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1 Scientific Committee on Health and Environmental Risks SCHER Critical review of any new eviden ce on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water SCHER adopted this opinion by written procedure on 16 May 2011

2 Fluoride and fluoridating agents of drinking water About the Scientific Committee s Three independent non-food Scientific Co mmittees provide the Commission with the scientific advice it needs when preparing po licy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commission's attention to the new or emerging problems wh ich may pose an actual or potential threat. They are: the Scientific Co mmittee on Consumer Safety (S CCS), the Scientific Committee on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), and are made up of external experts. In addition, the Commission reli es upon the work of the Euro pean Food Safety Authority (EFSA), the European Medicines Evaluation Agency (EMEA), the Eu ropean Centre for Disease prevention and Cont rol (ECDC) and the European Chemicals Agency (ECHA). SCHER Opinions on risks related to pollutants in the environmental media and other biological and physical factors or changing physical conditions which may have a negative impact on health and the environment, air quality, waters, waste and for example in relation to soils, as well as on life-cycle environmental assessment. It shall al so address health and safety issues related to the toxicity and eco-toxicity of biocides. It may also address questions re lating to examination of the toxicity and eco-toxicity of chemical, biochemical and biological compounds whose use may have harmful consequences for human health and the en vironment. In addition, the Committee will address questions relating to the methodologic al aspect of the assessment of health and environmental risks of chemic als, including mixtures of chemicals, as necessary for providing sound and consistent advice in its own areas of competence as well as in order issues in close cooperation with other European agencies. to contribute to the relevant Scientific Committee members Peter Calow, Stella Canna , Herman Autrup, Denis Bard, Ursula Ackermann-Liebrich Michaelidou, John Davison, Wolfgang Dekant, Pim de Voogt, Arielle Gard, Helmut Greim, Ari Hirvonen, Colin Janssen, Jan Linders, Boru t Peterlin, Jose Tarazo na, Emanuela Testai, Marco Vighi. Contact: European Commission DG Health & Consumers Directorate C: Public He alth and Risk Assessment Unit C7 - Risk Assessment Office: B232 B-1049 Brussels [email protected] © European Union, 2010 12781-6 978-92-79- ISSN 1831- 4775 ISBN AR-09-024-EN-N doi:10.2772/ ND- 38897 independent scientists e opinions of the Scientific Committees pr esent the views of the h T who are members of the committees. They do not necessarily reflect the views of the European Commission. The opinions are published by the European Commission in their original language only. http://ec.europa.eu/health/scientific_commi ttees/environmental_risks/index_en.htm 2

3 Fluoride and fluoridating agents of drinking water ACKNOWLEDGMENTS The members of the working group are acknowledged for their valuab le contribution to the opinion: Prof. U. Ackermann-Liebrich, University of Basel, CH Rapporteur human health part ) Prof. H. Autrup, University of Aarhus, DK ( Chair and Prof. D. Bard, National School of Public Health, Rennes, FR Prof. P. Calow, University of Sheffield, UK Prof. W. Dekant, University of Wurzburg, DE Dr. A. Gard, Montpellier 1 University, FR Dr. J. Linders, RIVM Bilthoven, NL ( Rapporteur environmental part) External experts: Dr. C. Chambers, SCCS Dr. P. Verger, EFSA Dr. H. Przyrembel, EFSA Prof. J. Ekstrand, Karolinska Institut, Stockholm, SE 3

4 Fluoride and fluoridating agents of drinking water ABSTRACT an growth and development, and for most Fluoride is not an essential element for hum organisms in the environment. A large variation in naturally occurring fluoride in drinking water is observed in EU Member States ranging from 0.1 to 8.0 mg /L. Fluoridation of drinking water is es, and hexafluorosilicic acid and recommended in some EU Member Stat hexafluorosilicates are the most commonly used agents in drinking water fluoridation. These compounds are rapidly and completely hydr olyzed to the fluoride ion. No residual fluorosilicate intermediates have been report ed. Thus, the main substance of relevance - to be evaluated is the fluoride ion (F ). Systemic exposure to fluoride through drinking water is associ ated with an increased risk of dental and bone fluorosis in a dose-res ponse manner without a detectable threshold. Limited evidence from epidemiological studies points towards other adverse health effects following systemic fluoride exposure, e.g. carcinogenicity, developmental neurotoxicity and reproductive toxicity; howe ver the application of the general rules of the weight-of-evidence approach indica tes that these observations cannot be unequivocally substantiated. The total exposure to fluoride was estimated for infants, children, and adults from all sources of fluoride, e.g. wa ter based beverages, food, dietary supplements, and the use of toothpaste. Contribution from other so urces is limited exce pt for occupational exposure to dust from fluoride containing minerals. The upper tolerable intake level (UL), as established by EFSA, was exceeded only in the worst case scenario for adults and childre n older than 15 years of age at a daily consumption of 2.8 L of drinking water, an d for children (6-15 years of age) consuming more than 1.5 L of drinking water when the level of fluoride in the water is above 3 e) the UL was exceeded when consuming mg/L. For younger children (1-6 years of ag more than 1 L of water at 0.8 mg fluoride/L (mandatory fluoridation level in Ireland) and assuming the worst case scenario for other sources. For infants up to 6 months old receiving infant formula, if the water fluoride level is higher than 0.8 mg/L, the intake of fluoride exceeds 0.1 mg/kg/day, and this level is 100 times higher than the level found in breast milk (less than 0.001 mg/kg/day). l fluoride application, e.g. fluoridated toothpaste, is to The cariostatic effect of topica maintain a continuous level of fluoride in the oral cavity. Scientific evidence for the protective effect of topical fl uoride application is strong, while the respective data for systemic application via drinking water are less convincing. No obvious advantage appears in favour of water fluo ridation as compared with to pical application of fluoride. However, an advantage in favour of water fluoridation is that caries prevention may reach disadvantaged children from the lower socioeconomic groups. In several environmental scenarios it wa s found that exposure of environmental organisms to levels of fluoride used for fluori dation of drinking water is not expected to lead to unacceptable risks to the environment. Keywords: fluoride, drinking water, fluoridating agents, silicofluorides, (hydro)fluorosilicic acid, sodium silicofluo ride, disodium hexafluorosilicate, hexafluorosilicic acid, dental fluorosis, tooth decays, environm ental risk, aquatic organisms. Opinion to be cited as: SCHER, Opinion on critical review of any new evidence on the hazard profile, health fluoride and the fl effects, and human exposure to uoridating agents of drinking water – 16 May 2011. 4

5 Fluoride and fluoridating agents of drinking water TABLE OF CONTENTS ACKNOWLEDGMENTS ... 3 ABSTRACT ... 4 1. BACKGROUND... 7 2. TERMS OF REFERENCE ... 8 SCIENTIFIC RA TIONALE... 9 3. Dissociation of hexafluorosilicic 3.1. ous solution ... 10 acid in aque proper ties... 11 3.2. Physico-chemical Pharmacokinetics of fluoride ions... 12 3.3. 3.3.1. Oral up take ... 12 rption ... 12 3.3.2. Dermal abso 3.3.3. Inhalation ... 12 Fluoride distribution, me tabolism and ex cretion ... 12 3.3.4. 4. N ... 13 OPINIO 4.1. Question 1-a ... 13 4.1.1. Dental and skeletal fluorosis ... 13 ity ... 15 4.1.2. Genotoxicity and Ca rcinogenic 4.1.3. Neurotoxicity ... 17 Reproductive and deve lopmental e 4.1.4. ffects ... 18 4.2. Question 1-b ... 19 4.2.1. Exposure to fluoride a ccording to it s source... 20 4.2.2. Integrated exposure to fluori de from all ma jor sour ces ... 22 4.2.3. Conclusion... 28 4.3. Question 1-c1... 28 4.3.1. Mechanism of fluoride action in caries prevention... 29 4.3.2. d fluoridation ... 29 Dental health an 4.3.3. Conclusion... 31 4.4. Question 1-c2... 32 4.5. Question 1-d ... 33 4.6. Question 2 ... 33 4.6.1. Introduction ... 34 4.6.2. Mechanism of action ... 35 Aquatic effects ... 35 4.6.3. 5

6 Fluoride and fluoridating agents of drinking water 4.6.4. Conclusions ... 39 SUMMARY... 39 5. 6. LIST OF ABREVIATIONS... 41 7. REFERENCES ... 42 6

7 Fluoride and fluoridating agents of drinking water BACKGROUND 1. for human growth and development but it is Fluoride is not considered to be essential considered to be beneficial in the prevention of dental caries (tooth decay). As a result, intentional fluoridation of drinking water and the development of fluoride containing oral foods (fluoridated salts) and supplements care products (toothpastes and mouth rinses), th century in several parts of the (fluoride tablets) have been employed since the early 20 world as a public health protective measure against tooth decay. Additional exposure to fluoride comes from naturally occurring water (tap and minera l), beverages, food, and to a lesser extent, from othe r environmental sources. A body of scientific literature seems to suggest that fluoride intake may be associated with a number of adverse health effects. Dent al fluorosis and effect s on bones (increased fragility and skeletal fluorosis) are two we ll documented adverse effects of fluoride g prolonged and high exposure intake. Systemic effects followin to fluoride have also been thyroid, developing br ain and other tissues, reported and more recently effects on the n types of osteosarcoma (bone cancer) have been reported. and an association with certai Individual and population exposures to fluoride vary consider ably and depend on the high variability in the levels of fluoride found in tap (be it natural or the result of intentional fluoridation of drinking wate individual dietary and oral r) and mineral waters, and on hygiene habits and practices. The emerging picture from a ll risk assessments conducted on fluoride is that there exists a narrow margin between the recommended intakes for the prevention of dental ca ries and the upper limits of exposure. Invariably, all assessments to-date call for continued monitori ng of the exposure of humans to fluoride entific developments on its hazard profile. from all sources and an evaluation of new sci Exposure assessment was conducted in the mo st recent evaluations by the European tolerable intake levels (UL) related to Food Safety Authority (EFSA), setting upper concentration limits for fluoride in natural mineral waters (EFSA 2005) and on calcium fluoride and sodium monofluo rophosphate as a source of fluoride (EFSA 2008a, EFSA ientific Committee on Consum er Products (fluoride in 2008b), and by the Commission Sc dental care products (SCCP 2009)). A similar approach was taken by the United States National Academies of Science in its 2006 re view of the United States Environmental Protection Agency’s water stan dards for fluoride (NRC 2006). There is a continuous controversy over the be nefit of fluoride and, in particular, the practices of intentional water fluoridation in tooth decay prevention. This has led to several countries discontinuing drinking wa ter fluoridation and others expanding it. Besides questioning the practice of intentional water fluoridation itself as being unnecessary or superfluous in the light of the high exposure to fluoride from other sources, opponents of water fl uoridation have pointed to reports showing that the health and environmental risks of the most commonly used fluoridating agents, silicofluorides (e.g. (hydro)fluorosilicic acid, sodium sili dium hexafluorosilicate or cofluoride, diso hexafluorosilicate or hexafluorosilicic acid), have not been properly assessed. Furthermore, they sugg of these chemicals in drinking water may est that the presence cause adverse effects on the health of human s and exert possible exac erbating effects on fluoride disposition in bone. The debate over water fluori questions from the European dation has prompted several Parliament, from Ireland and the United Kingdom where intentional water fluoridation is still practiced. In order to obtain updated advice on the issu e, the Commission considers it necessary to seek the advice of its Scientific Committee on Health and Environmental Risks (SCHER) who should work in close collaboration with the Scientific Committee on Consumer Products (SCCP), EFSA’s panel on dietetic products, nutrition and allergies (EFSA NDA) and EFSA’s panel on contaminants in the food chain (EFSA CONTAM) who have inions on fluoride. previously delivered op 7

8 Fluoride and fluoridating agents of drinking water In the preparation of this opinion, SCHER considered research articles and reviews published in peer-reviewed journals, reports from regulatory agencies and other pers submitted by di fferent stakeholders following a public organizations, as well as all pa call on the internet for submission of relevant scientific information. The preliminary opinion was published for public consultation for a period of three months; it was discussed at a public hearing, and addition al material was received. The scientific evaluated using the information available to the committee was weight-of-evidence approach developed by the EU Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). In general, the health risks of fluoridation of drinking water have been investigated within different areas such as epidemiologic studies, experimental studies in humans, experimental studies in anim als, and cell culture studies. A health risk assessment evaluates the evidence within each of these area s and then weighs together the evidence across the areas to produce a combined assessment. The general rules of to evaluate the documents on which the the weight-of-evidence approach were used opinion is based. 2. TERMS OF REFERENCE The Scientific Committee on Health and Environmental Risks (SCHER) is requested to: 1. Taking into consideration the SCCP opin ion of 20.09.05 (SCCP 2005) on the safety of fluorine compounds in oral hygiene products, the EFSA NDA opinion of 22.2.05 on the Tolerable Upper Intake Level of Fluoride, and the EFSA CONTAM panel opinion of 22.06.05, a. Critically review any information that is available in the public domain on the hazard profile and epidemiological evidence of adverse and/or beneficial health effects of fluoride. In particular the Co mmittee should consider evidence that has idence produced before which was not become available after 2005, but also ev considered by the SCCP and EFSA panels at the time. Conduct an integrated exposure assessm ent for fluoride covering all known b. possible sources (both anthropogenic and natu ral). In doing so, and in the case of uncertainties or lack of actual exposure data, the SCHER is requested to conduct a sensitivity analysis that includes a range of possible exposure scenarios (e.g. sources, age group), and describe using appropriate quantitative or qualitative means the weight-of-evidence behind each scenario, the uncertainties surrounding each scenario, and the probability of it occurring in real life. On the basis of its answers abov e, the SCHER is also asked: c. c1 – To evaluate the evidence of the role of fluoride in tooth decay prevention and rank the various ex posure situations as to their effectiveness in offering a potential tooth decay preventive action. c2 – To make a pronouncement as to whether there may be reasons for concern arising from the exposure of humans to fluoride and if so y give rise to particular concern identify exposure scenarios that ma for any population subgroup. d. Identify any additional invest igative work that needs to be done in order to fill data gaps in the hazard profile, the health effects and the exposure assessment of fluoride. 2. Assess the health and environm ental risks that may be associated with the use of the most common drinking water fluori dation agents, sili cofluorides (e.g. (hydro)fluorosilicic acid, sodium silicofluoride, disodium hexafluorosilicate or hexafluorosilicate or hexafluorosilicic acid), taking into account their hazard profiles, their mode of use in water fluoridation, their physical chemical behaviour and the possible adverse effects they may have in when diluted in water, d in some studies. exacerbating fluoride health effect s as reporte 8

9 Fluoride and fluoridating agents of drinking water SCIENTIFIC RATIONALE 3. Fluoride, whether naturally present or intent ionally added to water, food, consumer and medical products, is considered beneficial to prevent dental caries (tooth decay). However, the cause of dental caries is multi-factorial, and the causal factors include microorganisms in dental plaq ue, fermentable carbohydrates (particularly sucrose), time, and level of oral hygiene, which depends on socioeconomic the individual’s health status and educational status. Fluorides are ubiquitous in air, water and the lithosphere. Fluorine as an element is seventh in the order of frequency of occurrence, accounting for 0.06-0.09% of the AlF ). Cryolite (used for the earth’s crust and occurs as fluoride, e.g. cryolite (Na 6 3 production of aluminium) and rock phosphates (used for the production of fertilizers) is fluoride is insoluble and not biologically have fluoride contents up to 54%. Most of th available. Availability of fluoride from soil depends on the solubility of the compound, the acidity of the soil and the presence of water. Fluoride has been detected in the ash from has concluded that based upon available the Icelandic volcano eruption, but EFSA information, the potential risk posed by the fluoride for human and animal health through food and feed is not considered to be of concern in the EU. The concentration of fluoride in ground water in the EU is generally low, but there are large regional differences due to different geological conditions. Surface water usually has lower fluoride contents than ground water (most often below 0.5 mg/L) and sea water (between 1.2 and 1.5 mg/L). There are no systematic data on the concentration of fluoride in natural drinking water in EU Me mber States, but rudimentary data show large variations between and within countries, e.g. Ireland 0.01-5.8 mg /L, Finland 0.1- 3.0 mg/L, and Germany 0.1-1.1 mg/L. Bottled natural mineral water is increasingly being used as a major source of water for drinking. A large variation in the level of fluoride has been observed reaching up to th Commission Directive 2003/40/EC of 16 May 2003 establishing 8 mg/L (EFSA 2005). the list, concentration limits and labelling re quirements for the constituents of natural g ozone-enriched air for the treatment of mineral waters and the conditions for usin natural mineral waters and spring waters requ ires that waters which contain more than 1.5 mg/L must be labelled as not suitable for the regular consumption by infants and st January 2008, natural mineral waters shall, children under 7 years of age and that by 1 at the time of packaging, comply with the maximum concentration limit set out in Annex I for fluorides of 5 mg/L. WHO established a guidance value for naturally occurring fluoride in drinking water of 1.5 mg/L based on a consumption of 2 L wate r/day, and recommended that artificial fluoridation of water supplies should not exceed the optimal fluoride levels of 1.0 mg/L (WHO 2006). In Europe, only Ireland and sele cted regions in the UK and Spain currently concentrations ranging from 0.8 to 1.2 mg/L (Mullen 2005). fluoridate drinking water at rd November 1998 (Council Directive 98/83/EC) The Council Directive 98/83/EC of 3 determined a fluoride level (both natural and as a result of fluoridation) for water 1.5 mg/L. Recently, the US Department of intended for human consumption of less than Health and Human Services recommended a fl uoride level in water of 0.7 mg/L “to balance the benefit of preventing tooth decay while limiting any unwanted health effects” ). The parametric value (http://www.hhs.gov/news/press/2011pres/01/20110107a.html refers to the residual monomer concentratio n in the water as calculated according to specifications of the maximum release from the corresponding polymer in contact with the water. Fluoride intake from food is generally low, except when food is prepared with fluoridated water or salt. However, some teas (e.g. Camellia sinensis ) represent a significant source of fluoride intake. Fruit and vegetables, milk and milk products, bread and cereals contain between 0.02-0.29 mg/kg (EFSA 2005). Recently, EFSA (2008a, 2008b) has F as a source of fluoride in food supplements. 3 PO 2 and Na 2 permitted CaF 9

