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AR226-3014 L Study Title USP Biocompatibility Testing of H-21016 end B-21017 Study Completed on April 18, 1995 Contracting Laboratory North American Science Associates, Inc. 2261 Tracy Road Northvood, Ohio 43619-1397 for E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.0. Box 50 Newark, Delaware 19714 Study Honitor Susan A. Mackenzie, V.M.D., Ph.B., D.A.B.T. Medical Research Project No. Laboratory Project ID Haskell Laboratory Report No. 289-95 Page 1 of 11 * company Sanitized. Does not contain TSCA CBf DuPont HLO 289-95 GENERAL INFORMATION I f Substance Tested! Control Substance Synonys/Qther Codes: m NAmSA Lab. No.; Physical Form; Purity; Compositions Contaminantss CAS Registry No.; Substance Tested; Synonyms/Other Codes; Test Substance NAb SA Lab. No.s Physical Forms Purity; Compositions Contaminants; CAS Registry No.; Study Initiated-Completeds 02/15/95 - 04/18/95 - 2- K . Company Sanitized. Does not contain TSCA CBI O u f W t Central I m a r c h and Developnent Haskell Laboratory for Toxicology and Industrial Hedicins DuPont BLO 289-95 April 18, 1995 J. T. Sinners DuPont Non-Voven Old Hickory, Tennessee USP Biocoapatibility Testing of H-21016 and H-21017 Attached you will find reports fron North Anerican Science Associates, Inc. The results for the H-21016 and H-21017 sanples are: Test Results H-21016 H-21017 Intracutaneous Toxicity (USP) - Sodiun Chloride Extract - Cottonseed Oil Extract Pass Pass Pass Pass Cytotoxicity Testing (Agarose Overlay) Non-Toxic Non-Toxic Implantation Test (USP) NS NS non significant y lu lls ' Susan A. MacKensie, V.H.d T, Ph.D., D.A.i.T. Research Toxicologist -3- Company Sanitized. Does not contain T SC A ...-*-- '--.. ---- ................................... ...... . _... ...... HMJtWorld Leaderin Tenting -vice* for the M editai Device In a i t in D u P o n t HLO 2 8 9 -9 5 2261 Tracy Rood Northwood, CH43619 Phone 419*666*9455 FAX 419*606*2954 El DU PONT DE NEMOURS & CO s. HASKELL LAB FOR TOX & IND. MED it ELKTON RD PO BOX 50 NEWARK, DE 19714 I- ATTN: DR. SUSAN A MACKENZIE LAB NO. 95T 06035 00 P.O .N O . LQ X S70S07 H> KO h-21016 CYTOTOXICITY - AGAROSE O VERLAY, SOUD Test Article: H-21016 Test Article Description: Sheet - a 1 cm2 piece Procedure: A monolayer of L-929 mouse fibroblast cells w as grown to confluency and overlaid with Minimum Essential Medium supplemented with serum, antibiotics, neutral red, and 2% agarose. The test article, a 0 .5 cm x 0 .5 cm piece of 725871H as a positive control, and a 1.0 cm length piece of UP-1 as a negative control were placed on the enSdrfied overlay surface. Following incubation for 24 hours, the culture w as macroscopically examined for evidence of ceil decolorization to determine the zone of cell lysis. Any decolorized zone present was examined microscopically to confirm cell lysis. Score N (Nontoxic) Observations Normal cel! morphology in proximity to test sample. T (Toxic) Cellular death and degeneration associated with the area beneath the test sample and possibly extended beyond the perimeter of the test sample. Where a zone of lysis was observed, the distance from the edge of the sample to the edge of the zone w as measured and reported in millimeters (mm). Results: Test/Control Articles Test Article Negative Control: UP-1 NAmSA Positive Control: 725871 fi SCOT N N T Zone of Lvsis (mm) 0 0 7 Conclusion: The above test article w as nontoxic for L-929 mouse fibroblast cells under the above Comments: Not Applicable. Date Prepared: 3-28-95 Date Terminated: 3-29-95 Completed $ - 3 > -9r Approved_ -4 M G 030-110 Company Sanitized. Does not contain TSCA CB wipWjM KAiiiSAWorldLeaderin Tading Servicen for the M edical D evice Industry DuPont HLO 289-95 2261 Tracy Road Northwood. OH 