Arch Toxicol

DOI 10.1007/s00204-008-0327-5

REGULATORY TOXICOLOGY

The safety of synthetic zeolites used in detergents

Claudia Fruijtier-Pölloth

Received: 3 March 2008 / Accepted: 27 May 2008© Springer-Verlag 2008

Abstract Synthetic zeolites are replacing phosphates asbuilders in laundry detergents; workers and consumers may,therefore, increasingly be exposed to these materials and itis important to assess their safety. This article puts mecha-nistic, toxicological and exposure data into context for asafety assessment. Zeolites are hygroscopic compoundswith ion-exchanging properties. They may partially decom-pose under acidic conditions such as in the stomach releas-ing sodium ions, silicic acid and aluminum salts. The intactmolecule is not bioavailable after oral intake or exposurethrough the dermal and inhalational routes. Under currentconditions of manufacture and use, no systemic toxicity is tobe expected from neither the intact molecule nor the degra-dation products; a signiWcant eVect on the bioavailability ofother compounds is not likely. Zeolites may cause local irri-tation. It is, therefore, important to minimise occupationalexposure. The co-operation of detergent manufacturers withthe manufacturers of washing machines is necessary to Wndthe right balance between environmental aspects such asenergy and water savings and the occurrence of detergentresidues on textiles due to insuYcient rinsing.

Keywords Synthetic zeolites · Laundry detergents · Builders · Safety · Exposure

Introduction

Zeolites (CAS register numbers 1318-02-1 and 1344-00-9;EINECS 215-283-8) are naturally occurring or synthetic

crystalline aluminosilicates composed of (SiO4)4¡ and

(AlO4)5¡ tetrahhedra, which share oxygen-bridging verti-

ces and form cage-like structures in crystalline form. Theratio between oxygen, aluminum and silicon isO:(Al + Si) = 2:1. The frameworks acquire their negativecharge by substitution of some Si by Al. The negativecharge is neutralised by cations and the frameworks aresuYciently open to contain, under normal conditions,mobile water molecules (IUPAC 1979).

Applications of naturally occurring zeolites include useas materials for the construction industry, in paper, in agri-culture and in other applications. Tailored synthetic zeoliteswith deWned pore sizes have a wide variety of more special-ized applications, such as in laundry detergents, as adsor-bents, catalysts or molecular sieves and as catalysts in oilreWneries (Budavari 1989; IARC 1997; Wenninger et al.2000).

Due to their presence in laundry detergents, an evalua-tion of their safety is critical, the more so, as potential expo-sure of workers and consumers may be chronic andextensive.

Zeolites used in laundry detergents

This assessment focuses on synthetic zeolites used com-mercially in laundry detergents in Europe, i.e., zeolite A,zeolite P, zeolite X and zeolite Y. These zeolites belong to aclass of crystalline, non-Wbrous compounds deWned by thegeneralised molecular formula Nax[(AlO2)x(SiO2)y]·zH2O.The materials soften wash water by exchanging calciumions and, to a lesser extent, magnesium ions for sodiumions, thereby preventing precipitation of surfactants. Theyare used as pure powders, which do not contain additives orclay binders.

C. Fruijtier-Pölloth (&)CATS Consultants GmbH, Toxicology and Preclinical AVairs, Saarburgstr. 31, 82166 GräfelWng, Germanye-mail: claudia@catsconsultants.com

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Zeolites were introduced in the mid 1970s as detergentbuilders and nowadays about 30% of EU detergent powdersare zeolite based (Bajpai and Tyagi 2007). They areincreasingly substituting phosphates in laundry detergents,which are considered a major source of eutrophication. Inseveral European countries, only phosphate-free detergentsare on the market, i.e, in Austria, Germany, Norway, Italy,the Netherlands and in Switzerland (CSTEE 2003).

Zeolite A, zeolite P, zeolite X and zeolite Y diVer mainlyin their aluminum content due to isomorphic exchange of Siversus Al. This inXuences the crystal structure and therebythe ion-exchange selectivity. The ion-exchange capacityand rate of dissolution increase with increasing Al-content,as does the Na-content. At pH-values below 4.0, zeolitesmay hydrolyse and their crystal structure is partly destroyedreleasing sodium ions, silicic acid, and aluminum salts.Aqueous suspensions are alkaline (pH 10–10.5) (Cooket al. 1982).

Synthetic zeolites typically occur in crystal sizes of 1–10 �m, with the individual crystals belonging to a size dis-tribution which diVers from manufacturer to manufacturer.

Zeolite A (Fig. 1) is composed of sodalite cages con-nected by double 4-rings, and typically consists of 3–5 �m

cuboidal-shaped crystals. The pores of the cages have adiameter of 0.41 nm admitting molecules with minimumcross sections of up to about 4.0 Å (hence the term zeolite4 Å). Whilst calcium ions diVuse relatively easily into theinterstices, the smaller magnesium ions are impeded by ahydrated shell, and are therefore incorporated more slowly.

Special type P zeolites (zeolite MAP, maximum alumi-num P; Fig. 2) are zeolites of the gismondine family with aXexible, layered crystal structure and a high calciumexchange capacity that were developed for the use in deter-gents. The primary crystallites consist of platelets whichagglomerate during synthesis to give 1 �m spheroidal andhighly porous particles. Their interconnected channels havepore sizes of 0.31 £ 0.44 and 0.28 £ 0.49 nm (Carr et al.1997; Newsam 1986).

Zeolite X and Y (Fig. 3) were introduced more recentlyinto the detergent market. While the chemical compositionof these zeolites is practically identical to that of zeolite A,they have a more spherical morphology with cubo-octahe-dron building blocks linked to a faujasite structure via hex-agonal prisms. Due to their larger pore diameter of 0.74 nm(Newsam 1986) zeolites X and Y are capable of more read-ily including magnesium ions.

Fig. 1 Zeolite A framework type [taken from the IZA (Inter-national Zeolites Association) database of zeolite structures with kind permission of the IZA] and SEM picture [provided by EUZEPA (European Zeolites Producers Association)]

Fig. 2 Zeolite P framework type (taken from the IZA data-base of zeolite structures with kind permission of the IZA) and SEM picture (provided by EU-ZEPA)

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Main characteristics of the diVerent zeolite types used inlaundry applications are summarised in Table 1.