10 Fluoride and fluoridating agents of drinking water and gels) contain fluo ride at different Dental products (toothpaste, mouthwashes concentrations up to 1,500 mg/kg (1,500 ppm). The mean annual usage of toothpaste in EU Member States in 2008 was 251 mL (range 130-405 mL) per capita. The extent of systemically available fluoride from toothpas te depends on the percentage of toothpaste swallowed per application. Fluoride is widely distributed in the atmosphere, originating from the dust of fluoride containing soils, industry and mining activi ties, and the burning of coal. The fluoride content in the air in non-industrialized areas has been found to be low and is not considered to contribute more than 0.01 mg/day to the total intake. An upper tolerable intake level (UL) of 0.1 mg/kg BW/day for fluoride has been derived by the EFSA Panel on Dietetic Products, Nu trition and Allergies (NDA) (EFSA 2005) based on a prevalence of less than 5% of moderate dental fluorosis in children up to the age of 8 years as the critical endpoint, i.e. 1.5 mg/day for children 1-3 years of age, and 2.5 mg/day for children aged 4-8 years. For adul ts, an UL of 0.12 mg/kg BW/day was based on a risk of bone fracture, which converts on a body weight basis into 7 mg/day for 5 mg/day for children 9-14 years of age. populations aged 15 years and older, and Tolerable upper intake levels for fluoride have not been established for infants. For infants up to 6 months old, the UK Department of Health (UK DoH 1994) concluded that 0.22 mg F/kg BW/day was safe. Several pathologies have been linked to high levels of fluoride exposure but are mostly based upon circumstantial evidence. Thus, this opinion will focus on fluorosis of teeth and oxicity and reprotoxicity. bones, osteosarcoma, neurot Dissociation of hexafluorosilicic acid in aqueous solution 3.1. Hexafluorosilicic acid and hexafluorosilicates are the most commonly used agents in drinking water fluoridation an d it has been claimed that in complete dissociation of these agents in drinking water may result in human exposure to these chemicals. The toxicology of these compounds is incomple tely investigated. Recent studies have addressed the equilibrium of the free fluoride ion and fluorosilicate species in aqueous solutions over a wide concentration and pH range. In the pH-range and at the concentrations of hexafluorosilicates/fluoride relevant for drinking water, hydrolysis of hexafluorosilicates to fluoride was rapid and the release of the fluoride ion was essentially 19 F-NMR. complete. Residual fluorosilicate intermediates were not observed by sensitive are rapidly transformed to Other hydrolysis products of hexafluorosilicate such as Si(OH) 4 is present naturally in drinking water in large 4 colloidal silica (Finney et al. 2006). Si(OH) quantities and is not considered a risk. In summary, these observations suggest that human exposure to fluorosi licates due to the use of hexafluorosilicic acid or hexafluorosilicate for drinking water fluoridation, if any, is very low as fluorosilicates in water are rapidly hydrolyzed to fluoride, as illustrated in the following equation: − − )l(OH)aq()OH(Si)aq(F)aq(OH)aq(SiFH 2 6 6 + + ⇔ + 62 4 2 SiF and H SiF compounds used to fluoridate drinking water, show a Studies on Na 2 2 6, 6 pharmacokinetic profile for fluoride identical to that of sodium fluoride (NaF) (Maguire et al. 2005, Whitford et al. 2008). It therefore seems unlikely that the rate and degree of absorption, fractional retention, balance and elimination of fluoride will be affected if these fluoride compounds are added artificially in low concentrations, or if fluoride is naturally present in drinking water. Hexafluorosilicic acids used as fluoridating agents may contain some impurities. Concerns have been raised about several heavy metals present as low-concentr ation impurities in commercial hexafluorosilicic acid. The average concentrations of arsenic, mercury, lead and cadmium present in hexafluorosilicic acid are low – between 10 and 400 mg/kg SiF (CEN 12175-2006). Therefore, fluoridation of drinking water only contributes to a H 2 6 limited extent to the total exposure to th ese contaminants (expected drinking water 10

11 Fluoride and fluoridating agents of drinking water These calculated concentrations are at concentrations are between 3.0 and 16.2 ng/L). least two orders of magnitude below drinking water guideline values for these metals established by WHO and other organizations, and therefore are not regarded as an additional he alth risk. ridated drinking water increa ses human exposure to lead It has been claimed that fluo highly soluble lead due to solubilisation of lead from drinking water pipes by formation of complexes. The claim was based on relationships of drinking water fluoridation and blood lead concentrations observed in a case study (Coplan et al. 2007). Based on the available chemistry of fluoride in solution, the chemistry of lead and lead ions, and the concentrations of fluoride in tap water, it is highly unlikely that there would be an increased release of lead from pipe s due to hexafluorosi licic acid. The added concentrations of hexafluorosilicic acid do no t influence the pH of tap water, and do not form soluble lead complexes at the low concentrations of hexafluorosilicic acid present in the gastrointestinal tract after consumption of fluoridated drinking water (Urbansky and Schock 2000). Physico-chemical properties 3.2. - ) and As indicated in section 3.1, the main substance of concern is the fluoride ion (F therefore the identification an d the physico-chemical properti es of sodium fluoride (NaF) given in Table 1 are considered applicable. Table 1: Main physico-chemical properties of sodium fluoride (NaF). Substance Sodium fluoride Elemental symbol NaF + - Ionic form , F Na CAS-number 7681-49-4 EINECS-number 231-667-8 Molecular weight (M) 42 g/mol (Na: 23; F: 19) Melting point (MP) ca. 1,000°C Boiling point (BP) 1,700°C Vapour pressure (VP) 133 Pa at 1077°C Vapour pressure at 25°C (VP) 1.97E-5 Pa (conversion by EUSES) Water solubility (WS) 40,000 mg/L at 20°C Water solubility at 25°C (WS) 42,900 mg/L (conversion by EUSES) Octanol-water partition (log K Not appropriate ) ow 3 1.93E-8 Pa.m /mol (calculation by EUSES) Henry’s Law constant (H) 3 0.0006–0.03 dm /kg (estimation) (Bégin et ) Sorption capacity (K d al. 2003) (see 3.1) -1 Removal rate (R) 1.39E-06 d at 12°C (default) Bioconcentration factor (BCF) Not relevant operties where relevant in this opinion. SCHER agreed to use these physico-chemical pr 11

12 Fluoride and fluoridating agents of drinking water Pharmacokinetics of fluoride ions 3.3. Oral uptake 3.3.1. In humans and animals, ingested fluoride occurs as hydrogen fluoride (HF) in the acidic environment of the stomach and is effectively absorbed from the gastrointestinal tract, although there is no proved absorption from the oral cavity. Peak plasma levels are soluble fluoride compounds, typically seen within 30–60 minut es after ingestion. Highly such as NaF present in tablets, aqueous solu tions and toothpaste are almost completely , MgF , and AlF , are absorbed, whereas compounds with lower solubility, such as CaF 2 2 3 less well absorbed. Ingestion of fluoride with milk or a diet high in calcium will decrease fluoride absorption. Dermal absorption 3.3.2. No experimental data on the extent of dermal absorption of fluoride from dilute aqueous solutions are available. As fluoride is an ion it is expected to have low membrane permeability and limited absorption through the skin from dilute aqueous solutions at near neutral pH (such as water used for ba is exposure pathway thing and showering). Th is unlikely to contribute to the fluoride body burden. 3.3.3. Inhalation No systematic experimental data on the absorption of fluoride after inhalation are available. A few older occupati onal studies have shown uptake of fluoride in heavily exposed workers from fluoride-containing dusts, but it is unlikely that inhalation exposure will contribute significantly to th e body burden of fluoride in the general population. 3.3.4. Fluoride distribution, metabolism and excretion Once absorbed, fluoride is rapidly distributed throughout the body via the blood. The short term plasma half-life is normally in the range of 3 to 10 hours. Fluoride is distributed between the plasma and blood cells, with plasma le vels being twice as high as about 65% of the level in plasma (Ekstrand blood cell levels. The saliva fluoride level is 1977). Plasma fluoride concentrations are not homeostatically regulated, but rise and fall according to the pattern of fluoride intake. In adults, plasma fluoride levels appear to be directly related to the daily exposure of fluoride. Mean plasma levels in individuals living of 0.1 mg/L or less are normally 9.5 μg /L, in areas with a water fluoride concentration compared to a mean plasma fluoride level of 19-28.5 μ g/L in individuals living in areas with a water fluoride content of 1.0 mg/L. In addition to the level of chronic fluoride intake and recent intake, the level of plasma fluoride is influenced by the rates of bone accretion and dissolution, and by the renal clea rance rate of fluoride. Renal excretion is the major route of fluoride removal from the body. The fluoride ion is filtered from the plasma by the glomerulus and then partially reabsorbed; there is no tubular secretion of fluoride. Renal clearance rates of fluoride in humans average at 50 mL/minute. A number of factors, including urinary pH, urinary flow, and glomerular filtration rate, can influence urinary fluoride excretion. There are no apparent age related differences in renal clearance rates (adjusted for body weight or surface area ) between children and adults. However, in older adults (more than 65 year s of age), a significant decline in renal clearance of fluoride has been reported co nsistent with the age-related decline in glomerular filtration rates. Approximately 99% of the fluoride in the human body is found in bones and teeth. Fluoride is incorporated into tooth and bone by replacing the hydroxyl ion in hydroxyapatite to form fluorohy droxyapatite. The level of fluoride in bone is influenced by several factors including age, past and pr esent fluoride intake, and the rate of bone turnover. Fluoride is not irre versibly bound to bone and is mobilized from bone through bone remodelling. 12

13 Fluoride and fluoridating agents of drinking water a higher concentration has been reported for Soft tissues do not accumulate fluoride, but rrier limits the diffusion of the kidney due to the partial re -absorption. The blood-brain ba fluoride into the central nervous system, where the fluoride level is only about 20% that of plasma. Human studies have shown that fl uoride is transferred across the placenta, and there is a direct relationship between fluoride levels in maternal and cord blood. In humans, fluoride is poorly tran sferred from plasma to milk. The fluoride concentration in human milk is in the range of 3.8–7.6 μg/L. OPINION 4. 4.1. Question 1-a Critically review any information that is available in the public domain on the hazard profile and epidemiological evidence of adverse and/or beneficial health effects of fluoride. 4.1.1. Dental and skeletal fluorosis Dental fluorosis Dental fluorosis is a well-recognised condition and an indicator of overall fluoride absorption from all sources at a young age. Initially, fluorosis appears as white opaque ses the porous areas increase striations across the enamel surface, and in more severe ca in size and pitting occurs wi th secondary discoloration of the surface. The symptoms appear in a dose-response manner. For classifi cation of fluorosis, see Appendix I. The severity and prevalence of dent al fluorosis has been shown to be directly related to the fluoride concentration in drinking water. It is the daily total fluoride intake over a prolonged period of time, but only during the developmental phas e of the teeth that results in fluorosis. The pre-eruptive developments of the decidu ous and permanent teeth are critical phases Early ossification of the jaw an d development of deciduous tooth for dental fluorosis. buds occurs between 4-6 months in utero . Mineralisation of the permanent tooth buds continues slowly for 12-14 years. starts at the time of birth and Numerous studies have demonstrated that ex posure to fluoride levels during tooth development can result in dental fluorosis. Excess absorbed fluoride may impair normal development of enamel in the pre-eruptive t ooth. This will not be apparent until tooth eruption, which will be more than 4-5 years after exposure. The development and severity of fluorosis duration, and timing of fluoride is highly dependent on the dose, exposure during the period of enamel formation. Fluorosed enamel is composed of hypomine ralized sub-surface en amel covered by well- mineralized enamel. The exact mechanisms of dental fluorosis development have not been fully elucidated. It seem can affect the ameloblasts, s that fluoride systemically particularly at high fluoride levels, while at lower fluoride levels, the ameloblasts may ride on the mineralizing matr ix (Bronckers et al. 2009). respond to the effects of fluo The EFSA NDA panel considered that an intake of less than 0.1 mg F/kg BW/day in children up to 8 years old corresponds to no significant occurrence of “moderate” forms of fluorosis in permanent teeth (EFSA 2005). Figure 1 shows a plot of the Community Fluorosis Index versus the daily fluoride dose/kg bodyweight (Butler et al. 1985, Fejerskov et al. 1996, Richard et al. 1967). The plot shows a linear dose–response relationship and indicates that fluorosis may occur even at ve ry low fluoride intake from water. Enamel fluorosis seen in ar eas with fluoridate d water (0.7–1.2 mg/L F) has been attributed to early tooth brushing behaviou rs, and inappropriate high fluoride intake th fluoridated drinking water ed wi of infant formula prepar (Ellewood et al. 2008), i.e. use 13

14 Fluoride and fluoridating agents of drinking water (Forsman 1977). Similarly, enam el fluorosis may occur in non-fluoridated areas, in conjunction with the use of fluoride supplements and in combination with fluoridated toothpaste (Ismail and Hasson 2008). Fluorida ted toothpaste has been dominating the European toothpaste market for more than 30 years. Fluorosis Index* and daily fluoride Figure 1: Regression line between Dean’s Community dose from water per kg body weight. ying the frequency of ea ch category in the * Individual scores are calculated by multipl population by the assigned we ight. The sum of the weighted scores is then divided by the number of individuals exam ined (Dean 1942) (see also Fejerskov et al. (1988)). Skeletal fluorosis A number of mechanisms are involved in the toxi city of fluoride to bone. Fluoride ions are e-apatite structure to incorporated into bone substituting hydroxyl groups in the carbonat produce fluorohydroxyapatite, thus altering the mineral structure of the bone. Unlike hydroxyl ions, fluoride ions reside in the plane of the calcium ions, resulting in a structure that is electrostatically more stable and structurally more compact. Because bone the interface between the collagen and the strength is thought to derive mainly from mineral (Catanese and Keavney 1996), alteration in mineralization af fects bone strength. Skeletal fluorosis is a pathological condition resulting from long-term exposure to high levels of fluoride. Skeletal fluorosis, in some cases with severe crippling, has been reported in individuals residing in India, China and Africa, where the fluoride intake is exceptionally high, e.g. due to high concentration of fluoride in drinking water and indoor burning of fluoride-rich coal resulting in a high indoor fluoride air concentration. In Europe, skeletal fluorosis has only been reported in workers in the aluminium industry, fluorospar processing and superphosphate manufacturing (Hodge and Smith 1977). The study design for most of the available studie s is not suitable for estimating the dose- response relationship and development of a N/LOAEL for skeletal fluorosis because of other factors such as nutrit ional status and climate influence water intake (IPCS 2002). Effect on bone strength and fractures A large number of epidemiological studies have investigated the effect of fluoride intake on bone fractures. The amount of fluoride ta ken up by bone is inversely related to age. eleton, a relatively high prop ortion of ingested fluoride During the growth phase of the sk 14

15 Fluoride and fluoridating agents of drinking water rst year of life, which gradually will be deposited in the skeleton: up to 90% during the fi s of age. There is no clear association of decreases to 50% in children older than 15 year bone fracture risk with wate r fluoridation (McDonagh et al. 2000), and fluoridation at levels of 0.6 to 1.1 mg/L may actually lo wer overall fracture risk (AU-NHMRC 2007). It ride can weaken bone and increase the risk has been postulated that a high level of fluo ≥ 4 mg fluoride/L of bone fractures under certain conditions, and a water concentration will increase the risk of bone fracture (NRC 2006). Conclusion SCHER acknowledges that there is a risk for earl y stages of dental fluo rosis in children in EU countries. A threshold cannot be detected. The occurrence of endemic skel etal fluorosis has not been reported in the EU. SCHER concludes that there are insufficient data to evaluate the risk of bone fracture at the fluoride levels seen in areas with fluoridated water. 4.1.2. Genotoxicity and carcinogenicity Genotoxicity studies In general, fluoride is not mutagenic in pr okaryotic cells, howeve r sodium and potassium fluoride (500-700 mg/L) induced mutations at the thymidine ki nase (Tk) locus in cultured cells at concentrations that were slightly cy totoxic and reduced grow th rate. In contrast, fluoride did not increase the mutation frequency at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus ( 200-500 mg F/L). Chromosomal aberrations, mostly breaks/deletions and gaps, following exposure to NaF have been investigated in in frequency was observed in human assays, but no significant increase many in vitro fibroblasts at concentrations below 4.52 mg F/L and for Chinese hamster ovary (CHO) cells below 226 mg F/L. in vivo Positive genotoxicity findings were only observed at doses that were highly toxic to animals, while lower doses were genera lly negative for geno toxicity. Chromosomal aberrations and micronuclei in bone marrow ce lls were observed in Swiss Webster mice s were observed in Swiss Webster mice (up to 18 mg F/kg BW), however no effect nerations compared to low fluoride exposure following oral exposure for at least seven ge (EFSA 2005). Fluoride has only been reported to be positive in genoto xicity tests at high concentrations (above 10 mg/L), and this effect is most likely due to a general inhibition of protein synthesis and enzyme s such as DNA polymerases. There are conflicting reports on genotoxic e ffects in humans. An increase in sister chromatid exchanges (SCE) and micronuclei has been reported in peripheral lymphocytes uorosis or residents in fluorosis-endemic areas in China and from patients with skeletal fl India, while no increased frequency of chromosomal aberrations or micronuclei were observed in osteoporosis patien treatment. The quality of the ts receiving sodium fluoride former studies is questionable. Carcinogenicity studies Carcinogenesis studies have been conducted by the US National Toxicology Program (NTP). Male rats (F344/N) receiving 0.2 (control ), 0.8, 2.5 or 4.1 mg F/kg BW in drinking water developed osteosarcoma with a statis tically significant dose-response trend. However, a pair-wise comparison of the inci dence in the high dose group versus the control was not statistically significant (p =0.099). No osteosarcoma was observed in female rats. Thus NTP concluded that there was “equivocal evidence of carcinogenic activity of NaF in male F344/N rats”. In male Sprague Dawley (SD) rats receiving up to 11.3 mg F/kg BW/day, no osteosarcoma was observed, but only one fibrob lastic sarcoma (1/70) at the highest dose level, and no tumours in female rats. 15

16 Fluoride and fluoridating agents of drinking water high doses of 8.1 and 9.1 mg F/kg BW/day In a bioassay in B6C3F1 mice receiving the l of three osteosarcomas occurred, but no for males and females, respectively, a tota osteosarcomas occurred in the medium or high-dose groups. On the basis of the results from the most adequate long-term carcinogenicity studies, there is only equivocal evidence of carcinogenicity of fluoride in male rats and no consistent evidence of carcinogenicity in mice (ATSDR 2003). No carcinogenicity studies have been conducted using (hydro)fluorosilicic acid, sodium sodium hexafluorosilicate silicofluoride, di or hexafluorosilicate or hexafluorosilicic acid. Epidemiological studies Early epidemiological studies did not find a consistent relationship between mortality from all types of cancer and exposure for fl uoride, including the consumption of fluoride- containing drinking water. Concerns regarding the potential carcinogenic effect of fluoride have been focused on bone cancer due to th e known accumulation of fluoride in bones. Osteosarcoma is a rare form of cancer makin g it difficult to anal yse risk factors using epidemiology. cidence of osteosarcoma among males less Two studies from the US found a higher in than 20 years of age living in fluoridated communities compared with non-fluoridated communities (Cohn 1992, Hoover 1991). However, two case-con trol studies did not find an increase in osteosarcoma in young males consuming fluoridated drinking water (above0.7 mg/L) (Eyre et al. 2009). A recent study in the UK performed by McNally et al. did not find a statistically significant difference in osteosarcoma rates between areas with fluoride levels of 1 mg/L and those with lower fluoride levels. However, these results are described only in an abstract and the data cannot be assessed. In addition, the relevant age group does not seem to have been studied. One case-control study found an association between fluoride exposu re during childhood males, but not among females (Bassin 2006). and the incidence of osteosarcoma among The Harvard Fluoride Osteosarcoma study was conducted as a hospital based case- s limited to subjects below the age of 20. control study in 11 hospitals in the USA and wa The study consisted of 103 cases and 215 contro ls matched to the cases. The level of fluoride in drinking water was the primar y exposure of interest, and the estimated exposure was on the source of the drinking water (municipal, private well, bottled) and the subject’s age(s) while at each address. The level of fl uoride in drinking water was obtained from local, regional and national re gistries. For well wate r, water samples were analyzed in the laboratory, while a value of 0.1 mg/L was assumed for bottled water. As water consumption may vary based on the loca l climate, the fluoride exposure estimates were based on Centers for Disease Control and Prevention (CDC) recommendations for optimal target levels for the fluoride level in drinking water. The CDC target level for a warmer climate was 0.7 mg/L and for cold er climate was 1.2 mg/L. The exposure estimate was expressed as the percentage of climate-specific target levels in drinking water at each age, and grouped into le 30-99% and above 100%. ss than 30%, between Information on the use of fl uoride supplements and mouth rinses was also obtained. re assessment is based on retrospectively However, it is of concern that the exposu creased risk was only observed for males collected data. A statistically significant in exposed at the highest level (above100%) of the CDC optimal target level and when this exposure took place between 6 and 8 years of age. This coincides with the mid-childhood growth spurt in boys. The increased risk re mained after adjustment, e.g. socioeconomic factors, use of fluoride products. No in creased risk was observed in females. A preliminary conclusion was base d upon an intermediate eval uation and further research observation that fluoride exposure was was recommended to confirm or refute the associated with development of osteosarcoma. 16

