Guide Toxicological Effects of Veterinary Medicinal Products in Humans: Volume 1

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The most common within this last chemical type has been sulfathiazole, commonly used, in spite of its ban, in apiculture in China. Finally, malachite green along with its metabolite in animals, leucomalachite green and crystal violet also known as gentian violet, previously used in aquaculture can also be mentioned as contaminants detected.

Nitrofuran antibiotics are of outstanding significance among VD residues. Furaltadone [and its metabolite, 3-aminomorpholinomethyloxazolidone AMOZ ] frequently occurred in poultry meat e. The occurrence of furazolidone [and its metabolite, 3-aminooxazolidinone AOZ ] has been high in crustacean and fish shipments from South Asia, in egg products from India, pig and rabbit products from China, chicken from Thailand, and honey from Argentina.

Selected Publications

Residues of nitrofurazone [and its metabolite semicarbazide SEM ] were common in freshwater shrimp from South Asia, lyophilized egg powder from Brazil, India, and France, chicken from Brazil and Thailand, and pig and rabbit from China. Among antibiotics, chloramphenicol is known to widely occur in apiculture products. In addition, it has been detected in dairy products and commonly occurred in crustaceans and fish.

Moreover, it has been detected in rabbit and duck meat and pork from China and duck meat from Thailand, as well as in duck and goose feed in Germany, which may explain the current situation. Several changes have taken place by — The detection rate of AMOZ has decreased to a minimal level, and the statistics of AOZ occurrence has also improved, although the latter compound remains to occur in shrimp from Asia India, China, and Malaysia and rabbit from China. As a new emergence, it occurred in calf meat and also in animal feed above MRL in the Netherlands. The occurrence of SEM also shows a more favorable pattern by now, but as a new feature, it appeared in beef from Brazil and is a common contaminant of pangasius fish from Vietnam.

As a result, the reputation of this fish, very well tolerating dense rearing conditions and only slightly sensitive to water contaminants, is rather unfavorable. The improvements are significant for the residues of chloramphenicol as well. Its incidence in apiculture products has dropped to casual occurrence after honey from China has been forced out from the EU market. The same applies to other antibiotics as well, indicating that one of the greatest successes in European food safety has been the regulation of apiculture products. Nonetheless, occurrence of chloramphenicol remains detectable in shrimp from China and Vietnam, as well as pork from China.

Moreover, as it is still found in feed components from Belgium, France, and India, its casual occurrence has been indicated in various meat samples. Among non-steroid anti-inflammatory drugs, residues of phenylbutazone in horse meat used for the treatment of the common degenerative disorder, chronic arthritis in horses, emerged as a new problem. The use of phenylbutazone has been substantially limited in the United Kingdom UK , and it is currently registered for the treatment of race horses only.

However, it can strongly be anticipated that this food safety problem, used to remain hidden due to the lack of control, existed before as well. The few cases detected 55 cases between and were limited to the poultry industry and mostly to residues of clopidol 48 of the 55 cases used against coccidiosis and no longer permitted in the EU. No growth promoters are listed among the contamination cases found, which hints to the possibility that specific monitoring of these substances may not be sufficiently effective. It is well known that weight gain in cattle is promoted in the USA by the use of beta-blockers e.

Zilpaterol has been detected in horse meat from Mexico and surprisingly in poultry from Poland. In turn, wide scale monitoring of animal feed appears to be a problem that needs to be solved, as it would serve as an excellent prevention measure of contaminant dispersion. The most complex issue in the RASFF database from the aspect of analytical determination and assessment is unquestionably represented by pesticide residues.

Initial findings indicated severe warning signs as early as in , immediately after the launch of the operation of RASFF, yet pesticide residue levels remained to display a trend of continuous increase until recently. This segment with over 75 severe cases as an average annually on the basis of the last five years — is likely to be considerably underestimated among food safety hazards.