Mechanisms of action and biological activity

Zeolites are commercially used because of their adsorption,ion exchange, and/or catalytic characteristics. Catalyticapplications are performed with special zeolite types, nor-mally at high temperatures, and are therefore beyond thescope of this article.

Adsorption

The uptake of water or other molecules in zeolites is calledadsorption. The main driving force for adsorption is thehighly polar surface within the openings of the zeoliteframework (“pores”) enabling molecules smaller than the

respective pore diameter to be adsorbed whilst larger mole-cules are excluded (“molecular sieve”). Because they arehygroscopic, it is often diYcult to make precise measure-ments of key chemical characteristics for zeolites. Theadsorption process is fully reversible and of purely physicalnature. The structure of the zeolite remains intact duringthis process (Kerr 1989; Newsam 1986).

Ion-exchange

Another outstanding property of this class of compound istheir ion exchanging capability. Synthetic zeolites arecapable of exchanging their sodium ions with calcium andmagnesium ions and with other cations, including heavymetals and trace elements (Kerr 1989; Newsam 1986). Itis therefore possible, that the bioavailability of some ele-ments, such as e.g. Mg, Zn, Cu might be inXuenced byzeolites.

Fig. 3 a Zeolite X and zeolite Y framework type (taken from IZA database of zeolite structures with kind permission of the IZA). b Zeolite X, SEM picture (provided by EUZEPA). c Zeo-lite Y, SEM picture (provided by EUZEPA)

Table 1 Zeolites types used in laundry applications

Name Formula Synonyms Framework type Pore size (nm)

Zeolite A Na12[(AlO2)12(SiO2)12] ·27 H2O Zeolite 4A; Na 4A Zeolite; Linde type A; LTA (Linde type A) 0.41

Zeolite P Na6(AlO2)6(SiO2)6 ·5 H2O Zeolite MAP; Na–P GIS (gismondine) ca. 0.3

Zeolite X Na86[(AlO2)86(SiO2)106] ·264 H2O Zeolite type X; Linde type X FAU (faujasite) 0.74

Zeolite Y Na54[(AlO2)54(SiO2)138] ·245 H2O Zeolite type Y; Linde type Y FAU (faujasite) 0.74

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The cation exchange capacity (CEC) expressed in termsof milliequivalents per gram, is 5.48 mequiv. g/L for zeoliteA. Based on this CEC, 1 g zeolite A could bind 0.126 gNa+, 0.214 g K+, 0.067 g Mg2+, 0.11 g Ca2+, 0.103 g NH4

+

or 0.174 g Cu2+ (EFSA 2004).

Surface characteristics and cytotoxicity

Elevated rates of mesothelioma and lung cancer were foundamong residents in Turkish villages exposed to the natu-rally occurring Wbrous zeolite erionite. Since then severalstudies have been undertaken on the mode of action of erio-nite carcinogenesis and on the inXuence of surface charac-teristics. A few of these studies have in parallel investigatedzeolites of the non-Wbrous types. These studies are summa-rised below.

Fach et al. (2002) investigated interactions of threediVerent zeolite types (erionite, mordenite and zeolite Y) onNR8383 lung macrophage cells and the ability of the min-eral surface to produce hydroxyl radicals from H2O2 (Fen-ton reaction). Cell viability was similar for all threeparticles types and dosages in this study. Using ammoniumchloride as an endocytosis inhibitor, the authors concludedthat the dose-dependent oxidative burst was mainly fromphagocytised particles rather than due to particles attachedto the membranes. The oxidative burst of the three materi-als was comparable and was correlated inversely with parti-cle size (surface area). Iron on the surfaces of the threediVerent zeolites produced diVerent amounts of hydroxylradicals and followed the order erionite > mordenite >>zeolite Y. Hydroxyl radical production by zeolite Y was lit-tle or insigniWcant, i.e., comparable to water-coordinatediron. The diVerences observed between the three zeoliteswere assumed to be arising from diVerent coordination ofthe iron on the zeolite surface. The biological implicationof these data is that the size (surface area) of the mineralrather than its structure is the determining factor for the oxi-dative burst upon phagocytosis, whereas the structure of themineral plays a key role in determining the production ofiron-mediated hydroxyl radicals via the Fenton reaction.The authors conclude that the considerable toxicity of erio-nite may be due to its Wbrous nature and size, which ensurespenetration into the lungs, and its surface chemistry, whichpromotes the formation of hydroxyl radicals. Mordenite,with comparable morphology, is also expected to be toxicbecause of its eYcacy in the Fenton reaction.

These results conWrm earlier observations by others (Fubiniand Mollo 1995; Fubini et al. 1995; Prandi et al. 2001) whofound that only a fraction of the iron species on the mineralsurface of zeolite Y is in the right redox state and coordinationenvironment to participate in the Fenton reaction.

The Wbrous structure of erionite and mordenite is shownin Fig. 4 (erionite) and Fig. 5 (mordenite). The structural

diVerence between these Wbrous zeolites and the syntheticnon-Wbrous zeolites under review here is clearly visible (cf.Figs. 1–3 above).

Exposure

Synthetic zeolites are used as builders in detergents, asbinders, anticaking and coagulant agents in feed, and asodour absorbents in a wide variety of personal care prod-ucts. The most common use of synthetic zeolites is in laun-dry detergents. Zeolites are used in concentrations of up to40 % in laundry regular and compact powder formulationsas well as in laundry tablets, and in concentrations of up to60% in light duty laundry powders (CIR 2003; HERA2004; Prud’homme de Lodder et al. 2006; RPA 2006;Wenninger et al. 2000).

Fig. 4 Erionite, SEM picture

Fig. 5 Mordenite, SEM picture (SEM pictures provided by EUZEPA)

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Exposure to zeolites may occur through the oral, dermaland respiratory route of exposure.

