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Toxicity Assessment of Phoslock® & Lanthanum to Human Health June 2009 PWS Report Number: TR 023/09 Dr Anisul Afsar and Dr Sarah Groves Phoslock Water Solutions Limited Global Head Office 3/81 Frenchs Forest Road Frenchs Forest, NSW 2086, Australia Tel. +61 2 9453 0455 Table of contents
5.3.3. Mitigation/control strategies for not consuming Phoslock®/lanthanum
Phoslock® is a new but fast emerging effective P-inactivation and blue-green algaemanagement tool which was developed by the Commonwealth Scientific and IndustrialResearch Organisation (CSIRO), Australia. Phoslock® consists of bentonite clay (~95%)and lanthanum (~5%). In order to minimise any toxic impacts of Phoslock® to humanhealth, this toxicity assessment report has been constructed to analyse and interpretrelevant scientific literature and assessment studies using Phoslock® and/or lanthanumcarbonate or lanthanum chloride.
Bentonite is not considered toxic to humans. Bentonite has been approved as a foodadditive in Australia. In contrast to the toxicity of other similar products or metals such asalum or aluminium used in the water industry, lanthanum is used as a beneficial agent tohuman health. Lanthanum carbonate (Fosrenol®) has been used as a phosphate binderfor treatment of hyperphosphatemia in patients with chronic kidney disease who areundergoing dialysis. The bioavailability of lanthanum is extremely low, ≤0.0007% inanimals and 0.00127% (± 0.00080%) in humans. The majority of the oral dose oflanthanum carbonate is excreted in the faeces. The kidneys are not significantlyinvolved in the clearance of lanthanum from the human body; the main excretion routefor absorbed lanthanum being via the liver into bile. No effects of lanthanumaccumulation in bones have been observed. Studies have shown that lanthanum is notgenotoxic and the evidence that lanthanum does not cross the blood-brain barrier issubstantive.
We suggest that there is no risk to human health by a Phoslock® application to a waterbody (including drinking water reservoirs) at the Phoslock Water Solutions Ltd proposeddose rate of 100 g Phoslock®:1 g Filterable Reactive Phosphorus (FRP). The safetymargin is substantial and sufficient to ensure that the only exposure of lanthanum (inPhoslock®) would always be much less than the therapeutic dose used in patients withhyperphosphataemia. 1. Introduction
Phoslock® is a modified clay product that was developed by the CommonwealthScientific
phosphorus from water bodies and eliminate the chance of blue-green algal blooms. Phoslock Water Solutions Limited (PWS) manufactures and applies Phoslock® to waterbodies ranging from; recreational lakes; drinking water reservoirs; and, intensiveaquaculture ponds in order remove excess FRP (in the form of PO4) and control algalblooms.
Phoslock® consists of bentonite clay (~95%) and lanthanum (~5%). During themanufacturing process of Phoslock®, modified bentonite clay and lanthanum chloride(LaCl3) are mixed in an aqueous solution. The lanthanum (La) is adsorbed onto siteswithin the bentonite and becomes the active compound that removes phosphate. Bentonite (CAS No. 1302-78-9) consists of a group of clays formed by the crystallisationof vitreous volcanic ash that’s deposited in water. Bentonite has been used in food,agriculture, pharmaceutical, cosmetics, medical, detergent, paint, dyes, polishes, paperand drilling industries. Bentonite has been approved as a food additive in Australia(NICNAS, 2001).
Lanthanum was discovered in 1839 by a Swedish scientist, Carl Gustav Mosander. Lanthanum is one of 15 elements that are commonly known as the rare earth elements. Natural lanthanum is a mixture of two stable isotopes, 138La and 139La. Lanthanumbelongs to a group of elements known as the ‘lanthanides’. It is the most electropositive(cationic) element of the rare earth group, is uniformly trivalent, and its binding is almostexclusively ionic. It is a hard ‘acceptor’ with an overwhelming preference for oxygen-containing anions. Therefore, the most common biological ligands are the carboxyl andphosphate groups with which it can form very tight complexes (reviewed by Persy et al.,2006).
