MXPA98005223A - Synergistic antimicrobial compositions containing 1-hydroxymethylprazzol and a conserva - Google Patents

Abstract

Compositions are described which comprise a compound of the formula I wherein R and R independientemente are independently selected from hydrogen and alkyl from 1 to 4 carbon atoms, Rï is a portion selected from the group consisting of (a) hydrogen, (b) a halogen atom selected from group consisting of F, Cl, Br and I and (c) a nitro group, or the hydrochloride salt of the compound, and at least one preservative, which are effective synergistically compared to the respective components alone to control or reduce growth of microorganisms in or on a material or medium. Methods for controlling and / or reducing the growth of microorganisms and preventing decomposition caused by microorganisms with the use of the compositions of the present invention are described.

Description

SYNERGISTIC ANTIMICROBIAL COMPOSITIONS CONTAINING 1- HIPRQXIMETILPIRAZOL AND A CONSERVATIVE DESCRIPTION PE THE INVENTION The present invention relates to certain compositions and processes useful for controlling the growth of one or more microorganisms and for preventing the decomposition caused by bacteria and / or fungi in various products, materials or media, particularly products, materials or media industrial These materials or media include, for example, wood pulp, wood chips, wood, adhesives, coatings, animal skins including birds and reptiles, paper mill liquors, paper, optical brighteners, pharmaceutical and chemical formulations, cosmetics and formulations for bath, lubricants and geological drilling aids and auxiliaries, agrochemical compositions, paints, skins, woods, fluids for metal work, formulations of auxiliaries for industrial processes, water cooling towers, waste water, pasteurizers, tanning liquors, starch , petrochemicals, surfactants, defoamers, emulsions or polymers containing water, lipid-based materials, carbohydrate-based materials, protein materials, emulsions of acrylic latex paints and textiles. The novel processes and mixtures of the present invention show unexpected synergistic activity against microorganisms, including bacteria and fungi. Specifically, the invention is directed to the use of compositions comprising dimethylhydroxymethylpyrazole and at least one preservative. Many of the products, materials or media referred to above, when wet, are subjected to water treatments, or are placed in a humid environment, are susceptible to bacterial or fungal decay or degradation unless steps are taken to control such deterioration or degradation. To control the deterioration or degradation caused by microorganisms, several microbicides are used. Workers in the market have continued to look for improved biocides that have low toxicity and are capable of exhibiting a prolonged biocidal effect at normal use levels. Single preservatives can be used to control microorganisms, but many of them have low efficacy against bacteria and fungi unless extremely high concentrations are used. The 1-hydroxymethylpyrazoles can be used alone in low concentrations as biocides. This invention provides a microbicidal composition capable of controlling the growth of at least one microorganism, particularly fungi and bacteria, for extended periods of time. Additionally, the present invention provides compositions which are economical to use. Methods of controlling the growth of at least one microorganism are also objects of this invention. The present invention provides a composition comprising a 1-hydromethylpyrazole and at least one preservative, wherein the components are present in a synergistically effective combined amount to control the growth of at least one microorganism. The present invention also provides a method for controlling the growth of at least one microorganism in or on a material or medium susceptible to attack by the microorganism. That method comprises the step of adding to the material or medium a composition of the present invention in a synergistically effective amount to control the growth of the microorganism. The present invention also exemplifies the separate addition of a 1-hydroxymethylpyrazole and at least one preservative to the products, materials or media described above. According to this embodiment, the components are individually added to the system in such a way that the final amount of 1-hydroxymethylpyrazole and at least one preservative present in the system at the time of use is that quantity synergistically effective to control the growth of at least one microorganism. The compositions of the present invention are also useful for preserving various types of industrial media or materials susceptible to attack by microorganisms. Such means or materials include, but are not limited to, wood, pulp, wood chips, wood, adhesives, coatings, animal skins including birds and reptiles, paper mill liquors, paper, optical brighteners, pharmaceutical and chemical formulations, cosmetic formulations and for bath, lubricants and auxiliaries for geological drilling, agrochemical compositions, paints, skins, wood, fluids for metal work, formulations of auxiliary industrial processes, water cooling towers, waste water, pasteurizers, tanning liquors, starch, dyes , petrochemicals, surfactants, defoamers, emulsions or polymers containing water, lipid-based materials, carbohydrate-based materials, protein materials, emulsions of acrylic latex paints and textiles. The compositions may also be useful in agrochemical formulations for the purpose of protecting seeds or crops against microbial decomposition. Additional objects and advantages of the present invention will be indicated in part in the description which continues, and in part will be apparent from the description, or may be learned by the practice of the present invention. The objects and advantages of the present invention can be realized and obtained by means of the elements and combinations indicated particularly in the claims. It is understood that both the foregoing general description and the following general description are exemplary and explanatory only and are not restrictive of the present invention as claimed. When two chemical microbicides are combined in a product or added separately three results are possible: 1) The resulting product can produce an additive (neutral) effect. 