Document qk17mQ15zzwg87oOGEap5ZbBq

f Division of Biology and Safety Evaluation PROJECT NO. 81-2571 EMBRYOFETAL TOXICITY AND TERATOGENICITY STUDY 0F| [BY INHALATION IN THE RAT Final Report Submitted to: E. I. DuPont DeNemours Wilmington, Delaware 19898 Attention: Dr. H.M. Solomon Date: December 31, 1981 ffompafty Sanitized. Does not contain T S C A CBf Bio/aynamics Inc. PROJECT NO. 81-2571 EMBRYOFETAL TOXICITY AND TERATOGENICITY STUDY OF^PERFLUOROBUTYLETHENE (PFBE)Jb Y INHALATION IN THE RAT ABSTRACT This pilot study was conducted for E.I. DuPont , to "evaluate the embryotoxlc and/or teratogenic potential r H i t f | i n the pregnant rat. Mated CD female rats (seven females/group) were ^exposed by chamber Inhalation t o M i f a t dose levels of 1,000 and 70,000 ppm. Animals were exposed for six hours/day during the Day 6-15 gestation interval. Included in the study was a sham-air, chamber-exposed control group (seven mated females). All females were sacrificed on Day 21 of gestation and fetuses recovered at this time were weighed, sexed and evaluated for external, soft tissue and/or skeletal malformations. Fetuses processed for skeletal evaluation were also examined for the presence of ossification variations. No maternal mortality was encounte ed during the study and all females, control and treated groups were pregnant. No treatment-related effect was evident 1n body weight or food con sumption data for the low-dose group. At the high-dose level, mean body weight gain for the Day 6-16 gestation Interval (exposure period) was significantly lower than control. Mean food consumption data for the high-dose group was lower than control for the exposure (Day 6-16) and post-exposure (Day 16-21) Intervals; however, only during the exposure period was the difference from control data statistically significant. No adverse maternal effects were seen 1n physical 1n-life examination data liver weight data or gross postmortem examination data. Likewise, corpora lutea and uterine Implantation data, fetal weight and sexlng data and ossifica tion variation data did not appear to be adversely affected by treatment. . No increase in malformation rate was seen 1n the treated groups during the fetal external or skeletal evaluations. During the soft tissue evaluations, a slight increase 1n the Incidence of fetuses with malformations was seen only 1n the low-dose group. The most co,.mon observation noted during this evaluation Involved distention and/or tortuous condition of the ureter. Similar type observations were seen 1n the concurrent control group with a lower Incidence, and are noted frequently in our historical data for this strain of rat. In that a similar response was not noted at the higher exposure level, no treatment-related effect was indicai d. Company Sanitized. Does not contain T S C A C0 P.O.Box *3 East M illstone, New Jersey 08873 (201)873-2550 Telex: 844597 Cable: BIO/DYN S3 M i^o '/dj i i a i n i r I. i n 81-2571 TABLE OF CONTENTS I. INTRODUCTION....................................................... 1 II. MATERIALS.......................................................... 1 A. Test Substance.......................................... ..... 1 B. Test Animais..................... 1 III. METHODS A. Husbandry........... ................................. B. Mating...................... .................... C. Assignment to Groups............... .................. D. Identification of Animals............................ E. Experimental Outline..... ............................. F. Test SubsMnce Administration........................ 2 3 '3 3 *3 IV. EVALUATIONS A. In-Life................................................. B. Postmortem.................. ......................... 1. Sacrifice Method and Maternal Postmortem Procedure 2. Examination of the Reproductive System........... 3. Examination of Fetuses............ '.............. C. Statistical Evaluations................................ 4 4 4 5 5 6 V. RESULTS AND DISCUSSION A. Maternal Data........................ ......................... 7 1. Mortality Rate............... ............................. 7 2. Pregnancy Rates..... ..................................... 7 3. Body Weight Data..... .................................... 7 4. Food Consumption Data........................... ......... 8 5. Physical In-L1fe Observation Data........................ 9 6. Reproduction Data --Corpora Lutea and Uterine Implantation Data....................... ............... 9 7. Liver Weight Data........................ 11 8. Gross Postmortem Observations.......... 11 B. Fetal Data..................... ....................... ....... 11 1. Fetal Body Weight and Sex Distribution Data.............. 11 2. Fetal External Examination Data.......................... 13 3. Fetal Soft Tissue Examination Data............ 13 i 4. Ossification Variation Data...... ............ 15 5. Fetal Skeletal Examination Data...... ................... 16 iI Company Sanitized. Does not contain TSCACB1 ynainice Inc -81-22571 TABLE OF CONTENTS (CONT.) TABLES 1. Mean Maternal Body Weight Data - Gestation.................. 2. Mean Food Consumption Data.... .............................. 3. Corpora Lutea and Uterine Implantation Data....... .......... 4. Liver Weight Data........... ................................ 5. Mean Fetal Body Weights and Fetal Sex Distribution Data..... 6. Fetal Soft Tissue Evaluation - Summary of Malformation Data.......................................... 7. Fetal Skeletal Examination - Summary of Malformation Data.... 7 8 10 11 12 14 16 APPENDICES A. Statistical Analysis....................... ................. B. Individual Female Body Weight and Body Weight Change Data - Gestation...... ............................................ C. Individual Female Reproduction Data.............. .......... D. Individual Female Liver Weight Data......................... E. Individual Female Food Consumption Data.................... F. Adult Gross Postmortem Observations.... ......... ......... . G. Summary of Fetal External Examination Data................. H. Fetal Soft Tissue Examination Data.......................... I. Fetal Skeletal Examination Data............................ J. Fetal Ossification Variation Data Summarized.............. . K. Inhalation Report............................... K~' L. Personnel...................................................... L-l M. Quality Assurance Statement.................................... M-l Company Sanitized. Does not contain TSCA CBI -1- 81-25ttmn//d y li a iti Iob I n c . Revised: ^ X SetI* --- I. INTRODUCTION: Date: '/n't- This pilot study, conducted for E.I. DuPont DeNemours and Company, was designed to determine the teratogenic potential and/or degree of embryotoxi- city the pregnant rat. Test material was admini stered by chamber Inhalation to mated rats (seven females/group) at dose levels of 1,000 end 70,000 ppm. Included in the study was a chambered, sham-air control group. Species and strain of test animal, dose levels and route of test substance administration were established by the sponsor. Testing was conducted at Bio/dynamics, Inc., MettlerS Road, East Millstone, New Jersey 08873. Raw data to include fetal specimens were sent to sponsor for storage. II. MATERIALS: A. Test Substance: Suppl ier: Lot No.: E. I. DuPont DeNemours Wilmington, Delaware 19898 Haskell I14JP0 Description: Date Received: Amount Rece'" ed : Stoage: B. Test Animals: Species: Strain : Supplier: Colorless liquid 6 July 1981 Container #1: 24.900 kg Container #2: 26.475 kg Container #3:.26.650 kg Container #4: 26.500 kg Room Temperature Rat (albino) Crl:CD (SO) BR Charles River Breeding Laboratories Inc. Wilmington, Massachusetts Comity Ter a n q B. Test Animals (cont.): Justification for Animal Selection: Number of Animals Purchased: Placed on Test: Date Received: Age at Initiation of Hat ing: METHODS: A. Husbandry: Housing: Food: Water: Environmental Conditions: Generally recognized laboratory animal. This strain of albino rat was selected because this rat was used 1n recent acute and subacute testing. 5? females 21 females 30 July 1980 (56 days of .ge) Females - 69 days of age Males from an 1n-house mating colony of the same strain of rat were used 'or breeding purposes only. Females were housed individually (except during overnight mating inter vals) 1n stainless steel, suspended cages with wire mesh floors. Certified Purina Rodent Chow #5002 - available ad libitum during the non-exposure**Tnterval s . Tap water (Elizabethtown Water Company) available via automatic watering system ad libitum during the non-exposure Tntervals. During the exposure Intervals, animals did not have access to either food or water. Temperature: 70 - 78F Humidity: 4 2 - 7 0 % Photo period: 12 hours light/dark cycle. Company Sanatesi.BatsnM soniateTSCAcai -- 2S71 I l i o/c/ly n a jn i fj f e l u e . B * nightly 1n a 1:1fe,raetfiioe.d foVargimnaatlin9smweearrse wPelraecedtakweinthemaarllve <rnatsthe morning and females were considered mated 1f sperm w e J o b s e r l l d microscopically in the vaginal rinse. The day evidence of matiio was observed was designated Day 1 of gestatiori. 9 Dates of Mating: 11 August to 15 August 1981, C * t0 E rUpS: Females wh1ch mated "*re assigned to groups weights? * * W y "S t0 most nearly e<1ualize the Day 1 body * f Af ijna]s ,: Each mated female was identified with a metal eartag bearing 1t s animal number. The Individual animal identification nuBmib'e'rd^foapr,1ecaschPrfoejmeaclte.number comprised a unique E. Experimental Outline: . Group No. Test Substance3 I Sham-air cB?1- . -- " III Dose Level TppST No. of Females Mated -acrificed Day 21 of Gestation 0 (Chamber Control) 7 7 1,000 70,000 7 7 7 7 Treatment Scheduleb - n o t a t i o n Days) 6-15 6-15 6-15 F. Test Substance Administration: Route: Chamber Inhalation Treatment Schedule: Chamber Operation and Atmospheric Monitoring: Mated females were exposed daily, 6 hours/day from Day 6 to Day 15 of gestation, a 10-day treatment period. See Appendix K. CompanySanaTM. Dora TOtwnfcflnTSC/lcsi -=mz BT-7S71 Min/d> nu/nl<"> Jin- IV EVALUATIONS: A. In-life: Gross Physical Observations: Detailed Physical Examinations: Body Weights: Twice dally (morning; afternoon) females were evaluated for obvious signs of pharmacologic or toxicologic effects and mortality. Each female was given a detailed physi cal examination on Days 1, <5, 9 12. 15, 18 and 21 of gestation. During the treatment period, these examinations were performed In the afternoon following exposure. Females were weighed on Days 1, 6, 9, 13, 16 and 21 of gestation. Food Consumption: Food consumption was recorded during I the exposure (Days 6-9, 9-13 and 13-16) and post-exposure (Days 16-21) periods.' Food spillage was weighed and recorded during the same Intervals that feeder jars were weighed. B. Postmortem: 1. Sacrifice Method and Maternal Postmortem Procedure: All females were sacrificed with an overdose of carbon dioxide on Day 21 of gestation. The abdominal and thoracic cavities were opened and each female was given a gross postmortem examination. The uterus was then removed Intact (to Include the ovaries) from the abdominal cavity and weighed. Likewise, the liver was dissected free and weighed for each female. Maternal