Question

The DGIII has asked the Scientific Committee for Medicinal Products and Medical Devices (SCMPMD) to express its opinion on the suitability/safety of the "colours permitted for certain uses only" listed in Annex IV of EEC 94/36 [in particular: E 123 (Amaranth);E 127 (Erythrosin); E 161 (Canthaxanthine); E 173 (Aluminium); E 174 (Silver); E 175 (Gold)] for use in pharmaceutical products and the question of whether the use of these agents might represent a consumer health/safety concern.

The question to be examined by the SCMPMD regards the following colourant:

E 173 Aluminium

Answer

Considering the facts that 1) various aluminium salts are already used as therapeutic ingredients in a number of medicinal products (antiacids, antiulcer preparations, drugs used to control diarrhoea, etc.), and 2) that Annex IV of Directive 94/36 allows " quantum satis" use of this metal as a colouring agent in foods and beverages, it seems reasonable to allow the use of aluminium as a colourant in pharmaceutical products, particularly since the concentrations employed for this purpose are markedly lower than those present in medicinal products that contain aluminium as an excipient or active ingredient.

Main elements of the scientific justification of the answer.

In various classes of drugs administered peros (antiacids, antiulcer preparations, drugs used to control diarrhoea, etc.), aluminium is present as stable compounds at concentrations ranging from 35 and 1450 mg per dose. Administration of multiple doses during the day can provide a daily dose of aluminium salts of up to 5 grams. Considering the unlimited quantity of this metal (E 173, Aluminium) allowed as a colouring agent in foods, and the extremely low doses that would be ingested in the form of stable aluminium compounds in aluminium-based colourants (aluminium lacquers), i.e., 0.0002-30 mg / per single dose with a maximum daily dose of 150 mg, the use of E 173 as a colourant in pharmaceutical products is without a doubt acceptable, even considering the toxicological problems related to aluminium as a metal.

Full opinion

Terms of reference

The SCMPMD has been asked to respond to the following question:

Would use of colourants listed in Annex IV ("colours permitted for certain use only") of Directive 94/36, (in this case E173 Aluminium), in medicinal products represent a consumer health/safety concern?

Context of the question

EEC Directive 78/25, which deals with colouring agents that can be used in medicinal products, makes reference to the Directive issued on 23 October 1962 regarding colouring agents in food (OJL 115 f 11.11.1962 p. 2645). However, the EEC policy on food-colouring agents has been updated since then by Directive 94/36. Of particular interest in the latter document are Annex I, which lists all substances approved as food colourants, and Annex IV, which contains 10 such agents whose use is restricted to certain foods.

The pharmaceutical industry is questioning the scientific justification for excluding the use of Annex-IV colourants in medicinal products, citing in particular the clause in EEC Directive 78/25 that states, "Experience has shown that on health grounds there is no reason why the colouring matters authorised for use in foodstuff intended for human consumption should not also be authorised for used in medicinal products".

The question must be evaluated in relation to: 1) the maximum quantities and concentrations/unit of weight in foodstuffs, 2) those currently found in pharmaceutical products as active principle or excipient, and 3) the toxicological characteristics of the element.

E 173 (Aluminium) is used to decorate cakes, candies, and other sweets, and Annex IV of Directive 94/36 allows unlimited use ( quantum satis>) of this colourant in foods.

The standards for purity regarding E 173 (Aluminium) are reported in EC Directive 94/45 of the 26 July 1995 Commission, which deals with colourants that can be used in foods. The Directive notes that aluminium presents as a grey powder composed of finely ground particles of the metal and describes the method used to obtain this powder. Thanks to its malleability, the metal can also be transformed into ultra-thin sheets or films.

As the following table shows, aluminium salts are active principles in a number of orally administered drugs (Lione, 1985):

Aluminium phosphate (0.3-2.0 mg / vial) and aluminium hydroxide (0.22-2.0 mg / vial) are also found in injectable vaccines, some of which require administration of repeated doses. Parenteral nutrition solutions have a fairly uniform Al content ranging from 16-90 mcg/mL (mean 65 mcg/mL ± [SD]17) in the 23 samples analyzed by Fraga et al. (1992). The metal is also present as a contaminant in haemodialysis fluid (Flendrig et al., 1976; Parkinson 1979) and albumin solutions, which are also a common element in the treatment of chronic renal failure [9.1 ± 0.6 - 18.3± 2 (SD) m mol aluminium/L] (Maharaj et al., 1987), which are also a common element in the treatment of chronic renal failure. The concentration of aluminium in human plasma is less than 0.5 m mol/L (Maharaj et al. 1987)].