17 Fluoride and fluoridating agents of drinking water Conclusion SCHER agrees that epidemiological studies do not indicate a clear link between fluoride in drinking water, and osteosarcoma and cancer in general. There is no evidence from animal studies to support the link, thus fluo ride cannot be classified as carcinogenic. 4.1.3. Neurotoxicity Animal studies There are only limited data on the neurotoxicity of fluoride in experimental animals. One study in female rats exposed to high doses of fluoride (7.5 mg/kg BW/day for 6 weeks) resulted in alterations of spontaneous be haviour, and the auth ors noted that the observed effects were consistent with hype ractivity and cognitive deficits (ATSDR 2003). In a recent study, in which female rats were given doses of fluori de up to 11.5 mg/kg nces among the groups in learning or BW/day for 8 months, no significant differe performance of the operant tasks were ob de concentrations, served. Tissue fluori including seven different brain regions, were directly related to the levels of exposure (Whitford et al. 2009). The authors concluded th at ingestion of fluoride at levels more than 200 times higher than those experience d by humans consuming fluoridated water, had no significant effect on appetitive-based learning in female rats. Some animal studies have suggested a potential for thyroid effects following fluoride exposure. The available information is inconsistent and no effects on the thyroid were observed in long-term studies with fluoride in rats. Apparently, fluori de does not interfere with iodine uptake into the thyroid. However, after long-term exposure to high fluoride content in food or water, the thyroid glands of some animals have been found to contain increased fluoride levels (EFSA 2005). Human Studies There are limited data on neurotoxicity of fluoride in humans. It has been demonstrated that degenerative changes in the central nervous system, impairment of brain function, and abnormal development in children are caused by impaired thyroid function. or thyroid 3 oxine levels without significant changes in T Increases in serum thyr stimulating hormone levels were observed in residents of regions in India and China, with high levels of fluoride in drinking water, but these data are inconclusive due to the absence of adequate control for confounding fa ctors. Thus, fluoride is not considered to be an endocrine disruptor (ATSDR 2003). A series of studies on developmental effects of fluoride were carried out mostly in China in areas where there are likely to be less stri ngent controls over water quality. Thus it cannot be excluded that the water supply ma y be contaminated with other chemicals such as arsenic, which may affect intelligence quotient (IQ). The studies consistently show an inverse relationship between fluoride concentration in drinking water and IQ in children. Most papers compared mean IQs of schoolchildren from communities exposed to different levels of fluoride, either from drinking water or from coal burning used as a domestic fuel. All these papers are of a rather simplistic methodological design with no, or at best little, control for confounders, e. g. iodine or lead intake, nutritional status, housing condition, and parents level of education or income. Tang et al. (2008) published a meta-analysis of 16 studies carried out in China between 1998 and 2008 evaluating the influe nce of fluoride levels on the IQ of children. The authors conclude that children li ving in an area with high incidence of fluorosis and high ambient air fluoride leve ls have five times higher odds of developing a low IQ than those who live in a low fluorosis area. However, the paper does not follow classical methodology of meta-analysis and only uses un-weighted means of study results without taking into account the difference between cro ss-sectional and case-con trol studies. Thus it does not comply with the general rules of meta-analysis. Furthermore the majority of these studies did not account for major confo unders, a problem that cannot be solved in a summary. 17

18 Fluoride and fluoridating agents of drinking water intelligence and fluori Wang et al. (2007) carried out a study on the de exposure in 720 children between 8 and 12 years of age from a homogenous rural population in the Shanxi province, China. Subjects were drawn from control (fluoride concentration in drinking water 0.5 mg/L, n=196) and high fluo ride (8.3 mg/L) areas. The high fluoride ing to arsenic exposure; lo group was sub-divided accord w arsenic (n=253), medium arsenic (n=91), and high arsenic (n=180). The IQ scores in the high-fluoride group were significantly reduced compared to the contro l group, independent of arsenic exposure. The influence of socio-economic and genetic fa ctors cannot be completely ruled out, but is expected to be minimal. In a cross-sectional design, Rocha-Amador et al. (2007) studied the li nk between fluoride in drinking water and IQ in children from three rural communities in Mexico with different levels of fluoride (0.8 mg/L, 5.3 mg/L and 9.4 mg/L; in the latter setting children were supplied with bottled water) and arsenic in drinking water. The children’s IQ was assessed blind as regards fluori de or arsenic levels in drinking water. Socio-economic status was calculated according to an index including household flooring material, ’s education. Additional crowding, potable water availability, drainage, and father information about the type of water used for cooking (tap or bottled), health conditions, etc., was obtained by questionnaire. An inverse association was observed between fluoride in drinking water an d IQ after adjusting for rele vant confounding variables, including arsenic. Conclusion Available human studies do not clearly support the conclusion that fluoride in drinking water impairs children’s neurodevelopment at levels permitted in the EU. A systematic evaluation of the human studies does not sugge st a potential thyroid effect at realistic exposures to fluoride. The abse nce of thyroid effects in rodents after long-term fluoride gher sensitivity of rodents to changes in thyroid related administration and the much hi endocrinology as compared with humans do not support a role fo r fluoride induced s. The limited animal data can also not support the link thyroid perturbations in human between fluoride exposure and neurotox icity at relevant non-toxic doses. SCHER agrees that there is no t enough evidence to conclude that fluoride in drinking water at concentrations permitted in the EU may impair the IQ of children. SCHER also agrees that a biological plausibility for the link between fluo ridated water and IQ has not been established. 4.1.4. Reproductive and developmental effects Animal studies Most of the animal studies on the reproductive effects of fluo ride exposure deal with the male reproductive system of mice and rats. They consistently show an effect on spermatogenesis or male fertility . Sodium fluoride administered to male rats in drinking water at levels of 2, 4, and 6 mg/L for 6 months adversely affected their fertility and reproductive system (Gupta et al. 2007). In ar rats fed 5 mg/kg addition, in male Wist fluoride-treated spermatozoa capable of BW/day for 8 weeks, the percentage of d relative to control spermatozoa (34 vs. undergoing the acrosome reaction was decrease 55%), and the percentage of fluoride-treated spermatozoa capable of oocyte fertilization was significantly lower than in the control group (13 vs. 71%). It was suggested that sub-chronic exposure to fluoride caus es oxidative stress damage and loss of mitochondrial trans-membrane potential, resulting in reduced male fertility (Izquierdo- Vega et al. 2008). However, the fluoride do ses used in these studies were high and caused general toxicity, e.g. reduced weight gain. Therefore, the effects reported are likely to be secondary to the general toxicity. Multi-generation studies in mice did not demons trate reproductive toxicity at doses up to 50 mg F/kg BW. When mice were administered more than5.2 mg F/kg BW/day on days 6-15 after mating, no sign of adverse ef fect on pregnancy and implantation was 18

19 Fluoride and fluoridating agents of drinking water observed. Sperm mobility and viability were reduced in both mice and rats after 30 days of administration of 4.5 and 9.0 mg F/kg BW/day (ATSDR 2003). inking water with a fluoride content of 45 Serum testosterone increased in rats after dr and 90 mg/L for 2 weeks. Thereafter the leve l of serum testosterone decreased and was no different from the controls after 6 weeks. No effect was observed on several reproductive parameters in rats receiving up to 90.4 mg F/L for 14 weeks. Human studies Public Water Fluoridation (McDonagh et al. The National Health Service (NHS) review on 2000) did not find any evidence of reproduc tive toxicity in humans attributable to fluoride. Since then, no new ev idence seems to be available other than abstracts without methodological details. There is slight evidence that a high level of occupational exposure to fluoride affects male reproductive hormone levels. A significant increase in follicle-stimulating hormone (p<0.05) and a reduction of inhibin-B, free testosterone, and prolactin in serum (p<0.05), as well as decreased sensitivity in the FSH response to inhibin-B (p<0.05) was found when the high-exposure group was compared with a low-exposure group. Significant correlation was observed between urinary fluoride and serum concentrations of inhibin-B (p<0.028). No abnormalities were found in the semen parameters in either the high- or low-fluoride expo sure groups (Ortiz-Pérez et al. 2003). The alteration in the reproductive hormone levels after occupation al fluoride exposure is not relevant for drinking water exposure. Conclusion There is no new evidence from human studies indicating that fluoride in drinking water capacity. Few human studies have suggested influences male and female reproductive that fluoride might be associated with altera rmones and fertility, tions in reproductive ho but limitations in the study design make them of limited value for risk evaluation. Many experimental animal studies are of limited quality and no reprod uctive toxicity was observed in a multi-generation study. SCHER concludes that fluoride at concentrations in drinking water permitted in the EU does not influence the reproductive capacity. 4.2. Question 1-b Conduct an integrated exposure assessment of fluoride covering all known possible sources (both anthropogenic and natural). Exposure to fluoride occurs orally by inhalation and by dermal uptake, the former being the major route. Oral fluoride exposure is mainly by ingestion of water, water-based beverages, food (including fl uoridated salt and food supple ments) and swallowed dental hygiene products. t in ambient air within Europe is limited and does not Inhalation of fluoride presen contribute more than 0.01 mg/day to the tota l intake, except in occupational settings, e.g. aluminium workers where intake can be several milligrams. Fluoride might be a component of urban and ambient air pollution, especially in coal mining and coal burning communities, but information on the level of fluoride is limited and is restricted to industrial areas. Thus, inhalation exposure of fluoride is not considered important for the general population in the EU. However in some industrial areas exposure may occur, but no systematically collected data are available. At present, there are no reliable biomarkers to assess fluoride ex posure. Fluoride in blood, nails and hair samples has not been investigated systematically with respect to their use as an exposure biomarker. Urin e is commonly used to measure fluoride ations in urinary flow and pH which will exposure but is unreliable because of fluctu 19

20 Fluoride and fluoridating agents of drinking water sure is also a factor that influences the influence fluoride output. Past fluoride expo urinary fluoride output due to the large fraction of fluoride accumulated in the bone that is slowly released. Measurement of plasma fluoride will only give information on recent fluoride intake. 4.2.1. Exposure to fluoride according to its source Exposure to fluoride from food and water-based beverages There are no new EU data on fluoride in food . The level will to a large extent depend on the fluoride concentration naturally present in , or artificially added to, the water used for processing. In lieu of new data, EFSA consid ered the German background exposure to fluoride from food based on intake of m ilk, meat, fish, eggs, cereals, vegetables, posure corresponds to 0.042, 0.114 and 0.120 potatoes and fruit still to be valid. The ex mg/day for young children, older childre n, and adults, respectively (EFSA 2005). Exposure to fluoride from fruit juice, soft drinks, and mineral water was considered to be 0.011 and 0.065 mg F/day for younger and older children, respectively. The current assessment of exposu re to fluoride from drinking water is based on the EFSA concise database compiling the results of consumption surveys across European countries. However, this database is only for adult exposure. The mean consumption of water-based beverages, namely tap water, bottled water, soft drinks and stimulants, i.e. coffee, tea, cocoa, ranges from about 400 mL to about 1,950 mL with a median value of 1,321 mL/day/person. These figures are consistent with the default value for water consumption (2,000 mL/day) used by WHO. The value for total consumption of liquids t 700 mL/day/person at the lowest reported across European countries ranges from abou th percentile. These mean to about 3,800 mL/day/person at the highest reported 97.5 values show that due to human physiology and European climatic conditions, the total variability attributable to liquid consumption is close to a factor of 5. The exposure will thus mainly be driven by the level of fluoride in water for which the variability is about a factor of 30 (low fluoride levels in Germa ny vs. high fluoride levels in Finland). The major sub-categories of water-based beverages are soft drinks, bottled water, th percentiles for the consumption of a single stimulants, and tap water. The highest 97.5 category are 2,950, 2,400, 2,800 and 2,500 mL/d ay per adult respectively for tap water in Austria, stimulants in Denmark, soft drinks in Slovakia, and bottled water in Slovakia. th percentile for For each of these countries, the cons umption of one category at the 97.5 consumers only was summed with the mean co nsumption for the three other categories of water-based beverages for the whole po pulation. Total consumption ranged from 3,300 to 3,800 mL/day/person. Based on reported consumption of water-base d beverages, several scenarios have been developed. Scenario 1 corresponds to the median of mean consumption for all water- based beverages across European countries (1,321 mL) with the mean occurrence level of fluoride (0.1 mg/L). Scenarios 2 and 3 correspond to the highest consumption for high consumers of one of the relevant catego ries (3,773 mL) with the mandatory water fluoridation in Ireland (0.8 mg/L) (scenario 2) and the WHO guideline value for fluoride in drinking water (1.5 mg/L) (scenario 3). th percentile for Scenario 4 is a worst-case scenario based on the highest 97.5 consumption of tap water (2,950 mL in Austria) with the upper range for fluoride concentration (3.0 mg/L in Finland). Estimated fluoride expo sure from water-based beverages for adults and children (older than 15 years of age) in the different scenarios is shown in Table 2. 20

21 Fluoride and fluoridating agents of drinking water Adult and children (above 15 years of age) Table 2: systemic exposure to fluoride from water-based beverages*. Consumption Concentration of F Exposure Scenario (mL/day) (mg/day) (mg/L) 1 1,321 0.1 0.13 2 3,773 0.8 3.02 3 3,773 1.5 5.66 4 2,800 3.0 8.40 *Bottled mineral water was not included in these scenarios. Data on daily consumption of drinking wate r and other water-based products by children are sparse. The consumption data of drinking water and other water based products used by EFSA (2005) are from 1994 and seem to be low (under 500 mL for children less than 12 years old and under 600 mL/day for ch ildren aged between 12 and 15 years). Fluoride content of dental hygiene products In Annex III, part 1, of the amended Coun cil Directive 76/768/EEC related to cosmetic products, 20 fluoride compounds are listed, that may be used in oral hygiene products. The compounds which are most commonly inco rporated into toothpaste are sodium fluoride, sodium monofluoro-p hosphate and stannous fluori de. Other over-the-counter oral hygiene products containing fluoride include mouthwashes, chewing gums, toothpicks, gels and dental floss. These may contain up to a maximum of 1,500 mg F/kg (0.15% F). Toothpaste with lower fluoride content has been introduced onto th e market to reduce fluoride ingestion by young children in order to minimize the risk of fluorosis. However, there is no evidence for its caries-reducing effect. Toothpaste containing a higher concentration of fluoride ts with a high risk prescription for patien (more than 1,500 mg F/kg) is only available by of dental caries. It is estimated that in adults less than 10% of the toothpaste is ingested as the spitting reflex is well developed, whereas the estimated intake in children may be up to 40%. In children ingestion has been reported to be as high as 48% in 2 to 3 year olds, 42% in 4 year olds, 34 in 5 year olds, and 25% in 6 year olds. In children aged between 8 and 12 years, the ingestion is reported to be around 10% (Ellewood et al. 2008). The recommended quantity of toothpaste per a pplication is “pea size” (about 0.25 g), whereas the application corresponding to the length of the tooth brush head is considered a worst-case situation (0.75 g). Table 3: Estimated daily systemic fluoride exposu re from the use of common toothpaste on the EU market (10% or 40% systemic fluoride absorption). Systemic Systemic Type of Fluoride Total Amount fluoride fluoride used* fluoride toothpaste conc. absorption absorption (% F) (g/day) dose (mg /kg) (mg) 40% (mg) 10% (mg/day) 0.05 500 0.5-1.5 0.25-0.75 0.025-0.075 0.100-0.300 0.10 1,000 0.5-1.5 0.50-1.50 0.050-0.150 0.200-0.450 0.15 1,500 0.5-1.5 0.75-2.25 0.075-0.225 0.300-0.900 *Estimated toothpaste use with twice daily brushing. Prescribed fluoride supplements Prescribed fluoride supplements (tablets, lozenges, or drops) that are regulated as drugs case evaluation of s based on a case-by- may be recommended by qualified professional 21

22 Fluoride and fluoridating agents of drinking water th any prescribed drug, patient compliance is exposure to all other fluoride sources. As wi ements could be the source of up to 70% of a problem. It is estimated that fluoride suppl the reasonable maximum dietary exposure value in infants and young children (EFSA 2005). In addition, over the co unter fluoride suppl ement tablets, lozenges (from 0.25 to are available in some EU Member States. 1.0 mg) and fluoride containing chewing gums Dietary supplements and fluoridated salts /day would Calcium fluoride can be added as a dietary supplement: 1 mg CaF 2 correspond to 0.5 mg F/day, but due to the low bioavailability, the anticipated absorbed daily amount is estimated to be 0.25 mg F/day (EFSA 2008a). Sodium monofluorophosphate can be added as a dietary supplement: amounts between 0.25 and 2 mg fluoride per day have been cons idered to be safe (EFSA 2008b). Limits for the dietary supplements have not yet been set. ents was used in the integrated fluoride A value of 0.25 mg F/day from dietary supplem exposure assessment described below beca use it is highly unlikely that these supplements will be used in ar eas with fluoridated water, or that both food supplements are used at the same time. Many countries recommend the consumption of fluoridated salt and such products are available in at least 15 countries. The salt is fluoridated up to levels of 350 mg/kg. Figures about the proportion of fluoridated salt sold are available (Gotzfried et al. 2006). 4.2.2. Integrated exposure to fluoride from all major sources The ingested fluoride ion is readily absorbed, and it is assumed that all ingested fluoride ion is 100% bioavailable. In order to achieve an integrated fluori de exposure assessment from all sources previously discussed, water, food and toot hpaste are aggregated. Since the ingested d that there is 100% sy stemic bioavailability. fluoride ion is readily absorbed, it is assume Medicinal supplementation is not included in these assessments. Four scenarios were used for the current assessment of exposure to fluoride from drinking water based on the EFSA concise data base, compiling the re sults of consumption surveys across European countries (see Table 2). However, this database is only for adult exposure. EFSA (2005) considered the German background ex posure to fluoride from food based on intake of milk, meat, fish, eggs, cereals, vege tables, potatoes and fruit still to be valid. The fluoride concentration in food may be naturally present or acquired through food processing. In addition, EFSA (2008 a, 2008b) approved the addition of calcium fluoride sodium monofluorophosphate for nutritional purposes as a source of fluoride in food and by dietary supplementation to create supplemented foods. Oral hygiene products (mainly toothpaste) are a further variable source of fluoride depending on four variables; the fluoride concentration of the toothpaste, the quantity applied to the toothbrush, the number of ti mes teeth are brushed daily and the amount ingested after brushing and rinsing the teet h (see Table 3). The amount ingested after brushing is critical as it then becomes systemically available. Exposure of adults and children above 15 years of age Estimated fluoride exposures, from Table 2 for water-base d beverages for adults and children (older than 15 years of age) in th e different scenarios are used, and account for 18-95% of the total fluoride intake. The fluoride intake from food and supplem ented food with diet ary additives is 0.37 mg/day (0.12 mg/day food and 0.25 mg/d ay fluoride supplem ented food; EFSA 2005, an 1-6% of the total fluoride intake. EFSA 2008a, EFSA 2008b) and accounts for less th 22

