Phenolic microbicides

Phenolics act optimally in acidic and neutral media, i.e. in their undissociated state. In this respect, the pK values of phenol derivatives are interesting. The values for some important phenol microbicides are listed in Table 42. 

Due to the fact that OPP is really a broad spectrum microbicide and because of its favourable toxicity and ecotoxicity data OPP has become the most important phenolic microbicide used in numerous applications. 

OPP is an important active ingredient in disinfectants for hospitals, public buildings, households and animal stables. Very often it is formulated in combination with other phenolic microbicides, e.g. Chlorophen (Section 5.3.5) and/or PCMC (Section 5.3.1). 

Non-ionic surfactants have an adverse effect on the activity of all phenolic microbicides (III.5) including p-hydroxybenzoates (III.6) (Fig. 35, p. 376) anionic surfactants have considerably less effect. Cationic active ingredients (III. 16.1) are inactivated by anionic components. 

Due to the fact that OPP is really a broad spectrum microbicide and because of its favourable toxicity and ecotoxicity data it has become one of the most important microbicides which is used in numerous different applications. It is an important active ingredient in disinfectants for hospitals, public buildings, households and animal stables. Preferably OPP is used for heavy duty disinfection where there is a high risk of infection or of the presence of strong impurities, or wherever water with a high hardness is used. As a membrane active microbicide OPP performs best in an acidic, neutral or weakly basic environment, where it is in its undissociated form. Very often OPP is formulated in combination with other phenolic microbicides, e.g. with Chlorophen (7.3.5.) and/or PCMC (7.3.1.). Worthy of note is that such combinations exhibit virucidal efficacy against lipophilic, masked viruses. 

The ambient medium impairs the effectiveness of microbicides also if its constituents include those capable of interacting with a microbicide in competition with the constituents of the microbe cell. This is true of electrophilically active microbicides in general as far as the ambient medium contains nucleophilically active constituents with which the microbicide can react in competition with the corresponding cell constituents. It is also true, however, of membrane-active microbicides if adsorption of the microbicide on organic matter competes with the adsorptive processes on the cytoplasmic membrane or if such microbicides, e.g. phenol derivatives, become incorporated in micelles that are formed in certain media at levels above the critical micelle concentration with the result that the incorporated active substance molecules are no longer available for the antimicrobial effect (see III. 16, Fig. 34). 

The reversible adsorption of phenols at the cytoplasmic membrane damages the permeability barrier, thus causing leakage of intracellular substances from the metabolic pool. In this phase the effect is microbistatic and can be terminated by dilution. Relatively high phenol concentrations, however, lead to penetration and deterioration of the cell wall, accompanied by destruction of the microbe cell (microbicidal effect). 

However, the development of microbicidally active phenol derivatives started from phenol itself, from carbolic acid, the antiseptic properties of whidh were detected in 1860 and first used by Lister in 1867 to kill bacteria on medical instruments, surgical dressings and wounds. The development of chemical disinfection revolutionized progress in hospitals, particularly in surgery. It was possible to successfully employ and develop surgical techniques which in the past had been feasible but unpractical because of the associated unavoidable massive and generally fatal infections. 

The substance class of microbicidally active phenol derivatives, in short phenolics, was also developed. Hundreds of different derivatives were isolated, synthesized and investigated with the aim of finding phenol derivatives which were more effective and at the same time less toxic and less irritating to the skin than the parent chemical carbolic acid. Another objective was to find microbicidal phenol derivatives with chemico-physical properties which make them suitable for the protection of materials. This development, which can now be considered as completed, provided knowledge on the relationship between structure and effectiveness and on the mechanism of action of phenol derivatives. This is summarized in the following. 

Halogenation of phenol also leads to phenol derivatives which are much more effective than the starting substance. At the same time, the dissociation constant increases with an increase in the number of halogen atoms, i.e. the acidic character of the phenol derivatives becomes more distinctive. The combination of alkylation and halogenation (the latter with preference in the p-position) has led to microbicides which have attained great practical significance as substances for the protection of materials and disinfection, e.g. p-chloro-o-benzyl phenol, p-chloro-m-cresol, p-chloro-/M-xylenol. 

For the sake of completeness, the nitration of phenol and cresol must be mentioned. It particularly strengthens the bactericidal effect. Furthermore, nitro-phenols have specific biological properties since they are able to interfere with oxidative phosphorylation. However, nitrophenols are no longer of practical importance as microbicides. 

As already mentioned, phenol derivatives are membrane-active microbicides. They adsorptively coat the surface of the microbe cell then, at a higher concentration, they are dissolved more or less rapidly and well by lipoids depending on their chemico-physical properties (see above). They attack the cell wall and penetrate into the cell. There are reactions with the protoplasm and the cellular protein enzymes are also inhibited as a result the oxidoreductases and the enzymes of carbohydrate and protein metabolism react particulary sensitively. Whether the phenol derivatives act microbistatically or microbicidally is purely a question of the application concentration. At low concentrations in ambient medium, there is only reversible adsorption of the phenolic active substance at the cytoplasmic membrane and the related inhibiting effect. As stated above the cell wall is only penetrated and destroyed and the microbe cell killed at higher concentrations. 