Oral exposure may occur by accidental intake or byswallowing dust, particles too large to enter the deeperrespiratory tract (see below). The public may also beexposed indirectly through drinking water.

Because of their poor solubility in water and the ioniccharacter, zeolites are not expected to cross the intact skinbarrier (IUPAC 2001). Hence, dermal uptake is assumednegligible as long as the skin is undamaged. In the case ofdamaged skin, uptake of zeolites may occur in very limitedquantities as the poor solubility in aqueous systems and theionic nature of the compounds prevents any signiWcantuptake of the intact molecules by body Xuids.

Zeolite particle size is normally between 1 and 10 �m; inair or detergent formulations the zeolite particles quicklyaggregate to larger structures, which are trapped in theupper airways and swallowed. Only particles of intermedi-ate size, i.e. <10 �m, may penetrate deep into the lungs andreach the alveoli. Small particles may stay in the alveoli foryears, since alveolar membranes have no cilia to move theparticles out of the lungs toward the pharynx (IUPAC2001); they may also be taken up by macrophages.

Occupational exposure

Workers might be exposed to zeolites A, P, X or Y duringmanufacture of the substances or their processing. Expo-sure through the professional use of zeolite-containinglaundry detergents is, however, limited because zeolitesmay aVect the calendering process (A.I.S.E. 2000). Themost likely routes of exposure are inhalation of zeolite-con-taining dust and dermal contact with laundry powder orgranulate. Dust particles containing zeolites may be trappedin the upper respiratory tract and may be swallowed; if<10 �m, they may reach the lungs and alveoli.

Currently, there are no speciWc EU-wide occupationalexposure limits for zeolites. Many countries, however, haveregulated the maximum exposure to total dust and imple-mented limit values of 10 mg/m3 for total dust and 3 or5 mg/m3 for respirable dust.

Consumer exposure

Product types that contain zeolites include laundry regularand compact powder formulations, laundry tablets, andlaundry aids.

Consumers might be exposed to zeolites A, P, X or Ythrough dermal contact with detergents containing thesesubstances. Dermal contact may occur with undiluted laun-dry products (laundry pre-treatment, Wlling laundry powderin washing machine) or with diluted detergent solution(hand wash). Exposure may also occur from the inhalation

of detergent dust or aerosol particles during the Wlling of awashing machine or from detergent residues on the washedtextiles.

Zeolites reaching the aquatic environment may beingested by consumers with the drinking water. In aquaticenvironments, zeolites are converted to natural constituentsof water (OECD 2006). Hence, this exposure is not consid-ered to be of relevance.

Exposure during use of detergent

For Europe, the technical guidance documents give a fre-quency of washing with powder laundry products rangingfrom 1 to 21 times a week, with a typical frequency of 5times per week (EC 2003). The amount of washing powderused per task is reported as 75 g (range 20–200 g) byA.I.S.E. (2002). Exposure time during Wlling the machinewith laundry powder is short; the mean duration was mea-sured as 11 (§3) s (Weegels 1997). Data reported byA.I.S.E (van de Plassche et al. 1998) show an averagerelease of about 0.27 �g of total dust per cup of laundrypowder used for a machine washing. For granules, it isassumed that a maximum of 10% is present in the form ofpowder. The inhalation exposure is, therefore, expected tobe 10-fold lower than the exposure to a powder. For tablets,the inhalation and dermal exposure is considered negligible(Prud’homme de Lodder et al. 2006).

Modern detergent powders are designed to produce verylow levels of dust and not to contain Wne, respirable parti-cles. Comparing particle size distributions of zeolite-con-taining with zeolite-free detergents showed essentiallysimilar distributions with more than 99% of the particlesbeing larger than 100 �m in size and hence not in the respi-rable range; about 50% of the particles were in the 400 �mrange, and only 0.2 or 0.1% (w/w) of the particles werebelow 100 �m in the zeolite-free and zeolite-containingproducts, respectively. It is important to note that the pro-portion of smaller particles was not increased in the zeolite-containing product, and that the concentration of zeolite inthe Wner fractions was essentially the same as in the coarsefraction (Gloxhuber et al. 1983).

To assess consumer exposure to detergent dust, determi-nations were carried out by Gloxhuber et al. (1983) using aphotoelectric particle counter and by gravimetric determi-nation. In a model for testing pouring characteristics, thedust generation by a zeolite-containing detergent was com-pared with that of a reference substance (commercial deter-gent free of zeolite). DeWned quantities of the detergentswere poured out under standardised conditions and the par-ticles present at a distance of 10 cm from the Wlling holewere counted. In two similar studies, dust generation wasexamined in ten households, i.e., in cellars where washingtreated with detergents containing zeolite A were tumble-

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dried. The estimations were performed both by means ofthe particle counter and by gravimetry. The comparisonshowed that the addition of zeolite A to the detergent didnot alter the dust quality. Recently, Gudmundsson et al.(2007) identiWed particle emissions from textile handling intwo Swedish households. The authors assumed that the dustoriginated from textiles containing detergent zeolite resi-dues. The very limited data presented, however, do notallow any meaningful conclusion to be drawn from thisexperiment; furthermore, the authors’ assumption is in con-tradiction with the earlier published results by Gloxhuberet al. (1983) that are cited above.

Exposure of hands to zeolite-containing detergent pow-ders, either as such or in diluted solutions, may occur dur-ing the hand-wash of laundry or if laundry is pre-treatedwith laundry aids (pre-treatment bars or pastes, water con-ditioners) which may contain zeolites in concentrationsgreater than 30% (Prud’homme de Lodder et al. 2006). Theexposure time during these operations is generally short,i.e., approximately 15 min when laundry is washed byhand, and less than 1 min if stains are removed by spot-treatment with a detergent paste (HERA 2004). Though, itis important to consider potential local eVects such as irrita-tion or sensitisation in these scenarios. The systemic zeoliteexposure is considered not relevant based on the physico-chemical properties of zeolites that prevent them from read-ily passing the skin barrier.

A relevant consumer exposure to zeolites from the use ofdetergent formulations by the inhalational, oral or dermalroutes of exposure is therefore not to be expected undernormal conditions of use.

