Risk assessment of nitrate and nitrite in feed
2020; Wiley; Volume: 18; Issue: 11 Linguagem: Inglês
10.2903/j.efsa.2020.6290
ISSN1831-4732
AutoresDieter Schrenk, Margherita Bignami, Laurent Bodin, James Kevin Chipman, Jesús del Mazo, Bettina Grasl‐Kraupp, L.A.P. Hoogenboom, Jean‐Charles Leblanc, Carlo Nebbia, Elsa Nielsen, Evangelia Ntzani, Annette Petersen, Salomon Sand, Tanja Schwerdtle, Christiane Vleminckx, Heather Wallace, Vasileios Bampidis, Bruce Cottrill, María José Frutos Fernández, Peter Fürst, A. J. Parker, Marco Binaglia, Anna Christodoulidou, Petra Gergelová, Irene Muñoz Guajardo, Carina Wenger, Christer Högstrand,
Tópico(s)Agricultural safety and regulations
ResumoEFSA JournalVolume 18, Issue 11 e06290 Scientific OpinionOpen Access Risk assessment of nitrate and nitrite in feed EFSA Panel on Contaminants in the Food Chain (CONTAM), Corresponding Author EFSA Panel on Contaminants in the Food Chain (CONTAM) contam@efsa.europa.eu Correspondence:contam@efsa.europa.euSearch for more papers by this authorDieter Schrenk, Dieter SchrenkSearch for more papers by this authorMargherita Bignami, Margherita BignamiSearch for more papers by this authorLaurent Bodin, Laurent BodinSearch for more papers by this authorJames Kevin Chipman, James Kevin ChipmanSearch for more papers by this authorJesús del Mazo, Jesús del MazoSearch for more papers by this authorBettina Grasl-Kraupp, Bettina Grasl-KrauppSearch for more papers by this authorLaurentius (Ron) Hoogenboom, Laurentius (Ron) HoogenboomSearch for more papers by this authorJean-Charles Leblanc, Jean-Charles LeblancSearch for more papers by this authorCarlo Stefano Nebbia, Carlo Stefano NebbiaSearch for more papers by this authorElsa Nielsen, Elsa NielsenSearch for more papers by this authorEvangelia Ntzani, Evangelia NtzaniSearch for more papers by this authorAnnette Petersen, Annette PetersenSearch for more papers by this authorSalomon Sand, Salomon SandSearch for more papers by this authorTanja Schwerdtle, Tanja SchwerdtleSearch for more papers by this authorChristiane Vleminckx, Christiane VleminckxSearch for more papers by this authorHeather Wallace, Heather WallaceSearch for more papers by this authorVasileios Bampidis, Vasileios BampidisSearch for more papers by this authorBruce Cottrill, Bruce CottrillSearch for more papers by this authorMaria Jose Frutos, Maria Jose FrutosSearch for more papers by this authorPeter Furst, Peter FurstSearch for more papers by this authorAnthony Parker, Anthony ParkerSearch for more papers by this authorMarco Binaglia, Marco BinagliaSearch for more papers by this authorAnna Christodoulidou, Anna ChristodoulidouSearch for more papers by this authorPetra Gergelova, Petra GergelovaSearch for more papers by this authorIrene Munoz Guajardo, Irene Munoz GuajardoSearch for more papers by this authorCarina Wenger, Carina WengerSearch for more papers by this authorChrister Hogstrand, Christer HogstrandSearch for more papers by this author EFSA Panel on Contaminants in the Food Chain (CONTAM), Corresponding Author EFSA Panel on Contaminants in the Food Chain (CONTAM) contam@efsa.europa.eu Correspondence:contam@efsa.europa.euSearch for more papers by this authorDieter Schrenk, Dieter SchrenkSearch for more papers by this authorMargherita Bignami, Margherita BignamiSearch for more papers by this authorLaurent Bodin, Laurent BodinSearch for more papers by this authorJames Kevin Chipman, James Kevin ChipmanSearch for more papers by this authorJesús del Mazo, Jesús del MazoSearch for more papers by this authorBettina Grasl-Kraupp, Bettina Grasl-KrauppSearch for more papers by this authorLaurentius (Ron) Hoogenboom, Laurentius (Ron) HoogenboomSearch for more papers by this authorJean-Charles Leblanc, Jean-Charles LeblancSearch for more papers by this authorCarlo Stefano Nebbia, Carlo Stefano NebbiaSearch for more papers by this authorElsa Nielsen, Elsa NielsenSearch for more papers by this authorEvangelia Ntzani, Evangelia NtzaniSearch for more papers by this authorAnnette Petersen, Annette PetersenSearch for more papers by this authorSalomon Sand, Salomon SandSearch for more papers by this authorTanja Schwerdtle, Tanja SchwerdtleSearch for more papers by this authorChristiane Vleminckx, Christiane VleminckxSearch