Document ZJp0EOD1DpX9bpd9LgJbKXN9d

AR226-2777 Study Initiated/Completed 1U/1//7V - 12/14/7'; Material Submitted by Polyer Products Washington Works RAT SKIS ABSORPTION SUBACUTE STUDY WITH I. Introduction: effects related to One app l yoibngje--ct--oft--hila^ostnhueb a cute s shaved t u i dy nta wa ct s to skin de o t f e na ra ine ts a at n y v a toxi riou c s concentrations. Another ob ective was to define the correlation between the effects seen and determined blood organofluorine concent rat ions. II. Protocol and Procedures: A. General Protocol: Male ChR-CD rats were exposed denially to as an aqueous paste, at concentrations of either 20, 200 or 2,00 body weight. A control group of rats was exposed siaultaneoualy to water only. Four groups of 15, 8 wk old rats (initially weighing froa 210 to 245 gms) were exposed for 6 hrs/day (compound wiped off after 6 hrs), 5 days/wk for 2 wks. Doses were based on daily, individual body weights. Exposure period was lollowed by a A2-day recovery-observation period. Five rats per group were randomly selected for sacrifice on exposure day 1U, and recovery days 1A and ^2. Rats were collared oy securing l-l/^" II) x 2-1/2" 00 Teflon rings around their necks. Collars prevented ingestion of compound by rats when preening and grooming for 2 wk exposure period. After collaring, rats were housed individually and held for a 1 wk pretest period to ensure suitability. Compound was applied to the backs of each r-c on a J" x 1-1/2" area shaved free of hair. Less than U.5 ml of compound was applied in aqueous forw Co the shaved area. Daily 6 hr exposures' ended when compound was wiped from the rats backs with a gauze pad. Collars were removed after exposure day 10. Throughout the test period, Purina Rodent Chow and water were available ad libitum. All rats were weighed and observed daily (except weekends) throughout the exposure period and approximately every 3 days thereafter. SanUized.Does.olconlainTSCACB Company .... ^^^y^ '.la -"5-ll.Fa B. Clinical Pathology Procedure: After exposure day 10, recovery day 14 and 42, blood was taken froa the tails of 5 raea froa each group for heutology aeasureaents including: erythrocyte count, heaoglobin, heaatocrit, leukocyte and relative number of neutrophils, lyphocytes, eoainophila, onocytec, baaophila, mean cell voluae, Bean cell heaoglobin, aean corpuscular heaoglobin concentration* Clinical cheaiscry aeasureaents included alkaline phoaphatase, glutaalc-pyruvic cransaminase, glutaaic-oxaloacetic transaainase and total protein. C. Pathology Procedure: Gross autopsy and histopathologlcal exaainationa were done on 5 rats/group after exposure 10, and on recovery days 14 and 42, Histopathology was done on the bone aarrow, brain, cecua, colon, epididyidea, esophagus, eyes, heart, kidneys, liver, lungs, skin, saall intestines, spleen, stoaach, testes, thyaua, thyroid, trachea and lyaph nodes. Mean absolute and relative organ to body weight analyses were done on the following: Jiver, spleen, testes, kidneys and thymus. D. Organofluortne Analysis; After exposure 10 and on recovery days 14 and 42, blood was collected froa 5 rats/group by cardiac puncture for organofluorine determinations. E. Ocular Examinations: Eye exaainations were done on each rat after exposure 9, and on recovery days 13 and 41. Procedure included gross observation of the eyes using a bright light and semimicroscopic observation using a hand aagnifying laap and a slit-lamp biomicroscope. IV. Results; There was no difference in body weight gain between the controls and the -U nig/kg group during the test. The 2,OUU mg/kg and 200 mg/kg groups lost weight from exposure days 1 to 1U. Both groups recovered the weight loss and exhibited normal weight gain after exposure day 1U. A graph of the body weights is presented in Appendix IV. No rats died during exposure or recovery periods. A. CUnical Observations: There were no differences in clinical signs displayed by the control and the 2U mg/kg groups during the exposure or recovery periods. Racs exposed to concentrations