Aluminium is also found in pharmaceutical products as an excipient in the following forms: aluminium and magnesium silicate (30 mg per tablet (T) or capsule (C), 5-25 mg/ml syrup), aluminium hydroxide (0.015-70 mg / T or C), aluminium silicate (16.3-50 mg / T or C), aluminium stearate (2.5 mg/T or C, 5-10 mg/mL syrup), dihydroxyaluminium acetate (100 mg / T or C), dihydroxyaluminium sodium carbonate (22.5 mg / T or C), polysilicate of amorphous aluminium (30-35 mg / T or C), aluminium and sodium silicate (2 mg / T or C), aluminium silicate hydroxide (2 - 100 mg / T or C). Even with 5 such doses (i.e., 5 capsules or tablets or 5 mL of syrup) per day, the maximum daily dose of aluminium salts furnished by these products would be 10-500 mg.

Aluminium is also used as a support for other colourants (aluminium lacquer) in pharmaceutical products. A lacquer is generally an insoluble form of a synthetic water-soluble colourant, more precisely, a sodium or potassium salt of one of the regulation colouring agents that has been adsorbed to an extremely thin sheet of aluminium oxide. It is prepared from an aqueous solution of the colourant, which is induced to precipitate onto the aluminium oxide substrate by the addition of an agent such as aluminium sulphate. The resulting paste is then filtered, dried and ground.

Aluminium lacquers are stable compounds that are completely insoluble in water, and, compared to the soluble colourants from which they are prepared, they display much greater resistance to heat and light, as well as greater chemical purity. Moreover, thanks to their lack of water solubility, they can be applied to substrates before drying, which greatly reduces work time. On the other hand, the colour-conferring potency of a lacquer is considerably reduced. In products with aluminium lacquers of E 102, E 110, E 127, E 132, the quantity of aluminium ranges from 0.2 mcg-30 mg per dose, and therefore a maximum daily dose of 1 mcg - 150 mg.

In short, the maximum amount of aluminium ingested with medicinal products in the form of stable aluminium-compound excipients is less than 500 mg / day; as aluminium lacquer, no more than 150 mg / day; and as an active ingredient, 828-5000 mg / day.

- Toxicokinetics

Gastrointestinal absorption of Al ³⁺ ions is kinetically identical to that of other metal ions (Schafer et al., 1994).

It has been calculated that the daily intake of aluminium is 9-36 mg/kg; an average supply of about 5 to 20 mg Al/day seems to be likely (Goyer, 1996). Intestinal absorption is 1% or less (Wilhelm et al., 1990; Schafer et al., 1994). According to Greger (1992) the daily dose of aluminium absorbed by humans via the gastrointestinal tract ranges from 1-100 mg (mean: 24 mg) and 3-15 µg via the respiratory tract. In the case of aluminium-containing antiacids, when larger quantities are consumed (several grams), the absorption rate can drop to about 0.01%. The percentage of the ingested quantity that is absorbed from the GI tract increases in the presence of certain anions such as citrate, malate, or ascorbate. Citrate and ascorbate, for instance, can be present in the gut after ingestion of oranges, grapefruits or other citrus fruits (Furst et al., 1998).

At a gastric pH, ingested aluminium is ionized to Al+3, which is the form that is later absorbed. The fraction of the metal that is ionized cannot be quantified in absolute terms. The ionization process depends on the amount of gastric juice in the stomach and its pH, which are in turn influenced by physiological variables (e.g., gastric emptying rates), physical and chemical factors (e.g., the presence in the stomach of hot foods or those with high fat contents), and endocrine factors (e.g., gastrin secretion). All of the latter vary widely according to the individual and the specific situation. Nevertheless, blood levels of aluminium (which depend mainly on the quantity of Al ⁺³ absorbed) can be calculated, based on experimental evidence, and under natural condition, i.e. with standard food without deliberate addition of Al or Al ⁺³, they will generally be within a range of 5-14 m g/L, with a mean of approximately 7 m g/L (0.259 m mol/L) (Jones and Bennet, 1985; Maharaj et al., 1987; Van der Voet, 1992).

Aluminium is excreted for the most part by the kidneys (Kovalchik et al., 1978). In a normal subject, renal excretion of the metal rarely exceeds 20 µg a day, but this figure can increase to 3800 µg / day in a patient receiving parenteral nutrition solutions containing the metal (Klein et al., 1982).

When 5 to 125 mg Al/day is consumed, healthy male test subjects show a negative or an even aluminium balance, with no accumulation of aluminium in the organism.

Toxicological aspects

The central nervous system (CNS) is particularly vulnerable to the toxic effects of aluminium (Krishnan et al., 1988; Kandel 1991, Lukiw and McLachlan, 1995). There is a large body of evidence demonstrating that the metal is capable of penetrating the blood-brain barrier, probably by destroying membrane phospholipids (Kruck et al., 1991; Zatta et al., 1991). Some studies have also shown that aluminium can bind amino acids such as glutamate to form aluminium-glutamate complexes that allow it to reach the blood of the brain (Deloncle et al., 1990).

