Document LKa48RO3Kx9bQ7J4ZRKLyKZ43

f THE SOCIETY OF THE PLASTICS INDUSTRY, INC. 250 PARK AVENUE NEW YORK, NEW YORK 10017 * 212/687-2675 June 21, 1968 To: Members, SPI Food, Drug, and Cosmetic Packaging Materials Committee Re: Results and conclusions of the PMA-SPI cooperative study on polyolefin bottles for dry drug products Gentlemen: By now, you have received the minutes of the last meeting of subject Committee held in New York City on April 17, 1968. You will kindly note that in delivering a status report on the cooperative effort between SPI and the Pharmaceutical Manufacturers Association, Dr. W. B. Ackart, Union Carbide Corporation, River Road, Bound Brook, New Jersey, made reference to a somewhat lengthy report giving the experimental details, results and conclusions of the PMA-SPI cooperative study on polyolefin bottles for dry drug products. It was decided following our meeting on April 17 that it would be best to send the report under separate cover rather than attach it to the minutes of the last meeting, due principally to its unusual length. We are therefore attaching hereto details of a report entitled "Report of the Plastic Subcommittee for Methodology for Testing Plastic Containers for Tablets, Capsules, Oral Powders, Granules, and Ophthalmic Products." This report was prepared by Mr. W. W. Hilty of the PMA group and was published in the minutes of the October 1967, PMA meeting. Mr. Hilty has informed Dr. Ackart that the National Formulary has agreed to publish the methodology in the 1970 edition. Dr. Ackart wishes the undersigned to point out that at our April 17th SPI Committee meeting, we discussed the use of the term "plastic" rather than "polyolefin" both in the title and the first paragraph of the report. Dr. Ackart has called this to Mr. Hilty's attention and he has promised to substitute "polyolefin" for "plastic" in the galley proofs of the N. F. publication if it can possibly be done. Hopefully, the definition of "polyolefin" which was prepared by Dr. Robert Millers' SPI Technical Information Subcommittee will also appear as a footnote. Mr. Hilty has indicated to Dr, Ackart that he will do his best to have these changes made. If the members of the SPI Committee would like to comment on the attached document, please feel free to do so. Dr. Ackart tells us that he would welcome comments. THE SOCIETY OF THE PLASTICS INDUSTRY, INC Charles L. Condit Senior Staff Advisor PLASTICS WO X1GrBfTOGHtBOF-T1Ht9FUGTUBBF ASI 00000396 O', THE ''LAST 1C SUBCOMMITTEE FCL, METHODOLOGX FOR TESTING PLASTIC CONTAINERS FOR TABLETS, CAPSULES, ORAL POWDERS, GRANULES, AND OPHTHALMIC FRODUCTS October 10, 1967 This committee, in c ollnb or at ion with the Society of Plastic Industries, has studied various test methods as outlined and discussed in the interim report dated October 9, 196". From our discussions at this meeting it seems desirable that additional time be devoted to discussing and analysing the neaningfulnesc of the tests studied. In almost all cases the results obtained would indicate a minimum of, or lack of response to the particu3_ar property under study. We therefore request that the report available and the methodology attached be considered a progress report. We reopiosi that members of the Section avail themselves of the report, the methodology; and during the interim between this mooting and the meeting next Spring, make it a point to secure additional data on their own and be prepared to consider the merit of these and other tests that may be proposed. Respectfully submitted. ASI 00000397 FOR FOR REPORT OF THE PLASTIC SUBCOMMITTEE MKT HO DO LOOT FOR .TESTING PLASTIC CONTAINERS i A CAPSULES, ORAL POWDERS , GRANULES, AND OPHTHALMIC PRODUCTS October 9, 19&7 This subcommittee, in cooperation with the Socioty for Plastic Industries, has designed and conducted, a collaborative study of test procedures intended to provide a moans of measuring the consistency of plastic containers on