of 2UO ng/kg or the 2,000 mg/kg showed slight redness in the treatment areas throughout the test. Rats exposed to 2,000 ag/kg were salivating during the 2 wk exposure period and had wet stained perineal areas during the recovery period. Treated and control groups showed hair loss and cutaneous lesions in areas where collars rubbed the rats' necks. Treated and control rats also displayed red discharge from the nose and eyes while wearing collars. When collars were removed, discharge subsided. Neck irritation, red nose and eye discharge were probably not compound-related. B. Clinical Chemistry: After the last (10th) exposure the created groups showed dose-related increases in serum enzyme' activities such as alkaline phosphatase, GPT and GOT. In the 2,000 mg/kg group the serum total protein was lower than controls after the last (10th) exposure. In all treated groups the erythrocyte counts, hemoglobin and hematocrics were lower than controls on recovery day 14. These measurements fron the created groups were similar to controls after exposure 1U. Erychrocyce counts, hemoglobin and hematocrit measurements in the 20U mg/kg group remained lower than the control at recovery day i*l. The 20 ng/kg, and 2,OOU mg/kg showed measurements similar to controls at recovery day 42. Clinical /-'- ctiemist-ry results are reported in detail in Appendix 1. - 2 - Compn, SanW ^ no^ain rscACEN Vf.r'ViWp'-K-- "p of C. Pathology; Liver changes, basically charactcriicd by DIM or foci of coagulatlve necrosis containing large vesicular nuclei with aarkedly increased numbers, were seen in all treated groups of rats sacrificed following exposure 10. The Incidence and severity was dose-related although in each group there were rats which did not show this lesion. In the 2,000 ag/kg group, 3 rats sacrificed after 14 and 1 rat after 42 recovery days showed this lesion. None of the recovery raf In the 200 ag/kg group and 1 rat fron each recovery interval in the 20 ag group displayed the change. The liver lesion, both in terms of Incidence and severity, appears to be reversible. Coagulative necrosis of the epiderais at the dose site of 2 rats exposed co 2,'iUU mg/kg and sacrificed iomedlately after the last dose was observed* No other skin Lesions were observed microscopically and all other tissues and organs examined appeared normal. Details of pathologic results are presented in Appendix II. D. Organ and Body ^eigtt Analysts: There was a statistically significant Increase in the mean absolute and relative liver weights in all treated groups on exposure day 10. By recovery day 14, this increase was still significant in the 2,uOU and 20U mg/kg groups. At recovery day 42, che mean absolute liver weights were significantly increased in che 2,OUU ing/kg group only. On exposure day 10, che mean absolute spleen and kidney weights frosn the 2,000 ag/kg group were significancly less than controls and in the 20 ing/kg group the kidney weights were significantly greater than controls. The mean relative testicular weights from the 2,000 ag/kg group showed a statistically significant increase on exposure day 10. On recovery day 14, there was a statistically significant increase in the mean relative kidneys and testes weights of the 2,000 mg/kg and 200 ng/kg groups. Details of mean absolute and relative organ to body weight ratios are in Appendices V and VI. E. Organofluortne Analysis: Organofluorine measurements in each treated group were greater than controls after exposure 10, and recovery days 14 and 42. These increases were dose-related and appeared to be reversible with time. The controls had the lowest measurements of 10.2 ppm, 2.6 ppm and 0.6 ppm (after exposure 10, recovery days 14 and 42). The 2,000 mg/kg group averaged the highest values of 117.tf ppm, ^-.a ppn and tt.2 ppm. The 200 mg/kg group averaged 80.8 ppn, 26.2 ppm and 3.7 ppm. The 2U mg/kg group had average values of 52.4 ppm, 9.5 ppm and 1.2 ppm. There were rats in the 20 ng/kg group which had net values significantly greater than the controls. . [Ac recovery