Identifications were coded at time of sacrifice. Maternal sacrifices and subsequent fetal evaluations were performed blind in respect to dose group. h t was intended that food consumption be recorded during the pre-exposure interval (Days 1-3, 3-6 of gestation); however, due to technical error, these data w not recorded for either the control or treated groups. I -5- 8T-2571"iyd> i i u i n i c s I n i B. Postmortem (cont.): 2. Examination of the Reproductive System: Ovaries - each ovary was dissected free of the uterus, cleaned of connective tissues and evaluated for the presence and number of corpora lutea. Uterus - the number and relative location of the following were recorded for each uterine horn: Live fetuses Dead fetuses (dead fetus with no v I s i M e degeneration) . Late resorptions (recognizable dead fetus undergoing degeneration regardless of size) Larly resorptions (evidence of implantation but no recognizable fetus) ' Implantation sites (represents the sum total of fetuses [live and dead] and resorption sites [early and late]). Once fetuses have been removed from uterus and all implantation sites Identified, the placental/extra-embryonic tissues were removed and the uterus re-weighed (empty weight). Dates of Maternal Day 21 Sacrifices: 1 September to 4 September 1981 3. Fxami nation of Fetuses: Upon removal from the uterus, each fetus was given a gross exter nal examination for malformations, weighed, sexed and tagged for future identification. Fetal Soft Tissue Examination: Approximately one-half of the fetuses 1n each litter were valua- ted for soft tissue malformations by the Staples microdissection technique.2 Staples, R.E. (1974). Detection of Visceral Alteration 1n Mansnalian Fetuses. Teratology. 9:A37 (abstract). _ c mpanysanifoed. D es notconfa(n T8C 4 CBl -i - 6- 81-267fi|</d,vnu inlCK I n r . B. Postmortem (cont.): 3. Examination of Fetuses (cont.): Fetuses so processed were decapitated and heads fixed in Bouins solution to be processed by a razor blade slicing technique (Wilson3). At completion of the soft tissue evaluation, the decapitated, eviscerated fetal specimens were processed for staining of the skeletal structures using an Alizarian Red S staining procedure.4 stained fetal specimens were subsequently evaluated under a dissecting microscope for malformations and ossification variations. Fetal Skeletal Examinations: The remaining fetuses in each litter were eviscerated (external sexing data confirmed by internal inspection of the gonads) and processed for staining cf the skeletal structures using an Alizarian Red S staining procedure.* Stained fetal specimens were evaluated under a dissecting microscope for skeletal malformations and ossification variations. C. Statistical Evaluations: Data were compared between the control and each treated group. Statistical evaluations used for this study are discussed in Appendix A. ^Teratology, J.G. Wilson and J. Warkany, eds. (The University of Chicago Press, 1965) pp. 267-277. 4D.D. Crary, Stain Technology, 37 (1962) pp. 124-125. - Company Sanitized. Does not contain TSCA CBI v. RESULTS AND DISCUSSION: A. Maternal Data: 1. Mortality Rate: TOrt " t y occurred In the control or treated groups. 2. Pregnancy Rates: Pregnancy rates ere 101 1n eacl the control and treated groups, All females (control and treated groups) ere pregnant. 3. Body Weight Data: Nean maternal body eights and eight gain data for the control and treated groups are presented in Table 1. These data are summarized from data for Individual females presented In Appendix B. 1-0 Actual Cprr.a I 201 224 235 256 275 337 ( 0) 23 ".on) m 230 239 257 275 338 26 Mean 6-16 16-21 Actual Corr.a 51 VCMO 45 63 3 Corr.a 50 47 (" ,000)206 234* 237 253 270 338 29 36** 68 6 42 Coii!rr c | r i e c t e d X " 2frb ^ y rm f g h t S"f1nSf'DavS? r h I d 5 inti i*0 -0 5 ! **P<0.01. uterine eight empty uterine e?ght" 7 7 "e , 9 M * 3rs,lli Hean body eight data er* generally comparable betmeen the control and each treated group throughout gestation: hoe.er, on Day 6 of gestation, mean body eight for the high-dose group .as significantly higher than control Company Sanitized. Does not contain TSCA CBI -8- nJcb I 3. Body Weight Data (cont.): Hean body weight gain during the several gestation Intervals were considered comparable between the control and low-dose group. In the high-dose group, mean weight gains were comparable to control during the pre-exposure (Days 1-6) and post-exposure Intervals (Days 16-21 using actual and corrected Oay 21 weight data). During the exposure Interval (Days 6-16), mean weight gain for the high-dose group was significantly lower than control, hean weight gain for the high-dose group during the Day 6-21 Inter,.1 (,,sing corrected hay 21 weight data) was also lower than control; however, this difference from control was not statistically significant. 4. Food Consumption Data: Mean food consumption data for the exposure and post-exposure gesta tion intervals are presented in Table 2. These data are summarized from Indi vidual female data in Appendix E. Group TppnJ I (0) II (1,000) III (70,000) Table 2 - Mean Food Consumption Data Mean Food ConsumDtlon (gram/animal/dav} Uys <LJi -- rrm-- 21.6 25.6 20.4 24.8 18.7** 23.0 **p<0.r0 l T fr0m the COnt 31 9r0UP stat1st1ca" y significant: Company Sanitized. Does not contain TSCACBi Si- Mi -257I f * n a i n i c t , Inc. 4. Food Consumption Data (cont.): Mean food consumption data during the exposure period (Days 6-16) and post-exposure period (Days 16-21) were considered comparable between the control and low-dose group. In the high-dose group, mean food consumption during the exposure interval (Day 6-16) was significantly lowar than control values. During the Day 16-21 interval, mean food consumption for the high-dose group was lower than control; however, this difference was not statistically significant. 