There are several lanthanum compounds that are available commercially. These includeoxide, carbonate, chloride and fluoride. Among these compounds, lanthanum carbonatehas been used in the medical industry for preparing a pharmaceutical drug. Fosrenol®(La2(CO3)3), the FDA (US Food and Drug Administration) approved drug, is used as aphosphate binding agent for patients with hyperphosphataemia. Another application oflanthanum is found to be in water treatment, for removing oxyanions, such as phosphateand arsenate. It is this feature of lanthanum that is utilised in Phoslock®.
Lanthanum (La3+) is not influenced by redox reactions (as in the case of Al3+), and whenbound with PO4 forms the insoluble compound, LaPO4 (Rhabdophane). Lanthanum andlanthanum salts are not on the NOHSC List of Designated Hazardous Substances(NOHSC, 1999a) and they are unlikely to be classified as hazardous substances inaccordance with the NOHSC Approved Criteria for Classifying Hazardous Substances(NOHSC, 1999b). However, it has also been found that the free/unbound lanthanum(from the dissolution of LaCl3) can be toxic to aquatic organisms depending on theconcentration (Peterson et al., 1974). This issue limited its use significantly, until anappropriate carrier that could lock the lanthanum ions into its structure was discovered in
the mid 1990s by the CSIRO. Lanthanum toxicity and the availability of its free form wasdramatically reduced by incorporating the lanthanum ions into the structure of a highexchange capacity mineral, such as bentonite, hence the development of the innovativeproduct, Phoslock®.
laboratory and field studies on the ecotoxicity of Phoslock® and lanthanum using a rangeof aquatic organisms and the United States Environmental Protection Agency toxicitytesting criteria (summarised by Afsar & Groves, 2009). However, very little information isavailable on the toxicity of Phoslock® and/or lanthanum to human health. In order toensure that the innovative nutrient inactivation product ‘Phoslock®’ is safe in relation tohuman health, this report, therefore, summarises the properties of Phoslock® and thescientific information available on the toxicity of Phoslock® and lanthanum to humanhealth. 2. Properties of Phoslock®
Phoslock® was originally manufactured and applied in the form of a slurry, containing20% (w/w) of the active Phoslock®. A dry, free flowing granular form was developed in2004, resulting in ease of transportation and reduced application cost. Anotheradvantage of granular Phoslock® is that during the manufacturing (granulation) processsignificant dewatering of the slurry occurs that significantly reduces the amount ofresidual lanthanum associated with the product. With the introduction of the free flowinggranular form, the active Phoslock® concentration was increased to more than 90%(w/w). The major properties of granular Phoslock® are listed in Table 1. By adhering tostrict quality control measures, Phoslock Water Solutions Limited maintains a highconcentration of the active Phoslock® consistently in the supplied product. Moreover, thelow dust level and the acceptable degree of packaging stability of Phoslock® make thetransportation and the application of the product convenient as well as minimising anypossible health risk associated with dust levels to the personnel involved in theseprocesses. Physical & Chemical Properties Description
No deterioration of the packaging orphysical appearance of the product
Table 1: Summary of properties of Phoslock® granules. 3. Toxicity of bentonite to human health
Bentonite is not considered toxic to humans or the environment. In Australia, bentonitehas been approved as a food additive (NICNAS, 2001). Bentonite is utilised in theremoval of impurities in oils where its adsorptive properties are crucial. In drinks such asbeer, wine and mineral water, and in products like sugar or honey, bentonite is used asa clarification agent. Bentonite is used as an animal feed supplement, as a pelletizingaid in the production of animal feed pellets, as well as a flowability aid forunconsolidated feed ingredients such as soy meal. Bentonite is used as a filler inpharmaceuticals, and due to its absorption/adsorption functions, it allows pasteformation. Such applications include industrial protective creams, calamine lotion, wetcompresses, and antiirritants for eczema. In medicine, bentonite is used as an antidotein heavy metal poisoning. Personal care products such as mud packs, sunburn cream,baby and face powders, and face creams all contain bentonite.