day 14 one rat had organofluorine concent rat. ion of 3.1 ppm and recovery day 42, two rats had values of 0.9 ppm.] Control values appear somewhat elevated at the exposure 1U and recovery day 14; however, ail control rats received only distilled water, applied with unconcaminated, sterile syringes and were housed in separate rooms from treated groups from study onset co sacrifice. Results of the nonvolatile fluorine measurements are reported in Appendix III. IV. Summary: Three groups of hrs/day, 5 days/wk for 2 wks. weight. A 4th group, exposed 15 male ChR-CD rats were exposed denoally for 6 to concentrations of either 2,000 mg ^B9|kg body simultaneoulsly to distilled water, served'as a control. Groups of rats were sacrificed and examined immediately following exposure 10, after 14 recovery days (no additional exposures), and after 42 recovery days. Sanitized. Does not contain TSCACK Company During the 10-day exposure period, rat treated with either 200 or 2,000 mg/kg lBi weight followed by a normal growth after exposure period. Slight redneHu of the skin was seen in these 2 groups along with salivation in the 2,000 "K/kg Kroup only. Kats treated with 20 ag/kg showed normal body weights and no unuBiml clinical signs during the experiment. Clinical enzyoe determinations monitoring liver function (alkaline phoBptuiiase, GPT, GUT) showed dose-related increases in all treated groups after exposure 10. These values returned to normal at recovery day 14 and 42, Liver damage characterized by coagulative necrosis was seen in all treated groups following the 10th dose. The incidence and severity of liver damage was, in general, dose-related. Recovery was complete in the 20 mg/kg group 14 dnys following the 10th dose and was essentially complete in the 200 mg/kg group at the same time. On recovery day 42, reversal of liver damage was essentially complete in the 2,000 ing/kg group. Two rats exposed to 2,QUO mg/kg had coagulative necrosis of the epidermis at the dose sice following 10 exposures. Liver weights, both on an absolute and relative to body weight basis, showed a dose-related increase on exposure dey 10 with a return to normal weight seen in the 20 mg/kg group at 1- days and in the 200 mg/kg group at 42 days recovery. The increased liver weight persisted for 42 days in the 2,000 mg/kg group although a trend coward normal was seen. Blood organofluoride levels showed dose-related elevation on exposure day 10 followed by a decrease in the levels at recovery days 14 and again at 42. These values after the cench exposure ranged from 52 ppm (20 nig/kg), ol ppm (20U ing/kg), and llo ppn (.l.UUU ppm) to 1, 4, and o ppm (20, 20U, and 2,1)00 ppn, respectively), at recovery day 42. At a blood organofluoride concentration of approximately 1U ppm there were normal liver weight to body weight ratios, serum enzyme activity, no clinical signs or body weight differences from controls. One ran showed liver changes at this level. At a blood organofluoride level of approximately 50 ppm there were marked liver changes and significant increases in the mean absolute and relative liver weights. No other roxic effects were evident at this blood organofluoride concentration. 4 - ^con,B.nTSC*CBl comply s.^"-0063 . \. ^-^'-i;-y^r,f/pv' ^-wy. Report by: ^ ^^^ >^ o -<Lw^n^c^- r ^ (7Lynn S. Silber Technician Approved by: Gerald L. Kennedy Chief, Acute Investigations Section LSS:jrg ['Study Director; u. L. Uashiell Uate i.ssued.UctobeLiU, 1^8^ Keport No. 5ri9-U Date Rpissued: January 15, 1982 5 - nc-no^cont^-TSCACB^ Company San,.