CA1075602A - Antimicrobial resin compositions containing ortho-benzyl-para-chlorophenol - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compositions are disclosed which comprise resin, generally synthetic resin and a biologically effective amount of ortho-benzyl-para-chlorophenol. Preferred compositions include a phthalic acid derivative plasticizer-solvent to facilitate distribution of the ortho-benzyl-para-chlorophenol throughout the resinous body of art-icles formed of the composition.

Description

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The invention relates to antimicrobial-containing resin composi-tions, and more particularly synthetic resin compositions incorporating an aromatic derivative of a mono-halogenated phenolic antimicrobial compound, whlch subsequent to processing, exhibits a level of long._term persistent antimicrobial activi-tyO
In recent years considerable effort has been expended in attempting to develop biostatic-biocidal synthetic 1~ resin compositions wherein the antimicrobial activity of the composition is not significantly affectèd by temperatures and pressures normally encountered in the processing of the compositions into a myriad of final products.
As those well versed in the art of antimicrobial compounds are aware, it is well recognized that the bio-~1 static~biocidal activity of closely related compounds l generally varies consîderably. The variance in activi-ty is generally not only unpredic-tabl~ with respect to the compounds ~1 : .' .
per se, but is greatly magnified when such compounds are incorporated in synthetic resin compositions ~hat require the addition oP plasticizers, s-tabilizers, lubricants and , pigments in order to render the resin suitable for processing , .
i~ into final products.
Accordingly, the ~act that a glven compound has per se recogniæed antimicrobial activity does not in fact assure that such compound will have the same degree of, or any, antimlcrobacterial actlvity when incorporated in other ~ _2-.. '; ~ : ' : , :

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than an inert solvent-carrier. The class of biostats-biocides comprising halogenated phenols is a prime example. While the grea-ter germicidal activity of monohalogen substituted alkyl derivatives of phenol over phenol was recognized in the early l900's it was almost thirty years before some potent germi-cidal compounds were discovered among the aromatic derivatives of p-chlorophenol. Among these compounds was the benzyl derivative which was tested against test organisms of the typhoid colon group. The results proved promising and 10 eventually led to the commercial development of o-~enzyl-p~ ;
chlorophenol, a potent broad spectrum antimicrobial which in non-aqueous solution has for many years been utilized for the sanitizing of hard surEaces, laundering fabrics, and with dispersing agents, compounded into aqueous detergent compositions having high phenol coefficients.
Therefore, a substantial amount of experimentation is more often than not involved in the development of bio-static-biocidal resin compositions ~hat after processing into a final product retain an effective level of antimicro-bial activity over a period of time whereby such productsretain such activity during substantially the useful life of the product. It will thus be appreciated that the mere fact that a compound, per se, or in certain solvents or composi-tions, has antimicrobial properties does not render such comE~ound as an obvious antimicrobial additive for incorpora-tion in synthetic resin compositions, particularly such compositions that must be subjected to relatively high : . , . . . , . ~ . . . . . . . .

1~756~2 processing temperatures and pressures in order to produce a final consumer product.
Prior art attempts to provide antimicrobial synthetic resinous compositions, as distinguished from merely precluding microbial degredation of polymeric compositions, have often utilized organo-metallic compounds, particularly those based on mercury, tin, arsenic, copper as the active antimicrobial compound. Other classes of antimicrobial compounds include brominated salicylanilides, mercaptans, 10 quaternary ammonium compounds and carbamates, for example~
Generally, the above-mentioned compounds are characterized by serious drawbacks in that they are highly specific in their antimicrobial activity, highly toxic, and thermally degredated, whereby commercial utilization of such compounds is not practical or advisable.
While it is appreciated that many polynters inherently resist biological attack these polymers are seldom used without modification. Other materials such as plasticizers, stabilizers, lubricants, and fillers, necessary for providing ~0 resinous compositions that can be molded and extruded on a commercial scale, increases the pol~ner's vulnerability to fungi and bacteria since they act as a source of food fQr microorganisms. :,, Not the least of the problems associated wi~h the molding and extruding of an an~imicrobial thermoplastic composition is the provision of a composition capable of withstanding molding and extruding temperatures in the order .. . . ..