a batch-to-batch basis . Nine laboratories have participated in this study, in whole or in part, representing both tho pharmaceutical and the plastic .industries. The tost procedures studied represented tests for: (l) Acute Systemic Toxicity, which was designed to give an indication or measure of relative safety of the item under tost; (2) Heavy Metals; (3) Non-Volatile Residue; (U) Water Vanor Permeabil ity; (?) Light Transmission; and (6) Eye Irritation, designed to give a relative evaluation as to tho advisability of using this type of container for ophthalmic preparations. (l) In the Acute Systemic Toxicity study, the most notice able variable was the difference among laboratories in their response (72 hour weight gain in mice) to the solvent blanks. This was examined by an analysis of variance on a computer. Tho laboratory x treatment mean are shown in Tables I, II, and III. For each solvent, there was evidence of a significant laboratory plastic interaction. Because of this, any direct comparison of treatment (blank, plastic extracts) moans and of labora tory moans is of questionable value. In other words, the response to a particular treatment depends upon which laboratory i.s doing it. For this reason no treatment means or plastic means are shown in the tables. In only a few casos were there significant differences between tho blank response and the plastic extract response, and these wore in the direction of weight gain, which implies no significant toxicity in tho plastic extracts. ASI 00000398 PMA-SPI Collaborative Plastics Study Ac P. ~jy .0 c--n'ic 1 oxic i ty Table I %% Ethyl Alcohol in Sodium Chloride Injection, USP Mean 72-hour ueight gains in groups of mice, grams. (Number of surviving mice in parenthesos) bab oratorjos flank A____ ` 1.29(10) B h.85(20) Plastics Iolypropyleno (Continental Can) 1.35(10) High Density Polyethylene (Union Carbide) 'lamented High )cnsit;y Polyethylene (Owens-Illinois) 1.87(10) dbhyleno Butene Copolymer (Phillips Petroloum) U.55(10) U. 85 do) C ___ P -1.70(10) vO.U5(io) 0.70(10) -0.90(10) -O.hS(lO) -i.Ho(io) ____ E__ -1 .00 (20) -0.32 (AO) ASI 00000399 PMA-SPI Collaborative Plastics Study Acute Sya tomj c Tox 1 city Table TX Cottonseed Oil, USP Moan 21+ hour woight gain in groups of mice, grams. (Number of surviving mico in parentheses) I labor at or ies Blank 1.72(10) B U. 78(20) C 0(10) D 2.10(10) Plastics Polypropylene (Continental Can) High Density Polyethylene (Union Carbide) Pigmented High Density Polyethylene (Owens-1111 nois) Ethylene Dutone Copolymer (Phillips Petroleum) o.Ui(io) 1.26(10) 5.00(10) U.55(io) V o.ao(io) 1.20(10) 2.20(10) 1.65(10) ASI 00000400 -u- PMA-SPI Collaborative Plastics Study Acut% Systemic Toxicity T ablo ITI Polyethylene Glycol UOO, USP Mean weight gains in group3 of mice, grams. (Number of surviving mice in parentheses) : abor at or ie s Blank A -1.29(10) B -2.0$(13) C -1.16(6) P3 astj.es "'olypr onylenc (Continental Can) :igh Density 1 olycthylene (Union Carbido) igmented High 'ensity Polyethylene (Owens-Illinois) `thylene Butene Copolymer (Phillips Petroleum) -0.76(10) -0.71(10) 1.10(9) 0.2U(7) -2.629(6) -1.70(10) _____JD____ 2.90(10) 0.70(10) 0.80(10) ASI 00000401 -5- On the other hand, there appeared to be no practical dif ference v? 1thin laboratories whan comparing the several plastic extracts with the solvent blanks. There appeared to bo no significant difference among tho several forms of plastics. (2) Heavy Hctols tost results indicated no particular difficulty in any laboratory and no positive responses to the heavy metals test wero noted. (3) The test procedure for Non-Volatilo Residue appeared to work satisfactorily in all laboratories, and there appeared to be no evidence of non-volatile residue in any of tho plastics tested. One laboratory did have a significant amount of non-volatile residue in its blanks. (U) Water Vapor Permeability was originally tested under a procedure that proved inadequate for