Report Preparation: Cecelia A. Bozak, B.A. Study Monitor -10- 78-7185 Tabl e 1 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Summary of Exposure Conditions and Mortality Results Group Ja Date Exposed 1-24-79 Nominal Exposure Test Day of Last Concen- Material Chamber Length of Spontaneous tration DeliveredFlow Rate Exposure Mortality Death mg/l 9 lpm min. 45.97 44.13 16 60 5/10 2 11 1-25-79 24.09 23.13 16 60 111 3-1-79 7.05 6.77 16 60 IVb 3-8-79 13.9 13.38 16 60 10/10 6 8/10 10 0/10 - v 3-9-79 2.86 2.06 12 60 vi 3-12-79 6.49 4.67 12 60 VIIC 3-13-79 0.0 0.0 12 60 VIII 3-22-79 1.89 1.81 16 60 1/10 12 8/10 10 0/10 - 0/10 - ix 3-23-79 4.88 4.10 14 60 2/10 10 agroup I terminatedDay 2, not used in calculationof LC50bgroup IV terminatedDay 1, not used in calculationof LC50- CControl group. 78-7185 An Acute Inhalation Toxicity Study of T-2306 CoC in the Rat Expo sure and Post-Exposure Observations Key to Tables 2-9 akey: HOA A-G T No Observable Abnormalities Ano-Genital Removal from Chamber Table 2 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group I - 45.97 mgll Time Interval -HOAA (min.Into exposure) Reduced Eyes Activity Closed Excessive Excessive Labored Lacrimation Salivation Breathing Gaspi Mucoid Red Ma Nasal Nasal Yellow p Discharge Discharge A-G Fura oc Pretest 10 of 10 5 10 10 of 10 is 10 of 10 10 of 10 ome 30 10 of 10 10 of 10 some 45 10 of 10 10 of 10 60 10 of 10 10 of 10 some some some sofne 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 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 o 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 1 o 6 of 10 8 of 10 Table 3 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Time Inteval NoAa T m7 n-. into exposure) Exposure and Post-Exposure Observations Group 11 - 24-09 nmll Mucoid Labored Excessive Excessive Eyes Nasal Reduced I)ry BreathingLacrimationSalivation Closed Discharge Activity Rales Pretest 10 of 10 15 most 30 10 of 10 45 10 of 10 60 10 of 10 Ta Post- Exposure Period 120 180 240 300 most 4 of 10 2 of 10 1 of 10 1 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 6 of 10 1 of 10 1 of 10 6 of 10 4 of 10 3 of 10 4 of 10 Table 4 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Time Interval NOAA Tm7n.- into exposure) Reduced Eyes Activity Closed Exposure and Post-Exposure Observations Group III - 7.05 mg/l Mucoid Excessive Excessive Labored Nasal Lacrimation Salivation Breathi_ng Discharge Yellow A-G Fur Pretest 10 of 10 5 15 30 45 60 Ta Post- Exposure 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 1 of 10 7 of 10 5 of 10 10 of 10 7 of 10 3 of 1( 4 of 1( 78-7 Table 5 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group V - 2.86 mgll Mucoid Time Reduced Eyes Excessive Excessive Labored Nasal Yellow Dry Soft Bro Interval MDAA Activity Closed Lacrimation Salivation Breathing Discharge A-G Fura Rales Stool A-G Tm7n.- into exposure) Pretest 10 of 10 5 10 of 10 10 of 10 10 10 of 10 10 of 10 10 of 10 10 of 10 some is 10 of 10 10 of 10 10 of 10 10 of 10 some 30 10 of 10 10 of 10 10 of 10 10 of 10 some 45 10 of 10 10 of 10 10 of 10 10 of 10 some 60 10 of 10 10 of 10 10 of 10 10 of 10 some Ta I of 10 1 of 10 9 of 10 Post- Exposure Period 120 3 of 10 180 5 of 10 240 8 of 10 300 5 of 10 2 of 10 1 Of 10 6 of 10 4 of 10 3 of 10 1 of 10 1 of 10 5 of 10 2 of 10 1 of 10 2 of 10 1 of 10 1 of 10 1 of 10 1 of 10 1 3 of 10 2 of 10 2 of 10 78 Table 6 An Acute InhalationToxicityStudy