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of 400 to 500F. Temperatures of this order are necessary for the dispersion of the antimicrobial compound in a thermoplastic synthetic resin, pelletizing of the antimicrobial resinous com-position to facilitate handling for subsequent fusion of the pelletized resinous composition to mold or extrude articles and/
or film from high molecular weight high density polyethylene, polystyrene, polypropylene, and ilm grade polyvi~ylchloride without significant degradation of the active antimicrobial com-pound incorporated therein.
The present invention accordingly provides an antimi-crobial composition comprising a synthetic resin or polymer and an antimicrobially effective amount of ortho-benzyl-para-chlorophenol.
The present invention also provides a method of pro-ducing a polymeric article having antimicrobial properties, which comprises moulding, at a temperature of about 275F. to about -500F., a composition comprising a synthetic resin or polymer and an antimicrobially effective amount of ortho-benzyl-para-chlorophenol.
Compounding of the antimicrobial synthetic resinous compositions of the present invention is generally by post poly-merization addition of the crystalline ortho-benzyl-para-chloro-phenol to a high molecular weight generally rigid polymer.
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Alternatively dispersion of the antimicrobial compound may be ` effected by blending with the polymer which is heat~d to at least above a second transition .', .

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-tempera-ture. Still fur-ther~ -the antimicrobial compound may be dispersed in the finished polymer as a solution oF the ortho-. .
benzyl-para-chlorophenol in an or~anic solven-t, such as dioctylphthalate. The invention also contemplates the dis-persion of crys-talline ortho-benzyl-para-chlorophenol in a particulate dlluen-t vehicle, such as a micropulverized anhydrous sodium potassium aluminum silica-l:e prior to dis-persion in a fused or par-ticulate resin.
It has been found that the invention is particularly well suited for imparting antimicrobial properties to high molecular weight polyethylene, of both low and high density, regular grade polystyrene, high impact polystyrene, poly-propylene, high temperature polypropylene, and film grade :~
polyvinylchloride, for example. The ortho-benzyl-para-chlorophenol has been generally found to impart significant persistent antibacterial, antifungal and antiprotozal activity to articles and films molded and extruded from ~`
synthetic resinous compositions containing in the finished products a minumum of about 0.25% to 0.50% by weight of the active antimicrobial compounds. It will be appreciated tha-t the ortho_benzyl_para-chlorophenol may belincorporated in the ~;
resin at a use concentration of about 0.25% to about 0.50%
by weight whereby the antimicrobial resinous composition, which may include the usual fillers and plasticizers, may be in appropriate particulate or pelletized form fed direc-tly to conventional molding and extruding apparatus. As a practical matter 7 it has been found advisable to :incorporate .

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the antimicrobial ortho-ben~yl para~chlorophenol in resin at a concentration generally in excess of the use concentra-tion so that anti~icrobial compound loaded pellets or granules, may be physically admixed with non-antimicrobial containing resin to arrive at a finished molded or extruded product having the required use concentrati.on of ortho-benzyl-para-chlorophenol in resin intended ~or subsequent admixture with other compatible resin prior to molding or extruding is in the order of about 10% by weight. ~1hile the incorporation of more than 10% might be advantageous, it has been found -that problems of recrys-tallization of the ortho-benzyl-para-chlorophenol are sometimes encountered. However, i-t will be appreciated that the incorporation of greater~percentages of the antlmicrobial composi-tion is contemplated by the present invention, albeit necessarytto utilize a solvent or diluent system, other than that speciflcally set forth herein, to preclude recrystallization of -the ortho-benzyl-para-chloro-phenol in the antimicrobial resinous composition o~ finished molded or extruded product, Antimicrobial resinous compositions formulated in accordance with the present invention have been prepared wherein the concentration of ortho-benzyl para-chlcrophenol is in -the order of 0.25% to ln.0% by weight of the resin and any resin processing adjuncts admixed therewith. ~t will be ; appreciated however that these concentrations of ortho-benzyl_ :
para-chlorophenol are preferred and the invention broadly contemplates the inco~poration of any concentration of the :, ' ~,.' '' ..
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~756~2 compound that will provide an effective level of the anti-microbial compound ortho-benzyl-para-chlorophenol in a molded or extruded resinous product.
The following are examples of preferred modes of carrying forth the present invention with a plurality of polymers. The term polymer as used herein is intended to include generally solid synthetic monopolymers, copolymers, etc., which do not effect any signiEicant re-arran~ement of the ortho-benzyl-para-chlorophenol to a related but less effective compound, even though in a technical sense such degredation product exhibits antimicrobial activity.
Example I
Hi~h Molecular Weight Low Density Polyethylene 0.25%, by weight, of crystalline ortho-benzyl-para-chlorophenol was physically blended with th-e resin in particulate form and fed into an extruder barrel maintained at a feedstock end temperature of 250 to 250F and extruded and cut to form molding pellets. The ortho-benzyl-para-chlorophenol-polyethylene pellets were then molded into pill cups, as utilized in hospitals, in conventional injection - molding apparatus operating at a temperature of 280 to 320F.
Representative segments of the exterior and interior sides of the molded cups were then subjected to bacterio-logical testing as follows: ~
PROCEDURE: -Test Sample:
The sample was tested using the exterior and 10756~Z