The expected acute oral toxicity of bentonite in humans is very low (LD50>15 g/kg)(HSDB, 2000). In a 33 day dietary (2 and 6%) and a 90 day dietary (1, 3, and 5%) studyin chickens, no changes in behaviour, overall state, clinical and biochemical parametersand electrolytic composition of the blood occurred (NICNAS, 2001). Repeat dietaryadministration of bentonite did not affect calcium or phosphorus metabolism (NICNAS,2001). Bentonite did not cause fibrosis after one year of exposure of 60 mg dust (<5 µm)in a rat study (Tatrai, 1985).
Bentonite is not on the NOHSC List of Designated Hazardous Substances (NOHSC,1999a), and based on the available information, it is unlikely to be classified as ahazardous substance in accordance with the NOHSC Approved Criteria for ClassifyingHazardous Substances (NOHSC, 1999b) as it doesn’t meet the criteria of a hazardoussubstance. 4. Toxicity of Phoslock® and/or lanthanum to human health
Although no scientific study is available on the toxicity of Phoslock® to human health, alarge amount of scientific literature is available on lanthanum toxicity to human healthdue to lanthanum carbonate (Fosrenol®) being used as an oral drug in the medicalindustry. Phosphate accumulation in the human body and hyperphosphatemia areassociated with an increased mortality risk. Lanthanum carbonate (Fosrenol®) is aneffective
hyperphosphatemia in patients with chronic kidney disease who are undergoing dialysis. Tablets of 500, 750 and 1,000 mg are available for use in end stage renal diseasepatients (ESRD) with a mean Cmax of lanthanum 1,000 ng/L plasma (Behets et al.,2004). The FDA approved human dose rate for Fosrenol® (as appears on the Fosrenol®website - is 750 – 3,000 mg per day. Moreover, Fosrenol® hasalso just been approved for inclusion on the Australian Public Benefits Scheme(Pharmaceutical
carbonate dissociates in the acid environment of the upper gastrointestinal tract to
release lanthanum ions that allow the formation of lanthanum phosphate in the body. This insoluble lanthanum phosphate is eliminated in the faeces without significantabsorption of lanthanum. Efficacy and safety have been demonstrated in several PhaseIII clinical trials in both Europe and North America.
The accumulation of lanthanum in the body of dialysis patients is negligible, mainlybecause of its ultra-low gastrointestinal absorption and route of elimination. The kidneyis not significantly involved in the clearance of lanthanum; the main excretion route forabsorbed lanthanum being via the liver into bile (Damment & Pennick, 2007). Biliaryelimination (80%) and direct transport across the gut wall into the lumen (13%) representthe main routes of elimination. This implies that the removal of lanthanum is notdependent on renal function; of a lanthanum dose of 1 g/day in healthy volunteers, only0.00003% was excreted in the urine (Damment & Gill, 2003). The presence oflanthanum in the liver (Das et al., 1988) is consistent with excretion of lanthanum by theliver. However, clinical studies of up to four years have not disclosed any hepatotoxiceffect of the drug in patients treated with this phosphate binder (reviewed by Persy et al.,2006).