of T-2306 CoC In the Rat Exposure and Post-ExposureObservations Group Vt - 6.49 mg/l Time Interval__!RAa TmTn.into exposure) Reduced Eyes Activity Closed -MUCOT@F Excessive Excessive Labored liasal LacrimationSalivation BreathingR!lEh!M Yellow Dry A-G Fura -Rales 14oist Ma Rales Dis Pretest10 of 10 5 10 of 10 most some 10 of 10 10 of 10 most is 10 of 10 10 of 10 most most some most some most most 30 45 10 of 10 10 of 10 most some some most most MDST most 60Ta 10 of 10 10 of 10 M4DSoT f 10 8 of 10 1 of 10 1 of 10 4 of 10 Post- Exposure Period 120 min 180 min 240 min 300 min 4 of 10 3 of 10 3 of 10 2 of 10 2 of 10 3 of 10 2 of 10 1 of 10 2 of 10 2 of 10 3 of 10 3 of 10 1 of 10 1 5 of 10 7 of 10 6 of 10 2 of 10 1 of 10 2 of 10 -17- 78-7185 Table 7 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group VI 1 0 mg/l (Control) Time Interval NOAA Tm'ln. into exposure) 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 Table 8 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group VIII - 1.89 mg/l Time Interval NOAA Tm-Fn.into Exposure) Reduced Eyes Activity Closed Mucoid Excessive Excessive l.abored Nasal Yell Lacrimation Salivation Breathing Discharge A-G F Pretest 10 of 10 5 15 30 45 60 Ta Post- Exposure Period 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 inost 10 10 of 10 10 of 10 10 of 10 8 of 10 9 of 3 of 10 6 of 2 of 10 3 of 10 2 of 10 Time Interval NOAA Tm-Fn.into Exposure) Reduced Eyes Activity Closed Table 9 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Exposure and Post-Exposure Observations Group IX - 4.88 mg/l Mucoid Excessive Excessive Labored flasal Yell Lacrimation Salivation Breathing Discharge A-G Pretest 10 of 10 5 10 15 30 45 60 Ta I of 10 Post- Exposure 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 3 of 10 8 ol 2 of 10 3 of 1 oi 2 ol -20- 78-7185 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Physical Observations Key to Tables 10-17 N.O.A. - Agr. m i+@Act. - Act. - Exc.Lacr. - Exc.Sal. - A-G - Poor Cond. - No Observed Abnomalities. Agressive Behavior IncreasedActivity Reduced Activity Excessive Lacrimation Excessive Salivation Ano-Genital Poor condition Table 10 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Physical Observationsl Group I - 45.97 mg/l Behavior Respiration Ocular T-pearance Ur-ied Red Ri2est An. No. Sex Act. Nasal Material Yellow Discharge Rales Exc. Around Eye(s) Stains Poor Soft Red Lacr. Nose Closed A-G Area Cond. Stool Con 10 m I I 11 m 12 M 1 1 13 M 2 14 M I I 1 1 2 1 1 20 F I 21 F I 22 F I 23 F I 24 F I 1 1 1 1 2 1 1 I 2 1 2 2 1 1A total of 2 observationswere reported during the study. Group was terminatedon Day 2. norinalitiesobserved may exceed 2 since an animal may have been observed with more than one given observationperiod. Total numberof observationsmay also be less than 2 due to the an animal. Table 11 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Physical Observationsl Group 11 - 24.09 mg/l Behavior Respirati-o-n- Ocular lfppearance -.Uiqestion An. Act. No. sex N-OA Nasal Discharge Red Muc Red and/or Rrown Stains A-G Area Rales Labored Exc. Nat'l. Nasal Area Yellow Yellow Moist Breathing Lacr. ga Moist Red Oranqe Yellow rour Cond. Exc. Sal. Atax 30 N 31 N 32 M 33 N 1 1 34 N 1 40 F 41 F 42 F 43 F 44 F 3 2 1 1 1 1 2 11 1 1 1 1 1 1 2 2 1 1 3 3 2 3 1 1 2 2 1 2 1 1 2 2 3 2 1 4 1 1 1 2 2 2 1 4 2 1 2 2 1 1 4 3 ITotal number of observatii)nsmay exceed total number of days observed (usually 14, unless there were spontaneous deaths) served with more than one abnormality during an observationperiod. Table 12 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Physical Observationsl Group III - 7.05 mgll Resp-rrylon Nasal An. Discharae Rales Breathin No. Sex N.O.A. Red Muc-olu &--W--riT- Appearance Uigest Red Material Pilo- Stained A-G Poor Soft ConvulNasal Area Erection Orange Yel]oW Cond. Stool sions T so 51 N 52 M 53 H 54 M 60 F 61 F 62 F 3 63 F 64 F 1 1 1 1 I1 1 1 3 I 1 1 2 1 2 2 2 1 2 2 1 1 2 1 4 3 3 1 7 1 2 2 4 2 9 1 5 9 5 1 10 2 11 1 1 14 1 1 2 1 ITotal number of observations may exceed total number of days observed (14, exceptwhen there were spontaneousdeaths) sin observed with more than one abnormality during an observation period. Behavior @Nasal An. Discharge .No. Sex N.O.A.Mr Act. -Mcoid Table 13 An kute InhalationToxicityStudy of T-2306 CoC In the Rat Physical Observationsl Group V - 2.86 mgll Respiration Rales Breathing na ored R-A-n= Ocular Filg- Exc. Covering 'Lacr. Eye(s) AppeiFance Red Teiiow Material Stains Poor Nasal Area Hair loss A-G Area Cond. Digestion_ Soft Exc. Stool Sal. 90 11 1 91 m 8 92 N 10 1 21 31 93 N 9 3 1 94 H 5 2 1 1 100 F 4 2 12 101 F 12 1 102 F 2 6 1 103 F - 1 3 2 2 1 1 1 104 F 7 51 1 1 1 2 4 2 8-abdomen S-L.hind leg 1 8 I-B.hind 7 legs 2 7 1 2 2 11 11 1 2 ltotalnumber of observations may exceed total number of days observed since an animal may have been observed with more tha observation period. Table 14 An kute InhalationToxicityStudY of T-2306 CoC in the Rat An. No. Sex N 0 A PhysicalObservationsl Group VI - 6.49 ng/l Ber Respiration ocular --- Tp-pearance Dried Red/Brown 5tained A-G Nasal Discharae Rales Breathin @lymovering Exc. Material: Area k t !e-d-tu-c ed Ra!id Eye(sj-Lacr.Rose Mouth Forepaws llr-aF-en, OTg-estion Con- B Poor Exc. Soft vul- T Cond. Sal. Stool sions m 110 m ill N 1 112 N 113 N 1 114 " 1 1 1 1 1 120 F 121 F 122 F 2 1 123 F 1 124 F 6 2 2 12 1 2 2 1 1 1/0 1/0 2/0 2/0 0/1 1 2/0 1/0 5/0 9/0 1/0 7/0 6/0 1/0 3/0 1/0 1/0 2/0 2/0 2 2 1 1 2 3 11 3 6 11 1 2 1 21 21 21 2 1 2 ltotalnumberof observationsmay exceed total mm6er of days observed(usually14, except vhen an animal died spontaneously) observedwith more than one abnormalityduringan observationperiod. -26- 78-7185 Table 15 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Physical Observationsl Group VII - 0 mg/l Respiri-tion @ar@ance Other Tot-a7-- Nasal Dried material Hyper- Number An. Discharge Rales Around Nose sensitive of Days No. Sex N.U.A. Mucold Dry Moist Red Brown to Touch Observed 130 M 8 3 2 131 M 14 132 M 11 1 2 133 M 12 2 134 M 12 1 1 1 1 14 14 14 14 14 140 F 12 1 1 14 141 F 13 14 142 F 10 3 1 14 143 F 14 14 144 F 10 4 14 1A total of 14 observationswere reportedduring the study. Total number of abnormalitiesobserved may exceed 14 since an animal may have been observed with than one abnormalityduring any given observationperiod. Table 16 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Physical Observationsl Group VIII - 1.89 mg/l Respirati6-n Appearance Digest ut --Was-aT- Dried Red Stained A-G An. f)iseliargeRales Breathing Material Area Soft Exc. Sensil No. Sex N.0.A. Yu-co-i'TT-r@f@i s@t Nose Mouth Yellow BrEw-nStool Sal. To 150 M 7 151 m 9 152 14 113 153 M 13 154 M 6 3 2 2 1 1 41 1 1 1 1 1 160 F 1 4 7 2 1 5 161 F 8 2 .1 2 162 F 7 31 4 1 163 F 8 4 1 164 F 4 1 5 1 1 ltotalnumber of observationsmay exceed total number of days observed since an animal mai with more than one abnonnalityduring an observationperiod. 