43619 Phone 419-666-9455 FAX 419-666-2954 LAB NO. 95T 05035 00 P.O. NO. LGX 570607 El DU PONT DE NEMOURS & CO HASKELL LAB FOR TOX & IND. MED EUCTON RD PO BOX 50 NEWARK, DE 19714 , ATTN: DR. SUSAN A MACKENZIE f ID NO. H-21016 Bm b 1 Of 2 ; USP INTRACUTANEOUS TOXICITY TEST IN RABBITS Test Article: H-21016 Extracting Conditions: A 120 sq. am portion was covered with 20 ml of vehicle)) and extracted at 121 C for 1 houris). Control solutions (vehicle without test article) were prepared in a similar manner. Condition of Extracts: Testis): SC and CSO clear ControKs): SC and CSO clear Procedure: Two healthy New Zealand White rabbits free of significant dermal blemishes were used as test animals for each extract or pair of extracts. Animate were housed ndhridualy in suspended cages with daily access to food and water. Prior to injection, the fur was closely clipped from the back and from both skies of the spinal column of each rabbit. A 0.2 mi portion of the test extract was injected intracutaneously into five separate sites on the right side of the bade of each animal white 0.2 mi of the control solution was injected into five separate sites on the left side. Injection sites were examined 24, 48 and 72 hours after injection for erythema and edema. The average tissue reaction to the extract of Ore test article w as compared with the control. The requirements of the test were met if the difference was 1.0 or less and there was no evidence of necrosis or ischemia. Date Prepared: 3-29-95 Date Injected: 3-29-95 Date Terminated: 4-1-95 f r Comotetari^ - V>C fi- Approved Merla J. Hafaafca. BS. LAT - 5- company Sanitized. Does not contain TSCA Qfy N A iiiS ilWorldLeaderin TeetngServiceli far the M edical Device ln d u elrt DuPont HLO 289-95 2261 Tracy Road Northwood, OH 43619 Phone 41*666*455 PAX 419*666*2954 *2- LAB NO. 96T 05036 00 USP MTRACUTANEOUS TOXICITY TEST IN RABBITS ER ERYTHEMA 0 = No Erythema 1 Very Sight (barely perceptible) 2 = Wait-defined (pink) 3 = Moderate to Severe (red) 4 = Severe (beet redness) to slight eschar formation (injuries in depth) ED S EDEMA 0 = No Edema 1 " Very Sight Ibaraiy perceptible) 2 Slight (edges of area weft-defined by definite raising) 3 = Moderate (raised ~ 1 mm) 4 = Severe (raised > 1 mm, may extend Results: Extract Rabbit No. Site 1 24 HOURS ER ED 48 HI3URS ER ED 72 HOURS ER ED Sodium Chloride (SC) 86002 85984 Cottonseed Oil (CSO) 86002 85984 Test Control Test Control Test Control Test Control 0 0 0 0 2* 2* 1 1 0000 0000 0000 0000 1 2* 1 2* 1 2* 1 2* 2 1_ 2 1 2 12 1 0 0 0 0 1 1 2 2 i Average Test (-) Average Control I SC 0.0 - 0.0 1 CSO = 1 .5 -1 .5 Difference 0.0 0 .0 Comments: "Erythema extended beyond the injection sites. Pas X X Fais 6 Completed. Apptoved,,_____-- (See oeae H " 6- Company Sanitized. Does not contain TSC CSS NAm SAWorld Leaderin Testing Servtes fo r the M edical Device Industry DuPont HLQ 289-95 2261 Tracy Road Northwood. OH 43619 Phone 419*666*9455 FAX 419*666*2954 I' B DU PONT D E NEMOURS ft C O H ASKELL LAB FOR TO X & INO. MED SJCTON RO TO BOX 60 NEWARK. OE 18714 ATTN: OR. SUSAN A M ACKENZIE LAB NO. P.O. NO. ID NO. 96T 06036 00 USX 670607 H -21016 Test Artici: H-2101 6 U SP M USCLE IMPLANTATION TEST IN RABBITS - Preparation: The test article w as cut and trimmed to 1 mm x 10 mm. Sterilized by atcam. Procedural Two hoatthy adult Now Zealand White rabbits weighing at least 2.6 kg were used ae test animals. The back of each animal waa clipped of fur on both aides of the spinal column. Loose hair waa removed by alcohol w ipe after clipping and the paravertebral muscles ware anesthetized. Strips of sterile test article ware implanted into the right paravertebral muscle of each rabbit; strips of U SP control plastic ware implanted in the left paravertebral