^^, -"Q---0 HASKELL LABORATORY HO. 12037 CLINICAL PATHOLOGY REMRT PROCEDURE; Sixty male rats were divided into four groups of fifteen each. flx--e four groups were exposed dermal ly to 0 lag/kg, 20 ing/kg, 200 lag/kg and 2000 g/kg late' Blood wos taken from the tailf of five rats from each group after the posure, '.hen these rats were sacrificed for pathology. Fourteen day (RFC 1), blood samples were again collected from five rats froa each group and these were also sacrificed for pathology. Forty-two days after the tenth exposure (REC 2) blood was collected from the remaining five rats in each group. Heoatology measurements on the blood included the following: erychrocyte count (RBC), hemoglobin (Hb), hematocrit (Ht), leucocyte (WBC), and relative number of neutrophily (Neut), lyophocytes (Lymph), eosinophlls (Eosin), monocytes (Mono) and basophils (Baso). Mean cell colume (MCV), mean cell hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were calculated using the appropriate data. Clinical chemistry measurements included alkaline phosphatase (AP), glutamic-pyruvic tiransaminase (GPT), glutamic-oxaloacetic transamlnase (GOT) and total protein (TPROT). STATISTICS: The data were analyzed statistically by a one-way analysis of variance and least significant difference tests, comparing treated groups with the controls when the ratic of variance (F) indicated an effect due to treatment. Significance was judged at the 0.05 probability level. RESULTS: Results of the- clinical pathology measurements are summarized-in Table 1; statistical analysis in Table 2, A dose-related increase in the activity of the serum enzymes, GPT and GOT, in all groups occurred after the tenth treatment. The alkaline phosphatase activity in the serum of these groups was also higher than the controls at this time. The statistical analysis, however, indicated only the GOT in the group treated with 2000 ing/kg was significantly elevated. The serum total protein was also lower than the controls in this group. 6 - Company Sanitized. Does not contain TSCA CBI <y^m Increased actlvlt/oof the serum enzymes and a decrease In serum protein are associated with liver involvement.^ Similar effects have been observed in the serum enzymes.of rats InhallngMfBqplfi^ftuand in doga Ingesting --------jX^----B9' Fourteen and 92 days after the Fast treatment the serum enzymes-andcotar protein of the treated rats were not different than the controls. Erythrocyte counts, hemoglobins and hematocrits were lower than the controls in all treated groups 14 days after the last treatment. For the group created with 2000 mg/kg these measurements were also lower 42 days after the last treatment. BLM:JRB:ljm Date: February 29, 1980 Report hv. '^ftU^ '., ^mvA 0bby L. Moore Clinical Chemist ^LftifeftA^^ ^ Approved by: UJUoUhInI RR.. BOOalm-UeCsB Chie<^ Clinical Pathology Company Sanitized. Does iwi conSsirt 7SCA CB! AVERAGE CLINICAL LABORATOR Y TABLE I VALUES ON MALE RATS EXPOSED (DERMAL ^---- RBC X lO'/mm1 Hb g% Ht 7. MCV n1 MCH pg MCHC 7. WBC X lO'/iran' Neut 7. co Lymph 7 Eosin 7. Mono 7, Baso 7. AP W GPT IU GOT 1U TPROT g7. Exposure 0 TEN DAYS Concentration 20 200 mg/kg 2000 6.05 14.8 45 5.34 14. 1 45 5.23 14.0 47 6.30 14.6 44 75 84 89 70 25 27 27 23 33 16.3 23 32 ' 16.8 24 30 23.4 28 33 15.1 23 72 72 68 72 1.6 3.6 0 250 27 1.0 1.4 1.0 2.6 2.8 4.8 0 0 0 332 370 330 44 52 67 62 87 95 155 5.86 ,6.20 6.42 5.16 FOURTEEN DAYS Exposure 0 Concentration 20 200 niR/kR 2000 6.38 15.2 45 6.01 14.1 44 6.02 14.2 45 5.74 13.1 39 71 73 74 69 24 24 24 23 34 32 32 33 18.2 35 16.0 28 16.5 28 14.9 29 59 69 68 67 0.2 5.4 0 253 33 0.4 1.8 0 3.0 3.0 4.0 0 0 0 199 256 307 28 27 36 72 53 48 65 6.44 6.50 7.12 6.38 F Exposure 0 5.87 15.1 45 76 26 34 14.6 25 71 0.6 3.6 0 160 24 53 6.84 *"--------.-------------..- TS Comp.nySanil,l--ze--d,.Dnootocosnntaointc .-..-.... -.,.,,..-....-..-... ..^^.^.^ -------------<SP' ^.sy TABLE 2 SUM1ARY OF STA1riSTlCAL ANALYSIS FOR RATS EXPOSED (DERMAL ^^^--^ TEN DAYS Exposure Gone. mx/kg F 2000 200 20 FOURTEEN DAYS Ixooiw Cone. my/ka. F 2000 200 20 F 20 RBC 8.9 0 3.4 - 2.5 Hb 1.0 0 0 0 14.7 - - - 3.4 0 0 0 Ht 0.8 MCV 28.4 - MCH 25.9 - 20.8 - o - 9.9 ^ 1.9 0 0 0 2.4 i i- 1.0 0 0 0 0.2 MCHC 7.1 0 - 0 0 0 WBC 2.5 i io Neut 0.6 0 i 0 0 0 Lymph 0.6 0 0 0 1.3 0 0 0 5.0 0 0 0 0.9 0.2 0.5 0 0 0 1.4 0.7 0 0 0 1.5 Eos in 0.6 0 0 0 2.3 0 0 0 1.5 Mono I.I 0 Baso 0.0 0 AP 1.7 0 GPT 2.3 0 GOT 4.0 i- TPROT 15.2 - 0 0 0 0 0' 0 0 0 0 0 +. Q 1.2 0 0 0 0.2 0 0 0 0.0 0.0 4.9 + 0 0 0.4 1.1 0 0 0 0.2 2.9 0 0 0 1.0 5.8 0 + 0 4.7 cof 0 - not significantly different from control - significantly lower when + - significantly higher when compared to controls red to controls C,,,,p^ S..