Exposure through residues on textiles

Quantitative data on the amount of detergent residues ontextiles after laundering is scarce.

Under European washing conditions (German Mielewashing machine, 18 L water volume, 60°C, overnight linedrying), reported data on unsoiled polyester/cotton fabricsafter 10 washes were for linear alkylbenzene sulphonatebetween 20 and 2,000 mg/kg, and from 20 to 13,400 mg/kgfor fatty acid salts; for aluminum deposits the values rangedbetween 24 and 458 mg/kg and for silicon between 20 and622 mg/kg (Rodriguez et al. 1994).

Results reported by Matthies et al. (1990) from experi-ments performed with four diVerent household detergents,of which two contained zeolites (one with, one withoutphosphate binder) and two diVerent household washingmachines at 60°C showed that the amount of zeolite resi-dues was dependent on the amount of water used by themachines, the type of washing powder and the type of fab-ric. After 25 washes, zeolite concentrations were between1,050 ppm (=1,050 mg/kg; polyester fabric, washed with

phosphate-containing detergent powder) and 36,765 ppm(cotton fabric, washed with phosphate-free detergent pow-der). An increase of 10% in water use reduced the amountof zeolite residues by a factor of 2–4. Zeolite residues oncotton baby shirts were determined after 1 and 25 washes at95°C to be 2,900 and 8,300 ppm, respectively. The pH val-ues of the textiles increased from 9.1 (cotton, unwashed) to9.0 (after one washing), and 9.6–9.8 after 25 washes.

Sainio (1996) washed standardized 100% cotton textilestrips soiled with blood, red wine, cocoa and soot at 60°Cusing three diVerent detergents: one containing phosphate,and two containing zeolites (a concentrated detergent andan “ecological detergent”). The residues present in highestconcentration were anionic tensides (110–490 mg/kg).Electron microscopy showed that phosphate-free detergentsleft approximately 50% more particles on textiles than tra-ditional detergents (no quantitative data provided). Addi-tional rinses reduced the amounts of residues.

The ConsExpo model assumes 6,000 mg detergent resi-dues per kg fabric, based on 150 g of washing powder usedper 5 kg of laundry, and a deposition of 20% (Prud’hommede Lodder et al. 2006), while HERA (2004) assumes 5%deposition as a “worst-case scenario” in the case of zeolites.

Recently, Gudmundsson et al. (2007) identiWed particleemissions from textile handling in two Swedish house-holds. The authors assumed that the dust originated fromtextiles containing detergent zeolite residues. The very lim-ited data presented, however, do not allow any meaningfulconclusion to be drawn from this experiment.

In conclusion, the amount of detergent residues depos-ited on textiles is dependent on the composition of thedetergents, the conditions of washing and rinsing, and thetype of fabric. Values reported for zeolites range from lessthan 100 mg zeolite/kg fabric to up to 37,000 mg/kg fabric.Daily exposure through residues of laundry detergents ontextiles was calculated to be in the range of micrograms perkilogram bodyweight (HERA 2004). As zeolites are notexpected to be systemically available through dermaluptake, the systemic exposure through this route can beconsidered negligible.

Toxicology/safety

Zeolites for laundry applications have undergone extensiveinvestigation for their safety and toxicological properties inanimal studies, occupational surveillance and human volun-teer tests. The toxicological data on zeolites have recentlybeen summarised in peer-reviewed documents (OECD2006) and by industry (HERA 2004; Smulders et al. 2003).Methodological aspects of many of the key studies aredescribed in detail in the OECD document and are thereforenot reiterated here.

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Absorption, distribution, metabolism and excretion

At pH-values below 4.0, such as in the stomach, zeolitesmay partly hydrolyse and their crystal structure is partlydestroyed releasing sodium ions, silicic acid and aluminumsalts which could be taken up by the gastrointestinal tract.

In dogs, no appreciable gastro-intestinal absorption ofaluminum was found from orally administered zeolite A(30 mg/kg bw), sodium aluminosilicate (16 mg/kg bw) oraluminum hydroxide (675 mg/kg bw). About 2–3% of thesilicon in the administered zeolite A was taken up by thegastrointestinal tract (Cefali et al. 1995, 1996).

Rats dosed with up to 1,000 mg/kg bw of various sili-con-containing chemicals (zeolite A, sodium aluminosili-cate, sodium silicate or magnesium trisilicate) excretedurinary silicon in excess of background levels. The urine ofanimals dosed with zeolite A did not show any detectableincrease in aluminum (Benke and Osborn 1979).

After oral administration of 1,000 mg/kg bw of zeolite Ato rats, about 1% of the administered silicon was absorbedand eliminated via the kidneys and in the urine. Absorptionof aluminum could not be traced in the urine. The majorpart of the administered dose was excreted unchanged inthe faeces (Gloxhuber et al. 1983). Urinary excretion ofboth silicon and aluminum was slightly increased in ratstreated for 104 weeks with 1,000 ppm of zeolite A in theirdiet (Gloxhuber et al. 1983).

Inhalation of zeolite A by rats (20 mg/m3, 5 h/day, for13 days) resulted in the deposition of the substance in thelung parenchyma. The total weight of silicon in the lungs oftreated animals was signiWcantly higher (0.0822 §0.0294 mg) than that found in control lungs (0.0493 §0.0123 mg) (Gloxhuber et al. 1983).

Because of their physico-chemical properties, zeolitesare not expected to be absorbed through the intact skin.

Acute toxicity

Oral administration of synthetic zeolite particles (zeolitesA, Y, and X) produced a very little or no acute toxicity in avariety of animal species. Clinical signs were non-speciWc(sedation, dyspnoea, lateral posture, piloerection, hypoac-tivity) and were only observed at extremely high exposures(Gloxhuber et al. 1983; OECD 2006). It can be concludedthat these zeolites were non-toxic after acute oral exposure.

No abnormal clinical signs were observed after acutedermal exposure to high dose levels of zeolites A and Y(OECD 2006). It can be concluded that these zeolites werenon-toxic after acute dermal exposure.

