Document baGBXoXkraEDDDXknXNEV2KyZ

t I I --FORDfU PON'TUSE ON"LY1 AR226-2915 E. I. di| Pont de Nemours and Co., Inc. Has:ell Laboratory for Toxicology and Industrial Medicine Elikton Road, P. 0. Box SO, Newark, Delaware 19714 HASKELL LABORATORY REPORT NO. 143-84 -i SUBCHRONIC INHALATION TOXllciTY 0 3 SUMMARY: G roups of 25 male trl:CD* rats were exposed to 0.62, 2.5 or 10 mg/m o f f f l l l H N l n air. A control group was exposed simultaneously to air only. For^nfrafi per group, exposure was 6 hours/day, 5 days/week for 2 weeks. After the 10th exposure, blojod and urine samples were collected for clinical analysis, and 5 rats per group were sacrificed for pathological examination. Remaining rats were held for114 days post exposure and were given the same clinical and pathological ex|am1nations. The additional 15 rats per group were exposed 6 hours/day for 1, 5'# 6 or 10 exposures. These rats were serially sacrificed throughout the telst to obtain blood and urine samples for total fluoride analysis. ; Nonsignificant effects were observed in rats exposed to either 0.62 or 2.5 mg/m3 throughout the test. . At 10 mg/m3 , three rats died after being exposed to 1-3 exposures. Pathological examination revealed severe pulmonary congestion, edema and hemor rhage. The deaths appear to;be an acute response to the chemical because the rats showed no clinical signs prior to dying, and because the pathologic findings were similar to those found In acute testing. After 10 exposures, one of 5 rats examined pathologically showed microscopic edema, focal hemorrhage, and erythrophagotytosis by alveolar macrophages. Finally, rats exposed to 10 mg/m3 had significantly elevated mean lung weights both after 10 exposures and after 14 days recovery. Except for the deaths and the lung effects, no adverse clinical;signs, body weight, clinical chemical or patho logical effects were obser d. Both 0.62 and 2.5 mg/mJ? are "ng-effectu concentrations under the conditions of this test. A t 10 mg/m , all observed effects were localized in the lungs. No other o u a n ^ r (Jssues appear to be affected by repeated Inhalation exposure t o f m j ^ Company Sanitized. Does noi coniata TSGA.C3I s extremely toxic on an acute Inhalation basis, hal Concentration (ALC) for this material Is 42 The purpose of this study was to lealnhalatlon of sublethal concentrations II. PROCEDURE; A. Animals; Young adult male Crl:CD* rats were received from Charles River"breeding Laboratories, Kingston, New York. Rats were housed singly 1n 5 "xll"x^" suspende steel-mesh cages 1n rooms maintained at 50 +_ 10% relative humidity and 74 + 2F on a 12/12 hour light/ dark cyclei Rats Iwere assigned a unique Identification number which corresponded to a numbered card on the outside of the cage. Except during exposures, Purina Certified Rodent Chow* #5002 and water were availabjle ad libitum. Rats were quarantined for 1 week prior to testing. ;Rats were weighed and observed twice during the quarantine period.; B. Exoosure Protocol:! Groups of 25 rats, 8 weeks old and weighing between'"220-258 grams, were restrained 1n perforated, stainless steel cylinders, teats were exoosedjjose-onbr to design concentra- tlons of 0.50, 2.5, or 10 mg/nT o f f f l H H f e r t l c u l a t e . A control group was exposed simultaneously ttrair oniy: For 10 rats per group, exposure was 6 hours/day, 5 days/week for 2 weeks. Five rats per group were sacrificed after the 10th exposure, while 5 rats per group were alTowed|to recover for 14 days post exposure. Rats were weighed and observed dally throughout the exposure and recovery periods, weekends [Included when deemed necessary by the rats' condition. [ The remaining! 