78- Table 17 Acute InhalationToxicity Study of T-2306 CoC in the Rat Physical Observationsl Group IX - 4.88 mg/l 'Resi)iration Appearance Digest Uther Wrl-e@iRed An. 4-o. lex Nasal Material Stained Discharge Rales Breathing %-s-er- A-G Area H.O.A. Mucold -Try- T-TU-C-LFo-r-eUMouth Hea4 Hairloss le@ow @nLe Soft stool Convul- Body SensitiveFur Stal sions Tremors to Touch Red 170 N 1 171 m 5 172 M 173 N 8 174 M 5 1 2 2 5 2 2 3/0 1 211 4-B.fore- 1 2 1 3 2 1 5 6 paws 3 1 1 8 180 F 181 F 4 182 F 6 183 F 6 184 F 7 1 2 1 1 1 2 2 3 5 3 5/0 6 1 3/0 1 I-abdomen 3 9 5 1 1 4 6 ltotalnumber of observations may exceed total number of days observed (usually 14, except when an animal died spontaneous animal may have been observed with more than one abnonnalityduring an observation period. Table 18 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group 1 45.97 mg/l Animal Body Weights (g) Number Sex py u pM I Ra ed uay 4 uay uay 10 N 214 177 170b 11 m 229 198b 12 m 251 203 195b 13 m 240 197 182 14 m 221 171 172 Necropsy Obse B. lungs mottled pink and d purple and brown. B. lungs mottled dark red, B. lungs mottled pink and d dark purple and brown with on visceralsurfaceof L. Liver has white areas (appr lobes. B. lungs mttled pink and W N.O.A. No observed abnormalities. Key: R right;L = left;B = bilateral. agroup I terminatedon Day 2. bspontaneous death. Wn-Fmal Number Sex 20 F 21 F 22 F 23 F 24 F Table 18 (cont.) An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group 1 45.97 mgll Body- Wei u 1-@-T p.@.yZd uay 4 uay 7 202 169 162b 201 172 162 211 176 167b 204 180 169 201 172 164 Necropsy Obser B. lungs mottled pink and pu B. lungs mottled white, oran B. lungs mottled red and dar purple and brown. B. lungs mottled oange and r Liver mottled dark red and area (I cm x 4 cm) on visce medial lobe. B. lungs mottled pink and or liverlightbrown in color. N.O.A. No observed abnormalities. Key: R right;L - left;B = bilateral. agroup I terminatedon Day 2. bspontaneous death. Animal Number Sex 30 m 31 Ni 32 m 33 m 34 m Table 19 An Acute InhalationToxicity Study of T-2306 CoC in the Rat ln(iividualBody Weights and Necropsy Observations Group Il 24.09 mg/l Body Weights Cg) 0 DR I Day 2 Day 4 Day D 266 221 193a 243 212 Igoa 230 199 1,1)3a 278 148 227 310a 227 192 175 157a Necropsy Obser B. lungs mottled dark red an dark red and tan. I)pperhal lower half dark red. Small with gas. B. lungs mottled red and dar dark brown, black, and purp brown and purple. Spleen Small intestinesyellow and 13.lungs mottled red and dar dark brown, purple, and tan yellow and pink in color. B. lungs mottled orange, red mottled purple, black, and of all lobes; visceralsurf brown. Small intestinedis of abdominal fat around adr B. lungs mottled orange and purple, and black; white ar L. lobe (approx..5 cm x 2 surface of medial lobe (app of abdominal fat around adr N.O.A. No observed abnormalities. Key: R right;L = left;B = bilateral. bspontancous death. Table 19 (cont.) An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group 11 24.09 mg/l Animal Number Sex py 0 Body Weights (g) I Day 2 Day 4 Uay U 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 Necropsl Observ B. lungs bright red in color all lobes slightlydistended red in color with tan areas per half of spleen light red dark red. B. lungs bright red in