US 2006O142291A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0142291 A1 Beilfuss et al. (43) Pub. Date: Jun. 29, 2006

(54) USE OF FORMALDEHYDE AND Publication Classification FORMALDEHYDE-RELEASING COMPOUNDS IN A COMPOSITION FOR (51) Int. Cl. CONTROLLING MYCOBACTERA AOIN 43/66 (2006.01) AOIN 43/80 (2006.01) (76) Inventors: Wolfgang Beilfuss, Hamburg (DE); AOIN 35/02 (2006.01) Info Krull, Kummerfeld (DE); Ralf Gradtke, Tornesch (DE); Katrin AOIN 43/52 (2006.01) Steinhauer, Hamburg (DE) AOIN 47/28 (2006.01) (52) U.S. Cl...... 514/241; 514/393: 514/372: Correspondence Address: 514/697; 514/588 AIR LIQUIDE 2700 POST OAKBOULEVARD, SUITE 1800 HOUSTON, TX 77056 (US) (57) ABSTRACT (21) Appl. No.: 11/288,665 (22) Filed: Nov. 28, 2005 The invention relates to the use of a bactericide selected Foreign Application Priority Data from formaldehyde and formaldehyde-releasing compounds (30) in a composition for controlling mycobacteria, for example Dec. 7, 2004 (DE)...... 10 2004 O59 041.9 in a cooling lubricant. US 2006/0142291 A1 Jun. 29, 2006

USE OF FORMALDEHYDE AND liquids and significantly reduce the risk observed using HHT FORMALDEHYDE-RELEASING COMPOUNDS IN of occupational diseases on handling these liquids. A COMPOSITION FOR CONTROLLING 0008. It has now surprisingly been found that, by the use MYCOBACTERA of a bactericide selected from formaldehyde and formalde 0001. This application claims the benefit of priority under hyde-releasing compounds the abovementioned object is 35 U.S.C. S 119 (a) and (b) to German Application No. DE achieved and the problems of the prior art are overcome. The 10 2004 059041.9, filed Dec. 7, 2004, the entire contents of invention is thus based on the finding that formaldehyde and which are incorporated herein by reference. formaldehyde-releasing compounds (different from HHT) in a composition for controlling mycobacteria 0002 The present invention relates to the use of formal dehyde and formaldehyde-releasing compounds in a com 0009 i) even in the case of overdose do not promote position for controlling mycobacteria, for example in a the growth of mycobacteria and cooling lubricant. 0010 ii) are more active against mycobacteria, that is to say at the same concentration are more active than 0003. A mycobactericidal activity of formaldehyde is HHT and/or the same activity against mycobacteria is generally known (see, inter alia, S. S. Block, ed., Disinfec tion, Sterilization and Preservation, 5" edition, 2001, Lip achieved at a lower concentration than with HHT. pincott, Williams & Wilkins). Furthermore, DE 19842 116 0011. The invention thus consists in the use of a bacte A1, DE 199 61 621 A1 and DE 197 22858 A1 describe the ricide selected from formaldehyde and formaldehyde-releas use of formaldehyde- and formal-containing formulations in ing compounds in a composition for controlling mycobac cooling lubricants. teria which is characterized in that in the case of overdose of the bactericide, no promotion of the growth of mycobacteria 0004. However, it has been found that, for example in the OCCU.S. metalworking industry, occupational diseases due to process fluids and cooling lubricant emulsions occur which belong 0012. The invention also consists in the use of a bacte to the group of the exogenous allergic alveolitides (hyper ricide selected from formaldehyde and formaldehyde-releas sensitivity pneumonitis (HP)). Exogenous allergic alveoliti ing compounds in a composition for controlling mycobac des are acute, Subacute and chronic lung inflammations teria which is characterized in that the activity of the which are caused by inspired antigens. These include farm bactericide against mycobacteria is greater at the same er's lung, bird breeder's lung and air-conditioner disease, concentration than the activity of 2.2.2"-(hexahydro-1,3,5- and also a number of more rarely observed disorders. triazine-1,3,5-triyl)triethanol or the same activity against Exposure to cooling lubricants is, in addition, associated mycobacteria as using 2.2.2"-(hexahydro-1,3,5-triazine-1,3, with asthma and possibly even cancer. 5-triyl)triethanol is achieved at a lower concentration of the bactericide. 0005 Mycobacteria are under discussion as a possible cause of exogenous allergic alveolitides. Mycobacteria are 0013. According to the invention, mycobacteria are pref comparatively resistant to biocidal active compounds, in erably controlled in industrial products, such as cooling particular at concentration ranges as are customarily used in lubricant emulsions, water-based process liquids, cleaning process liquids. Therefore, active preparations are being compositions and rinsing liquids. sought which, in customary concentrations, actively Sup 0014. The formaldehyde-releasing compound used press the growth of microbacteria in process liquids and according to the invention is preferably selected form 3,3'- significantly reduce the risk of occupational diseases on methylenebis5-methyloxazolidine), 1,3-bis(hydroxymethy handling these liquids. Previously, for this, inter alia, bac 1)urea, (ethylenedioxy)dimethanol, 2-(2-butoxyethoxy tericides based on phenols have been proposed. )ethoxymethanol, tetrahydro-1,3,4,6- tetrakis(hydroxylmethyl)imidazo[4,5-dimidazole-2.5(1H, 0006 Because the biocidal active compound which has 3H)-dione, C.C.'