2) The products in the product can produce an antagonistic effect, or 3) The chemicals in the product can produce a synergistic effect. An additive effect has no economic advantage over the individual components. The antagonistic effect can produce a negative impact. Only a synergistic effect, which is less possible than an additive or antagonistic effect, can produce a positive effect and therefore has economic advantages. The microbicidal compositions that combine 1-hydroxymethylpyrazole and at least one conservative demonstrate an unexpected synergistic effect compared to the respective components alone. In this way, these compositions achieve a superior microbicidal activity, that is, greater than the additive at low concentrations against a wide variety of microorganisms. Examples of microorganisms include, but are not limited to, fungi and bacteria such as Aspergillus niger (ATCC 9642) and Pseudomonas aeruginosa (ATCC 15442). Preferably, the compositions of the present invention have low toxicity. 1-Hydroxymethylpyrazole is a compound that has the formula where R and R "are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms, R" is a portion selected from the group consisting of (a) hydrogen, (b) a halogen atom selected from the group consisting of F , Cl, Br and I and (c) a nitro group, or the hydrochloride salt of the compound. The preparation of 1-hydroxymethylpyrazole is described in U.S. Patent Nos. 4,801,361 and 5,335,432 and references to which reference is made in these Patents, all of which are incorporated herein by reference. 3, 5-Dimethyl-1-hydroxymethylpyrazole is commercially available and is sold under the trademark Busan® 1504 or Busan® 1104 (Buckman Laboratories International, Memphis, Tennessee) and is also easily synthesized from commercially available raw materials. As described in the Product Profile and Analytical Method of Buckman Laboratories (1992) for Busan ® 1504 (both incorporated herein in their entirety for reference), Busan ® 1504 is a broad spectrum, non-ionic bactericide and fungicide developed for the conservation of aqueous systems and aqueous emulsified. Busan ® 1504 is active over a wide pH range and is stable under both alkaline and acidic conditions. In addition, Busan ® 1504 can be formulated in cationic, anionic and nonionic systems. Busan ® 1504 is also compatible with proteins. Busan ® 1504 is a crystalline water soluble solid that has 1-hydroxymethyl-3,5-dimethylpyrazole as an active ingredient. The preservative can be any preservative that will produce a synergistic effect when combined with 1-hydroxymethylpyrazole. Examples include hexahydro-1,3,5-tris (2-hydroxyethyl) -s-triazine, bis 1,4- (bromoacetoxy) -2-butene; 2-bromo-2-nitropropane-1,3-diol; dimethylhydantoin; imidazolididinylurea (also known as N, N 1 -methylenebis (N 1 - [1-hydroxymethyl) -2,5-dioxo-4-imidazolidinyl] urea; diazolidinylurea (also known as N- (hydroxymethyl) -N- (1,3-dihydroxymethyl) -2,5-dioxo-4-imidozolidinyl) -N- (hydroxymethyl) urea) mixture of 5-chloro-2-methyl-4-iso-thiazolin-3-one and 2-methyl-4-iso-thiazolin- 3 -one, l- (3-chloroalyl) -3,5,7-triaza-1-azoniadamantane chloride, and C 1 -C 6 alkyl hydroxybenzoate In addition, mixtures of these preservatives can also be used. such mixtures in combination with dimethylhydroxymethylpyrazole, at least one of the preservatives in the mixtures has a synergistic relationship with the dimethylhydroxymethylpyrazole The preservatives useful in the invention are commercially available or can be synthesized from commercially available raw materials Examples of commercially available preservatives include , but are not limited to, Busan ® 1210 (bis 1, 4- (bromoacetoxy) -2-butene dis buildable from Buckman Laboratories International), Kathon CG (mixture of 5-chloro-2-methyl-4-isotriazolin-3-one and 2-methyl-4-isothiazolin-3-one available from Rohm & Haas), Dowicil 200 (CIS isomer of 1- (3-chloroalyl) -3,5,7-triaza-l-azonia adamantane chloride available from Dow Chemical Co.), Propyl Paraben (C? -C6 alkyl hydroxybenzoate) ) available from several sources), Busan ® 1506 (hexahydro-1, 3, 5-tris (2-hydroxyethyl) -5-triazine available from Buckman Laboratories International), Sodium Omadine (2-pyridinatiol-1-sodium oxide available from Olin Chemical Co. ), Germall II (N- (hydroxymethyl) -N-Cl, 3-dihydroxymethyl-2, 5-dioxo-4-imidozolidinyl) -N- (hydroxymethyl) urea or diazolidinylurea available from Sutton Laboratories), Bronopol (2-bromo-2-nitropropane-l, 3-diol available from Boots Chemical, and Glydant (dimethylhydantoin available from Sutton Laboratories) The preservative can be chosen based on compatibility with materials or media. criteria such as solubility in the fluid system and lack of reactivity with the fluid, material or media in question In view of the present invention, the compatibility is easily determined by a person having ordinary experience in the art by adding (eg, applying on the surface, incorporating in the fluid, material or media, and the like) the preservative to the material or media to be used When it is used in a fluid system it is preferable that the preservative be freely soluble in the particular fluid resulting in a uniform solution or dispersion, as these terms are used herein, "avoiding" (which includes mitigating) decomposition is to be understood that the present invention "in effect" controls the growth of at least one microorganism, responsible, at least in part, for decomposition. It is further understood that by "controlling" (ie preventing) inhibits the growth of at least one of these types of microorganisms. In other words, there is no growth or essentially no growth of at least one microorganism. "Controlling" the growth of at least one microorganism keeps the population of the microorganism at a desired level, reduces the population to a desired level (including at undetectable limits, eg, zero population), and / or inhibits the growth of the microorganism . In this way, the substrates or materials susceptible to attack by these types of microorganisms are conserved from this attack and the resulting decomposition and other harmful effects caused by the microorganisms. Additionally, it will be understood that "controlling" the growth of at least one microorganism also includes reducing bioestically and / or maintaining a low level of microorganisms in such a way that the attack by microorganisms and any resulting decomposition or other harmful effects is mitigated, i.e. , the rate of growth of the microorganism or rate of attack of the microorganism is decreased or eliminated. In the following discussion of the preferred embodiments, component (a) is 3,5-dimethyl-1-hydroxymethylpyrazole and component (b) is a preservative. As described above, components (a) and (b) are used in synergistically effective amounts. The proportions by weight of (a) to (b) vary depending on the type of microorganisms, material or medium to which the composition is applied. Generally, the ratio of component (a) to component (b) is in the range preferably from 0.1 to 99, more preferably from 1:30 to 30: 1, and more preferably from 1: 5 to 5: 1.