color. brown, and black; brown and faces of medial and left lob Absence of abdominal fat aro kidneys. B. lungs mottled pink, red, purple, brown and black. Sl in color. B. lungs bright dark red. Li brown in color. Ileum, duo( tended with gas. Half of sl color. Stomach Impacted wil 8. lungs mottled orange, red mottled black, brown, and p green in color and distende abdominal fat covering adre dorsal body wall. N.O.A. No observed abnormalities. Key: R right;L = left;B = bilateral. bspontaneous death. Table 20 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group III - 7.05 mg/l Animal Number Sex p2L U Bory Weights (g) 1, Day Z Uay 4 uay D 50 m 291 251 245a 51 m 286 249 237 212a 52 m 297 262 248a 53 m 288 263 259a 54 m 265 242 237 231 2]la Necropsy Obser B. lungs mottled orange and and tan. Small intestines distended with gas. Thymus dark red in color. 9 Both surfaces of L. lateral B. lungs mottled dark and li dark red and tan. Thoracic amount of fluid T',iyinucsongested: B. lungs red. Liver congested. B. lungs mottled red and whi N.O.A. No observed abnormalities. Key: R right;L = left;B bilateral. bspontaneous death. Table 20 (cont.) An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group 111 7.05 mg/l Animal Number Sex PM U Body Weights (g) 1. Day Z Uay 4 uay / U 60 F 220 189 184 174 155a 61 F 213 186 177 165 152a 62 F 229 208 205 190 192 216 63 F 214 197 189 178 165 148 64 F 221 206 203 190 173a Necropsy Obse B. lungs mottled orange and foci on L. lobe. Livermot Small intestinesdark green B. lungs mottled pink and re green areas (.5 cm x 1 cm) and R. lobes. Small intest and distendedwith gas. Po dark brown in color. Dista black in color. Stomachdi N.O.A. Absence of abdominal adipose B. lungs mottleddark red an brown and tan with some pur yellow in color. N.O.A. No observed abnormalities. Key: R right;L n left;B = bilateral. aspontaneous death. Table 21 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group V 2.86 mg/l Knimal Body Weights (g) Number Sex PM 0 P-@l Dal 2 Day 4 uay 7 90 m 250 233 232 231 253 291 91 m 248 234 230 239 255 302 92 m 232 208 193 185 211 252 93 *4 225 208 2.1)3 221 238 268 94 m 254 230 218 196 182 242 Necropsy Observat 0. lungs have purplefoci. B. lungs have red foci. B. lungs have purple foci. N.O.A. Red focus on diaphragm surface 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 167a Anterior and middle lobe of R. of L. lung mottled tan and puy caval lobe of R. lung and posi L. lung bright red in color. (I ciixi .5 c!,no)n visceralsu Absence of abdominal body fat kidneys. 104 F 213 198 193 186 190 204 N.O.A. N.O.A. No observed abnorinalities. '(ey:R right;L = left;B = bilateral. aspontaneous death. Table 22 An Acute InhalationToxicity Study of T-2306 CoC in the Rat indivi-dualBody Weights and Necropsy Observations Group VI 6.49 mg/l Animal Body WeigfitsC-g) Number Sex PU 0 Di-y 1. Day 2 Day Day I 110 m 274 238 223a III m 112 m 113 m 254 220 202 179a 237 215 202 170a 234 205 197 168a 114 m 281 254 236a Necropsy Observ B. lungs mttled orange and ( dark red and brown; light b surfaceof R. lobe (approx. intestinesyellow-greenin ( gas. Absence of abdominal adrenal glands. B. lungs mottleddark and li and duodenum yellow in colo liver mottleddark red and Liver mottled dark red and 1 B. lungs mottled red, tan, a foci. Liver motttledbrown half of stomach cream color body fat. B. lungs mottled orange and red and da@k brown. Small in color