muscla of each rabbit. The animale w ere euthanatized 2 days after implantation and the entire paravertebral muscle on each side of the vertebrae w as removed. Cross sections of the m uscles were made to locate the implants. The tissue surrounding the implant w as examined macroscopcatty. . Results of M acroscopic Examination: Score Scoring Key Encapsulation 0 1 2 3 4 0 -0 .6 0 .6 - 1 .0 1 .1 -2 .0 2 .1 -3 .0 fc3.1 Average: 0 .0 0 .0 Average Itestl - Average (control) 0.0 No capsule or adverse reaction (other than mMmal hemorrhage) Up to 0 .6 mm capsule or reaction area 0 .6 to 1.0 mm capsule or reaction area 1.1 to 2 .0 mm capsule or reaction area > 2 .0 mm capsule or reaction area Reaction Index Not Significant Trace Slight Moderate Marked M acroscopic: The reaction waa not significant as compared to the USP negative control implant material. C om m ents: 'Previous use history traceable in laboratory record*. Com pleted. ilWLfjtLiMarte J . Hafctehe. B8. LA` T U O I 4-8 0 7 ompany Sanitized. Does not contain TSCA CBp DuPont HliO 289-95 World Leader in Tenting Services m t t S A fo r the M edical Device Induntrv 2261 Tracy Road Northwood. OH 43619 Phone 419*666*9455 FAX 419*666*2954 El DU PONT DE NEMOURS & CO HASKELL LAB POR TO X & IND. MED ELKTON RD PO BOX 50 NEWARK, DE 19714 ATTN: DR. SUSAN A MACKENZIE LAB NO. 95T 05034 00 P.O. NO. LGX 570507 ID NO ' H-21017 CYTOTOXICITY - AGAROSE OVERLAY, SOUD Test Article: H-21017 Test Article Description: Sheet - a 1 cm2 piece Procedure: A monolayer of L-929 mouse fibroblast cells was crown to confluertcy and overlaid with Minimum Essential Medium supplemented with serum, antibiotics, neutral red, and 2% agarose. The test article, a 0 .5 cm x 0 .5 cm piece of 725871H as a positive control, and a 1.0 cm length piece of UP-1 as a negative control were placed on the solidified overlay surface. Following incubation for 24 hours, the culture w as macroscopically examined for evidence of cell decolorization to determine the zone of cell lysis. Any decolorized zone present was examined microscopically to confirm cell lysis. Score N (Nontoxic) Observations Normal cell morphology in proximity to test sample. T (Toxic) Cellular death and degeneration associated with the area beneath the test sample and possibly extended beyond the perimeter of the test sample. Where a zone of lysis was observed, the distance from the edge of the sample to the edge of the zone w as measured and reported in millimeters (mm). Results: TPSt/Contfol Articles Test Article Score N Zone of Lvsis 1mm) 0 Negative Control: UP-1 N 0 NAmSA Positive Control: 72S871H T 6 Conclusion: The above test article was nontoxic for L-929 mouse fibroblast described test parameters. , Comments: Not Applicable. Data Prepared: 3-28-95 Data Terminated: 3-29-95 under the above ie Competed 5 - -)<; Approved. M G 030-110 Company Sanitized. Does not contain TSC A CBf DuPont HLG 289-95 HAhiSAf Wortd Leader tn Testing Servicen fur the M edical Device Industry 226! Tracy Road Northwood. OH 43619 Phone 419*666*9455 FAX 419466*2954 El DU PONT DE NEMOURS & CO HASKELL LAB FOR TOX A IND. MED ELKTON RD PO BOX SO NEWARK, DE 19714 ATTN: DR. SUSAN A MACKENZIE LAB NO. 96T 05034 00 P.O. NO. LGX 670607 ID NO. H-21017 USP INTRACUTANEOUS TOXICITY TEST IN RABBITS Test Article: H-21017 Extracting Conditions: A 120 sq. cm portion was covered with 20 mi of vehicle(s) and extracted at 121 C for 1 hour(s). Control solutions (vehicle without test article) were prepared in a similar manner. Condition of Extracts: Testis): SC and CSO clear ControKs): SC and CSO clear Procedure: Two healthy New Zealand White rabbits free of significant dermal blemishes were ?