15 rats per group were exposed 6 hours/day for 1, 5, 6 or 10 exposures. These rats were serially sacrificed throughout the exppsure and recovery periods to obtain blood and urine samples for total fluoride analysis. i C. Test Material; Purity: Composition: Contaminants: Synonyms: Other Codes: Submitted by Chemicals A P'gments Dept. Jackson Laboratory - 2 - Company Sanitized, Does no! contain TSCACB| 0. Generation: L I q u I d f l H B r a s pimped Into a Spraying Systems* Nebulizer. A1r Introducenft the nebulizer aerosolized the test material, and swept the aerosol stream through a cyclone. The cy clone removed large particles by Inertial Impaction, while aero dynamic particles passed through the cyclone and Into the exposure chamber. E. Analytical: At 20 to 40 minute Intervals, calibrated volumes of chamber atmosphere were drawn through pre-we1ghed, glass-fiber filters. Filters were weighed on a Cahn* 26 Automatic Electro balance. Atmospheric concentration was determined from the filter weight differential! before and after sampling. Chamber temperatures were monitored with thermometers. Parti cle size (mass median diameter) and percent of respirable particu late were determined with a Sierra* Cascade Impactor. Relative humidity was measured with a Bendix* Model 566 Psychrometer. F. Clinical Measurements: Overnight urine samples were collected from 10 rats per group after the 9th exposure, and from 5 rats per group after the 13th dayjof recovery. Samples were analyzed for volume, osmolality, pH, blood, sugar, protein, bilirubin, urobilinogen, and ketone. Each sampjle was noted for color and transparency, and the sediment from each! sample was examined microscopically. Unused portions of the samples were saved for subsequent fluoride ' analysis. Blood samples;were collected from the jugular vein from 10 rats per group aftpr the 10th exposure, and from 5 rats per group after the 14th day;of recovery. Samples were analyzed for erythro cyte count, hemoglobin concentration, mean corpuscular volume, platelet count, leukocyte count, and relative numbers of neutro phils, band neutrophils, lymphocytes, atypical lymphocytes, eosino phils, monocytes add basophils. Hematocrit, mean corpuscular hemo globin, and mean eorpuseular hemoglobin concentration were calcula ted from the erythrocytic data. Serum activities of alkaline phosphatase and alpnlhe aminotransferase, and serum concentrations of urea nitrogen, Creatinine, total protein and cholesterol were also measured. - G. Pathology: Five rats from each group were sacrificed after the 10th exposure and dfter the 14th day of recovery for gross and histopathologic examination. The heart, nasal cavities, lungs, trachea, liver, pancreas, esophagus, stomach, duodenum, jejunum, Ileum, cecum, colon, kidneys, urinary bladder, sternebrae with bone marrow, spleen, thymus, thymic lymph nodes, mesenteric lymph nodes, thyroid, testes, eplld1dym1des, adrenal glands, parathyroid, brain, and eyes were examined microscopically. I 3" Company Sanitized Does ni contain TSCACBJj H. Oraan and Body Weight Analysis: At each sacrifice, mean organ weights and orgarUto-body weight ratios were calculated for the heart, liver, lungs, kidneys, spleen, thymus and testes. 