the task. This pro cedure was revised to incorporate specific instructions as ,outlined by the Plastic Industry representatives. The ros'ults of this test as it is now incorporated in the pro posed methodology appoar to yield a significant laboratory effect. However, on a relative basis they will provide a means of evaluation. (3) In an attempt to provide a test procedure for light trans mission it became apparent quickly that this can be measured only under very complex conditions involving special equipment not generally available in the usual laboratory in the pharmaceutical industry. The reason for this is that polyolefins refract light and scatter it so, that unless all refracted and scattered light is measured no true value of transmitted light can be obtained. Therefore, it seems pertinent to delete this as an evalu ation test and indicate that if a non-transmittant light substance is desirable it should contain a pigment such a3 t it anium oxide . (6) The Eye Irritation Test was found to be workable and to yield results that indicated plastic containers can be evaluated in this manner so far as eye irritation is con cerned , (?) An additional test for Apparent Density has been added to this list of test methods. It has"boon checked in one pharmaceutical firm and several plastic industry firms and is described in the Book of A5TM Standards, Part 26, June 1965, ASTM Designation: D 1622-63. ASI 00000402 ASX 0 0 0 0 0 4 0 3 WATER VAPOR PERMEABILITY Weight Change Rate, gm./day Material A. High Density Polyethylene (UCC) B. Polypropylene (Continental Can) C. Ethylene-Butene Copolymer (Phillips) D. Pigmented High Density Polyethylene (Owens-Illinois) Monsanto .00^90 .00733 .00368 .00627 UCC Trial 1 .0066 UCC Trial 2 .0061? ,0d6< .00700 .00U8 .00369 .0046 .00431 Material A. High Density Polyethylene (UCC) B. Polynropylene (Continantal Can) C . Ethylene-Butene Copolymer (Phill'ips ) D. Pigmented High Density Polyethylene (Owens-Illinois) Permeation Factor P = JtW (100) .01639 BA2 Monsant 0 UCC Trial 1 0.776 0.851 UCC Trial 2 0.803 1.093 0.616 0.961 0.854 1.044 0.656 0.546 0.403 0.375 Lilly .00328 .00449 .00199 .00331 l ON l Lilly 0.320 0.510 0.238 0.232 i 1'iC '.`1C. r a - ?, d in e \ and !/d i n o cu".r',:if.j e e l y and arcs attached too thus report. m X n t1 i-.' kz. r,c-?r r-f rrr`po[iin3 lii-iVos o p i n 5 o; j o X th .. C o;.irn. tec that the "b O o d g `' C S u e o * x ca p a a a following P. - Ji-- h' "l O <J n , rccciimoncl6icarj cr.n III ISJCOCILLU'CAL TLSX3 a , Heavy_Hot ala The teat procedure for heavy me inIs presented no 'problem;;, and la a tr a iplit forvnrd * donee ver, the study indicated there; were no pociuive response a to the teen. It is there fore recommended the limit;; be cot at "not bore than 3 ppm .f b . Hon-VoX-'n lie do s i duo Although the toot methodology is accurate rad pro c lac , it is recommended that no limits be c ; t nhl ish d fo" phis test. The non-volatile residue- vlll vary dependent upon p 1: o ty ne of plant i.c b o in r; t c ct c d . c . AjpH Tho p;; difference between the c?a-.-'.xtract ar.C the BJL_nnl:_ is again dependent, to a. large do. proa, upon the typo of material being.tested. Ivor, by establishing a limit for the ApH of 2 .'A several cf the p?. fistic material tested would not meet this limit; ehcrofcm.-, no specific limits arc recommended c.t this tine. cl, viator v apor_?orncabHit 7,' U a in z the revised procedure received from the plastics industry, the tost appeared to bo vorbable . As was indicated by Dr. ?rcun:.,s statistical summary, the? a appeared to be n ci-'n if leant laboratory cf.f0c.p5 ho ..'..'.an-, it is believed iho teal is quite, reliable but un !'a..; 111 ar to most laboratories, Yherrfore , ad tj ^ 1 omO tosl'r'.g by this method would bo necessary before any mo or. 5 a jful limits could bo establiahed . BIOLOGICAL TB3?3 a . Acv; te 5-t r,10n 1.c Y onf c5.t y If ar.y animals tractc-d vita the La `.