and distendedwith d(xninalbody fat. H.O.A. No observed abnormalities. Key: R right;L - left;B = bilateral. aspontaneous death. Animal Number Sex 120 F 121 F 122 F 123 F 124 F Table 22 (cont.) An Acute InhalationToxicityStudy of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group VI 6.49 mg/l Body Weights (g) 0 Day I Day Z uay 4 b-@7 Dal Necropsy Observa 214 193 185 176 168 172 B. lungs mottled pink and red. fat. 227 202 192 178 160a B. lungs bright red in color. patches of brown and dark red 220 199 190 176 162 201 B. lungs mottled pink and whit covering adrenals and kidneys 218 192 183a B. lungs mottled dark red and dark red and brown. Small in in color. Absence of abdomin 209 182 171a B. lungs mottled orange and re and dark red. Absence of abd N.O.A. No observed abnormalities. Key: R right;L c left;B = bilateral. aspontaneous death. 78 Table 23 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights atid'4ecrol)sOybservations Group VII - 0 mg/l (control) Animal - gddy Weights (g) Number Sex Day 0 Uay I Day 2 Day_4 Ual ir-.LT-T- Necropsy Observation 130 m 241 238 242 249 257 290 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 re 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 B. lungs mottled red and pink with 142 F 216 213 219 215 226 231 13.luiijpsink -iiitdlairk red foci. L. kidney has dilated pelvis. 143 F 208 210 21 ? 21:1 211!i @)?(i 144 F 203 201 204 209 210 219 B. lungs mttled pink and red. N.O.A. No observed abnor:nalities. Key: R right;L = left;8 = bilateral. Table 24 An Acute InhalationToxicityStudy of T-2306 CoC in the Rat IndividualBody Weights and Necropsy Observations Group VIII - 1.89 mg/l Animal Body Weights (g) Number Sex P2L U Py I Day Z Day 4 Day_l D Necropsy Observ 150 m 264 240 226 208 210 265 B. lungs have numerous red an 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 153 m 286 264 264 270 289 318 B. lungs mottled tan and pink few white foci of L. lobe. 154 m 274 248 242 240 251 293 B. lungs mottled pink and gre@ 160 F 215 198 186 175 200 211 B. lungs mottled pink and ora 161 F 212 191 184 192 189 219 B. lungs mottled pink and red lung has two large white foc 162 F 230 202 190 178 196 226 B. lungs mottled pink and ora 163 F 228 208 204 199 206 224 B. lungs mottled pink and tan 164 F 204 188 179 169 166 195 B. lungs have numerous white N.O.A. No observed abnormalities. Key: R right;L - left;8 - bilateral. Kn-tmal Number Sex PR U 170 m 228 171 m 255 172 m 257 173 m 239 174 m 240 180 F 217 181 F 207 182 F 204 183 F 213 184 F 225 Table 25 An Acute InhalationToxicity Study of T-2306 CoC in the Rat Individual Body Weights and Necropsy Observations Group IX - 4.88 mg/l Body Weiihis@@g) 1. Day z Day 4 uay_7 Day 14 Necropsy Observ 206 195 171a B. lungs brightred in color. and brown. 230 220 194 191 269 B. lungs pink with dark foci. 242 242 240 249 288 B. lungs mottled pink and bei 215 204 197 209 264 B. lungs pinkish-redwith da 224 220 211 206 246 B. lungslighttan in color 193 185 167 147a B. lungs mottled pink and re on visceralsurfacesof R. has brown area (.5 cm diame Small intestinesyellow-gr with gas. Absence of abdom 194 196 181 188 215 B. lungs pink with dark red 189 186 185 174 205 B. lungs mottled pink and wh 189 184 169 174 222 B. lungs mottled pink and ta 195 190 177 b 213 B. lungsmottled lighttan a N.O.A. No observed abnormalities. Key: R right;L - left;B - bilateral. bspontaneous death. bbody weight not recorded.