3 10I. Blood and Urine Fluoride Analysis: Overnight urine s M p l e s collected from to rats per group after the 1st, 5th, 6th, and 9th exposures and 3rd, 6th and 13th days of recovery for analysis of total fluoridj. The following collection scheme was used: o after 1, 5, and 6 exposures and 3 days of recovery 6 rats per group o after 9th!exposure - 10 rats per group o after 6 d*ys recovery - 3 rats per group o after 13 days recovery - 5 rats per group Samples from each group were pooled 1n pairs (except for the odd sample per group ion days 6 and 13 of recovery). Samples collected following 6 exposures and after 3, 6, and 13 days recovery were not analyzed. Vena cava blood samples were collected from 3 to 5 rats per group after the jst, 5th- 6th, and 10th exposures, and after the 3rd, 7th, and 14th days of recovery. Samples were collected from the 5 rats per group sacrificed for -pathologic examination after the 10th exposure and 14th day of recovery, and from 3 rats per group at the remaining intervals. Blood samples were analyzed Individually (samples collected after the 6th exposure and after the 3rd. 7th andi14th days of recovery were not analyzed). Urine and bjood samples were analyzed for total fluoride by combustion In an oxyhydrogen torch. Samples were analyzed by E. Kissa, Chemicals and Pigments Department, Jackson Laboratory. II!. ESULTS Exoosure Data: Wean exposure concentrations were 0.62, 2.5^and l m g / m , compared to design concentrations of 0.50, 2.5 and 10 m g/m , respectively. D*ily concentrations are presented in Table I. Chamber temperatures ranged between 22-27 C. Relative humidity ranaed from 31-61%-* -4 contain T S C A CSf Exposure No. 1 2 3 4 5 6 7 8 9 10 Overall*1 Table 1: Atmospheric Concentrations 3 Design Concentration - 0.50 mg/m Particulate Concentration (mg/m3 )" Mean S.b. Range Xb Resplrable Mass Median Diameter of Respirable Particulate (um) 0.64 0.74 0.46 0.58 0.66 0.54 0.62 0.74 0.64 0.62 0.28 0.43 0.45 0.14 0.34 0.53 0.55 0.32 0.56 0.40 0.62 0.41 0.047-0.97 0.21 -1.7 0.013-1.3 0.30 -0.80 0 -1.3 0.15 -1.6 0.12 -1.9 0.19 -1.1 0.15 -1.5 0.27 -1.5 0 -1.9 91 89 92 1.3 1.4 1.6 Design Concentration 2.5 mg/m 3 Exposure No 1 2 3 4 5 6 7 8 9 10 Overall*1 Particulate Concentration mg/to3 )" Mean S.D. Range 2.6 0.55 1.8 -3.5 2.6 0.69 1.7 -4.3 2.4 1.2 0.19-4.7 2.5 0.71 1.5 -3.8 2.3 0.85 1.3 -3.8 2.2 0.58 1.6 -3.4 2.8 0.67 1.5 -3.9 1.2 0.70 0.38-2.2 3.5 1.4 . 2.5 -7.6 2.9 0.65 . 2.2 -4.6 2.5 0.99 0.19-7.6 Xb Resplrable 93 93 91 Mass Median Di ameter of Respirable Particulate (um) 1.8 1.8 1.6 ^ a r t i c u l a t ^ c o niccfwitratlon represents combined concentrations. jrartlcles with aerodynamic diameter less than 10 um. Calculated for respirable portion of atmosphere, lean and standard deviation of all samples from all exposures. 