There has been much discussion regarding the possible involvement of aluminium in the pathogenesis of dementia of Alzheimer type (DAT), but its role in this neurodegenerative disease is at present uncertain. In vitro studies have revealed damage to brain cells induced by the metal at concentrations similar to those found in the brains of DAT patients. Epidemiological studies have shown a close correlation between the incidence of DAT and the level of aluminium in drinking water, and experimentally induced aluminium encephalopathy is associated with the same cognitive and behavioural changes seen in DAT. On the whole, attempts to connect DAT with excessive or chronic exposure to aluminium have failed to produce conclusive results. Nonetheless, toxic concentrations of aluminium high enough to induce encephalopathy in laboratory animals have also been found in other degenerative neurological illnesses such as Parkinson disease (Hirsch et al., 1991) and amyotrophic lateral sclerosis (Kobayashi et al., 1990; Yasui et al., l991a, b), providing additional evidence of the neurotoxic potential of this metal.

Aluminium is also involved in the pathogenesis of vitamin D-resistant osteomalacia, which is often associated with dialysis encephalopathy (Flendrig et al., 1976; Parkinson et al., 1979, Maharaj et al. 1987).

Elliot et al. (1978) were the first to suggest that aluminium might be toxic to the erythropoietic system when they first reported the association between anemia and dialysis encephalopathy. This hypochromic / microcytic anaemia is one of the earliest signs of aluminium toxicity caused by contaminated haemodialysis fluid, and it regresses promptly when dialysis is suspended (Short et al., 1980). The intraperitoneal administration of aluminium to rats has also been found to provoke significant microcytosis and reduced production of erythrocytes (Kaiser et al., 1984).

Klein et al. (1984) have reported several cases of moderate-severe hepatic toxicity in children receiving total parenteral nutrition.

Aluminium has also been implicated in the pathogenesis of pulmonary fibrosis (in some cases, fatal) in workers exposed to dusts and smoke containing the metal (McLaughlin et al., 1962).

The systemic effects of aluminium are usually not found in persons with a normal renal function.

Intravenous administration of 135 µg (~ 6.75 mg / kg) of aluminium (as AlCl3 6H2O) reportedly increases the frequency of fatal internal hemorrhage in rats (Wide, 1984). Higher doses administered intraperitoneally to pregnant rats caused growth retardation and skeletal defects in the fetus (Elinder and Siogren, 1986). Injection of chicken eggs with aluminium chloride (3-18 mg) tends to provoke malformations and death of the embryo (Gilani and Chatzinoff, 1981).

In a study by Agarwal et al., (1996) , aluminium was administered orally (in the form of aluminium lactate) at doses of 0, 5, 25, 250, 500 o 1000 mg/kg/day to pregnant rats from the 5 ^th through the 15 ^th day of gestation, and the effects on the offspring were analysed in terms of birth weight, anogenital distance, time of vaginal opening, regularity of estrus cycles, duration of gestation, number of oocytes ovulated, and gonad weight. Apart from initial irregularities in the estrus cycles of the group treated with 250 mg/kg/day, no changes were found.

The damage caused by aluminium cited above was caused (in all cases) by daily doses pro kg far, far higher than those that could possibly be reached in humans by ingestion of pharmaceuticals containing the metal as an active principle (5 g/day or 71 mg/kg/day), as an excipient (500 mg/day or 7.1 mg/kg/day), and, certainly, as a colourant (150 mg/day or 2.14 mg/kg/day).

Opinion

According to Annex IV of Directive 94/36, aluminium (E 173) can be used quantum satis to colour foods and beverages. The metal is also used as stable aluminium compounds in pharmaceutical products in quantities that are 5.5-33 times higher than those that could be ingested pro die in the form of a stable co-colourant (e.g., in lacquers). It should also be recalled that aluminium is employed in medicinal products as stable excipients at levels that are 1.6-10 times lower than those found in drugs based on the metal as an active ingredient.

Therefore, the use of aluminium (E173) as a colouring agent in medicinal products may be considered acceptable.

A recent EFPIA communication (Feb. 17, 1999; March 10, 1999) affirms that aluminium is no longer used for this purpose in medicinal products. The results of EMEA inquiries (June 16, 1998) reflected the total quantity of all colouring matters used in pharmaceutical products, including those used for packaging (e.g. blisters).The problem therefore seems to have been resolved for aluminium itself (E173), and aluminium lacquers, which are still used and stable, can be also considered acceptable in the doses currently found in medicinal products.

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