Aluminium trilactate

Endpoint summary

Description of key information

No human or animal data on toxicokinetics are available for the substance Aluminium trilactate.
An in vitro dermal penetration study conducted with Aluminium trilactate is available. The results from this study are supported by a read-across to the moieties of Aluminium trilactate - Lactic acid and Aluminium is used for hazard assessment. This read-across approach is adequate as the salt Aluminium trilactate will dissociate into Lactic acid and Aluminium ions in aqueous solutions. 
Lactic acid is a natural component of many foods and as metabolic intermediate a key substance in several physiological processes. No concern arises from Lactic acid or the Lactate ion.
Oral as well as dermal bioavailability of Aluminium is considered to be low. After absorption, Aluminium distributes to all tissues. As an element, Aluminium is not metabolised. It is eliminated primarily by the kidneys and excreted in the urine.

Key value for chemical safety assessment

Absorption rate - oral (%):

1

Absorption rate - dermal (%):

0.1

Absorption rate - inhalation (%):

2

Additional information

No human or animal data on toxicokinetics are available for the substance Aluminium trilactate. For dermal penetration an in vitro study conducted with Aluminium trilactate is available.

Thus, a read-across to the moieties of Aluminium trilactate - Lactic acid and Aluminium is used for hazard assessment. This read-across approach is adequate as the salt Aluminium trilactate will dissociate into Lactic acid and Aluminium ions in aqueous solutions.

 

For Lactic acid a safety assessment report (Andersen, 1998), an assessment by US EPA (United States Environmental Protection Agency) (2008) as well as a safety evaluation by EFSA (European Food Safety Authority) (2011b) is available. The absorption, distribution and elimination properties of aluminium and several Aluminium compounds in humans and experimental animals has been extensively assessed by EFSA (2008, 2011a), ENVIRONMENT CANADA (2010),US ATSDR (United States Agency for Toxic Substances and Disease Registry)(2008),WHO IPCS EHC (World Health Organistion International Programme on Chemical Safety Environmental Health Criteria)(1997), Krewski et al. (2007) andFAO/WHO JECFA (Joint Food and Agriculture Organisation of the United Nations/World Health Organisation Expert Committee on Food Additives) (2007).These are taken into consideration for the hazard assessment of Aluminium trilactate.

 

Absorption

Lactate as a natural component of very many foods, in particular fruits and fermented milk products, is absorbed via the gastrointestinal tract. In humans as well as in most species, Lactic acid or rather the Lactate ion is also an endogenous substance and as normal metabolic intermediate a key substance in several physiological processes especially the energy metabolism and the gluconeogenesis (c.f. textbooks on biochemistry and physiology).

The Lactate turnover rate in human has been estimated to be of the order of 81 ± 2 mg/kg bw/h (cited in Andersen, 1998). The oral bioavailability is highly pH dependent (nearly 100% at pH 2; app. 7.5% at pH 5; Andersen, 1998).The dermal absorption of Lactic acid is also reviewed there: The total absorption (receptor fluid, total skin) is reported to be 30.4±3.3% at pH 3 and 9.73±2.03% at pH 7.

 

Oral bioavailability of Al depends on factors like solubility of the administered Al compound, pH, presence of complexing ligands and originally administered Al dose (Krewski et al, 2007). EFSA (2008) states that the low pH in the stomach would solubilise most of the ingested Aluminium compounds. In acidic aqueous solutions with pH <5, the aluminium ion exists mainly as Al³⁺, e.g. hydrated Al³⁺(Al(H₂O)₆)³⁺). The increase in pH by passing to the intestines will result in the formation of complexes of Aluminium with hydroxide and finally the formation of insoluble Aluminium hydroxide at neutral pH. Therefore, as the pH is neutralised in the duodenum, the Aluminium ion is converted to Aluminium hydroxide and the majority is then expected to precipitate in the intestine, with subsequent excretion, leaving only a minor fraction available for absorption.