Inhalation studies in rats and hamsters of synthetic zeo-lite A produced no signiWcant pulmonary inXammation orinterstitial Wbrosis. No clinical eVects were observed afteracute exposure to zeolites A, Y and X, with 1-h inhalation

LC50 values in rats of >18,300 mg/m3, and >2,300 mg/m3

for zeolites A and Y, respectively (Gloxhuber et al. 1983;OECD 2006).

Local tolerance

Zeolite A, Y and X were slightly or moderately irritating tothe eyes of rabbits (OECD 2006). Instillation of 10 mg zeo-lite A in the rabbit eye caused a foreign-body reaction forup to 48 h after the administration (Gloxhuber et al. 1983),possibly explained by mechanical irritation or pH change inthe aqueous environment.

Zeolite A, Y and X were not or very slightly irritating tothe skin of rabbits (OECD 2006). Repeated administrationfor 21 days of an ointment containing 10% zeolite A to rab-bit skin did not elicit any skin reactions nor did bathing ofhairless mice with a 2.5% zeolite A suspension. Humanskin tolerated without reaction a 24-h exposure to a 1% sus-pension of zeolite A in a patch test (Gloxhuber et al. 1983).

Forty volunteers with seborrhoic or sebostatic skin werepatch tested with textile probes containing zeolite residuesin concentrations between 1,050 and 36,765 ppm (Matthieset al. 1990). The patches were applied under occlusive con-ditions for 48 h. A second series of textiles containing2,900 or 8,300 ppm zeolite residues were provided to 30children (7 months to 6 years of age); the textiles wereworn between 1 and 11 days. In neither group, any skinreactions were found.

Skin and respiratory sensitisation

Zeolite A was not a skin sensitiser in limited animal tests;there is no evidence from human experience that syntheticzeolites may induce respiratory sensitisation (OECD 2006).There was no evidence of skin sensitisation in a guinea-pigmaximisation test (Gloxhuber et al. 1983).

Genotoxicity

In vitro

Ames tests performed with Salmonella typhimurium strainsTA98, TA100, TA1535, TA1537 and TA 1538 and E. coliWP2 (uvrA) both in the absence and the presence of meta-bolic activation at concentrations up to 10,000 �g/plateshowed no evidence of mutagenic activity of zeolite A(Prival et al. 1991; Zeiger et al. 1987).

In vivo

Sodium aluminum silicate was evaluated for its cytogeneticeVects in male rats by the US Food and Drug Administra-tion in oral single dose and repeated dose experiments

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(NTIS 1979). The test material did not induce chromo-somal aberrations in bone marrow cells nor dominant lethalmutations at the investigated dose levels of up to 5,000 mg/kg bw.

Repeated dose toxicity and carcinogenicity

Key elements of repeated dose toxicity studies are summa-rised in Table 2.

Oral route

No adverse eVects were observed in Wistar rats that werefed zeolite Y for a week at dose levels of 0, 800, 2,000 or5,000 mg/kg bw/day. Body weights as well as liver andkidney weights were not diVerent from controls (UnionCarbide Corporation 1977 as cited in OECD 2006).

In a 90-day feeding study with Wistar rats, the NOAELof zeolite A was determined to be 5,000 ppm or approxi-mately 250–300 mg/kg bw/day (OECD 2006; Gloxhuberet al. 1983). At 10,000 ppm eVects regarding the functionand histopathology of kidneys and bladder were found (i.e.,diminished urine secretion, hematuria, and ketone bodies inthe urine, 12/20 male animals revealed urinary calculimainly composed of Si). The histological examinationshowed a hyperplastic reaction of the transitional bladderepithelium in rats with calculi. At 10,000 ppm, silicon con-centrations of kidneys were signiWcantly higher than incontrols. No signiWcant diVerences were found with regardto the concentrations of iron in blood, copper and cobalt inthe liver, and zinc, aluminum, and copper in the kidneys.

In COX-SD rats fed zeolite A for 160–200 days, theNOAEL was 75 mg/kg bw/day (Procter & Gamble 1975,1976 as cited in OECD 2006). At 1,000–2,000 mg/kg bw/day (LOAEL) a signiWcant increase in the incidence ofbladder and kidney stones was observed. Other than this,there was no evidence of an alteration of urine parametersor kidney function.

In an oral chronic toxicity and carcinogenicity study(Gloxhuber et al. 1983; OECD 2006) groups of 50 maleand 50 female rats were fed 0, 10, 100 and 1,000 ppm ofzeolite A (corresponding to about 0.6, 6.0 or 60 mg/kg bw/day) in the diet for 104 weeks. Satellite groups of 15 malesand 15 females were used for initial and interim investiga-tions. Body weights and mortality rates of the treatedgroups were not signiWcantly diVerent from the controlgroup. Excretion of both silicon and aluminum in the urinewas slightly higher in the 1,000 ppm group, but was notsigniWcantly diVerent from controls. In animals that haddied during the study or were sacriWced because of theirpoor condition, the main causes of death or ill health werebasophilic adenoma and adenocarcinoma of the pituitarygland, adenoma and Wbroadenoma of the mammary glands,

subcutaneous Wbroma and some tumours of the genitaltract. No signiWcant incidence of a particular type of tumouror of spontaneous mortality was evident in any group. Notreatment-related Wndings were seen in any of the organsexamined histologically, and there was no indication of anytreatment-related induction of neoplasms.

If a cow is brought into a state of negative calcium bal-ance, the calcium homeostatic mechanisms are activated,thereby preparing the animal for the sudden draw on cal-cium around calving and preventing milk fever. In order tobind calcium in the intestinal tract and thereby decreasefeed calcium availability, zeolite A may be added as feedsupplement. Treatment for 2 weeks with 500 g/day of zeo-lite A was shown to signiWcantly reduce milk fever inci-dence in dairy cows. This treatment also reduced feedintake and induced transient hypophosphataemia; it mayreduce serum magnesium levels. Serum levels of copperand zinc were unaVected (EFSA 2007; Thilsing-Hansenand Jørgensen 2001).