for more papers by this authorHeather Wallace, Heather WallaceSearch for more papers by this authorVasileios Bampidis, Vasileios BampidisSearch for more papers by this authorBruce Cottrill, Bruce CottrillSearch for more papers by this authorMaria Jose Frutos, Maria Jose FrutosSearch for more papers by this authorPeter Furst, Peter FurstSearch for more papers by this authorAnthony Parker, Anthony ParkerSearch for more papers by this authorMarco Binaglia, Marco BinagliaSearch for more papers by this authorAnna Christodoulidou, Anna ChristodoulidouSearch for more papers by this authorPetra Gergelova, Petra GergelovaSearch for more papers by this authorIrene Munoz Guajardo, Irene Munoz GuajardoSearch for more papers by this authorCarina Wenger, Carina WengerSearch for more papers by this authorChrister Hogstrand, Christer HogstrandSearch for more papers by this author First published: 04 November 2020 https://doi.org/10.2903/j.efsa.2020.6290 Requestor: European Commission Question number: EFSA-Q-2019-00098 Panel members: Margherita Bignami, Laurent Bodin, James Kevin Chipman, Jesús del Mazo, Bettina Grasl-Kraupp, Christer Hogstrand, Laurentius (Ron) Hoogenboom, Jean-Charles Leblanc, Carlo Stefano Nebbia, Elsa Nielsen, Evangelia Ntzani, Annette Petersen, Salomon Sand, Dieter Schrenk, Tanja Schwerdtle, Christiane Vleminckx and Heather Wallace. Acknowledgements: The Panel wishes to thank the following for the support provided to this scientific output: Elena Rovesti. The Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output. Amendment: The reference Lammarino has been corrected to Iammarino on page 12 and in the references list. To avoid confusion, the original version of the Scientific Opinion has been removed from the EFSA Journal, but is available on request, as is a version showing all the changes made. Adopted: 24 September 2020 This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2020.EN-1941/full Amended: 16 Nov 2020 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract The European Commission asked EFSA for a scientific opinion on the risks to animal health related to nitrite and nitrate in feed. For nitrate ion, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) identified a BMDL10 of 64 mg nitrate/kg body weight (bw) per day for adult cattle, based on methaemoglobin (MetHb) levels in animal's blood that would not induce clinical signs of hypoxia. The BMDL10 is applicable to all bovines, except for pregnant cows in which reproductive effects were not clearly associated with MetHb formation. Since the data available suggested that ovines and caprines are not more sensitive than bovines, the BMDL10 could also be applied to these species. Highest mean exposure estimates of 53 and 60 mg nitrate/kg bw per day in grass silage-based diets for beef cattle and fattening goats, respectively, may raise a health concern for ruminants when compared with the BMDL10 of 64 mg nitrate/kg bw per day. The concern may be higher because other forages might contain higher levels of nitrate. Highest mean exposure estimates of 2.0 mg nitrate/kg bw per day in pigs' feeds indicate a low risk for adverse health effects, when compared with an identified no observed adverse effect level (NOAEL) of 410 mg nitrate/kg bw per day, although the levels of exposure might be underestimated due to the absence of data on certain key ingredients in the diets of this species. Due to the limitations of the data available, the CONTAM Panel could not characterise the health risk in species other than ruminants and pigs from nitrate and in all livestock and companion animals from nitrite. Based on a limited data set, both the transfer of nitrate and nitrite from feed to food products of animal origin and the nitrate- and nitrite-mediated formation of N-nitrosamines and their transfer into these products are likely to be negligible. Summary Following a request from the European Commission, the European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain (CONTAM) assessed the risk to animal health related to the presence of nitrate and nitrite, in feed. The previous risk assessment from the CONTAM Panel on nitrite as an undesirable substance in feed (2009) has been re-evaluated in the light of the