-,lo ;hov only a 1 1 pit s: y 'ir, of toxicity, and net more plan o j arj.r.al rd.ov:. gross symptoms of toxicity 0 Cl t/ f+ ^ u _ i %s C 0 w f? l\ J, C- ASX 00000408 -3 2- repeated using the sane number of mice. 0:< the re: t q ;> h , nil a n i in a 1 s t r eat a cl c j i o Vi the orv'inlo el ;ould r\ no significant, react.ion. above the riJ.anb ani. coin hr; the observation period. Sve Irritation If any should On the s ho n't d Blanl ir ritchili ty of either eye be repeated u a in z "'ri s ' ayn n repeat tost, all animals t shovr no'Kiore- si.grrifi car.a r rj5 reals during the ohearvat :: noteCoe, ;n; .03a uvdo o r oi r ab b i t r . ; t c d w i th the S ar.vc I_c e o 1. c n ab ov c ah e a p eric d. ASI 00000409 PLASTICS - C,KLKPAL TrJSTS AND APPARATUS The following Phycicochenicai and Biological Test Procedures are the result of uhe combined efforts of lie Plastics Committee of the Quality Control Section of the Pharmaceutical Manuf a c turei'S Association ana interested representatives from The Plastic Industry. The tests are general in scope but applicable for testing a wide variety of plastic containers in uc.e today. 'The purpose of this study is to establish procedures for monitoring batch to batch production of plastic materials v/hich may come into contact with pharmaceutical compounds. ASX 00000410 ^ 1- - GENERAL TEGTU, PROCESSES APIA APPARATUS POP PLASTICS PLASTICS - CONTAINERS FOR INJECTIONS Plastics can be of natural origin or produced synthetically and are generally divided into two broad categories in accordance with their ro:;p:;EM: to applied bout, thun uro clur.c J f icil n-o being either therrno'pias ti_c or thermosetting. A thermoplastic material is usua 11 y rigid~~at normal temperatures but vill soften upon, the application of heat and deform under pressure while a thermosetting material vill undergo physical and chemical changes under influences of heat, pressure or catalysts to become substantially iriflus ible and insoluble. Very few plastics are single chemical entities but rather consist of a mixture of homologous compounds having a wide range of.molecular weights. Moreover, plastics frequently contain other substances such as residues from the polymerization process, plasticizers, s f- -v o J lizers , antioxidants, pigments and lubricants. DEFINITIONS For the purpose of these tests for plastics, the following definitions apply: A Containor is the device which holds the drug and which is or nay be in direct contact with the drug. The Sample is the plastic specimen under test or the extract prepared fr'oa-such a specimen. A Blank consists of the same quantities of the same extracting medium used for the extraction of the specimen under test treated in the same manner as the extracting medium containing the specimen under test. A Negative Control is a plastic specimen which gives no reaction under the conditions of the test. . ASI 00000411  2 in indiviuual monographs. Moreover, these test procedures are de signed to test the suitability of a plastic for use as a container, or accessory thereto. Since the tests az-e based on the extraction of n p.lac.Uc, it in o a q eu t I n- .1 that tho ti r> c f f-nr. t e d amount Of the plastic be used. Tne specified surface area must be for extraction at the designated temperature. Special distilled water is to be used. Water equivalent to Sterile Water for Injection (U.3.P. XVII, page 754) is suitable SPECIAL APPAk Oven - Use a forced-circulation model, which will maintain an operating temperature of 70 * 1C. Cleon all glassware thoroughly with chromic acid cleaning solution and, if necessary, with hot nitric acid followed by prolonged rinsing with distilled water. EX T;< A C T10 C On TA IN Eli S Use only containers such as ampuls or screw-cap culture test tubes, of oorouilicr.tc- glass. If used, culture test tubes are closed with screw caps having suitable rubber liners. The exposed surface of the rubber liner is protected with an inert solid disk O.Qp mjii. to C.075 mm. in thickness. A suitable disk can be fabricated from a polytetraflucreshylene resin. 