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h t a id 2d l k3 : l-Kun CLtU-HLTH-SCI-LIB The Toxicity and Safety Testing of DisposaDie Medical and Pharmaceutical Materials* By JOHN H. BREWER and HAROLD H. BRYANT Many disposable surgical and pharmaceutical materials are not adequately tested for their toxicity and compatibility with tissues. Sug gested techniques are described for testing these items. By the use of such teats die various items available may be checked and a choice made between those which should not be used and those which have been ade^ quately tested and are found to be satisfactory. must be carefully tested by chronic and acute testing methods before being employed.- Tests which simulate actual conditions of use should be employed, with added tests to give a large degree of safety. The responsibility of the manufacturer. does not end with the careful checking of the original formulation, but tests on each individual lot ecause of high labor cost and an inadequate B supply of properly trained personnel, the must be performed, since plasticizers, coloring agents, and plastics may change from lot to lot demand for disposable, ready-to-use medical andwithout the manufacturer's knowledge. pharmaceutical materials has resulted in the The Food and Drug Administration has been introduction of many such items in the commer very interested in those plastic formulations cial market. Disposable syringes, needles, vials, used for food containers, and a number of pub-' catheters, drain tubes, and countless other items licatious have appeared stating which plasticizers are now available. For the most part these are and other substances may or may not be used for made of plastic or one of the newer, lighter weight such items. This has led to some false sense alloys. Many of these items offer advantages of security on the part of the surgical suppliers; over the original re-usable item. The throw they felt that since their formulations met away hypodermic needle, for instance, cannot these requirements that they were entirely satis transfer infectious hepatitis from one patient to factory and met all the requirements for medical another, and, since the needle point does not use. A great deal of harm may have been done have to .withstand repeated injection, it can be by the labeling of some plastic tubings as medical made much sharper. More care can be given to grade tubing, without adequately testing the . its sterilization in autoclaves or gas sterilizers material by imbedding samples in animals. with the proper controls than by the busy Drains and indwelling catheters made from some physician with an office sterilizer. Also, the of this material cause tissue reaction and necrosis individual needle can be sealed in the final which is open to bacterial infection. package before sterilization, and it maintains Although the TJ. S. P. has certain sterility sterility until the time of use. and toxidty requirements for plastic tubing Other disposable items have similar advantages assemblies -used in blood collection and trans over the original rc-usable ones. By changing the fusion, no such requirements or tests are out plasticizers or other chemicals in the plastic formulations, catheters may be made with any lined by dther the U. S. P. or FDA for tubing to flexibility desired. From a pharmaceutical be used for drains or indwelling catheters. point of view, bottles and pharmaceutical "glass One has only to recall the reports in publica ware** which will not break have many advan tions of the AMA on reactions to improperly tages. The pharmacist must take care, how tested plastic formulations used in watch bands, ever, in the use of these materials, since some of belts, etc., to understand how much more the plasticizers may be leeched out and react important is the adequate testing of plastics for with the drugs stored in them. Or they may be surgical and medical use. permeable to, or soluble in, the solvents which Several years ago the authors were asked by a they contain. firm, which was planning to manufacture a plas-J\J tic-hubbed hypodermic needle, to develop todtj|"k The individual plastic or alloy formulations and safety tests for this item. The procedural Rerirc4 Aocmt 81, 1959, from the Bioteric*! Research ru.bormU.riei, HysiOB, Wcateett & Duaninz, Inc,, Balti. devised would be used to determine whether thex^ mere. ilo. Tho report with the dctUoiamt of routine mttbod* irfaleh tre applied tv products of the Bectos, Dfcfcxmpfi Co., Rotbtrfortf. is. JH mod It reported witii Um pcfmifcvioa of thtt Company. Prpeated to the Sricotifie Section. A. Pw. A.. CioelratU Attract 1060. plastic formulations, which met their physical ^ specifications, would also prove ncmtoxic under q all the uses to which needles would be subjected.