5. Physical In-I1fe Observation Data: A similarity was seen between the control and treated groups 1n the types and incidences of observations noted during the detailed physical in-life evaluations. No treatment-related effect was evident. 6. Reproduction Data - Corpora Ltea and Uterine Implantation Data: Corpora ltea and uterine Implantation data for the control and treated groups are presented in Table 3. These data are summarized from indi vidual female data in Appendix C. The mean numbers of corpora ltea, Implantations and fetuses (live and dead) were comparable between the control and each treated group. Likewise, the mean percentage of resorptions to Implants and the mean percentage of resorptions plus dead fetuses to implants were comparable between these same groups. - - The one dead fetus seen during the study was recovered from the litter of low-dose female No. 2579. No treatment-related effect was evident 1n corpora ltea or uterine implantation data. Company Sanitized. Does not contain TSGA C8$ =rtr- liaitjir.'ta Iiir . 31^2571' Table 3 - Corpora Lutea and Uterine Implantation Data Parameter: No. Pregnant Females: Mean No./Pregnant Female Corpora lutea: Implantations: Resorptions Total No .: Mean/pregnant female: Mean X of Implants: No. of dams with 100% resorptions: Live Fetuses Total No.: Mean/pregnant female: Dead Fetuses Total No.: Mean/pregnant female: Mean % fetal deaths per Implant: Mean X resorption and fetal deaths/implant: (i) 7 14.9 13.3 2 0.3 2.0 0 91 13.0 0 0.0 0.0 2.0 Group (ppm) II (1,000) 7 13.0 12.7 5 0.7 5.7 0 83 11.9 1 0.1 1.0 6.7 hi W.OOO) 7 15.0 12.6 3 0.4 3.2 0 85 12.1 0 0.0 0.0 3.2 No statistically significant differences from the control group. Company Sanitized. Does not contain TSCACBS 44 h i #/ -- 2571 /t*'V,ul,l<'K Jn< - 7. Liver Weight Data: Mean liver weight data (absolute and relative to Day 21 corrected body weights) are summarized in Table 4. Liver weight data for individual females are presented in Appendix D. Table 4 - Liver Weight Data Group (ppm) I (0) II (1,000) m (70,000) Mean Liver Weight (grams) 14.6 14.0 14.9 Mean L1v.-r/Body Weight Ratio8 (x 100) 5.34 5.06 5.38 No statistically significant differences from the control group. aUsing the corrected Day 21 body weights. . Mean liver weights, both absolute and relative to Day 21 corrected body weights, were comparable between the control and treated groups. 8. Gross Postmortem Observations: Observations noted during the gross postmortem evaluations of females sacrificed on Day 21 of gestation, are presented 1n Appendix F. No treatment-related effect was evident from these evaluations. B. Fetal Data: 1. Fetal Body Weight and Sex Distribution Data: Mean fetal body weight and fetal sex distribution data are presented in Table 5. These data are presented for Individual Utters 1n Appendix C. Company Sanitized. Does no! contain TSCACSS Table 5 - Mean Fetal Body Weights and Fetal Sex D istrib u tio n Data Group Tppn) I (0) lie (1,000) III (70,000) Mean Fetal Weight _____ grains) 3.49 3.65 3.57 Sex Distribution3 .1 No. ` Ratio 40/51 0.8 46/37 1.2 48/37 1.3 Percent Male Fetuses 44.0 55.4 56.5 arStffai iSi iCa1]yu SJ9nrf1cant differ`ices from the control group. jTotal Number of Male Fetuses/Total Number of Female Fetuses. "Data not analyzed statistically. Excludes data for the one dead fetus recovered In this group. Mean fetal weight data were considered comparable between the control and treated groups. No stunted fetuses5 were recovered in either the control or treated groups. Likewise, no fetuses were calculated as being stunted6 In respects to littermates 1n these same groups. Fetal sex distribution data revealed a preponderance of males 1n each of the treated groups with an Increase 1n number of females 1n the control group. The differences In sex distribution are attributed to normal biological variability noted with this parameter and the relatively small group sizes Involved. No treatment-related effect was evident In fetal body weight or fetal sexing data. - Sstunted fetuses - fetuses that weigh 1 gram or less. Calculated stunted fetus (see Appendix A: page A-5). Company Sanitized. Does not contain TSCA CB| -1 3 - .] "^ 5^1 ^ ` l y n n i n l e * . l n 2. Fetal External Examination Data: Observations noted during the fetal external examinations are summar ized In Appendix G. No external malformations were seen In the 84 low-dose fetuses (seven litters), or 85 high-dose fetuses (seven litters). In the control group, one fetus had a darkened, raised area on its back (thoracic region). No other external malformations were seen 1n the 90 remaining fetuses from this group (seven litters). 