Reaction mass of aluminium chloride, iron dichloride, magnesium chloride and manganese dichloride

Endpoint summary

Additional information

The test substance is an aqueous solution of metal chlorides and free hydrogenchloride.

The irritation/corrosion potential of this mixture has therefore to be regarded as a summary of the effects of the different ingredients. Due to the relative concentrations for toxicokinetic FeCl2, MnCl2, AlCl3 and HCl are regarded. MgCl2 as the only other substance of high concentration is disregarded as it is a salt of a strong acid and a strong base and therefore has no effect on pH and as its overall toxicity is very low, excluding cytotoxic effects.

FeCl2:

 

Introduction

Iron is an essential element, and plays an important role in biological processes, and iron homeostasis (biochemical mechanisms maintaining constant concentration in the cell) is under strict control. (McCance and Widdowson, 1938). Absorption, storage, mobilisation and excretion of iron are all regulated at the surface of cells by a homeostatic mechanism. (Hostynek, 1993). The counter ions of the soluble inorganic iron salts in question enter the body’s normal homeostatic processes, and are not discussed further.

Absorption

Oral:

In humans the absorbance and uptake of iron salts from the digestive system is usually rather poor to the extent that treatment of simple anaemia by such means is of limited effectiveness. This is because iron can only be absorbed as the ferrous ion, but the ferrous ion can only exist in an acid medium. Therefore once in the small intestine the ferrous ion cannot exist. Iron absorption in the rat is higher than humans (Mahoneya and Hendricksa, 1984); consequently, rat studies are considered unreliable models for iron toxicology in humans. Uptake is facilitated by the formation of iron chelates such as those with citrate and ascorbate that are present in the diet and in their absence iron absorption by the small intestine is very poor. Additionally, the presence of appreciable amounts of plant tannins may complex iron and further prevents its absorption. The result of this low solubility and low uptake by the human gut means that for healthy individuals, the presence of non-complexed iron in the diet rarely results in iron overload conditions.

There is some evidence that water-soluble iron salts are better absorbed than water-insoluble iron compounds. In both humans and animals, iron absorption from the digestive tract is adjusted to a fine homeostasis with low iron stores resulting in increased absorption and, alternately, sufficient body stores of iron decreasing absorption (Elinder, C.G., 1986).

Significant differences in iron absorption from salts and food have been noted between rats and humans, with uptake significantly higher from identical meals in rats (Reddy, M.B. and Cook, J.D., 1991), although rats poorly absorb haem (Bjorn-Rassmussen, E., 1974). Dietary enhancers and inhibitors appear to affect non-haem iron absorption in humans to a greater extent than in rats (Reddy M.D. and Cook, J.D., 1991). Growth requirements for iron in the rat are greater, and the dietary intake is about 100 times greater than that of humans, expressed on a body weight basis (WHO, 1983).

Dermal:

The water solubility (228 g/l) of ferrous sulfate suggests that it is unlikely to be absorbed across the lipid-rich stratum corneum. However, there are no reports of percutaneous absorption of iron in non-chelated form to support this prediction. Percutaneous absorption of iron has been reported only for chelated forms administered as ointments in mice. (Hostynek, J.J., 1993). There are no reliable acute or repeated dose dermal studies that can be consulted for evidence of absorption via the dermal route.

Inhalation:

In contrast to the wealth of data available on the human toxicology of ingested iron salts, there is no data available on the potential for adverse health effects via inhalation. There are no reliable acute or repeated dose inhalation studies that can be consulted for evidence of absorption via the inhalation route.

Distribution

The average adult stores about 1 to 3 grams of iron in his or her body.Iron is almost never found in the free ionic state in living cells in appreciable concentrations; it is chaperoned in the form of protein complexes immediately it is absorbed from the diet. In the blood plasma it is transported (as FeIII) by the protein transferrin, which passes it on to dividing cells, particularly the cells in the bone marrow that are the precursors of the red blood cells. This is mediated by the transferrin receptor. Transferrin, which binds iron with high affinity is only 20-35% saturated, thus the concentration of unbound iron is very low (0.5–1.5 mg/L (9–27 µmol/L, Tenenbein, 2001). Iron is stored principally in the liver in the large proteins haemosiderin and ferretin, although these are also found in all cells and in the blood in lower concentrations. Ferritin exists as hollow spheres of 24 protein subunits and iron is taken up in the FeII state but stored as FeIII. As with transferrin, it is stored in a redox-inactive (and therefore non-toxic) form. Ferritin is also important in recycling iron within the body and is an important biological indicator of iron balance. One consequence of the parsimonious conservation of iron is that if there is an excess of the element within the body, there is no biochemical mechanism for its excretion and this may result in both severe and chronic symptoms if large amounts are ingested.

