Patent Grant
6919364
Reference is hereby made to the following applications: application Ser. No. 09/088,300, filed Jun. 1, 1998, now U.S. Pat. No. 6,068,861 issued May 30, 2000; application Ser. No. 09/296,499, filed Apr. 22, 1999, now U.S. Pat. No. 6,110,387 issued Aug. 29, 2000; application Ser. No. 09/323,348, filed Jun. 1, 1999, now U.S. Pat. No. 6,303,038 B1 issued Oct. 16, 2001; application Ser. No. 09/404,184, filed Sep. 24, 1999; application Ser. No. 09/442,025, filed Nov. 17, 1999, now U.S. Pat. No. 6,306,441 issued Oct. 23, 2001; application Ser. No. 09/451,319, filed Nov. 30, 1999; application Ser. No. 09/451,344, filed Nov. 30, 1999; application Ser. No. 09/456,781, filed Dec. 8, 1999; application Ser. No. 09/483,896, filed Jan. 18, 2000; application Ser. No. 09/484,687, filed Jan. 18, 2000; application Ser. No. 09/484,844, filed Jan. 18, 2000; application Ser. No. 09/484,891, filed Jan. 18, 2000; application Ser. No. 09/484,938, filed Jan. 18, 2000; application Ser. No. 09/487,816, filed Jan. 18, 2000; application Ser. No. 09/506,911, filed Feb. 18, 2000; application Ser. No. 09/658,839, filed Sep. 8, 2000; application Ser. No. 09/663,788, filed Sep. 18, 2000; application Ser. No. 09/663,948, filed Sep. 18, 2000, now U.S. Pat. No. 6,299,909 B1 issued Oct. 9, 2001; application Ser. No. 09/732,601, filed Dec. 7, 2000; application Ser. No. 09/775,516, filed Feb. 2, 2001; application Ser. No. 09/778,228, filed Feb. 6, 2001; application Ser. No. 09/785,890, filed Feb. 16, 2001; application Ser. No. 09/893,581, filed Jun. 28, 2001; application Ser. No. 09/974,622, filed Oct. 9, 2001; and application Ser. No. 10/029,329, filed Dec. 21, 2001 entitled “Microbiological Control in Poultry Processing” of which the owner is one of the two owners of the present application.
Animal processing for meat products is an area in which microbiological control is of vital importance. By the very nature of the processing involved there are numerous opportunities for the live animals to be exposed to various pathogens in the form of mobile bacteria. The thought of handling, processing and consuming bacteria-infested meat is revolting in the extreme. Furthermore, new government rules and standards require that additional attention be paid to both production and processing areas to assure reduced contamination of consumer meat.
Heretofore certain halogen-containing compositions have been proposed for use as additives to animal drinking water as a potential way of reducing bacterial activity. For example U.S. Pat. No. 4,822,512 describes tests in which a formulation composed of 1.5 parts of sodium chloride, 50 parts of potassium persulfate triple salt, 5 parts of sulfamic acid, 10 parts of malic acid, 18.5 parts of sodium hexametaphosphate and 15 parts of sodium dodecylbenzene was added to drinking water for poultry and day-old chicks. As to the results of these tests, the patent reports only that as compared to a control group the birds and chicks given this formulation gained more weight. In a paper published in Poultry Science, 1982, 61, 1968-1971, Mora, Kohl, Wheatley, Worley, Faison, Burkett, and Bodor report results of studies in which 15-day old broilers were given untreated drinking water or water treated with 200 ppm of 3-chloro-4,4-dimethyl-2-oxazolidinone (CDO). The authors concluded that during the 8-week period of the tests no significant differences were noted in the amounts of food or water consumed, that no statistically significant differences were seen between the weights of the test groups and their respective controls, and that no significant gross differences in internal organs were observed that could be attributed to the ingestion of the CDO. More recently, U.S. Pat. No. 6,099,855 teaches administration via drinking water to baby chicks and to 6-week-old male and female broilers infected with Salmonella typhimurium of pH-buffered redox-stabilized compositions comprising halide and oxyhalide ions. See also related U.S. Pat. Nos. 5,830,511; and 6,004,587. A product of this type, viz., Aquatize® biocide (Bioxy Incorporated) is believed to be a composition of this type.
One ubiquitous source of microbial contamination in animal processing is animal fecal matter. It would be of considerable benefit if a highly effective way could be found of reducing the bacterial content of animal fecal matter.
This invention fulfills the foregoing need by providing and utilizing certain water-based compositions for reducing microbial contamination in and from animal fecal matter. Compositions of this invention have proven to be highly effective against fecal microbial contamination when used as drinking water for the animals. In addition, this invention makes possible the provision of microbiocidally-effective drinking water compositions for animals which result in little, if any, reduction in food and water consumption, and little, if any, adverse effect on intestinal condition of animals consuming such compositions. Moreover, microbiocidal agents used pursuant to this invention can be produced economically in straightforward processing from relatively low cost raw materials and because of their effectiveness when used as components of animal drinking water, can provide microbiological control on an economical basis consistent with the needs of the meat processing industry.
In one of its embodiments this invention provides a method of reducing fecal contamination in an animal, which method comprises providing to the animal drinking water containing a microbiocidally-effective amount of halogen-based microbiocide resulting from mixing with water:
Another embodiment of this invention is drinking water for animals, especially poultry, cattle, sheep, or swine, wherein said drinking water contains a microbiocidally-effective amount of halogen-based microbiocide resulting from mixing A), B), C), or D) above with water. In this connection, the term “animals” includes ruminants and monogastrics, such as domestic animals and pets, farm animals, animals raised for harvest, and so-called wild animals whether in zoos or in the wild. Such drinking water is useful in reducing the spread of diseases resulting from exposure to bacteria or other pathogens often contained in animal fecal matter. Such drinking water is preferably used in a facility for processing of animals for at least one meat product, such facility having at least one container of drinking water accessible to at least one animal prior to slaughter. The sanitation of the facility is improved and fecal bacterial contamination of the animals is reduced by the presence in such drinking water of a microbiocidally-effective amount of halogen-based microbiocide resulting from mixing A), B), C), or D) above with water.
A microbiocide from each of A), B), and C) has been shown to be effective against fecal bacteria when used in drinking water for such animals as poultry, cattle, and swine. Moreover, tests conducted under actual service conditions have indicated that at least 1,3-dibromo-5,5-dimethylhydantoin, N,N′-bromochloro-5,5-dimethylhydantoin, and an alkaline aqueous solution of product formed in an aqueous medium from bromine chloride and sodium sulfamate and sodium hydroxide did not create excessive mortality or weight gain loss in baby chicks prior to sacrifice.