23 Fluoride and fluoridating agents of drinking water For these scenarios, also factored is ~10% sy stemically available fluoride from “adult” 0.15% F toothpaste. Thus 0.075 mg F/day is systemically available from 0.5 g/day (low end) toothpaste application and 0.225 mg F/ day from 1.5 g/day (high end) toothpaste application. Table 4: The aggregated daily system ic exposure to fluoride (mg/day) for adults and children older than 15 years of age. beverages from the Column A Fluoride levels estimated in water and water-based scenarios in Table 2. Aggregated fluoride from water an d food (the sum of fluoride intake from Column B water given in Column A an d fluoride intake from food of 0.37 mg F/day). Aggregated fluoride from wate r (Column A), food (0.37 mg F/day) and Column C 0.075 mg F/day from toothpaste application (low end). Column D Aggregated fluoride from wate r (Column A), food (0.37 mg F/day) and 0.225 mg F/day from toothpaste application (high end). F intake from Aggregated F Aggregated F Aggregated F water intake intake intake (mg/day) (mg/day): (mg/day): (mg/day): water and water, food, water, food, food toothpaste toothpaste 0.075 mg F/d 0.225 mg F/d B Scenario A D C 1 0.13 0.50 0.58 0.73 2 3.02 3.39 3.47 3.62 3 5.66 6.03 6.11 6.26 9.00 4 8.40 8.77 8.85 All calculations are rounded to 2 decimal places. The upper tolerable intake limit (UL) for fluo ride (7 mg/day) for adults and children over in areas with high levels of natural fluoride in water, the age of 15 is only exceeded ults and children over the age of 15 living whereas the UL would not be exceeded for ad ridated drinking water. in an area with fluo Exposure of children under 15 years old This group is split into three age groups, children from 12-15 years old, children from 6- 12 years old and children from 1–6 years old. For all age groups, data were sparse and there was the additional factor of behavioural development. Calculations for the exposure to fluoride are performed for four different fluoride concentrations in water ranging from 0.1 mg/L to 3.0 mg/L. Since current data on water ble, the calculations are based on three consumption for this age group are not availa different levels of daily consumption of water: 0.5 L, 1.0 L, and 1.5 L. It must be noted that the EFSA estimates for total fluoride exposure of children in these age groups are limited, but were used to es timate the fluoride intake from food and supplemented food with dietary addi tives (EFSA 2005, EFSA 2008a, EFSA 2008b). The contribution from fluoride toothpaste is variable, depending on how well the spitting response is developed. When well developed, ~10% of the toothpaste (systemically available fluoride) is ingested and if not developed, ~40% of the toothpaste (systemically available fluoride) is ingested. The fluoride concentration of the toothpaste and the quantity of toothpaste applied to the toothbrush is critical. 23

24 Fluoride and fluoridating agents of drinking water Exposure of children (12-15 years of age) Estimates of total daily systemic exposure to fluoride for childre n from 12-15 years old d food with dietary are shown in Table 5. The fluoride intake fr om food and supplemente additives is estimated at 0.43 mg/day (0. 114 mg/day food, 0.065 mg/day water-based pplements; EFSA 2005, EFSA 2008a, EFSA beverages and 0.25 mg/day dietary su 2008b). The contribution from toothpaste is calculated for ~10% systemically available fluoride from “adult” 0.15% F toothpas and rinsing responses are well te only, since the spitting developed. Thus 0.075 mg F/d is systemic ally available from 0.5 g/day (low end) toothpaste application and 0.225 mg F/d from 1.5 g/day (high end) toothpaste application. to fluoride (mg/day) for children 12 Table 5: Aggregated total daily systemic exposure . up to 15 years of age Column A Fluoride intake from water at 0.1, 0.8, 1.5 and 3.0 mg F/L. Column B Aggregated fluoride intake fr om water (Column A) and food (0.43 mg F/day). Column C water (Column A), f ood (0.43 mg F/day) Aggregated fluoride intake from and systemically available fluoride (0.075 mg F/day) from the application of 0.15% F toothpaste (low end). Column D Aggregated fluoride intake from water (Column A), food (0.43 mg F/day) and systemically available fluoride (0.225 mg F/day) from the application of 0.15% F toothpaste (high end). F intake Aggregated Aggregated F intake (mg/day): Drinking water from F intake water, food, 0.15% toothpaste water (mg/day): Low application High application (mg/day) water and 0.075 mg F/day 0.225 mg F/day food A B C D 0.1 mg F/L 0.70 0.55 Consumption 0.5 L 0.05 0.48 Consumption 1.0 L 0.1 0.60 0.75 0.53 0.15 0.58 Consumption 1.5 L 0.80 0.65 0.8 mg F/L Consumption 0.5 L 0.4 0.83 0.90 1.00 Consumption 1.0 L 1.23 1.30 1.45 0.8 Consumption 1.5 L 1.2 1.63 1.70 1.85 1.5 mg F/L Consumption 0.5 L 0.75 1.25 1.40 1.18 1.5 1.93 Consumption 1.0 L 2.15 2.00 Consumption 1.5 L 2.25 2.68 2.75 2.90 3.0 mg F/L Consumption 0.5 L 1.5 1.93 2.00 2.15 Consumption 1.0 L 3.0 3.43 3.50 3.65 5.15 5.00 Consumption 1.5 L 4.5 4.93 24

25 Fluoride and fluoridating agents of drinking water 8 and 14 years is 5 mg/day extrapolated The estimated UL for children aged between from the UL for adults for whom the critical endpoint is an increased risk of bone fracture (EFSA 2005). This reference value was used for children aged 12-15 years despite the fact that not all molars will have erupted. The UL for children aged 12-15 years is only exceeded if 1.5 L water containing 3.0 mg F/L is consumed, and if 0.15% fluoride toothpaste and more than the recommend ed “pea size” application is used. The UL could be exceeded with additional exposure from tw o other sources: fluoridated salt as a condiment or in food preparatio n and/or from the consumption of bottled mineral water with high fluoride content. Exposure of children (1-12 years of age) The estimated total daily systemic exposure to fluoride for child ren between 6-12 years old and 1-6 years old is shown in Tables 6 nce current data on and 7, respectively. Si water consumption for children are sparse, the estimation of fluoride exposure is based upon water consumption at levels of 0.5 L, 1.0 L and 1.5 L. In warmer countries, the daily water consumption would be higher. The intake of fluoride from food is estimated to be 0.303 mg/day. This figure is the sum from the following sources: 0.042 mg/day from food; 0.011 mg/day from water based beverages; and 0.25 mg/day from fluorida ted dietary supplements(EFSA 2005, EFSA 2008a, EFSA 2008b). Due to different tooth brushing behaviours, i.e. spitting and rinsing responses, two different exposures were de veloped for children aged 6-12 years and 1-6 years, respectively. For children between 6 and 12 years old the contribution from toothpaste is ~10% systemically available fluoridebecause the spitting response is well developed. Both toothpaste for adults (0.15% F) and childre n (0.05% F) are considered. Thus for the “adult” toothpaste, 0.075 mg F/day is system ically available from 0.5 g/day (low end) toothpaste application and 0.225 mg F/da y from 1.5 g/day (high end) toothpaste application, whereas for the “children’s” toothpaste, 0.025 mg F/day is systemically te application and 0.075 mg F/day from 1.5 available from 0.5 g/day (low end) toothpas g/day (high end) toot hpaste application. Total daily systemic exposure to fluoride (mg/day) for children 6-12 years of Table 6: age. Column A Fluoride intake from wate r at 0.1, 0.8, 1.5 and 3.0 mg F/L. Column B Aggregated fluoride intake fr om water (Column A) and food (0.30 mg F/day). Column C Aggregated fluoride intake from water (Column A), f ood (0.30 mg F/day) and 0.025 mg F/day from the applic ation of 0.05% F toothpaste (low end). Column D Aggregated fluoride intake from water (Column A), f ood (0.30 mg F/day) and systemically available fluoride (0.075 mg F/day) from either the application of 0.05% F toothpaste (hig h end) or the application of 0.15% F toothpaste (low end). Column E Aggregated fluoride intake from water (Column A), f ood (0.30 mg F/day) (0.225 mg F/day) from the application and systemically available fluoride of 0.15% F toothpaste (high end). 25

26 Fluoride and fluoridating agents of drinking water Aggregated F intake: F Aggregated Aggregated Drinking water water, food, 0.05% intake F intake: F intake toothpaste from water, from water water food, and food 0.15% toothpaste 0.025 mg 0.225 mg 0.075 mg F/day F/day F/day A B C D E 0.1 mg F/L 0.05 0.35 0.38 0.43 Consumption 0.5 L 0.58 Consumption 1.0 L 0.40 0.43 0.48 0.63 0.1 0.15 0.48 0.53 0.68 Consumption 1.5 L 0.45 0.8 mg F/L 0.4 0.70 0.73 0.78 0.93 Consumption 0.5 L Consumption 1.0 L 0.8 1.13 1.18 1.33 1.10 1.2 Consumption 1.5 L 1.53 1.58 1.73 1.50 1.5 mg F/L 0.75 1.28 Consumption 0.5 L 1.13 1.05 1.08 Consumption 1.0 L 1.5 1.83 1.88 2.03 1.80 2.25 2.58 2.63 2.78 Consumption 1.5 L 2.55 3.0 mg F/L 1.5 1.80 1.83 1.88 2.03 Consumption 0.5 L 3.0 Consumption 1.0 L 3.33 3.38 3.53 3.30 Consumption 1.5 L 4.80 4.83 4.88 5.03 4.5 The UL for children aged between 4 and 8 years is 2.5 mg/day based on a prevalence of less than 5% of moderate de ntal fluorosis as the critic al endpoint (EFSA 2005). This value was used as the reference value for th e children aged 6-12 years. Thus the UL for if 1.5 L water containing 1.5 mg F/L is children in the 6-12 years category is exceeded consumed, independent of tooth-brushing behaviour. The spitting response is not well developed in children aged between 1 and 6 years and ~40% systemic fluoride availability from toothpaste will be used. Toothpastes for children (0.05% F) and for adults (0.15% F) are considered. Thus, for the 0.05% F toothpaste, 0.1 mg F/day is systemically avai lable from 0.5 g/day (low end) toothpaste application and 0.3 mg F/day from 1.5 g/day (high end) toothpaste application. For the 0.15% toothpaste, 0.3 mg F/day is systemically available from 0.5 g/day (low end) toothpaste application and 0.9 mg F/day from 1.5 g/day (high end) toothpaste application. Estimate of total daily systemic exposure to fluoride for children 1 up to 6 years Table 7: of age. Column A Fluoride intake from wate r at 0.1, 0.8. 1.5 and 3.0 mg F/L. Column B Aggregated fluoride intake from water (Column A) and food (0.30 mg F /day). Column C Aggregated fluoride intake from water (Column A), food (0.30 mg F /day) and from the application of 0.05% F toothpaste (0.10 mg F /day) low end 26

27 Fluoride and fluoridating agents of drinking water Aggregated fluoride intake from water (Column A), food (0.30 mg F /day) Column D (0.30 mg F/day) from either the and systemically available fluoride application of 0.05% F toothpaste (hig h end) or the application of 0.15% F toothpaste (low end). Column E water (Column A), food (0.30 mg F /day) Aggregated fluoride intake from and systemically available fluoride (0.9 mg F/day) from the application of 0.15% F toothpaste(high end). F Aggregated Aggregated F intake: Aggregated Drinking water intake F intake water, food, 0.05% F intake: from from water toothpaste water, water and food food, 0.15% toothpaste 0.90 mg 0.30 mg 0.10 mg F/day F/day F/day A B C D E 0.1 mg F/L 0.05 0.45 0.65 1.25 Consumption 0.5 L 0.35 0.1 0.40 0.50 0.70 Consumption 1.0 L 1.305 Consumption 1.5 L 0.45 0.55 0.75 1.35 0.15 0.8 mg F/L Consumption 0.5 L 0.4 0.70 0.80 1.00 1.60 1.40 1.10 Consumption 1.0 L 0.8 2.00 1.20 Consumption 1.5 L 1.2 1.80 2.40 1.50 1.60 1.5 mg F/L 0.75 1.05 1.15 1.35 1.95 Consumption 0.5 L 1.5 1.80 1.90 2.10 2.70 Consumption 1.0 L 2.25 2.55 2.65 2.85 3.45 Consumption 1.5 L 3.0 mg F/L 2.10 1.5 1.80 1.90 2.70 Consumption 0.5 L Consumption 1.0 L 3.0 3.40 3.60 4.20 3.30 4.5 Consumption 1.5 L 4.90 5.10 5.70 4.80 The estimated UL for children under 3 years ol d is 1.5 mg/day based on a prevalence of less than 5% of moderate de ntal fluorosis as the critic al endpoint (EFSA 2005) and was used for children aged between 1-6 years. Thus if more than 1.0 L , the UL is exceeded water containing 0.8 mg F/L is consumed and tooth-brushing with the 0.15% fluoride toothpaste is included. If 1.5 L of water is consumed at this fluoride concentration, the UL is exceeded even withou t exposure to toothpaste. Exposure of infants up to 12 months of age Many infants are fully or partially breast fed during the early months of life. Fluoride intakes by fully breast-fed infants are low, but fluoride intakes by partially breast-fed infants and by formula-fed infants are differe nt. This depends primar ily on the fluoride are the infant formula products. content of the water used to prep For infants, up to the age of 6 months, the main food source is milk, either solely breast milk or formula or a combination of both. Since the fluoride content of breast milk is low 27

28 Fluoride and fluoridating agents of drinking water g/L), exposure to fluoride in breast-fed infants is low (less than 0.001 mg/kg/day). μ (~6 fluoride intake depending on infant’s feeding pattern. Table 8 shows the wide range of Table 8: from formulas (simplified from Estimated systemic fluori de exposure of infants Fomon and Ekstrand (1999). Infant formula Fluoride intake mg/kg/day Drinking water F conc. mg/L F conc. as fed Formula intake Formula intake Formula intake 170 formula mg/L* 150 120 ** ** ** mL/kg/day mL/kg/day mL/kg/day 0.1 0.20 0.03 0.03 0.02 0.8 0.80 0.14 0.12 0.10 1.5 1.42 0.24 0.21 0.17 3.0 2.74 0.47 0.41 0.33 *Assumes that 145 g of formula with a fluoride concentration of 0.7 mg/kg is diluted with 880 mL of drinking water to make 1 litre of formula. **Mean energy intakes are approximately 114 kcal/kg/day from birth to 2 months of age and 98 kcal/kg/day from 2 to 4 months. An exclusively formula-fed infant consuming 667 kcal/L formula will therefore consume approximately 0.17 L/kg/day from birth to 2 months of age and approximately 0.15 L/kg/day from 2 to 4 months. The fluoride concentration of the water is the main exposure source in formula-fed formula prepared using water containing 0.8 infants. An infant solely fed with an infant mg F/L ingests 0.137 mg F/kg/day compared with 0.001 mg F/kg/day for an infant who of the fluoride intake of infants between 6 is solely breast fed. An accurate assessment and 12 months old has not been addressed as such calculations would be full of assumptions, considering the variability of the different feeding patterns of infants in the EU Member States. Tolerable upper intake levels for fluoride have not been established for infants (EFSA 2005). For infants up to 6 months old, the UK DoH (1994) concluded that 0.22 mg F/kg BW/day was safe, while the US IOM (1999) de rived an UL for fluoride of 0.1 mg/kg BW/day. Conclusion 4.2.3. Fluoride in drinking water is the major sour ce of fluoride in the general population. However, in children aged between 2 and 6 years the contribution from the use of fluoridated 1,500 mg/kg toothpaste (1.5% fluo ride) can account for up to 25% of the total systemic dose. As the water fluoride co ncentration increases, the percentage of the daily systemic exposure from fluoride in toothpaste decreases. As a worst case scenario, (using 0.15% F toothpaste and unsupervised the daily exposure would be less than 40% application), and if application is supervised and 0.05% F toothpaste is used, the daily exposure would be less than 10% of systemic fluoride from other sources. There are no data of sufficientl y high quality on sources and le vels of fluoride to perform a full uncertainty analysis within the European context. The exposure assessment is very conservative both with respect to the level of fluoride in water either naturally present or artificially added, and the consumption data are based upon 95% of the highest intake of any water-based beverage. 4.3. Question 1-c1 fluoride in tooth decay prevention and To evaluate the evidence of the role of rank the various exposure situations as to their effectiveness in offering a potential tooth decay preventive action. 28

29 Fluoride and fluoridating agents of drinking water 4.3.1. Mechanism of fluoride action in caries prevention Fluoride treatment regimens have been developed to prev ent dental caries. Systemic fluoride is easily absorbed and is taken up into the enamel during the period of pre- eruptive tooth formation. The predominant bene ficial cariostatic effe cts of fluoride in erupted teeth occur locally at the tooth surface. This could be achieved by fluoridated toothpaste, fluoride-containing water, fluoridated salt, etc. maintaining elevated intra- oral fluoride levels of the teeth, dental biofilm and saliva throughout the day. 4.3.2. Dental health and fluoridation Figure 2 indicates that inde pendent of the fluoridation policies across the EU Member States, there has been a cons istent decline over time in tooth decay in 12 year old children from the mid-1970s, regardless of whet her drinking water, milk or salt are fluoridated. Figure 2 – Trends in tooth decay in 12 year olds in European Union countries (from Cheng et al. 2007). le error regarding the figures from Germany It should be noted that there is a probab because the data were collected during the unification peri od. Moreover water fluoridation was not practised in West Germa ny, and in East Germany only in certain regions and intermittently. Therefore, Germany should be placed under “no water- fluoridation”. A vast number of clinical studies have conf irmed that topical fluoride treatment in the form of fluoridated toothpaste has a signif icant cariostatic effect. Other preventive regimens include fluoride su given during the period of pplement and fluoridated salt tooth formation. In the 1970s, fluoridation of community drinking water, aimed at a particular section of the population, namely children, was a crude but useful public health measure of systemic fluoride treatment. However, the caries preventive effect of systemic fluoride treatment is rather poor (Ismael and Hasson 2008). In countries not using water fluoridation, impr oved dental health can be interpreted as the result of the introduction of topical fluoride preventive treatment (fluoridated toothpaste or mouth rinse, or fluoride treatments within the dental clinic). Other preventive regimens include fluoride supplements, fluori dated salt, improved oral any change that may result or care system practices, or hygiene, changes in nutrition 29