5 - Company Sanitized. Does not contain TSCAGBi Exposure No. 1 2 3 4 5 6 7 8 9 10 Overall Table 1: Atmospheric Concentrations (cont'd) 3 Design Concentration - 10 mg/m Particulate Coacentration (mg/m3 )5 Mean S.D. Range Respi*rable b Mass Median Diameter PaofrtRiecsuplaitreabl(uern)c 8.9 2.3 8.9 2.0 13 3.2 12 3.1 10 2.0 11 2.4 10 3.3 11 3.0 9.8 2.2 8.5 1.7 6.6 - 14 5.7 - 12 10 - 21 5.8 - 16 8.1 - 14 7.1 - 14 6.4 - 18 7.4 - 17 6.3 - 13 5.8 - 11 91 92 92 2.0 2.1 2.1 10 2.9 5.7 - 21 Particulat^oncentratlor represents combine b C o n c e n t r a t i o n s . I ^ ^ r e r g n ^ o ^ l i r t i c l e s with aerodynamic diameter less than 10 urn. j Calculated for respirable portion of atmosphere. Mean and standard deviation of all samples from all exposures. B. Clinical Signs: Mean body weights for test rats were indistin guishable from controls throughout the test (Figure I, Appendix I). . 3 Except for 1 rat exposed to 2.5 mg/m which had brown disco lored fur and hair loss on the head during the recovery period, clinical signs for rats exposed to 0.62 and 2.5 mg/m were indis tinguishable from controls. 3 At 10 mg/m , 1 rat was found dead the morning after the first exposure, 1 rat died during the 3rd exposure, and 1 rat was found dead the morning after the 3rd exposure. No adverse clinical signs were observed 1n these rats before they died, or in surviving rats at any time. C. Clinical Pathology1 : No treatment-related clinical chemical or hematologic effects were observed at any expc jre oncentration at either sacrifice. - 6 C o ' X M . y S a n m z e d D no*contain T S C A CBf # 3 Rats exposed to 2.5 mg/m shotted a statistically significant increase In erythrocyte count and decrease 1n mean corpuscular hemoglobin after 10 exposures. These changes were not interpreted as being biologically significant or treatment-related because the changes were not dose-related, and were within the range of expected biological variation. ? D. Pathology : No adverse gross or microscopic effects were seen In rats exposed to either 0.62 or 2.5 mg/m at either sacrifice. 3 The 3 rats which died from exposure to 10 mg/m exhibited severe pulmonary congestion, edema and hemorrhage, which appeared to be caused by damage to Type I pneunocytes and endothelial cells in the alveolar capillaries. The lung edema was both intraalveo lar and interstitial, and was especially pronounced in the peri vascular and peribronchial regions. The intraalveolar edema wa characterized by homogeneous eosinophilic proteinic'. *'u1d and fine fibrin. These deaths are considered to be an a u t response to a single exposure, rather than the result of successive exposures, because the pathologic lesions seen are identical to those found during acute studies, and because no changes In any other organs were observed. The 10 mg/nr exposure concentration is considered to be a more "precise" ALC, based on the larger number of animals (25 versus 6 per group) and the longer exposure duration (6- versus 4-hour exposures). One of five rats examined after the 10th exposure showed microscopic edema, focal hemorrhage, and erythrophagocytosis by alveolar macrophages. Phagocytosis is a common clearance mechanism to remove foreign particulates, and erythrophagocytosls 1s phagocy tosis of hemorrhagic materials. The erythrophagocytosls appears to be a recovery mechanism following an acut insult, rather than a response to repeated insult. No other changes were seen in any other rats either after the 10th expos .re or the 14th day of recovery. E. Organ and Body Weight Analysis3 ; No biologically-significant organ weight changes were found in rats exposed to either 0 62 or 2.5 mg/nr at either sacrifice. 