In preferred embodiments, the halogen-based microbiocide added to the drinking water for the animals is (a) a bromine-based microbiocide comprising an overbased aqueous microbiocidal solution of one or more active bromine species, said species resulting from a reaction in water between bromine or bromine chloride, a mixture of bromine chloride and bromine, or a combination of bromine and chlorine in which the molar amount of chlorine is either equivalent to the molar amount of bromine or less than the molar amount of bromine, and a water-soluble source of sulfamate anion, or (b) at least one 1,3-dibromo-5,5-dialkylhydantoin in which one of the alkyl groups is a methyl group and the other alkyl group contains in the range of 1 to about 4 carbon atoms, or (c) both of (a) and (b) hereof. Such bromine-based microbiocides are more effective than corresponding chlorine-based microbiocides against various microorganisms. In addition, these bromine-based microbiocides tend to be less odorous than chlorine-based microbiocides, and are essentially devoid of unwanted bleaching activity. Moreover, while some of the bromine-based microbiocides may possibly react with nitrogenous species, such as are present in fecal matter, the resultant bromamines would also possess microbiological activity. Thus such side reactions would not materially decrease the microbiological effectiveness made available to the meat processor by use of these bromine-based microbiocides in the animal drinking water. Furthermore, bromamines generally do not exhibit obnoxious properties toward workers in the processing plant whereas chloramines resulting from use of certain chlorine-based microbiocides under the same conditions tend to be powerful lachrymators.
In particularly preferred embodiments, the halogen-based microbiocide added to the drinking water for the animals is at least one 1,3-dibromo-5,5-dialkylhydantoin in which one of the alkyl groups is a methyl group and the other alkyl group contains in the range of 1 to about 4 carbon atoms. Such bromine-based microbiocides are especially effective against fecal bacteria when used in the practice of this invention. 1,3-Dibromo-5,5-dimethylhydantoin is particularly preferred for use in the practice of this invention.
The aqueous microbiocidal solutions used as animal drinking water pursuant to this invention can be formed from microbiocides of types B) and/or C) above by mixing such microbiocidal agent(s) in undiluted form (i.e., in solid form such as powder, particles, granules, tablets, etc.) or as a preformed aqueous solution thereof with water to be used as drinking water for the animals. To form the finished suitably dilute animal drinking water solution of this invention the solids can thus be added to, mixed with, or dissolved in water in proportions such that the desired microbiocidally effective amount of one or more halogen species is present in the water as the result of a single step operation where the intended end use dosage level is achieved without further dilution. Alternatively the solids can be added to, mixed with, or otherwise introduced into water using proportions that result in a more concentrated solution (or slurry) which then is diluted with water one or more times to form a final solution in which the desired microbiocidally effective amount of one or more halogen species is present in the water. In all such cases, the resultant suitably dilute microbiocidal solution of this invention containing the appropriate microbiocidally effective amount of one or more halogen species the can then be used as animal drinking water to reduce fecal microbial contamination. The microbiocides of type A) above are typically prepared or provided in the form of a preformed aqueous concentrate containing, say, at least about 50,000 ppm (wt/wt) and preferably at least about 100,000 ppm (wt/wt) of active bromine and thus the concentrate is added to and mixed with, or diluted in stages, whichever is desired, to form the suitably dilute microbiocidal solution of this invention for use as animal drinking water. Such concentrates typically have an atom ratio of nitrogen from sulfamate to active bromine that is greater than about 0.93, and preferably greater than 1, and has a pH of at least about 12 and preferably in the range of about 13 to about 14. An aqueous concentrate of type A) is available in the marketplace as Stabrom® 909 biocide (Albemarle Corporation). Such commercially-available concentrates will typically contain in the range of about 145,000 to about 160,000 ppm of active bromine.
Other embodiments, features and advantages of this invention will be still further apparent from the ensuing description and appended claims.
One group of halogen-based microbiocides for use in this invention is an aqueous microbiocidal solution of one or more active halogen species, said species resulting from a reaction in water between bromine, chlorine, or bromine chloride, or any two or all three thereof, and a water-soluble source of sulfamate anion. If sulfamic acid is used in forming this microbiocide, the solution should also be provided with a base, preferably enough base to keep the solution alkaline, i.e., with a pH above 7, preferably above about 10 and most preferably about 13 or above. The lower the pH, the more unstable the solution, and thus if the solution is prepared on site for immediate use, the use of a base is not essential. However, it is preferable to employ a concentrated microbiocidal solution manufactured elsewhere, and in such case the concentrated solution would be provided as an overbased solution with a pH of, say, about 13 or more. Often such concentrated solutions will contain over 50,000 ppm (wt/wt) of active halogen, preferably at least about 100,000 ppm (wt/wt) of active halogen. Active halogen content is determinable by use of conventional starch-iodine titration. For convenience, products of this type are sometimes referred to hereinafter as sulfamate-stabilized bromine chloride or more simply, SSBC.
One preferred group of this type is a bromine-based microbiocidal solution formed by reacting bromine or, more preferably bromine chloride, a mixture of bromine chloride and bromine, or a combination of bromine and chlorine in which the molar amount of chlorine is either equivalent to the molar amount of bromine or less than the molar amount of bromine, in an aqueous medium with sulfamic acid and/or a water-soluble salt of sulfamic acid. Except when made on site for immediate use, such solutions should be highly alkaline solutions typically with a pH of at least about 12 and preferably at least about 13, such pH resulting from use of a base such as sodium hydroxide or the like, in producing the solution. The solution typically contains at least 100,000 ppm (wt/wt) of active bromine, e.g. as much as 145,000 to 160,000 ppm of active bromine. Processes for producing concentrated aqueous microbiocidal solutions of this type are described in U.S. Pat. No. 6,068,861, issued May 30, 2000, and U.S. Pat. No. 6,299,909 B1, issued Oct. 9, 2001, all disclosures of which are incorporated herein by reference. Concentrated solutions of this type are available in the marketplace, for example, Stabrom® 909 biocide (Albemarle Corporation).
It will be appreciated that even where the microbiocide is made from bromine chloride, a mixture of bromine chloride and bromine, or a combination of bromine and chlorine in which the molar amount of chlorine is either equivalent to the molar amount of bromine or less than the molar amount of bromine is used, the microbiocide is bromine-based as most of the chlorine usually winds up as a chloride salt such as sodium chloride since an alkali metal base such as sodium hydroxide is typically used in the processing to raise the pH of the product solution to at least about 13. Thus the chlorine in the product solution is not present as a significant microbiocide.