Foetal exposure

It has been found that extremely elevated maternal serum iron concentrations are not accompanied by corresponding increases in foetal serum iron levels (Curryet al.,1990). This finding suggests that the foetus is protected from the effects of excess iron in the mother.

Metabolism

These water soluble inorganic iron salts do not undergo metabolism per se. As already mentioned iron is bound to transferring for transport to the bone marrow or contained within storage forms.

Excretion

About 1 mg of iron is lost each day through sloughing of cells from skin and mucosal surfaces, including the lining of the gastrointestinal tract (EVM, 2003). Menstruation increases the average daily iron loss to about 2 mg per day in pre-menopausal female adults (Bothwell and Charlton, 1982). No physiological mechanism of iron excretion exists. Consequently, absorption alone regulates body iron stores (McCance and Widdowson, 1938).

The daily losses of iron from the human body correspond to a biological half-time of iron of 10 to 20 years. The yearly lung clearance of iron dust is estimated to be 20-40% of the deposited amount (data obtained from iron welders) (Elinder, 1986).

References

Bjorn-Rassmussen.et al., (1974) Food iron absorption in man. Applications of the two-pool extrinsic tag method to measure heme and nonheme iron absorption form the whole diet. J. Clin. Invest., 53, 247-255.

Bothwell and Charlton (1982) A general approach of the problems of iron deficiency and iron overload in the population at large. Seminars in Hematology 19, 54.

Curryet al.,(1990) An ovine model of maternal iron poisoning in pregnancy. Ann. Emerg. Med., 19, 632- 638.

Elinder (1986) Iron. In: Friberg L, Nordberg GF, Vouk VB, eds., 1986. Handbook on the toxicology of metals. 2nd ed., the: Elsevier, 277-297 (Vol II).

EVM, 2003.

Hostynek (1993)Metals and the Skin. Critical Reviews in Toxicology 23(2): 171-235.

Mahoneya and Hendricksa (1984)Potential of the rat as a model for predicting iron bioavailability for humans Nutrition Res. 4, 913 -922.

McCance and Widdowson (1938)The absorption and excretion of iron following oral and intravenous administration. J. Phys. 94, 148.

Reddy. and Cook (1991) Assessment of dietary determinants of nonheme-iron absorption in humans and rats. Am. J. Clin. Nutr., 54, 723-728.

Tenenbein (2001) Hepatotoxicity in Acute Iron PoisoningClin. Toxicol.39, 721-726

WHO (1983)571. Iron.Toxicological evaluation of certain food additives and contaminants.WHO Food Additives Series, No. 18, 1983, nos 554-573 on INCHEMhttp://www.inchem.org/documents/jecfa/jecmono/v18je18.htm

 

MnCl2:

 

Citation from 7NIC-164 - Manganese, Elemental and Inorganic Compounds: TLV® Chemical Substances Draft Documentation, Notice of Intended Change:

“Manganese absorption occurs mainly in the pulmonary alveoli after inhalation or in the gastrointestinal tract after ingestion. Manganese is absorbed through the epithelium of the gastrointestinal and respiratory tracts. Gastrointestinal absorption is about 3-5% of ingested dose (ATSDR, 2000). Manganese metabolism in humans is rigorously controlled by homeostatic mechanisms that have an effect mainly on gastrointestinal absorption and excretion. The manganese absorbed via the gastrointestinal tract is sequestered by the liver. Manganese is mainly eliminated in the feces. Most is excreted via the biliary tract and likely undergoes enterohepatic circulation.

Manganese disposition in vivo is influenced by the intake and stores of iron (Fe) in the body. Both metals compete for the same binding protein in blood (transferrin) and other transport systems (divalent metal transporter) (Roth and Garrick, 2003). Anemic humans and iron-deficient rats have increased intestinal absorption of manganese. Among workers, the level of manganese in blood appears to be influenced by iron status, even at physiological iron levels (Ellingsen et al., 2003). It is possible that an excess of Fe may inhibit uptake of Mn across the blood brain barrier.

For occupational exposures, the inhalation pathway is especially important, where the absorption rate is close to 100% for fine dusts deposited in the alveoli (Beliles, 1994); larger particles depositing in proximal airways are carried towards the digestive tract by mucociliary clearance (ATSDR, 2000). Morrow (1970) determined a half-life of about 66 days in humans after inhalation of sub-micronic particles of 54Mn02. Manganese has been shown to be an essential element in the nutrition of humans and for many animal species, being involved in the formation of connective tissue and bone, in carbohydrate and lipid metabolism, and as a catalyst in several metabolic pathways (Wedler, 1994). There are no welldefined symptoms of manganese deficiency for humans.