The bioavailability of lanthanum is extremely low, ≤0.0007% in animals (Damment & Gill,2003), with the majority of an oral dose being excreted in the faeces. In the human body,the absolute bioavailability of lanthanum (administered as lanthanum carbonate) wasalso extremely low (0.00127% ± 0.00080%), with individual values in the range of0.00015% to 0.00224% (Pennick et al., 2006). Studies have shown that oral doses oflanthanum carbonate are only minimally absorbed by the gut – in dogs, the rate ofabsorption is 0.00005% (Pennick et al., 2003) – with the majority of an oral dose beingexcreted in the faeces. This is in contrast to other water treatment products such asaluminium; when administered, 0.06 – 0.10% was absorbed from the gastrointestinaltract (Johanneau et al., 1997; Coburn et al., 1991). Moreover, in contrast to lanthanum,absorbed aluminium eliminated mainly via kidney and biliary excretion is negligible(Coburn et al., 1991).
No effects of lanthanum on bones have been observed in animals with normal renalfunction loaded with lanthanum at doses up to 2000 mg/kg/day for two years (Dammentet al., 2003). Patients treated with lanthanum carbonate for one year did not experienceany of the aluminium-like toxic effects on bones expressed as either osteomalacia oradynamic bone desease (De Bror & D’Haese, 2004). On the other hand, rats withchronic renal failure loaded with very high doses (1,000 – 2,000 mg/kg/day) oflanthanum carbonate for 12 weeks showed an impairment of bone mineralisation(Behets et al., 2004). However, several further studies produced evidence that theobserved lesions were pharmacologically mediated and resulted from phosphatedepletion induced by the administration of high doses of lanthanum carbonate ratherthan being the consequence of a direct toxic effect of the compound (reviewed by Persyet al., 2006). Further evidence of the absence of any direct toxicity of lanthanum onbones includes the fact that the bone lanthanum concentration does not correlate withthe various histomorphometric bone parameters, and the effects of lanthanum on bonemimic those induced by feeding a low phosphate diet, are normalized with phosphaterepletion (Damment & Shen, 2005), and are similar to those observed in rats treatedwith sevelamer (Behets et al., 2005).
Studies have shown that lanthanum is not genotoxic and that lanthanum carbonate isunlikely to present a latent hazard in therapeutic use (Damment et al., 2005). There isno evidence from studies that lanthanum crosses the blood-brain barrier (Evans, 1990;Behets et al. 2005; Damment & Shen, 2005). In fact, lanthanum is routinely used astracer to investigate the integrity of this barrier, as lanthanum ions cannot cross theplasma membrane and are excluded from passing between vascular endothelial cells inthe central nervous system (CNS) by tight junctions (Kato et al., 1989; Xu & Ling, 1994). Furthermore, lanthanum is almost completely bound in plasma to a variety of proteins(>99.9%), effectively limiting access to some tissue compartments, especially the brain(Pennick et al., 2006).
The acute oral toxicity of lanthanum chloride in rats is very low (LD50 = 2370 – 4184mg/kg) (Cochran, 1995; Sax, 1984; RTECS, 2000). In a study by giving lanthanumchloride subcutaneous injections to frogs, mice and rats determined LD50 to be >1,000,3,500 and >500 mg/kg for frogs, mice and rats respectively (Sax, 1984). 5. Risk assessment of Phoslock® to human health
The possibility of direct exposure of Phoslock® and/or lanthanum to the human body isvery limited during or after an application of Phoslock® to a water body. PWS hasidentified the following potential hazards associated with the application of Phoslock®,potential pathways of these hazards to human body, risks associated with thesehazards, and control or mitigation strategies. 5.1. Hazard 1: Phoslock® dust 5.1.1. Pathway - Inhalation of Phoslock® dust or contact to skin
One possibility of Phoslock® exposure to human body is via inhaling Phoslock® dust orcontact to skin during manufacture and/or application. 5.1.2. Risk associated with Phoslock® dust inhalation or contact to skin