Another group of halogen-based microbiocides for use in this invention is one or more N,N′-dihalo-5,5-dialkyl hydantoins in which one of the halogen atoms is chlorine and the other is bromine or chlorine, and in which the alkyl groups, independently, each contain from 1 to about 4 carbon atoms. Suitable compounds of this type include, for example, such compounds as 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dichloro-5,5-diethylhydantoin, 1,3-dichloro-5,5-di-n-butylhydantoin, 1,3-dichloro-5-ethyl-5-methylhydantoin, N,N′-bromochloro-5,5-dimethylhydantoin, N,N′-bromochloro-5-ethyl-5-methylhydantoin, N,N′-bromochloro-5-propyl-5-methylhydantoin, N,N′-bromochloro-5-isopropyl-5-methylhydantoin, N,N′-bromochloro-5-butyl-5-methylhydantoin, N,N′-bromochloro-5-isobutyl-5-methylhydantoin, N,N′-bromochloro-5-sec-butyl-5-methylhydantoin, N,N′-bromochloro-5-tert-butyl-5-methylhydantoin, N,N′-bromochloro-5,5-diethylhydantoin, and mixtures of any two or more of the foregoing. A mixture of 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dichloro-5,5-diethylhydantoin is available under the trade designation Dantochlor® biocide (Lonza Corporation). N,N′-bromochloro-5,5-dimethylhydantoin is available commercially under the trade designation Bromicide® biocide (Great Lakes Chemical Corporation). Another suitable bromochlorohydantoin is composed of a mixture of a predominate amount by weight of N,N′-bromochloro-5,5-dimethylhydantoin together with a minor proportion by weight of 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dichloro-5-ethyl-5-methylhydantoin. A mixture of this latter type is available in the marketplace under the trade designation Dantobrom® biocide (Lonza Corporation) which is believed to contain about 60 wt % of N,N′-bromochloro-5,5-dimethylhydantoin, about 27.4 wt % of 1,3-dichloro-5,5-dimethylhydantoin, about 10.6 wt % of 1,3-dichloro-5-ethyl-5-methylhydantoin, and about 2 wt % of inerts. As between the 1,3-dichloro-5,5-dialkylhydantoins and N,N′-bromochloro-5,5-dialkylhydantoins, the latter are preferred as they have greater microbiocidal effectiveness.
When a mixture of two or more of the foregoing N,N′-dihalo-5,5-dialkylhydantoin biocides is used pursuant to this invention, the individual biocides of the mixture can be in any proportions relative to each other.
It will be understood that the designation N,N′ in reference to, say, N,N′-bromochloro-5,5-dimethylhydantoin means that this compound can be (1) 1-bromo-3-chloro-5,5-dimethylhydantoin, or (2) 1-chloro-3-bromo-5,5-dimethylhydantoin, or (3) a mixture of 1-bromo-3-chloro-5,5-dimethylhydantoin and 1-chloro-3-bromo-5,5-dimethylhydantoin. Also, it is conceivable that some 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dibromo-5,5-dimethylhydantoin could be present in admixture with (1), (2), or (3).
An even more preferred system for use in the practice of this invention is a bromine-based microbiocidal solution of a 1,3-dibromo-5,5-dialkylhydantoin in which one of the alkyl groups is a methyl group and the other alkyl group contains in the range of 1 to about 4 carbon atoms. Thus these preferred biocides comprise 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dibromo-5-ethyl-5-methylhydantoin, 1,3-dibromo-5-n-propyl-5-methylhydantoin, 1,3-dibromo-5-isopropyl-5-methylhydantoin, 1,3-dibromo-5-n-butyl-5-methylhydantoin, 1,3-dibromo-5-isobutyl-5-methylhydantoin, 1,3-dibromo-5-sec-butyl-5-methylhydantoin, 1,3-dibromo-5-tert-butyl-5-methylhydantoin, and mixtures of any two or more of them. Of these biocidal agents, 1,3-dibromo-5-isobutyl-5-methylhydantoin, 1,3-dibromo-5-n-propyl-5-methylhydantoin, and 1,3-dibromo-5-ethyl-5-methylhydantoin are, respectively, preferred, more preferred, and even more preferred members of this group from the cost effectiveness standpoint. Of the mixtures of the foregoing biocides that can be used pursuant to this invention, it is preferred to use 1,3-dibromo-5,5-dimethylhydantoin as one of the components, with a mixture of 1,3-dibromo-5,5-dimethylhydantoin and 1,3-dibromo-5-ethyl-5-methylhydantoin being particularly preferred. The most preferred member of this group of microbiocides is 1,3-dibromo-5,5-dimethylhydantoin. This compound is available in the marketplace in tablet or granular form under the trade designation Albrom® 100 biocide (Albemarle Corporation). Preferred is 1,3-dibromo-5,5-dimethylhydantoin in granular form with a compression strength of at least 15 pounds per inch and more preferably at least 20 pounds per inch, which is devoid of any binder or other additive component that tends to increase the compression strength of the granules, and which has not been melted to form the granules.
To determine the compression strength of granules, individual granules are subjected to crush strength testing utilizing a Sintech® 1/S compression apparatus (MTS Systems Corporation, Edenprairie, Minn.) equipped with Testworks software, which software is installed in the 1/S compression apparatus as supplied by MTS Systems Corporation. The apparatus includes a horizontal circular-shaped load cell interfaced with a computer, a digital micrometer also interfaced with the computer, and a vertical screw-driven piston that is disposed above the load cell and adapted to apply a downward force perpendicular to the load cell. The procedure for measuring crush strength involves measuring the thickness of the granule with the micrometer to provide a digitized input to the computer. Next the granule is placed on the load cell with the piston in contact with the upper surface of the granule. Then the apparatus is activated whereby the piston commences applying a progressively increasing downward force to the granule. At the same time, the load cell continuously measures the downward force being applied to the granule, and the input of such measurements is transmitted to the computer. When the force being applied reaches the point where the amount of force suddenly decreases to 10% of the immediately preceding force, the granule has reached the breaking point, and the application of the force is immediately terminated by the software program. From the inputs to the computer, two values are provided, namely the pounds of force at the breaking point of the granule, and the pounds of force per inch thickness of the granule at the breaking point. Thus the greater the force applied, the greater the strength. Typically, the test is conducted thirteen times using thirteen randomly selected granules. The results are then averaged.
When a mixture of two or more of the foregoing 1,3-dibromo-5,5-dialkylhydantoin biocides is used pursuant to this invention, the individual biocides of the mixture can be in any proportions relative to each other.
The halogen-based microbiocides used pursuant to this invention are typically employed in drinking water at dosage levels in the range of about 0.5 to about 25 ppm (wt/wt) expressed as Cl2 equivalent. However whenever deemed necessary or appropriate, departures from this range are permissible and are within the scope of this invention.
Methods for producing 1,3-dibromo-5,5-dialkylhydantoins are known and reported in the literature.
The amount (concentration) of the selected microbiocide utilized in the practice of this invention may vary depending on various factors such as the particular microbiocide being used, the species, age and size of the animal(s) to which the drinking water is to be provided, the duration of the time during which the treated drinking water is to furnished to the animal(s), the nature and frequency of prior microbiocidal treatments, if any, to which the animal has been subjected, the types and nature of the microorganisms to which the animal has been exposed, and so on. In any event, a microbiocidally-effective amount of the microbiocide of this invention will be introduced into the water to be supplied to the animal(s) being treated. such that the amount of microbes or bacteria in the fecal matter of the animal is reduced. Yet the amount of such microbiocide should not be such as to (i) inhibit the animals from ingesting the treated water or (ii) leave excessive residues from the microbiocide in the edible portions of the animals. Optimal amounts of the microbiocide in the drinking water can be determined by performing preliminary tests with the particular microbiocide and type of animal being processed, using as a general guideline a microbiocidally-effective amount of active halogen in the range of about 1 to about 100 ppm (wt/wt), preferably in the range of about 4 to about 50 ppm (wt/wt), and more preferably in the range of about 4 to about 30 ppm (wt/wt) of active bromine. If the actual active halogen present is chlorine, these values are divided by 2.25. Thus the animal drinking water compositions of this invention for use with fowl, cattle, sheep, or swine will typically contain microbiocidally-effective amounts of active halogen in these ranges. In these concentration ranges, active chlorine or bromine content can be determined analytically by use of the conventional DPD test procedure. In the case of the 1,3-dibromo-5,5-dialkylhydantoins used pursuant to this invention, in ordinary situations concentrations will typically be within the range of about 1 to about 50 ppm (wt/wt) (i.e., about 0.5 to about 25 ppm wt/wt expressed as chlorine equivalent. Preferably the concentration of the 1,3-dibromo-5,5-dialkylhydantoin(s) in the water will be in the range of about 4 to about 20 ppm wt/wt, and more preferably in the range of about 5 to about 10 ppm of the 1,3-dibromo-5,5-dialkylhydantoin(s) in the water. It will be understood that departures from the foregoing ranges can be made whenever deemed necessary or desirable, and such departures are within the spirit and scope of this invention.
