Document rx4eRgdo52QrOynrdmwD47rzE

Attachments to Letter to C. Auer dated May 18,2000 Studies and Other Information on Certain Perfluorooctane Sulfonate-Related Compounds R l^ I 2. FOSA Perfluorooctanesulfonamide Acute Toxicity 373. O S 0 0 1) Acute Oral Toxicity Screen with T-3421 in Albino Rats, Safety Evaluation Laboratory, Riker laboratories, Inc., Project No. 0883AR0287, 3M Reference No. T3421 (KTZ-15), January 17, 1984 2) Acute Ocular Irritation Test with T-3421 in Albino Rabbits, Safety Evaluation Laboratory, Riker laboratories, Inc., Project No. 0883EB286, 3M Reference No. T3421 (KTZ-15), August 24,1983 ] 3) Primary Skin Irritation Test with T-3421 in Albino Rabbits, Safety Evaluation Laboratory, Riker laboratories, Inc., Project No. 0883AR0288, 3M Reference No. T3421 (KTZ-15), August 9, 1983 Studies in Progress 1) Protocol, Feces Method Development Metabolism Study for Perfluorooctanesulfonate Derivatives [N-EtFOSE, PFOS, and FOSA], 3M Strategic Toxicology Laboratory, Study Nos., T-636.17; T-6295.21; T-7132.3; ST-41, In-Life Start Date November 22, 1999, In-Life End Date November 24, 1999 2) Protocol, Pharmacokinetic Study of Perfluorooctane Sulfonamide [FOSA] in Rats, 3M Strategic Toxicology Laboratory, Study Nos., T132.2; ST-39, In-Life Start Date October 4, 1999, In-Life End Date November 2, 1999 3) Protocol, Cell Proliferation Study with N-Ethyl Perfluorooctanesulfonamido Ethanol (N-EtFOSE; 3M T-6316.11), Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; 3M T-6295.16), and N-Ethyl Perfluorooctanesulfonamide (PFOSA 3M T-7091.1) in Rats, Pathology Associates International, Study No. 1132-100 epa- ots 000811800I OOOfillBDOI -2- 000109 C:;. c - << -"D ,A>! 'A _ s. Experim ent No.! C onducted A t: D ates C onducted: C onducted By: R eview ed By: A cute O ra l T o x ic ity S creen w ith T-3421 in A lbino R ats 0883AR0287 S afety E v alu atio n L aboratory R iker L a b o rato rie s, In c. S t. P au l, M innesota A ugust 2, 1983 to Septem ber 7, 1983 n J b -c D. M. M a rk o e , J r . , BS 1 T o x ico lo g ist Study D ire c to r n J z o fo ' D ate dc: M. T . C a se W. C . M cCorm ick S u p e rv iso r, T oxicology T e stin g 000110 1. Summary The a c u te o r a l to x ic ity sc re e n w ith T-3421 was con d u cted from A ugust 2, 1983 to Septem ber 7, 1983 a t R ik e r L a b o ra to rie s , I n c ., S t. P a u l, M innesota u sin g m ale and fem ale a lb in o r a t s ran g in g in body w e ig h t from 191-258 gram s. The t e s t a r t i c l e was a d m in is te re d by g a s t r i c in tu b a tio n a t d o sag e le v e ls o f 5 ,0 0 0 , 2 ,0 0 0 , 500 and 200 mg/kg body w e ig h t w ith m o r t a l i t i e s o f 1 0 /1 0 , 1 0 /1 0 , 10/10 and 2/10 n o ted r e s p e c tiv e ly from one h o u r to s ix days p o s t dose a d m in is tra tio n . The untow ard b e h a v io ra l r e a c tio n s w hich o c c u rre d d u rin g th e 14 day o b s e r v a tio n p e rio d g e n e r a lly c o n s is te d o f h y p o a c ti v it y , le th a rg y , p ro s tra tio n , d ia rrh e a and unkempt appearance w ith th e o n set o c c u rrin g from 1-30 m inutes to day fo u r p o s t dose a d m in is tra tio n . C lo n ic c o n v u ls io n s w ere n o te d i n