Dermal route

There were no data available.

Inhalation route

Unpublished industry studies by the respiratory exposureroute are summarised in the OECD SIDS document (OECD2006). Further to this information, the Procter & GambleCompany performed a study in the mid-1970s at HazletonLaboratories Inc. using groups of 3 female and 3 maleCynomolgus monkeys. These animals were exposed to 0, 1,6 and 50 mg/m3 zeolite A dust for 6 h/day, 5 days a weekfor a period of 6, 12 or 24 months. Group mean values formass median diameters were between 2.8 and 3.8 �m, indi-cating that a fraction of the generated dust has reached thealveolar region of the lungs in these studies. A positive con-trol group received quartz dust at 50 mg/m3. The exposureof the positive control group and of the high exposuregroup was discontinued after 55 weeks. There were no clin-ical signs reported except for episodes of diarrhea that hadto be treated medically. Compound-induced histomorpho-logical changes were seen neither in the upper airways norin any of the non-respiratory tract organs examined. Thehistopathological eVects observed in the lungs of animals ofall groups in a dose-dependent manner were macrophageaccumulations accompanied by sporadic bronchiolitis andalveolitis. No evidence of progressive pulmonary Wbrosiswas observed. After a 90-day recovery period, these reac-tions had diminished in severity but had not fully disap-peared in the mid and high dose group. In the 1 mg/m3 dosegroup, these eVects were not evident after the 90-day recov-ery period. No increase in the incidence of neoplastic

123

Arch Toxicol

Tab

le2

Rep

eate

d do

se a

nim

al to

xici

ty d

ata

for

zeol

ites

NO

AE

L n

o ob

serv

ed a

dver

se eV

ect l

evel

LO

AE

L lo

wes

r ob

serv

ed a

dver

se eV

ect l

evel

Com

poun

dT

ype

of s

tudy

Spec

ies

Dos

es/r

esul

tsR

efer

ence

Ora

l rou

te

Zeo

lite

A14

days

Cow

500

g/da

y in

fee

d: r

educ

ed c

alci

um b

ioav

aila

bilit

y,

hypo

phos

phat

aem

ia (

tran

sien

t), r

educ

ed f

eed

inta

keE

FSA

(20

07);

Thi

lsin

g-H

anse

n an

d Jø

rgen

sen

(200

1)

Zeo

lite

A90

days

Rat

NO

AE

L: 5

,000

ppm

in d

iet (

ca. 2

50–3

00m

g/kg

bw

/day

)L

OA

EL

: 10,

000

ppm

in d

iet (

ca. 5

00–6

00m

g/kg

bw

/day

; eV

ects

on

kidn

ey, u

rina

ry b

ladd

er)

Glo

xhub

er e

tal.

(198

3); O

EC

D (

2006

);

Zeo

lite

A16

0–20

0da

ysR

atN

OA

EL

: 1,2

50pp

m in

die

t (ca

. 75

mg/

kg b

w/d

ay)

LO

AE

L: 2

0,00

0pp

m in

die

t (1,

000–

1,20

0m

g/kg

bw

/day

; eV

ects

on

kidn

ey u

rina

ry b

ladd

er)

Pro

cter

& G

ambl

e 19

75, 1

976,

in:

OE

CD

(20

06)

Zeo

lite

A2

year

sR

atN

OA

EL

: 1,0

00pp

m in

die

t (ca

. 60

mg/

kg b

w/d

ay;

high

est t

este

d do

se)

Glo

xhub

er e

tal.

(198

3); O

EC

D (

2006

)

Zeo

lite

Y7

days

Rat

NO

AE

L: 5

,000

mg/

kg b

w/d

ay (

no h

isto

path

olog

y pe

rfor

med

; hi

ghes

t tes

ted

dose

)U

nion

Car

bide

Cor

pora

tion

197

7, in

; O

EC

D (

2006

)

Der

mal

No

stud

ies

avai

labl

e

Inha

latio

n

Zeo

lite

A6,

12,

24

mon

ths

Mon

key

LO

AE

L 1

mg/

m3 (

spor

adic

inX

amm

ator

y re

acti

ons

in lu

ngs;

re

vers

ible

)P

roct

er &

Gam

ble

1976

, 197

7, in

: O

EC

D (

2006

)

Zeo

lite

A22

mon

ths

Rat

LO

AE

L 2

0m

g/m

3 (gr

eyis

h-w

hite

dep

osit

s; r

espi

rato

ry

dise

ase,

als

o in

con

trol

s)G

loxh

uber

eta

l. (1

983)

Oth

er r

oute

s

Zeo

lite

AIn

trap

erit

onea

l, 1–

50m

gR

atInX

amm

atio

n, d

epos

its

of in

ject

ed m

ater

ial;

not W

brog

enic

, no

t sili

coge

nic

Glo

xhub

er e

tal.

(198

3)

Zeo

lite

MS

4A

, M

S 5A

Intr

aple

ural

, int

rape

rito

neal

, su

bcut

aneo

us, 2

5m

gR

atN

o tu

mou

rs a

fter

intr

aple

ural

or

subc

utan

eous

inje

ctio

n;

1/40

with

mes

othe

liom

aft

er in

trap

erito

neal

inje

ctio

n of

MS4

AM

alto

ni a

nd M

inar

di (

1988

)

123

Arch Toxicol

changes was reported. A limitation of this study are thepotential side eVects caused by the medical treatment of theanimals, and the associated uncertainty in deriving the no-observed-adverse eVect-level (NOAEL).

A group of 15 male and 15 female Wistar rats wereexposed to 20 mg/m3 of zeolite A for 5 h/day, three times aweek for 22 months. The test material consisted of particlesranging from 0.5 to 10 �m, with most being less than 5 �min diameter. Moderate to extensive signs of respiratory dis-ease were seen in treated and control groups. Greyish-whitedeposits were seen in the phagocytes of the alveoli or theperibronchiolar or perivascular areas as well as in the peri-bronchiolar lymph nodes near the hilus. Isolated depositswere also seen in the mediastinal lymph nodes. No connec-tive tissue reactions or other reactions were seen aroundthese deposits. No tumours of the respiratory tract werediagnosed (OECD 2006; Gloxhuber et al. 1983).