The following weight proportions of dimethylhydroxymethylpyrazole are also preferred to the following preservatives: Busan® 1504: Busan® 1210 80: 0.01 to 1: 2 Busan® 1504: Kathon CG® 80: 1 to 1: 2 Busan® 1504: DOWICÍ1 200 ™ 10 : 1 at 1:20 Busan® 1504: Propil Parabeno 8: 1 at: 10 Busan® 1504: Methyl Paraben 8: 1 at 1:80 Busan® 1504: Busan ® 1506 16: 1 at 1:30 Busan® 1504: Sodium Omadine 50: 0.1 to 1:10 Busan® 1504: Germall II® 4: 1 to 0.1: 25 Busan® 1504: Germall 115® 0.8: 1 to 0.1: 16 Busan® 1504: Bronopol® 80: 1 to 1:60 Busan ® 1504.-Glydant® 7: 1 to 0.1: 25 Depending on the specific application, the composition can be prepared in liquid form by dissolving the composition in an organic solvent. The preservative can be prepared in an emulsion form by emulsifying it in water, or if necessary, adding a surfactant. Additional chemical additives such as corrosion inhibitors, operating agents and insecticides can be added to the previous preparation. The synergistic activity of the combinations described above has been confirmed using standard laboratory techniques as illustrated below. The following examples are proposed to illustrate, not limit, the present invention. Microbiological evaluation A. Fungal evaluation Mineral glucose mineral medium is used. To prepare the medium, the following ingredients are added to one liter of deionized water: 0.7 g of KH2P0, 0.7 g of MgSO4.7H20, 1.0 g of NH4N03, 0.005 g of NaCl, 0.002 g of FeS04.7H20, 0.002 g of ZnS04 .7H20, 0.001 g of MnS04.7H20, 10 g of glucose. The pH of the medium is adjusted to 6 with INOH NaOH. The medium is distributed in 5.0 ml quantities in test tubes and autoclaved at 121 ° C for 20 minutes. The fungus is grown, A. Niger, on inclined agar of dextrose and potato for 7 to 10 days and prepare a spore suspension prepared by washing the spores of the agar inclined to a sterile saline solution. After the addition of the biocides in the desired concentrations to the medium of mining salts and sterile glucose, the suspension of fungal spores (0.1 ml inoculum) is added. The final spore concentration is approximately 10 6 cfu / ml. Inoculated media are incubated at 28 ° C for 10-14 days. B. Bacterial evaluation. Nutrient broth growth medium is used. To prepare the medium, the following ingredients are added to one liter of deionized water: 0.8 g of NaCl, 1.0 g of glucose and 1.0 g of tryptone. The pH of the medium is adjusted to 6 with 1 N HCl. This is distributed in quantities of 5 ml in test tubes and autoclaved for 20 minutes at 121 ° C. After the addition of the biocides in the unattended concentrations to the nutrient medium, 100 microliters of a suspension of Pseudomonas aeruginosa cells of approximately 10 6 cfu / ml are added and incubated at 37 ° C for 5-7 days. In the Examples, a synergistic effect is demonstrated in separate experiments by testing 3, 5-dimethyl-1-hydroxy ethyl pyrazole, designated as Component A and the corresponding preservative or its salt as component B in a series of tests in various proportions and a range of against the fungus, Aspergillus niger and also against the bacterium, Pseudomonas aeruginosa using the methods described above. They are taken as the extreme points for synergism calculations, the lowest concentration of each mixture or compound which completely avoids the growth of the fungus for approximately two weeks (10-14 days) and the bacteria for approximately one week (5-7 days) ). The end points for the various mixtures are then compared to the end points for the pure active ingredients alone in flasks or test tubes prepared concomitantly. Synergism is demonstrated by the method described by Kull, E.C., Eisman, P.C., Sylwestrwicz, H.D., and Mayer, R.L. 1961. Applied Microbiology. 