>-^. o no. con.a.n T .:y;i\-il;i;''K:^''>VO'-K';'' ";: . r,iv ',.;..r-1 CSNTUL BUBABCH WO SVieumOVS KPAR1MBHT 8ASKBU. LABOBAIOKY FOR TOXICOLOGY AND IMDUSTRIAL MEDICINE APPENDIX IZ Octanoic acid, pentadecafluoro-, a--ontua W aalt H-12.037 - PetrochMd.cala Depart--nt Subacute Deraal Toxicity Study May 27. 1980 CMf-CD Baf ^-wgas^^^ Introduction Male ChBSt-CD rats were arranged into four treataenc groupa as follows; Group I - Group II Group III - Group IV - Distilled water control (0.05 ol) 2,000 mg/kg (as an aqueous paste) 200 mg/kg (as an aqueous paste) 20 mg/kg (as an aqueous paste) Results The morphologic changes observed at necropsy are reported in Table I. 'Representative sections were prepared for histonorphologic evaluation froo bone marrow (sternum), brain, cecum, colon, epididymides*, esophagus, eyes, heart, kidneys*, liver*, lungs*, skin (control area), skin (treated area), small intestine (duodenum), spleen*, stomach, testes*, chynus*, thyroid, trachea, and lymph node (mediastinal). The results of histomorphologic evaluation of tissues 10 Company Sanitized. Does not contain TSCA CBI fron the control and high-dosed racs are presented In Table Il< Upon finding a compound-related effect In the cutaneous and hepatic tissues of animals in the high dose group, similar tissues were examined microscopically from all animals in the intermeciate (200 mg/kg) and low dose (20 og/kg) groups. The results of these examinations are reported in Table III. Compound-related histooiorphologic changes are summarized for between group comparisons in Table IV. Discussion and Conclusions A compound-related hepatic effect was observed in rats from all three compound-treated groups (Table IV). Affected livers contained one or more foci of coagulative necrosis. The Kupffer cells, within the foci of hepatocellular necrosis, contain large vesicular nuclei and were markedly increased in number. Inflammatory cells were occasionally present within and at the periphery of the necrotizing legions. Dermal lesions at the site of compound application were observed in two animals in the high dose (2,000 ing/kg) group (Tables II and IV). Affected areas of skin were characterized by coagulative necrosis of the epidermis and papillary and reticular demiis. A minimal lympho-histocytic inflammatory infiltrate was present in the subadjacent der-r.is bordering the necrotir zones. The remaining hiscomorphologic changes shown in Table ! were changes that were observed with similar frequency in the control and coc. pound-treated groups and/or were lesions which commonly occur in laboratory-reared rats. n- Compas\y Sanitized. Does not contain TSCA CB! Summary The dermal application of octanoic acid, pentadecafluoro- aoBooiua salt Jl^^^^^lfor 10 days resulted in hepacocellular necrosis and necrosis of cutaneous tissue at the sice of application. * - Tissue weighed Report by: ^yiWTM^^-/^fct^\ Rftaayymmoand M*. Everett, D.V.M., Ph.D. Senior Research Pathologist RME:vlm . Date Issued: May 27, 1980 Approved by: ^^^ ^NUi^ ^ ' William C.'Krauss, D.V.H. Chief, Pathology Section 12 - Company Sanitized. Does not contain TSCACB1 DERMAL MACROSCOPIC OBSERVATIONS RECORDED DURING NECROPSIES OF Chtf-CD CONTROL AND TEST HALE RATS TREATED Vt ----------<---J APPLICATION WITH OCTANOIC ACID. PENTADECAFLUORO- AHMONIUM SALTJ RaC No. Aaount of Autoly sia Recorded During Necropsy Group 1 - Control Males 12 Days on Test; 0 Recovery Days 263204 None 263205 None 2632U6 None 2&32U7 None 2632Utf None Mode of Death* S S S S S Observations N.A.D.t Thyus - pink N.A.D. N.A.D. N.A.D. 2b Days on Test; 13 Recovery Days 2&3209 None S 263210 None 263211 263212 263213 None None None Thyaus - right lobe - dark red Lungs - all lobes - red foci Thynus - right lobe aottling pin-head sized - dark red N.A.D. Salivary Lymph Nodes - large, mottled red Thynus - pink * Mode of Death: E Sacrificed in extremis; FD - Found Dead; S - Sacrificed t