interior sides randomly vs. each organism.
Test Media:
A.A.T.C.C. Bacteriostasis Agar Test Or~anisms:
Staphylococcus aureus 6538 Escherichia coli 4352 Streptococcus faecalis 14506 TnCubation:
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24 hours at 37C
RESULTS: Zone o~ Inhibition in mm.
Organism 1 2 3 Av~.
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S. aureus 3.0 3.0 3.0 3.0 E. coll 6.0 5.0 5.0 5.3 S. aecalis 3.0 3.0 3.0 3.0 CONCLUSION: The data obtained indicates that the submitted sample exhibits bacteriostatic properties against S. aureus, E. coli, and S. aecalis when tested as specified~
Example II
; Example ~ was repeated with the exception that 10.0% by weight, of ortho-benzyl-para-chlorophenol was `
incorporated and the pellets so obtained admixed with high molecular weight low density polyethylene pellets containing no ortho-benzyl-para-chlorophenol to arrive at a blend con~ -centration of 0.50% by weight, of the antimicrobial compound ~,r~
in finished articles molded from the composit~ion. The results of bacteriological tests were substantially the same as with respect to Example I~
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Example III
High Molecular Weiqht Hiqh Density Polye~lene 0.25%, by weight, of crystalline ortho-benzyl-para-chlorophenol was physically blended with particulate film grade high molecular weight high density polyethylene and fed into an extruder barrel maintained at a feedstock end temperature of 280 to 320F and extruded and cut to form pellets. The pellets were fed to an extruder apparatus ~;;
operating at 480F and extruded into tubular stock which was slit to form sheet material. In separate runs material of 1, 5 and 7 mils was extruded. Representative portions of the film were sub~ected to bacteriological testing and found to exhibit antimicrobial activity comparable to the samples of Example I.
In addition, human patch tests and animal oral toxicity tests were conducted as follows:

PROCEDURES:
A. Human Patch Test 'ren (10) test subjects, five (5) male and five (5) ~`
female were selected at random. A skin area on the inner surface of the right forearm of each subject was designated for the position of the patch. The sample of 3 cm2 was placed , in direct contact-with the skin at the designated site of application. The patch was then covered with a Pressoplast "Schwartz" patch having a 1 ~/2" x 1 1/2" cellophane center -to retard evaporation of any volatile constituents of the test sample~ The patch remained in contact with the skin for -10- '' .. :. . : :.: , , ~ , . . .