two a n im a ls p r i o r to d e a th , t r a n c i e n t a lo p e c ia was n o te d in two a n im a ls, w h ile dyspnea and s a l i v a t i o n w ere n o te d i n one a n im a l d u rin g th e stu d y . A ll re a c tio n s su b sid ed by day elev en or d e a th p reclu d ed re c o v e r y . Body w e ig h t g a in s were n o te d in a n im a ls w hich s u rv iv e d th e s tu d y p e rio d . N ecropsies perform ed a t term in atio n of th e study rev ealed no v is ib le le s io n s w h ile hyperem ic o r hem orrhagic lungs a n d /o r hem orrhagic i n t e s t i n a l t r a c t g e n e ra lly w ere n o ted in th e an im als which d ie d d u rin g th e co n d u ct o f th e s tu d y . The a c u te o r a l LD50 o f T-3421 i s g r e a t e r ,th a n 200 m g/kg an d l e s s th a n 500 m g/kg in m ale and fem ale a lb in o r a t s . In tro d u ctio n The o b j e c t iv e o f t h i s s tu d y was t o d e te rm in e th e a c u te o r a l LD50 o f T-3421 in a lb in o r a t s . T his stu d y was co n d u cted in a c c o rd a n c e w ith th e Food and Drug A d m in is tr a tio n 's Good L a b o ra to ry P r a c t i c e R e g u la tio n o f 1978. The raw d a ta g e n e ra te d by th e Study D ire c to r and th e f i n a l r e p o r t a re s to re d in th e conducting la b o ra to ry 's arc h iv es 000111 2. M ethod and R e s u lts Young a lb in o ra ts^ - w ere used in t h i s t e s t . A ll an im als w ere h e ld u n d e r q u a ra n tin e fo r s e v e ra l days p r io r to te s tin g w ith on ly an im als w hich ap p e are d to be in good h e a lth and s u ita b le as t e s t anim als a t th e i n it ia t io n o f th e s tu d y u s e d . The r a t s w ere housed in s to c k c a g es in te m p e ra tu re and h u m id ity c o n tr o lle d rooms and p e rm itte d a s ta n d a rd la b o ra to ry d ie t~ p lu s w a te r ad lib itu m e x c e p t d u rin g th e 16 hour p e rio d im m ed iately p r io r to g a s t r i c in tu b a tio n when food was w ith h e ld . F iv e m ale and fiv e fem ale r a t s w ere a d m in iste re d th e t e s t m a te ria l a t p re s e le c te d dosage le v e ls . Ih e d o ses were a d m in iste re d a t a c o n s ta n t volum e o f 10 m l/k g d i r e c t l y i n t o th e stom achs o f th e r a t s u sin g a hypoderm ic s y rin g e equipped w ith an in tu b a tio n n ee d le . A fter g a s tr ic a d m in istra tio n of th e t e s t m a te ria l, th e r a ts w ere r e tu r n e d to t h e i r cag es and o b se rv e d f o r th e fo llo w in g 14 d a y s . I n i t i a l , se v e n day and f i n a l body w e ig h ts , m o r t a l i t i e s (T a b le 1) and a d v e rs e r e a c ti o n s (T ab le 2) were re c o rd e d . A n e c ro p sy was co n d u cted on a l l a n im a ls t h a t d ie d d u rin g th e stu d y a s w e ll a s th o se e u th a n a tiz e d a t th e end o f th e 14 day o b s e rv a tio n p e rio d (T ab le 1 ). The p r o to c o l, p r in c i p a l p e rs o n n e l in v o lv e d i n th e stu d y , com position c h a ra c te r is tic s and Q u ality A ssurance sta te m e n t a re c o n ta in e d i n A ppendices I - IV. a K in g L a b s , O re g o n , WI -- R a l s t o n P u r i n a L a b o r a t o r y Chow, R a l s t o n P u r i n a , S