current requirements on data quality. The CONTAM Panel assessed nitrate and nitrite as ions. Nitrates are generally highly soluble in water and play a substantial role as nutrients for plants used for feeds. In veterinary medicine, potassium nitrate is used as diuretic in pigs, cattle and horses. It is also used as a vasodilator, bronchodilator and as an antidote for cyanide poisoning. Sodium nitrite is an authorised feed additive (EU Register of Feed Additives pursuant to Regulation (EC) No 1831/2003). Under acidic conditions, nitrite could form N-Nitroso compounds (NOCs), including genotoxic and carcinogenic N-nitrosamines, when reacting with some secondary amines in the feed or endogenously in the stomachs of animals. There is limited information on the absorption, distribution, metabolism and excretion (ADME) of nitrate and nitrite in farm and companion animal species. In ruminants, there is a rapid and dose-related absorption of nitrate and nitrite, with a complex interconversion between the two anions followed by a rapid excretion, mainly via urine. The main metabolic pathway in the rumen involves bacterial NADH- or FADH-nitroreductases mediating a two-step reduction of nitrate, first to nitrite and then to ammonia, which represents an important nitrogen source for bacterial protein synthesis. Nitrate reduction successfully competes with carbon dioxide reduction, limiting the biosynthesis of methane by the rumen bacteria, one of the most potent greenhouse gases. In pigs, the extent of nitrate reduction to nitrite is much lower than in ruminants. The reduction occurs in the intestine, but also takes place in the oral cavity due to an extensive salivary recirculation. Little is known about the kinetics of nitrate/nitrite in horses, in which nitrate reduction to nitrite is brought about by an active caecal and colonic microflora and is reportedly intermediate between ruminants and pigs. No relevant data on the kinetics of nitrate/nitrite in rabbits, poultry, dogs, cats, fur animals or fish have been identified in the literature. The nitrate itself has a low order of toxicity compared to nitrite, the latter causing the formation of methaemoglobin (MetHb), a molecule with very limited oxygen carrying capacity. Methaemoglobinaemia is the major adverse effect resulting from MetHb formation. Interspecies differences in the rate of MetHb formation are mainly related to the extent and the rate of nitrate reduction to nitrite, which is highest in ruminants, lower in horses and lowest in the other monogastric species. The mode of action (MoA) can be described for several effects of nitrate and nitrite in farmed and companion animals, such as increase in oxidative stress, the depression of thyroid function and the decrease in blood pressure. The MoA underlying other effects (vitamins A and E depletion, abortion and effects on fertility) are still to be unraveled. The generation of MetHb, resulting from the reaction between nitrite and oxyhaemoglobin, is considered the mediator of most adverse effects following exposure to nitrate and nitrite in ruminants. However, studies to investigate the methane-reducing potential of nitrate in ruminant diets have demonstrated that feeding strategies (encapsulation, fractionation, even distribution and gradual exposure to nitrate in the diet) and ruminal adaptation to nitrate help to maintain asymptomatic MetHb levels. In order to derive a reference point for nitrate in cattle that is protective for all feeding regimes, the CONTAM Panel considered oral dose-response studies involving direct feeding of nitrate, once a day, to non-adapted cattle, with post-prandial MetHb measurements. New literature reviewed by the CONTAM Panel suggests that there is limited evidence for clinical signs occurring in most ruminant species and categories when MetHb levels remain below 10%. Therefore, this value was used to define the benchmark response for cattle. The CONTAM Panel calculated a BMDL10 of 64 mg nitrate/kg body weight (bw) per day as the reference point for nitrate ion in adult cattle. Based on the literature reviewed, the BMDL10 defined for adult cattle is also applicable for lactating cows and calves. However, the association of MetHb formation with reproductive