The majority of the findings have been related to pesticide active ingredients not enrolled on the EU positive list of registered compounds. Related PPPs, however, may be legally used in exporting non-EU countries, and therefore, their residues may be found in feeds or in foods of animal origin produced there.

In such cases, shipments with any detectable amounts of the given residue are rejected, even if the level remains below the earlier MRL. Approximately two-thirds of pesticide residues reported by RASFF between and belonged to the first group, i. Moreover, the proportion of RASFF notifications among the target analytes specified appears to be quite even.

A recent, severe, but isolated issue has been the case of insecticide fipronil found in eggs and egg products in Its veterinary use is against fleas, mites, and ticks mostly on dogs and cats, e. In PPPs, it is used against a wide range of insect pests. After gradual limitations of its use e. Over the years, residues of this insecticide have been found in commodities of plant origin notified in most cases as border rejection , yet it was found in eggs from Belgium in at concentrations up to 1.

Proportions of the PPPs reported during the 4-year period below. It has to be noted, however, that contamination is not always detected immediately at source, and in such cases, the consigner country is an importer that further exports the commodity reported in RASFF. Claims may be and are mostly related to products originated from outside the EU. The network of the notification cases not only illustrate the actual relations of complaints but also provide a more accurate picture of the control system within the EU.

The network map shows that most non-compliance cases were identified in relation to Vietnam and the main notifiers were Germany and Belgium. Notifier and consigner countries are designated with blue and red circles, respectively, with the number of reported cases indicated near the country code and circle sizes proportional with numbers of reported cases. Thicknesses of the connecting lines dashed line for single and solid line for multiple case notifications are proportional with overall notification cases in the given relation, and colors of the connecting lines corresponding to the risk assessment category of the contamination cases found red: severe cases were identified; gray: no severe cases, but cases of undecided severity were identified; and green: solely non-severe cases were identified.

Note that Europe is shown larger than proportional on the background world map for better connectivity visibility. Within the 5-year period between and , there occurred notifications, 67 nearly one-fifth of which were domestic notifications with the notifier and consigner country being the same , indicating either domestic production or unidentified import.

Consigning countries of extensive non-compliances included Vietnam, India, China, and Brazil 88, 50, 34, and 23 notifications, respectively. Vietnam scores particularly poor in the notifications regarding VD residues, as otherwise the country is ranked at a much better, 14 th position in the overall RASFF notifications from until the first quarter of 1, notifications. As for the other three countries, China, India, and Brazil are ranked 1 st , 3 rd , and 12 th in the overall RASFF notifications nearly 5,, 2,, and 1, notifications, respectively.

For VD residues, the overall severity rank increased from to , but later displayed a favorable decreasing trend along with a parallel decrease in the number of all notifications. The network is dominated by a Germany—Vietnam axis 31 notifications, 11 of which were severe , along with strong notification connections also at other source countries mentioned above.

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The notifications toward Vietnam were assessed predominantly as severe by Spain, Italy, the Netherlands, and Switzerland and to a less degree by Germany, Belgium, and the UK. Predominantly severe notifications were reported toward India by Belgium, France, and the UK, with less severity from Germany. Although the RASFF documentation reports notifications only, and not the overall number of samples analyzed, it indicates that lead monitoring EU countries for all food and feed contaminants on the basis of their reported notifications are Italy 7, RASFF notifications from until the first quarter of , followed by Germany, the UK, Spain, the Netherlands, France, Belgium, and Denmark 6,, 5,, 3,, 3,, 2,, 1,, and 1, notifications, respectively.

These same countries were reporting the highest numbers of VD residues found between and but in a slightly different order: Germany, Belgium, the UK, Italy, Denmark, France, the Netherlands, and Spain 63, 59, 42, 31, 25, 21, 19, and 16 notifications, respectively. The numbers of notification cases in the official monitoring in each country indicate that not only the operation of the food safety sector at the European level is a determining factor, but the national food safety organizations, of which the Federal Institute of Risk Assessment BfR in Germany is of outstanding weight, also represent an equally important contribution.