As can be seen from the above, there are two different types of analytical procedures that are used for determining active halogen content, whether active chlorine, active bromine or both. In the case of the more highly-soluble microbiocides used pursuant to this invention, to measure concentrations in the vicinity of above about, say, 2475 ppm (wt/wt) of active bromine or, say, above about 1100 ppm of active chlorine, starch-iodine titration is the preferred procedure. In the case of the less soluble microbiocides used pursuant to this invention, (i.e., the dibromodialkylhydantoins) to measure concentrations in the vicinity of above about, say, 1300 ppm (wt/wt) of active bromine or, say, above about 580 ppm of active chlorine, starch-iodine titration is the preferred procedure. On the other hand, where concentrations are below levels in the foregoing vicinities, the conventional DPD test procedure is more suitable, as this test is designed for measuring very low active halogen concentrations, e.g., active chlorine concentrations in the range of from zero to about 11-12 ppm (wt/wt) or active bromine concentrations in the range of from zero to about 25-27 ppm (wt/wt). In fact, where the actual concentration of active chlorine is between, say, about 11-12 ppm and about 1100 ppm (wt/wt), or the where the actual concentration of active bromine is between, say, about 25 ppm and about 2475 ppm (wt/wt), the test sample is typically diluted with pure water to reduce the actual concentration to be in the range of about 4 to about 11-12 ppm in the case of active chlorine and to be in the range of about 4.5 to about 12 ppm in the case of active bromine before making the DPD analysis. It can be seen therefore that while there is no critical hard-and-fast concentration dividing line between which procedure to use, the approximate values given above represent a practical approximate dividing line, since the amounts of water dilution of more concentrated solutions when using the DPD test procedure increase with increasing initial active halogen concentration, and such large dilutions can readily be avoided by use of starch-iodine titration when analyzing the more concentrated solutions. In short, with suitably dilute solutions use of the DPD test procedure is recommended, and with more concentrated solutions use of starch-iodine titration is recommended.
The starch-iodine titration procedure for determination of active halogen has long been known. For example, chapter XIV of Willard-Furman, Elementary Quantitative Analysis, Third Edition, D. Van Nostrand Company, Inc., New York, Copyright 1933, 1935, 1940 provides a description of starch-iodine titration. While details of standard quantitative analytical procedures for determination of active halogen in such product solutions by starch-iodine titration may vary from case to case, the results are normally sufficiently uniform from one standard procedure to another as not to raise any question of unreliability of the results. A recommended starch-iodine titration procedure is as follows: A magnetic stirrer and 50 milliliters of glacial acetic acid are placed in an iodine flask. The sample (usually about 0.2-0.5 g) for which the active halogen is to be determined is weighed and added to the flask containing the acetic acid. Water (50 milliliters) and aqueous potassium iodide (15%, wt/wt; 25 milliliters) are then added to the flask. The flask is stoppered using a water seal. The solution is then stirred for fifteen minutes, after which the flask is unstoppered and the stopper and seal area are rinsed into the flask with water. An automatic buret (Metrohm Limited) is filled with 0.1 normal sodium thiosulfate. The solution in the iodine flask is titrated with the 0.1 normal sodium thiosulfate; when a faint yellow color is observed, one milliliter of a 1 wt % starch solution in water is added, changing the color of the solution in the flask from faint yellow to blue. Titration with sodium thiosulfate continues until the blue color disappears. The amount of active halogen is calculated using the weight of the sample and the volume of sodium thiosulfate solution titrated. In this way, the amount of active halogen such as active chlorine or active bromine in an aqueous product solution, regardless of actual chemical form, can be quantitatively determined.
The standard DPD test for determination of low levels of active halogen is based on classical test procedures devised by Palin in 1974. See A. T. Palin, “Analytical Control of Water Disinfection With Special Reference to Differential DPD Methods For Chlorine, Chlorine Dioxide, Bromine, Iodine and Ozone”, J. Inst. Water Eng., 1974, 28, 139. While there are various modernized versions of the Palin procedures, the recommended version of the test is fully described in Hach Water Analysis Handbook, 3rd edition, copyright 1997. The procedure for “total chlorine” (i.e., active chlorine) is identified in that publication as Method 8167 appearing on page 379, Briefly, the “total chlorine” test involves introducing to the dilute water sample containing active halogen, a powder comprising DPD indicator powder, (i.e., N,N′-diethyldiphenylenediamine), KI, and a buffer. The active halogen species present react(s) with KI to yield iodine species which turn the DPD indicator to red/pink. The intensity of the coloration depends upon the concentration of “total chlorine” species (i.e., active chlorine”) present in the sample. This intensity is measured by a colorimeter calibrated to transform the intensity reading into a “total chlorine” value in terms of mg/L Cl2. If the active halogen present is active bromine, the result in terms of mg/L Cl2 is multiplied by 2.25 to express the result in terms of mg/L Br2 of active bromine.
In greater detail, the DPD test procedure is as follows:
The duration of the period during which an animal drinking water composition of this invention is made available to the animal(s) can be varied, depending upon such factors as the type, size and age of the animal(s) and the identity of the particular microbiocide being used pursuant to this invention. Typically, with fowl such as chickens, ducks, geese, or turkeys entirely satisfactory reductions in fecal microbiological contamination may be achieved within periods of about 1 to about 10 days after making the treated drinking water continuously available to the fowl. On the other hand with larger animal species such as cattle, sheep, or swine, beneficial reductions in fecal microbiological contamination may be achieved in periods in the range of about 1 to about 30 days after making the treated drinking water continuously available to such animals. In the case of animal harvesting, usually the drinking water treated pursuant to this invention will be provided to the animal(s) for a period just prior to slaughter. However, it is possible to provide the treated drinking water of this invention to animal(s) which are not to be slaughtered, such as dairy cows, egg-producing hens, horses, mules, or donkeys, as well as domestic animals such as cats, dogs, and rabbits, as well as zoo animals and animals in the wild such as deer, ducks, geese, and wild turkeys. In these situations the bacterial count of fecal matter from the animal can be controlled.
In providing a drinking water composition of this invention to an animal, various regimes can be used. In the case of processing of animals for meat products, typically the period of availability of the treated water will directly precede slaughter. However, if desired, an intermediate period can be provided during which ordinary drinking water is furnished to the animal before slaughter. Other regimes can be used especially where the animal is not to be slaughtered. Here it is possible to periodically furnish the animal a drinking water of this invention for short periods of time in between periods where the animal is provided with ordinary drinking water not treated pursuant to this invention.