effects in pregnant cows such as late abortions and still births has not been clearly demonstrated. There was insufficient information to set a separate reference point for nitrate for ovines and caprines. They have not been demonstrated to be more sensitive to nitrate than bovines, and therefore, the BMDL10 identified for adult cattle may also be applied for these animal species. The CONTAM Panel could not identify any appropriate studies which could be used to determine reference points for nitrite in bovines, ovines or caprines. In pigs, a dose of nitrate of 410 mg/kg bw per day and a dose of nitrite of 20 mg/kg bw per day do not induce clinical signs and can be considered as the reference points. The CONTAM Panel could not identify any appropriate studies to establish a reference point for nitrate and nitrite in species other than ruminants and pigs. The dietary exposure was estimated considering a final data set which contained 1,542 nitrate analytical data points for nitrate and 1,561 for nitrite. The data were sampled in 15 different European countries between 2010 and 2019 and were mainly reported by only three countries, while other countries submitted only a limited number of data sets. The highest mean nitrate concentrations were observed for the feed category 'forages and roughage, and products derived thereof', in particular for clover meal and lucerne, and for the feed 'tubers, roots, and products derived thereof', and in particular for potatoes. For categories with ≥ 5 analytical results, the highest nitrite mean concentrations were observed for the feed category 'tubers, roots, and products derived thereof', in particular for sugar beet molasses. Even higher nitrite mean concentrations were measured for 'other plants, algae and products derived thereof', in particular for sugar cane molasses, but this is based only on four analytical results available (of which two were left censored), and therefore should be considered only indicative. Estimates of exposure were hampered by the lack of data for many of the feeds commonly used in the diets of farmed and companion animals. Therefore, all exposure estimates are likely to be underestimated. In ruminants, nitrate toxicity is most commonly reported in ruminants fed fresh herbage; however, due to the absence of any data on nitrate levels in fresh grass, it has not been possible to estimate exposure for those livestock most susceptible to nitrate toxicity. Due to insufficient data on levels of nitrite in feeds most commonly used in livestock diets, no reliable estimates of exposure could be calculated. The highest estimated dietary exposure of cattle to nitrate from feed was for beef cattle fed a grass silage-based diet (53 mg/kg bw per day). For sheep and goats, the categories 'lactating sheep' and 'goats for fattening' had the highest exposure estimates to nitrate from grass silage-based diet, with 46 and 60 mg/kg bw per day, respectively. In non-ruminants, the exposure estimates are low (from mean upper bound (UB) 0.3 mg/kg bw per day in cats to 5.6 mg/kg bw per day in laying chicken). However, these might be underestimates as a result of lack of data on the main ingredients in their diets. The risk characterisation of exposure to nitrate is evaluated taking into consideration the comparison between the mean UB exposure estimates and the identified reference points for adverse effects. In ruminants, the BMDL10 of 64 mg nitrate/kg bw per day was compared with the highest estimated mean exposures of 53 and 60 mg nitrate/kg bw per day calculated for beef cattle and fattening goats, respectively, when fed grass silage-based diets. This comparison indicates that the exposure may raise a health concern, considering the uncertainty in the high exposure estimates for grass silage and for other forages that may contain relatively high levels of nitrate but for which data are missing. There are some examples in the literature indicating successful adaptation of the ruminants to nitrate in feed, suggesting that the BMDL10 calculated may be conservative. However, due to the large variability in the design and outcome of these studies, it is not possible to set a different reference point for animals which have undergone long-term