1 PNOC Su'd RE Preparation ci Sample - Select from a homogeneous plastic sample The~'a'moiTjiX""ris{'(71 in~the Table I for each 10 ml, of extracting medium and subdivide the ample "ap indicated. Remove particulate matter, such as lint and free particles, by treating each subdivided sample as follows: Place the cuts in a clean 250 ml., glass-stoppered graduated cylinder of borosilicate glass, and add about l60 ml. of water for injection. Agitate for about 'j>0 seconds and drain off the wafer. Repeat this step and dry those pieces prepared for the extraction in a oven not exceeding 5. j_RrPte - Do not clean the plastic with a dry or vet cloth or by rinsing or washing with an organic solvent, a surfactant, et-cTJ ASI 00000412 -3TABLE I - SUHFACS AREA OF PLASTIC TO 3 USED FORM 0? PLASTIC Film or sheet THICK S' ESS* a b AKOUBT OF PLASTIC PER 10 ml. EXTRACTING ALLIUM SO cm.2 total surface area 50 cm.2 total surface area SUBDIVIDED JIT TO Strips of about 10 cm. x 0.5 cm. Tubing at Length = 60 cm.2 Sections of I.D. circumference + 0,0. oircmrlerence about 10 cm. x 0.5 cm. of Length * 50 cm.2 I.D. circuafercnce + 0. D. circumferer.cc Monofilament a Length = 60 cm.2 c iroujnf ercnce b Length = 50 ca.a circumference Sections of about 10 cm. Slabs, tubing, and molded items c 2.0 Cm. (based on material of specific gravity 1.0) Pieces of about 0.5 cm. in over all diameter. *a =. 0.5 mm. (0. 020 in.)> b = 0.5 mm. to 1 mm. (0,020 in. to O.OkO in.) ; c - 1 mm. ( 0. CLO In. } jAvail thickness of tubing. o o o o o AS I IcolCii j 11 Lj o j . x .t` tj. i, o c x I* 2 * i c L i o n l\ t.bjjvO u,i c nun to meii i m a. of special distilled water, Al* 0 prepare one 100 ml. Bln n k of t h e medi utj., Kxtract by he;.t in.1 n . n even at 70 for 27 b ur s . A] ':: tan ccii l.a j i;r to r ex xrxc,. 1 OIi v i; r e . 11O t Tne extraction conciit i o n g g j: 0 u i_e not in aby instance cause uhvsic ;<1 changes such as fus ion or m e 11 i of the plasti pieces in any way beyond u slight udher c n c e v o n c portion to ar,.'. her. Always add the cleaned pieces ir.d T \ r' ' ljy to the extraction me a iuirr/ Cool r.l 1 containers to about COM t empem t. u r but not bole w 22 s haa ka e vlgorou and decant each extract > using aseptic prccau Ti.ons , Into a sterile vessel. S t o r the _ X true ta at a tenperatyiv between 22' i 10, and test within h o f e Zh hours. pH Change - ;anfardizo a pH meter with a standard buffer solution (page 91122)).. Rinse the electrodes several times with .special dietiile: water. Prepare a portion of the jiluuk solution for pH determination by the addition of 0-50 ml. of "cturated potassium chlorine solution to 100 ml. of the autoclaved flank solution. Rinse the electrodes, with this sc-lotion, then tnke-~~p~R measurements on successive portions of the solution until a reproducible result is obtained. Rinse the electrodes sever;,! times with ssppee; cial distillerti wo i.er. Prepare a portion of the Sample Hxiiract solution for pH determine, h ion by the addition of O.jJO ml. of saturated notassium chloride solution to 100 ml, of the autoclaved Semple xtrua t. 'Ringe the electrodes with this solution, then take pH rcsciinx;j on successive portions of the solutio until a reproducible result o b i, iea. no p fIi change (/6?II) is t. n c difference between the pH of the Blank solution and the Sample Extrac solution. HEAVY METALS (pave 8r(6} Pipette 20 r.,1, aliquots of the blank ana Sample Extract solui non? into separate 'Header tubes. / f. (1 ~pp3.M ul . (~j> ppm), and 10 ml. (5 ppm Leu Solution into ; parate Kessler tubes. Add 2 ml. of dilute acetic;acid to al f i v e Lubes, Dilute each tube to 25 ml. with special distilled water. A-i i. 10 ml. of freshly prepared hydrogen sulfide T.3. to each tube, mix (preferably with a stirring rod having a Ifcop at the lower c id) , a 13 O'. to stand for 5 