For practical use of microbicidal phenol derivatives, it is very frequently necessary to improve their solubility, especially their solubility in water and hence to shift the distribution ratio towards the aqueous phase. If phenol derivatives... 

Corresponding to the mechanism of action, the microbicidal phenol derivatives are effective over a wide spectrum including bacteria, yeasts and fungi. However, there are different effectiveness peaks depending on the type and number of the substituents. Therefore the combined application of various phenol derivatives sometimes allows the application concentrations to be reduced this is to be aimed at for many reasons. Phenol derivatives are not effective against resistant bacterial spores, at least not at room temperature. However, they are very effective against lipophilic viruses but deficient in their activity against viruses with hydrophilic properties. 

Table 43 presents an overview of the activity spectrum of phenol derivatives which have gained especial importance as microbicides. 

It is frequently claimed that phenolics, particularly chlorinated phenolics, possess high oral toxicity, are percutaneously toxic and are generally difficult to degrade. Such blanket condemnations of the phenolics are based on invalid generalizations not confirmed by the facts. It is therefore in no way justified to disqualify the whole class of microbicidal phenolic compounds out of hand simply because some of them are described, correctly, as highly toxic, persistent, ecotoxic or... 

From the facts there is no foundation for a blanket rejection of phenol derivatives. On the contrary it must be assumed, for many reasons, that it will not be possible to dispense with special phenolics as microbicides for material protection. After all, some of them, such as o-phenyl-phenol and / -chloro-m-cresol, meet the requirement now expected of such microbicides very satisfactorily. 

Tert.amylphenol is used as an active ingredient in disinfectants together with other microbicidal phenolic compounds which close the gap for Pseudomonades in the activity spectrum of / -tert.amylphenol. 

The a.m. mixture of benzylphenols is used as an active ingredient in disinfectants, generally in combination with other active phenolics able to close the gap for Pseudomonades. The fact that the MICs are higher than the microbicidal concentrations demonstrates that the benzylphenols are sensitive to organic matter. As a preservative for material protection the mixture has not gained importance because of unfavourable solubility properties. 

As a rule it has to be stated that halogenated alkylphenols are more active and broader in effectiveness than the alkylphenols. It is therefore in no way astonishing that some of the most important phenol derivatives in practical application are found in this class of phenolics. Among others Klarmann et al. (1933) have carried out systematic examinations of the relationship between chemical structure and antimicrobial activity with regard to halogenated alkylphenols. However, one should not overestimate the value of the data obtained when decisions and selections have to be made for practical application, as other properties of the microbicidal compounds, such as water-solubility, partition coefficient, activity in the presence of interfering factors encountered in practice, and toxicity, are of the same or of even more importance. Although there are available a lot of data and experience, often the optimum compound and formulation must be determined by experiment. 

PCMC is most effective between pH 4 and 8, where, in fact, contrary to other phenol derivatives only PCMC is sufficiently water soluble. By comparing the microbicidal concentrations of PCMC with those of PCMC-Na, solutions of which have pH values higher than 8, one notices a distinctive decrease in the activity of PCMC in alkaline media (Table 49). 

Chloro-2-cyclopentyl-phenol is very effective against fungi (MIC 10-50 mg/litre) and Staphylococci and Salmonella (microbicidal cone, in 10 min 400 mg/litre) but insufficiently active against Pseudomonades. However, due to its toxicological properties it is no longer used as an active ingredient in disinfectants. 

Among the non-halogenated phenol derivatives OPP is the one which has been most intensively investigated with regard to its toxicity. The results are in general very favourable. Besides that OPP is a microbicide well known and widely used for many years that means it presents a long history of human exposure without any adverse effects. The most important toxicity data are indicated in the following ... 

The pressure hydrolysis of chlorobenzene under alkaline conditions to phenol gives OPP and PPP as by-products (5-6%). The ratio of OPP/PPP is 2/1. Separation by fractional distillation is possible. Although the efficacy and activity spectrum of PPP are similar to those of OPP (Section 5.4.1), PPP has no importance as a microbicide for material protection or as an active ingredient in disinfectants. The reasons for this are the unfavourable solubility properties of PPP and the difficulty of providing PPP in larger quantities at reasonable costs. 

The microbicidal activity is considerably reduced in the presence of organic matter. Much more than for other phenol derivatives the efficacy of trichlorophenols depends on pH variations. 2,4,6-trichlorophenol also exhibits insecticidal effectiveness. Nowadays it is still used as an active ingredient in wood preservatives especially for the anti-sapstain treatment of freshly cut and sawn timber, moreover in preservatives for the leather industry and for functional technical fluids, e.g. protein containing formulations, concrete additives. But altogether the product as a microbicide is on the decline because of its toxicity/ecotoxicity and its intensive adherent phenolic odour. 

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