30 Fluoride and fluoridating agents of drinking water these countries. This suggests that water from improved wealth and education in fluoridation plays a relatively minor role in the improvement of dental health. The role of fluoride on dental health has b een demonstrated by co mparing the efficiency of naturally occurring low and high fluoride co ncentrations in tap water to prevent dental caries. A recent study showed an inverse a ssociation between fluoride concentration in and dental caries in both pr imary and permanent teeth in non-fluoridated drinking water ely 20% at the lowest level of fluoride Denmark. The risk was reduced by approximat less than 0.125 mg, and the reduction was exposure (0.125-0.25 mg/L) compared to approximately 50% at the highest level of fluoride exposure (more than 1.0 mg/L) (Kirkeskov et al. 2010). The data were adjusted for socio-economic factors. Water fluoridation ve a beneficial effect , but the range could Water fluoridation was considered likely to ha be anywhere from a substantia l benefit to a slight risk to children's teeth with a narrow margin between achieving the ma ximal beneficial effects of fl uoride in caries prevention and the adverse effects of dental fluorosis (McDonagh et al. 2000). s that fluoridation of drin king water reduces caries The available evidence suggest prevalence, both as measured by the propor e caries free and by tion of children who ar the mean change in dmft/DMF T score (decayed, missing and filled deciduous –dfmt– or 1 rate quality (UK-CRD 2003), . The studies were of mode permanent –DFMT– teeth) supported by a Canadian review (Locker 1999), wi th the addition that the effect tends to be more pronounced in the deciduous dentit ion. The few studies of water fluoridation discontinuation do not suggest signif icant increases in dental caries. The effect of water fluoridation tends to be maximized among children from the lower socio-economic groups, so that this sect ion of the population may be the prime beneficiary. There appears to be some evid ence that water fluoridation reduces the inequalities in dental health across social classes in 5 and 12 year-olds, using the in the proportion of caries-free children dmft/DMFT measure. This effect was not seen among 5 year-olds (McDonagh et al. 2000). In a recent review, Health Canada has concluded that the optimal concentration of fl uoride in drinking water for dental health was 0.7 mg/L ( http://www.hc-sc.gc.ca/ewh-semt/alt_formats/hecs- sesc/pdf/consult/_2009/fluoride-fluorure/consult_fluor_water-eau-eng.pdf ). In a study of students (16-year olds) living on the border between th e Republic of Ireland (fluoridated water) and Northern Ireland (non-fluoridated water) it was found that some perience among the adolescent s was explained by parental of the variance in decay ex employment status. The higher decay experi ence in lower socio-economic groups was more evident within the non-fluoridated grou p, suggesting that wa ter fluoridation had reduced oral health disparit ies (CAWT 2008). Similarly, Truman et al. (2002) and Parnell et al. (2009) concluded that water fluoridation is effective in reducing the cumulative experience of dental caries wi thin communities, and that the effect of water fluoridation tends to be maximized among children fr om the lower socio-economic groups. offers additional benefits over alternative topical methods Furthermore water fluoridation because its effect does not depe nd on individual compliance. The benefits of water fluoridation for adult an terms of reductions d elderly populations in in coronal and root decay are limited (Seppä et al. 2000a, Seppä et al. 2000b). Fluoridated foods and dietary supplements There is no consistent information on the e fficiency of fluoridate d milk compared with non-fluoridated milk on dental health. For permanent teeth, after 3 years there was a significant reduction in the prevalence of DMFT (78.4%, p<0.05) between the test and control groups in one trial, but not in the other. The latter study only showed a significant 1 e number of teeth with carious lesions, the number DMFT/dmft score is calculated from the observation of th of extracted teeth, and the number of teeth with fillings or crowns. 30

31 Fluoride and fluoridating agents of drinking water reduction in the prevalence of DMFT until the fourth (35.5%, p<0.02) and fifth (31.2%, p<0.05) years. For primary teeth, again ther e was a significant reduction in the DMFT (31.3%, p<0.05) in one study, but not in the other. The studies suggest that milk al in the prevention or reduction of caries especia fluoridation is benefici lly in permanent dentition, but the available data are too limited to reach a conclusion (Yeung et al. 2005). However, recent studies have concluded th at milk fluoridation may be an effective method for preventing dent al caries. (AU-NHMRC 2007). The effectiveness of fluo ride supplemented foods ha s not been investigated systematically. The effectiveness of salt fluori dation at reducing de ntal caries has been assessed in cross-sectional studies in Mexico , Jamaica and Costa Rica. These studies are all considered of simplistic methodological quality. However, the data suggest that salt fluoridation reduces ca ries in populations of children aged 6-15 years (AU-NHMRC 2007). Several studies from Switzerland suggest that the decline in caries after introduction of fluoridated salt is not drasti tained by introducing dental cally different from the one ob hygiene in schools (Marthaler 2005). The benefits of preventive sy stemic supplementations (salt or milk fluoridation) are not istent evidence that the use of fluoride proven. There is also only weak and incons supplements prevents dental caries in primar y teeth. Available evid ence indicates that such supplements prevent caries in perman ent teeth, but mild to moderate dental fluorosis is a significant side effect. (Ismail and Hasson 2008). Topical fluoride treatments Topical application of fluoride in the oral ca vity has two advantages: a) application at the site of action; and b) reducing the systemic exposure since in subjec ts with an adequate spitting response, only a percentage (adult s 10%, young children 40%) of the fluoride applied becomes systemically available. The effectiveness of topical fluoride treatments (TFT), i.e. fluoride varnish, gel, mouth al health have been compared (Marinho et al. 2002, Marinho rinse, or toothpaste on dent et al. 2003a, Marinho et al. 2003b, Marinho et al. 2003c, Ma rinho et al. 2004a, Marinho s were made with a placebo treatment in et al. 2004b, Salanti et al. 2009). Comparison children between 5 and 16 years old for at le ast 1 year. The main outcome was caries ge in decayed, missing and filled tooth surfaces. There increment measured by the chan was substantial heterogeneity, but the directio n of effect was consistent. The effect of topical fluoride varied accordin g to the type of control group used, the type of TFT used, mode/setting of TFT use, initial caries levels and intensity of TFT application, but was not or other fluoride sources. Supervised use of influenced by exposure to water fluoridation self-applied fluoride in children increases the benefit. The relative effect of topical fluoride may be greater in those who have higher ba seline levels of D(M)FS. These results are clearly in favour of a beneficial effect of to pical fluoride treatment. There was no evidence of adverse effects of topical fluoride treatm ents (Marinho et al. 2003b). The authors did not consider analyses on specific time-windows or by regions. The same authors also found that the combin ed regimens achieved a modest reduction (10%; 95% CI: 2-17%) of dental caries compared with toothpaste used alone (Marinho at any topical fluoride modality is more et al. 2004a). There was no clear evidence th effective than any othe r (Salanti et al. 2009). The AU-NHMRC (2007) and a group of Swedish scientists (Petersson et al. 2004, Twetman et al. 2004) carried out addi tional reviews on the to pic. The results do not challenge the above conclusions. point out that long-t erm studies in age groups other et al. (2004) However, Twetman than children and adolescents are still lacking. 4.3.3. Conclusion Water fluoridation as well as topical fluoride applications (e.g. fluoridated toothpaste or 31

32 Fluoride and fluoridating agents of drinking water ily on permanent dentition. No obvious varnish) appears to prevent caries, primar tion compared with topical prevention. The advantage appears in favour of water fluorida effect of continued systemic ex posure of fluoride from whatever source is questionable once the permanent teeth have erupted. SCHER agrees that topical application of fluoride is most effective in preventing tooth decay. Topical fluoride sustains the fluoride levels in the oral cavity and helps to prevent caries, with reduced systemic av pulation-based policies, e.g. ailability. The efficacy of po drinking water, milk or salt fluoridation, as regards the reduction of oral-health social disparities, remains insu fficiently substantiated. 4.4. Question 1-c2 To pronounce itself as to whether there may be reasons for concern arising from the exposure of humans to fluoride and if so identify particular exposure scenarios that may give rise to concern in particular for any particular population subgroup. Fluoride is not essential for human gr owth and development. EFSA (2005) has established upper tolerable intake levels of 1.5 and 2.5 mg fluoride/day based upon the induction of moderate dental fluorosis as the critical endpoint for effect for children aged 1-3 years and 4-8 years, respectively. The estimated UL for children between 9 and 14 years is 5 mg/day extrapolated from the adult to lerable intake level. An UL of fluoride for adults of 7 mg/day was established using increa sed risk of non-verteb ral bone fracture as the critical endpoint (EFSA 2005). There are no new scientific data th at justify changi ng these values. Based upon the exposure scenarios discussed in 4.2.2 for infants, children, and adults d beverages, food, food supplement and the and the intake of fluoride from water-base use of toothpaste, the UL was only exceeded in the worst case scenarios. Water-based beverages were the major fluo ride sources and healthy adults and children over 15 years, consuming large quantities of drinking water (more than 3 L) and living in areas with high natural concentrations of fluoride (more than 3.0 mg/L) exceeded the UL. The contribution of fluoride from toothpaste was significant in children due to ingestion of a large proportion of the toothpaste used ( 40% absorption), thus for healthy children under the age of 15, the combin ation of high levels of fluoride in water and high water consumption would result in fluoride intakes that greatly exceed the ULs for the respective age groups. Children and adults when living in areas with fluoridated drinking water (less than 0.8 mg/L) did not exceed the UL under normal consumption and usage. The UL for children 6-12 years old is exceeded if more than 1.0 L water containing 1.5 mg F/L is consumed and tooth-brushing with the 1.5% fluoride toothpaste is unsupervised. For children aged between 1-6 years, the UL is exceeded if more than 1.0 L water containing 0.8 mg F/L is consumed and tooth-brushing is carried out with the 0.15% fluoride toothpaste. If 1.5 L of water is consumed at this fluoride concentration, the UL is posure to toothpaste. exceeded even without ex The UL for children between 12-15 years of age is exceeded if 1.5 L water containing 3.0 mg F/L is consumed, and if regular 1,500 mg/kg fluoride toothpaste and more than the recommended “pea size” application is used. In these older children, the spitting and rinsing response is better develo ped, so that ~10% of the fl uoride present in toothpaste becomes systemically available. A special concern is for groups that have a high intake of supplemented food containing fluoride, e.g. sodium monofluo rophosphate, and who are livi ng in areas where the level of fluoride in drinking water is higher than 1 mg/L. The susceptibility to develop dental fluorosi s depends on the timing of the systemic rculating fluoride by developi ng teeth. Other subpopulations exposure and the uptake of ci 32

33 Fluoride and fluoridating agents of drinking water uoride exposure includ susceptible to adverse effects of systemic fl e the elderly, with nutritional and metaboli c deficiencies as these may alte r bone composition leading to skeletal fluorosis. There is no strong eviden ce that fluoride exposu re in sub-populations with endocrine disorders (diabetes, thyroid dysfunction) have an increased risk for adverse health effects. Conclusion SCHER agrees that for adults and children over the age of 12 years the total intake of fluoride from all major sources is below the upper tolerable intake level (UL) in most parts of EU including areas wi th fluoridated drinki ng water, except for those living in 3 mg/L) and uoride at high concentrations (above areas with water naturally containing fl water-based beverages. with a high intake of SCHER concludes that for child ren aged between 6-12 years, the UL is not exceeded if the water consumption is less than 1.0 L/day for children living in areas with fluoridated water (below 1.5 mg/L) and using regular fl uoridated toothpaste. For children between 1- 6 years old the UL is exceeded if they co nsume more than 0.5 L a day, and use more than the recommended quantity of regular fluoridated toothpaste. There is no UL for infants up to 12 months of 8, when the fluoride age. As shown in Table concentration in drinking water is above 0.8 mg/L, the exposure to fluoride is estimated to exceed 0.1 mg/kg/day. This amount is 200 times higher than the amount found in breast milk. 4.5. Question 1-d that needs to be done in order to fill Identify any additional investigative work data gaps in the hazard profile, the health effects and the exposure assessment of fluoride. Fluoride in drinking water has been shown to have a beneficial effect on caries prevention, but could also induce enamel fluorosis within a very narrow margin of exposure, and the adverse effect depends on the period of exposure – windows of susceptibility. Several other adverse health effects have been postulated to be due to fluoride exposure, i.e. osteosarcoma, developmental neurotoxicity, and reproductive toxicity. However, most of the information on these endpoints is of limited quality with inaccurate exposure information, and the observed effects occur only at high exposure levels not relevant for the European situation. Additional research on potential adverse heal th effects at realistic EU exposure levels may provide new data to support the risk assessment process. Exposure assessment is the critical step for health effect studies, t hus it is recommended to: 1) Develop and validate new biomarkers for long-term fluoride exposure. 2) Develop standardized methods for exposure assessment integrating all routes of exposure. 3) Collect information on fluoride in food and bioavailability of fluoride. 4) Conduct epidemiological studies, taking advantage of the existing mother-child cohorts to investigate the role of fluoride intake on incidence of dental fluorosis and dental health. 4.6. Question 2 Assess the health and environmental risks that may be associated with the use of the most common drinking water fluoridation agents such as silicofluorides (e.g. (hydro)fluorosilicic acid, sodium silicofluoride, disodium hexafluorosilicate 33

34 Fluoride and fluoridating agents of drinking water or hexafluorosilicate or hexafluorosilicic acid) taking into account their hazard profiles, their mode of use in water fluoridation, their physical chemical behaviour when diluted in water, and the possible adverse effects they may have in exacerbating fluoride health effects as reported in some studies. Introduction 4.6.1. The adverse effects of the benefits for dental health fluoride exposure in humans and have been discussed in sections 4.1 and 4. will not be discussed 4, respectively and further. in drinking water due As already indicated in section 3.1, the presen ce of fluorosilicates id or hexafluorosilica te for fluoridation, if any, is very low to the use of hexafluorosilicic ac as fluorosilicates and other species are ra pidly hydrolyzed in water to fluoride. Therefore, this environmental risk assessment will focus only on the fluoride ion. fluorides occur naturally and are ubiquitous; natural As indicated in section 3, compartments and geological circumstances. background levels vary with environmental nment from human activities besides the fluoridation of Fluorides also enter the enviro m, the production of some drinking water. These can invo lve the production of aluminiu building bricks, and the production and use of fertilizers. Hence SCHER interprets this part of the requ est as follows: to what extent does the fluoridation of drinking water specifical ly lead to adverse ecological impacts? If there were detailed information on exposure and physico-chemical conditions available this approach would therefore consider the extent to which fluoridation adds to the natural background, taking account of regional variations. It should also possibly take nds that integrate both natural and human account of continental and regional backgrou sources. It would not consider the extent to which fluoridation might add to other anthropogenic sources at specific sites (e .g. point source emissions from aluminium smelting or diffuse emissions from agricultural use of fertilizers). The scenario of interest will therefore focus on the environmental exposures arising water, personal hygi ofrom the use of fluoridated water as drinking ene, washing clothes and washing dishes. Most of this flows to the environment in drainage water and via ider losses due to leakages from water sewage treatment works. SCHER did not cons supply pipes and from the use of tap water in irrigation, and therefor e soil contamination, ll documented. However, we have focussed on the losses since these outputs are not we through sewage treatment works. In this rout e most of the fluoride s remain in solution during sewage treatment and pass to the aq uatic environment in this way (Walton and Conway 1989). Therefore a negligible amount ss to the terrestrial of fluorides may pa environment if sludge is spread on land; and/or to atmosphere and land if sludge is subjected to incineration. In the aquati c environment water chemistry will drive distribution between water and sediments. Based on the phys ico-chemical characteristics of fluoride it is expected that the contamination of soil and the atmosphere are very electronegative chemic limited. Fluoride is the most al in the Periodic Table and is highly reactive. Hence in the aquatic environment fluorides are likely to occur as the fluoride is will be the focus of the exposure and anion (Walton and Conway 1989) and therefore th effect assessments for the aquatic ecosystems. ent effectively would have requ ired detailed information on To carry out this risk assessm ambient exposures and physico-chemical condit ions at sites where water is fluoridated. Hence as a pragmatic approach SCHER has assumed further: (1) that the fluoride concentrations in waters used as a source of drinking water reflect local background concentrations; and (2) that those authoritie s that practice fluoridation would not add fluoride if these background levels exceed ed the legally-specified concentrations for in the EU. Hence worst case fluoride in water for human consumption of 1.5 mg/L environmental exposure concentrations will be equal to these legally-specified maxima. On that basis SCHER has used the legally defined concentration for Ireland (0.8 mg/L) and the WHO standard (1.5 mg/L) as approp riate total exposure levels – see section 34

35 Fluoride and fluoridating agents of drinking water (scenario 3 in the human he 4.2.1. The value of 3.0 mg/L alth assessment – see section 4.2.1) has not been used in this environm ental assessment since this was based on is no added environmental risk here. Finally, natural concentrations in Finland – i.e. there crease in concentrations of lead from the indirect side effects, such as the possible in action of fluoride in lead water pipes (section 3.1) ar e not considered since these scenarios are speculative and difficult to anticipate. - should be considered as the Therefore, SCHER is of the opinion that: 1) fluoride as F only acting agent; 2) the only source of fluoride in this opinion is the application of fluoride in water supply system s and other sources of fluoride are excluded with respect to potential effects in the environment; 3) as a pragmatic approach it is assumed that the worst-case exposure from fluoridation will be no greater than the allowed legal limits; and 4) the focus of attention for the risk a ssessment should be the aqueous phase of the aquatic environment. The physico-chemical properties are mentioned in section 3.2. 4.6.2. Mechanism of action Fluorides are not essential for most organisms. However, there is evidence that at low lation growth rates of some aquatic algal concentrations fluorides can enhance the popu species (Camargo 2003). Some algae are able to tolerate fluoride levels as high as 200 - /L. mg F The adverse effects of fluoride on organisms seem to ar ise from the disruption of key metabolic pathways through the impairment of enzymes, including those involved in nucleic acid synthesis. However, the me chanistic details are as yet unclear. In fish and invertebrates, fluoride toxicity decreases with increasing calcium and chloride concentrations in the water. The decrease of toxicity with calcium is mainly due to the F, CaF (PO . An ) and MgF formation/ precipitation of innocuous complexes such as Ca 3 5 2 4 2 increase in the concentration of chloride io ns might elicit a response in organisms for fluoride excretion. Based on observations in natural media, Camargo (2003) concluded l and genetic adaptation to high fluoride that it should be evident that physiologica concentrations can occur in wild fish populations. 4.6.3. Aquatic effects The analysis of the aquatic effects was based on a bibliographic search. From this it covered most of the relevant studies appeared that the review of Camargo (2003) validated by the SCHER. Given the good qu ality of this review, SCHER has therefore based much of the following analysis of the effects on the information cited in this review . Additional information from field studie s (Sigler and Neuhold 1972) did not lead to a conclusive safe level. SCHER concluded that the review of Ca margo offered sufficient information of good quality to perfor m a risk assessment for the environment . Fish Freshwater Acute effects The most valid data available (96h tests with measured conc entration) were reviewed by Camargo (2003) and Metcalfe-Smith et al . (2003). The most sensitive fish was . In worst case soft water conditions (total hardness of 17 mg Oncorhynchus mykiss (Camargo 2003). /L) the LC 96h was 51 mg/L fluoride ion CaCO 50 3 Chronic effects (2009) found the lowest NOEC in fish in 90 Among valid data in the literature, Shi et al. - /L (measured). days in Acipenser baerii (sturgeon): 4 mg F 35