The microbiocides introduced into water to form animal drinking water compositions of this invention can be used alone or in combination with one or more other microbiocides suitable for use in the drinking water of the animal, such as for example Aquatize® biocide (Bioxy Incorporated, 3733 National Drive, Suite 115, Raleigh, N.C. 27612-4845), sodium hypochlorite (Clorox® bleach), Alcide® biocide (Alcide Corporation, 125 Main St. Westport Conn.), and ozone which is available from various suppliers.
The practice and advantages of this invention are illustrated by the following non-limiting Examples.
Comparative tests were conducted to determine the effect, if any, on the fecal bacteria counts of broilers receiving dosages of several different microbiocidal compositions. These compositions were administered to female broilers via drinking water during the both the last day of feed consumption and an ensuing 9-hour period of feed withdrawal (i.e., during a total period of 33 hours prior to processing). The test period began when broilers were 56 days of age and continued through the 9-hour feed withdrawal period. A total of 100 birds of a chick strain were housed at hatch and used in the tests. Each test group contained 10 female broilers randomly assigned into a given replicate group containing 10 female broilers per group. Ten test groups were employed. Sacrificial processing of the broilers began immediately after the end of the 9-hour period. Food and water consumption during the test period were determined. In addition, fecal bacteria and ending intestine condition were measured at the end of the 9 hours of feed withdrawal.
The biocides tested were Aquatize® biocide (Bioxy Incorporated), sodium hypochlorite (Clorox® bleach), and 1,3-dibromo-5,5-dimethylhydantoin (hereinafter sometimes referred to as DBDMH. Table 1 shows the experimental design used in these tests. The microbiocides used in these tests were used only in the final 24-hour period during which for consumption was present and during the ensuing 9-hour period of feed withdrawal, the 33-hour period.
The drinking water solutions of 1,3-dibromo-5,5-dimethylhydantoin of this invention formed using the following procedure. A stock solution of DBDMH was prepared by stirring 100 g of DBDMH into 10 liters (10,000 mL) of water for 20 minutes. After filtration, the resulting clear solution contains 1300 mg per liter as Br2. This corresponds to 580 mg per liter (or 580 ppm Cl2 when expressed as Cl2. The diluted solutions of DBDMH used in these tests were then formed as follows:
The following test protocol was used in the tests:
Table 2 summarizes the results of this group of tests in terms of change in water consumption in the final 33-hour period and the mean fecal bacteria reduction resulting from use of the respective microbiocidal compositions.
The procedure of Example 1 was repeated except that the experimental design set in Table 3 was used.
The solutions of 1,3-dibromo-5,5-dimethylhydantoin of this invention were formed using the following procedure. A stock solution of DBDMH was prepared by stirring 100 g of DBDMH into 10 liters (10,000 mL) of water for 20 minutes. After filtration, the resulting clear solution contains 1300 mg per liter as Br2. This corresponds to 580 mg per liter (or 580 ppm Cl2 when expressed as Cl2.) The diluted solutions of DBDMH used in these tests were then formed as follows:
In addition to water consumption and mean fecal bacteria reduction as determined in Example 1, determination were also made of the mean feed consumption in terms of grams per bird during the final 24-hour period of feed availability before slaughter. In addition, visual observations were made of intestinal redness of the dispatched fowl. The intestinal redness scale used was as follows: 0=small intestine is clear; 1=less than one-third is red; 2=between one-third and one-half of the intestine is red; 3=more than one-half of the intestine is red.
Tables 4 and 5 summarize the results of these tests. In Table 4 the change in water consumption is that occurring in the 33-hour period prior to slaughter. In Table 5 the mean consumption is in terms of grams per bird during the final 24-hour period during which was available to the birds.
Comparative tests were conducted to determine the fecal bacteria counts, if any, of beef steers reared in a feedlot setting and receiving either no disinfecting agent, Aquatize® biocide, sodium hypochlorite solution (Clorox Bleach), or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) administered via drinking water when administered the last two days of feed consumption (48 hours prior to processing). A total of 15 beef steers weighing 800-950 pounds housed in individual pens were used in the study. These steers were offered normal drinking water with either no disinfecting agent (Control), or specified dosages of Aquatize®, Clorox Bleach, or DBDMH. Each drinking water solution (contaminated with E. coli) was offered continuously ad libitum during the 48-hour period, at which time fecal sample collection occurred. The fecal material samples were taken by anal swab from each steer for total fecal bacteria evaluation. Food consumption, water consumption, fecal bacteria, and ending intestine condition were measured at the end of the study. Each group of steers treated with a given biocide consisted of 5 steers, thus providing five replicates for a total number of 15 animals on study (plus controls). Table 6 shows the experimental design used in these tests.
The results of these tests are summarized in Table 7.
Comparative tests were conducted to determine the fecal bacteria counts, if any, of swine reared in a typical commercial setting and receiving either no disinfecting agent, Aquatize® biocide, sodium hypochlorite solution (Clorox bleach), or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) administered via drinking water when administered the last two days of feed consumption (48 hours prior to processing). A total 15 pigs weighing 230-250 pounds each housed in individual pens were used in the study. The pigs were offered normal drinking water with either no disinfecting agent (Control), or specified dosages of Aquatize®, Clorox bleach, or DBDMH. Each drinking water solution (contaminated with E. coli) was offered continuously ad libitum during the 48-hour period, at which time fecal sample collection occurred. The fecal material samples were taken by anal swab from each pig for total fecal bacteria evaluation. Food consumption, water consumption, fecal bacteria, and ending intestine condition were measured at the end of the study. Each group of pigs treated with a given biocide consisted of 5 replicates of 1 pig per replicate for a total of 5 animals in each test group. Table 8 describes the experimental design of these tests.
Table 9 summarizes the results of this study.
A study was made to determine the efficacy and safety of various drinking water treatments provided to immature broilers housed in battery cages for 21 days. In these tests, the drinking water for newly hatched chicks was treated with various chemicals and the chicks were provided with drinking water from given supply of a given treated water for a period of 21 days. Upon completion of the study, birds were examined for differences, if any, in body weight gain, feed efficiency, and fecal bacteria counts resulting from use of the various water treatments. Potential mortality was the key measure of safety. This study was conducted in compliance with the Food and Drug Administration's Good Laboratory Practices regulations (21 CFR Part 58), Adequate and Well-Controlled Studies (21 CFR Part 514.117), New Animal Drugs for Investigational Use (21 CFR Part 511), and CVM Guidelines for Conduct of Clinical Investigations: Responsibilities of Clinical Investigators and Monitors for Investigational New Animal Drug Studies, October, 1992. The chemicals added to the respective sources of the drinking water were hypochlorite solution (Clorox bleach), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH; Albemarle Corporation), N,N′-bromochloro-5,5-dimethylhydantoin (often referred to herein as BCDMH), and sulfamate stabilized bromine chloride (often referred to herein as SSBC) (Stabrom® 909 biocide; Albemarle Corporation).