<as test animals for each (tract or pair of extracts. Animals were housed i y suspended cages with daily access to food and water. Prior to injection, the fur was cVmmhf clipped from the back and from both skies of the spinal column of each rabbit. A 0.2 ml portion of the test extract was injected intracutaneously into five separate sites on the right side of tiie back of each animal while 0.2 ml of the control solution was injected into five separate sites on the left side. Injection sites were examined 24, 48 and 72 hours after injection for erythema and edema. The average tissue resetion to the extract of the test article was compared with the control. The requirements of the test were met if the difference was 1.0 or less and there was no evidence of necrosis or ischemia. Date Prepared: 3-29-95 Date Injected: 3-29-95 Date Terminated: 4-1-95 Approved Merle J . Heteaka. BS. LAT .... V TTtUtf0\143-A8A0A0 Company Sanitized. Does not containT S C A CBls. `yyo'w fwffgl f L 6 NAmSAWorldLeaderm Testing Services for the M edical Device Industry DuPont HLO 289-95 2261 Tracv Road Northwood, OH 43619 Phone 419*666*9455 FAX 419*666*2954 -2- LAB NO. 95T 05034 00 USP MTRACUTANEOUS TOXICITY TEST M RABBITS ER = ER YTH EM A 0 * No Erythema 1 = Very Sight (barely perceptible) 2 - Well-defined (pink) 3 - Moderate to Severe (red) 4 = Severe (beet redness) to slight eschar formation (injuries in depth) ED ** ED EM A 0 No Edema 1 = Very Sight (barely perceptible) 2 a sight (edges of area well-defined by definite raising) 3 = Moderate (raised - 1 mm) 4 = Severn (raised > 1 mm, may extend beyond the area of exposure) Average Test () Average Control SC = 0.0 - 0.0 CSO - 1.8-1.8 Difference 0.0 0.0 Comments: 8Erythema (tended beyond the sites. Passes X X Fails im Completed. i (S e e n a o s l I -------------------------- _ 10 - company Sanitized. Does not contain TSCACSjt NjIhiKAWorldleader m Tailing Service* for the M edical Device Industry DuPont HLO 289-95 2261 Tracy Road Northwood, OH 43619 Phone 419*666*9455 FAX 419*666*2954 LAB NO. 8ST 06034 00 P.O . NO. LAX 670607 B DU PONT DE NEMOURS & C O HASKELL, LAB FOR TO X 6 IND. MED EUCTGN RD PO BOX 3 NEWARK. D E 19714 ATTN: DR. SUSAN A M ACKENZIE ID NO. -21017 USP M USCLE IMPLANTATION T ES T IN RABBITS Teat Article: Preparation: 21017 The ta rt article w as cut and trimmed to 1 mm x 10 mm. Sterilized b ataam. Procedure: Two healthy adult New Zealand White rabbit* weighing at least 2 .6 kg ware used a s test animals. The back of each animal w as clipped of fur on both side* of the spinal column. Loose hair w a* removed by alcohol w ipe after clipping and the paravertebral m uscles warn anesthetized. Ship s of starito test articla V w ar* implantad into tha right paravertebral muscle of seen rabbit; strips of U8P control plastic w ar* e implanted in the left paravertebral muscle of each rabbit. r. The animals w ars suthanstizad 2 day* after implantation and the entire paravertebral muscle on each side of tha vertebra* w as removed. Cross sections of tha muscles w ars made to locate the implants. The tissue surrounding tha implant w as examined macroscopically. Results of M acroscopic Examination: } Score Scoring Key Encapsulation 0 No capsule or adverse reaction (other than minima! hemorrhage) 1 Up to 0 .6 nun capsule or reaction area 2 0 .6 to 1.0 mm capsule or reaction area 3 1.1 to 2 .0 mm capsule or reaction area 4 > 2 .0 mm capsule or reaction area Reaction Index f: 0- 0.6 Not Significant 0 .6- 1.0 Tree* 1. 1-2.0 Slight 2.1-3.0 Moderate f 9:3.1 Marked Avarsga: 0 .0 0 .0 lt s Average (test) - Average (control) - 0 .0 M acroscopic: Tha reaction w as not significant as compared to the USP negative control implant material. i Comments: Not Applicable, ! Cwwplala^^OQS liAix&flklApproved Marts J. Hefaaka. SB. LAT U M kJbL L TU014-S07 ** ~ Company Sanitized. Does not contain TSCA CBjl