36 Fluoride and fluoridating agents of drinking water Marine water Despite of a generally protective effect of chloride ions, Camargo (2003) listed some toxicity data in his review, wh ich were taken as worst case. Acute effects 96h more than 500 mg/L (NOEC lethality 500 mg/L). Cyprinodon variegatus : LC 50 Chronic effects Mugil cephalus: NOEC 113d on juvenile development = 5.5 mg/L. Invertebrates Freshwater Acute effects A large number of valid toxicity values in invertebrates at 48h were described in mith et al. (2003). The most sensitive species was an Camargo (2003) and Metcalfe-S - 48h of 14.6 mg F /L (measured concentrations) amphipod: Hyalella azteca, with an EC 50 /L (Metcalfe-Smith et al. 2003). with hardness 140–150 mg CaCO 3 Chronic effects - 28d of about 4 mg F /L on Hyalella azteca Metcalfe-Smith et al. (2003) found an IC 25 growth (calculated from the article data on controlled concentration in spiked sediment and overlaying water). Marine water Acute effects - ions, Camargo (2003) reported some toxicity Despite the general protective effect of Cl - 96h being 10.5 mg F /L in the arthropod Mysidopsis bahia . data, the lowest EC 50 Chronic effects and Camargo (2003) reported that the female fecundity of Grandidierella lutosa lignorum estuarine amphipods was shown to be the most sensitive endpoint in a 90 day life-cycle - /L. It is test, with a maximum allowable toxicant concentration (MATC) of 4.15 mg F - was observed to stimulate female fecundity. noticeable that below this value, F Algae Freshwater Acute effects According to Camargo (2003), among algae species for which growth was not stimulated - Selenastrum 96h was shown to be 123 mg F /L in by fluoride ions, the lowest EC 50 capricornutum. Chronic effects Scenedesmus quadricauda In the same species selection, growth of an algae species with sensitivity generally similar that of was shown not to be Selenastrum capricornutum, - . /L in 175h This value can therefore be taken as worst case NOEC inhibited by 50 mg F for algae. Marine water Acute effects s are less sensitive to fluoride ions. The As a general observation marine algal specie 36

37 Fluoride and fluoridating agents of drinking water - lowest EC 96h value of 82 mg F /L was shown in Skeletonema costatum . 50 Chronic effects riments with marine algae cited in Camargo (2003), the In the chronic exposure expe lowest tested concentrations of fluoride wa s 50 mg/L, and the duration was more than 16 on was observed. At 100 mg/L, days. For algae tested at this concentration, no inhibiti t at most at 30%. Therefore 50 mg/L can be the growth of some species was inhibited, bu taken as worst case NOEC 72h for algae. Conclusion on effects ta as presented in Table 11 and considered SCHER agreed to use the ecotoxicological da these data sufficiently reliable to be acce pted and used in the risk assessment for the environment. From this data set based on the most sensitive taxa, it is evident that r sensitivity. Therefore, the PNEC for both freshwater and marine organisms are of simila freshwater and marine wate r was derived from the whol e data set, applying an Assessment Factor (AF) of 10 to the lowest NOEC. (SCHER and its predecessor do not accept the additional safety factor of 10 from freshwater to marine water stated in the TGD). The most sensitive trophic level is the invertebrate one. The chronic toxicity in (juvenile growth). As the raw data set is not is expressed as IC Hyalella azteca 25 available in the publication, it is not possible to check if this value is close to the LOEC or NOEC. Therefore the data were not used to avoid excessive uncertainty. The chronic toxicity in Grandidierella sp, very close to the latter value, was used. It is expressed as MATC (female fecundity), from which an NO EC can be derived according to the REACH guidance (MATC/ √ 2). The PNEC such derived is 0.29 mg/L. However, this value has to be discussed in the light igo-element. Camargo (2003) reported from of fluoride ion character as essential ol Connell and Airey (1982) that fluoride concentration belo w the defined 4.15 mg/L MATC might stimulate Grandidierella sp female fecundity. It is also likely that in most of organisms, fluoride ions stimulate growth and reproduction as essential element. Therefore, using a PNEC such derived has no real meaning, as concentrations below toxic concentrations are considered beneficial. In such a view, Camargo (2003) suggested to use ecologically relevant sensitive endpoints as direct quality levels for safe life in freshwater. Net-spinning caddisf ng adult salmons, living in ly larvae and upstream-migrati found to be the most sensitive organisms, soft waters with low ionic content, were affected by fluoride concentrations higher than 0.5 mg/L. So it is assumed that concentrations lower than this threshol d are safe for these extremely sensitive organisms, and therefore for aquatic ecosystems. Table 11: Summary of effect data for fluoride in mg/L. Value (mg/L) ndpoint Organism E Freshwater Fish (acute) ( Oncorhynchus mykiss) LC 51 (96 h) 50 Invertebrates (acute) ( Hyalella azteca ) EC (96 h) 14.6 50 ) EC Algae (acute) ( Selenastrum capricornutum 123 (96 h) 50 Freshwater Fish (chronic) ( Acipenser baerii ) NOEC (90 d) 4 Invertebrates (chronic) ( Hyalella azteca ) EC 4 (28 d) 25 NOEC (16 d) 50 Algae (chronic) several species Marine water Fish (acute) ( Cyprinodon variegatus ) LC (96 h) more than 500 50 10.5 (48 h) Invertebrates (acute) ( Mysidopsis bahia ) LC 50 37

38 Fluoride and fluoridating agents of drinking water Skeletonema costatum ) EC Algae (acute) ( (96 h) 82 50 Marine water ) NOEC (113 d) 5.5 Mugil cephalus Fish (chronic) ( NOEC (90 d) = ) Invertebrates (chronic) ( 2.9 Grandidierella sp. √ 2 MATC/ Algae (chronic)several species NOEC ( ≥ 16 d) 50 No-effect in both waters PNEC 0.29 Risk characterization tion can be carried out by a A simplistic risk characterisa ssuming that the fluoridation level is 1 mg/L, that all domestic waters entering sewage treatment works contain is flows through the system. This means that fluoride at this level and that most of th tration in a typical output would be no more than 1 mg/L worst case fluoride ion concen due to fluoridation – though th is will be diluted to a variable extent by rainwater inputs. This means that the effluent would only have to be diluted in receiving water by a factor of at least 3.5 (only 2 if the sensitive spec ies safety threshold is considered) for the fluoride concentration to be reduced below the worst case PNEC of 0.29 for freshwaters– something which seems extremely plausible fo r most circumstances (default dilution factor taken in the TGD is 10 (TGD 2003). Dilution for effluents entering the marine environment would have to be greater; but again that s eems plausible (the default dilution factor taken in TGD for ma rine ecosystems is 100 (TGD 2003)). out on the consequences of fluoridation of The only detailed work that has been carried drinking water for concentrations of F in sewage treatment e ffluents was done by e conclusion from the simplis tic assessment. This paper Osterman (1990) and supports th presents a mass balance approach to develop a series of mathematical equations that describe the fate of fluoride added to dr inking water in a typical municipal water de entering the aquatic system from all management system. The ionic mass of fluori sources was calculated, its di stribution followed and its fate examined. The city of Montreal in Canada was used as an example but it is SCHER's view that this approach can be applied broadly. In this system fluo ride was added to obtain levels between 0.7 l and the characteristics of the water supply and 1.2 mg/L. Based on the fluoridation leve situation in Montreal, the estimated daily aver age fluoride concentration at less than 1km distance from the effluent outfall was 0.22 to 0.34 mg/L. If this is compared with the safe threshold of 0.5 mg/L, no unacceptable risk for aquatic organisms is expected. Clearly this study is focused on a particular site. To check the generality of the results, SCHER further has carried out an analysis using the European Union System for the nces (EUSES) (EC 2004). Evaluation of Substa designed to be a pplied for organic and SCHER recognizes that this model has been hydrophobic substances in the framework of new and existing substances and biocides (EC 2004) but is of the view that treated ca utiously the model can give further insight into the likely consequences of fluoride for aquatic systems. The addition of fluoride to drinking water is analogous to the addition of disinfectants to drinking water and this version of EUSES has been adopted in the following analyses. In addition it should be kept in mind that the scenarios included in EUSES are conservative. The following assumptions have been adopted by SCHER: 1. addition of fluoride according to PT5 in analogy to drinking water disinfection; 2. the dose applied is 0.8 (normal dose) and 1.5 mg/L, based on the Council Directive 98/83/EC of 3 November 1998 on the quality of water intended for human consumption (see section 4.2.1, human part); 38

39 Fluoride and fluoridating agents of drinking water the physico-chemical characteristi cs are as indicated in Table 1; 3. the effect data are as indicated in Table 11. 4. The following 2 cases are presented: - Case 1: a dose of 0.8 mg F 1. /L as the normal dose for fluoridation of drinking water, - /L, based on the reference dose of WHO (2006), 2. Case 2: a dose of 1.5 mg F The main results of the calculation of the risk characterisation ratios (RCR), defined as tal Concentration (PEC) and the Predicted the ratio between the Predicted Environmen No-Effect Concentration (PNEC) are that case 1 leads to an RCR of 0.276 and case 2 to an RCR of 0.517 (see Appendix II). From these different lines of evidence, SCHER deduces that fluoridati on of drinking water the environment as RCR-values are below 1. will not result in unacceptable effects to 4.6.4. Conclusions Based on three lines of evidence, a simplistic risk assessment, mass balance modelling and a modified EUSES analysis, SCHER is of th e opinion that adding fluoride to drinking - /L and the reference dose level of WHO (1.5 water at concentrations between 0.8 mg F - /L) does not result in unacceptable ri sk to water organisms. Due to the mg F view that there will be little partition to electronegativity of the F ion SCHER is of the solids in the sewage treatment process. It follows that sewage sludge is unlikely to become contaminated and, in turn, this means that the contamination of soils and terrestrial systems is unlikely from this source. contamination from leakage from the water There is still the possibility of direct soil using tap water. SCHER was not able to carry out risk supply system and by irrigation assessments here due to lack of exposure data . If there were the possi bility of significant exposures in particular sites from these sour ces then more work would be necessary to asses risk to the soil ecosys the incineration of sewage tem. Atmospheric releases from sludge are unlikely. 5. SUMMARY Fluoride, either naturally present or intent ionally added to water, food and consumer products, e.g. toothpaste, is generally consid ered beneficial to pr event dental caries. Considering previous opinions from EFSA and SCCP, SCHER has reviewed the newest king water and intake information in the area on risk and benefit of using fluoridated drin of fluoride from all sources. SCHER concludes: Hydrolysis of hexafluorosilicates, used for dr inking water fluoridation, to fluoride was rapid and the release of fluori de ion was essentially complete . Therefore, the fluoride ion is considered the only relevant subs tance with respect to this opinion. There is a risk for dental fluorosis in child ren with systemic fluo ride exposure, and a threshold cannot be detected. The occurrence of endemic skeletal fluorosis has not been reported in the EU general population. There is not sufficient evidence linking fluoride in the drin king water to the development of osteosarcoma. Fluoride intake from drinking water at the level occurring in the EU does not appear to hamper children’s neurodevelopment and IQ levels. 39

40 Fluoride and fluoridating agents of drinking water Human studies do not suggest adverse thyroi d effects at realisti c human exposures to fluoride. There is no new evidence from human studies indicating that fluoride in drinking water influences male and female reproductive capacity. The upper tolerable intake level (UL) is no t exceeded for adults and children between 12 and 15 years living in areas with fluoridated drinking water where the concentration of fluoride does not exceed 0.8 mg/L. The UL was exceeded in childre n between 6 and 12 years living in areas with fluoridated drinking water (with levels above 0.8 mg/L) when consuming more than 1 L water/day and using adult toothpaste containing 0.15% fluoride. The UL is exceeded in child ren between 1 and 6 years of age living in areas with fluoridated drinking water (at fluoride concentration levels above 0.8 mg/L) when consuming more than 0.5 L water and using ad ult toothpaste containing 0.15% fluoride. For infants, when the fluoride concentration in drinking water is above 0.8 mg/L, the exposure to fluoride is esti mated to exceed 0.1 mg/kg/day. g. fluoridated toothpaste or Water fluoridation as well as topical fluoride applications, e. varnish, appears to prevent caries, primar ily on permanent dentition, but topical application is the more efficient measure. In children, a very narrow margin exists be tween achieving the be neficial effects of fluoride in caries prevention and the adverse effects of dental fluorosis. Exposure of environmental organisms to the le vels of fluoride used for fluoridation of drinking water is not expected to lead to unacceptable risks to the environment. 40

41 Fluoride and fluoridating agents of drinking water 6. LIST OF ABREVIATIONS AF Assessment factor Australian Government Nati onal Health and Medical Research AU NHMRC Council Agency for Toxic Substanc es and Disease Registry (US) ATSDR BW Body weight CAWT Co-operation and Working Together CDC Centers for Disease Co ntrol and Prevention (US) CHO Chinese hamster ovary (cells) dmft/DMFT Decayed, missing or filled deciduous/permanent teeth D(M)FS Decayed (missing) or filled tooth surfaces DNA Deoxyribonucleic acid ECDC European Centre for Disease prevention and Control European Chemicals Agency ECHA EFSA European Food Safety Authority EFSA CONTAM EFSA’s panel on contaminants in the food chain EFSA NDA EFSA’s panel on dietetic products, nutrition and allergies EMEA European Medicines Evaluation Agency EU European Union European Union System for the Evaluation of Substances EUSES F Fluoride ion FSH Follicle-stimulating hormone HGPRT Hypoxanthine-guanine phosphoribosyltransferase IPCS International Programme for Chemical Safety (WHO) IQ intelligence quotient MATC Maximum allowable toxicant concentration National Health Service NHS NMR Nuclear Magnetic Resonance No/lowest observ ed adverse effect level N/LOAEL No observed effect concentration NOEC NRC National Research Council NTP National Toxicology Program (US) PEC Predicted environmental concentration PNEC Predicted no-effect concentration Product-type 5: Drinking water disinfectants from the Biocidal PT5 Products Directiv e 98/88/EC (“BPD”) RCR Risk characterisation ratio SCCS Scientific Committee on Consumer Safety SCCP Scientific Committee on Consumer Products SCE Sister chromatid exchanges Scientific Committee on Emergi fied Health Risks SCENIHR ng and Newly Identi SCHER Scientific Committee on Health and Environmental Risks SD Sprague Dawley SSCP Scientific committee for consumer products TGD Technical guidance documents TFT Topical fluoride treatment Tk Thymidine kinase UK United Kingdom UK DoH UK Department of Health UK COT UK Committee of Toxicology UL Upper tolerable intake level US United States US IOM US Institute of Medicine WHO World Health Organization 41

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45 Fluoride and fluoridating agents of drinking water 1967; 74:389-97. Rocha-Amador D, Navarro ME, Carrizales L, Morales R, Calderón J. Decreased intelligence in children and exposure to fluoride and ar senic in drinking water. Cad Saude Publica 2007; 23 Sup 4:S579-87. Salanti G, Marinho V, Higgins JP. A case study of multiple-treatments meta-analysis demonstrates that covariates should be considered. J Clin Epidemiol 2009; 62:857-64. the safety of fluorine co mpounds in oral hygiene SCCP. Opinion SCCP/0882/05 on products for children under the age of 6 years. Scientific Committee on Consumer Products; 20 September 2005. Available from: URL: (accessed http://ec.europa.eu/heal th/ph_risk/committees/04_sccp/docs/sccp_o_024.pdf 12 May 2011). SCCP. Clarification on the Opinions SCCNFP/0653/03 and SCCP/0882/05 on the safety of fluorine compounds in oral hygiene products for children under the age of 6 years. Scientific Committee on Consumer Products; 21 January 2009. Available from: URL: (accessed th/ph_risk/committees/04_sccp/docs/sccp_o_169.pdf http://ec.europa.eu/heal 12 May 2011). trends 1992-1998 in two low-fluoride Finnish Seppä L, Kärkkäinen S, Hausen H. Caries towns formerly with and without fl uoridation. Caries Res 2000a; 34:462-8. Seppä L, Kärkkäinen S, Hausen H. Caries in the primary dentition, after discontinuation of water fluoridation, among children receiv ing comprehensive dental care. Community Dent Oral Epidemiol 2000b; 28:281-8. Shi X, Zhuang P, Zhang L, Feng G, Chen L, Liu J, et al. The bioaccumulation of fluoride − ) in Siberian sturgeon ( Acipenser baerii ) under laboratory conditions. ion (F Chemosphere 2009; 75:376-80. view. J Wildl Dis 1972; 8:252-4. intoxication in fish: a re Sigler WF, Neuhold JM. Fluoride Tang QQ, Du J, Ma HH, Jiang SJ, Zhou XJ. Fluoride and children s intelligence: a meta- ’ analysis. Biol Trace Elem Res 2008; 126:115-20. TGD. Technical Guidance Do cument on Risk Assessment in support of Commission Directive 93/67/EEC on Risk Assessment fo r new notified substances Commission Regulation (EC) No 1488/94 on Risk Asse ssment for existing substances. Directive 98/8/EC of the European Parliament and of th e Council concerning the placing of biocidal products on the market; 2003. Thylstrup A, Fejerskov O. Clin ical appearance of dental fl uorosis in permanent teeth in relation to histologic changes. Community Dent Oral Epidemiol 1978; 6:315-28. Truman BI, Gooch BF, Sulemana I, Gift HC, Horowitz AM, Evans CA, et al. Reviews of evidence on interventions to prevent dental caries, oral and pharyngeal cancers, and sports-related craniofacial injuries. Am J Prev Med 2002; 23 (1 Suppl):21-54. Twetman S, Petersson L, Axelsson S, Dahlgren H, Holm AK, Källestål C, et al. Caries- preventive effect of sodium fluoride mouthrinse s: a systematic re view of controlled clinical trials. Acta Odontol Scand 2004; 62:223-30. UK-CRD. What the 'York review' on the fluorida tion of drinking water really found. Centre for Reviews and Dissemination: York, UK; 2003. UK-DoH. Dietary reference values for food en ergy and nutrients for the United Kingdom. Report of the Panel on Dietary Reference Va lues of the Committee on Medical Aspects of Food Policy, Department of Health. London, UK: Stationary Office; 1994. Urbansky ET, Schock MR. Can fluoridation affect lead(II) in potable water? lution. Int J Environ Stud 2000; Hexafluorosilicate and fluoride equilibra in aqueous so 57:597-637. 45

46 Fluoride and fluoridating agents of drinking water US-IOM. Dietary reference values for calcium, phosphorus, magnesium, vitamin D and fluoride for the United Kin gdom. Standing Committee on the Scientific Evaluation on Dietary Reference Intakes, Food and Nutritio n Board, Institute of Medicine. Washington DC, USA: National Academy Press; 1999. Walton BT, Conway RA. In: Bodek I, Lyman WJ, Reehl WF, Rosenblatt DH, editors. Environmental inorganic chemistry: properti es, processes, and estimation methods (Society of Environmental Toxicology and Ch emistry). New York, USA: Pergamon Press; 1989. Wang SX, Wang ZH, Cheng XT, Li J, Sang ZP, Zhang XD, et al. Arsenic and fluoride exposure in drinking water: children’s IQ and growth in Shanyin County, Shanxi province, China. Environ He alth Perspect 2007; 115:643-7. Whitford GM, Sampaio FC, Pinto CS, Maria AG, Cardoso VE, Buzalaf MA. Pharmacokinetics of ingested fluo ride: lack of effect of chemic al compound. Ar ch Oral Biol 2008; 53:1037-41. Whitford GM, Whitford, JL, Hobbs SH. Appetitive-b ased learning in rats: lack of effect of chronic exposure to fluoride. Neurotoxicol Teratol 2009; 31:210-5. WHO. Guidelines for drinki ng-water quality. Geneva, Switzerland: World Health Organization; 2006. Yeung CA, Hitchings JL, Macfarlane TV, Thre lfall AG, Tickle M, Glenny AM. Fluoridated milk for preventing dental caries. Coch rane Database Syst Rev 2005; 3:CD003876. 46