N.A.D. - No abnormalities detected. iCGKWany Sanded.'Dee? not contain TSCA CBI 53 Days on Test; 41 Recovery Days 263215 None 263217 263218 263219 2b3277 None None None None Lungs - few dark red foci 0.5 to 1.0 on in diameter, few grey streaks Nose - red discharge Skin - neck - irritation Lungs - grey Bottling 1 to 3 on in diameter Skin - neck - necrotic area 1.5 x 0.2 cm; skull - necrotic area 3 OB in diaaeter Thymus - left lobe - dark red Liver - lobular markings prominent N.A.D. /' Does not contain TSCA CBJ ~ 14 -Company Sanitized. Group 11 - 2000 lag/leg Males j^2 Days on Test; 0 Recovery Days 26322U None 263221 None 263222 None 203223 None 263224 None Animal - Chin Liver - heavy Nose - red discharge Perlneal Area - wet and stained Skin - chin - stained and moist Eyes - red discharge Liver - heavy Nose - red discharge Perlneal Area - stained, wet Skin - Irritation Spleen - small Urine - bright yellow Animal - very Chin Liver - heavy Nose - red discharge Perineal Area - stained, wet Skin - irritation Thymus - very small Urine - stained red Liver - heavy Nose - red discharge Perineal Area - stained, wet Skin - test area - dark red crusty area 0.8 cm in diameter Spleen - small Thynus - snail Urine - bright yellow Eyes - red discharge Liver - heavy Nose - red discharge Perineal Area - stained, wet Skin - irritation Compaq Sanif.zed^ . nDoo--ss^-^tc^5'"12^05' TABLE I (Cont'd) DERMAL MACROSCOPIC OBSERVATIONS RECORDED DURING NECROPSIES OF ChRO-CD CONTROL AND TEST MALE RATS TREATED BY APPLICATION WITH QCTANOIC ACID. PEHTADECAFLUORO- AMMONIUM SALT Rat No. Aaount of AuColyis Recorded During ___Necropsy____ 26 Days on Teat; 13 Recovery Day 263225 None 263226 None Mode of Death* 263227 None 2H3228 2&3229 None None 53 Days on Test; 41 Recovery Days 2b3231 None S 2&3232 None S 263234 None S 263235 None S 263236 None S Obtrvtioir Liver - heavy Liver - left lobe - numerous pale brown foct up co 1 r in diameter, heavy Liver - heavy Thymus - right lobe - moccling dark red Liver - heavy Liver - heavy N.A.D. N.A.D. N.A.D. N.A.D. N.A.D. SCAC^ .snoiconiitai"^ - 16 - ComP^5c"at^66-006 DERMAL MACROSCOPIC OBSERVATIONS RECORDED DURING NECROPSIES OF ChRO-CD CONTROL AND TEST MALE RATS TREATED BY APPLICATION WITH OCTANOIC ACID. PENTADECAFLUORO- --..mrwvw- I AnrMUMKOjnNiIUUHM SSAALLTTJ^^^^^M Rat No. Amount of Autolysis Recorded During Necropsy Group III - 200 mg/kg Hales 12 Days on Test; 0 Recovery Dayis 2o3238 None 263239 None 263240 263241 None None 2632.42 None Mode of Death* S S s 5 Observation* Liver - heavy Liver - cyatic lobe - grey area 0.8 cm In diameter, heavy Liver - heavy Liver ~- hheeja>vy> Nose - red discharge Perineal Area - stained, wet Skin - neck - Irritation Eyes - red discharge Liver - heavy Nose - red discharge Thynus - pink 26 Days on Tesc; 13 Recovery Days 263243 None 263244 None 2t).)_.5 None 2b3246 2b324b None None Liver - heavy Liver - heavy Thyaus - pink Liver - slightly heavy Testes - right - yellowish-white subcapsular screaks Kidneys - right - hydrocephrosis Liver - heavy Liver - heavy Lungs - few pin-head size red foci scattered throughout - 17 - . ^ ^ ^ ' San'^1-*' ^ ^ - cowy3^ . TSCA^ TABLE I (Cont'd) DERMAL MACROSCOPIC OBSERVATIONS RECORDED DOPING NECROPSIES OF ChB9-CD CONTROL AND TEST HALE BATS TREATED BY APPLICATION WITH OCTAMOIC ACID. PEHTADECAFLUORO- AKHOMIUM SALT Rat No. Amount of Autolyaii Recorded During Necropsy____ 53 Dayg on Teat; 41 Recovery Pays 263249 None 26325y None Mode of Death* S S 263251 263252 None None 263253 None Obaervtion Skin - test area - thick Lung* - floe grey Bottling cactered throughout N.A.D. Skin - teat area - alightly chick Thyua - right lobe - pink Testes - alightly all ^-"TSC'C61 s.