9: 538-541 where QA / Qa + QB / Qb is less than 1 Qa (Busan ® 1504) = concentration of compound A in parts per million, acting alone, which produces an endpoint. Qb (conservative) = Concentration of compound B in parts per million, acting alone, which produces an extreme point. QA (Busan® 1504) = Concentration of compound A in parts per million, in the mixture, which produces an extreme point. QB (conservative) = concentration of compound B in parts per million, in the mixture, which produces an extreme point. When the sum of QA / Qa and QB / Qb is greater than one, antagonism is indicated and when the sum is equal to one, additivity is indicated. When the sum of this value is less than one, there is synergism. This method for demonstrating synergism of the compositions of this invention is a widely used and acceptable process. More detailed information is provided in the article by Kull et al. Additional information regarding this procedure is contained in U.S. Patent No. 3,231,509, which is incorporated herein by reference. In general, however, an effective fungicidal and bactericidal response can be obtained when the synergistic combination is employed in concentrations in the range of about 0.1 to about 10,000 rpm of a 1-hydroxymethylpyrazole, preferably about 0.1 to about 5,000 ppm, and more preferably about 1 to about 2,000 ppm, and from about 0.1 to about 5,000 ppm and more preferably about 1 to about 3,000 ppm. Table 1 Summary of synergism in the antibacterial test (against Ps. Aeruginosa) Combination Synergism Range SI * BS1504 + BS1210 Yes 0.48 - 0, .75 BS1504 + Kathon CG Si 0.58 - 0, .75 BS1504 + Dowicil 200 Si 0.79 - 0. .93 BS1504 + Propyl Paraben Si 0.67 - 0, .83 BS1504 + Methyl Paraben Si 0.68 - 0, .92 BS1504 + BS1506 Yes 0.70 - 0, .97 BS1504 + Sodium Omadine Si 0.68 - 0. .98 BS1504 + Germall II Yes 0.73 - 0. .98 BS1504 + Germall 115 If 0.77 - 0, .96 BS1504 + Bronopol Si 0.75 - 0. .96 BS1504 + Glydant Si 0.75 - 0. .96 Summary table of synergism in the antifungal test (against A. niger) Smergism Combination Range SI * BS1504 + BS1210 Yes 0.21 - 0.72 BS1504 + Kathon CG Si 0.79 - 0.96 BS1504 + Dowicil 200 Si 0.55 - 0.77 BS1504 + Propyl Paraben No BS1504 + Methyl Paraben No BS1504 + BS1506 Yes 0.67 - 0.93 BS1504 + Sodium Omadine Si 0.34 - 0.77 BS1504 + Germall II Yes 0.73 - 0.97 BS1504 + Germall 115 No BS1504 + Bronopol Yes 0.69 - 0.93 BS1504 + Glydant Si 0.68 - 0.97 SI = 1 (additive) or IF > 1 (antagonist) is not included. Table 3 Combination of Busan 1504 with Busan 1210 against Ps. Aeruginosa BS1504 BS1210 growth SI BS1504 BS1210 Growth SI (ppm) (ppm) (ppm) (ppm) 10 0 + 30 1 + 20 0 + 30 2 + 40 0 + 30 5 + 80 0 + 30 10 + 100 0 + 30 20 + 120 0 - 40 1 + 140 0 - 40 2 + 160 0 - 40 5 + 180 0 - 40 10 + 200 0 - 40 20 - 0.58 0 10 + 50 1 + 0 20 + 50 2 + 0 30 + 50 5 - 0.48 0 40 + 50 10 - 0 50 + 50 20 - 0 60 + 60 1 + 0 80 - 60 2 + 0 100 - 60 5 - 0.56 2 + 60 10 - 10 5 + 60 20 - 10 10 + 70 1 + 10 20 + 70 2 + 20 2 + 70 5 - 0.65 5 + 70 10 - 20 10 + 70 20 - 20 20 + Table 4 Combination of Busan 1504 with Busan 1210 against A. Niger BS1504 BS1210 growth S? BS1504 BS1210 Growth YES (ppm) (ppm) (ppm) (ppm) 300 0 + 100 0.2 + 400 0 + 100 0.4 + 500 0 + 100 0.6 + 600 0 - 100 0.8 - 0.27 700 0 - 100 1.0 - 800 0 - 100 1.5 - 0 0.2 + 100 2.0 - 0 0.5 + 200 0.1 + 0 0.8 + 200 0.2 + 0 1 + 200 0.4 - 0.38 0 2 + 200 0.6 - 0 4 + 200 0.8 - 0 8 - 200 1.0 - 0 16 - 200 1.5 - 10 0.2 + 300 0.1 - 0.51 0.5 + 300 0.2 - 10 0.8 + 300 0.4 - 10 1.0 + 300 0.6 - 10 1.5 + 300 0.8 - 10 2.0 - 0.27 300 1.0 - 10 4.0 - 300 1.5 - 50 0.2 + 400 0.05 - 0.67 50 0.5 + 400 0.1 - 50 0.8 + 400 0.2 - 50 1.0 - 400 0.4 - 50 1.5 - 0.21 400 0.6 - 0.65 50 2.0 - 400 0.8 - 50 4.0 - 400 1.0 - 400 1.5 - Table 5 Combination of Busan 1504 with Kathon CG against Ps. Aeruginosa BS1504 BS1210 growth YES BS1504 BS1210 Growth YES (ppm) (ppm) (ppm) (ppm) 10 0 + 30 1 + 20 0 + 30 2 + 40 0 + 30 5 + 80 0 + 30 10 - 0.75 100 0 + 30 20 - 120 0 - 40 1 + 140 0 - 40 2 + 160 0 - 40 5 - 0.58 180 0 - 40 10 - 200 0 - 40 20 - 0 10 + 50 1 + 0 20 - 50 2 + 0 30 - 50 5 - 0.67 0 40 - 50 10 - 0 50 - 50 20 - 0 60 - 60 1 + 0 80 - 60 2 + 0 100 - 60 5 - 0.75 2 + 60 10 - 10 5 + 60 20 - 10 10 + 70 1 + 10 20 - 70 2 - 0.68 2 + 70 5 - 20 5 + 70 10 - 20 10 - 0.67 70 20 - 20 20 - Table 6 Combination of Busan 1504 with Kathon CG against A. Niger BS1504 KN CG growth SI BS1504 KN CG Growth SI (ppm) (ppm) (ppm) (ppm) 300 0 + 200 5 + 400 0 + 200 10 + 500 0 + 200 15 4. 