 

References:

Agency for Toxic Substances and Disease Registry (ATSDR): Toxicological Profile for Manganese. US Department of Health and Human Services Pub No PB2000108025 (2000).

Beliles RP: The Metals. In: Patty's Industrial Hygiene and Toxicology, 4th ed, Vol II, Part C, Toxicology, pp 2106- 2124. GD Clayton, FE Clayton (Eds). John Wiley & Sons, New York (1994).

Ellingsen DG; Haug E; Ulvik RJ; et al.: Iron status in manganese alloy production workers. J Appl Toxicol 23:239-247 (2003).

Morrow P: Retention rate of inhaled submicron manganese dioxide. In: Inhaled Particles III, Vol II. WH Walton (Ed).Press,,(1970).

Roth JA; Garrick MD: Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. Biochem Pharmacol 66:1-13 (2003).

Wedler FC: Biochemical and Nutritional Role of Manganese: An Overview. In: Manganese in Health and Disease, pp 1-36. DJ Klimis-Tavantzis (Ed). CRC Press,,(1994).

ALCl3:

Refer to assessment reports / publications and references herein:

Assessments reports

OECD SIDS Initial Assessment Report for(2003). Aluminiumchloride, basic CAS 1327 -41 -9

OECD SIDS Initial Assessment Report for(2003). Aluminium hydroxy chloro sulphate, CAS 39290 -78 -3

OECD SIDS Initial Assessment Report for(2003). Aluminium sulphate, CAS 10043 -01 -3

IUCLID Data set (2000), Aluminiumchloride, basic CAS 1327 -41 -9

IUCLID Data set (2000), Dialuminiumchloride pentahydroxide, basic CAS 12 327 -41 -9

IUCLID Data set (2000), Aluminium chloride hydroxide sulphate, CAS 39290 -78 -3

IUCLID Data set (2000), Aluminium sulphate, CAS 10043 -01 -3

 

Toxicology, Toxicokinetics and Health effects

Frumkin H. and Gerberding J.L. (2008) Toxicological Profile for aluminium. Agency for Toxic Substances and Disease Registry,department of Health and human services.

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.

Animal studies, in vivo studies:

The aluminium substance described here was tested in a comparative absorption/ excretion study (Wenker, 2007) with the goal to select the most readily absorbed salt as the test material in a subsequent OECD 422 repeated dose / reproductive toxicity screening study. Male and female rats were given a single dose equivalent to 200 mg AlCl3 (i.e.40.48 mg Al3 +.) Urine and faeces were collected ofer a five-day period and analysed for Al content. Bile was not collected since available literature data indicate that Al3 +

is not excreted in bile. Concentration in pre-dose urine & faeces was subtracted from the subsequent five 24-hr interval findings in order to correct for endogenously present Al. More than 90% of the Al was excreted in faeces, but the huge pre- and post-dose inter- and intra-individual differences in faecal Al content prohibit more exact quantification. Oral absorption, as evaluated by urinary excretion, of aluminium was very low, and more or less similar between other Al compounds. Less than 0.04% of dosed Al was recovered in urine of male rats, while in female rats the excretion of other Aluminium salts Aluminium chloride hydroxide sulphate and aluminum sulfate was even less than 0.01%. For aluminium chloride, basic excretion in urine was 0.028% in males and 0.026% in females. A subsequent combined 28 -day repeated dose and reproductive screening study was therefore performed with this aluminum substance (Beekhuizen, 2007).

This study confirms the findings from previous reviews that gastrointestinal absorption of ingested aluminium is poor, possibly due to transformation of salts into insoluble aluminium phosphate in the digestive tract, brought about by phosphate in the diet and by pH changes.

 

HCl:

 

Hydrogen chloride and its aqueous solution hydrochloric acid, are corrosive or irritating depending on their concentration and cause direct local effects on the skin, eye and gastro-intestinal or respiratory tract. In contact with water hydrogen chloride rapidly dissociates and its effects are thought to be as a result of changes in pH, i.e. the local deposition of H+, rather than the effects of hydrogen chloride/hydrochloric acid. The chemistry of this substance is well understood; as an inorganic salt it dissolves in water to form hydrogen and chloride ions, both of which are physiological electrolytes.

Concentrated hydrogen chloride is corrosive to skin. At concentrations lower than those that cause corrosion, hydrogen chloride will have no systemic toxicity. Dermal exposures should be controlled on the basis of the potential risk to local effects (irritation, corrosion) to the skin. Concentrations that are lower than those that are irritant will only add to the body’s pool of electrolytes.