^^0065 18 - Co,' n^5 l--^... -. ... TABLE I (Cont'd) DERMAL MACROSCOPIC OBSERVATIONS RECORDED DURING NECROPSIES OF ChB-D CONTROL AND TEST MALE RATS TREATED VS APPLICATION HITH OCTAHOIC ACID. PEMTADECAFLUORO- AMMOMIOM SALT Rat: No. Group IV - Aaount of Autolysis Recorded During Necropsy____ 20 g/kg Males 12 Pays on Teat; 0 Recovery Pays 263254 None 263256 None Mode of Death* 263257 263258 None None 263259 None Obaervtiona Liver - heavy Liver - heavy Skin - neck - scaly, cruaty Liver - heavy Liver - heavy Thyus - left lobe - pink Liver - heavy 26 Days on Test; 13 Recovery Days 263260 None S 263261 2o3262 2b3265 253268 None None None None Liver - slightly heavy Lungs - grey ottling scattered throughout Skin - neck - necrotic area N.A.D. N.A.D. Skin - neck - necrotic area 8 oa in diameter 53 Days on Test; 1 Recovery Days 263269 None S 263270 None S 263271 None 263276 None 263278 None - 19" N.A.O. Skin - test area - slightly chick N.A.D. N.A.D. Skin - cost area - slightly thick ^c^ . ^co^^ ft%T^V^' ssd.y0^'" CaS^ TAHLK l_l IIISTOM(IHyHl)l.(,l(; OBSERVATIONS <lf TISSUES HUM HALT. Chll* -1;P KAfS THKATKU BY UKMtAI. APPLICATION WITH UCTANOIC ACIH, PCHTAMX-ArLUOlO- AHWMIUH SA TiBBtie** .iifl OhnervnlIon*** Mode of Orolll* l>y on Teat fcovry Ony Aninjl Nrber 261- one Harrow (ternim); rain: Cecir: Colon: Epidldylilcn: P-r IVBBr.ilur l.yphncyt (< Inf I It rnt li<n, rurnl/Mull llncnl Hlliltrrol PprlrpidIdymnI Fnt, NpulrnphiIIr Inflni--ntlon, Unllalerol PerlvBoilnr l.yiphocytic Inf 111 rat l-i, Focal/Bultlfocal, Unllrffi Perlepldldynl fut. PyogfnuloBalniin Indx--ntlon, rornl/Bult I focal , Dllati-rul EaophanuB; Ryii: Rellnjil RoBett*. Unllnterol Henrt: " ss S \i 17 U U0 U n 1 U0 0 4 '> 6 Urc>up 1 - (;nilultl S S S S S S S 3 S S S S- If IX 12 26 26 26 2b ^1 '*) H ! i1 U U 11 11 11 1} 11 41 41 > 41 41 T- 1 2 tt 0 2 '2" 2 0 11 2 1 1 2 2- 1 1 1 > 1B9 0 2 1^ 789 NMNMMNHH N N 11 N N N N U HHNNONNU H N H N HHNNNMNN NMNNHMHN N N H N L N M I, N I. N N H N N I. NN NNN H N NN NNN N N N N N N H N NNH NHN N N NNKN NN N N H N ___ JT-T-S- S C8roup5 12 12 12 12 12 26 0 0 U 0 0 11 N N tl M N 0 N MHM NNN NN N H N 1. N N N * Mode of Death* E - STrlllced <ln trei, r - Pound (J, .1 - Sacrificed. ** TIaflue Accounting Coda! A Autolyl* preventc'l ccplef evaluation; K AulolylB praaat, tiaaii al Klow ---- disruption of tiBaue prevanted cowpletu eviuntlon: L - Lexton o--erved; N No (lo ob--re4| 0 Tr not a hiBtowirphologlcrl evaluation. Severltr of llon Code: I Hint--I changl 2 - Hlld cimeel )- Hodrate rhnnke, Harked che( f Clm|e prei R - Bllnfrnl rluinir preent, everlty not xrnded. Company Sanitized. Does not co TABLC II (Cont'd) ! 1IHSTM(liniOI.<i|C OBSEHVATI (IMS or n SSIJES FROM HAI.K L'h- CD RATS TREATED BY 0 CMtAL AftLICATIUN WITH UUT^LHIIIC ACir', 1'tinuit.r.A^LUOIIO- AT--OM1U Tliioiw** and ObaTVofnn*** Hoilr of Dpnth* [tay on Tft Recovery--"M" ... An(I Mlirbpr 26.)- Group I - Control!1 ? g- 1 !i s s a ^ i a 3 1 5 A T il il ij 12 12 12 12 12 26 26 26 26 2ft 1 S1 0000 0 --^- 7- T -2 2" H 0 1) 11 11 41 41 41 41 41 2 ! Z 7- 22222} 0 0 0 H l 1 0 0 1 1 1 1 4 ^ 6 / a 9 o i i i < / B i Kidney: PronlBfll Tubulair EGplitlhhrflllir, eiieneratlon., Focal//Bluulll(lflocral Prrlvaiiriilnr Lyphorytic Infl Itrni lon/i Intrrnt If Inl Npphrltl*, Submitr, FornI Hrdull*. f;yt/. Tubular l.lver: ElrnMr>liil lAry Hnrtopolflii PertvBrular, l.ypt>-hlBltcyl Ic Innllrnilon/8 Fociu of Celluirr Alteration. Bfophlllr CpntrolobulT Vacuolar Ctnplfrlc Changr HepiitocellulT Cojgulitiv Kecroal* With Kupffpr Cell rrotlf*ralon r(broil*, foc*l Perlporfl Lyphocytic 'n/ltrt Ion/* Prlporil Pibrajlf nd H--Blilrln Depoittlon, Hul(l(ocl CantrolobulT Slnuoldl Refill l-ung: Perlvcuirr Lyphocytic Infiltration/a Graniilu--touB lnfl----tlo>, rocjI/Hrll lloral HIt.tlnrytoBln. Focal/Hull I fool Lyph Nodpa (Hr<lJ*Bt Innl ); Corlex, 11--orrhjge N N N N N N L N L 1. H N N N N 1 I I HL NNNN N N N H N N N N N N L L 2 I 2 2 I OIIMUHONONNINO 0 0 ff-T- 8 12 12 12 C0 0 2 22 0 12 R l Groi 5 < 12 12 2 00 1 22 2 L N 1. N H M 1 L I. H I 2 Company Sanitized. Does no TAHI.e IJ (,<;"ilt''lj III.STllrfDRPHOI.UII: OBSKKVATHtNS r T1SS1WS FROM HALE (;iill-CU RATS TRCATKU BV Uf.RMAI. APPLICATION WITH (X;TAHOIC AC1I), PRNTADECAFLUOTO- ArMOHHIH 8 Ttue** nix) ObaorvatIon*** Mode of Death* Dny on Tent Kecovory On y__ Anl--1 Nil--her 26)- Group 1 Cc>nl<> 1 S .S S S S S S 3 S S S 12 12 12 12 12 26 26 26 2A 26 T- -s~ S "?' 53 11 M M 222 -T 0 0 0 0 0 2 2 2 ,^,,. 