exposure to elevated levels of nitrate. Based on the comparison of mean exposure estimates of 2.0 mg nitrate/kg bw per day in starter pigs' feeds with a no observed adverse effect level (NOAEL) of 410 mg nitrate/kg bw per day identified for pigs, their risk of adverse health effects from feeds containing nitrate was considered very low, although the absence of data on certain key ingredients in the diets of this species is likely to have resulted in an underestimation of levels of exposure. The health risk from the exposure to nitrate in species other than ruminants and pigs and to nitrite in farmed and companion animals could not be assessed due to the limited data available. There might be formation of toxic N-nitrosamines in feed, and in particular fishmeal, due to the presence of nitrite and secondary amines, although there was no statistical correlation between concentrations of nitrate, nitrite and N-nitrosamines shown in the very old studies available. No recent information is available on N-nitrosamine intoxication of animals, due probably to the setting of maximum limits of nitrite in fishmeal (30 mg/kg). A limited number of old studies with few animal species showed little, if any, formation of N-nitrosamines due to the reaction of nitrite with secondary amines endogenously. However, these studies were made under specific experimental feeding conditions which may be unlikely to be met under commercial feeding practices. The evidence to assess the risk from the endogenous production of N-nitrosamines is very limited and there is no information to link it with adverse effects in farmed and companion animals. Based on a limited data set, both the transfer of nitrate and nitrite from feed to food products of animal origin and the nitrate- and nitrite-mediated formation of N-nitrosamines and their transfer into these products are likely to be negligible. More information is recommended on nitrate and nitrite regarding their toxicokinetics and adverse effects in animal species other than ruminants and pigs, at realistic dietary exposure levels. Occurrence data of nitrate and nitrite in feeds for rabbits, horses, poultry, dogs, cats, fur animals and fish are needed. In addition, collection of occurrence data on nitrate and in particular on nitrite and N-nitrosamines formed due to the presence of nitrate and nitrite in the different major feeds, especially in forages, is recommended in order to produce reliable exposure estimates. More occurrence data of nitrate and nitrite in fresh and ensiled herbages should be sought, e.g. from the annual analysis performed by EU commercial laboratories for livestock farmers, in order to better estimate exposure by ruminant livestock and horses. Finally, more data are needed on the endogenous formation of N-nitrosamines in the different species and on the transfer of nitrate, nitrite and N-nitrosamines, formed due to the presence of nitrate and nitrite in feed, to food products of animal origin. 1 Introduction 1.1 Background and Terms of Reference as provided by the requestor BACKGROUND Maximum levels for nitrite in feed have been established by Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed. EFSA adopted a scientific opinion on nitrite as undesirable substance in feed in 2009. EFSA concluded in its Opinion that for pigs and cattle, as representative sensitive food producing species, the margins of safety with respect to the respective no observed adverse effect level (NOAEL) are sufficient. It considered furthermore that the presence of nitrite in animal products does not raise any concern for human health. Directive 2002/32/EC has been amended as regards nitrite in 2010 and 2011 to take into account the outcome of the EFSA Opinion. A report on European Union controls for nitrite and feed was submitted in 2014 for discussion by the UK delegation to the Standing Committee on Plants, Animals, Feed and Food. The report concluded that 'on the basis of the data reported by EFSA and considered in detail in the review by Cockburn et al. (2013), along with the fact that there has been no evidence of any problems of poisoning from nitrite in feed being reported in UK animal production, it is concluded that there appears to be little evidence to