The MRLs specified, e. They are, indeed, inert per definitionem in the main effect of the formulation they are used in, but they may also exert adverse side effects. Emerging information on the hazards of risks related to formulant additives indicates that some of these excipients should be included among target analytes in RASFF; in other words, MRLs should be defined for these substances as well. The EU-wide regulation of adjuvants and co-formulants is being planned; however, their monitoring is hindered by the facts that analytical methods for their determination are often missing, and quantitative analysis is often problematic for these complex, in given cases not fully described substances.

Moreover, the effect of these excipients on the residue levels recorded for the active ingredient is hardly studied. Beside the active ingredients, several additives can also be found in formulated animal therapeutic agents and feed additive products, as well as in the formulated pesticide preparations.

KNW Animal Health Consulting: Selected Publications

Among additives, classified into several groups by their function, adjuvants are a minor group of substances, used for the primary purpose to enhance the biological effect of the active ingredient 13 , Thus, adjuvants e. Further groups of additives are not used for the purpose of amending formulation efficiency but implement other purposes related to application, such as the promotion of safe use and application ensured by colorants and odorants For example, the warning effect of the red dye used to be applied in carbofuran-based formulations or the unpleasant smell of odorants applied in obsoleted formulations containing paraquat or diquat used to serve the purpose of lowering the possibility of human poisoning during use and application of the formulations 55 , Additionally, other groups of additives consist of various trapping agents and attractants, which also do not affect directly the efficiency of the active ingredient 13 , 57 , As seen from the above, the often seen practice of using additives and adjuvants as synonymous words is incorrect.

A characteristic feature in the chemical structure of different surfactants is the simultaneous presence of hydrophobic and hydrophilic moieties; therefore, surfactants show both lipophilic and hydrophilic properties 59 , The estimated annual world production of surfactants was at 15 million tons in Besides the industrial e. Surfactants enhance the efficiency of formulations by increasing the water solubility, bioavailability and biological activity of the active ingredients 62 , Surfactants may be used to solubilize drugs through micellar dispersion in VDs 64 , furthermore, are applied in feed additives applied in drinking water as stabilizers to prevent decomposition of the active ingredient s in the preparation In addition, surfactants or wetting agents enhance drug solubility and membrane permeability, prolong gastrointestinal residence time, and protect the active ingredient from luminal degradation and metabolism in the gut wall Enhancement of bioavailability of polar compounds without affecting solubility characteristics can be achieved by absorption enhancers e.

Conversely, surfactants also applied to increase the in vitro solubility of lipophilic compounds 70 , Formulation is of particular importance for PPPs, as additives may aim not only to improve the solubility, adsorption, or penetration of the active ingredient in these formulations but also to enhance environmental stability, bioavailability, and capability to reach the site of action. Surfactants are generally classified according to the type of their hydrophilic part; therefore, anionic, cationic, non-ionic, and amphoteric surfactants can be distinguished Various anionic surfactants, containing functional groups capable to dissociate to form anions as the polar part of the molecule [e.

Anionic surfactants can enhance the biological efficacy of the active ingredient 73 , 74 through direct binding to it 75 or modification of its adsorption. Moreover, they can act as enzyme activators or inhibitors by binding to the enzyme protein in a concentration-dependent manner and their binding affinity depends on the length of the alkyl chain in the surfactant LASs can inhibit alkaline phosphatase and acid phosphatase enzymes 77 , and sodium dodecyl sulfate SDS improves the intestinal absorption of active ingredients, e.

Further surfactants, e. Perfluorinated sulfonates and carboxylic acids, including perfluorooctanoic acid and perfluorooctane sulfonate—suspected environmental endocrine disruptors—have been in use for over 50 years Sulfonates are among the most widely used anionic surfactants in personal care and household products 81 , The polar part of cationic surfactants contains cation-forming functional groups.