600 0 + 200 20 + 700 0 + 200 25 - 0.87 800 0 - 200 30 - 0 10 + 200 35 - 0 20 + 300 5 + 0 30 + 300 10 + 0 40 - 300 15 + 0 50 - 300 20 - 0.87 0 60 - 300 25 - 0 70 - 300 30 - 0 80 - 300 35 - 10 10 + 400 1 + 10 20 + 400 2 X 10 30 + 400 4 + 10 40 + 400 8 + 50 10 + 400 16 - 0.90 50 20 + 400 20 - 50 30 + 400 25 - 50 40 - 400 30 - 100 10 + 500 1 + 100 20 + 500 2 + 100 30 - 0.87 500 4 + 100 40 500 8 + 500 16 500 20 500 25 Table 7 Combination of Busan 1504 with Dowicil 2000 against Ps Aeruginosa BS1504 DW200 SI BS1504 DW200 SI (ppm) (ppm) Growth (ppm) (ppm) Growth 0 + 30 10 0 0 + 30 20 + 0 0 + 30 30 0 0 - 30 40 + 100 0 - 30 50 + 120 0 - 30 60 + 140 0 - 30 70 + 160 0 - 40 10 + 180 0 - 40 20 + 00 0 - 40 20 + 100 + 40 40 + no + 40 50 + 120 + 40 60 + 130 + 50 10 + 140 + 50 20 + 150 + 50 30 - 0.79 160 + 50 40 -f. 180 - 50 50 - 0.90 0 30 50 60 - 0 40 60 10 + 0 50 + 60 20 - 0.86 0 60 + 60 30 - 0 70 + 60 40 - 0 20 + 60 50 - 0 30 + 60 60 + 0 40 + 70 10 - 0.93 0 50 70 20 -0 60 + 70 30 -0 70 + 70 40" Table 8 Combination of Busan 1504 with Dowicil 200 against A. Niger BS1504 DW200 growth SI BS1504 DW200 growth SI (ppm) (ppm) (ppm) (ppm) 300 or + 200 20 + 400 or + 200 50. 500 or + 200 80 - 0.55 600 or + 200 100 - 700 or 200 120 - 800 or 200 150 - 0 100 + 200 200 - 0 200 + 200 250 - 0 300 200 300 - 0 400 300 W + 0 500 300 20 X 0 600 300 40 X 10 50 + 300 60 - 0.63 100 + 300 80 - 10 200 0.68 300 100 - 10 250 300 120 - 10 300 300 150 - 0 50 + 300 200 - 0 100 + 400 10 + 0 150 + 400 20 + 0 200 0.74 400 40 X 0 250 400 60 - 0.77 0 300 400 80 - 00 50 + 400 100 - 100 100 + 400 120 - 00 150 0.64 400 150 - 00 200 400 200 - 00 250 100 300 Table 9 Combination of Busan 1504 with Propilparaben against Ps Aeruginosa BS1504 PPB growth 51 BS1504 PPB growth SI (ppm) (ppm) (ppm) (ppm) 40 0 X 40 500 X 60 0 + 40 600 X 80 0 + 40 700 - 0.80 100 0 + 40 800 - 120 0 - 50 200 + 140 0 - 50 300 X 160 0 - 50 400 X 180 0. 50 500 - 0.75 0 200 + 50 600 - 0 400 + 50 700 - 0 600 X 60 100 X 0 800 + 60 200 + 0 900 X 60 300 + 0 1000 + 60 400 - 0.77 0 1200 X 60 500 - 0 1500 - 60 600 - 0 2000 - 70 50 + 10 700 + 70 100 + 10 800 + 70 200 - 0.72 900 + 70 300 - 20 600 + 70 400 - 20 700 + 70 500 - 20 800 + 80 10 - 0.67 900 + 80 20 - 30 500 + 80 40 - 30 600 + 80 60 - 30 700 0.72 80 80 - 30 800 80 100 80 200 80 300 - Table 10 Combination of Busan 1504 with Propilparaben against A. Niger B, S150.4 P. PB ~ growth YES B. S150.4 P, PB grew 7m ~ ientto s7 ~ (ppm) (ppm) (ppm) (ppm) 300 0 + 200 10 X 400 0 + 200 20 X 500 0 + 200 40 X 600 0 + 200 60 X 700 0 - 200 80 X 800 0 - 200 100 + 0 50 4. 200 150 + 0 100 + 300 10 + 0 150 + 300 20 + 0 200 - 300 40 + 0 250 - 300 60 + 0 300 - 300 80 + 0 400 - 300 100 + 0 500 - 400 10 + 10 50 + 400 20 X 10 80 + 400 40 + 10 100 + 400 60 X 10 150 + 400 80 + 50 50 + 400 100 + 50 80 + 50 100 - 50 150 + 100 10 + 100 20 + 100 40 + 100 60 + 100 80 X 100 100 X 100 150 + Table 11 Combination of Busan 1504 with Methyl Paraben against Ps Aeruginosa BS1504 MPB growth SI B51504 MPB growth YES (ppm) (ppm; (ppm) (ppm) 40 0 + 30 400 + 60 0 + 30 500 - 1.07 80 0 + 30 600 - 100 0 + 30 700 - 120 0 - 30 800 - 140 0 - 40 300 + 160 0 - 40 400 + 180 0 - 40 500 - 1.15 200 + 40 600 - 0 400 + 40 700 - 500 + 50 300 + 600 - 50 400 + 700 - 50 500 + 800 - 50 600 + 900 - 50 700 - 1.56 1000 -. 