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Key value for chemical safety assessment

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As no studies investigating the toxikokinetic properties of reaction mass of aluminium hydroxide and aluminium nitrate and aluminium sulphate are available in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from supporting substances (structural analogues) e.g.aluminium compounds was considered.Aluminium oxide, aluminium hydroxide and aluminium metal are insoluble in water under standard conditions. Based on these physico-chemical characteristics, it is likely that under physiological conditions, the absorption and associated bioavailability of aluminium hydroxide, aluminium oxide and aluminium metal will be low. Following oral absorption, aluminium is present in the body as the ionic species (Al3+), which is the determining factor the systemic effects of aluminium, including acute toxicity. Hence, it can be assumed that Al3+is the substance of biological interest and the toxicological effects can be attributed mainly to Al3+.

Following absorption of the substance used for read-across like aluminium salts (e.g., aluminium nitrate, aluminium chloride, aluminium sulphate, etc.) aluminium is present in the body as Al3+as well. Therefore, with appropriate consideration of bioavailability differences, it is reasonable to consider data obtained from aluminium salts, generally more soluble, in the hazard identification of the highly soluble aluminiumsulfatenitrate.

In conclusion, in terms of hazard assessment of toxic effects, available data for human health endpoints for various aluminium compounds can be read-across to aluminiumsulfatenitrate since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007; ATSDR, 2008).

 A detailed justification read-across is provided in the technical dossier (see IUCLID Section 13) as well as in the Chemical Safety Report (see Part B).

 

Absorption/Excretion

CAS 132741-9 (aluminium chloride basic), CAS 10043-01-3 (aluminium sulphate), CAS 39290-78-3 (aluminium chloride hydroxide sulfate)

Absorption and excretion of aluminium chloride basic, aluminium sulphate and aluminium chloride hydroxide sulfate was tested in rats according to OECD guideline 417. The test substance was administered once in a dose level of 200 mg/kg AlCl3 equivalents to aluminium chloride basic, aluminium sulphate and aluminium chloride hydroxide sulfate (correspondent respectively to 0.450. 0.447 g and 0.883 of test solution/kg bw). The following parameters were evaluated: mortality, clinical signs, and body weights. Urine and faeces were collected and weighed at predose and at 24 hours intervals after dosing until 120 hours.

No mortality was observed in the study. No treatment related findings were noted.  

Except for one male, no treatment related findings were noted. The male displayed slight hunched posture and slight piloerection from day 3 onwards just for aluminium polychlorosulphate)

Significant aluminium concentrations were present predose, in urine as well as faecal samples (although predose concentrations were very variable for the urine data). This indicates that aluminium exposure can also occur from external sources, outside dosing alone. Therefore, concentration data of aluminium obtained after dosing were corrected for the predose sample.

The excretion of aluminium in urine was very low, <0.5% in both sexes. Excretion occurred mainly in the first 24 hours after dosing. Most of the aluminium was excreted in the faeces, indicating that aluminium is not absorbed after oral administration. In general, excretion took place during the first 24 hours after dosing. In some cases, the percentage of aluminium excreted in faeces was >100%. This is due to the fact that animals can also be exposed to aluminium from outside sources.

The average oral absorption of aluminium chloride basic was 0.028% for males and 0.026% for females.

The average oral absorption of aluminium sulfate was 0.037% for males and 0.001% for females. These data s indicates that aluminium salts absorption is very low. There seems to be a gender difference in the absorption of aluminium Sulphate, with the males having the higher absorption.

The average oral absorption of aluminium chloride hydroxide sulfate was 0.031% for males and 0.007% for females. This indicates that absorption is very low. These data s indicates that aluminium salts absorption is very low. Moreover, there seems to be a gender difference in the absorption of Aluminium Sulphate, with the males having the higher absorption.

This toxicokinetic study revealed that oral absorption of 200 mg/kg bw AlCl3 molar equivalents aluminium chloride basic, aluminium sulphate and aluminium chloride hydroxide sulfate was very low.

 

 

Aluminium compounds

In a study (Dziwenka, 2008) relative biodistribution of aluminium following repeated, oral administration of various aluminium salts was evaluated.