3. Fetal Soft Tissue Examination Data: Observations noted during the fetal soft tissue evaluations are summarized in Appendix H. These malformation data are mmarized in Table 6. Company Sanitized. Does not contain T S C A CBI Table 6 - Fetal Soft Tissue Evaluation - Summary of Malformation Data Group (ppn) 1 (0) II (1,000) III (70,000) Observation Ureters - tortuous: unilateral: bilateral: Total directed: Ureters - tortuous: unilateral: bilateral: Ureters - tortuous and distended: unilateral: Liver - small dark discolored area on median lobe: Total anectea: Ureters - tortuous and distended: unilateral: Ureters - tortuous: bilateral: Total affected: Fetuses Affected/ Total Examined No. ------ E 1/48 1/48 T/TS 2.1 2.1 TTT 2/43 2/43 4.7 4.7 2/43 4.7 1/43 w 2.3 TO 1/44 1/44 2/44 .2.3 2.3 O U t t e r Affected/ Total Examined "RT---------- r 1/7 14.3 1/7 14.3 Wf T O 2/7 28.6 1/7 14.3 2/7 28.6 14.3 7T7 14.3 14.3 TOT No statistically significant differences from the control group. The most common observations noted during the soft tissue evaluations Involved distention and/or the tortuous condition of the ureter(s). These types of observations were seen In two of 48 control fetuses (4.2), six of 43 lowdose fetuses (14.p%) and two of 44 high-dose fetuses (4.5*). The significance of these types of ureter observations is unclear. In these same fetuses with ureter observations, the bladders were noted as filled (indicating a patency between ureter and bladder) and no kidney malformations (e.g., severely dis Company Sanitized. Does not contain T S C A CE +5- ~81 Mlo -257T / dy,'U *n i n e Jnc*. tended renal pelvis, absence of r m a , papt||je) ^ ^ These ^ r r'at,0"S (,'e - dlStendedl t0rt""5 - - > freguently ; rat fetuses! h , s t m -- * - of such ureter obser,at)o,,s ` ( Pre!e"tin9 '67 ,et"s '0 Utters). tbat no dose relationship as apparent 1n the Incidence these nreter observations, no treatment-related effect was Indicated. noted d , " H ! T " CePt,0n ^ "r M e r bSerViti0nS' * * * * " observation I",' Sft t1SS"e ................. .... discolored area on TOd'" " '0,,e f the fetus. observation as ....... one ,o-dose 0 treatment-related effect on the fetes was evident from da, collected boring the soft tissue evaluations. < Ossification Variation Data: The types of ossification variations seen during the skeletal examination and the Incidence of fetuses (1 liters)'effected are presented ppendix d. ossification variations .ere seen 1 ,, 87/,, control fetuses, 70/84 0 6; ,e`7 ind 77/85 s- - Incidence of 95.8*. 9.3* ,,,d 0 0 . respectively. These Incidences .ere p a r a b l e het.een the control and treated groups, Tbe mean percentage of fetuses per litter .1th ossification s for the control, lo- and high-dose group as 95.3*, 89.1* and 91 o* respectively. These data ere comparable beteen the control and each treated ' group. . The types and Incidence, of ossification variations seen r e similar h e t e n the control and treated groups. No tre.tment-related effect was evident in these data. Company Sanitized. Does not contain TS CA CB i 5. Fetal Skeletal Examination Data: Observations ,,,,ted during the fete, sleleta, eve,nations are svnm an ze d ,n Append,, Malforwatlon ^ ^ j# ^ ? ^ 7 ' Fgtal Ske'eta' - W , f ....... Group Tppm) I (0) II (1.000) III (70,000) Malformation Angulated Ribs and .Shortened flihe ----- TotaTT Fused Sternebrap lo tah " Fused Sternebrae and midllne cleft Fetuses Affected/ _ Total Examine NO. ---------------" T T - 1/91 W 1/84 T/S7 1.1 1.2 17? 1.2 177 U t t e r Affected/ Total Ut te rs -- Evaluated No. a ------------- 1 - $ 14.3 1773 14.3 1777 14.3 1777 " S l e t ,,fr s t:fdeed" b T t t 3nrS r of 1, ,,ers Per litter b '"Cld'"C' *' Ske'eti' " h . Per fetus end ter basis, was comparable between the control ,,,d treated groups. defect ct. No ho J" at*. th* COntr 1 9r"1'' ne felUS skeletal ^ f o r m a t i o n s were seen a" In t"h'i"s'g`reodu/pshorte' ned rib Fused sternebrae were seen ,n two treated group fetuses. the n r :r,rd *** ~r r j T 0?e ,rtUS ,r" " " tter f ^ * Fusion flf h r / t6r f feTO,e B- 3578> * * second through the . n(d, ,n6c,(^fb was a,so evident through this fused selen, 6 Company Sanitized. Does nnl conlainTSCA *** -17- j - 29jyfdd y amivi, jnt. The sternehral fusion defects ..... , . treated groups ere dissimilar respects to t V 7 ^ ^ "" ^ " " * - ~ ~ -- . ...... . - - - - - i r r r - r r z r , r r , : .... - -- fetuses (9 5 1) th , ( * K e,9ht of 84 'ow-dose es (9.5*) and three of 85 hlgh-dose fetuses (3 5*, Th,, of malformed fef es per ,,tt r f .. ` Percentages andee per litter for the control, loe- M,,h a 4 - * . P.8* and 3.3*. respect,TM,y . though these ^ "" 1ow-dose group differ , 6 T"Creased In *he group, differ, ces from control were not s t a t i s t i c . . Likewise, no dRoseel-aretliatoinosnhshifpn was evi<dent in these values. * -significant. *PPeer to he embr,oto,,1c or ter.toge , n t s Per dose level. r er ,nha,st,on at ^ " "* pre9"a"t rats " 'ted ^Stoumdy7 TDicrfecitro5r i 3 r r T X Date Company Sanitized. Does not contain TSCA CC: Company Sanitized. Does not contai;<tSDACSI --- -- A-l Embryofetal r .A?pendf* A study T y Inhalation l,, the Bat 81-2571 Statistical Analysts ara? -- . the [meter a"a 'J's,s * the Indicated statist! ! st*tlstlca! procedure e ,, r.. . rePorted for h Body Height - Davs I a subgtreastcatitnigongfam.dua'.f t e r u3,s 1)6:abnyd 21 2' " P 6-16, 16-21 by subtracting *e m k s , * - 3. Reproduction Data *: S f f ,utaa J- Mean number of resorotftl0n sites: da Mean number iroli aniP for\S: s % ' J' ` - O p t i o n s t o , o p ,, ,, t! " '? U d ^ "^ ^ s)7'etlve A A A A A A and 1 ^ 7 " " ata " Da* s 3-6. 6-76 External? K f T ? f * fetuses "Ith walformations: Sue'or skeletal " V iS S M i fS ii- varfationsi fetuses w1tb ossification B Per litter**9* f mi]f0rmed fetuses ^ t l o n ^ p e r U t t S ? * " Wlth os^ c e t 1 o n Company Sanitized. Does not contain TSCACBI ce d u r e ^ f ^ e d e d fFTM l ^ ^ n l q u ^ " made by th-. a had equal va rf an ra c^rst* Bartlett's f-oc*^0Wed by a m u l t i n i aPPrPn`ate <0ma>ms usm Z's r g g ^ & s s r . ^ s r s ^ .!1 ` t . ^ ,, 7 7 <,ifferM irom = ^ n k t e s t .' 7 b-- - - - `s r x r ^ * " & ? * " -- , A statistical * A c interaction Parametric cas /J test for trend in ft. _, ^ s u a n s a a r - M .