3 Rats exposed to 10 mg/m had significant increases in mean lung weights compared to controls after both the 10th exposure and the 14th day of recovery. However, these changes were small, and were not significant on an organ-to-body weight basis. No other organ weight changes were found 1n this group at either sacrifice. 3 After 10 exposures, rats exposed to 0.62 mg/m had signifi cantly decreased mean spleen weight. This change is not considered biologically significant as 1t was not obser. 1 at higher concen trations (Appendices II and III). - 7 - Company Sanitized. Does not contain TSC.CS! F. Blood and Urinary Fluoride Analysis: 1. Data: Mean blood and Ui Inary fluoride concentrations are presented in Tables II and III. Individual sample data are reported 1n Appendix IV. T^ble II: Blood Fluoride Concentrations Exposure Concentration (mg/m3 ) Mean Blood Total Fluoride ConcentratioMi (ug/g)a After 1 After 5 After 10 Exposure Exposures Exposures Control 0.62 2.5 10 0.2 + 0.2 0.2 7 0.3 0.3 + 0.3 0.3 + 0.3 0.2 + 0 b 0.9 + 1.0 0.5 + 0.2. 0.4 7 0.4 0.1 + 0.1 0.3 7 0 0.3 7 0.1 0.4 7 0.1 Mean valueis represent an average of 3 Individual blood b samples, except where Indicated. D Two samples only. Tajble H I ; tiri ne Fluor e Concent'at .n., Exposure Concentration (mg/nrx Mean Urine Total Fluoride Concentrations (ua/a)a " T rier 1---------After"?----- After 9 Exposure Exposures Exposures Control 0.62 2.5 10 0.8 + 0.2 1.0 7 0.5 1.1 7 0.3. 1.3 + 0.2 0.4 + 0.4 0.3 + 0.1 1.9 7 2.9 l.l + 0.4 1.5 + 0.6 1.1 7 0.2 1.5 + 0.4 1.9 + 0.4 a Mean values represent an average of 3 pooled urine samples, b except where indicated, D Two samples only. 4 2. Discussion : No Significant dose-related Increases in blood or urinary f T u o H d e concentrations were observed after l. or 9 or 10 exposures. Further, blood fluoride concentrate id not significantly Increase with an Increasing number of explores. Urinary fluoride concentration after S exposures was lower than concentrations after 1 and 9 exposures. However, concentra tions after t and 9 exposures were similar. Although the decreased concentration after 5 exposures was statistically 8 - Company Sanitized. Does noi contain TSCACBS significant, this change Is Interpreted as being an artifact of analysis because concentrations after 1 and 9 exposures Mere not significantly different, and because no dose-related differences between test and control animals were observed at any time Interval. Because no biologically-slgnlfleant changes In either blood or urinary flourlde concentration were observed either among dose levels within each sampling Interval, or among sampling Intervals, analysis of the remaining samples (collected after the 6th exposure and sfter 3, 6 or 7, and 13 or 14 days post exposure) was deemed unnecessary. IV. CONCLUSION: Repeated exposure to either 0.62 or 2-5 mg/m*234 of particulate caused no adverse effects. At 10 mg/m3 , 3 of 25 ftts died after being exposed to 1-3 exposures. All effects observed at this concentration were localized in the lungs. No signs of systemic toxicity were observed In any grdup under the conditions of this test. Mackey, Joyce L. and Raymond M. Everett, "Clinical Pathology Report No. 1-84", MR-4932-001, H-15.048, February 9, 1984. 2 Lee, K. P. and J. G. Aftosmis, "Pathology Report No. 77-83", MR-4932-001, H-15,048, December 21, 1983. 