Among these, the representatives of primarily use are quaternary ammonium compounds QACs , applied as disinfectants and cleaners, due to their advantageous adsorptive and bactericidal properties, in agricultural practice and veterinary medicine In the molecular structure of non-ionic surfactants, a polyethylene glycol PEG moiety is connected to alkylphenols [i. In enterosolvent capsules used in veterinary medicine, water-miscible non-volatile and non-ionic surfactants are used for formulating poorly water-soluble compounds Moreover, non-ionic surfactants are generally used as emulsifying or dispersing agents, emulsion stabilizers and binders in VDs, and feed additives Non-ionic surfactants are generally applied as detergents in the industry and as formulating agents in PPPs Additives for industrial use, such as cocamide monoethanolamine and diethanolamine DEA , are used as foaming agents in different soaps, shampoos, and cosmetics, but despite their advantageous characteristics for industrial purposes, cocamide DEA has been classified to category 2B, possible human carcinogen, by the International Agency for Research on Cancer Alkyl polyglycosides APGs , glyceryl laurate e.

Polyethermethylsiloxanes, as trisiloxane surfactants, are often used in pesticide formulations to enhance the activity, efficiency, and the rain fastness of the active ingredient, due to their hydrophobic properties A particular feature of OP ethoxylate Triton X , as a non-ionic surfactant, is its capability for the lysis of integral membrane proteins; therefore, Triton X is substantially used in biochemical studies 90 , Non-ionic surfactants are considered to exert lower toxicity than cationic, anionic, and amphoteric surfactants 59 , However, the toxicity profile of tallow derivatives e.

Due to their zwitterionic structure, e. In turn, amphoteric surfactants gained extensive use in cosmetics but are also widely used as adjuvants in agrochemicals. Their main groups are betaines, sultaines, iminodiacids, and acyl ethylene diamines 58 , Natural surface-active substances are produced by plants, animals, and microorganisms These biosurfactants, such as monoacylglycerols and their derivatives e. Additional biosurfactants used in veterinary preparations include wax and fat compounds e.

Several various anionic and neutral biosurfactants are known, but cationic biosurfactants have been described extremely rarely, probably due to their toxic effect Generally, biosurfactants are considered biodegradable and relatively non-toxic Biosurfactants, such as surface-active sophorolipids, assure surface-lowering properties, advantageous biodegradability, and low ecotoxicology, and are used in cosmetics, pharmaceuticals, and medical preparations due to their biological effects and activity Generated wastes by the oil and fat industries, such as residual oils, lard, and tallow, are additional sources of cationic biosurfactants for fabric softeners.

These substances are manufactured from biological resources via industrial chemical synthetic processes, therefore, are considered industrial chemicals. As seen above, surfactants derived from animal tallow, as non-ionic substances, have wide application in formulation of both veterinary products and PPPs. Yet, the biological origin cannot be considered as a guarantee for favorable toxicological characteristics, as indicated by several examples.

Despite possible TSE risk connected to tallow is considered by the Scientific Steering Committee of the EC, originated from protein impurities may be present in the final products , the EFSA scientific opinion document states that in general, the risk can be regarded as minimal on the basis of the calculated levels of exposure evaluated by quantitative risk analysis. The conditions of the application of concerning animal by-products e.

Upon being separated from animal fat via heat treatment e. POEA consists of a tallow amine moiety and two chains of repeating ethoxylate units. The tallow amine moiety is a mixture of amines derived from palmitic acid, stearic acid, oleic acid and other minor components Non-ionic hydrogenated tallow glycerides are used as dispersing agents, emulsifying agents, emulsion stabilizers, and binders in VDs Similarly, polyethoxylated mono- and diglycerides of tallow fatty acids are also listed in the corresponding EU lists of authorized substances.

Thus, certain substances, e. Certain substances, e. In , the estimated global use of major classes of surfactants was 1. Moreover, the annual global production of synthetic surfactants was about 7. In the USA alone, the quantity of produced surfactants was at 3. In , the total consumption of secondary alkane sulfonates was at about 0.