^ ^Sficdgc^p, g y Hoii'uiig1Sanid % )^ AaJNaOrVt-Alett"s''s' T'esstt SKfi.'iS ' Trend & 8s n'i%X& ' '*" ^ *,f|fftigtical Me th od T " "" -------- - il964). l iPP 296-298 PP. 277-279 J ," 1PP. Pp. 482 PP. 13? PP. 149-152 PP- 160-154 PP- J20-123 PP- 327-329 ^ 253QSr SAC SAC 0 HAw HAW SAC SAC HAW SAC . Company Sanitized. Does not contain TSCA CBI jwbryofetal 8,"^71 V bvafnhei 1c1ty StUdy l by Inha,a" " in the fiat .- p . " " ^ - K r t etest'fop tgtjs. bChf-square: Snedecor 7 7 7 t o - rest": V 1"- --------------- -- _ 8Mferro"' it ; : Ha^ A r-fge's Test: A n tU tge^ "^ 'L 6 * 'c ffifr T jlg " f f l a g a a a Company Sanitized. Does not contain TSCA CBI 8J-P571 A+ K+ t L F J #' A++ ** K++ ft L+ F+ J+ H (P^rametr1c1A m A ) ! 9n1fiCntly control C(Dunnett l ) TM 1 from - Parametric) among T"Wa]1is. non- toetheSdZseeieveij.near7y re]ated Lack of fiti Jonckheere's test, fxact test. ^ Wishers DoesCompany Sanitized. not contain rsCACBi Itone.; eratogenfeity study by Inhalation in the Rat Statistical Analysis (cont.) ^'elated ... , , r m 0r ,ess sre " * ' * * si E^sss^ ^ ^ '5?v~- as5*tt>5SS3Kae... M"axi<mum st un te d---M--h.f ,M -U , . _ . calculatetud astunntteeadss.."". ^ M t i s v i S T ,, 7 * o, ^ r a ^ S t ! ,, 6 - to " - *.: a - - If *he lightest fetus was a Cr f f ,, . s " 5 5 - S T `A s * , a ~ , 2 . . . ,, S ^ S S a S -r the litter. * MLW must be ^calculated after eludino ?i\e excl,|Jed ts u m g a i . s, '-'tuses in l Hated too. Company Sanitized. Does not contain TSCA CBI contain T S CA CB! 81-2571 ofl c, t y s t u d y Inhalation in the Rat Individual Female Reproduction Data Croup Tppny rrenal, e Corpoorfa _**? Lutea Rsorptions * or nsr (O) [Chamber Control) 1576 1577 1578 1579 1580 1581 1582 A15 21 15 13 14 13 13 II 12 12(1,000) Total 104 Mean 14.9 S.E.M. N : 1.1 7 2576 2577 2578 2579 2380 2581 2582 12 13 14 15 14 :i III !10,000) Total Mean S.E.M. N 91 13.0 0.5 7 3576 3577 3578 3579 3335558881?0 14 16 14 17 15 16 13 Total ; 105 Mean ; 15.0 S.E.M.: N: 0.5 7 A- A- 11 0 15 IE 15 0 13 14 0 IE 13 0 12 0 93 2 103..63 0.3 0.2 77 1112 IE IE 13 14 IE 0 13 14 IE IE 0 89 5 12.7 0.7 0.4 0.2 77 13 IE .15 IE 13 0 16 0 60 13 IE 12 O 81182..26 3 0.4 0.2 77 A. A. 0.0 4 6.7 5 0.0 9 0.0 9 7.1 2 0.0 5 0.0 6 13.8 40 2.0 5.7 1.3 1.0 77 8.3 9 9.1 4 7.7 7 0.0 7 7.7 7 7.1 3 0.0 9 39.9 46 5.7 6.6 1.5 0.9 77 7.7 7 6.7 11 0.0 5 0.0 7 0.0 1 7.7 8 0.0 9 2.1 48 3.2 6.9 1.5 1.2 -- Fetuses frvoa, lj , iI vy eg " Iemale ToTTT r head A7 1A1- 9 14 6 15 4 11 13 13 8 13 6 12 0 0 0 0 0 0 0 51 7.3 0.9 7 62 5 6 5 10 3 91 13.0 0.5 7 11 10 12 13 12 13 12 0 0.0 0.0 7 0 0 1 1 ( r (1 37 5.3 1.0 7 5 3 8 9 5 4 3 R3 11.9 0.4 7 12 14 13 16 6 12 12 1 0 0, 7 O 0 0 0 0 n 85 0 12.1 0.0 1.2 0.0 77 Mean Fetal Height (grant) A3.59 3.32 3.11 3.31 3.61 3.51 3.98 24.43 3.49 0.11 .7 4.01 3.53 3.71 3.44 3.44 3.46 3.98 25.57 3.65 0.10 7 3.87 3.36 3.<13 3.42 3.25 3.77 3.49 s t a n s n r a ? ! y s f o n t (*-) see Append!* A. f * Early Resorption. erences fron the control group, * ............" -- -- - M fetus,, to Company Sanitized. Does not contain TSCACPI D-l jt F.HBHYuFETAL GrrV B TuXl KlB u y Appendix iIrNyHaa L.\'Ad T D Tl fO,ilj<AIrTJjGTFr;iFj.ijH:i:, vl 7ur>y iWPV~PUAL FEMALE LltfEh WEIGnl D/.Ih TErtHiNAL AN Bopy wi.a NG tGH; 11 VEil ftGHI I. IGH j GHG/TBh b U loo ) GFJJP i - PPhy 1155 i767 'd/'d 11'55dooo2O1 A- 222222266/6on9mi663.......a00o00 11o4A-..24 15.;> 114... oJ 1 ;1 '9 . 5 A- 3.1 5555.o.26A:J61 iJ.91 5.5 j HEAN 27,,.7 >P o . 9 E 7 . 4 W7 hMixXiv 226554..00 1 A. 6 ' .0 0.4 7 1 J; i 16 . 2 $.4 0.24 0.09 7 54 . 9 1 .60 byiver weight divided corrected Day 21 body weight X IDO. J' I Company Sanitized. Does not contain TSCACBI IfcriALAiiOW IN IJEicm:arTr ,tupr liJ^jviru/iL frre.umHaLlrf, Li^'iiTfFp.Lh vrF.iC,,HT PA77, AM 1GiPiiy*ii,,i'7jA.L a W O iG/i; Lj.VEA iiQti I l,"i']>: ( HX/*r100nb) b J P Xi. . v 10O PPM; 222222555jj5O3o1j1Ti2OJ1io1 22p2222o7r:17u#2CoJ4i.......CG0uaoU 1- r .11111'oJJ5`3*A....25.0~61 l45i5*34...3.o42*7252177 MEAii 2 7 r . a 2P 1o.p SE >O U1 Ml-iAi XW 226^7A..00 1A. 0 5 . Do ,1 1 0.23 0.4 O. 1 1 11 ''32..56 54..4777 * ,00. Company Sanitized. Does not contain tscacbi D-3 Appendix D (ont.) EMRyoFETALiox:c:ry a np t e h a i 'jgf.iU c i j y rup y x /JHALATIOW I ItIF. ht.i INPiViPUAL FEH.-iLE LJVEh hf.iGHi PI,i TERMINAL AN BODY wl.a NO iGpjj LIVER w GHI wi. OHG/Iiiwb (6M) ( X 100 ) GROUP lij. - {/OuCiO PPM; -5 75 j5 H 5 7o j>5 o0 j5j 1 ;iG2 262.0 27 3.0 272.0 2y j .0 2 jj .0 26o .0 2 1j .0 '2.7 .i| 15 .0 15.o 1o.c 'j.2 4 .l-j 5.27 5.51 5.39 5 .Oh 5. 7 5 . 6 `; I'ihrtiK 27 6.6 op 13 5 E 5.1 NJ HIN 26 2.0 MAX 2 ^ .0 1. __ 0.5 7 12.7 1o .6 5. -.6 0.27 0. '0 1 *J.d5 5.69 ^Corrected Day 21 body weights (see Appendix B). Liver weiqht divided by corrected Day 21 body weight X 100. Company Sanitized. Does ot contain T S C A C B J ,,Embryofetal E-l Appendix E 1-2571 eratogentcity Study by Inhalation ln the Rat 7Gtrwoufp FCTale Female Wo. Hay: 3 - 6 on. 6-16 16 - 21 I CO) (Chamber Control) 1576 1577 1578 1579 1580 1581 1582 II O.oon) Total : Mean : S.E.M.: N: 2576 2577 2578 2579 2580 2581 2582 III (70,000) (Utdi ; Mean : S.E.M.: N: 3576 3577 3578 3579 3580 3581 3582 Total : Mean : S.E.M.: N; A " " '" 17.0 18.0 35.0 17.5 20.5 18.7 18.7 18.7 0.0 1 18.3 18.3 18.3 0.0 1 For explanation of statistical symbols (A'* A++L+ 20.7 21.1 21.4 21.1 21.2 20.7 24.7 150.9 21.6 0.5 7 20.7 18.3 2129..26 23.9 17.5 20.7 142. 