1000 - 60 200 X 1500 - 60 300 + 0 400 + 60 400 + 0 500 X 60 500 X 0 600 1.08 60 600 - 1.50 0 700 - 70 50 X 0 800 - 70 100 + 0 900 - 70 200 + 0 400 + 70 300 + 0 500 + 70 400 + 0 600 1.16 70 500 - 1.41 0 700 - 80 10 + 0 800 80 20 + 80 50 + 80 100 + 80 200 + 80 300 + Table 12 Combination of Busan 1504 with Methyl Paraben against A Niger 0 MPB imient0 SI BS1504 MPB credmient0 sT (ppm) (ppm) (ppm) (ppm) 300 0 + 200 100 X 00 0 X 200 200 X 00 0 + 200 400 + 00 0 + 200 600 + 700 0 X 200 800 - 1.25 00 0 - 300 50 X 200 + 300 100 X 400 + 300 200 + 600 + 300 400 + 800 - 300 600 + 1000 - 300 800 - 1.37 2000 - 400 50 + 0 200 + 400 100 X 0 400 + 400 200 + 0 600 + 400 400 X 0 800 - 1.01 4 40000 6 60000 - 1.25 0 1000 - 400 800 + 0 200 + 500 10 • X 0 400 + 500 50 + 0 600 + 500 100 + 0 800 - 1.06 500 200 + 0 1000 - 500 400 + 00 100 + 500 600 - 1.37 00 200 + 600 10 + 00 400 + 600 50 X 00 600 + 600 100 + 00 800 - 1.13 600 200 + 600 400 + 600 600 - 1.50 Table 13 Combination of Busan 1504 with Busan 1506 against Ps. Aeruginosa BS1504 BS1506. . YES BS1504 BS1506 YES (ppm) (ppm) growth (ppm) (ppm) growth 40 0 + 20 10 + 60 0 + 20 20 X 80 0 + 20 30 + 100 0 + 20 40 + 120 0 + 20 50 + 140 0 - 20 60 + 160 0 - 20 70 - 0.73 180 0 - 30 5 + 0 20 X 30 10 + 40 + 30 20 + 60 + 30 30 + 80 + 30 40 + 100 + 30 50 + 120 - 30 60 + 140 - 40 1 + 160 - 40 5 X 180 - 40 10 + 200 - 40 20 + 10 + 40 30 + 5 20 + 40 40 + 5 30 + 40 50 + 5 40 + 50 1 + 50 + 50 5 + 5 60 + 50 10 + 70 + 50 20 + 5 80 0.70 50 30 + 10 20 + 50 40 + 10 30 + 10 40 + 10 50 + 10 60 + 10 70 + 10 80 + Table 14 Combination of Busan 1504 with Busan 1506 against PA. Niger BS1504 BS1506 SI BS1504 BS1506 SI (ppm) (ppm) growth growth (ppm) (ppm) c 300 0 + 200 50 + 400 0 X 200 100 + 500 0 + 200 150 + 600 0 + 200 200 + 700 0 - 200 250 - 0.91 800 0 - 200 300 - 0 100 + 300 20 + 0 200 + 300 40 + 0 300 + 300 60 + 0 400 - 300 80 + 0 500 - 300 100 + 0 600 - 300 150 + 10 100 + 300 200 - 0.93 200 + 300 250 - 10 300 - 0.76 300 300 - 10 400 - 400 20 + 0 100 X 400 40 + 0 200 + 400 60 + 0 300 - 0.82 400 80 + 50 400 - 400 100 + 100 50 + 400 150 + 100 100 + 400 200 - 100 150 + 400 250 100 200 + 400 300 100 250 - 0.77 100 300 - 100 400 ~ Table 15 Combination of Busan 1504 with Sodium Omadine against Ps Aeruginosa BS1504 SOMD growth ^ * BS1504 SOMD growth YES (ppm) (ppm) (ppm) (ppm) 40 0 + 40 10 + 60 0 + 40 20 X 80 0 + 40 40 + 100 0 + 40 60 - 0.93 120 0 - 40 80 - 140 0 - 40 100 - 160 0 - 50 10 + 180 0 - 50 20 + 0 20 + 50 40 - 0.82 0 40 X 50 60 - 0 60 X 50 80 - 0 80 + 50 100 - 0 100 - 60 10 + 0 120 - 60 20 + 0 150 - 60 40 - 0.90 0 200 - 60 60 - 0 300 - 60 80 - 10 40 X 60 100 - 10 60 + 70 10 - 0.68 80 + 70 20 - 10 100 - 70 30 - 20 20 + 70 40 - 20 40 + 70 50 - 20 60 0.76 70 60 - 20 80 - 80 10 - 0.77 100 - 80 20 - 30 20 + 80 30 - 30 40 X 80 40"30 60 0.85 60 50 - 30 80 - 80 60 - 30 100 Table 16 Combination of Busan 1504 and Sodium Omadine against A. Niger, BS1504 SOMD growth SI BS1504. SOMD growth YES (ppm) (ppm) (ppm) (ppm) 300 0 + 200 0.2 + 400 0 + 200 0.5 + 500 0 + 200 1 + 600 0 X 200 2 + 700 0 + 200 4 - 0.65 800 0 - 200 8 - 0 1 X 200 16 - 0 5 + 300 0.2 X 0 10 - 300 0.5 + 0 20 - 300 1 + 0 30 - 300 2 + 0 50 - 300 4 - 0.77 0 80 • 300 8 - 0 160 - 300 16 - 10 1 + 400 0.1 + 10 5 + 400 0.2 X 10 10. 400 0.4 + 10 20 - 400 0.8 + 50 1 + 400 1 + 50 5 + 400 2 - 0.70 50 10 - 400 4 - 50 20 - 400 8 - 100 0.5 + 400 16 - 100 1 + 500 0.1 + 100 2 + 500 0.2 + 100 4 0.53 500 0.4 + 100 8 - 500 0.8 + 100 16 500 1 0.72 500 2 500 4 - 500 8 500 16 Table 17 Combination of Busan 1504 and Germall II against P. aeruginosa BS1504 in growth SI BS1504 in growth SI (ppm) (ppm) (ppm) (ppm) 40 0 + 40 50 + 0 0 + 40 80 + 0 0 + 40 100 - 00 0 X 40 120 - 20 0 - 40 140 • - 40 0 - 40 160 - 60 0 - 50 20 X 80 0 - 50 40 + 50 + 50 80 - 0.98 80 + 50 WO - 100 + 50 120 - 120 + 50 140 - 140 - 60 20 + 160 - 60 40 + 180 - 60 80"- 200 - 60 100 - 0 100 + 60 120 -0 120 0.94 60 140 -0 140 - 70 20 + 0 160 - 70 40 - 0.87 0 180 - 70 60 -0 100 + 70 80 -0 120 - 70 100 -0 140 - 70 120 -0 160 - 70 140 -0 180 - 80 10 X 0 50 + 80 20 - 0.81 0 80 + 80 40 -0 100 0.96 80 50 -0 120 - 80 60 -0 140 - 80 80 -0 160 - 80 100 ~ Table 18 Combination of Busan 1504 with Germall II against A. Niger.