Unfortunately, no details are readily available regarding the proportion of surfactants used in VDs and PPPs within these global trade values, but practically all of the chemical classes mentioned earlier are represented in this segment as well with the corresponding registration requirements considered. Thus, consumable surfactants registered to be used in VDs include castor oil ethoxylates, sorbitan esters, and their ethoxylated derivatives, as well as lecithin. Nonetheless, substances of less uniform characteristics, e.

The reported global production of surfactants was 8. In , the estimated annual world production of surfactants was at 15 million tons Production and global use of non-ionic surfactants are continuously growing In , it was estimated to The overall surfactant market has been showing a constant growth in the last years, with the USA, China, Western Europe, and Asia being responsible for the largest rate of surfactant consumption Additives used as surfactants in VDs, feed additives, or PPP formulations may have adverse effects on the environment and on non-target organisms.

Surfactants may influence the embryonic development and hormonal balance of vertebrates, mainly in aquatic habitats, and genotoxic effects have been indicated for several types of surfactants — Lewis and Supernant investigated the effects of three types of surfactants, anionic C Singh and co-workers investigated the effects of several surfactants on fish species. Interestingly, the toxic effect of monoalkyl QAC surfactants was not proven to increase with the alkyl chain length in the molecules Anionic LASs have been shown to be uptaken by fish from water via the gills rather than the skin.

The concentration of LAS surfactants increases rapidly in the liver and other internal organs of fish juveniles Bioaccumulation in the aquatic environment is higher than in the terrestrial environment in the case of LASs Pavlic et al. Non-ionic detergent decyl polyglycoside exerted higher toxicity than anionic e. Jurado and co-workers investigated the effects of three APGs of different polymerization rates and alkyl chains, and toxicity increased with the alkyl chain length An opposite role of the alkyl chain length of AEOs in the acute toxicity on the water flea, Daphnia magna , has been found in several studies , LAS detergents caused abnormalities in the development in several marine invertebrates NPs and OPs, as biodegradation products of APEs, exert toxicity on freshwater and marine fish species and induce estrogenic responses , Given APEs, e.

Thus, the estrogenic activity of APs was demonstrated both in vitro and in vivo At molecular level, APs are capable to bind to estrogen receptors in fish and mammals , and to activate reporter genes regulating estrogen-responsive elements , Moreover, in aquatic animals, APs are capable to interfere with steroid metabolism and steroid hormone receptor activity Antiandrogenic activity due to altering aromatase activity and impeding the function of aryl hydrocarbon receptors has also been detected Moreover, possible enhancing effects of given active ingredients e.

The toxic effect of additives in PPPs has been clearly demonstrated by several studies in which formulated pesticide products were proven to be more toxic than their active ingredient alone , Recently, the investigation of the combined toxicity of the worldwide most used herbicide active ingredient glyphosate and surfactant POEA as its most common formulant received special attention, as scientific evidence indicated higher individual toxicity of the surfactant or combined synergistic effects between the active ingredient and surfactants.

The acute toxicity of glyphosate, a glyphosate-based formulation, and the surfactant applied in given formulation on aquatic invertebrates and fish species were investigated by Folmar et al. In a later study, ethoxylated adjuvants used in glyphosate-based formulations proved to be nearly ten thousand times more toxic than the toxicity of the active ingredient This finding has been reconfirmed in numerous additional studies , ; moreover, several studies verified POEA as the most toxic component on D.

The permeability of cell membranes can be affected by POEA, resulting in the enhancement of the absorption capacity of the biologically active agents, their cytotoxicity and effects on the cells inducing apoptosis or necrosis On the basis of these findings, POEA as a formulating agent was proposed to the MSs to be excluded from glyphosate-based pesticide formulations in the EU in Interactions may occur between the active ingredients and additives used in formulated VDs, feed additives or pesticides.