20.4 0.8 7 18.2 - 18.1 19.4 20.0 18.3 19.2 17.6 130.8 18.7** 0.3 7 A26.4 25.4 26.6 22.4 23.0 25.6 29.6 179.2 25.6 0.9 7 2224..88 24.6 2207..84 25.6 27.6 173.6 24.8 0.9 7 26.2 20.0 19.2 26.6 27.6 17.4 24.0 161.0 23.0 1.5 7 L+i ,, , ` L+) see Appendix A. Sartlbed. D o co,,lain TSC ^ F-l C. , rApwpeenntdnixx fF ryo ^ ^ j 9jtfc1 ty and Teratogenicity Study ofB y Inhalation m the Rat Pathology Report * Summary of M u lt Stoss C o h o rt , Observations 81-2571 tbey ,,ooe > grossly , ZT "^ ,d , r 7 " SUrV<Ved t0 the -o,, M M i n a t f 0 n - *rph'*'' d u t i e s observed j?u r : ; r ,n the trMted -- * * < elated t,, the .amtntstretfoo of the tost article. Company Sanitized. Does not contain TSCA CBS F-2 Appendix F (cont.) 81-2571 II (1,000) 2576 2577 2578 2579 2580 2581 2582 H I 3576 (70,000) 3577 3578 3579 3580 3581 3582 T r r T T r r r T r T t t T + + + + + + + + + + + + + + ': -- - n w u n t . t0*y 2' of Gestst,<>")CR * Right. ' N.O.A. jjffig (?1: moderately hollow. n .o .'a .* N.O.A. N.O.A. N.O.A. N.O.A. N.O.A. N.O.A. Lungs: small and dark red in color; diaphragmatic hernia. (*i-` moderately hollow. n* UaA N.O.A. N.O.A. N.O.A. N.O.A. N.O.A. N.O.A. N.O.A. I/O n o f confeftr G-l .Embrvofetal t,.. g, o f M ^ ^ ^ M H M H U ^ U e r a t o g e n l d t y Study |by Inhalation in the Rat 81-2571 Sunniary of Fetal External Ex.TM,nation flata Upper mid-dorsal - dart m areas. dark ble-black, raised (1 .000) A t0ta1 f 84 fetuses ere evaluated representing 7 litters, (70,000) A t0ta1 f 85 fetuses ere evaluated representing 7 litters. bA etort a T f s f ' i t u s wwe?reteevvaTMluaaftteedT rteprneSs'enting 7 litters. Iji f Company Sanitized. Does noi contain TSCACBI ji ! H-l - bryofetaj_ Tox1cAippjen^d^i^xTHeratogen1city Study RI-2571 ^ TM | h y Inhalation In the Rat Fetal Soft Tissue Examination Data 3*0 111 Fema1 e Fetus Fetus No. No. -- fex - , Malformationfs)a b IId (1 ,000) 1579 1580 2576 7 13 3 7 2577 2578 11 5 11 M Ureter (L) - (S) tort,,n,.c, F iiters (B ) " (S) distended and tortuous. ^ terM T7Tor?uoiis!S) t6rt""Si (L ) - M Liver - small, dark discolored arp* 0" med'" 1obe near clef* (approx. 0.3 cm in diarn.)'" M Ureters (B) - (s) tort,,TM,*, F Ureter (L) - (SI tnrt..n,,c, M Ureter (R) - (s) tort,,,,: 2579 3 F Ureter (L) - (S) dir ended and tortuous. 2581 9 F Ureter (R) - (s) distended and tortuous. IIIe 3578 (70,000) 1 9 F Ureters (B) - (s) tortuous. F i eTer - (S) distended and (M) tortuous. f a ? - I S h t ? . y ,ffIUSDS " '^,,observable malformations. c" til dj ii*] tii % L+eft: ?! Jetuses 8 = B0th;,S = Slightly; M = were evaluated representing M7odleirtatteerlsy,, ea tnf-ai r fetuses were evaluated representing 7 litters A total of44 fetuses were evaluated representing9 7littlil! Company Sanitized. Does not contain TSCA CBt r. , Appendix [ fjf|^ ^ ^ ^ t o i TeyraItnohgeanla1tcilotny 1sntutdhye Rat 1579 IIC ( 1,000) III* (70,000) 2580 3578 1 Ribs (Right side! . 6th-8th, H th and shortened.'ated' * h a"d 10th ribs 10 1st and 2nd sternebrae fused. 4 2nd-5th sternebrae fused; cleft evident ^ v e n t r a l r d d - H o e of'fused s t d TM . bA etotaienof 91*^fetus e s ^ e re fse.rvJ b]e "1 format ions. SA total of 84 fetuses e q u a t e d representing 7 1 i,- m A t f . of 85 fetu.es ere 2 7& | j j ! i f . AppJe-nldi* J 81-2571 H ^ | ^ t ^ n d T eratogen1city Study Inhalation In the Rat Fetal Ossification Variation Data Suamarited No. of Fetuses Examined Intact: Without heads: Total: No. of Litters Evaluated: No. of Fetuses With at Least One Ossification Variation: Nj>. of Litter; Containing at Least One Fetus with an Ossification Variation: Hean s Fetuses with Veriation/L1tter: 43 48 I 7 87 7 95.3 II ,000) 41 43 84 7 75 7 69.1 111 T7.000J 41 44 85 7 77 7 91.0 No^of Fesses (Littral with Ossification veri.t > -- X 351 -- tot----- r - Type of Ossification Variations: Cranial Ossifications*: Parietal Incompletely Ossified: Nalar Incompletely Ossified - Unilateral: Bilateral: Hyoid Incompletely OssifiedUnossified: Sternebrae Asymmetric (small) Sternebrae Wo. j; 2: 3: 4: 65:: Unossified Sternebrae Wo. 2: 3: 4: 5: 6: I (1) 2.3 1 O 2.3 2 (2) 4.7 0 0.0 9 (3) 20.9 0 0.0 IS (5) 16.5 7 (5) 7.7 27 (6) 29.7 0 0.0 57 (7) 62.6 0 0.0 0 0.0 0 0.0 0 0.0 26 2 if! 228..26 Ribs: 0.0 0.0 0.0 0.0 I5 (P2>) 2.4 12.2 0.0 0.0 (1) 2.4 (1) 2.4 3 12) 3.6 15 7) 17.9 8 (5) 9.5 26 (7) 31.0 0 0.0 56 (7) 66.7 0.0 ( I ) 1.2 0.0 0.0 10.7 if! 2.4 2 2) 2.4 819 6 ) 22.4 6 ) 9.4 19 ( 7 ) 22.4 0 0.0 55 (7) 64.7 0 0 0 0 19 13) 6 r2) 0.0 0.0 0.0 0.0 22.4 7.1 Rudimentary Structures* Unilateral: Bilateral: 12 Rib pairs: 14 Rio pairs. 3 (2) 2 (1) 2 (1) 0 3.3 2.2 2.2 0.0 H) 0 0 0 1.2 0.0 0.0 0.0 5 (3) 2 (1) 0 (I) 5.9 2.4 0.0 1.2 bTh ?0t ,na*2*ed statistically. *si*j;,MrKr25,^ r , ^ ::,^Mr . ** w ;[ : S! s 33S|I* .... .... Small discrete ossification(s) adjacent t# the`iIt*i4Ct fetuse evaluated, vertebral transverse process(es). * * th 1 thoracic or first lumbar S C A Cf  ^ e u , & 5 S % < g L . ' ..... 81-2571 Inhala, (on in the Rat fetal Ossification Variation Data Sunr,ar,d III 776.000) No. of fetuses with Ossification Variations*B.c Verteoral Column:7 N0` A Ho. Cervical V. Trans. Proc. Incompletely Ossified - Unilateral: 81 lateral; Cervical Ossifications - Uni lateral: I (I) 1.1 I 0) 1.1 oo oo 0 1 (1) 1.2 0.0 Thoracic V. Centra - I (I) 1.1 0 0.0 0 0.0 Incompletely Ossified: Unosslfled: Lumbar v. Trans. Proc. *3 (7) 47.3 0 0.0 <1 (7) 48.8 2 (2) 2.4 33 (7) 38.8 0 0.0 Incompletely Ossified: Sacral V. Trans. Proc. fused to Centra Unilateral: Bilateral: Incompletely Ossified Uni lateral: Bilateral: Unosslfled Unilateral: Bilateral: Pelvic Ossifications 1 {) 1.1 (Z) 4.4 2 (2) 2.2 l (*) 7.7 6 (3) 6.6 3 (3) 3.3 1M 1.1 I (1) I? 3 (3) 3.6 5 (2) 6.0 M l ) 1.2 3 (1) 3.6 1 (1) 1.2 4 (2T 4.8 0 0.0 0 0.0 0 0.0 ' (1) 1.2 D 0.0 0 0 0.0 0.0 Penis Incompletely Ossified Unilateral: Bilateral: Pubis Unosslfled [bilateral): Distal Phalanges Unosslfled Forelimbs: Hindi imbs: Netacarpals Unosslfled: * 0.0 1 (1) 1.1 > 0.0 (3) 4.4 (6) 44.0 (1) 1.1 1 (1) 1.2 0 0.0 1 (1) 1.2 12 O) 14.3 30 (5) 35.7 1 (1) 1.2 0 0.0 0 0.0 0 0.0 235 ((63)) 5.9 27.1 0 0.0 PThfs ina,yzed statistically. $S - o?etVusat?tnh0t h r Ved duri" ----------- - as noted dur,n& 1 X PPeSent Of " Company Sanitized, Does not contain TSCACBI Appendix K project n o . 