The test was initiated with 1040 healthy chicks (approximately 50% being males and 50% being females). The birds were weighed and randomly placed in cages at hatch. E. Coli was administered to the birds at hatch to 3 days post hatch via drinking water treatment (Os inoculation) using a grown live culture of 105 E. Coli per mL of drinking water. The test materials in the drinking water were administered for the total test period of 21 days. Twelve treatment groups plus a control group were fed for 21 days, not counting any mortality which occurred.
A common commercial basal starter feed devoid of coccidiostats and antibiotics was administered ad libitum for the duration of the trial, with all chicks fed the same diets. No medications such as arsenicals, and no vaccinations were given during the entire experimental feeding period composed of day of hatch to day 21 post hatch.
The test groups used in this study are identified in Table 10.
The procedures used in forming the drinking water solutions identified in Table 10 were as follows:
On day of hatch the mean body weights of the treatment groups were compared to the control group. Groups with mean weights greater or less than one standard deviation of the mean control group were subjected to another randomization to assure equal distribution of weight among all of the groups tested. The broiler chicks were housed in battery cages. In all, 39 cages were used in this test. Each cage served as an experimental unit. The cages were located in a room of wood/cinder block structure with metal roof and low ceiling insulated to R value of 19 for the roof and 12 for the side walls. No cage touched any other cage from the side so as to ensure prevention of cross-contamination. Each cage was a separate free-standing cage, and the cages were separated by a wire partition. A cross-house ventilation system and ceiling fans were evenly spaced in the wood/cinder block structure. Room humidity was not monitored. Warm room brooding was provided using forced air heaters during day of hatch to day 21 post hatch. Also, continuous 24-hour lighting was provided by means of incandescent lights. Cages, aisles, feeders and waterers were sanitized prior to bird placement on day of hatch. Because no contaminants that could interfere with study objectives are expected in the feed, no assays for potential contaminants were performed. Drinking water for use by the respective test groups was provided ad libitum at all times. The facility tap water was supplied via well and subjected to regulation by the U.S. Environmental Protection Agency. Water supplied to the test facilities was subject to quarterly analyses for mercury, lead, conductivity, pH, fluoride and coliform. Since no contaminants that might interfere with study objectives were expected to occur in the water, no assays for other potential contaminants were performed.
The observations, tests and measurements used were as follows:
Data generated during the study was subjected to the following statistical tests: For all parameters, the multi-factorial procedure was used to compare means of treatment groups, using ANOVA (Analysis of Variance). Means will further be separated using Least Significant Difference.
Table 11 summarizes the results of this series of tests.
1NOTE:
Table 12 summarizes in tabular form the schedule of events which took place during the experimental program of Example 5. Tables 13 through 15 present and summarize the data from the experimental program of Example 5 in greater detail. In Tables 13-15 bleach is sodium hypochlorite, DBDMH is 1,3-dibromo-5,5-dimethylhydantoin, BCDMH is N,N′-bromochloro-5,5-dimethylhydantoin, and SSBC is active bromine formed from bromine chloride, sodium sulfamate, and sodium hydroxide in water (Stabrom® 909 biocide).
While chemists understand what is meant by “aqueous” in connection with a solution or medium or the like, it is probably desirable to state for anyone who may make it a profession to quibble over every word someone uses, just what “aqueous” means. The adjective “aqueous” means that the solution or medium or whatever other noun the adjective modifies, can be water whether highly purified or of ordinary purity such as emanates from the faucet. Besides naturally-occurring trace impurities that may be present in, say, potable water in general, such as ordinary well water or municipal water, the adjective “aqueous” also permits the presence in the water of dissolved salts that are formed in the course of forming a bromine-based microbiocide in the water, e.g., by reaction between bromine chloride and sodium sulfamate in an overbased aqueous solution. Also “aqueous” permits the presence in the water of the amount of the halogen-based microbiocide itself to the extent that it may dissolve in the water, plus any dissolved reactant(s) that may remain after the reaction. Also the water may contain a few atoms that may dissolve from the vessel in which the reaction takes place, plus air-borne impurities that may find their way into the water. The point here is that the term “aqueous” does not restrict the medium or solvent to absolutely pure water—the aqueous solution or medium or the like can contain what would normally be present and/or reasonably be expected to be present in it under the particular circumstances involved when employing ordinary common sense. Nor does the term “water” denote that it must be absolutely pure; but normally water itself before being used in the practice of the invention will not contain as many things as, say, an aqueous medium in which a chemical reaction such as the reaction between bromine chloride and sodium sulfamate has taken place or in which a bromine-based microbiocide has been dissolved.
Compounds referred to by chemical name or formula anywhere in this document, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another component, a solvent, or etc.). It matters not what preliminary chemical changes, if any, take place in the resulting mixture or solution, as such changes are the natural result of bringing the specified substances together under the conditions called for pursuant to this disclosure. Also, even though the claims may refer to substances in the present tense (e.g., “comprises”, “is”, etc.), the reference is to the substance as it exists at the time just before it is first contacted, blended or mixed with one or more other substances in accordance with the present disclosure.
Except as may be expressly otherwise indicated, the article “a” or “an” if and as used herein is not intended to limit, and should not be construed as limiting, the description or a claim to a single element to which the article refers. Rather, the article “a” or “an” if and as used herein is intended to cover one or more such elements, unless the text expressly indicates otherwise.
As used herein the term “microbiocidally-effective amount” denotes that the amount used controls, kills, or otherwise reduces the bacterial or microbial content of the fecal matter of an animal by a statistically significant amount as compared to fecal matter from the same type of animal receiving the same type of feed under the same type of conditions. The term “substantially exclusive” as used hereinafter means, quite simply, that it matters not if by chance or design ordinary drinking water is given to an animal during a period when a treated drinking water of this invention is otherwise being provided to the animal, provided that the animal receives enough of the treated drinking water of this invention to result in a decrease in its fecal bacterial content. In such cases, interruptions in the administration of the drinking water of this invention to the animal are within the contemplation and scope of the present invention. Also, the term “water-soluble” merely denotes that the substance has enough solubility in water to serve its intended purpose and function. The substance need not be soluble in all proportions or even highly soluble in water.
All documents referred to herein are incorporated herein by reference in toto as if fully set forth in this document.
This invention is susceptible to considerable variation within the spirit and scope of the appended claims.