justify maximum levels for nitrite in feed materials. Furthermore, it should be noted that establishing maximum levels for nitrite in feeds does not necessarily protect livestock from poisoning. It is well known that endogenous conversion of dietary nitrate to nitrite occurs, and therefore it is the levels of nitrate in the diet which are likely to have the greatest impact on nitrite exposure. However, there are currently no maximum levels for nitrate in feed.' End of 2014, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) published an opinion on nitrite and nitrate in feed. It was concluded that 'The maximum levels of nitrite established for feed materials and compound feed can be deleted from EU legislation. Taking into account current knowledge, it is inappropriate to establish maximum levels of nitrate in feed.' Extensive discussions in the Standing Committee on Plants, Animals, Food and Feed did not result into an unequivocal view on how to proceed as regards the existing provisions on nitrite in feed and the Committee considered that before concluding, it would be necessary to have an EFSA comprehensive Opinion on the risks for animal health related to the presence of nitrite and nitrate in feed. Indeed, endogenous conversion of dietary nitrate into nitrite occurs and it is very likely that the presence of nitrate in feed has the largest impact on nitrite animal exposure. Therefore, it is appropriate to provide for a comprehensive assessment of the risks for animal health related to the animal exposure to nitrite (following presence in feed and endogenous conversion from nitrate into nitrite) and to nitrate itself. TERMS OF REFERENCE In accordance with Art. 29 (1) of Regulation (EC) No 178/2002, the European Commission (EC) asks the European Food Safety Authority to provide an opinion on the risks for animal health related to the presence of nitrite and nitrate in feed. 1.2 Interpretation of the Terms of Reference EFSA issued a scientific opinion in 2009 on nitrite as an undesirable substance in animal feed (EFSA, 2009). The European Commission now asked EFSA to update its previous Opinion in response to reports challenging the appropriateness of setting maximum levels of nitrite in animal feeds. Because of the conversion of nitrate to nitrite in the gastrointestinal tract of animals, the European Commission requests a comprehensive assessment of the risks for animal health related to the exposure to both nitrite and nitrate. The CONTAM Panel assessed nitrate and nitrite as ions. The chemical formulas NO2- and NO3- are also used for clarity when concentrations or doses are reported. The CONTAM Panel considered that it would best respond to this mandate by addressing the following questions: Are there new data since its last Opinion indicating any additional toxicological effects of nitrate and nitrite, in farmed and companion animals? What are the critical effects for each animal species and category and can reference points be identified for these effects? Which feed materials used in the EU are the main sources of nitrate and nitrite and what are the levels of nitrate and nitrite in these feeds? What are the estimates of exposure to nitrite and nitrate, in feed of different animal species and categories in the European Union? What is the estimated risk to animal health due to nitrate and nitrite at the current exposure? What are the levels of nitrate and nitrite transfer from feed to food products of animal origin, and would these levels be acceptable? What are the levels of the nitrate- and nitrite-mediated formation of N-nitrosamines (in feed and endogenously) and their transfer into food products of animal origin and would these levels be acceptable? 