The MSDS of Phoslock® states that the ‘rare earth modified clay’, or Phoslock® is a non-hazardous and non-dangerous good. No risk has been associated with contact ofPhoslock®. However, through inhalation or contact to skin, a person may feel discomfortor some irritation may occur. 5.1.3. Mitigation/control strategies for dust inhalation or contact to skin
Although Phoslock® is a non-hazardous substance; PWS has taken several protectivemeasures to prevent inhalation and/or contact to skin or eyes. During manufacturing andapplication to a water body, all workers must wear personal protective equipment (PPE)including eyewear, gloves, work clothing, boots, face masks etc. During application,public access should be restricted to the application area until the Phoslock® hasdispersed. The MSDS of Phoslock® states that if inhaled, a person should be removed
from the contaminated area. In case of contact, skin should be flushed with runningwater. 5.2. Hazard 2: Phoslock® and/or lanthanum in water 5.2.1. Pathway - Drinking Phoslock® treated water
Another possibility of Phoslock® exposure is via drinking Phoslock® treated water soonafter application. Through drinking Phoslock® treated water, a person can uptakelanthanum. 5.2.2. Risk associated with drinking Phoslock® treated water
Lanthanum uptake via drinking Phoslock® treated water may cause some negativeeffects on human health if the concentration exceeds the recommended daily uptakelimit prescribed by e.g. Fosrenol®. 5.2.3. Mitigation/control strategies for drinking Phoslock® treated water
The possibility of lanthanum uptake via drinking Phoslock® treated water is very limited. However, this is further reduced by ensuring the water body is kept off line after theapplication for few days (~7 days) until the Phoslock® clay particles associated withlanthanum have settled on the bottom (with dissolved La concentrations beingcontinuously monitored after the Phoslock® application). On the other hand, oncedissolved/free lanthanum binds with anions, they also sink and settle on the sediment asan insoluble complex which reduces the chance of lanthanum exposure to the humanbody when drinking Phoslock® treated water. Moreover, most water treatment would beexpected to remove residual lanthanum as it removes aluminium at the time oftreatment. The quantities of Phoslock® applied in the water body are determined by theconcentration of phosphate available in the water body and the portion of totalphosphorus that has the potential to be released as FRP. Therefore, the availability offree lanthanum in the water column for a prolonged period of time is highly unlikely.
Once lanthanum binds with phosphate, it is no longer free or bioavailable. Thelanthanum-phosphate (LaPO4) complex is known to have extremely low solubility andable to form even when there are low concentrations of phosphate present in the waterbody and at low pH. The extent of the insolubility of lanthanum-phosphate complexeswere studied by Firsching & Brune (1991) and Firsching & Kell (1993). The authorsreported its solubility product, Ksp, in freshwater to be -26.15 (Firsching & Brune, 1991)and in seawater -27.92 (Firsching & Kell, 1993), making it the least soluble among therare-earth-phosphate complexes and far less soluble than aluminium and ferricphosphate complexes.
In case of lanthanum ingestion via drinking even a large volume of Phoslock® treatedwater, there is no risk to human health. The FDA approved the human dose rate forFosrenol® or La2(CO3)3 (as appears on the Fosrenol® website) at 750 – 3,000 mg perday. This being the case, applying Phoslock® on a reservoir at the dose rate of 50 ppm
(a typical dose rate of Phoslock® in a water body with an average concentration ofphosphorus and alkalinity) and accepting that 100% of La (5% La in the product) will beleached out of the product (which will not happen because alkalinity and PO4 will “soakup” the “free” La), then: the person would need to drink 300 L of reservoir water per dayto ingest the minimum dose of La that corresponds to the lowest Fosrenol® daily intake. The maximum daily dose of Fosrenol® is 3,000 mg and therefore the average personwould need to drink 1,200 L of reservoir water per day to get the maximum dose of Lathat is the Fosrenol® daily intake. These large volumes of water could not be drunk by aperson per day and therefore an application of Phoslock® would never deliver as muchas La that a Fosrenol® tablet delivers. Therefore, even ingestion of Phoslock® directlyafter an application would not pose a risk to human health risk. 5.3. Hazard 3: Lanthanum accumulation in fish 5.3.1. Pathway - consuming Phoslock®/lanthanum accumulated fish