, BS150, 4 G, ep, l II C ^ reci .mi. In SI B, S150, 4 G «er *« mui p «creci -mi • en- SI (ppm) (ppm) _t0 (ppm) (ppm) t0 300 0 + 200 250 X 400 0 X 200 500 + 500 0 + 200 1000 + 600 0 + 200 1500 - 0.85 700 0 + 200 2000 - 800 0 - 300 250 + 0 500 + 300 500 + 0 1000 + 300 1000 - 0.77 0 1500 X 300 1500 - 0 2000 + 300 2000 - 0 2500 - 400 100 X 0 3000 - 400 250 X 10 500 + 400 500 + 10 1000 + 400 1000 - 0.90 1500 + 400 1500 - 10 2000 X 400 2000 - 10 2500 - 500 100 + 50 500 X 500 250 + 50 1000 + 500 500 + 50 1500 + 500 1000 - 50 2000 - 0.86 \ 500 1500 - 50 2500 - 600 100 + 100 500 + 600 250 + 100 1000 + 600 500 - 0.95"100 1500 - 0.73 \ 600 1000 - 100 2000 - 600 1500 - 700 100 + 700 250 + 700 500 - 700 1000 - 700 1500" * Table 19 Combination of Busan 1504 and Germall 115 against P. aeruginosa BS1504 G115 growth SI BS1504 C115 SI (ppm) growth (ppm) (ppm) (ppm) 40 0 X 30 100 X 60 0 + 30 200 X 80 0 + 30 300 + 100 0 + 30 400 - 120 0 X 30 500 - 140 0 - 30 600 - 160 0 - 40 50 X 180 0 - 40 100 X 0 100 + 40 200 X 0 200 X 40 300 - 0.88 0 300 X 40 400 - 0 400 X 40 500 - 0 500 - 50 50 + 0 600 - 50 100 + 10 100 + 50 200 + 10 200 + 50 300 - 0.% 300 + 50 400 - 10 400 + 50 500 - 10 500 - 60 50 X 10 600 - 60 100 X 20 100 X 60 200 - 0.83 200 + 60 300 - 20 300 + 60 400 - 20 400 - 0.94 60 500 - 20 500 - 70 20 X 20 600 - 70 50 X 70 100 + 70 200 - 0.90 70 300 - 80 20 + 80 50 X 80 100 - 0.77 80 200 - 80 300 - Table 20 Combination of Busan 1504 with Germall 115 against A. Niger BS1504 Gepn 11? Growing SI BS1504 Germ 115 Growing (ppm) (ppm) -to (ppm) (ppm) to 300 0 + 200 1000 + 400 0 + 200 2000 + 500 0 + 200 3000 X 600 0 + 200 4000 X 700 0 + 200 5000 + 800 0 - 200 6000 X 0 2000 + 200 7000 - 1.05 0 4000 + 300 1000 + 0 5000 + 300 2000 + 0 6000 X 300 3000 + 0 8000 - 300 4000 X 0 10000 - 300 5000 - 1.00 2000 X 300 6000 - 10 4000 + 400 1000 + 10 5000 + 400 2000 + 10 6000 + 400 3000 + 10 7000 X 400 4000 - 1.00 8000 + 400 5000 - 50 2000 + 400 6000 - 50 4000 + 500 1000 + 1.03 50 5000 + 500 2000 + 50 6000 + 500 3000 - 1.00 50 7000 + 500 4000 - 50 8000 1.06 500 5000 - 100 2000 X 500 6000 - 100 4000 + 100 5000 + 100 6000 + 100 7000 + 100 8000 1.12 Table 21 Combination of Busan 1504 and Bronopol against P. aeruginosa BS1504 Bronopol _. SI BS1504 Bronopol SI (ppm) (ppm) ^ ^ (ppm) growth 0 0 + 30 0.5 + 0 0 + 30 1 + 0 0 + 30 2 - 0.75 100 0 + 30 3 - 120 0 - 30 4 - 140 0 - 30 5 - 160 0 - 40 0.5 + 180 0 - 40 1 + 0 0.5 + 40 2 - 0.63 1 + 40 3 - 2 + 40 4 - 3 + 40 5 - 4 - 50 0.2 X 5 - 50 0.5 + 8 - 50 1 + 10 - 50 2 - 0.92 0 0.5 + 50 3 - 0 1 + 50 4 - 0 2 + 60 0.2 + 0 3 - 0.83 60 0.5 + 0 4 - 60 1 + 0 5 - 60 2 -. 0 0.5 + 60 3 - 0 1 + 60 4 - 0 2 + 70 0.2 + 0 3 - 0.92 70 0.5 + 0 4 - 70 1 - 0.83 0 5 - 70 2 - 70 3 - 80 0.2 + 80 0.5 + 80 1 - 0.92 80 2 - 80 3 - Table 22 Combination of Busan 1504 with Bronopol against A. Niger BS1504 Bronopol 51 BS1504 Bronopol 51 (ppm) (ppm) Growth (ppm) (ppm) Growth 300 0 + 200 100 + 400 0 + 200 200 + 500 0 + 200 300 + 600 0 + 200 400 - 0.86 700 0 - 200 500 - 800 0 - 200 600 - 0 300 + 200 700 - 0 400 + 300 50 + 0 500 + 300 100 0 600 X 300 200 X 0 700 - 300 300 - 0.86 0 800 - 300 400 - 1000 - 300 500 - 0 300 + 300 600 - 10 400 + 300 700 - 0 500 + 400 50 + 0 600 - 0.87 400 100 + 0 700 - 400 200 - 0.86 0 800 - 400 300 - 0 300 + 400 400 - 0 400 + 400 500 - 0 500 + 400 600 - 0 600. 0.93 500 20 + 0 700 - 500 50 + 0 800 - 500 100 - 0.86 00 100 + 500 200 - 00 200 + 500 300 -00 300 + 500 400 -00 400 + 500 500 -00 500 - 0.86 600 20 + 00 600 - 600 50 + 00 700 - 600 100 - 600 200 - 600 300 - 600 400 - Table 23 Combination of Busan 1504 with Glydant against P. aeruginosa BS1504 Glydant Growth- SI BS1504 Growth Glydant SI (ppm) (ppm) (ppm) (ppm) 40 0 + 30 100 + 60 0 + 30 200 + 80 0 + 30 300 _ 0.96 100 0 + 30 400 _ 120 0 + 30 500 _ 140 0 - 30 600. 160 0 - 40 50 + 180 0 - 40 100 + 0 100 X 40 200 X 0 200 + 40 300"0 300 + 40 400. 0 400 - 40 500. 0 500 - 50 25 + 0 600 - 50 50 + 10 100 + 50 100 + 10 200 + 50 200. 0.86 300 0.82 50 300. 10 400 - 50 400 _ 10 500 - 60 25 + 10 600 - 60 50 + 20 100 + 60 100 + 20 200 + 60 200. 0.93 300 0.89 60 300. 20 400 - 60 400 • 20 500 - 70 10 X 20 600 - 70 25 + 70 50 + 70 100 - 0.75 70 200 - 70 300 • 80 10 + 80 25 + 80 50 X 80 100 X 80 200 + 80 300 Table 24 Combination of Busan 1504 with Glydant against A. Niger BS1504 Glydant growth SI BS1504 Glydant growth SI (ppm) (ppm) (ppm) (ppm) 300 0 + 200 250 X 400 0 + 200 500 X 500 0 + 200 1000 - 0.68 600 0 + 200 1500 - 700 0 - 200 2000 - 800 0 - 300 250 X 0 500 + 300 500 X 0 1000 + 300 1000 - 0.83 0 1500 X 300 1500 - 0 2000 + 300 2000 - 0 2500 - 400 100 X 0 3000 - 400 250 + 10 500 X 400 500 + 10 1000 + 400 1000 - 0.97 1500 X 400 1500 - 10 2000 + 400 2000 - 10 2500 - 500 100 + 0 3000 - 500 250 + 0 500 + 500 500 - 0.91 0 1000 X 500 1000 '- 0 1500 + 500 1500 - 0 2000 0.87 600 50 + 0 2500. - 600 100 + 0 3000 - 600 250 + 00 500 + 600 500 - 00 1000 + 600 1000 - 00 1500 + 700 50 00 2000 0.94 700 100 + 00 2500 - 700 250 - 00 3000 700 500 700 1000 -

Claims (16)