 

The latest review of EFSA (2011a) addresses a study on oral bioavailability of Al from twelve different Al-containing compounds. According to EFSA this study is in line with other earlier available data on absorption of Al. The available data indicate that the oral bioavailability of Al in humans and experimental animals is low - approximately 0.1 to 0.4% from drinking water, approximately 0.02 to 0.21% from food according to EFSA (2011a) and Krewski et al. (2007). Oral absorption of Aluminium can vary at least 10-fold depending on the chemical forms present in the intestinal tract. Carboxylic acids, e.g. Citrate or Lactate can form complexes with Aluminium and so may enhance oral absorption of Aluminium (Krewski et al., 2007). Following administration of AlCl3, the oral bioavailability was in the range of 0.06 to 0.2% in the rat, whereas in rabbit absorption of 0.57, 1.16, 0.7 to 1.9, and 2.18% as chloride, nitrate, lactate, or citrate are reported. Differences in physiology of the stomach and/or gastric pH in these two animal species are made responsible for the differing result. Krewski et al. (2007) conclude that the oral bioavailability of the aluminium ion is < 1%. According to ENVIRONMENT CANADA (2010) Al absorption is enhanced by organic ligands compared to inorganic ligands (citrate > tartrate, gluconate, lactate > glutamate, chloride, sulphate, nitrate). In terms of absorption, Al citrate may be taken as worst case substance with a higher oral absorption than the registered substance Aluminium trilactate according to these data.

In an in vitro dermal skin absorption test according to OECD guideline 428, 5 human skin biopsies were exposed to Aluminium trilactate for 8 h in Franz-type diffusion cells at nominal dose of 210.74 µg Al/cm². Untreated biopsies served as control. Samples from the receptor fluid were taken after 0, 1, 2, 4, 6, 8, 10 and 24 h after application.

After 8 and 24 h the diffusion cells were washed to remove the excess test material. The results of recovery are summarised as non-absorbed dose (skin washing and tape stripping), amount associated with the skin preparation and absorbed dose (receptor fluid, receptor chamber washing, receptor samples including wash out and receptor chamber elution).

Although the mean total recoveries are below the quality criteria put forward in the test guidelines, the study is assessed to be valid in general. The main contents of Aluminium trilactate (measured as Aluminium contents) were detected in the washing solution after eight hours (85.69%). Almost no test substance was found in receptor fluid and receptor chamber washing fluid. In conclusion, 0.06% of Aluminium trilactate (expressed as Aluminium) was absorbed through human skin over a treatment period of 8 hours under the test conditions used.

 

Dermal absorption of Al salts is generally thought to be very low. Al salts are used in antiperspirants because they suppress eccrine sweating. Their mechanism of action is thought to be either neutralisation in the sweat duct to form a hydroxide precipitate, or denaturation of keratin in the cornified layer that surrounds the opening of the sweat duct. Both mechanisms predict that little Al would be absorbed through the sweat duct (cited in: Krewski et al., 2007).

 

The assumption of low dermal absorption is supported by a study on dermal uptake of Aluminium chlorohydrate: A single dose of 84 mg Al-26 labelled Aluminium chlorohydrate was applied to a single underarm of two adult subjects with blood and urine samples being collected over 7 weeks. Tape-stripping and mild washings of the skin were also collected for the first 6 days. Results indicate that ca. 0.012% of the applied aluminium was absorbed through the skin (Flarend, 2001, cited in Krewski et al., 2007).

 

One newer publication on dermal absorption of Al is also available, which is not yet taken into account by the existing reviews. The results from this study also support the predicted low dermal uptake of Aluminium (Pineau et al., 2012):

In an in vitro dermal skin absorption test according to OECD guideline 428, 10 human skin biopsies – either as intact skin or stripped skin - were exposed to Aluminium chlorohydrate as 3 cosmetic formulations (aerosol base, roll-on emulsion, stick) for 24 h in a Franz diffusion chamber.

After 24 h the diffusion cells were washed to remove the excess test material. Al was measured in the receptor fluid as well as in epidermis, dermis and 3 horny layers. 

In accordance to Guidance on information requirements and chemical safety assessment, Chapter R.7c Endpoint specific guidance, inin vitroexperiments only the amount of test substance that is found in the receptor fluid (=percutaneous penetration) is to be taken as systemically available. Following this guidance document, the dermal uptake of Al in this experiment was between 0.028 and 0.061% on intact skin and 0.037% on stripped skin.