47 Fluoride and fluoridating agents of drinking water Appendix I Classification of dental fluorosis The dictionary definition of fluorosis is “a n abnormal condition (as mottled enamel of unds” or “a pathological condition resulting human teeth) caused by fluorine or its compo from an excessive intake of fluoride (usually from drinking water)”. This is a very simplistic definition since mottling of the enamel of teeth is common and may have many causes including caries, childhood infections, developmental abnormalities and trauma. own in Table A 1. The generally applied classification of de ntal fluorosis is sh arance of fluorotic enamel changes Table A 1: Classification of the clinical appe characterising the single tooth surf ace (Thylstrup and Fejerskov 1978). Score Clinical appearance Normal translucency of the enamel remains after prolonged air drying. 0 Narrow white lines located corre 1 sponding to the perichymata. Smooth surface : More pronounced lines of opacity which follow the 2 perichymata. Occasionally there is confluence of adjacent lines. Occlusal surfaces : Scattered areas of opacity less than 2 mm in diameter and pronounced opacity of the cuspal ridges. Smooth surface : Merging and irregular cl oudy areas of opacity. 3 Accentuated drawing of the perichymat a often visible between opacities. Occlusal surfaces : Confluent areas of marked opacity. Worn areas appear almost normal but usua rim of opaque enamel. lly circumscribed by a : The entire surface exhibits marked opacity or appears Smooth surfaces 4 chalky white. Parts of the surface exposed to attrition appear less affected. Occlusal surfaces : Entire surface exhibits marked opacity. Attrition is often pronounced shortly after eruption. : Entire surface displays marked opacity Smooth and occlusal surfaces 5 with focal loss of outermost enamels (pits) less than 2 mm in diameter. Smooth surfaces : Pits are regularly arranged in horizontal bands less than 6 2 mm in vertical extension. Occlusal surfaces : Confluent areas less than 3 mm in diameter exhibit loss of enamel. Marked attrition. Smooth surfaces : Loss of outermost enamel in irregular areas involving 7 less than one-half of the entire surface. Occlusal surfaces : Changes in the morphology caused by merging pits and marked attrition. Smooth and occlusal surfaces : Loss of outermost enamel involving more 8 than 1½ or one-half? Smooth and occlusal surfaces : Loss of the main part of the enamel with a 9 the surface. Cervical rim of almost change in anatomical appearance of unaffected enamel is often noted. 47

48 Fluoride and fluoridating agents of drinking water Appendix II - Case I Operational dose (0.8 mg F /L) IDENTIFICATION OF THE SUBSTANCE Sodium fluoride General name S CAS-No 7681-49-4 S EC-notification no. S NA 231-667-8 S EINECS no. 42 [g.mol-1] S Molecular weight PHYSICO-CHEMICAL PROPERTIES 1000 S Melting point [oC] [oC] S Boiling point 1.7E+03 1.33 [hPa] Vapour pressure at test temperature S Temperature at which vapour pressure was measured 1.077E+03 [oC] S 1.97E-05 [Pa] O Vapour pressure at 25 [oC] Water solubility at test temperature 4E+04 [mg.l-1] S Temperature at which solubilit y was measured 20 [oC] S [mg.l-1] O Water solubility at 25 [oC] 4.29E+04 ?? [log10] D Octanol-water partition coefficient 1.93E-08 Henry's law constant at 25 [oC] [Pa.m3.mol-1] O ENVIRONMENT-EXPOSURE RELEASE ESTIMATION [1 "", IC=15/UC=39] Industry category 15/0 Others D Use category 39 Biocides, non-agricultural D Fraction of tonnage for application [-] D 1 ENVIRONMENT-EXPOSURE RELEASE ESTIMATION [INDUSTRIAL USE] Use specific emission scenario Yes D Emission tables A3.16 (general table), B3.14 (general table) S D Emission scenario Main category industrial use III Non-dispersive use D S Scenario choice for biocides (5) Drinking water Fraction of tonnage released to air [-] O 1E-05 0.75 O Fraction of tonnage released to wastewater [-] [-] O Fraction of tonnage released to surface water 0 1E-03 [-] Fraction of tonnage released to industrial soil O Fraction of tonnage released to agricultural soil 0 [-] O 1 [-] O Fraction of the main local source Number of emission days per year 365 [-] O Local emission to air duri ng episode 0 [kg.d-1] O Local emission to wastewater dur 1.6 [kg.d-1] O ing episode Intermittent release No D ENVIRONMENT-EXPOSURE RELEASE ESTIMATION TOTAL REGIONAL EMISSIONS TO COMPARTMENTS Total regional emission to air 0 [kg.d-1] O Total regional emission to wastewater O 0 [kg.d-1] Total regional emission to surface water O 0 [kg.d-1] [kg.d-1] O Total regional emission to industrial soil 0 0 [kg.d-1] O Total regional emission to agricultural soil ENVIRONMENT-EXPOSURE PARTITION COEFFICIENTS SOLIDS-WATER PARTITION COEFFICIENTS 6E-03 [l.kg-1] S Solids-water partition coefficient in soil sediment 1.5E-03 [l.kg-1] S Solids-water partition coefficient in Solids-water partition coefficient su spended matter 3E-03 [l.kg-1] S Solids-water partition coefficient in raw sewage sludge 9E-03 [l.kg-1] S ENVIRONMENT-EXPOSURE DEGRADATION AND TRANSFORMATION Characterization of biodegradability Not biodegradable D Degradation calculation method in STP First order, standard OECD/EU tests D O 0 [d-1] Rate constant for biodegradation in STP [d-1] Rate constant for biodegradation in surface water 0 (12[oC]) S 48

49 Fluoride and fluoridating agents of drinking water 6.93E-07 Rate constant for biodegradation in bulk soil [d-1] (12[oC]) O aerated sediment [d-1] Rate constant for biodegradation in 6.93E-07 (12[oC]) O 6.93E-07 [d-1] Rate constant for hydrolysis in surface water (12[oC]) O [d-1] Rate constant for photolysis in surface water 6.93E-07 O ENVIRONMENT-EXPOSURE SEWAGE TREATMENT LOCAL STP [1 "", IC=15/UC=39][INDUSTRIAL USE] OUTPUT 1.85E-08 [%] Fraction of emission directed to air by STP O [%] O Fraction of emission directed to water by STP 100 3.73E-04 O [%] Fraction of emission directed to sludge by STP 0 [%] Fraction of the emission degraded in STP O 0.8 [mg.l-1] O Concentration in untreated wastewater the STP-effluent 0.8 Concentration of chemical (total) in O [mg.l-1] Concentration in effluent exceeds solubility No O 7.55E-03 O Concentration in dry sewage sludge [mg.kg-1] 0.8 O PEC for micro-organisms in the STP [mg.l-1] ENVIRONMENT-EXPOSURE RELEASE ESTIMATION [tonnes.yr- Tonnage of substance in Europe 0 1] O Regional production volume of substance 0 [tonnes.yr- 1] O ENVIRONMENT-EXPOSURE DISTRIBUTION LOCAL SCALE [1 "", IC=15/UC=39][INDUSTRIAL USE] Concentration in air during emissi 8.23E-14 [mg.m-3] O on episode point source 8.23E-14 [mg.m-3] O Annual average concentration in air, 100 m from Concentration in surface water during emission episode (dissolved) 0.08 O [mg.l-1] ter (dissolved) Annual average concentration in surface wa 0.08 [mg.l-1] O O Local PEC in surface water during emissi on episode (dissolved) 0.08 [mg.l-1] Annual average local PEC in surface water (dissolved) [mg.l-1] O 0.08 ing emission episode [mg.kgwwt- Local PEC in fresh-water sediment dur 0.0627 1] O sode (dissolved ) [mg.l-1] Concentration in seawater during emission epi O 8E-03 (dissolved) 8E-03 [mg.l-1] O Annual average concentration in seawater sode (dissolved) 8E-03 [mg.l-1] O Local PEC in seawater during emission epi 8E-03 [mg.l-1] O Annual average local PEC in seawater (dissolved) emission episode 6.27E-03 [mg.kgwwt- Local PEC in marine sediment during 1] O aged over 30 days 9.53E-06 [mg.kgwwt- Local PEC in agric. soil (total) aver 1] O Local PEC in agric. soil (total) av 4.76E-06 [mg.kgwwt- eraged over 180 days 1] O Local PEC in grassland (total) averaged over 180 days 1.06E-06 [mg.kgwwt- 1] O Local PEC in groundwater under agricultural soil [mg.l-1] O 3.88E-05 ENVIRONMENT-EXPOSURE DISTRIBUTION REGIONAL AND CONTINENTAL SCALE CONTINENTAL 0 [mg.l-1] O Continental PEC in surface water (dissolved) Continental PEC in seawater (dissolved) [mg.l-1] O 0 0 [mg.m-3] O Continental PEC in air (total) Continental PEC in agricultural soil (total) 0 [mg.kgwwt- 1] O Continental PEC in pore water of agricultural soils 0 [mg.l-1] O 0 [mg.kgwwt- Continental PEC in natural soil (total) 1] O Continental PEC in industrial soil (total) 0 [mg.kgwwt- 1] O 0 [mg.kgwwt- Continental PEC in sediment (total) 1] O Continental PEC in seawater sediment (total) 0 [mg.kgwwt- 1] O ENVIRONMENT-EXPOSURE DISTRIBUTION 49

50 Fluoride and fluoridating agents of drinking water REGIONAL AND CONTINENTAL SCALE REGIONAL 0 [mg.l-1] O Regional PEC in surface water (dissolved) 0 O Regional PEC in seawater (dissolved) [mg.l-1] 0 [mg.m-3] O Regional PEC in air (total) 0 Regional PEC in agricultural soil (total) [mg.kgwwt- 1] O Regional PEC in pore water of agricultural soils [mg.l-1] O 0 Regional PEC in natural soil (total) [mg.kgwwt- 0 1] O [mg.kgwwt- Regional PEC in industrial soil (total) 0 1] O Regional PEC in sediment (total) 0 [mg.kgwwt- 1] O 0 [mg.kgwwt- Regional PEC in seawater sediment (total) 1] O ENVIRONMENT-EXPOSURE BIOCONCENTRATION hworms ?? [l.kgwwt-1] D Bioconcentration factor for eart fish ?? [l.kgwwt-1] O Bioconcentration factor for ENVIRONMENT-EXPOSURE SECONDARY POISONING [1 "", IC=15/UC=39][INDUSTRIAL USE] Concentration in fish for secondary ?? [mg.kgwwt- poisoning (freshwater) 1] O Concentration in fish for secondary ?? [mg.kgwwt- poisoning (marine) 1] O ?? [mg.kgwwt- Concentration in fish-eating marine top-predators 1] O Concentration in earthworms from agricultural soil ?? [mg.kg-1] O ENVIRONMENT - EFFECTS MICRO-ORGANISMS Test system Respiration inhibition, EU Annex V C.11, OECD 209 D EC50 for micro-organisms in a STP ?? [mg.l-1] D EC10 for micro-organisms in a STP [mg.l-1] D ?? NOEC for micro-organisms in a STP ?? [mg.l-1] D PNEC for micro-organisms in a STP ?? [mg.l-1] O Assessment factor applied in extrapolation to PNEC micro ?? [-] O ENVIRONMENT - EFFECTS FRESH_WATER ORGANISMS S LC50 for fish 51 [mg.l-1] L(E)C50 for Daphnia [mg.l-1] S 14.6 [mg.l-1] S EC50 for algae 123 ?? [mg.l-1] D LC50 for additional taxonomic group NOEC for fish [mg.l-1] S 4 NOEC for Daphnia 2.9 [mg.l-1] S NOEC for algae 50 [mg.l-1] S NOEC for additional taxonomic group [mg.l-1] D ?? PNEC for aquatic organisms 0.29 [mg.l-1] O PNEC for aquatic organisms, intermittent releases 0.146 [mg.l-1] O ENVIRONMENT - EFFECTS MARINE ORGANISMS LC50 for fish (marine) 500 [mg.l-1] S 10.5 L(E)C50 for crustaceans (marine) [mg.l-1] S EC50 for algae (marine) S 82 [mg.l-1] [mg.l-1] D LC50 for additional taxonomic group (marine) ?? 5.5 [mg.l-1] S NOEC for fish (marine) [mg.l-1] S 4.2 NOEC for crustaceans (marine) 50 [mg.l-1] S NOEC for algae (marine) NOEC for additional taxonomic group (marine) ?? [mg.l-1] D PNEC for marine organisms 0.029 [mg.l-1] O ENVIRONMENT - EFFECTS FRESH-WATER SEDIMENT ORGANISMS LC50 for fresh-water sediment organism ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- EC10 for fresh-water sediment organism 1] D EC10 for fresh-water sediment organism ?? [mg.kgwwt- 1] D [mg.kgwwt- EC10 for fresh-water sediment organism ?? 1] D 50

51 Fluoride and fluoridating agents of drinking water ?? NOEC for fresh-water sediment organism [mg.kgwwt- 1] D [mg.kgwwt- NOEC for fresh-water sediment organism ?? 1] D ?? [mg.kgwwt- NOEC for fresh-water sediment organism 1] D 0.227 [mg.kgwwt- PNEC for fresh-water sediment-dwelling organisms 1] O ENVIRONMENT - EFFECTS MARINE SEDIMENT ORGANISMS ?? [mg.kgwwt- LC50 for marine sediment organism 1] D EC10 for marine sediment organism ?? [mg.kgwwt- 1] D EC10 for marine sediment organism ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- EC10 for marine sediment organism 1] D NOEC for marine sediment organism ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- NOEC for marine sediment organism 1] D NOEC for marine sediment organism [mg.kgwwt- ?? 1] D PNEC for marine sediment organisms [mg.kgwwt- 0.0227 1] O ENVIRONMENT - EFFECTS TERRESTRIAL ORGANISMS LC50 for plants ?? [mg.kgwwt- 1] D [mg.kgwwt- ?? LC50 for earthworms 1] D ?? [mg.kgwwt- EC50 for microorganisms 1] D LC50 for other terrestrial species ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- NOEC for plants 1] D NOEC for earthworms ?? [mg.kgwwt- 1] D NOEC for microorganisms ?? [mg.kgwwt- 1] D NOEC for additional taxonomic group ?? [mg.kgwwt- 1] D [mg.kgwwt- NOEC for additional taxonomic group ?? 1] D PNEC for terrestrial organisms [mg.kgwwt- 0.0356 1] O Equilibrium partitioning used for PNEC in soil? O Yes ENVIRONMENT - EFFECTS BIRDS AND MAMMALS 28 days D Duration of (sub-)chronic oral test ?? [mg.kg-1] O NOEC via food for secondary poisoning ?? PNEC for secondary poisoning of birds and mammals O [mg.kg-1] ENVIRONMENT - RISK CHARACTERIZATION LOCAL [1 "", IC=15/UC=39][INDUSTRIAL USE] 0.276 [-] O RCR for the local fresh-water compartment ?? RCR for the local fresh-water compartment, statistical method O [-] RCR for the local marine compartment 0.276 [-] O RCR for the local marine compartment, statistical method ?? [-] O RCR for the local fresh-water sediment compartment [-] O 0.276 [-] O RCR for the local marine sediment compartment 0.276 2.67E-04 [-] RCR for the local soil compartment O RCR for the local soil compartment, statistical method ?? [-] O RCR for the sewage treatment plant ?? [-] O RCR for fish-eating birds and mammals (fresh-water) [-] O ?? RCR for fish-eating birds and mammals (marine) ?? [-] O RCR for top predators (marine) ?? [-] O RCR for worm-eating birds and mammals ?? [-] O ENVIRONMENT - RISK CHARACTERIZATION REGIONAL 51

52 Fluoride and fluoridating agents of drinking water 0 O RCR for the regional fresh-water compartment [-] [-] O ?? RCR for the regional fresh-water compartment, statistical method 0 [-] RCR for the regional marine compartment O ?? [-] O RCR for the regional marine compartment, statistical method ediment compartment 0 RCR for the regional fresh-water s O [-] RCR for the regional marine sediment compartment 0 [-] O O [-] RCR for the regional soil compartment 0 ?? RCR for the regional soil compartment, statistical method O [-] HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE Purification factor for surface water 1 [-] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE CONCENTRATIONS IN INTAKE MEDIA [1 "", IC=15/UC=39][INDUSTRIAL USE] Local concentration in wet fish ?? [mg.kg-1] O ue of plant ?? [mg.kg-1] Local concentration in root tiss O Local concentration in leaves ?? [mg.kg-1] O of plant ?? [mg.kg-1] O Local concentration in grass (wet weight) Local concentration in drinking water 0.08 [mg.l-1] O Local concentration in meat (wet weight) [mg.kg-1] O ?? et weight) Local concentration in milk (w ?? [mg.kg-1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE DOSES IN INTAKE MEDIA [1 "", IC=15/UC=39][INDUSTRIAL USE] Daily dose through intake of drinking water 2.29E-03 [mg.kg-1.d- 1] O Daily dose through intake of fish ?? [mg.kg-1.d- 1] O ?? [mg.kg-1.d- Daily dose through intake of leaf crops 1] O Daily dose through intake of root crops ?? [mg.kg-1.d- 1] O Daily dose through intake of meat [mg.kg-1.d- ?? 1] O [mg.kg-1.d- Daily dose through intake of milk ?? 1] O 2.35E-14 [mg.kg-1.d- Daily dose through intake of air 1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE FRACTIONS OF TOTAL DOSE [1 "", IC=15/UC=39][INDUSTRIAL USE] ?? [-] Fraction of total dose through intake of drinking water O Fraction of total dose through intake of fish ?? [-] O [-] O Fraction of total dose through intake of leaf crops ?? ?? [-] Fraction of total dose through intake of root crops O Fraction of total dose through intake of meat ?? [-] O Fraction of total dose through intake of milk ?? [-] O Fraction of total dose through intake of air [-] O ?? [mg.kg-1.d- Local total daily intake for humans ?? 1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE CONCENTRATIONS IN INTAKE MEDIA Regional concentration in wet fish ?? [mg.kg-1] D ?? [mg.kg-1] D Regional concentration in root tissue of plant Regional concentration in leaves of plant ?? [mg.kg-1] D Regional concentration in grass (wet weight) [mg.kg-1] D ?? Regional concentration in drinking water ?? [mg.l-1] D Regional concentration in meat (wet weight) ?? [mg.kg-1] D Regional concentration in milk (w et weight) ?? [mg.kg-1] D HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE DOSES IN INTAKE MEDIA 52