t . L o u i s , MO 000112 TABLE 1 ACUTE ORAL TOXICITY STUDY - ALBINO RATS w ith T-3421 M o r ta lity , N ecropsy and Body W eight D ata Dose -- A nim al (m g/kg) Sex Number 5000 M 3R3553 3R3554 3R3555 3R3556 3R3557 5000 F 3R3573 3R3574 3R3575 3R3576 3R3577 2000 M 3R3558 3R3559 3R3560 3R3561 3R3562 2000 F 3R3578 3R3579 3R3580 3R3581 3R3582 500 M 3R4070 3R4071 3R4072 3R4073 3R4074 500 F 3R4106 3R4107 3R4108 3R4109 3R4110 I n d iv id u a l Body W eights (g) T e s t Day Numbers 0 *7 14 208 (Day 6) 210 (Day 2) 197 (Day 6) 219 (1 Hour) 214 (Day 6) -- Number Dead Number T e ste d 5/5 191 (1 Hour) - 207 (1 H our) 207 (1 Hour) - 192 (1 Hour) 209 (Day 1) -- 5/5 195 (Day 6) 207 (Day 6) 209 (Day 6) 217 (Day 6) 207 (Day 2) -- 199 (Day 6) 218 (1 Hour) 201 (1 Hour) 205 (Day 1) 203 (1-iHour) - 210 (Day 3) 212 (Day 4) 213 (Day 6) 217 (Day 5) 216 (Day 4) -- 204 (Day 6) 200 (Day 4) 205 (Day 5) 221 (Day 3) 198 (Day 4) - 5 /5 5/5 5/5 5 /5 Percent Dead 100 100 100 100 100 100 000113 BEST COPY AVAILABLE TABLE 1 (concluded) ACUTE ORAL TOXICITY STUDY - ALBINO RATS w ith T-3421 M o r ta lity , N ecropsy and Body W eight D ata a Dose ~ A nim al Sex Number 200 M 3R4075 3R4076 3R4077 3R4078 3R4079 200 F 3R4111 3R4112 3R4113 3R4114 3R4115 I n d iv id u a l Body W eights (g) T e s t Day N um ber: 0 7 14 251 (Day 6) 236 274 297 253 303 336 25B 302 345 248 249 297 Number Dead Number T e ste d 1/5 220 230 243 212 242 242 217 236 236 238 253 2 57 225 (Day 5) - 1/5 4. P ercent Dead 20 20 N ote: F ig u re s in p a re n th e s is in d ic a te tim e o f d e a th a -- T est a r tic le ad m in istered as a suspension in w ater. The a p p r o x im a te o r a l LD50 i s g r e a t e r t h a n 200 m g /k g a n d m ale and fem ale a lb in o r a t s . le s s th a n 500 m g/kg in fa s te d N ecropsy N ecropsy o f th e an im als w hich su rv iv e d th e o b s e rv a tio n p e rio d re v e a le d no v i s i b l e le s io n s w hile n ecro p sy o f th o se an im als w hich d ie d d u rin g th e conduct o f th e stu d y g e n e ra lly had hyperem ic o r hem orrhagic lu n g s. H em orrhagic sm a ll in te s tin e was n o ted a t th e 500 m gA g d o se l e v e l and one a n im a l from th e 200 m gA g d o se g ro u p . One in c id e n c e o f m o ttle d l i v e r was n o ted a t th e 5,000 m gA g le v e l . 000114 TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS W ith T-3421 Summary o f R e a c tio n s *9 R eactions Dose mg/kg Sex 5000 M H ypoactivity L ethargy S aliv atio n Dyspnea D iarrhea Unkempt A ppearance 5000 F H ypoactivity L e th arg y P ro stratio n 2000 M H ypoactivity L ethargy P ro stratio n D iarrhea Unkempt A ppearance 2000 o O 07 F H ypoactivity L ethargy P ro stratio n D iarrhea Unkempt A ppearance O bservation P eriods __________________________ .