Groups of 20 male and 20 female Fischer 344 rats wereexposed in inhalation chambers to a mean respirable dustconcentration of 0 or 10 mg/m3 of a synthetic non-Wbrouszeolite (chemical composition identical to erionite). Expo-sures were for 7 h/day, 5 days/week for 12 months. All ani-mals were observed for their life span. Three males andthree females per group were killed at 3, 6, 12, and24 months after exposure. Oregon Wbrous erionite and cro-cidolite were used as positive controls. The mean survivaltime for animals exposed to the synthetic non-Wbrous erio-nite was 797 days, 504 days for animals exposed to Oregonerionite, 718 days for animals exposed to crocidolite, and738 days for untreated animals. One pleural mesotheliomaand one pulmonary adenocarcinoma were seen in the non-Wbrous erionite-exposed rats. No neoplasms were found incontrols; 27 mesotheliomas were found in Oregon erionite-treated rats and 1 squamous-cell carcinoma of the lungswas found in crocidolite-treated rats (Wagner et al. 1985).

No adverse health implications of long-term workerexposure to synthetic zeolites have been reported (OECD2006).

Other routes

Long-term carcinogenicity bioassays with zeolite types MS4A (sodium aluminum silicate) and MS 5A (calcium alumi-num silicate), administered by intraperitoneal, intrapleural,and subcutaneous injection in Sprague-Dawley rats, wereundertaken by Maltoni and Minardi (1988). In these stud-ies, groups of 20 male and 20 female Sprague-Dawley ratseach were administered 25 mg of the test material in 1 mlof water or the solvent alone by single intraperitonel, intra-pleural or subcutaneous injection. All animals were keptuntil spontaneous death. Full necropsy and histopathologicexaminations were performed in each animal on the tissueat the site of injection, brain and cerebellum, thymus, lungs,

liver, kidneys, adrenals, spleen, pancreas, stomach, uterus,gonads, subcutaneous, mediastinal and mesenteric lymphnodes, and any other organs with pathologic lesions.

At the site of injection, only one tumour was found: aperitoneal mesothelioma, which was observed at necropsyin a male rat treated by intraperitoneal injection with MS4A, 141 weeks after treatment. No other diVerences werefound between the treated and control groups. According tothe study authors, the spontaneous onset of peritoneal mes-otheliomas in the breed of rats used at the institute is infre-quent, but not exceptional (3 cases in 1,179 rats). Theresponsiveness of the model used to the mesotheliomato-genic eVects of particles is high. Under the same experi-mental conditions, the intraperitoneal injection of 25 mgcrocidolite caused the onset of peritoneal mesotheliomas in97.5% of animals, and the intrapleural injection of 25 mgerionite produced pleural mesotheliomas in 87.5% of ani-mals.

Gloxhuber et al. (1983) studied the silicogenic activityof zeolite A (pure and formulated material) in several ani-mal studies. Doses between 1 and 50 mg of zeolite A, sus-pended in 0.5 mL Tyrode’s solution were administered bysingle injection intraperitoneally into Wistar rats.

Injections of quartz DQ12 served as positive controls;animals were sacriWced after 3, 6 or 11 months and exam-ined histologically. Zeolite application led to an inXamma-tion of abdominal organs and to deposits of theadministered material in the regional lymph nodes, theabdominal cavity and the mediastinum without Wbrogenicor silicogenic eVects. At study end deposition seemed inmany rats to be reversible with exception of the highestdose level. Administration of zeolite A induced deposits onthe capsule of the liver, spleen and kidney. The administra-tion of quartz led to the formation of quartz typical lesionswithin the abdomen.

Reproductive and developmental toxicity

No signs of toxicity to reproductive organs by syntheticzeolites were reported in the unpublished studies reviewedby OECD (2006), or in the studies reported by Wagneret al. (1985) and Gloxhuber et al. (1983).

Type A Zeolite (“Arogen 2000”, JM Huber Corp.) con-taining 15.8% sodium 19.0% silicon, and 20.1% aluminumwas tested for its teratogenic potential (Nolen and Dierk-man 1983). Studies were performed using the standardFDA Segment II protocol using Sprague-Dawley rats andNew Zealand rabbits. Zeolite A in distilled water was givento rats by gavage at concentrations of 74 or 1,600 mg/kg ofbody weight on days 6–15. Rabbits were given doses of 74,345, and 1,600 mg/kg of Zeolite A by oral gavage on days6–18. Vehicle controls were included but no details wereprovided. Type A zeolite produced no adverse eVects on the

123

Arch Toxicol

dam, the embryo, or the fetus in either the rats or rabbits atany of the doses tested.

Food grade aluminosilicate with a Na:Al:Si ratio of1:1:13 has been tested for teratogenic potential by the USFood and Drug Administration and was found to have noeVects in rats, mice, rabbits and hamsters (NTIS 1973).

Discussion

Synthetic and naturally occurring zeolites are used in avariety of applications, including the use as desiccants,adsorbants, catalysts and molecular sieves. The syntheticzeolites A, P, X and Y are increasingly used in laundrydetergents to substitute phosphates as builders. Workersand consumers may, therefore, repeatedly be exposed tothese materials. This article puts mechanistic, toxicologicaland exposure data into context for a safety assessment.

Exposure to zeolites may occur through the oral, dermaland respiratory route. Oral exposure may occur by swal-lowing airborne zeolite dust particles that were trapped inthe upper respiratory tract because of their size, or throughzeolite-containing drinking water. Oral exposure may alsooccur by accidental intake of zeolite-containing detergents.The acute and repeated dose toxicity of laundry zeolitesafter oral exposure has been investigated in several animalstudies and was shown to be extremely low, most probablybecause of their low systemic bioavailability. Most of theingested amount remains undissolved in the gastrointestinaltract and is excreted unchanged in the faeces; part of thezeolites decomposes under the acidic conditions of thestomach to release silicon and aluminum species whichcould be absorbed by the gastrointestinal tract.