Combined toxicity of active ingredients has been confirmed recently in several studies ; furthermore, the individual toxicity of several additives was verified as well , , The simultaneous application and presence of non-ionic amine oxide-based surfactants and anionic surfactants in formulations has been proven to result in synergistic effects between the surfactants , As a consequence of the above mentioned results, the assumption that additives used in formulations are inactive inert ingredients has been falsified is numerous cases and should be considered significantly questionable on the basis of the scientific evidence.

Combined effects of various active ingredients and surfactants have been confirmed in veterinary medicine as well. Antagonistic effects between various bacteriostatic and bactericidal compounds and synergistic effects between antiseptic anionic tensides and other disinfectants e. Combined toxicity and synergistic effects between active ingredient and formulating agents used in formulation of PPPs; moreover, the individual toxicity of surfactants applied in formulations were proven by several studies , , , Various PPPs used in chemical plant protection were proven to be more toxic than the corresponding active ingredient, especially to aquatic organisms , The toxicological evaluation of surfactants and other ingredients is essential for proper and effective ERA of formulations used in veterinary and agricultural practice.

Little information is available regarding the environmental fate of adjuvants e. As a result of the significant production and industrial, agricultural, and domestic use, surfactants, their metabolites, and decomposition products can easily enter into environmental matrices, including soil, sediment, surface water, and even drinking water 58 , , A significant source of pollution is chemical plant protection, and also inadequate or uncontrolled management and treatment of wastewater and sewage sludge.

Among different groups of environmental endocrine disruptors, e. Surfactants may sorb directly onto the surface of the solid phase in soil and sediment, or may interact with sorbed surfactant molecules as well — The adsorption capacity of surfactants is highly dependent on their physico-chemical characteristics The degradation of APEs is faster in water than in sediment , and their metabolites are degraded more easily under aerobic than under anaerobic conditions , In contrast, fatty AEOs are equally degradable in aerobic and anaerobic environments Most of the surfactants can be degraded by microorganisms; however, various surfactants, such as LAS, dehydrogenated tallow dimethyl ammonium chloride, and APG, show environmental persistence under anaerobic conditions 60 , Surfactants bound to the surface of soil or sediment particles e.

Moreover, OP and NP compounds and their ethoxylates have been detected even in human breast milk indicating substantive human exposure. Residues of agrochemicals, e. Moreover, the two groups displayed opposing trends in time. The initial high number of reported cases in for VD residues has successfully been pushed to a level below cases annually by In contrast, the number of notification cases for pesticide residues shows a gradual increase from a low approximately 50 cases annually initial level until , with a drop only in , still representing over cases annually. These opposing tendencies are explained by differing toxicology background in the two sectors, the assessment of VDs being deeply rooted in the evaluation of human pharmaceuticals.

Yet, the fact that most commonly found VD residues to date are antibiotics remains to be a substantial concern. Network analysis of connections between notifying and consigning countries reveal a Germany—Vietnam axis with main notifier countries being Germany, Belgium, the UK, and Italy 63, 59, 42, and 31 notifications announced, respectively and main consigning countries of extensive non-compliances being Vietnam, India, China, and Brazil 88, 50, 34, and 23 notifications received, respectively. Toxicity problems may emerge not only due to the active ingredients but also due to additives used for formulation of veterinary pharmaceuticals and pesticides.

During the production of VDs, feed additives, and PPPs, significant amounts of different surfactants are applied.


Surfactants in VDs are mainly used as disinfectants, surface cleaning supplies, agents for animal bath, emulsifying and dispersing agents, emulsion stabilizers, and binders. In feed additives surfactants promote better digestibility and availability of nutrients. In pesticide formulations, the efficiency of the applied active ingredient is enhanced by the use of surfactants as adjuvants.