__________ Number A ffe c te d /N u m b e r D osed ______M in u te s______ ____________________________________D a y s 1-30 60 120 12 3456 2/5 0/4 2/5 3/5 4/4 1/5 0/5 1/5 0/4 3/3 3/3 - - * 4/4 0/3 4/4 3/3 3/3 3/3 3/3 * * 1/5 0/3 4/5 1/3 0/1 2/3 1/1 2/5 2/5 3/5 3/5 1/5 2/5 2/5 1/2 0/2 3/5 1/2 0/2 2/2 * 5/5 4/4 4/4 - --* 0 /5 0/5 5/5 4/4 4/4 -- -- * 4/4 4^4 " it 1/1 1/1 1/1 -- -- * 0 /1 1/1 1/1 1/1 1/1 1/1 -* --* 9 10 11 12 13 14 v R eactions Dose mg/kq Sex 500 M H ypoactivity C onvulsions 500 H y p o a c tiv ity A taxia 200 M C onvulsions 200 F A lopecia TABLE 2 (concluded) ACUTE ORAL TOXICITY SCREEN - ALBINO RATS w ith T-3421 Summary o f R e a c tio n s ^ COPYAVAILABLE M inutes 1-30 60 120 O bservation Periods Number A ffected/N um ber Dosed DaY9_ 10 11 12 13 14 2/3 1/1 * 1/3 0/1 3/3 2/2 * 1/4 0/3 1/5 0/4 2 /4 2/4 - 2/4 0/4 9 TT0 0 0 Key: Blank in d ic a te s no s ig n if ic a n t re a c tio n s - o b se rv a tio n s in ad v e rte n ly m issed over weekend * T o ta l D eath tST COPY AVAILABLE Riker Experiment No.:. APPENDIX I PROTOCOL O'. .'3 VC 7 T E S T :. /.cute 7r: 1 T o x ic it-* /car. SPONSOR: 3M. M 'zii 1 C h o -.ira l C O N D U C TED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota T E S T A R T IC L E :____________________________________________________________________________ CO NTR OL ARTICLE: i2- PROPOSED STARTING/COMPLETION DATE O F TES T: J-l/ l - _ ~ . TEST SYSTEM: f l i b a . O P A T CD S O U R C E : K ' /->-> i f - Q `f T - C O W , *0 1 3 Sex: Number: . - Weight Range: 2 *-' - . 3 / 0 ` ~ 7 7: Division O B JE C T IV E : The objective of this test will be to characterize the a c u te ______ 2ZSi__________toxicity of the test article in albino ______ . .. fto "------------- were selected as a test system for reproducibility of response, historical use, ease in handling and general availability. METHOD: The animals will be housed in stainless steel suspended wire mesh cages in temperature and humidity controlled rooms during both the quarantine and test periods, with food and water offered ad libitum6. Each animal will be identified by color coding, according to the laboratory's standard operating pro cedure, which will correspond to the animal numbers on a card affixed to the outside of the cage. A single dosage of 3, mg/kg will be administered each animal, however, if this dosage level does not adequately characterize the toxicity of the test article, additional animals will be administered the test article at supplemental dosage levels. Any additional dosage levels will be documented and filed with this protocol. The test article will be administered to the animals in the form received from the sponsor. After administration of the test article, the animals will be returned to their cages and observed for any untoward behavioral reactions for the following 14 days. Initial and final body weights will be recorded. A gross necropsy which will include, but not be limited to heart, lungs, liver, kidneys and general gastro intestinal tract will be conducted on all animals which die during the conduct of the test as well as the animals surviving the test period. Any gross abnormalities which are observed during the conduct of the necropsy will be recorded with specific mention to the organ and/or site observed. The acute medial lethal dose (LDso) of the test article will be calculated, if possible, using a probit analysis method at the end of the observation period. All raw data generated by the study director and the final report will be stored in the Riker Laboratories' Archive, St. Paul, Minnesota. __________ - Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri k Foci? (3t u-M T H h 'rLD F O P A. l(s<- t?.I os'. T o Po t A/ It,. - V -i-'d-'i-'Vi C. . :cf o rn ic i. Sponsor O- .