1~7~;i6C12 a period of twenty-four (24) hours. Upon removal of the patch the resulting reaction was evaluated. Read~ngs were also made after 72 hours and the results were incorporated into the final evaluation.
After a five (5) day rest period the ten (10) sub-jects utilized in the first phase of the test program were again exposed to the sample for twenty-four (2~) hours. The procedure followed the pattern as descriibed in the first phase of the test. A positive reaction in the second phase and a negative reaction in the first indicate the presence of sensitizing agents producing an allergic reaction.
B. Ac~lte oral Toxici~y An aqueous extract of the submitted sample was prepared by placing 100 gms of sample in 200 mls of distilled water with a pH of 7 o rrhe closed glass container was then placed in an oven maintained at 65C for seven (7) days.
Ten (1~) Sherman Strain albino rats (5 male and 5 female) each weighing between 200 gms and 250 gms were ` selected for the test. Prior to the administration of the ;
extract, the food was withheld from the rats for 24 hours.
The animals were then weighed and grouped according to the dosage to be administered.
The extract was then fed to the rats by direct stomach intubation using a syringe with a "ball-point" needle.
The-animals were retained in their individual wire mesh cages in the conditioned animal room for observa~ions of overk toxic manifestations for a period of fourteen ~14) days.
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~L~75~02 Results:

A. Human Patch Test Primary Reaction Reaction Combined Subject Sex 2~ hrs. 72 hrs. Avera~e

2 M 0 0 0

3 M 0 0 0

4 M 0 0 0 8 F 0 0 0 `
~ 9 F 0 0 0 Second r~

M 0 0 0 `

! 8 F 0 0 0 . 9 F O O O
F O O O
B. Acute Oral Toxicit~ -Dosage per K~ Mortality of Body Wei~ht Ratio _ 25 mils 0/10 observation: -The animals in acute oral toxicity test showed no overt toxic effect during the observation period.
Example IV
Example III was repeated with the exception that the concentration of ortho-benzyl-para-chlorophenol incorpo-rated in the high density polyethylene was increased to 10.0%

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and the antimicrobial containing pellets admixed with high density polyethylene pellets to provide a finished film havin~ 0.50% by weight of ortho-benzyl-para-chlorophenolO
The film was subjected to backerologixal testing and found to have antimicrobial activity comparable to the composition of Example II.
Example V
Example IV was repeated with the exception that about 25% by weight of a micropulverized complex of silicates, namely anhydrous sodium potassium aluminum silicate was admixed with the ortho-ben~yl-para-chlorophenol as an inert diluent to assist in uniformly dispersing the antimicrobial comp~und throughout the resin matrix. The film was subjected to bacteriological testing and found to have antimicrobial activity comparable to the composition o~ Example IV.
Example VI
An intimate admixture of particulate polystyrene with 0.25%, by weight, of ortho-benzyl-para-chlorophenol was int~roduced into an extruder barrel wherein the ~eedstoc~ end of the extruder barrel was maintained at a temperature in the range of 265 to 420F and the antimicrobial polystyrene extruded and chopped into molding pellets. The pellets were then fed to an injection molding apparatus operating at a temperature in the range of 4~0F and pill cups molded from -the composition. Results of tests for antibacterial activity were comparable to the results set forth with regard to Example I.

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Example VII
Example VI was repeated with the exception that high impact polystyrene, i.e., which contains butadiene copolymer was substituted for regular grade polystyrene.
Example VIII
Example VII was repeated with the exception that ~
10.0%, by weight, of crystalline ortho-benzyl-para-chloro- ~ ~-phenol was dissolved in dioctyl phthalate and the solution of the antimicrobial compound incorpor,ated in the high impact polystyrene heated to a temperature in the order of 375F.
Example X
Polypropylene, of a molecular weight in excess of 40,000 was heated in an extruder barrel maintained at a temperature in the range of 275 to 325F at the ~eedstock end and 0.25% by weight, of ortho-benzyl-para-chlorophenol incorporated therein, the extruded antimicrobial composition chopped into pellets. Pill cups were formed from the pellets by injection molding at a temperature in the range of 320 to 480F. Test results as to the antibacterial activity of the molded product was comparable to the results set forth with regard to Example Io Example XI
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~ xample X was repeated with the exception that 10.0%, by weight, of ortho-benzyl-para-chlorophenol was incorporated and the antimicrobial loaded pellets dilluted with sufficient non~loaded polypropylene pellets to arrive at a concentration of 0.50% antimicrobial compound in the molded articles.