3 Data were statistically analyzed by a one-w.- analysis of variance. Compa rison of test rats with controls by least significant difference and Dunnett test 1s considered valid only when the ratio of variance (F) Indicates a significant among-to-within croup variation. Significance is judged at the 0.05 probability level. 4: Data were statistically analyzed by a two-way analysis of variance using logrlthmlc values of concentrations. Significance is judged at the 0.05 probability level. -9 Company Sanitized. Does not contain TSCACBf Work and Report by/ (JMbry P. Koechert Technician Supervised by: J e u u A ^ ft K'/> Laura A. Kl rfney Cheml st Study Director: Approved by ft/*- *-* IGerald L. KennedyH; r r Section Supervissor Acute Investigations errtal7 2A Date Issued: June 27, 1984 - iidv Initiated/Comoleted: Number of pages in this repdrt: 19 Manager, Toxicology Division Company Sanitized. Does noi contain TSCACB| - 10 - 3 ?3Qcl/> afl> w(O0 o. k S' i? 5 BODY WEIGHT (GRAMS) ao.oo 360.00 F IGURE I H~15,048 I-- _J?RAT growth 1 1 1 I > 1 T- r I , ,I curve , ) -- I-- I-- I-- p 340.00 320.00 300.00 280.00 260.00 240.00 220.00 C ontrol 0.62 mg/m3 15.00 TEST DAYS * -0 2 .5 mg/m3 A----- A 10 mg/m3 20.00 25.00 30.00 GROUP CONTROL 0.62 MG/N3 2.5 MG/H3 10 M3/M3 ANOVA(l) TREND(2) LSD<3> DUNNETTU) 3ARTLETT<5) INTERVAL Id T 6 $ iiAtf 230. 232. 234 i 235 0.343 0.15$ r*nn 9.4021 0.253 i.X 4* .*xi0*4* . 23^.2 ;.* J 3 2 . 4 22?.4 : :^|35,2 -, 234 .0 ' ;'T- '40.7t .^...(2T*i3,4i.tA.-2V. ,-r... V|30.8 ' 0.198 o.iol: 7.1443 :9.6?3i >;.?2 i." $.127 ^ , 0. On l* 74613 ' '?;0785 &226 4. 236.3 241.6 243.7 241,9 0.309 0.148 9.2146 9.7951 0.422 s. 241,1 241.8 243.2 244.9 0.044 0.414 6.7588 10.65/3 0.7/3 GRGU? 6. CONTROL 0.62 rtS/.13 2.5 H3/H3 15 h3/M3 vNGVAd; iREND(2) LSH3 DLNMETT(4 ? B,AR TL E T T<5> ; 241;> 2 43s.!I 24?. 2 'VI..* 0.16: 8.3891! 1. 207! i 5,.S3:1 3. mi in: 4 u1 0.310 0.431 r.sn/ 11.2113 0.2g5 ?. S'**'>0*5 '268,7 on?? . 0,;:4 .G'i-; JO. SO`'4 A.;-: 10. 11. 272.7 ?72.6 274.3 277,8 0.601 '223 8.7943 : 7005 0.46/ 278,4 277.3 275.7 278.0 0.940 0,84? 9.3964 d .4331 -i ;94 3t--i7'. i'i r e v # $ in fesT.:jpTS- M .:>fj TROUP C ONTROL .62 MG/H3 .5 WS/H2 t1- iO HS/N3 12. , 75.6 : 272.1, 275.5 282.8;- ANnvAm rREWDt 2 > LSD<3> DUMNETT'4> BARTl.E i'T('5/ <273 ; 0159 U .1202 1-1.5305 0.186 :;3 - - Company Sanitized. Does noi contain TSCACSf i fl i. I jir. r f M :L ;.r E MEAN BODY WEIGHTS <115*048 - R06T-EXPOSPE PERIOD GROUP NTERVAL6 IN TEST M $ S 1 6 *. f'V :L 17. CONTROL 0.62 MG/M3 2.5 MG/M3 10 MG/M3 ANQVA(l) T R E N D (2) LSD(l) DUNNEft(4j BARTLETT(5) 2 9 3 18 O'2931 0294. 297. 4 0.221 0.92 13,3655 16.5815 0.40k 298*4 v..: 300*8 290*4 V 302.2 : :|08.8 So1 .2 j3-V>.2 -: a -'0~.. . 0.336 -i:''?. 0.695 0.934 ' '.889 14.*?94 : 16^0582 18.2117 ; i 4 9221 ' . ;0.673 4 M 73 ,,1 IS. 313.4 516.7 106.8 :l2.9 0.536 0.590 13.6466 16.930. 0.867 19. 321.2 113.0 313.8 322.8 0.629 0.980 15.4636 19.1946 0.654 ROUP CONTROL 0.2 MG/.MZ 2.5 NG/M3 10 .18/13 m MOVAI TREND<2 > -5IH3) Z -:-'lETT( 4; BAR:LETT(5) INTERVALS IN TEST flffe: 22 :4o*> <;f:342. > 334335. 23, ---* 'Wl*m 24. U . 347*2 * | M . 8 346.8 , . 31.8 347 ..2 .0,83'* 0.92II 18.398: 23.44M 0.94- 0.867 0.836 19.8060 24.5719 0.782 0^ 917 S.fSi .. C ,*13 25. 360.8 lai.4 3L4.4 759.2 V.379 '.631 20.2392 O.Piv 26. 354.0 364.0 355.3 362.2 0.835 0.691 27.1596 j3.o 948 2.590 4b. :&*> . 