11 11 11 11 13 41 41 41 41 41 2 2 2 2 ? 2 2- 0 n 1) 0 0 0 1 1 1 1 1 4 l A I 11 9 0 I 2 1 } B 4 1 Skin (Unlrentnd Site)! N N N H H N N N N N N H 1. N N Head and Neck, ParakeraloslB, Hypcrk-rnloissIin., Inllltrrtlon by Neutrophllr 1 Skin (Treated Site)! N N NH NN N NNNH NKN OrrmntII In, Acute Hoc rot I ring Swill Intent Inp ((hmdenir); NN NNNNN NNN NN HNN Splc-riii H N H N N N N N N N N M N 11 StoMrh: L N NN NH N NNN NN N H N Glandiiliir/NnnKlanrfiiljr. Ijiilna Prnprin/ liilMKiroiin, Eirlnoplllllc InfI It ratlon/r / Ulnndulnr, NrcrontB with Yellow PIgapnl UcpoRltlnn. FocxI/MkiIt I forxl Honglanduljir Portion, Uriiui Proprli Tectes: Spematir Cell Atrophy, UnllMternI Thyur! EdeiuM N NNN NNN N NH NN HL M 3 NN NN NNN H HN Cortex, Lyphold Atrophy Cortex, HiMrl4erln Deporltlon, MnltltucuIIlI Thyroid: 0 N N NN N L N N MM H N N Cyt, S>]uaiou Cell l.lncd Trachea: P P M M MM MN N N HN Urtiia Proprtr, Lypha-hlBtlocytIr Ind ltrtlrn La-lM Propria, Lyphocytic Infiltration/* ?- T-T S S I ;roup 5 12 12 12 12 12 26 "Ta- 0 0 0 1) 22222 0 12 14 N NHH NNL LMN P P N N N N N N H MN N N H L H P 2 N 1 1 1 N N MN L 0 P ^ized- Does not co ComP^53" TABLF. Ill IIISTriMOKPlllll^ll: OBSERVATION", W TISSUT.R PROH HALK (:hB-CH "AT8 TKBATEDJ1T 11EKHAL APPLICATION WITH UCTANUIC ACID, rgNTAUgCAFtWO- AMM0111UM Hode of tenth* Drya on TrBt covery Day TiBnw-- nnd ObaprvntIon*** Anita I Nuiaher 261- Llwen Httpatocdiulai Nerroala MIth Kupffer Cell ProlKeration, Focal/Hull I (ocrl FTlportal ribroala, Hultlfocnl Perlportnl Lyphorytic Infl 1 trnr lon/n Centrnlohulnr SInuBold*! Rrtnula F.xtrnBpdulInry HewilupoleslH Skin (Untreoi.ed Site): Ulrerntlon with Acute llrrnuil I ( IM Hrck, lllcpratlve, Chronic-Act I vc DcTBJit It |W, FOC* I fhin (Trrnted Site): S S i (iroiJD 111 - 200 g/k % & S S S ri S S { S !* 8 17 12 12 12 12 fh 26 26 26 26 51 S1 Sl S1 11 0 U n n 11 11 41 41 41 41 41 000 ii 2-2 n 2 ? 2 -7" 7--T 12 7 2 i i i 44 444 444^S 8 9 0 1 2 1 4 i 6 1 9 0 1 ; 1. 1. N N H L N N 1. N H H N i I I NHNL N P N NN N NNNNNHHNNNNMIIN Gro s 5 I s s 12 12 12 12 12 2 ( 0 0 0 0 1 222222 467890 H I. M M N H N prfol. MoIe ot Death:E - S<rrlH<-ed In xtrgl, I' - Found Dead. S. - Sacrificed. * TIrue Acroiintlnn Code; A Autolyli prevented roMplele eviuatloni K - Autolyl* tlue evaluation dtTuptlon of tirue prpvented romplete VIE I lint Ion; L Leainn obaerveds H - Ho lealon ob--rv4| 0 - Tim-- not hiatoamrphologtcal evnlnation. ** Severity of Lealon Code; I - Hlnl--1 rhange; 2 " Mild rhan|f; 1- Hoderale rhan||e. Mar--a chan{ P - Clu--.e pra B - Bilateral chana prenent, aeverlty not Rraden. Sanr^.ooesn.,,<^< croor Cpntpa"^";!- "IB^r """""'^ TABLE IV SUMMARY OF INCIDENCES OF HISTQMOKPHOLOGXC OBSERVATIONS OF TISSUES FROM HALE ChB-CD RATS TREATED BY DERMAL ApPLICATU WITH OCTANOIC ACID. PgNTADECAFLUORO- AMMOMIUM SALTF Group Designation Doae Recovery Days Nuaber In I 6"1g3/^41 ________Treatment Group____555 Tissue/Observations ir II 2W09S/}W 0 15 5 5 5 Liver: Hepacocellular Necrosis with Kupffer Cell Proliferation, Focal/Multifocal Skin (Treated Site): Dermatitis, Necrotizing 555555 000331 050550525050 m 2d00lMl"/kfgf 5 55 iv 26 03M/UZi 5 55 555555 300211 505050505050 - 2* ~ not contain TSCA' - companySan. ^n-0e0s65" APPENDIX III AVERAGE ORGANOFLUORINE VALUES FOR GROUPS I. II. Ill AHD IV Sroup Sto. I II III IV Dose mq/kq J 2,JJO 20-") Total Nonvolatile Fluorine (ppm) Exposure Recovery Recovery Day 10 Day 14 Day 42 10.2 2.6 0.6 117.8 44.8 8.2 80.8 26.2 3.7 52.4 4.5 1.2 25 Company Sanitized. Does not contain TSCA CBI -".'W ".Wffiqpy-:'--. !-..---^ " ."-'-' '': '' ' ' ' "'-it' INDIVIDUAL ORGANOFLUORIDB VALUES (PPH) FOR GROUPS I, IX, III AND IV Group T Group II Group III Group IV Exposure Day 10 14.0 8.0 16.0 11.0 2.0 104.0 133.0 144.0 116.0 92.0 91.0 41.0 72.0 122.0 70. J 52.u 58.0 53.0 51.0 48.0 Recovery Day 14 3.4 3.3 3.1 2.3 1.2 44.0 41.9 36.7 67.2 34.2 26.8 25.9 18.2 29.1 30.8 17.6 6.5 3.1 10.8 9.5 Recovery Day 42 0.3 0.8 0.4 0.4 0.8 5.0 4.2 7.0 13.9 10.7 2.8 2.1 5.9 5.9 1.8 0.9 1.0 0.9 1.9 * Insufficient blood sample 26 Company Saniiizsd, Does not contain TSCACBS