1. CLAIMS 1. A composition characterized in that it comprises a) a compound having the formula (I) where R and R 'are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms, R "is a portion selected from the group consisting of (a) hydrogen, (b) a halogen atom selected from the group consisting of
2. F, Cl, Br and I and (c) a nitro group, or the hydrochloride salt of the compound; and b) at least one curative selected from hexahydro-1,3,5-tris (2-hydroxyethyl) -s-triazine, bis 1,4- (bromoacetoxy) -2-butene; 2-bromo-2-nitropropane-1,3-diol; dimethylhydantoin; imidazolididinylurea; diazolidinylurea; a mixture of 5-chloro-2-methyl-4-iso-thiazolin-3-one and 2-methyl-4-iso-thiazolin-3-one; 1- (3-chloroalyl) -3,5,7-triaza-1-azoniadamantane chloride; and C? -C6 alkyl hydroxybenzoate; wherein the components (a) and (b) are present in a synergistically effective combined amount. 2. The composition according to claim 1, characterized in that the compound of the formula I is 3,5-dimethyl-1-hydroxymethylpyrazole.
3. 3. The composition according to claim 1, characterized in that the microorganism is a bacterium or a fungus.
4. 4. The composition according to claim 3, characterized in that the bacterium or the fungus is Aspergillus niger or Pseudomonas aeruginosa. The composition according to claim 1, characterized in that the weight ratio of (a) to (b) is from about 0.1: 99 to about 99: 0.1. 6. The composition according to claim 5, characterized in that the weight ratio of (a) to (b) is from about 1:30 to about 30: 1. 7. The composition according to claim 6, characterized in that the weight ratio of (a) to (b) is from about 1: 5 to about 5: 1. 8. A method for controlling the growth of at least one microorganism in or on a material or medium susceptible to attack by the microorganism characterized in that it comprises the step of adding to the material or medium a composition comprising: (a) a compound having the formula (I) where R and R 'are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms, R "is a portion selected from the group consisting of (a) hydrogen, (b) a halogen atom selected from the group consisting of F, Cl, Br and I and (c) a nitro group, or the hydrochloride salt of the compound; and (b) at least one curative selected from hexahydro-1,3,5-tris (2-hydroxyethyl) -s-triazine, bis 1,4- (bromoacetoxy) -2-butene; 2-bromo-2-nitropropane-1,3-diol; dimethylhydantoin; imidazolididinylurea; diazolidinylurea; a mixture of 5-chloro-2-methyl-4-iso-thiazolin-3-one and 2-methyl-4-iso-thiazolin-3-one; 1- (3-chloroalyl) -3,5,7-triaza-1-azoniadamantane chloride; and C? -C6 alkyl hydroxybenzoate; in a synergistically effective combined amount to control growth. 9. The method according to claim 8, characterized in that the compound of the formula I is 3,5-dimethyl-1-hydroxymethylpyrazole. The method according to claim 8, characterized in that the microorganism is a bacterium or a fungus or mixture thereof. 11. The composition according to claim 10, characterized in that the bacterium or the fungus is Aspergillus niger or Pseudomonas aeruginosa. The method according to claim 9, characterized in that the material or medium is wood, pulp, wood chips, wood, paints, dyes, skins, adhesives, coatings, animal skins, tanning liquors, factory liqueurs, paper, fluids for metal work, starch, petrochemicals, emulsions of acrylic latex paints, pharmaceutical formulations, water cooling towers, cosmetics and toilet formulations, textiles, water plant effluents and entrants, waste water, lubricants of geological drilling or agrochemical compositions. 13. The method according to the claim 9, characterized in that the material or medium is in the form of a solid, dispersion, emulsion or solution. A method for preventing the decomposition of a material or medium caused by bacteria or fungi characterized in that it comprises the step of adding to the material or medium a composition comprising: (a) a compound having the formula (I) where R and R 'are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms, R "" is a portion selected from the group consisting of (a) hydrogen, (b) a halogen atom selected from the group consisting of F, Cl, Br and I and (c) a nitro group, or the hydrochloride salt of the compound; and (b) at least one curative selected from hexahydro-1,3,5-tris (2-hydroxyethyl) -s-triazine, bis 1,4- (bromoacetoxy) -2-butene; 2-bromo-2-nitropropane-1,3-diol; dimethylhydantoin; imidazolididinylurea; diazolidinylurea; a mixture of 5-chloro-2-methyl-4-iso-thiazolin-3-one and 2-methyl-4-iso-thiazolin-3-one; 1- (3-chloroalyl) -3,5,7-triaza-1-azoniadamantane chloride; and C? -C6 alkyl hydroxybenzoate; in a synergistically effective combined amount to avoid and / or mitigate decomposition. 1
5. 5. The method of compliance with the claim 14, characterized in that the compound of the formula I is 3,5-dimethyl-1-hydroxymethylpyrazole. 1
6. 6. The method of compliance with the claim 8, characterized in that the components (a) and (b) can be added separately to the material or medium.