4. ah A ^ r f a w W rami r 13 - Company Sanitized. Doesnoicontain TSCACSf ( 1) P VAIUE of f-TST t poo pNE-PACTOR ARALV8EE Of UAftIARCS. <* indicates P valu less then 0. 05) i (2) P VALUE OF TEBT FOR LINEAR TREND OVER GROUPS (* indicates P va lu i le 8t thin 0.05) (3) LEAST SIGNIFICANT DIFFERENCE - Siven a significant Ulpha=0.05) F RATIO* ans U i n * differing bv aur* than the I.RD are i . r l..Jllu w liferent with a false positive (alpha error rate of 6,OS. tthhainn tthheiNDnUnNLNEST?TTs tart i\s tii c,`e8i iiMsnitg nMifdinc a nd tlyi diffferefnt r,oacnthl,e-,.'lon*roanl b*eanno. wxth a variable-wise fa lse e t s i l i v e (alrha) error .Ml* uf 0.05. "LETTS TEST FOR EOUAl VARIANCE P VALUE. + oIGNIFICANTLY DIFFERENT (fj<0.05) frun CONTROL ROUP bv LSD. # oIGNIFICANTLY DIFFERENT <Fk 0.05) fro CONTROL .ROUP te DUNNETT TEST and LSD. 14 - Company Sanitized. Does noi contain YSCA,CSJ GROUP i fAPPIENDIX II r j M MEAN ORGAN WEIGHTS [ P i !H1'Sr048 - AFTER 10 EXPOSURES F NAL UT. HEART LUNG j CONTROL 0.62 MG/M3 2.5 M0/N3 IO MG/M3 26?. 266. 270. < 282. ( 0.) 1.) 0.) 0.) 0.92< 0s|8< 0.1?I< f87( 0.00) 0.44) 0.78) 0.32) 1.23 120 1.23 ( 134( 0.00) 0.61) 0.93) 0.03)i TEST - HOMOGENEITY TEST - TREND BARTLET"3 TEST j TOUP 0. 304 0. 107 0. 581 LIVE os 3 0.425 0*362 SPLEEN 0.041 0.023 0.066 KIDNEY I 1 J\\ ' A1.i CONTROL 8, 76( 0.00 Y 0.48( 0.00) 2.16( 0.00) 0.62 MG/M3 8.70< 0.93) 0.400 0.02)1 2.21 ( 0.73) j ) 2.5 MG/M3 10 MG/H3 ?.42< ?.39( 0.35) 0.245 0.48 ^ O'.494 0.95) 0.74) 2.33C 2.20( 0.26) 0.78) "e s r - h o m o g e n e :n 0 4`>75 - 0.027 TEST - TRENI. 0. 153 : 0.2jS3 BARTLETTS '"EST *30 ;/.:i.#l jRBUP 1 - TESTIS 1 .cL'THYMLS *" *** ---------- -- CONTROL O.o2 M3/M3 ?.5 M0/M3 10 MG/M3 .256( 2.63( ..88: 2.78 < 0.00) 0.62) 0.02) 0.10) 0.(-J-: 0.00) 069< 0.07) 0.54< 0.39) 0.58< o.y-r) VEST - -OMOGENEITV TEST - TRENI PARTLETTS TEST 0.( 8? c.o 38 0.1 41 I .. :. 0.963 0,26? L 0.4f6 0,685 0,607 0.331 ---- 'jj i.+il r/i fi A * "3-4 i vdiues j:. parentheses - P VALUE OF .STUDENT T Ie ST COUPARISON CF TREATHENf HEAR TO CONTROL MEAN. .!0`i-'SEHlTf - ? VALUE 5'ff ? TEST OF rWrlFTHER p MEANS ARE E-2UAL. TREND - P VALLE OF P F3T liF WHETHER-HJ . b 'OSE-RELATEP . CHANGE IN GROUP MfliANS. EAST; E-T3 TEST VALUE OF T E S T O F H G N Q F i v i T i T ijF V A R I A N C E f - SIGKIFCANTUY M -FERNT t - SIGNIFICANTLY DIFFER-NT (F'O.0S> ;P<0.05) FROM FRN CONTROL CNTROL GROUP GROUP By BY LSD l SD AND DUNNETT": TEST 15 Company Sanitised. Does not contain TSCACBI j GROUP __ MEAN O M A N EIGHTS WlS.048 - AFTER 14 AYS RECOVERY FINi L UT. HEART LUNG CONTROL 0.62 HG/M3 2.5 HG/H3 iO MG/H3 354 364. ( 356. ( 362. ( 0.) 0.) W> TEST - HOMOGENEITY TEST - TREND &ARTLETTS TEST GROUP 0.83 5 0 o1 1 0.57 0 ' LIVES 1,14 1 *1 7 1 Itift i.i6< ` .00) 0.55) 0.79) o.ri) 0.940 0.806 0.330 SPLEEN l.46< 134 1.46C 1.61< 0.0<M 0.18) 0.94) 0.01)t 0.035 0.044 0.222 KIDNEY CONTROL 0.42 MG/M3 2.5 HG/M3 10 fil/H3 13.634 14.03C 13.38( 13.741 MO) 0.76) 0.79) 0.46) "!E?T HOMGGEfiEIT f :svr TREND LARTLETT5 TEST 0* 9`9 0.9S 3 0.2;9 GROUP 0.63X 0.65< 0.62( o.?i< 0.00) 0.56) 0.86) 0.08) 0.20? 0.148 *4 THYMUS 2.67 ( 2.86T 2.93( .87 < 0,00) 0.17) 0.06) 0.15) 0,255 0.127 0.817 CONTROL ').2 HO/*13 2,5 MG/M3 :r, K3/M3 3.121 3.10 ( 3.C4t 3. lit 0.00) 9.83) 0.41 > 0.91) 0.63X Oi?Oi 0.5?