81-2571 m o m n j L roxicirr a teratogenicitt STUDY DrB * $ B'' INHA1-flT,0N IN THE RAT Company Sanitized. Does not contain TSCA C S J * I ntkoductiqh -1. ' The purpose of this stun potential and degree of Pregnant rat. Two groups of female rats ^ j - o r 6 nr/day f r m Bay 6 81-2571 * 4t"sp^ the 9r"P - * = * nly to houseline ... r SeStatf0n' 4 -- t cootTM, teiti"9 "ere 'm - * 70,000 parte " HEldOPs " o n (ppm). Se'K t e d for * ' -- 5t S e r ial DeHi-- p ~ 4 * ^ c Z p Z r , ! ' " * r ,,m er iB,) , ,h * w * ;:.r ; r ; ^ :s p :7 -- ~ - - r , a , ,,at J r;; O 7 a o maintained at a temperature of 45.c . G-^0, ^ **" f ,, st tllat ** " f" '" r4te " f 7.0 liters per mi,,,,te 7 " ' * * >ter b,tl'* "" l i n e ory air. B * Chamber f)pa r3rffTn 0 1 e exPsure chamber. Jn* tiUat.. Tne a", m U W n exposed in a glass chanter with , , Ers- The average airflow r.r. .a V'" ne of "O' " d e l a t e d to provide one co, r"Sh ^ 9 " eiloilibrium tine of 12.g ,, , ,, ,, 7 ''r ^ C ` i&aospherir t - p n , ^ Chamber concent itions were control every half h e ....... . a0g.KAC (tei3) # 7 ChiSber " * 7' ,pm- *W ^ *"< Ch4- - including the oot 1/8" Chronosorb ,02 column, at . temperature * " * * " * ' * SiX ** ChrMM-- 4 o r a t i o n and d e t e d n a t j ^ ~^ Chamber concentrations were Company Sanitized. Does not contain TSCA CBI U - METHODS fCont.) Appendix K (cont.) -2- 81-2571 C * Atmospheric Sampling fcont.^ determined by comparing the Iinntteeagrraatteedd Gg.Cr. area *to responses obtained with primary gas standards. The g r m e g .c . sampling sequence was Groups I, II, m , j etc. However, because of .He carry-over o f ^ , ,, the sampling ,, ,, , s , ' J ".ge . to control, this sequence wes re v e r e d Dey 2 .,,d on Day 6 tne sampling tim. was Increased from 8 to 9 minutes. ChamOer oxygen ,as monitored daily (4 times per day for tHe first t.0 days and twice dally thereafter) using an MSI) s t a b l e Oxygen .ndic.tor (Type E). Chamber air temperatures were recorded hourly during the exposures. f C o m p a n y Sanitized. Does m l ^ k a r i T S C A C j Company Sanitized. Does not r? -3- 111. fiiscussrn 01-2571 f th' concentrettons * " * fro. the control cKmber n u ^ "* ,s " thi ^ J ^ f TM , M ,, dose t; c; ' ~ -- in, sequence end W* `0 * W cerr^eer `".ten th i rm ,i" der f * * ntro, exposures J STM " " on nut present ut . ,, . ` `! ** ^ ^ < * * 'then > e r y " * " W " ne.ntr.ti. u l,, th, * ~-- -- ne. ene ^ -- Group 9 e P l a n t e d below: 1 (Control) ^ (900 ppir) 111 l 7 0 S Ppm) in some cases Mean 24.6 25.0 24.6 Range 20.0- 28.0 2J.5- 28.0 2222..00-- 2266..55 "'re * * * <.te content "" 7 d,nss *. < * hfs(ler (, ; ; s ; ; tb* h"` f t t . exposure c h , . ,, tM s occurred ^ 4tn<>SPherfc' ^ - u r e t>ke" a fte r ` " . e t e r es f r e e of pn tem M r4ture es temperatures n + Physical contact Mink , . v tures* nt associated with < H 9h cl,dmber ^ " * ' * * on tne cheZer. P' 4C""e"t * " " *'* -- * Dfrector, Inhaiatfon company Sanitized. Does not contain TSCA C B I Date 8/17/81 8/18/81 8/19/81 8/20/81 8/21/81 8/22/81 8/23/81 8/24/61 8/25/81 8/26/81 8/27/81 8/28/81 8/29/81 " ryo.f^ Appendi-x4 -K (coni.) IBUfC I i;c,tL .,,J ?r ?t og ?ni ity stuiy fby Inhalation In the Rat Group I (Control) 1-2571 Test Ray 21 3 4 65 7 8 109 1121 13 Exposure Number 1 2 3 4 5 6 7 8 109 1112 13 Analytical* Dally fiean Concentration Cumulative Mean Concentration [ppm] 25.2 26.1 7.60 63..1605 12..0800 60..1020 3.35 0.00 0.00 0.81 25.2 25.7 19.6 15.6 13.7 IT. 9 10.4 9.06 8.73 8.19 7.45 6.83 6.36 multiport sampfing"system.attribUted t0 carr*-over of test material in the Company Sanitized. Does not contain TSCACBI uate 8/17/81 8/18/81 8/19/81 8/20/81 8/21/81 8/22/8] 8/23/81 8/24/81 8/25/81 8/26/8] 8/27/8] 8/28/81 8/28/81 Appendix K (cont.) -5- Embryofpta] Toxicity inrf0?01'^ 81-2571 Test tejL Number 1 2 3 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 109 1121 13 rouP II (1000 PPm) -2=??P!=- S S Ccumulativeuai iy -Anaivtlcai Mean Ccncentrat* Mean "U*iITtovminal - (ppm; 922 942 966 993 1050 1010 1OT 0 1000 11002200 1090905 993 922 932 943 556 975 981 985 987 990 993 993 994 994 995 1080 1050 1060 1040 996 1040 111010204000 1070 l1i0o6r0 Mean: loso Company Sanitized. Does not contain TSCAC8I -6 -Appendix K ( c o n i . ) Embryofetal Tpxicitv JniC?nt'* H I (70,000 p S ) 81-2571 st"*' Date 8/17/81 8/18/81 8/19/81 8/20/81 8/21/81 8/22/81 8/23/81 8/24/81 8/25/81 8/26/81 8/27/81 8/28/81 8/29/81 Jest Exposure `D u i li *n**ft*<`* 21 3 4 5 6 7 8 9 10 1121 13 21 3 4 5 6 7 8 9 10 11 12 13 ' 74000 75300 69200 72100 69500 71200 69300 69500 697 00 70400 69900 70200 69600 (PpmJ 7400C 74700 72800 72700 72000 71900 71500 71300 71000 71000 70900 70800 70700 Itominal i^ly Mean Concent ration (ppm) 72000 72200 69300 70700 72206 65500 68200 69100 70100 69100 69100 68700 68100 Mean: 69600 Company Sanitized. Does noicontain SCA CBj L- ^ j | | i | | g ^ ^ ^ y A^ppJenedirx aL t oInh9eanlaicti7otny isntudthye Rat 81-2571 C o m p an y Sanitized. Does not contain TSCACl Appendix M 8 " u T , tr " oe 8 T U D r HO. f__ S - 2 5 7 ..TEST substance/ art icle_J j V T B T u d T SPONSOR, E.I. Dupont OeNemours *>ATE(S) OF inspection 9/1/81 9/4/81 /23-71/25/8 12/9/87 & 12/10/81 r *nd STRUEDPYORBTIESDECtToOR 9/2/81 9/4/81 12/3/81 12/77/81 REPORTED to management 9/21/87 & 10/9/87 9/8/87 & 9/22/81 12/30/87 1/5/82 12/78/87 72/23/87 Company Sanitized. Does not contain T S C A CBI