.O."-trimethyl-1,3,5-triazine-1,3,5-(2H4H, been predominantly used in cooling lubricants is 2.2.2"- 6H)-triethanol and mixtures thereof. Frequently, mixtures of (hexahydro-1,3,5-triazine-1,3,5-triyl)triethanol (HHT), Substances and Substances which are not clearly identified inadequate activity against mycobacteria and even specific which are in dynamic equilibrium are present. The formal growth promotion of mycobacteria when this bactericide is dehyde-releasing compounds preferably used according to overdosed has been suspected. Therefore, at least one inter nationally active enterprise of the automobile industry has the invention are condensation products of formaldehyde (or stipulated that triazines and other compounds releasing paraformaldehyde) and alkanolamines and/or glycols and/or formaldehyde shall no longer be permitted to be used as urea or urea derivatives. Accordingly, the following are used bactericides in the formulations of metalworking fluids according to the invention, for example: (MWFs). The search for alternatives has therefore been 0015 a) the condensation product of isopropanolamine restricted to bactericides whose action is not based on the and paraformaldehyde (active compound: 3,3'-methyl specific biocidal activity of formaldehyde condensation enebis5-methyloxazolidine), if appropriate stabilized products (it is assumed that the hydrolysis of formaldehyde with antioxidants, condensation products on the cell wall of the mycobacterium 0016 b) the condensation product of isopropanola effectively denatures its peptidoglucan structure and thus mine, paraformaldehyde and urea, if appropriate stabi leads to cell death). lized with antioxidants, 0007. It was an object of the invention to provide bacte 0017 c) the condensation product of isopropanola ricides which, when used in customary concentrations, mine, paraformaldehyde, urea and ethylene glycol, if actively suppress the growth of mycobacteria in process appropriate stabilized with antioxidants, US 2006/0142291 A1 Jun. 29, 2006

0018 d) the condensation product of paraformalde 0026. According to the present invention it is possible to hyde, ethylene glycol, butyl diglycol and urea (active control mycobacteria more actively, in particular in cooling compounds: (ethylenedioxy)dimethanol. 2-(butoxy lubricants. This includes the fact that the inventively used ethoxy)ethoxymethanol and 1,3-bis(hydroxymethy bactericides can be overdosed without the risk of promotion 1)urea), of the growth of mycobacteria occurring. Here, the expres sion “overdosing denotes a concentration of the bactericide 0019 e) the condensation product of paraformalde which is higher than the minimum usage concentration of hyde, ethylene glycol and urea (active compounds: the bactericide. The “minimum usage concentration of the (ethylenedioxy)dimethanol and 1,3-bis(hydroxymethy bactericide is the concentration at which it is sufficient to 1)urea), reduce the number of mycobacteria of a sample, or to inhibit 0020 f) the condensation product of isopropanolamine the growth, significantly, preferably by the factor 10, more and paraformaldehyde (active compound: C.C.'.O."-tri preferably by the factor 100, and particularly preferably by methyl-1,3,5-triazine-1,3,5-(2H4H.6H)-tri-ethanol), the factor 1000. 0027 Certain concentration ranges have proved to be 0021 g) the condensation product of formaldehyde (or surprisingly active for the inventively used bactericide. For paraformaldehyde) and glyoxal and urea, or of form example, the condensation product of paraformaldehyde, aldehyde (or paraformaldehyde) and glycoluril, (active ethylene glycol, butyl diglycol and urea (active compounds: compound: tetrahydro-1,3,4,6-tetrakis(hydroxymeth (ethylenedioxy)dimethanol, 2-(butoxyethoxy)ethoxymetha yl)imidazo[4,5-dimidazole-2.5(1H.3H)-dione). nol and 1,3-bis(hydroxymethyl)urea), even at a usage con 0022. In addition, preference is given to benzyl alcohol centration of 0.15% by weight, is active against M. chelo hemiformal (the condensation product of benzyl alcohol and nae, whereas 0.3% by weight of HHT is necessary therefor. formaldehyde) and 4.4-dimethyloxazolidine, 1-(3-chloral The required amount of formaldehyde-releasing compound lyl)-3,5,7-triaza-1-azoniatricyclo3.3.1.13.7decane chlo can therefore be selected to be lower for the same activity. ride, bronopol. 