53 Fluoride and fluoridating agents of drinking water ?? Daily dose through intake of drinking water [mg.kg-1.d- 1] D [mg.kg-1.d- Daily dose through intake of fish ?? 1] D ?? [mg.kg-1.d- Daily dose through intake of leaf crops 1] D ?? Daily dose through intake of root crops [mg.kg-1.d- 1] D [mg.kg-1.d- Daily dose through intake of meat ?? 1] D ?? Daily dose through intake of milk [mg.kg-1.d- 1] D Daily dose through intake of air ?? [mg.kg-1.d- 1] D HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE FRACTIONS OF TOTAL DOSE ?? [-] Fraction of total dose through intake of drinking water D Fraction of total dose through intake of fish ?? [-] D Fraction of total dose through intake of leaf crops ?? [-] D Fraction of total dose through intake of root crops ?? [-] D D ?? [-] Fraction of total dose through intake of meat D Fraction of total dose through intake of milk ?? [-] Fraction of total dose through intake of air D ?? [-] ?? Regional total daily intake for humans [mg.kg-1.d- 1] D HUMAN HEALTH - RISK CHARACTERIZATION CURRENT CLASSIFICATION No D Corrosive (C, R34 or R35) D No Irritating to skin (Xi, R38) No D Irritating to eyes (Xi, R36) No D Risk of serious damage to eyes (Xi, R41) Irritating to respiratory system (Xi, R37) D No May cause sensitisation by inhal No D ation (Xn, R42) May cause sensitisation by skin contact (Xi, R43) No D May cause cancer (T, R45) No D D No May cause cancer by inhalation (T, R49) Possible risk of irreversible effects (Xn, R40) No D 53

54 Fluoride and fluoridating agents of drinking water - Case II WHO reference use (1.5 mg F /L) IDENTIFICATION OF THE SUBSTANCE S General name Sodium fluoride CAS-No 7681-49-4 S NA S EC-notification no. S EINECS no. 231-667-8 [g.mol-1] S 42 Molecular weight PHYSICO-CHEMICAL PROPERTIES 1000 [oC] Melting point S [oC] S Boiling point 1.7E+03 1.33 S Vapour pressure at test temperature [hPa] 1.077E+03 [oC] S Temperature at which vapour pressure was measured 1.97E-05 O Vapour pressure at 25 [oC] [Pa] [mg.l-1] S Water solubility at test temperature 4E+04 Temperature at which solubilit 20 [oC] S y was measured Water solubility at 25 [oC] 4.29E+04 [mg.l-1] O ?? D Octanol-water partition coefficient [log10] 1.93E-08 Henry's law constant at 25 [oC] [Pa.m3.mol-1] O ENVIRONMENT-EXPOSURE RELEASE ESTIMATION 0 [tonnes.yr- Tonnage of substance in Europe 1] O 0 [tonnes.yr- Regional production volume of substance 1] O ENVIRONMENT-EXPOSURE RELEASE ESTIMATION [1 "", IC=15/UC=39] Industry category D 15/0 Others D Use category 39 Biocides, non-agricultural 1 [-] D Fraction of tonnage for application ENVIRONMENT-EXPOSURE RELEASE ESTIMATION [INDUSTRIAL USE] D Yes Use specific emission scenario Emission tables A3.16 (general table), B3.14 (general table) S D Emission scenario Main category industrial use D III Non-dispersive use S Scenario choice for biocides (5) Drinking water 1E-05 O [-] Fraction of tonnage released to air 0.75 [-] Fraction of tonnage released to wastewater O 0 [-] O Fraction of tonnage released to surface water 1E-03 [-] Fraction of tonnage released to industrial soil O Fraction of tonnage released to agricultural soil 0 [-] O [-] O Fraction of the main local source 1 365 [-] Number of emission days per year O Local emission to air duri ng episode 0 [kg.d-1] O Local emission to wastewater during episode 3 [kg.d-1] O Intermittent release D No ENVIRONMENT-EXPOSURE RELEASE ESTIMATION TOTAL REGIONAL EMISSIONS TO COMPARTMENTS 0 [kg.d-1] O Total regional emission to air 0 [kg.d-1] O Total regional emission to wastewater Total regional emission to surface water 0 [kg.d-1] O Total regional emission to industrial soil 0 [kg.d-1] O Total regional emission to agricultural soil [kg.d-1] O 0 ENVIRONMENT-EXPOSURE PARTITION COEFFICIENTS SOLIDS-WATER PARTITION COEFFICIENTS Solids-water partition coefficient in soil 6E-03 [l.kg-1] S Solids-water partition coefficient in sediment 1.5E-03 [l.kg-1] S S Solids-water partition coefficient su 3E-03 [l.kg-1] spended matter Solids-water partition coefficient in raw sewage sludge 9E-03 [l.kg-1] S ENVIRONMENT-EXPOSURE DEGRADATION AND TRANSFORMATION 54

55 Fluoride and fluoridating agents of drinking water Not biodegradable D Characterization of biodegradability First order, standard OECD/EU tests Degradation calculation method in STP D [d-1] Rate constant for biodegradation in STP 0 O 0 Rate constant for biodegradation in surface water [d-1] (12[oC]) S Rate constant for biodegradation in bulk soil 6.93E-07 [d-1] (12[oC]) O aerated sediment 6.93E-07 [d-1] Rate constant for biodegradation in (12[oC]) O 6.93E-07 Rate constant for hydrolysis in surface water [d-1] (12[oC]) O 6.93E-07 [d-1] O Rate constant for photolysis in surface water ENVIRONMENT-EXPOSURE SEWAGE TREATMENT LOCAL STP [1 "", IC=15/UC=39][INDUSTRIAL USE] OUTPUT 1.85E-08 [%] Fraction of emission directed to air by STP O 100 [%] O Fraction of emission directed to water by STP Fraction of emission directed to sludge by STP 3.73E-04 [%] O Fraction of the emission degraded in STP 0 [%] O 1.5 O Concentration in untreated wastewater [mg.l-1] [mg.l-1] the STP-effluent O Concentration of chemical (total) in 1.5 No O Concentration in effluent exceeds solubility 0.0141 [mg.kg-1] O Concentration in dry sewage sludge 1.5 [mg.l-1] O PEC for micro-organisms in the STP ENVIRONMENT-EXPOSURE DISTRIBUTION LOCAL SCALE [1 "", IC=15/UC=39][INDUSTRIAL USE] on episode 1.54E-13 [mg.m-3] O Concentration in air during emissi point source 1.54E-13 [mg.m-3] O Annual average concentration in air, 100 m from Concentration in surface water during emission episode (dissolved) 0.15 [mg.l-1] O [mg.l-1] O Annual average concentration in surface wa ter (dissolved) 0.15 Local PEC in surface water during emissi on episode (dissolved) [mg.l-1] O 0.15 0.15 O Annual average local PEC in surface water (dissolved) [mg.l-1] [mg.kgwwt- ing emission episode 0.117 Local PEC in fresh-water sediment dur 1] O 0.015 [mg.l-1] Concentration in seawater during emission epi sode (dissolved) O (dissolved) 0.015 [mg.l-1] O Annual average concentration in seawater sode (dissolved) 0.015 Local PEC in seawater during emission epi O [mg.l-1] Annual average local PEC in seawater (dissolved) 0.015 [mg.l-1] O ng emission episode 0.0117 [mg.kgwwt- Local PEC in marine sediment duri 1] O aged over 30 days 1.79E-05 Local PEC in agric. soil (total) aver [mg.kgwwt- 1] O Local PEC in agric. soil (total) av eraged over 180 days 8.93E-06 [mg.kgwwt- 1] O Local PEC in grassland (total) averaged over 180 days 1.98E-06 [mg.kgwwt- 1] O Local PEC in groundwater under agricultural soil 7.27E-05 [mg.l-1] O ENVIRONMENT-EXPOSURE DISTRIBUTION REGIONAL AND CONTINENTAL SCALE CONTINENTAL 0 [mg.l-1] O Continental PEC in surface water (dissolved) Continental PEC in seawater (dissolved) [mg.l-1] O 0 0 [mg.m-3] O Continental PEC in air (total) Continental PEC in agricultural soil (total) 0 [mg.kgwwt- 1] O Continental PEC in pore water of agricultural soils 0 [mg.l-1] O 0 [mg.kgwwt- Continental PEC in natural soil (total) 1] O Continental PEC in industrial soil (total) 0 [mg.kgwwt- 1] O 0 [mg.kgwwt- Continental PEC in sediment (total) 1] O Continental PEC in seawater sediment (total) 0 [mg.kgwwt- 1] O ENVIRONMENT-EXPOSURE DISTRIBUTION REGIONAL AND CONTINENTAL SCALE REGIONAL 55

56 Fluoride and fluoridating agents of drinking water 0 O Regional PEC in surface water (dissolved) [mg.l-1] 0 O Regional PEC in seawater (dissolved) [mg.l-1] 0 [mg.m-3] O Regional PEC in air (total) 0 Regional PEC in agricultural soil (total) [mg.kgwwt- 1] O Regional PEC in pore water of agricultural soils [mg.l-1] O 0 0 Regional PEC in natural soil (total) [mg.kgwwt- 1] O 0 Regional PEC in industrial soil (total) [mg.kgwwt- 1] O 0 [mg.kgwwt- Regional PEC in sediment (total) 1] O Regional PEC in seawater sediment (total) 0 [mg.kgwwt- 1] O ENVIRONMENT-EXPOSURE BIOCONCENTRATION Bioconcentration factor for eart D hworms ?? [l.kgwwt-1] Bioconcentration factor for O fish ?? [l.kgwwt-1] SECONDARY POISONING [1 "", IC=15/UC=39][INDUSTRIAL USE] Concentration in fish for secondary poisoning (freshwater) ?? [mg.kgwwt- 1] O Concentration in fish for secondary ?? [mg.kgwwt- poisoning (marine) 1] O Concentration in fish-eating marine top-predators ?? [mg.kgwwt- 1] O ?? [mg.kg-1] O Concentration in earthworms from agricultural soil ENVIRONMENT-EXPOSURE ENVIRONMENT - EFFECTS MICRO-ORGANISMS Test system Respiration inhibition, EU Annex V C.11, OECD 209 D EC50 for micro-organisms in a STP ?? [mg.l-1] D EC10 for micro-organisms in a STP [mg.l-1] D ?? NOEC for micro-organisms in a STP ?? [mg.l-1] D PNEC for micro-organisms in a STP ?? [mg.l-1] O Assessment factor applied in extrapolation to PNEC micro ?? [-] O ENVIRONMENT - EFFECTS FRESH_WATER ORGANISMS S LC50 for fish 51 [mg.l-1] L(E)C50 for Daphnia [mg.l-1] S 14.6 [mg.l-1] S EC50 for algae 123 ?? [mg.l-1] D LC50 for additional taxonomic group NOEC for fish [mg.l-1] S 4 NOEC for Daphnia 2.9 [mg.l-1] S NOEC for algae 50 [mg.l-1] S NOEC for additional taxonomic group [mg.l-1] D ?? PNEC for aquatic organisms 0.29 [mg.l-1] O PNEC for aquatic organisms, intermittent releases 0.146 [mg.l-1] O ENVIRONMENT - EFFECTS MARINE ORGANISMS LC50 for fish (marine) 500 [mg.l-1] S 10.5 L(E)C50 for crustaceans (marine) [mg.l-1] S EC50 for algae (marine) S 82 [mg.l-1] [mg.l-1] D LC50 for additional taxonomic group (marine) ?? 5.5 [mg.l-1] S NOEC for fish (marine) [mg.l-1] S 4.2 NOEC for crustaceans (marine) 50 [mg.l-1] S NOEC for algae (marine) NOEC for additional taxonomic group (marine) ?? [mg.l-1] D PNEC for marine organisms 0.029 [mg.l-1] O ENVIRONMENT - EFFECTS FRESH-WATER SEDIMENT ORGANISMS LC50 for fresh-water sediment organism ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- EC10 for fresh-water sediment organism 1] D EC10 for fresh-water sediment organism ?? [mg.kgwwt- 1] D [mg.kgwwt- EC10 for fresh-water sediment organism ?? 1] D 56

57 Fluoride and fluoridating agents of drinking water ?? NOEC for fresh-water sediment organism [mg.kgwwt- 1] D ?? NOEC for fresh-water sediment organism [mg.kgwwt- 1] D ?? [mg.kgwwt- NOEC for fresh-water sediment organism 1] D PNEC for fresh-water sediment-dwelling organisms 0.227 [mg.kgwwt- 1] O ENVIRONMENT - EFFECTS MARINE SEDIMENT ORGANISMS LC50 for marine sediment organism ?? [mg.kgwwt- 1] D EC10 for marine sediment organism [mg.kgwwt- ?? 1] D ?? [mg.kgwwt- EC10 for marine sediment organism 1] D [mg.kgwwt- EC10 for marine sediment organism ?? 1] D ?? [mg.kgwwt- NOEC for marine sediment organism 1] D ?? [mg.kgwwt- NOEC for marine sediment organism 1] D ?? NOEC for marine sediment organism [mg.kgwwt- 1] D 0.0227 PNEC for marine sediment organisms [mg.kgwwt- 1] O ENVIRONMENT - EFFECTS TERRESTRIAL ORGANISMS LC50 for plants ?? [mg.kgwwt- 1] D LC50 for earthworms [mg.kgwwt- ?? 1] D EC50 for microorganisms ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- LC50 for other terrestrial species 1] D NOEC for plants ?? [mg.kgwwt- 1] D NOEC for earthworms ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- NOEC for microorganisms 1] D NOEC for additional taxonomic group ?? [mg.kgwwt- 1] D ?? [mg.kgwwt- NOEC for additional taxonomic group 1] D [mg.kgwwt- 0.0356 PNEC for terrestrial organisms 1] O Equilibrium partitioning used for PNEC in soil? Yes O ENVIRONMENT - EFFECTS BIRDS AND MAMMALS 28 days D Duration of (sub-)chronic oral test NOEC via food for secondary poisoning ?? [mg.kg-1] O PNEC for secondary poisoning of birds and mammals ?? [mg.kg-1] O ENVIRONMENT - RISK CHARACTERIZATION LOCAL [1 "", IC=15/UC=39][INDUSTRIAL USE] RCR for the local fresh-water compartment 0.517 [-] O ? [-] O RCR for the local fresh-water compartment, statistical method ? RCR for the local marine compartment 0.517 [-] O RCR for the local marine compartment, statistical method ?? [-] O 0.517 RCR for the local fresh-water sediment compartment O [-] RCR for the local marine sediment compartment [-] O 0.517 [-] O RCR for the local soil compartment 5.01E-04 ?? [-] RCR for the local soil compartment, statistical method O RCR for the sewage treatment plant ?? [-] O RCR for fish-eating birds and mammals (fresh-water) ?? [-] O RCR for fish-eating birds and mammals (marine) ?? [-] O RCR for top predators (marine) ?? [-] O RCR for worm-eating birds and mammals ?? [-] O ENVIRONMENT - RISK CHARACTERIZATION REGIONAL O RCR for the regional fresh-water compartment 0 [-] 57

58 Fluoride and fluoridating agents of drinking water ?? [-] O RCR for the regional fresh-water compartment, statistical method 0 O [-] RCR for the regional marine compartment ?? [-] RCR for the regional marine compartment, statistical method O ediment compartment 0 [-] O RCR for the regional fresh-water s 0 [-] RCR for the regional marine sediment compartment O RCR for the regional soil compartment 0 [-] O [-] O RCR for the regional soil compartment, statistical method ?? HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE Purification factor for surface water 1 [-] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE CONCENTRATIONS IN INTAKE MEDIA [1 "", IC=15/UC=39][INDUSTRIAL USE] Local concentration in wet fish ?? [mg.kg-1] O Local concentration in root tiss ue of plant ?? [mg.kg-1] O of plant ?? [mg.kg-1] O Local concentration in leaves ?? Local concentration in grass (wet weight) O [mg.kg-1] Local concentration in drinking water 0.15 [mg.l-1] O Local concentration in meat (wet weight) ?? [mg.kg-1] O Local concentration in milk (w et weight) ?? [mg.kg-1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE DOSES IN INTAKE MEDIA [1 "", IC=15/UC=39][INDUSTRIAL USE] Daily dose through intake of drinking water 4.29E-03 [mg.kg-1.d- 1] O ?? [mg.kg-1.d- Daily dose through intake of fish 1] O Daily dose through intake of leaf crops ?? [mg.kg-1.d- 1] O [mg.kg-1.d- ?? Daily dose through intake of root crops 1] O Daily dose through intake of meat [mg.kg-1.d- ?? 1] O [mg.kg-1.d- Daily dose through intake of milk ?? 1] O Daily dose through intake of air 4.41E-14 [mg.kg-1.d- 1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT LOCAL SCALE FRACTIONS OF TOTAL DOSE [1 "", IC=15/UC=39][INDUSTRIAL USE] Fraction of total dose through intake of drinking water [-] O ?? ?? [-] O Fraction of total dose through intake of fish Fraction of total dose through intake of leaf crops O ?? [-] [-] O Fraction of total dose through intake of root crops ?? ?? [-] O Fraction of total dose through intake of meat ?? [-] O Fraction of total dose through intake of milk ?? Fraction of total dose through intake of air [-] O Local total daily intake for humans [mg.kg-1.d- ?? 1] O HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE CONCENTRATIONS IN INTAKE MEDIA ?? [mg.kg-1] D Regional concentration in wet fish Regional concentration in root tissue of plant [mg.kg-1] D ?? Regional concentration in leaves ?? [mg.kg-1] D of plant Regional concentration in grass (wet weight) ?? [mg.kg-1] D Regional concentration in drinking water [mg.l-1] D ?? ?? [mg.kg-1] D Regional concentration in meat (wet weight) Regional concentration in milk (w et weight) ?? [mg.kg-1] D HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE DOSES IN INTAKE MEDIA ?? Daily dose through intake of drinking water [mg.kg-1.d- 1] D 58

59 Fluoride and fluoridating agents of drinking water ?? Daily dose through intake of fish [mg.kg-1.d- 1] D ?? Daily dose through intake of leaf crops [mg.kg-1.d- 1] D ?? [mg.kg-1.d- Daily dose through intake of root crops 1] D Daily dose through intake of meat ?? [mg.kg-1.d- 1] D ?? Daily dose through intake of milk [mg.kg-1.d- 1] D [mg.kg-1.d- Daily dose through intake of air ?? 1] D HUMAN HEALTH - EXPOSURE ASSESSMENT HUMANS EXPOSED VIA THE ENVIRONMENT REGIONAL SCALE FRACTIONS OF TOTAL DOSE Fraction of total dose through intake of drinking water ?? [-] D Fraction of total dose through intake of fish ?? [-] D [-] D Fraction of total dose through intake of leaf crops ?? ?? [-] D Fraction of total dose through intake of root crops Fraction of total dose through intake of meat [-] D ?? Fraction of total dose through intake of milk ?? [-] D ?? D Fraction of total dose through intake of air [-] Regional total daily intake for humans [mg.kg-1.d- ?? 1] D HUMAN HEALTH - RISK CHARACTERIZATION CURRENT CLASSIFICATION Corrosive (C, R34 or R35) No D No Irritating to skin (Xi, R38) D Irritating to eyes (Xi, R36) No D No D Risk of serious damage to eyes (Xi, R41) Irritating to respiratory system (Xi, R37) No D May cause sensitisation by inhal ation (Xn, R42) No D May cause sensitisation by skin No D contact (Xi, R43) May cause cancer (T, R45) No D May cause cancer by inhalation (T, R49) No D D No Possible risk of irreversible effects (Xn, R40) 59

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