 

According toUS ATSDR(2008) and Krewski et al. (2007), the percentage of Al absorbed following inhalation exposure is in the range of 1.5 to 2%

However, inhalation is not a likely route of exposure for Aluminium trilactate. The test substance has a high melting point (> 300°C, see section 7.2) and thus a very low vapour pressure, so the potential for the generation of inhalable forms is low. The use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur.

 

Distribution

Lactate is distributed equivalently to total body water. It diffuses readily across cell membranes, primarily by passive transport (Andersen, 1998).

 

After absorption, Aluminium distributes to all tissues in humans (EFSA, 2011a). The major physiological compartment of Aluminium is the skeleton. Krewski et al. (2007) suggests that approximately 58%, 26%, 11%, 3%, 0.95%, 0.3%, 0.25% and 0.2% of the Aluminium body burden would be in the bone, lung, muscle, liver, brain, heart, kidney and spleen, respectively.

 

There is evidence, that Al can bind to transferrin (Tf), the plasma protein for iron transport and is transported to organs and tissues by transferrin-receptor mediated endocytosis. The Al-Tf complex may also cross the blood-brain-barrier, although there has been evidence for a further mechanism, independent of transferring which can transport Aluminium citrate across the blood-brain-barrier (cited in EFSA, 2008).

 

Al can also reach the placenta and fetus and to some extent distribute to the milk of lactating dams (cited in EFSA, 2008).

 

Metabolism and Excretion

Lactate and its oxidation product pyruvate are key substances in numerous physiological processes and play a central role in the anabolism as well as the catabolism. Ultimately any absorbed or endogenously produced lactate will be oxidised into carbon dioxide and water (c.f. textbooks on biochemistry and physiology).

 

Aluminium as an element is not metabolised, but can be found attached to other chemicals. Al is assumed to exist in four different forms in organisms: as free ions, as low-molecular-weight complexes, as physically bound macromolecular complexes, and as covalently bound macromolecular complexes. Al has a high affinity for proteins, polynucleotides, and glycosaminoglycans, thus, much of the Al in the body may exist as physically bound macromolecular complexes with these substances (US ATSDR, 2008).

 

The total body burden of Al in healthy humans has been reported to be approximately 30–50 mg (cited in Krewski et al, 2007). In animal studies reviewed by EFSA (2008) it was found, that Al is not equally distributed throughout the body of rats following dietary exposure. Al was found to a larger extent in spleen, liver, bone, and kidneys than in brain, muscle, heart, and lung. Three days after withdrawal of Al from the diet, Al concentrations in these tissues decreased significantly.

 

Al absorbed from the blood is eliminated primarily by the kidneys, and excreted in the urine; less than 1.5% of the total absorbed Al is eliminated by biliary excretion. Unabsorbed aluminium is excreted in the faeces. Excretion of Al may be lower in premature infants compared to full-term infants (Krewski et al., 2007).

 

Concerning elimination and half life of Al, EFSA (2008) stated: “Multiple values have been reported for the elimination half life of aluminium in humans and animals, suggesting that there is more than one compartment of aluminium storage from which aluminium is eliminated.

Within the first day after receiving a single injection of 26Al citrate, approximately 59% of the dose was excreted in the urine of six subjects. At the end of 5 days, it was estimated that 27% of the dose was retained in the body. However, when 26Al levels were monitored for more than 3 or 10 years in a single subject that received the injection, half-lives of approximately 7 years and 50 years were estimated.

Initial half-lives of 2 – 5 hours were reported in rats, mice, rabbits and dogs after intravenous injection of soluble aluminium salts. When the sampling time was prolonged the half-life of aluminium in rabbits was estimated to be 113, 74, 44, 42, 4.2 and 2.3 days in spleen, liver, lung, serum, kidney cortex, and kidney medulla, respectively. A second half-life in the kidney greatly exceeded 100 days. In rats, the whole organism elimination half-life was estimated to be 8 to 24 days in serum, kidney, muscle, liver, tibia and spleen.