1.3 Additional information 1.3.1 Chemistry, production and use of nitrate and nitrite Physico-chemical properties of nitrate, nitrite and some selected salts used in food, feed and as fertilisers are depicted in Table 1. Table 1. Physico-chemical properties of nitrate, nitrite and some selected salts Parameter Nitrate Sodium nitrate Potassium nitrate Calcium nitrate (anhydrous) Calcium nitrate (tetra-hydrate) Ammonium nitrate Nitrite Sodium nitrite Potassium nitrite Formula NO3- NaNO3 KNO3 Ca(NO3)2 Ca(NO3)2 × 4 H2O NH4NO3 NO2- NaNO2 KNO2 CAS Registry number 14797-55-8 7631-99-4 7757-79-1 10124-37-5 13477-34-4 6484-52-2 14797-64-0 7632-00-0 7758-09-0 Molecular mass (g/mol) 62.01 85.00 101.11 164.09 236.15 80.04 46.01 69.00 85.10 Solubility in water (25°C) Highly soluble Freely soluble Freely soluble 1,290 g/L (20°C) 1,877 g/L (20°C) 820 g/L (20°C) 2,810 g/L (20°C) Melting point (°C) 306.5 (decomposes at 380°C) 334 (decomposes at 400°C) 561 45 169 (decomposes at > 170°C) 270 (decomposes at > 320°C) 441 (decomposition starts at 350°C Nitrate (NO3-) is a polyatomic anion that can form salts with a number of elements of the periodic table. Nitrates naturally occur ubiquitously in the environment, are involved in the nitrogen cycle and build large deposits especially in the form of sodium nitrate (NaNO3) in some regions, e.g. the Atacama-Desert in Chile, thus the trivial name Chile saltpetre for NaNO3. They have various uses in feed and food, such as in the production of fertilisers, and food preservatives. Nitrates are generally highly soluble in water and play a substantial role as nutrients for plants. Thus, they are found in all plants, especially in green leafy vegetables. Regarding feed and food, sodium nitrate and potassium nitrate are of special importance. Sodium nitrate is a white crystalline, slightly hygroscopic powder. Potassium nitrate is a white crystalline powder or transparent prisms having a cooling, saline, pungent taste. Sodium nitrate (E 251) and potassium nitrate (E 252) are authorised food additives in 24 food categories in the European Union in line with the Annex II of Regulation (EC) No 1333/20081 . They are commonly used as preservatives and combined with nitrite salts in curing mixtures (i.e. sodium chloride solutions) for meats to develop and fix the colour of meat, to inhibit microbial growth and to develop characteristic flavours (EFSA ANS Panel, 2017b). In veterinary medicine, potassium nitrate is used as diuretic in pigs, cattle and horses. Two other nitrate that are used especially in fertilisers are calcium nitrate (Ca(NO3)2) and ammonium nitrate (NH4NO3). Anhydrous Ca(NO3)2 is colourless, hygroscopic and thus absorbs easily moisture and forms tetrahydrates. NH4NO3 is a colourless crystalline salt Nitrite (NO2-) is the anion of inorganic nitrite salts. Natural occurrence of nitrite in the environment is a consequence of the nitrogen cycle, but usually nitrite is found in very low concentration. Nitrite is formed in nature by the action of nitrifying bacteria as an intermediate stage in the formation of nitrate. Synthetically, nitrites of the alkali earth metals can be produced by reacting a mixture of nitrogen monoxide (NO) and nitrogen dioxide (NO2) with the corresponding metal hydroxide solution, as well as through the thermal decomposition of the corresponding nitrate. Nitrite can be reduced to nitric oxide or ammonia by many species of bacteria. The most important nitrites in feed and food are sodium nitrite (NaNO2) and potassium nitrite (KNO2). Sodium nitrite is a white to slightly yellowish crystalline powder. It is hygroscopic, has a melting point of 270°C and decomposes above 320°C. It slowly oxidises in the air to sodium nitrate. It is used in various applications and the manufacturing of numerous compounds. In human and veterinary medicine, NaNO2 has been used as a vasodilator, bronchodilator and as an antidote for cyanide poisoning. In veterinary medicine, the substance is intended for use (together with other antimicrobial agents or biocides) as an antiseptic by topical application to the teats of dairy cows after milking in order to prevent mastitis. NaNO2 is authorised as food additive E 250 in line with Annex II of Regulation (EC) No 1333/2008. As a food additive, it stabilises the colour of preserved fish and meats and also inhibits the growth of Clostridium botulinum, the bacterium, which produces the botulinum toxin. Potassium nitrite (KNO2) is a white to slightly yellow crystalline powder. KNO2 is an authorised food additive coded E 249 in line with the Annex II of Regulation (EC) No 1333/2008. It is used as a colour fixative in fish products and in pickling and curing meat, sometimes in combination
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