Aluminium sulphate

Endpoint summary

Description of key information

Upon uptake into the biological systems the inorganic salts in the sulfate category will dissociate into the sulfate ion and the corresponding cations. Aluminiun, potassium, magnesium and calcium will enter the body electrolyte pool and are not expected to play a significant toxicological role except at extremely high doses.   All cells require inorganic sulfate for normal function. Sulfate is among the most important macronutrients in cells and is the fourth most abundant anion in human plasma (300 µM). All cells need active transport systems for influx/efflux of sulfate (Markovich, 2001).  The absorption of sulfate depends on the amount ingested. 30 - 44 % of sulfate was excreted in the 24-h urine after oral administration of magnesium or sodium sulfate (5.4 g sulfate) in volunteers. At high sulfate doses that exceed intestinal absorption, sulfate is excreted in feces. Intestinal sulfate may bind water into the lumen and cause diarrhea in high doses. Sulfate is a normal constituent of human blood and does not accumulate in tissues. Sulfate levels are regulated by the kidney through a reabsorption mechanism. Sulfate is usually eliminated by renal excretion. It has also an important role in the detoxification of various endogenous and exogenous compounds, as it may combine with these to form soluble sulfate esters that are excreted in the urine (EPA, 2002).
Dermal absorption:
 Results indicate that only 0.012% of the applied aluminium was absorbed through the skin. At this rate, about 4 microg of aluminium is absorbed. 
The amount of aluminum absorbed from regular use would be 0.25 μg/d.
A QSAR model predicts that the permeability of alumimium sulphate to human skin is quite low. The permeability coefficient was determined to be 0. 4.87e-005 mg/cm2, which is around 0.12% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)= 7.58e-009 cm/hr.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

0.012

Additional information

ABSORPTION, DISTRIBUTION & EXCRETION:

In mammals GI absorption of ingested aluminum is poor due to transformation of aluminum salts into insoluble aluminum phosphate (AlPO4)in digestive tract, brought about by pH changes and presence of phosphatein diet. At higher doses, such as 200 mg aluminum/kg as aluminum sulfate,intestinal absorption is about 10% in rats ... .

Venugopal, B. and T.D.Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978., p.107]

 

No increases in urinary excretion of aluminum or in aluminumdeposition in organs of rats when twice normal aluminum concentration wasgiven as ... sulfate in food. When concentration was increased to about 15 times normal, both urinary excretion and organ deposition were enhanced.

Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology ofMetals. New York: Elsevier North Holland, 1979., p. 278]

 

In rats retention of aluminum in bone, liver, and testes ... increasedwith large ingested doses such as 200 mg aluminum/kg in the form of aluminum sulfate ... Level in brains of ... rats increased /SRP: to alevel/ tenfold that of control.. Excretion is mainly fecal, representing both unabsorbed ... and aluminum excreted into digestivetract from liver via bile.

Venugopal, B. and T.D. Luckey. Metal Toxicityin Mammals, 2. New York: Plenum Press, 1978., p. 107]

 

Spring wheat plants (Triticum aestivum (L.) cvs. Kadt and WW 20299) weregrown in culture and exposed to aluminum as aluminum sulfate. Aluminumuptake by roots of 9-day old plants at pH= 4.1 during 2 hr (initialuptake) could be divided into a free diffusible component and a boundfraction which was non-exchangeable with calcium. Two types of aluminumbinding sites were identified: one insensitive to low temp (2 deg C) andone existing only at 22 deg C. At 2 deg C and 200 uM aluminum, uptakereached approx 1.2 umol aluminum/g fresh wt within 50 min and remained atthis level. At 22 deg C, aluminum uptake did not reach equilibrium within150 min and was characterized by a rapid uptake (0.50 umol aluminum/gfresh wt)for less than 20 min, followed by another phase at 0.19 umolAluminum/g fresh wt/hr. The initial uptake of aluminum increased underconditions which favored leakage of phosphorus from the roots; uptake ofaluminum from 50 uM aluminum was about twice as high in high phosphorusplants compared to low phosphorus plants. With 1X10-4 dinitrophenolpresent in the external soln, aluminum uptake increased by approx 70% at150 and 250 uM aluminum and by approx 25% at 50 uM aluminum in bothcultivars.

[Pettersson S, Strid H; J Plant Physiol 134 (6): 672-7 (1989)]

 The kinetics of aluminum sulfate were studied in rats who received 0.1mg/kg aluminum sulfate, administered as an intravenous bolus injection.The aluminum sulfate content of blood samples was determined by flamelessatomic absorption spectrophotometry. Increasing the administered dosesignificantly increased the elimintion half-life, with a correspondingdecrease in systemic clearance and a significant increase in volumes ofdistribution. At both doses, blood-plasma ratios ranged from 0.8 to 1.0,indicating considerable uptake or binding of aluminum sulfate by bloodcells.