7a-ethyldihydro-1H.3H,5H-oxazolo 3,4-c 0028. When use is made of an inventive bactericide (or a oxazole. plurality of inventive bactericides in combination), if appro 0023 The effects which are surprisingly observed also priate in a mixture with one or more other active com occur when use is made of a mixture of the inventively used pounds, the recommended usage concentration is thus pref bactericide with one or more active compounds. This is erably less than 0.3% by weight, such as less than 0.25% by shown in the activity of Such an inventive mixture as weight, for example 0.1 to 0.2% by weight, preferably 0.1 to compared with the activity of HHT and if appropriate also 0.15% by weight. in comparison with the activity of a mixture of HTT with the 0029. The advantages of the present invention follow, in active compound(s). According to the invention, the bacte particular from the following examples. ricide is thus used, preferably together with one or more other active compounds selected from 3-iodo-2-propinylbu EXAMPLES tyl carbamate, N-cyclohexyl-N-nitrosohydroxylamine salts (preferably the potassium salt), phenols such as o-phe Method for determining the activity of bactericidal solutions nylphenol, p-chloro-m-cresol, p-chloro-m-Xylenol, alcohols against mycobacteria: Such as phenoxyethanol, phenoxypropanols, thiabendazole 0030 Mycobcobacteria culturedltured ini accordanced Witith or its salts, p-(diiodomethyl)sulfonyltoluene, 2-bromo-2- DGHM (2001)', (bromomethyl)pentanedinitrile, isothiazol-3-ones such as 5-chloro-2-methyl-2H-isothiazol-3-one and/or 2-methyl 0031) 5 ml of double-concentrated test solution are 2H-isothiazol-3-one, 1,2-benzisothiazol-3(2H)-one, n-bu admixed with 5 ml of double-concentrated liquid tyl-1,2-benzisothiazol-3(2H)-one and 2-octyl-3(2H)isothia medium (7H9 medium), Zol-3-one and also salts of 2-mercaptopyridine N-oxide, 0032 addition of 0.1 ml of mycobacterial suspension such as the sodium or zinc salt (Pyrion-Na, Zn-pyrithione). (titre: 1x10-8x10 CFU/ml; production of the myco According to the invention, particularly preferably use is bacterial suspension in accordance with DGHM made of mixtures with Pyrion-Na and/or isothiazolones, for (2001), example mixtures with 1,2-benzisothiazol-3(2H)-one or 2-octyl-3(2H)-isothiazol-3-one. 0033 incubation of the test tubes at 28°C. or 37° C. (depending on the mycobacterial test strain) for 3 0024. The invention further relates to the use of isothia weeks (static culture), Zol-3-ones to increase the mycobactericidal activity of form aldehyde and formaldehyde-releasing compounds. As 0034 study of the inhibitory activity of the individual ensues, in particular, from the examples, isothiazol-3-ones, dilutions by examination for optical turbidity, caused which are not known themselves as typical mycobactericidal by bacterial growth, and also additional streaking on active compounds, Surprisingly increase the mycobacteri 7H10-agar, cidal activity of formaldehyde and formaldehyde-releasing 0035 incubation of the agar plates for 3 weeks at 28° compounds. C. or 37°C. (according to test strain), 0025. According to the invention, the bactericide is pref 0036 inspection of the agar plates for mycobacterial erably used for controlling M. chelonae, M. immunogenium, growth. M. abscessus, M. avium and M. terrae, preferably non tuberculous rapidly-growing mycobacteria, Such as M. 0037 Gebel, J., H. P. Werner, Kirsch-Altena, K., Ban immunogenium and M. chelonae. semir, K. (2001): Standardmethoden der DGHM Zur US 2006/0142291 A1 Jun. 29, 2006 3

Prüfung chemischer Desinfektionsverfahren Standard 2. Use of a bactericide selected from formaldehyde and methods of the DGHM German Society for Hygiene formaldehyde-releasing compounds in a composition for and Microbiology for testing chemical disinfection controlling mycobacteria, characterized in that the activity methods, mhp Verlag, Wiesbaden. of the bactericide against mycobacteria is greater at the same 0038 All percentages are by weight (% by weight). concentration than the activity of 2,2'2"-(hexahydro-1,3,5- triazine-1,3,5-triyl)triethanol or the same activity against 0.039 Expressions used in the examples mean as follows: mycobacteria as using 2.2.2"-(hexahydro-1,3,5-triazine-1,3, 0040) M. terrae: ATCC 15755 (37° C.), 5-triyl)triethanol is achieved at a lower concentration of the bactericide. 0041) M. chelonae: ATCC 35725 (28° C.), 3. Use according to claim 7, characterized in that the 0.042) M. chelonae: ATCC 19236 (37° C.), formaldehyde-releasing compound is selected from 3,3'- 0.043 M. immunogenium: ATCC 700505 (280 C., 370 methylenebis(5-methyloxazolidinel 1.3-bis(hydroxymethy C.), 1)urea, (ethylenedioxy)dimethanol, 2-(2-butoxyethoxy OO44 : C diluted MIC luti )ethoxymethanol, tetrahydro-1,3,4,6- O b. t stration 1n und1 lute test SOut1On tetrakis(hydroxymethyl)imidazo[4,5-dimidazole-2.5(1H, (0.6% strength), 3H)-dione, C.C.'.O."-trimethyl-1,3,5-triazine-1,3,5-(2H4H, OO4S MIC:: MinimumM InhibitoryInhibito Concentration. trat 6H)-triethanol-triethanol and mixturest thereofthereof.