^* ` Several arbitrary tests were developed; some BFG14868 F^EBUWV1I2*'9 2 10:35 FROM CLEU-HLTH-SCI-LIB PAGE.003 actually simulated conditions of use and others were developed to give a margin of safety. It was found that a few coloring materials could not be used since they would leech out on long o intact with saline, which might occur during use- Some formulations were found to be toxic and could not be used. In like manner, some plasticizers were found to be unsatisfactory. thought necessary to test an uil metal needle for toxicity, since no plasticizers or epoxy resins were involved. Since it was known that some of the al loys used contained a small amount of lead to facili tate manufacture, we decided to submit these needles to the same test. A floccular precipitate de veloped in the saline, and on intravenous injection into the mice killed all of the ten mice within a few minutes. When this floccular material was sub mitted to the bleb'type of test, all the test sites gave positive skin reactions. TEST PROCEDURES These sudden deaths and positive skin tests could not possibly be due to the small amount of lead The specific tests which are applied to needles are elated from these hubs since less than 1 mg. of weight as follows: Each needle hub formulation is checked, loss occurred during the saline soaking. The deaths using the following solvents: 0.0% saline, 5.0% must be due to embolism of the floccular material ethyl alcohol, sesame oil. and polyethylene glycol, which occurs with aluminum and saline. These ,ince these would represent the most common sol tests were repeated with distilled water, and only a vents used in parenteral products. Not less than slight haze was seen. However, when this material 20 needles ore covered with each of the above men was made isotonic with sodium chloride for intra strua. 1.5 ml. per needle. The overlay preparations, venous injection, the floccular precipitate developed along with control portions of the four solvents, are and death resulted in the mice, although uot to the held at 37 for eighteen to twenty-four hours. . same extent since the amount of precipitate was not The clnates are decanted after vigorous agitation to as great. No deaths Occurred when this material aid elution of possible surface reaction products. was given intraperitoneally or when the; experi The following tests are then performed: menter was very careful not to disturb the precipi Acute Toxicity.--Fifteen healthy mice, weighing tate and only injected the supernatant liquid. 18-22 Gin., are injected with each of the menstrua, This type of safety test docs not simulate actual paralleled by five mice using the control solutions. conditions of use since the entire surface area is in The saline and ethyl alcohol cluates are injected In contact with the solution. In the actual use type of travenously, 1.0 mL per mouse. The sesame oil and test in which the needles were placed on the syringe polyethylene glycol ore injected intraperitoneally, and 0.25 toL saline drawn into the syringe and al 1.0 ml. per animal of the first, while a dilution of the lowed to stand, as might occur in a dermatologic polyethylene glycol is used which is just below the dime where large numbers of allergens are being level causing toxic manifestations in previous con tested, positive skin tests did occur in the blebs trol studies. The animals are observed for seventy- raised on the rabbits, provided the material was n two hours. mixed by shaking and the precipitate which formed BUb Reactivity.--Each of the four elution men expelled. To determine whether or not this ma a& strua is injected intiacutancously, 0.2 mL into each terial might also cause false positive reactions in of ten sites, paralleled by ten 0-2-tnL control blebs humans, dermatologists repeated these tests, making in the backs of two rabbits. The. first three are in sure that they mixed the material before injection. & jected undiluted. whOe the polyethylene glycol is About 40% false positive reactions on two series of fs, diluted to contain 20 mg. in the 0.2-ml. bleb volume. tests employing this technique were obtained. The The sites are observed for seventy-two hours for number of reactions in the animals and humans is erythema, edema, or necrosis, Pyxogeadcity.---Ten needles arc heated in 200 mi. proportional to the amount of precipitate which is injected. If the syringe is handled very carefully Sl saline to not less than 85" for one hour and the U. S. so that most of the precipitate remains in the syringe, P. pyrogen test on the decanted eluate performed. fewer positive reactions will result. it . m After the original formulation study, production control tests are ran, using the saline overlay only. To simulate actual conditions of Use, as in derma tological work, needles are attached to a small syringe and 0.26 ml. saline is drawn Into the syringe, From the point of view of the hospital pharmacist nr laboratory technician, aluminum-hubbed needles should not be used on a pilkin or other type dispens ing syringe, which is placed back in the flask of & leaving the needle caaottla filled. These art placed saline each time in order to fill it and then remains i in a tray and held twenty-four hours at 37, and in the saline. When used in blood grouping or j/t i hen blebs raised on a rabbit. Since only a very other tests employing washed red cells, the small vuiaQ urea of the inside of the hub is actually In con amount of aluminum eluted may caiise agglutination tact with the solution, one might never expect to of the red cells and lead to erroneous results. This obtain any toxic reaction. In this manner it has finding was noted by one of the blood banks that been possible to observe toxicities on some of the was usingsaline from a bottle to which an aluminum formulations discussed above. needle was attached and which remained in contact with the saline for a long period of time. For disposable syringe* a slightly different tech- ^ OBSERVATIONS nique must be employed in testing. Each syringe formulation is studied, using the solvents discussed wl Although these tests were designed for plastic hubs, some interesting findings were noted when experimental lots of aluminum hub needles were Mibroitted to these tests. At first it was not under needle testing. With the syringes, the barrels of 20 units are filled with the solvent and allowed to warm to 37 for twenty-four hours. The eloatcs are then combined and tests for acute toxicitv and O CD BFG14869 0L8t^IOii9 21530003 t>00 39d an-IDS-HUH-AB-ID UOdd 9S ' 0 I 36 i 31 83d October J9G0 StiK.vriKif liiitriux (KS Kig. :i. Intramuscular implant; scvcnty-iw,, hours. ,,,, reaction. 