minutes and view downward over a white surfac i. Deter- mine the amount of heavy metals (as lead) in the Blank and 1 .r.iple Extract solutions by comparing the amount of darkening in ea h sTolution against that in the standard solutions. If the. JuUi ? k o r Sample Extract solution is darker than the highest staurnru, "repod t the procedure using larger quantities of Standard Lean. Solut i c; n. Th c* Heavy Metals content the difference oetvce: the JiiatiK anc be if. a 1 c tvx o r a e t \ a .t 11 e s * K0KV0LATILH RESIDUE Pipette 50 i.E into separac aliquots of the Blank and Sat:;> 1 e Extract solutions previously tared crucibles that have been dried to ASI 00000414 C 02, J 0 UJ1 . r- _ ^ ^: i "c i: r.\c r 't, r. c *4 a- ./ c c V 1 ' A 4. L .1 O , i Lf t . 1 n l l 0 determine \ 4- o i* * >: v a u o r a Ci on c,, s V c n :n b a u> h, v. s i n;, a c u r r e u t of air, to dry nc a. hr y t h e c r u c ibi e c '"t a 4> 105 over, fee* i hour. Cool 3. ?A kl V/ 0 * i- [-c "w d' - I f 0 r, C .1 y * c 0 r. cl Vi c 4. a out; . ue.3 , insues ij la 1 i C crv.c l ole r e tj e a L e a _tl ,/r rc" -ti. vr *a r. s "k* he C V ttorat 0 r. a r. d d r y In ; period truce sue}: Ala : * -;/ c re e p a 1 c n Li th e Ft 1 Is of 1/ h e c :* u c .i b 1 "e . j Th c difference ob fained from t he Wr'.r.jDlC? r n >..' c and the Plant is "the noi.v olat1? f residue. appapj' DtwsifY Scope: - Thic v. i o.i cover." a pi'occc.ui*c icr determin: ng the; apparent der.iity of plastic materials It is intended for rigid cellular pPci3Yi.es Apparatus - (ly analytical balance, (2) Micrometer Dial Gauge or calipers. Test Spec it.on - (1) The specimen shall :;c of a shape whose volume can be cu j_-ou.,uted, (2) The specimen shall he free from surface shin whenever possible, ( b) The specimens should he conditioned and tested i,. r. r-.'s or enclosed space maintained at 2;j0 J1 and 50 2 percent relative humidjay. PK0CEDUA3 Weigh a minimum of five test 5')-.ci!,ons and record'the weight, Measure the five specimens with - sliding e&.lii>er gauge or with steel scale or tape and calculate the volume. Measure all dimen sions to a precision of I 1 percent. Calculate the density to three significant figures by using the fcCLloving formula: Wo x O.OolS T Where D -- density of specimen in grams per cubic centimeter Ws *= weight of specimen in grams V == volume of specimen in cubic, inches WATER VAPOR PERMEABILITY Dcf In 1 io or. - Water vapor permc.nbi.3ity is a pro;, only of polyolefins describing their aoiliwy to trancm.it water vapor from one sine of a sheet or film, to the other side. Water vapor permeability may be defined one quantity of water vapor passing through a specified . c.. r. ,, of piastres per unit of time, per unit of area, under controlled conditions o: temperature and relative humidity. APPARATUS Constant temperature ar.d relative humidity cabinet 100?* t 2, fh-P g 2',; rod ..time him id it y, , calcium, chloride ( anhydrous) -h or 8 r/.esh, pcflye u'.iylene/alumir.uiTi laminate, heat sealing iron, calipers ar.d rule; capable of measuring to the nearest hundredth inch, and an analytical balance. ASI 00000415 Proceii ure : b- v c x q i h e e "t c on ,,a me: withou c, the cap, Do uermiro the ue Ii G J o C. ic plastic container, Determine the total surffi.ee a r e a o f t n c t-o ^:O i* C O "C G 1 11 *J X G 1., , nc the calipers to measure the diameters o.l the body ( D) ana r.eek (d) and tiie height ( h) of the conisincr from the shoulder to the bottom. The surface area can be calculated as follows: A = 21?D x h + (2 x 2 ITS) ) -ir(d) 42 hot e ; ' formula is' only correct when the area between it he shoulder c)f I J neck minus the top opening G equivalent to the area of the bottom. Containers shaped a: e r e n t o c c c, 1. c ul a r o a accordingly. Moreover, no calculi non is r.i a a e lor the area of the n c e rC.j Place the anhydrous calcium chloride into tne plastic container to be test>. 