Additives used for the production of preparations applied as VDs, animal feed supplements and PPPs according to the current regulation, are considered as inert or inactive ingredients According to current legislation, simpler ERA of additives is sufficient than the requirements for the active ingredients. Regulatory requirements, health RA, and ERA of active ingredients used in VDs are very strict, similar to the legal requisites regarding human medicines. In case of pesticide formulations, full toxicology tests are required for the active ingredient s , but not for the formulated preparation.

The determination of MRLs for VDs includes all components used in the veterinary preparations and vaccines with pharmacological or pharmacodynamic activity In contrast, MRLs are set for pesticide active ingredients and their metabolites only and not for their adjuvants In addition, the quantity of acceptable daily intake ADI-value of different formulations is typically determined on the basis of studies conducted with the active ingredient and not with the formulated preparations Recently, additive, synergistic, or antagonistic effects between the active ingredient s and additives, as well as individual toxicity of surfactants, have been demonstrated by several studies , , , On the basis of the scientific evidence, the properties of these substances and their role in various biological interactions, these substances cannot be considered as unequivocally inactive ingredients by ecotoxicological and toxicological aspects in ERA of VDs, animal food supplements, and PPPs.

Therefore, full toxicological assessment and evaluation of the adjuvants e. AS conceived the concept of the review. SK did the literature search, wrote the initial draft of the manuscript, and prepared the figures and tables. PB provided use and trade information, as well as physico-chemical data and descriptors of surfactants used in the formulation of VDs and PPPs. BD and AS oversaw the project, edited the manuscript, and took responsibility for the integrity of the data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The opinions expressed and arguments employed in this publication are the sole responsibility of the authors and do not necessarily reflect those of the OECD or of the governments of its Member countries. National Center for Biotechnology Information , U.

Journal List Front Vet Sci v. Front Vet Sci. Published online Sep 4. Author information Article notes Copyright and License information Disclaimer. Specialty section: This article was submitted to Veterinary Epidemiology and Economics, a section of the journal Frontiers in Veterinary Science. Received Apr 27; Accepted Aug The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract Chemical substances applied in animal husbandry or veterinary medicine and in crop protection represent substantial environmental loads, and their residues occur in food and feed products. Keywords: veterinary drugs, pesticides, active ingredients, additives, adjuvants, surfactants, ecotoxicity. Introduction Large quantities of various chemical compounds and their formulations are used in several fields of agriculture, such as veterinary medicine, animal husbandry, animal nutrition, and chemical plant protection, and these substances may have adverse effects on the environment.

Legal Regulations for the Registration of VDs and Pesticides Authorization and distribution of agrochemicals are strictly regulated worldwide. Veterinary Drugs Extensive control of VDs is required in the EU, and thus, the requirements are very strict not only for quality and efficacy but also for safety, including animal and human health and environmental risk assessment ERA , similarly to the assessment and regulation of human medicines. Registration Requirements for Formulation Additives On the basis of the current legislation, substantially simpler ERA is sufficient for these substances compared to the active ingredients.

Safety Assessment of the Active Ingredients Safety assessment of agrochemicals is an issue of emphasized importance worldwide. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Excipients, Additives, and Adjuvants Beside the active ingredients, several additives can also be found in formulated animal therapeutic agents and feed additive products, as well as in the formulated pesticide preparations. Surfactants A characteristic feature in the chemical structure of different surfactants is the simultaneous presence of hydrophobic and hydrophilic moieties; therefore, surfactants show both lipophilic and hydrophilic properties 59 , Table 1 Various types of surfactants used for general purpose.

Table 2 Various types of surfactants used in veterinary drugs or disinfectants. Table 3 Various types of surfactants used in feed additives. Table 4 Various types of surfactants used in plant protection products.

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Anionic Surfactants Various anionic surfactants, containing functional groups capable to dissociate to form anions as the polar part of the molecule [e. Cationic Surfactants The polar part of cationic surfactants contains cation-forming functional groups. Non-Ionic Surfactants In the molecular structure of non-ionic surfactants, a polyethylene glycol PEG moiety is connected to alkylphenols [i. Amphoteric Surfactants Due to their zwitterionic structure, e. Biosurfactants Natural surface-active substances are produced by plants, animals, and microorganisms Tallow Derivatives Generated wastes by the oil and fat industries, such as residual oils, lard, and tallow, are additional sources of cationic biosurfactants for fabric softeners.