No observed adverse eVect levels (NOAELs) in animalstudies were around 60 mg/kg bw/day with higher doses(around 200–300 mg/kg bw/day) inducing eVects on thekidney and urinary bladder after long-term ingestion. Noother signs of systemic toxicity were observed; in particu-lar, there was no inXuence on electrolytes and trace elementconcentration of plasma and organs. EVects on kidney andurinary bladder were due to long-term silicon uptake fromdecomposed zeolites by the gastro-intestinal tract followedby increased silicon concentrations in kidney and urinewith the formation of silicon containing calculi in the uri-nary tract and mechanical irritation of the bladder epithe-lium by these concrements. Whilst an increase in siliconlevels could be shown in animal studies after oral zeoliteexposure to high doses, no increase was found in the alumi-num levels of tissues, urine or blood plasma. Nevertheless,the uptake of aluminum released from zeolites in the gas-trointestinal tract could be seen as a potential safety con-cern because of the recognised eVects of aluminum onreproduction and the developing nervous system. These

eVects led to the replacement of the previous provisionaltolerable weekly intake level of aluminum of 7 mg/kg bwby a new proposed value of 1 mg/kg by the Joint FAO/WHO Expert Committee on Food Additives (JECFA,2006). Aluminum was also considered as potentially neuro-toxic. As the absorption of free aluminum by the gastro-intestinal tract is however minimal, i.e. less than 0.1%, thecontribution to the body burden from orally ingested laun-dry zeolites is negligible. Furthermore, humans are fre-quently exposed to aluminum through their diet, drinkingwater, and utensils used during food preparations andeYcient excretion mechanisms exist in the human body tomaintain homeostasis.

Under the current conditions of manufacture and use, nosigniWcant eVects of synthetic zeolites on the bioavailabilityof other compounds, including trace elements, are to beexpected.

Synthetic zeolites released into the aquatic environmentwere shown to be converted into natural occurring alumosi-licate species and natural constituents of waters, sedimentand soils (Cook et al. 1982). A direct exposure to zeolitesthrough the drinking water is therefore not expected.

Serious eVects after accidental oral ingestion of deter-gent formulations and cleaning agents have been reported(e.g. BfR 2005). These eVects are generally attributed to thecorrosivity and severe irritation of mucosal membranes thatmay be caused by ingredients other than zeolites if swal-lowed in large quantities. In view of the ion exchange prop-erties, however, zeolites may be expected to alter the ioniccomposition, pH and buVering capacity of the gastrointesti-nal tract under conditions of overexposure. Except for epi-sodes of diarrhoea in monkeys exposed to high doses ofzeolite A dust by inhalation (and probably having swal-lowed most of the particles) no adverse gastrointestinaleVects have however been reported from animal studiesperformed with high zeolite exposures.

Dermal exposure to zeolites may occur in occupationalsettings or in households when detergents are handledeither as such or in solutions. Because of their physico-chemical properties zeolites are however not expected to betaken up through the intact skin. Systemic exposure is,therefore, not expected to be relevant. Zeolites in aqueousenvironment form alkaline suspensions (pH 10–10.5)which may cause skin or mucous irritation. It is, therefore,recommended that personal protection equipment is wornby workers. Dermal exposure to zeolites by consumers ishowever very limited as the contact time when unpackinglaundry powder or tablets is short, and the solutions usedfor the hand-wash of laundry are diluted.

Since the poorly soluble zeolite particles are smallenough (1–10 �m) to enter the lungs, short-term inhalationof these materials could overload lung clearance mecha-nisms, causing temporary irritation. Formation of NaOH

123

Arch Toxicol

may add to the irritant action of zeolites in the airways. Aszeolites are hygroscopic and quickly agglomerate to largerparticles, most of the material will however be retained inthe upper airways or be swallowed. Particles that reachedthe lung are deposited there and may cause histopatholo-gical eVects such as macrophage accumulations accompa-nied by inXammatory eVects such as bronchiolitis andalveolitis. From animal studies and medical surveillancethere is no evidence that inhalation of these types of zeolitecan cause silicosis or tumours.

Zeolites A and X induced no gene mutations in vitro. Invivo clastogenesis studies showed no evidence of inductionof chromosomal aberrations. It is important to note that eri-onite—a naturally occurring Wbrous zeolite—has beenshown to be genotoxic and to induce mesothelioma inhumans and animals. Though the mechanism of action isnot fully understood yet, it is believed that the Wbrous shapeand surface properties of erionite play a signiWcant role inthe carcinogenic process. A comparative study of the bio-logical response and chemical reactivity of several zeolites(erionite, mordenite, zeolite Y) concluded that the toxicityof zeolite Y would be very low.

Depending on the conditions of washing and rinsing,detergent residues may remain after the wash on textiles.For zeolites, residue concentrations of up to 37,000 mg/kgfabric have been measured. Although it is not expected thatzeolites penetrate the intact skin barrier and therebybecome bioavailable, these deposits of crystalline materialmight possibly cause eVects on sensitive skin by mechani-cal irritation (“intolerance reactions”). Co-operation ofdetergents manufacturers with manufacturers of washingmachines is, therefore, important to Wnd the right balancebetween environmental aspects such as energy and watersavings and the risk of detergent residues on textiles due toinsuYcient rinsing.

Conclusion

Based on available mechanistic and toxicological data andtaking into account exposure information, it is concludedthat the synthetic zeolites A, P, X and Y as currently used indetergent formulations are safe for consumers under theconditions of the recommended use. This is in accordancewith earlier opinions on the safety of zeolites (BfR 2007;CSTEE 2003; OECD 2006). Due to irritant eVects of theundiluted materials on mucous membranes and the respira-tory tract, the exposure of workers should be controlled.The co-operation of detergent manufacturers with the man-ufacturers of washing machines is necessary to Wnd theright balance between environmental aspects such asenergy and water savings and the occurrence of zeolite res-idues on textiles due to insuYcient rinsing.

Acknowledgments This work was funded by the members of EU-ZEPA (European Zeolites Producers Association).

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