Aluminium persists for a very long time in the rat brain following intraveneous injection of very small doses of 26Al. A half-life of 150 days has been reported. However, this estimate is not expected to have a high degree of accuracy as brain samples were not obtained for at least 3 half-lives. Based on calculations for offspring of rats that were given 26Al injections daily from day 1 to 20 postpartum and thereafter examined on days 40, 80, 160, 320 or 730 postpartum, elimination half-lives of approximately 13 and 1635 days in the brain were suggested. Half-lives of 7 and 520 days were suggested for parietal bone. For liver and kidneys half-lives were suggested to be 5 and 430 days and 5 and 400 days, respectively. In blood the values were 16 and 980 days.

There is little published information on allometric scaling of aluminium elimination rates that can be used to extrapolate these results from the rat to the human. For aluminium in the brain 150 days is approximately 20% of, and 1365 days exceeds, the rat’s normal life span. For comparison, the whole-body half-life of aluminium in the human was estimated to be 50 years.”

 

 

References

Andersen (1998) Final Report on the safety assessment of glycolic acid, […], and lactic acid, ammonium, calcium, potassium, sodium, and TEA-lactates […], International Journal of toxicology, 17, Suppl. 1

EFSA (2008) Safety of aluminium from dietary intake, The EFSA Journal 754, 1-34, available via internet: http://www.efsa.europa.eu/de/efsajournal/pub/754.htm

EFSA (2011a) STATEMENT OF EFSA On the Evaluation of a new study related to the bioavailability of aluminium in food, EFSA Journal 2011;9(5):2157, available via internet: http://www.efsa.europa.eu/de/efsajournal/pub/2157.htm

EFSA (2011b)Scientific Opinion on the evaluation of the safety and efficacy of lactic acid for the removal of microbial surface contamination of beef carcasses, cuts and trimmings,EFSA Journal 2011;9(7):2317, available via internet: http://www.efsa.europa.eu/de/efsajournal/pub/2317.htm

Environment Canada (2010)Environment Canada Priority Substance List Assessment Report, Follow-up to the State of Science Report, 2000 Aluminium Salts (Final Content), available via internet: http://www.ec.gc.ca/lcpe-cepa/default.asp?lang=En&n=491F0099-1 and http://www.ec.gc.ca/lcpe-cepa/documents/substances/sa-as/final/al_salts-eng.pdf

FAO/WHO JECFA (Joint Food and Agriculture Organisation of the United Nations/World Health Organisation Expert Committee on Food Additives)(2007) Safety evaluation of certain food additives and contaminants. WHO FOOD ADDITIVES SERIES: 58, World Health Organization, Geneva, 2007, available via internet: http://whqlibdoc.who.int/publications/2007/9789241660587_eng.pdf

Flarend et al. (2001) A preliminary study of the dermal absorption of aluminium from antiperspirants using aluminium-26. Food Chem Toxicol. 2001 Feb;39(2):163-8

Krewski, et al. (2007). Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide, A Report Submitted to the US Environmental Protection Agency. J Toxicol Environ Health B Crit Rev. 10 Suppl 1:1-269. Available via internet: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782734/

Pineau A et al. (2012) In vitro study of percutaneous absorption of aluminum from antiperspirants through human skin in the Franz diffusion cell. Journal of Inorganic Biochemistry 110 (2012) 21–26

US ATSDR (United States Agency for Toxic Substances and Disease Registry)(2008) Toxicological profile for Aluminium, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service, Agency for Toxic Substances and Disease Registry, available via internet: http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=191&tid=34

US EPA (United States Environmental Protection Agency)(2008) Supporting Documents for Initial Risk-Based Prioritization of High Production Volume Chemicals; Sponsored Chemical Lactic Acid (CASRN 50-21-5), available via internet: http://www.epa.gov/hpvis/rbp/Lactic%20Acid_Web_SuppDocs_August%202008.pdf

WHO IPCS EHC (World Health Organistion International Programme on Chemical Safety Environmental Health Criteria)(1997) Aluminium (Environmental health criteria; 194), IPCS, World Health Organization, Geneva, available via internet: http://www.inchem.org/documents/ehc/ehc/ehc194.htm