[Pai SM, Melethil S; J Pharm Sci 78 (3/89): 200-2 (1989)]

 

A single low dose oral exposure to /(26)Al-labelled/ aluminum sulfate canresult in a substantial increase in brain aluminum levels in rats. In 6 ofthe 8 exposed rats, brain aluminum levels were 10 to 300 times higher thancontrol values (brain aluminum levels in the remaining 2 rats were similarto control levels).

[DHHS/ATSDR; Toxicological Profile for Aluminum (July1999). Available from, as of May 21, 2004:

 

Two groups of rats were maintained on diets containing 180 ppm or 2835 ppmaluminium (as sulfate for 26 days). Analysis of tissues for aluminiumcontent, showed significantly increased retention in liver, brain, testes,blood and femur of rats in the higher test group. In these balance studieswith mice 25-30% retention was found, whereas 10% absorption is reportedafter aluminium treatment in rats. 

[Joint FAO/WHO Expert Committee onFood Additives; WHO Food Additives Ser 24: Aluminum (1989). Availablefrom, as of June 4, 2004:

 

Aluminum reabsorption by the kidney of rats treated with up to 800micrograms of aluminum-sulfate (10043013) or aluminum-citrate (31142560)was determined by calculation of the filtered load of aluminum which wasobtained from measurements of the filterability of aluminum from theplasmaand the glomerular filtration rate. The excretion ofaluminum-citrate was found to be markedly higher than that ofaluminum-sulfate. A decrease in the percentage of ultrafilterable aluminumwas seen with increasing plasma aluminum concentrations. The percentage ofultrafilterable aluminum-citrate was considerably higher than that seenfor aluminum-sulfate over the range of plasma aluminum concentrations. Theexcretion of aluminum-citrate, however, for any given filtered load, wasnot significantly different from the excretion of aluminum-sulfate. Theauthors conclude that the aluminum filtered following aluminum-sulfateexposure may be a form of aluminum-citrate which is then easily reabsorbedand that aluminum removal by the body may be enhanced by preventing thetubular reabsorption of this easily filtered aluminum species.

[Lote CJ etal; Hum Exp Toxicol 14 (6): 494-499 (1995)]

 

0.1 mg/kg of aluminum sulfate was administered as a bolus to rats via the portal or systemic route. Blood aluminum concentrations declined in amonoexponential fashion, with half-lives of 0.7 h (portal) and 1.08 hsystemic). Corresponding systemic clearances were approximately 48.9 and35.1 ml/kg/h. Systemic availability following portal administration was0.66, indicating a significant first-pass effect. Biliary aluminumrecovery was negligible following both routes. Bile flow decreasedimmediately following injection of aluminum via the portal route only;flow remained suppressed throughout the study. Liver recovery of aluminumat 8 h post administration was higher with the portal route.

[Xu ZX et al;J Pharm Sci 81: 160-163 (1992)]

 

MECHANISM OF ACTION:

Glioma (C-6) and neuroblastoma (NBP2) cells were utilized to assessearly changes in oxidative parameters consequent to a 48-hr exposure toaluminum sulfate. A 500-uM concentration of this salt produced asignificant increase in reactive oxygen species (ROS) production and asignificantdecrease in glutathione (GSH) content in glioma cells.

However, the same concentration of the aluminum salt did not lead to anysignificant changes in the neuroblastoma cells. Mitochondrial respiratoryactivity in glioma cells was also found to be significantly higher in thealuminum treated cells. As judged by morin-metal complex formation,aluminum can enter glioma cells much more readily than neuroblastomacells. 

[Campbell A et al; Free Radic Biol Med 26 (9-10): 1166-1171(1999)] 

 

The aim of this work was to assess by in vivo brain microdialysiswhether chronic administration of aluminium in the drinking water (2.5%aluminium sulfate) also impairs the glutamate-nitric oxide-cGMP pathway inthe cerebellum of rats in vivo. Chronic exposure to aluminium reducedNMDA-induced increase of extracellular cGMP by ca 50%. The increase inextracellular cGMP induced by the nitric oxide generating agentS-nitroso-N-acetylpenicillamine was higher (240%) in rats treated withaluminium than in controls. Immunoblotting experiments showed thataluminium reduced the cerebellar content of calmodulin and nitric oxidesynthase by 34 and 15%, respectively. Basal activity of soluble guanylatecyclase was decreased by 66% in aluminium-treated rats, while the activityafter stimulation with S-nitroso-N-acetylpenicillamine was similar tocontrols. Basal cGMP in the cerebellar extracellular space was decreasedby 50% in aluminium-treated rats. These results indicate that chronicexposure to aluminium reduces the basal activity of guanylate cyclase andimpairs the glutamate-nitric oxide-cGMP pathway in the animal in vivo.