1 and fill to the shoulder nock opening. Deal the container with polyethylene/alurjinum laminate, cap with the conventional closure an., weigh. Place the container into the controlled atmosph cabinet. the container after day, p days, "( days. Id days. ;. ! hole After removal of the container from the cabinet, a.'; lev'only enough time for the container to cool to a mb I on temporal t,re before weighing. vScpiace bottle immediately after weir; ing. At each weighing interval, shake container in order to expose the fresh surface of calcium chloride to vapor inside container"fj Plot the total weight gained against time interval (days) pn linear graph Tjapor. Determine the weigh- gain per day by calculating the slope of the l.Ane at equilibrium, i.e. where the curve becomes line towaz'u the end of the test. The last p points should be oh a sir&i line. Further testing until equilibrium is reached may be nccessar The water vapor permeability is calculated from the following form V.V.P. = , Gms_. \ Wt. ' day-1' Container (Grams), ,ClOQ, Density f Vm" 00000416 AS I L 1 0 L 0 Lr 1 C J l Ij 7 PLASTIC CONTAINERS The following biological test procedure:-; tire designed to test the suitability of a plastic for use as a container, or accessory thereto. The object of*bach procedure provided is to test the reaction of living animal and of normal animals to the presence cf portions of the plastic or of injections of extracts of it. These tests are designed for application to plastics in the condition in which they are used, If a plastic is to be exposed to any cleansing or r, t or i. 11 xn t * coo process prior to its onibucu, then the tests are to bo conducted on a dapple Tire;; a red from a specimen pre-conditioned by the same processing. Care must be exercised in the preparation of the extracts to prevent eontarnina tion with microorganisms find other foreign matter. EXTRACTING MEDIA The following are used as extracting media: SODIUM CHLORIDE INJECT I OR (see page (195 >. 1 in 20 SOLUTION of ALCOHOL in Sodium Chloride POLYETHYLENE GLYCOL 400 ( see pagcr~t87f)7 COTTONSEED OIL (see page 151). Injectioft. APPARATUS Oven - Use an oven, preferably a forced-draft model, which will maintain operating temperatures of 50" or 70 within Z 1C. Extraction Containers - Use only containers, such as ampuls or scr ovUcap culture test tubes,, of boros illcate glass. If used, culture test tubes are closed with screw caps having suitable rubber liners. The exposed surface of the rubber liner is completely protected with an inert solid disk 0,05 nun. to 0,075 mm. in thickness. A suitable disk can be fabricated from a polytetrafluorethylene resin. PREPARATION 0E APPARATUS Clean all glassware thoroughly with chromic acid cleansing mixture, or if necessary with hot nitric acid, followed by prolonged rinsing with purified water. Clean cutting devises by an appropriate method (e.g., successive cleaning with acetone and methylene chloride) prior to use in subdividing a specimen. Clean all other equipment, by thoroughly scrubbing with a suitable detergent and prolonged rinsing with nurified water. Render containers ana devises and administration of test material, sterile and dry by a suitable process. QTote - If ethylene oxide is used as the sterilising age; allow adequate time for complete de-gassing TEST ANIMALS - For the Acute Systemic Toxlaity Test select healthy, not previously used albino mice each weighing between 17 and 2p G;n. ALjj5 id- ASX 00000417 :c: ** W G . ` U lj >' w1 ' 1 ' and v ate r, commonly C O UTu.t s 11, i o n, ai 1 :i b en.ly id' , ' i--ci..ic- iovii'ci.1. bi-cr i'ooii Ter laboratory uni mala am; Known as to For r ho Eye Irrisat Z' a a b I t;.- 'with no vis. a i:'j l . t ioloci healthy, thin-skinned albino PROChbNdE P r c p a r a t i o n of fample - ta 1 n 6 Grn . Of a representative saw, p.l e from a a a i: ^ n u o a:) iJiiLb tic i) uaij.