<: 0.71 ( 0.00) 0.40) 9.66) 0.32) o_ CO tsst - h c .iogE''f :rr ;i-.1 TREND ?AFTI.FTT5 I.T3T 9 :: _IIIiIIIItIIIItIt in C.V>3 0.7'h 0.425 6.578 0 .76 iHAansasattss.ssxs>fieia: VALUE CF STUDENT T TEST COMPARISON Off. T-FMMENT MEAN TO CONTROL MEAN. HOMOGENEITY - P VALUE OF F TigT OF HETHfti GRSUR MEANS ARE EQUAL. o VALUE jF F Si (IF WHETHER THERE 18 DOSE-RELATED THA!Jrj GROUP "E W 8 . '. : TSS* * P '/ALL'* '* Er OF HOMOGENEITY of variance < - SIGNIFICANTLY DIFT.-T :NT >'*.0S- .'frgM CONTROL 3R0UP Si LSD I - SIGNIFICANT!.' DIFFER^ NT <PO.03> FROM CONTROL GROUP BY LSD AND TjL'f.NETT'S ifST - 16 - Sempany Sanitized. Does not contain TSCk CiB >1 r~j4 f. i [ GROUP t APPENDIX III QRGAN-TO-BODV WEIGHT RATIOS 15.048 - AFTER 10 EXPOSURES HEART LUNG LIVER CONTROL 0.62 MG/M3 2.5 M8/M3 10 MG/M3 0.34( 0.33( 0.33( 031 ( 0.00) 0.46) 0.26.) 0.03) TEST - HOMOGENEITY TEST - TREND 3APTLETIS TEST 0.12 6 O.Oi 5 0,5;1 GROUP sPLEEN 0.46< 0.4S( 0.44< 0.4IM 0.00) C.92) 0.34) 0.44) 0.576 0.567 0.570 KIDNEY 3.24( 3.26( 3.38 t 3.39( 0.00) 0.91) 0.41) 0.38) 0. ?17 0.289 0.038 TESTIS CONTROL 0.62 H8/M3 \5 MG/M3 0 MG/M3 0.1S< 0.1$< 0 .1T ( M7< 0.00) 0.02) 0.6?' 0.72) TEST - HOMOGENEITY TEST - TREsT 3ART .ETT3 TEST 0.06 3 o./iS . 0*36 1 HKOUP THYMUS 0.80< 0.831 0.841 0.7fi( 0.00) 0.46) 0.40) 0.52) 0.413 0.565 0.236 093< 0.991 I.04C 0.99( 0.00) 0.47) 0.16) 0.53) 0.544 0.406 0.362 IInirIIti --iiIi*I-- IIIItIIIII1tIIIlIIIII1 CONTROL. .62 MG/P3 2.5 HG/M3 10 HO/13 0.22( 0,26< 0.20< 0,20< 0.60) 0.04)+ 0.21) 0.40) 'EST - KCKCEFNEITY ; r-T - TPEiND U6RTI.ETTS *Zf.r O o 0.06 1 0.57 -= rras:c::s::ss*sss::ssi:e: V^lui'S in -s"b..uhesiis :s:=ccs=asss5 sssassAtt:::.ssss P VALUE OF STUDENT T TEST COMPARISON TREATMENT MEAN TO CONTROL MEAN. HOMOGENEITY - P VALUE OF F tRT OF WHETHER GROUP MEANS ARE EG'JAL. IKCNG - P VALUE OF F TEST OF WHETHER THERE IS DOSE-RFLATED CHANGE TH GROUP-t.EAlls. . :'RTLETTS TJ?T - F' VALUE OF TEST OF HOHCGENEITv OF VARIANCE S5SS- - SIGNIFICANTLY DIFFERS T fp^fi.CS) FROM CONTROL GROUP BY L5T# - SIGNIFICANTLY DIFFEREDT (FIO.OS) FROM CONTROL GROUP BY LSI- AM- DUNNETT'3 TEST - 17 - Company Sanitized. Does no! GROUP 4 ORGAN-TO-BQDY WEIGHT RATIOS 15r040 - AFTER 14 DAYS RECOVERY HEART LUNG LIVER CONTROL 0.62 HC 'Mi ?.*; H3/M3 10 MG/M3 ":.3T HOMOGENEITY r E S ! - rfffcNO P A R 'i.S m TEST G2GJi> 0.32 ( 0.32 0,321 0.32( 0.00) 0.97) 0.92) 3.87'. 0.9? 0.9 0.59' FLESH 0.41 ( 0.421 0.44 { 0.45 ( 0.00) 0.70) 0.87) 0,13) 0.319 0.1*8 0.9S KIDNEY 3.841 3.83C 3.761 3.79( 0.00) 0.94) 0.70) 0.82) 0.965 0.721 0.509 TESTIS CONTROL 0.42 MG-'M3 2.5 iMG/M.r 10 MG/.M3 ' "-SY - riCMwGENI.'ITY T"eT - TREND (.RTLTTG TES T 3P0UP 0.13; 0.18 o.ir( 0.20; 0.00) 0.83) 0.75) 0.12/ 0.257 0.13)7 V 11? 7 1YMUS CPNTfii 0-=2 .TC/M3 '<> MC/M3 1/M3 C -18 0. j91 0.J71 0.20-, 0.00) 0.49) 0.435 0.36) 'EST - '-C/"?ru;Tr 'S'- - TR.'.T 3A.( l'T .; I,-.'. 0.181 7.411 35) 0*764 0.78< 0.82< 0,79 9.00) 0.56) o .n ) 0.63) 0.5:00 0.30 0.219 0 89 ( 0.35( 0.861 0.861 0.00) 0.43) 0.47) 0.54) 0.343 0.56S 0.089 1 'i r & r CMG CF NE m " r VrtL!j P Ja l u OF STUDENT T R&T ..2Mf r s h " F TREATMENT MEAN:T0 C # a O-. i e a n , Kr 7)S|T. WHETHER I roi e ^ = FRE EGL A L . 'r-'P - ? VAil; CF r TEST Cf WhTKER T*SR t$, Stfl-R?' rei? -`^ E IN 3RSUP - 2 TEST h y;*.-jE o/ O ' C y n T t V # VARIANCE . cirir^VVTL DirrREf,F i?<0.05) FROM CONTROL GROUP BY LSD l' S E H ' S TrS fIr" RN * LSD AND 1S - TSCA.CB1 BLOO m Table 1 - Blood mMitm PllBHd ni6itrat1on ( u f l M