[Hermenegildo C et al; Neurochem Int 34 (3): 245-253 (1999)]

 

Aluminum salts have been shown to stimulate (3)H-thymidine incorporation in primary cultures of bovine brain microvessel endothelial cells. Aluminum chloride or sulfate salts in concentrations between 0.01 to 100 uM were, in general, most effective in stimulating thymidine uptake bybovine brain microvessel endothelial cells with maximal efects observedafter a 24 hr exposure to the metal. Concentration of aluminum saltsgreater than 100 uM inhibited thymidine incorporation. Cell numbers werenot affected by exposure to concentrations of the aluminum salts less than approx 100 uM. Concentrations producing half maximal stimulation of bovinebrain misrovessel endothelial cell thymidine incorporation were approx,0.3 uM and 0.5 uM, for aluminum chloride and aluminum sulfate,respectively. These findings indicate that bovine brain microvesselendothelial cells are sensitive to lower concentrations of aluminum saltsthan other mammalian cell types. Hydroxyurea completely inhibitedthymidine incorporation into bovine brain microvessel endothelial cells inthe presence and absence of aluminum suggesting that thymidineincorporation into bovine brain microvessel endothelial cells isrepresentative of DNA synthesis. Endothelial cell growth factor stimulatedboth measured DNA synthesis and bovine brain microvessel endothelial cellnumbers in the primary culture system. Aluminum had only slight effects onDNA synthesis in edothelial cell growth factor stimulated bovine brainmicrovessel endothelial cells. In contrast to endothelial cell growthfactor, aluminum then, appears to provide a stimulus for DNA synthesis butnot subsequent mitosis in bovine brain microvessel endothelial cells.

Results from this study are consistent with previous studies in other celltypes and with current knowkedge of the effects of aluminum on the blood brain barrier in vivo. /Aluminum salts/

[ Audus KL et al; Res Commun ChemPathol Pharmacol 60 (1): 71-85 (1988)]

 

Two groups of rats were maintained on diets containing 180 ppmor 2835 ppm aluminium (as sulfate for 26 days). Analysis of tissuesfor aluminium content, showed significantly increased retention inliver, brain, testes, blood and femur of rats in the higher testgroup (Ondreickaet al., 1966). In these balance studies withmice 25-30% retention was found (Ondreickaet al., 1966) whereas10% absorption is reported after aluminium treatment in rats (Kortus, 1967).

 

Dermal absorption:

 

Utilization of antiperspirant with aluminum would contribute to the body burden if aluminum passes through the skin barrier. There is some evidence from case studies, described below, that small amounts of aluminum do reach the systemic circulation. However, to date, no data for dermal bioavailability are available from controlled studies of more than one or two individuals.

In the study of Flarend et al. (2001), 26Al-chlorohydrate (aluminum complex in antiperspirant) was applied to a single underarm of one man and one woman. The cumulative urinary excretion after 43 days following the application accounted for 0.0082% (male) and for 0.016% (female) of the applied dose.

After correcting this fraction for the aluminum not excreted in urine (15% of the absorbed dose), this application was estimated to result in a dermal bioavailability of about 0.012%. On the basis of these data, the authors estimated that the amount of aluminum absorbed from regular use would be 0.25 μg/d.

Guillard et al. (2004) reported on one clinical case in which a woman who used an antiperspirant cream with aluminum chlorohydrate over four years showed elevated levels of aluminum in plasma and urine (10.47 μg/dL in plasma12).

When the woman discontinued use, concentrations in her urine and plasma dropped to reported normal values after the third and eighth months, respectively.

References: Olivier Guillard PhD, Bernard Fauconneau PhD, Didier Olichon PhD, Geneviève Dedieu and Roger Deloncle PhD, Hyperaluminemia in a woman using an aluminum-containing antiperspirant for 4 years ,The American Journal of Medicine,Volume 117, Issue 12, 15 December 2004, Pages 956-959 ,

 

A QSAR model predicts that the permeability of alumimium sulphate to human skin is quite low. The permeability coefficient was determined to be 0. 4.87e-005 mg/cm2, which is around 0.12% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)= 7.58e-009 cm/hr.