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- Examp~e XII
Particulate film grade polyvinyl chlorlde was admixed with 0.25%, by weight, of ortho-benzyl-para-chloro-phenol in an extruder apparatus wherein the feedstock end of the extruder barrel was maintained at a temperature in the range of 275 to 325F and pellets formed. The pellets were extruded in conventional apparatus, maintained at the extruder head at about 480F, to form film ranging in thickness from 0.5 mils to 7.0 mils. Bacteriological tests indicated anti-microbial activity comparable to that set~forth with regardto 3xample ~

Example XIII
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Pellets produced in accordance with Example II, wherein brown and blue identifying colorant was added, which -- . - , pellets were molded at different times and stored under normal storage conditions for two and three years respectively were subjected to analysis to determine the antibacterial activity.
The tests showed the following:

' Samples Identified as: (1) "Brown" ~ellets (2) "Blue" Pellets Test Performed: Antibacterial Activity Method Empl~yed: AATCC Test Method 90-1970 Antibacterial Activity of Fabrics, Detection of: Agar Plate Method Test Media: AATCC Agar and Blood Agar Plates Te~t Organisms: Staphylococcu _aureus . , Pseudomonas aeru~inosa Escherichia coli ;
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Test Organism (Cont.): Streptococcus virldans (alpha hemoLytic) Incubation: 24 hours at 37C
16 hours at 4~C, then 8 hours at Zone of Inhibition in Millimeters Organism Medium 37C 4C, then 37C
.
Brown Blue Brown Blue S. aureus AATCC 5.0 5.0 7.0 7.0 BAP 4.0 2.0 3.0 2.Q
Ps. aeruginosa AATCC 0.0 0.0 0.0 0.0 BAP 7.0 3.0 2.0 0.0 -E. coli AATCC 1.0 0.0 1.0 0.0 `~
BAP 0.0 0.0 2.0 0.0 ; :~
S. viridans AATCC No growth No growth BAP 3.0 2.0 4.0 3.0 CONCLUSION:
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The Brown Pellets and the Blue Pellets exhibited antibacterial action against S. aureus, E. coli and S. viri-dans grown on AA~CC Agar and antibacterial action against ~;
S. aureus, Ps. aeruginosa, E. coli and S. viridans grown on Blood Agar when tested by the Standard Methods. The diffe-rences in the diameters of the zones o~ inhibition may be interpreted as indicative of the relative susceptibility of the various organisms to the agent contained in the pellets.
The presence of a de~inite zone of inhibition of any size may b- regarded as si~nificant.

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Claims (10)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. An antimicrobial solid synthetic resinous compo-sition in which in the fabrication of articles and films is subjected to relatively high temperature, consisting essentially of the incorporation of a antimicrobially effective amount of ortho-benzyl-parachlorophenol.

2. The composition of claim 1 wherein 0.25% to 10.0 by weight, of ortho-benzyl-para-chlorophenol is present in the resinous composition.

3. The composition of claim 1 including a particulate inert inorganic diluent to assist in dispersing the ortho-benzyl-para-chlorophenol in the resinous composition.

4. The composition of claim 1, 2 or 3 wherein the relatively high temperature is in the order of about 275°F to about 480°F.

5. The composition of claim 1, 2 or 3 wherein the solid synthetic resinous composition comprises a synthetic resin selected from the group consisting of polyethylene, polystyrene, polystyrenebutadiene copolymer, polypropylene and polyvinyl chloride.

6. An antimicrobial composition of matter capable of withstanding molding temperatures in the order of about 275°F

to about 500°F without significant loss of antimicrobial activity, the essential constituents of which are (1) a solid synthetic polymer and (2) at least an antimicrobially effective amount of ortho-benzyl-para-chlorophenol.

7. The composition of claim 5 wherein 0.25% to 10.0%
by weight, of ortho-benzyl-para-chlorophenol is present in the composition.

8. A polymeric article of manufacture having antimi-crobial properties, subsequent to molding temperatures in the order of about 275°F to about 500°F, comprised of (1) a solid synthetic polymer and (2) at least an antimicrobially effective amount of ortho-benzyl-para-chlorophenol.

9. The article of manufacture of claim 8 wherein 0.25% to 10.0%, by weight, of ortho-benzyl-para-chlorophenol is present in the polymeric article.

10. A method of producing a polymeric article having antimicrobial properties, which comprises moulding, at a temperature of about 275°F to about 500°F, a composition as claimed in claim 1.