Sprague Dawley rats (n = 5 per sex per group) were orally gavaged with formulations of aluminium citrate, sulfate, nitrate, chloride and hydroxide, each delivering a dosage of 30 mg/kg bw elemental aluminium. Control animals were similarly dosed with deionized water. Animals were dosed daily for either 7 days or 14 days, followed by blood and organ collection. Blood/organs were analysed for aluminium, manganese, iron and copper concentrations. Animals were maintained on low aluminium feed (9 μg/kg) and water (2 ng/mL) for a 2 week period prior to and during dosing. In-life observations included body weights, food and water consumption and general health. There appeared to be little influence of treatment on aluminium levels in most tissues for either sex. Significant differences did exist between controls and treated animals for bone (day 7 males) and kidney (day 7 males and day 14 females). For aluminium citrate treatment these differences were highest: concentration of aluminium in the bone (day 7 males) was 0.61 μg/g, 239% above controls, in kidney (day 7 males) it was 0.60 μg/g, (+200%), and in kidney (day 14 females) it was 0.90 μg/g, (+350%). Concentrations of aluminium in these tissues for other treatments were much lower by comparison.

A surprising result was that for most tissues, the concentration of aluminium was less after 14 days dosing than it was after just 7 days dosing, regardless of sex or treatment. The differences were statistically significant primarily in the case of blood and bone. This phenomenon occurred in controls as well. These results suggest that dosing had little influence on systemic levels of aluminium in most tissues, and the observed concentrations were likely the result of previous exposure to aluminium from regular feed and water (i.e., prior to the 2 week predose period).

The decline in systemic concentrations likely reflected clearance of previously deposited aluminium, and that treatment had little effect (with the exception of bone and kidney). The only tissue that had a pattern in which aluminium concentration was higher after 14 days compared with 7 days was spinal cord. This was true of every group (including controls) and sex, with the majority (7 of 12) of the differences being statistically significant.

The other neuronal tissue examined, brain, was largely neutral, showing little change between day 7 and 14. This may suggest poor clearance in neuronal tissues and, in the case of spinal cord, bioaccumulation. It is possible that if animals were maintained on the low aluminium feed/water for a longer pre-dose period, baseline levels in blood and tissue would be low enough to observe an influence from treatment.

Obviously, higher dosing would have had a more observable effect on systemic aluminium, but the solubility of salts limited the ability to deliver a higher dosage of aluminium via a bolus administration.

Dermal absorption

 

Flarend et al.(2001)studied the uptake of aluminium from aluminium chlorohydrate-containing antiperspirant using26Al as a tracer. The study was carried out using two human volunteer subjects, one male and one female. 0.4 mL of 21%26Al-ACH solution was applied to an area 3”x4” in the left axilla of the two volunteers. Application was done using a pre-soaked (deionized water) cotton swab. The area was allowed to air dry afterwards. After the ACH had been applied and left to dry, the area was occluded with a bandage with adhesive edges that did not contact the area of ACH application. Each morning for the next 6 days strips of tape were applied to the axilla and then stripped away, the area gently washed with towelettes, and the bandage, tape strippings and towelettes sealed in freezer bags and stored in a refrigerator until analysis. The female subject developed a mild irritation to the bandage adhesive that required cessation of their use after 4 days. Blood samples were taken by venipuncture before ACH application (0 hours) and also at 6 and 14 hours post-application; then on days 1, 2, 3, 4, 5, 6, 7, 9, 11, 14, 18, 24, 32, 42 and 53 after application. Twenty-four hour urine samples were collected daily for the first 11 days after application; then from days 13 to 14, 17 to 18, 23 to 24, 31 to 32, 41 to 42, and 52 to 53. The samples were preserved using 10-20% (by volume) conc. HNO3.26Al in the samples was determined by accelerator mass spectrometry. ICP-MS was used to measure Al levels in a subset of urine samples to ensure that the amount of Al in the urine would not influence the results from the AMS analyses. Based on the amounts of26Al in the bandages, tapes and towelettes, 48% of the Al applied to the underarm of the male subject was recovered from the skin surface in 6 days; 31% was recovered in 4 days in the female subject. Levels of26Al in the blood showed a clear increase after the application of ACH and26Al could still be detected 15 days after application. Although26Al could be detected in the blood, the levels were too low for reliable estimation of the % absorbed. Results showed that 0.0082% of the estimated absorbed26Al was eliminated in the urine of the male subject and 0.016% in the urine of the female subject. In conclusion, aluminium is absorbed into the systemic circulation on single occluded application of aluminium chlorohydrate to underarms. Based on urine measurements, 0.012% of the applied aluminium was absorbed showing that aluminium does not cross the dermal barrier effectively.