`Date Study Director 000117 rC E tV E D JUN 13 1933 , -. \;Mt-MW'*A. iTijvn"'I Dat< Form 1917M&-A-PWO 1ST COPY AVAILABLE R ik er E xp erim en t No. ; 0883AR0287 APPENDIX I ( c o n c l u d e d ) D e v ia tio n s a n d /o r Am endments t o P r o to c o l 8. Weekend o b s e rv a tio n f o r A ugust 6 and 7 w ere in a d v e r te n tly m issed and on S e p te m b e r 3 r d . ____________________________ _________________ __________________ _ ________________________________________________ D. M. M a rk o e , J r . ________1 0 / 5 / 8 3 Study D ire c to r D ate Due to a d e la y i n stu d y co n d u c t th e p ro p o sed c o m p le tio n d a te sh o u ld be am ended t o 1 / 8 4 . ______________________________________________ __________________________________________ D . M. M a rk o e , J r . _________ 1 2 / 2 9 /8 3 Study D ire c to r D ate Study D ire c to r D ate Study D ire c to r D ate 000118 Study D ire c to r Date BEST COPY AVAILABLE APPENDIX I I P r in c ip a l p a r tic ip a tin g p erson n el In volved in the seud? Name D. M. M arfcoe, J r . , BS K. L. E b b en * , BS X. D. O 'M a lle y , BS 0. C. pecore F u n c tio n le x ic o lo g ist Study D irecto r S u pervisor le x ic o lo g y T estin g S en ior le x ic o lo g is t A cute le x ic o lo g y S u pervisor Anim al L aboratory 9 00119 APPENDIX I I I T est an d /o r C ontrol A rtic le C h a ra cte riz atio n lo . T -3 4 2 -1 1 . The id e n tity s tre n g th , u n ifo rm ity , co m p o sitio n , p u r ity o r o th e r p e r tin e n t c h a ra c te riz a tio n s o f th e t e s t and/or c o n tro l su b stan ces have b e e n d e t e r m i n e d a n d d o c u m e n te d a s o f 2j- fix s)S s/S -- X' ' 2 . The m ethod o f s y n th e s is o r o r ig in o f th e t e s t an d c o n tr o l s u b s ta n c e s , in c lu d in g t h e i r am ount and th e m ethod o f b io a s s a y ( i f a p p lic a b le ) i s docum ented. .S y e s v ni o The s t a b i l i t y o f th e t e s t a n d /o r c o n tro l su b sta n c e s have been d e te r m in e d o r w i l l b e d e t e r m i n e d a s o f 2 - T~u . t & 3 i e .< The above in fo rm a tio n and docum entation a re lo c a te d in th e s p o n s o r's r e c o rd s. Sponsor s h s l& j D ate ..b . 6O C- A c ri !b . Q c u + S f " .5 2 3 > (* - f 000120 p JUN H 1S83 4 L ifcTY EVALUATi*'.- BEST COPY AVAILABLE APPENDIX IV QUALITY ASSURANCE STATEMENT A cute T oxicology L a b o ra to ry S tu d ie s S tu d y N o. : f t 7 ' b f t f t 7C 3 'S? li. T h is s h o r t term stu d y was a u d ite d by C om pliance A u d it, and th e f in a l r e p o r t exam ined a g a in s t th e raw d a ta on / The r e s u l ts o f th e a u d it w ere r e p o r te d to th e stu d y d ir e c to r and t to m anagement on >r / ? '/< !______ o In a d d itio n 'to th e d a ta a u d it, d iff e re n t s ig n ific a n t phases fo r s tu d ie s underw ay in th e A cute T o x ico lo g y L a b o rato ry a re in s p e c te d w eekly on a r e c u r rin g c y c le , and th e f a c i l i t i e s a re exam ined by C om pliance A u d it on a th r e e m onth s c h e d u le . D ate n 000121