* J. O . Cut i n L o g mm. x g mm. pie cur; - Sieve ana save a 1 1 t h e jy i c c e s th a \, pas ^-J 4v- hr j U gh a1No. 6 sieve (g.g 6 n n, ) b u t a r e r e L ained on a No, i j V o ( 2* C j mm.). Place 1.0 Gm. Zf f the Sample pie C r` Ti in a ^laj S -- G top P 0 V * G. _j_ () 0 m 1. g r a d 2 . a t e 1 c y 1 i 21 d e r of b o r o s 1.1 i c a V e glass and c 1 O' n b \ 70 ml. of \7 aier i\ j r J nj e c t i'or. each time. Allov the p or b j. o,: i G:1 <?. j'i j. ~l or 1 ab 0 r i. bo c-ectirns \r l h n ^ .*, a d i s e a r 1 i ng i. in e w ash va t c r J o c r a ill dry, and, in addxtio n further dry t h o s e j. oucnded for o y b i' a c a J, n Kj o f i....r. s c cd Oil in an 0 v eii, uclo v/ 50 for I hour. I'repav u :l n <i 1 O h Y, 0 G*oie - t)o not clean V i t h a dry or vet cloth or wit h a ji ,, .{' "a n i c o.l v 0n a j su j' .1.*nc mnt ^ Gtc 11 Add 20 ml. portion:, of t h q ap pro }; r ') a o c Extracting Media to s operate extraction containers and place a properly prepare^ Cample of the plastic to be rested in each of the two extruelion containers, Clcs< each con t a 1o r w i t h a suitable cap or pressure sensitive tape end d i S p e re t h e pieces of plastic by swirling in the extraction Medium. (Repeat tnese directions for each ex tract ini; medium required for testing.) Prepare one 20. C mi. Blau 1 for each extracting medium for parallel injections and caripurj.sons . Extract by heating in an oven at 70" for 2k hours. The extraction should not result in gross physical, chances in the samples, such as fusion of the two portions in any way beyond a slight adherence of one:portion to another. Cool to about room temperature, but not below 25*, shake vigorously and decant each extract, using aseptic precautions, into a dry sterile vessel. Seal ana store the extracts at a temperature of 25, and do not use for tests after 2k hours. A C b SYSTEMIC TOXICITY TEST The acute systemic toxicity lost is acs: .gned to determine the biological response of mice to plastics boy the single duose innjj<ection cf specific extracts prepared from a pin tic. Ox' importance J ; the contact of x he extracting medium with the available surface area of t h v. p ,1 u s t i e and the time and temperature during extraction, too proper cooling, agi ration and decanting process, as veil as the acey-ujc: handling am: storage of the extracts following extraction. (dote Eaon cx... xc u must be agitated vigorously prior to withdrawal ck icn inject ion do ,c to insure even distribution of the extracted roa- 'C G i` * Procedure : For this tea l, the mice are individually identified in a suitable manner (color, coding, ear-nicking, etc.). Each mouse in the Sample and Blank groups is weighed and the initial weights recorded. ASI 00000418 - 9- Inject j t'.to t;rs ci .:.u mice each the . \ Blank as outlined, in the table below: .. c* : ij.' i,,] e and INJECTION Pit0C I'DUR 1 ______________ #l_ EXTRACT OR BLANK 1 in 20 Solution of Alcohol in sodium Chloride Injection Cottonseed Oil Polyethylene Glycol 400 DOSE per Kg. 50 ml. 50 nil. 10 Gm. ROUTE 1. V. I. P. I. P. 1WJ EUTJ, OK . (n]./sec 0.1 *** *** Observe the animals immediately after injection, and at 4, 24, 48, and "(2 hour intervals. EYE IRRITATIOK VEST The eye irritation test is designed to test for eye .Irritating properties possibly present in plastic containers used for ophthalmic products by using the eye of albino rabbits. Procciure : The extracting,media to be tested for the eye Irritation test is the extracts from (l) Sodium Chloride injection and (2) Cottonseed Oil. Form a cup using the lower lid of the left eye of a suitably restrained albino rabbit. Instill, approximately 0.2 ml. of the Blank, being careful to bring the solution in contact with ns muen eye surface as possible. Maintain this contact for ai least JO seconds before allowing the lid to position normally. Repeat this procedure with the right eye, instilling the Sample extract. Repeat the above procedure using three rabbits. Examine the eyes at 24, 48, and 72 hour intervals for possible irritation. A3I 00000419