 

 

 

Bioaccumulation (Ondreka, 1966)

 

CAS 10043-01-3 (aluminium sulphate)

Two studies (Ondreka, 1966) about toxicokinetics were conducted. In the first experiment 1 group of rat received a low dose of aluminium and the other a high. Aluminium concentrations in different tissues were measured after the treatment

In the second study 1 group received first a low dose of aluminium followed by a higher dose. The effect on phosphorus is examined.

The results of both studies show that aluminium accumulates in various tissues, especially in the skeleton, liver and testes. And a high intake of aluminium caused a negative phosphorus balance in the rat, with an increased output of phosphorus in the faeces.

 

Bioavailability

 

Aluminium compounds

 

The fraction of aluminium that enters the bloodstream of the rat following the ingestion of aluminium citrate, aluminium chloride, aluminium nitrate, aluminium sulphate, aluminium hydroxide, finely divided aluminium metal, powdered pot electrolyte, FD&C Red 40 aluminium lake, SALP, Kasal, sodium aluminium silicate was evaluated (Priest, 2010). The test materials were prepared using26Al as a radioactive tracer. Aluminium citrate, aluminium chloride, aluminium nitrate, aluminium sulphate were used as aqueous solutions. Aluminium hydroxide, aluminium oxide, SALP, Kasal, and sodium aluminium silicate were suspended in water with added 1% carboxymethylcellulose (to maintain a suspension). The solutions and suspensions were administered through feeding tubes. The particle sizes of FD&C red 40 aluminium lake, powdered pot electrolyte and aluminium metal were too large to pass through feeding tubes; they were mixed with honey and added to the back of the rat tongue.

An initial experiment was conducted to measure the fraction of bloodstream aluminium that is retained by the rats by day 7 post-injection. Twelve rats were injected intravenously with 0.5 ml of aluminium citrate solution containing 0.19ng of26Al. Six control animals received citrate injections containing no26Al. The animals were sacrificed on day 7 post-injection. To address issues related to possible contamination of samples by external radionuclide from urine and faeces, in six rats the retained aluminium fraction was determined in short carcasses excluding tissues potentially contaminated by urine and faeces (the pelt, gastrointestinal tract, paws, feet and heads). In the other six rats, the retained aluminium fraction was determined in full carcasses (except pelts). The fraction of26Al uptake excluded by the analysis of the reduced samples was determined by comparing the results for short carcasses with the results for full carcasses. The resulting correction factor was then used in the main study (ingestion) to determine Al content in the full carcass from the Al content in the short carcass.

In the main (ingestion) study each compound was administered to 6 rats. Six control animals received water. Seven days after the administration, the rats were sacrificed, their short carcasses were ashed in a muffle furnace, and a white ash was sent for analysis to. At the university, a known amount of stable isotope27Al was added to each sample, the samples were dissolved in acid, and aluminium was extracted by precipitation. The26Al:27Al ratio was determined by accelerator mass spectrometry (AMS). The amount of26Al in each sample was calculated and corrected to account for the amount discarded with the unanalyzed tissues. The fraction of26Al absorbed was calculated by reference to the26Al administered and the26Al fraction retained at 7 days post-injection (determined in the initial experiment).

 

The highest fractional uptake of26Al (~0.21%) was seen for aluminium sulphate and the lowest (~0.02%) for aluminium oxide with 10-fold difference between the two values. The insoluble compounds (hydroxide, oxide and powdered pot electrolyte) administered as suspensions were less bioavailable than soluble compounds. The results for D&C Red 40 aluminium lake and for sodium aluminium silicate were closer to the results for soluble salts, which the authors explain by possible release of26Al from particulates by partial dissolution in the gastrointestinal tract. The bioavailability of Al metal, SALP and Kasal could not be determined because the amount of26Al present in the samples was not sufficient to determine the26Al/27Al ratio. A reanalysis is being conducted. The authors suggest that the bioavailability of aluminium metal particles may be considerably lower than that of soluble aluminium compounds.

The authors compared the results of these analyses with the results of human volunteer studies using26Al-labelled compounds and found that the results were consistent. It was concluded that the compounds tested “present no unique biological hazard as a consequence of their bioavailability” and that the rat is a suitable experimental model for studying metal bioavailability relevant to humans.

 

References

 

ATSDR (Agency for Toxic Substances and Disease Registry) (2008).Toxicological Profile for Aluminum, Atlanta, Department of Health and Human Services, Public Health Service.

 

Krewski, et al. (2007).Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide, A Report Submitted to the Environmental Protection Agency. J Toxicol Environ Health B Crit Rev. 10 Suppl 1:1-269