Figure 5. Ecotoxicological Effects of Surfactants Additives used as surfactants in VDs, feed additives, or PPP formulations may have adverse effects on the environment and on non-target organisms. Combined Effects: Synergism, Additive Effect, and Antagonism Interactions may occur between the active ingredients and additives used in formulated VDs, feed additives or pesticides. Environmental Fate of Surfactants Little information is available regarding the environmental fate of adjuvants e.

Conclusion Residues of agrochemicals, e. Author Contributions AS conceived the concept of the review. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Footnotes Funding. Disclaimer The opinions expressed and arguments employed in this publication are the sole responsibility of the authors and do not necessarily reflect those of the OECD or of the governments of its Member countries.

References 1. Perspectives in veterinary pharmacology and toxicology.

Pdf Toxicological Effects Of Veterinary Medicinal Products In Humans Volume 1

Front Vet Sci 3 The Council of the European Communities. OJ L :1— OJ L — The Commission of the European Communities. OJ L44 — The European Commission. OJ L :4— OJ L :7— OJ L :1—8. Woodward KN. Regulation of veterinary medicines. In: Woodward KN, editor. OJ L31 :1— Environmental risk of chemical agriculture. Engineering Tools for Environmental Risk Management. OJ L70 :1— Pesticide Residues in Food Rome: Rep No.

European Commission. Data EU Pesticides Database. Directorate-General for Health and Food Safety; Comparison of the legal regulations of pesticides and hazardous chemicals in the European Union with emphasis on genotoxic and endocrine disrupting effects. Acta Phytopathol Entomol Hung 47 2 — Ecotoxicological behavior of some cationic and amphoteric surfactants biodegradation, toxicity and risk assessment. In: Chamy R, Rosenkranz F, editors. Biodegradation — Life of Science. Rijeka: InTech; Technical Guidance Document on Risk Assessment.

Luxembourg: OJ L84 :1— OJ L :9— OJ L :3— Brussels: EU Commission; OJ L6 :7— OJ L95 :1— Recent advances in food analysis. Anal Bioanal Chem 10 —6. Gallo M, Ferranti P. The evolution of analytical chemistry methods in foodomics. J Chromatogr A :3— High Throughput Analysis for Food Safety. New Jersey: Wiley; Big data in food safety: an overview. Crit Rev Food Sci Nutr 57 11 — The European Council. Veterinary Pharmaceuticals in the Environment. ACS Symposium Series. Evaluating Veterinary Pharmaceutical Behavior in the Environment. Review of antimicrobial resistance in the environment and its relevance to environmental regulators.

Front Microbiol 7 London: European Medicines Agency; Terminology, classification, and chemistry. In: Hogdson RH, editor. Adjuvants for Herbicides. Foy CL. Adjuvants: terminology, classification, and mode of action. Adjuvants and Agrochemicals. Camouflaging of seeds treated with pesticides mitigates the mortality of wild birds in wheat and rice crops.

Sci Agric 67 2 — Gramoxone SL 2. Chapter 1 surfactants: properties, production and environmental aspects. Compr Anal Chem 40 :1— Di Corcia A. Characterisation of surfactants and their biointermediates by liquid chromatography-mass spectrometry. J Chromatogr A 1—2 — Ying GG. Fate, behavior and effects of surfactants and their degradation products in the environment. Environ Int 32 — Kosswig K. In: Wiley VCH, editor.

Weinheim: John Wiley and Sons; Broze G. Detergents: technical and practical challenges. In: Broze G, editor. Handbook of Detergents Part A: Properties. New York: Marcel Dekker; Advances in surfactants in agrochemicals.

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