This is a continuation-in-part of application Ser. No. 09/893,581, filed Jun. 28, 2001 now abandoned.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2130805 | Levine | Sep 1938 | A |
| 2392505 | Rogers | Jan 1946 | A |
| 2398598 | Rogers | Apr 1946 | A |
| 2779764 | Paterson | Jan 1957 | A |
| 2795556 | Quinn | Jun 1957 | A |
| 2888787 | Paterson | Jan 1959 | A |
| 2920997 | Wolf et al. | Jan 1960 | A |
| 2971959 | Waugh et al. | Feb 1961 | A |
| 2971960 | Waugh et al. | Feb 1961 | A |
| 3121715 | Waugh et al. | Feb 1964 | A |
| 3147219 | Paterson | Sep 1964 | A |
| 3147259 | Paterson | Sep 1964 | A |
| 3152073 | Morton | Oct 1964 | A |
| 3170883 | Owen et al. | Feb 1965 | A |
| 3308062 | Gunther | Mar 1967 | A |
| 3328294 | Self et al. | Jun 1967 | A |
| 3345371 | Paterson | Oct 1967 | A |
| 3412021 | Paterson | Nov 1968 | A |
| 3558503 | Goodenough et al. | Jan 1971 | A |
| 3589859 | Foroulis | Jun 1971 | A |
| 3626972 | Lorenzen | Dec 1971 | A |
| 3711246 | Foroulis | Jan 1973 | A |
| 3749672 | Golton et al. | Jul 1973 | A |
| 3767586 | Rutkiewic | Oct 1973 | A |
| 4032460 | Zilch et al. | Jun 1977 | A |
| 4078099 | Mazzola | Mar 1978 | A |
| 4119535 | White et al. | Oct 1978 | A |
| 4126717 | Mazzola | Nov 1978 | A |
| 4136052 | Mazzola | Jan 1979 | A |
| 4199001 | Kratz | Apr 1980 | A |
| 4237090 | DeMonbrun et al. | Dec 1980 | A |
| 4242216 | Daugherty et al. | Dec 1980 | A |
| 4270565 | King, Sr. | Jun 1981 | A |
| 4293425 | Price | Oct 1981 | A |
| 4295932 | Pocius | Oct 1981 | A |
| 4327151 | Mazzola | Apr 1982 | A |
| 4331174 | King, Sr. | May 1982 | A |
| 4382799 | Davis et al. | May 1983 | A |
| 4427435 | Lorenz et al. | Jan 1984 | A |
| 4427692 | Girard | Jan 1984 | A |
| 4451376 | Sharp | May 1984 | A |
| 4465598 | Darlington et al. | Aug 1984 | A |
| 4465839 | Schulte et al. | Aug 1984 | A |
| 4476930 | Watanabe | Oct 1984 | A |
| 4490308 | Fong et al. | Dec 1984 | A |
| 4532330 | Cole | Jul 1985 | A |
| 4534963 | Gordon | Aug 1985 | A |
| 4537697 | Girard | Aug 1985 | A |
| 4539071 | Clifford et al. | Sep 1985 | A |
| 4546156 | Fong et al. | Oct 1985 | A |
| 4560766 | Girard et al. | Dec 1985 | A |
| 4566973 | Masler, III et al. | Jan 1986 | A |
| 4571333 | Hsiao et al. | Feb 1986 | A |
| 4595517 | Abadi | Jun 1986 | A |
| 4595691 | LaMarre et al. | Jun 1986 | A |
| 4597941 | Bottom et al. | Jul 1986 | A |
| 4604431 | Fong et al. | Aug 1986 | A |
| 4621096 | Cole | Nov 1986 | A |
| 4642194 | Johnson | Feb 1987 | A |
| 4643835 | Koeplin-Gall et al. | Feb 1987 | A |
| 4654424 | Girard et al. | Mar 1987 | A |
| 4659359 | Lorenz et al. | Apr 1987 | A |
| 4661503 | Martin et al. | Apr 1987 | A |
| 4662387 | King, Sr. | May 1987 | A |
| 4677130 | Puzig | Jun 1987 | A |
| 4680339 | Fong | Jul 1987 | A |
| 4680399 | Buchardt | Jul 1987 | A |
| 4681948 | Worley | Jul 1987 | A |
| 4692335 | Iwanski | Sep 1987 | A |
| 4698165 | Theyson | Oct 1987 | A |
| 4703092 | Fong | Oct 1987 | A |
| 4711724 | Johnson | Dec 1987 | A |
| 4713079 | Chun et al. | Dec 1987 | A |
| 4728453 | Choy | Mar 1988 | A |
| 4745189 | Lee et al. | May 1988 | A |
| 4752443 | Hoots et al. | Jun 1988 | A |
| 4759852 | Trulear | Jul 1988 | A |
| 4762894 | Fong et al. | Aug 1988 | A |
| 4767542 | Worley | Aug 1988 | A |
| 4770884 | Hill et al. | Sep 1988 | A |
| 4777219 | Fong | Oct 1988 | A |
| 4780197 | Schuman | Oct 1988 | A |
| 4801388 | Fong et al. | Jan 1989 | A |
| 4802990 | Inskeep, Jr. | Feb 1989 | A |
| 4803079 | Hsiao et al. | Feb 1989 | A |
| 4822512 | Auchincloss | Apr 1989 | A |
| 4822513 | Corby | Apr 1989 | A |
| 4846979 | Hamilton | Jul 1989 | A |
| 4867895 | Choy | Sep 1989 | A |
| 4883600 | MacDonald et al. | Nov 1989 | A |
| 4886915 | Favstritsky | Dec 1989 | A |
| 4898686 | Johnson et al. | Feb 1990 | A |
| 4906651 | Hsu | Mar 1990 | A |
| 4919841 | Kamel et al. | Apr 1990 | A |
| 4923634 | Hoots et al. | May 1990 | A |
| 4925866 | Smith | May 1990 | A |
| 4929424 | Meier et al. | May 1990 | A |
| 4929425 | Hoots et al. | May 1990 | A |
| 4964892 | Hsu | Oct 1990 | A |
| 4966716 | Favstritsky et al. | Oct 1990 | A |
| 4992209 | Smyk et al. | Feb 1991 | A |
| 4995987 | Whitekettle et al. | Feb 1991 | A |
| 5034155 | Soeder et al. | Jul 1991 | A |
| 5035806 | Fong et al. | Jul 1991 | A |
| 5047164 | Corby | Sep 1991 | A |
| 5055285 | Duncan et al. | Oct 1991 | A |
| 5057612 | Worley et al. | Oct 1991 | A |
| 5076315 | King | Dec 1991 | A |
| 5118426 | Duncan et al. | Jun 1992 | A |
| 5120452 | Ness et al. | Jun 1992 | A |
| 5120797 | Fong et al. | Jun 1992 | A |
| 5137563 | Valkanas | Aug 1992 | A |
| 5141652 | Moore, Jr. et al. | Aug 1992 | A |
| 5179173 | Fong et al. | Jan 1993 | A |
| 5192459 | Tell et al. | Mar 1993 | A |
| 5194238 | Duncan et al. | Mar 1993 | A |
| 5196126 | O'Dowd | Mar 1993 | A |
| 5202047 | Corby | Apr 1993 | A |
| 5208057 | Greenley et al. | May 1993 | A |
| 5218983 | King | Jun 1993 | A |
| 5259985 | Nakanishi et al. | Nov 1993 | A |
| 5264136 | Howarth et al. | Nov 1993 | A |