A third possibility of Phoslock® exposure is via consuming Phoslock®/lanthanum that hasaccumulated in aquatic organisms such as fish. 5.3.2. Risk associated with consuming Phoslock®/lanthanum accumulated fish
Lanthanum uptake via consuming Phoslock® accumulated in fish may cause somenegative effects on human health if the concentration exceeds the recommended dailyuptake limit prescribed by e.g. Fosrenol®. 5.3.3. Mitigation/control strategies for not consuming Phoslock®/lanthanum accumulated fish
The risk via consuming Phoslock®/lanthanum accumulated fish harvested fromPhoslock® treated water after application is reduced as shown in a fish healthinvestigation, after three successive applications of Phoslock® in Lake Okareka (NewZealand). Lake Okareka fish health monitoring report (Landman et al., 2007)demonstrated that trout and koura accumulated La only in the liver and hepatopancreastissues, not in the flesh/muscle following the application of Phoslock®. It was alsodemonstrated that the accumulated La was removed from the fish liver andhepatopancreas tissues within few months and the concentrations of La returned tobaseline before another Phoslock® application one year later, suggesting a biologicalcapacity to depurate lanthanum by the Lake Okareka biota (Landman et al., 2007). Thisis also consistent with the findings that the main excretion route for absorbed La inhumans or animals is via the liver into bile (Damment & Pennick, 2007).
The highest concentration of La measured in the liver of male and female trout in LakeOkareka after one and two months of Phoslock® application was 1.2 and 0.8 mg/kgrespectively (Landman et al., 2007). Similarly, the highest concentration of La in thehepatopancreas tissues of male and female trout was 0.8 and 1.0 mg/kg respectively(Landman et al., 2007). Therefore, in total the highest concentration of La in one troutwas 2.0 mg/kg. This being the case, applying Phoslock® on a reservoir at the dose ratesimilar to Lake Okareka, a person would need to consume 375 kg of fish per day to
ingest the minimum dose of La that corresponds to the lowest Fosrenol® daily intake. The maximum daily dose of Fosrenol® is 3,000 mg and therefore the average personwould need to consume 1,500 kg of fish per day to get the maximum dose of La that isthe Fosrenol® daily intake. These large quantities of fish would not be consumed by aperson per day and therefore an application of Phoslock® would never deliver as muchas La to fish body that a Fosrenol® tablet delivers. Moreover, fish liver andhepatopancreas tissues are not generally consumed by humans. However, evenconsumption
hepatopancreas tissues harvested from Phoslock® treated water body will not pose anyrisk to human health. 6. Conclusion
In conclusion we consider that a Phoslock® application to a water body includingdrinking water reservoirs at applicable dose rates shows that there is no identifiable riskto human health. The margin of safety in the case that all lanthanum is leached out ofthe product after application to a water body such as a drinking water reservoir issubstantial and sufficient to ensure that exposures from ingestion of lanthanum wouldalways be significantly much less than the therapeutic dose used in patients withhyperphosphataemia. References
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Indication: Hypoglycemia (Adults <80mg/dL, Peds <40, Dose: If temperature >101ºF and pt has not taken in last full term newborns <30, low birth weight infants <20) hour, give Acetaminophen 1000mg PO or Ibuprofen and AMS or other signs such as tremors/weakness/nausea/intense hunger. Oral glucose Peds: See dosing chart (pg 27 of Protocols). Give Acetaminoph
24 de agosto de 2011 Lista Prohibida 2012 RESÚMEN de las PRINCIPALES MODIFICACIONES y NOTAS EXPLICATIVAS INTRODUCCIÓN Los miembros de la Comunidad Antidopaje deben saber que se ha prestado una meticulosa consideración a los pertinentes comentarios recibidos en respuesta a la distribución del borrador de la Lista 2012. Se hace salvedad que no todas las sugerenc