21530004- FEB 12 '92 10:38 FROM CLEU-HLTH-SCI-LIB PAGE.006 656 Journal of the American Pharmaceutical Association VoL AO, No. 10 bleb reactivity simulating those for the needle' may be in contact with the body tissues for a longer chutes are performed. period of time are also implanted for stxty-dny Plastic syringe plungers and rubber plunger tips periods. These implant sites are then evaluated by are studied by elution, in much the same manner as grots examination and histologically by a competent described above for needles, except that 10 On. of clinical pathologist. Likewise, those formulation; the test material may be covered with SO ml. of the likely to be used in contact with the central elation menstruum rather than by using 20 test nervous system are implanted for seventy-two bourn items. and sixty days in the cerebral cortex of the rabbit Control testing of approved formulations in for careful evaluation. The implantation procedure syringe assemblies is performed by drawing 1.0 ml. of hiu proved to be the most useful of the tests devised 0.0% soliue into the syringe plus 1.0 ml. of air, and to determine tissue compatibility of a plastic formu eluting the assembly for eighteen to twenty-four lation. hours at 37*. Twenty units are so eluted and the Pyrogenicity it studied by heating 10 Cm. of the dilates combined for acute toxicity and bleb reac formulation in 200 ml. of saline to not less than (B* tivity tests. for one hour, and subjecting the eluate to the stand Other plastic items: indwelling catheters, drama, ard O. S. P. pyrogen test procedure. stomach tubes, intravenous feeding tubes, and tub When a number of the medical grade tubings were ing for general medical use are dsn tested. Plastic tested, some were found to be entirely satisfactory formulations developed for use in contact with body and produced no reaction in contact with the tissues, tissues, especially where the normal epithelium has as shown in Figs. 1 and 3. Other samples of tub been interrupted, are tested for acute toxicity, bleb ing produced a very severe reaction, as shown iti reactivity, tissue reaction, and pyrogenic!ty. Figs. 2 and 4. Tan grams of the material is cut into relatively small pieces and covered with fid mL of sterile 0.9% saline; a like preparation is made using 5.0% ethyl SUMMARY AND CONCLUSIONS alcohol. These overlays are then warmed to 37* for twenty-four hours, along with control portions It is felt that before use of any material which of the two menstrua. The overlays are then vigor may produce pathological conditions, that unless ously shaken and the elution menstruum decanted. there is proof that such testing has been done on Acute toxioty is determined by infecting the un diluted eluates and control solution in doses up to 1.0 ml., both intravenously and intiaperitoneally, in mitt weighing 16-22 Cm. This is equivalent to each lot produced, similar tests on each lot of material purchased should be run. As stated above, some of these tests are severe injecting the eluate from 10 Cm. of the plastic per and do not simulate actual conditions of use, Kg. of body weight. Bleb reactivity is determined in a manner smmlat- ing that described above under needle testing. Tissue reaction or toxicity exhibited by the tissue* in contact with the plastic material is studied by im but were designed to give a margin of safety. They may also explain some of the reactions which have been encountered in the use of these "throw-away" type products which, until now. planting sections roughly 1.6 X 10 mm. in size could not be accounted for. subcutaneously and intramuscularly In the rabbit. At least four such sections are implanted subcutane ously, paralleled by four knows nonreaetive con trols; a like number arc implanted intramuscularly in a second animal. The implants are allowed to Jt is realized that the tests described arc not ideal for all of the different disposable items available. The purpose of this paper is to stimu late the hospital pharmacist or other persons remain in place for seventy-two hours, after winch the Animal* arc sacrificed and the implant eifr* ex amined for surrounding reactive material The acute, serenty-two-hour tests are evaluated by careful gross examination only. Those formula- responsible for the purchase of disposable medical supplies to make sure that adequate sterility and toxicity testing has been performed, and that the items arc satisfactory for the purpose tions which pass the acute implant tests and winch for which they arc to be employed. fC 8 Effects neut of : prior toil witl exoto . highly i| ever, the t time in Iby Dipl* wMrim. ; , Cblorprc* of mice [SFKOlSAltATl agent of w s.alleviation < : is we! in bscte is known tha tly prolonghi tons indicated, i nologieel n tinfe a previous : is caps time of ; lethal doa , or DipU cor eaeper dr stress, towith a MATER animals u and female :mkx. Attn thermostat Idaysprior i withheld afte ecmcU Mb) : of animal injected with : received I and expen ehwenlatedw Tetanus toon* 0.3 It glyci IMjthHiaMtTi KOwttear *Uya 16, K. Y. ROnpUvd u-MJh syxalw. New. I |6mMlbng|i p C*_ lafiaat ** TOTRL PFIGE . 006 ** UFOI 4.87? ret) U 3C i e! : t-KUI'l l^LtV-hL I M"bL i --L 1 id HHtit . 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