| 5264229 | Manning et al. | Nov 1993 | A |
| 5286479 | Garlich et al. | Feb 1994 | A |
| 5320829 | Garlich et al. | Jun 1994 | A |
| 5338461 | Jones | Aug 1994 | A |
| 5339889 | Bigham | Aug 1994 | A |
| 5384102 | Ferguson et al. | Jan 1995 | A |
| 5389384 | Jooste | Feb 1995 | A |
| 5389390 | Kross | Feb 1995 | A |
| 5403813 | Lichti et al. | Apr 1995 | A |
| 5407598 | Olson et al. | Apr 1995 | A |
| 5409711 | Mapelli et al. | Apr 1995 | A |
| 5414652 | Mieda et al. | May 1995 | A |
| 5422126 | Howarth et al. | Jun 1995 | A |
| 5424032 | Christensen et al. | Jun 1995 | A |
| 5443849 | Corby | Aug 1995 | A |
| 5460833 | Andrews et al. | Oct 1995 | A |
| 5464636 | Hight et al. | Nov 1995 | A |
| 5476116 | Price et al. | Dec 1995 | A |
| 5490983 | Worley et al. | Feb 1996 | A |
| 5490992 | Andrews et al. | Feb 1996 | A |
| 5525241 | Clavin et al. | Jun 1996 | A |
| 5527547 | Hight et al. | Jun 1996 | A |
| 5565109 | Sweeny | Oct 1996 | A |
| 5565576 | Hall et al. | Oct 1996 | A |
| 5578559 | Dolan et al. | Nov 1996 | A |
| 5589106 | Shim et al. | Dec 1996 | A |
| 5591692 | Jones et al. | Jan 1997 | A |
| 5603941 | Farina et al. | Feb 1997 | A |
| 5607619 | Dadgar et al. | Mar 1997 | A |
| 5610126 | Barford et al. | Mar 1997 | A |
| 5614528 | Jones et al. | Mar 1997 | A |
| 5622708 | Richter et al. | Apr 1997 | A |
| 5670451 | Jones et al. | Sep 1997 | A |
| 5670646 | Worley et al. | Sep 1997 | A |
| 5679239 | Blum et al. | Oct 1997 | A |
| 5683654 | Dallmier et al. | Nov 1997 | A |
| 5750061 | Farina et al. | May 1998 | A |
| 5753602 | Hung et al. | May 1998 | A |
| 5756440 | Watanabe et al. | May 1998 | A |
| 5763376 | Ward et al. | Jun 1998 | A |
| 5780641 | Yerushalmi et al. | Jul 1998 | A |
| 5795487 | Dallimier et al. | Aug 1998 | A |
| 5808089 | Worley et al. | Sep 1998 | A |
| 5830511 | Mullerat et al. | Nov 1998 | A |
| 5859060 | Platt | Jan 1999 | A |
| 5889130 | Worley et al. | Mar 1999 | A |
| 5891499 | Balsano | Apr 1999 | A |
| 5900512 | Elnagar et al. | May 1999 | A |
| 5902818 | Worley et al. | May 1999 | A |
| 5922745 | McCarthy et al. | Jul 1999 | A |
| 5942126 | Dallmier et al. | Aug 1999 | A |
| 5942153 | Heydel | Aug 1999 | A |
| 5958853 | Watanabe | Sep 1999 | A |
| 5972864 | Counts | Oct 1999 | A |
| 5981461 | Counts et al. | Nov 1999 | A |
| 5984994 | Hudson | Nov 1999 | A |
| 6004587 | Mullerat et al. | Dec 1999 | A |
| 6007726 | Yang et al. | Dec 1999 | A |
| 6007735 | Creed | Dec 1999 | A |
| 6015782 | Petri et al. | Jan 2000 | A |
| 6037318 | Na et al. | Mar 2000 | A |
| 6068861 | Moore, Jr. et al. | May 2000 | A |
| 6083500 | Wooley et al. | Jul 2000 | A |
| 6099855 | Mullerat et al. | Aug 2000 | A |
| 6110387 | Choudhury et al. | Aug 2000 | A |
| 6123870 | Yang et al. | Sep 2000 | A |
| 6156229 | Yang et al. | Dec 2000 | A |
| 6172040 | Naidu | Jan 2001 | B1 |
| 6270722 | Yang et al. | Aug 2001 | B1 |
| 6284144 | Itzhak | Sep 2001 | B1 |
| 6287473 | Yang et al. | Sep 2001 | B1 |
| 6299909 | Moore, Jr. et al. | Oct 2001 | B1 |
| 6306441 | Moore, Jr. et al. | Oct 2001 | B1 |
| 6322822 | Moore, Jr. et al. | Nov 2001 | B1 |
| 6342528 | McKenzie et al. | Jan 2002 | B1 |
| 6348227 | Caracciolo, Jr. | Feb 2002 | B1 |
| 6448410 | Howarth et al. | Sep 2002 | B1 |
| 6495698 | Howarth | Dec 2002 | B1 |
| 6508954 | Elnagar et al. | Jan 2003 | B1 |
| 6565868 | Howarth et al. | May 2003 | B1 |
| 6605253 | Perkins | Aug 2003 | B1 |
| 6605308 | Shane et al. | Aug 2003 | B2 |
| 6638959 | Howarth et al. | Oct 2003 | B2 |
| 6680070 | Howarth et al. | Jan 2004 | B1 |
| Number | Date | Country |
|---|---|---|
| 1230825 | Dec 1987 | CA |
| 2042430 | Nov 1991 | CA |
| 2163596 | Sep 1996 | CA |
| 0106563 | Apr 1984 | EP |
| 0177645 | Apr 1986 | EP |
| 0228583 | Jul 1987 | EP |
| 0177845 | Apr 1988 | EP |
| 0206725 | Dec 1988 | EP |
| 0550137 | Jul 1993 | EP |
| 0581826 | Feb 1994 | EP |
| 0584955 | Mar 1994 | EP |
| 1054243 | Jan 1967 | GB |
| 1139188 | Jan 1969 | GB |
| 1600289 | Oct 1981 | GB |
| 2267487 | Dec 1993 | GB |
| 2273106 | Jun 1994 | GB |
| 56158333 | Dec 1981 | JP |
| 7299468 | Nov 1995 | JP |
| WO 8802987 | May 1988 | WO |
| WO 8910696 | Nov 1989 | WO |
| 8910696 | Nov 1989 | WO |
| 9015780 | Dec 1990 | WO |
| WO 9628173 | Sep 1996 | WO |
| WO 9630491 | Oct 1996 | WO |
| WO 9715652 | May 1997 | WO |
| 9720546 | Jun 1997 | WO |
| 9720909 | Jun 1997 | WO |
| WO 9720909 | Jun 1997 | WO |
| WO 9720548 | Aug 1997 | WO |
| 9734827 | Sep 1997 | WO |
| WO 9743264 | Nov 1997 | WO |
| WO 9743392 | Nov 1997 | WO |
| 9743392 | Nov 1997 | WO |
| 9804143 | Feb 1998 | WO |
| 9815609 | Apr 1998 | WO |
| 9906320 | Feb 1999 | WO |
| 9932596 | Jul 1999 | WO |
| 9955627 | Nov 1999 | WO |
| 0034186 | Jun 2000 | WO |
| WO 0034188 | Jun 2000 | WO |
| WO 0152827 | Jul 2001 | WO |
| WO 0153209 | Jul 2001 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20030113402 A1 | Jun 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09893581 | Jun 2001 | US |
| Child | 10028631 | US |