Iso HCHO thiazolone content (%) in (%) in undiluted Activity at MIC (% COCC- MIC test M. terrae M. chelonae M. chelonae M. immunogenium M. immunogenium Example trate solution Composition (37° C) (28° C.) (37° C.) (28° C.) (37° C.) 1 47 (0.28)* a) O.15 O.3 O.3 sO.O75 sO.O75 2 45 (0.27)* b) O.3 O.3 O.3 s0.075 s0.075 3 46 (0.28)* 0.004 a), 2-octyl-3(2H)- sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 isothiazol-3-one 4 40.5 (0.24)* c) sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 5 39.5 (0.24)* c), 2-mercaptopyridine sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 N-oxide sodium salt (0.0067%)* 6 34.8 (0.21)* 0.0068 d), 2-octyl-3(2H)- sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 isothiazol-3-one 7 45.5 (0.27)* 0.0068 e), 2-octyl-3(2H)- sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 isothiazol-3-one 8 4.6 (0.028) 0.0055 d), 5-chloro-2-methyl- sO.O75 O.15 sO.O75 O.15 sO.O75 : 2-isothiazol-3-one, 2-methyl-2H isothiazol-3-one 9 20 (0.12)* 0.0055 g), 5-chloro-2- sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 methyl-2H-isothiazol 3-one: 2-methyl-2H isothiazol-3-one 10 46.5 (0.28)* e) sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 11 34.8 (0.21)* d) O.15 O.15 O.15 sO.O75 sO.O75 12 33.4 (0.2)* 0.0068 d), 2-octyl-3(2H)- sO.O75 sO.O75 sO.O75 sO.O75 sO.O75 isothiazol-3-one 13 27.5 (0.17)* f) O.15 O.3 O.3 sO.O75 sO.O75 Comparison 1 31.5 (0.19)* 2,2'2"- O.3 O.3 O.3 sO.O75 sO.O75 (hexahydro-1,3,5- triazine-1,3,5-triyl) triethanol (HHT) Comparison 2 0.006 2-octyl-3(2H)- >0.3 >0.3 >0.3 >0.3 >0.3 isothiazol-3-one Comparison 3 0.0056 5-chloro-2-methyl-2H- O.3 O.3 >0.3 O.3 O.3 isothiazol-3-one, 2 methyl-2H-isothiazol 3-one

What is claimed is: 4. Use according to claim 7, characterized in that the 1. Use of a bactericide selected from formaldehyde and bactericide is used in a mixture with one or more other active formaldehyde-releasing compounds in a composition for compounds selected from 3-iodo-2-propinylbutyl carbam controlling mycobacteria, characterized in that in the case of ate, N-cyclohexyl-N-nitrosohydroxylamine salts (preferably overdose of the bactericide, no promotion of the growth of the potassium salt), phenols such as o-phenylphenol, isothia mycobacteria occurs. Zol-3-ones such as 5-chloro-2-methyl-2H-isothiazol-3-one US 2006/0142291 A1 Jun. 29, 2006 and/or 2-methyl-2H-isothiazol-3-one, 1,2-benzisothiazol genum, M. abscessus, M. avium and M. terrae, preferably M. 3(2H)-one, n-butyl-1,2-benzisothiazol-3(2H)-one and 2-oc tyl-3(2H)-isothiazol-3-one and also salts of 2-mercaptopy chelonae and M. immunogenium. ridine N-oxide, such as the sodium or zinc salt (Pyrion-Na. 6. Use of isothiazol-3-ones to increase the mycobacteri Zn-pyrithione), preferably in a mixture with Pyrion-Na, cidal activity of formaldehyde and formaldehyde-releasing 1,2-benzisothiazol-3(2H)-one or 2-octyl-3(2H)-isothiazol compounds. 3-one. 5. Use according to claim 7, characterized in that the mycobacterium is selected from M. chelonae, M. immuno