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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

- fertility: ambiguous results, not sufficient for classification

Additional information

The test substance is a watery solution of metal chlorides and free hydrogenchloride.

The toxicity of this mixture has therefore to be regarded as a summary of the toxicity of the different ingredients. Due to the relative concentrations for acute toxicity FeCl2, MnCl2, AlCl3 and HCl are regarded. MgCl2 the only other substance of high concentration is disregarded due to the low overall toxicity of this substance and as both chloride and magnesium ions are essential for cellular life and present in every cell in high abundance.

Summary:

Calculations are based on the following composition:

	% (w/w) in solution	MW (Metal) g/mol	M = mol/L	mol % Metal		MW (compound) g/mol	% (w/w) in solution	% (w/w) dry substanz
Fe	9.5224	55.85	1.7050	62.7	FeCl2	126.75	21.60	63.18
Al	0.6813	26.98	0.2525	9.3	AlCl3	133.34	3.38	9.881
Mg	0.6497	24.30	0.2674	9.8	MgCl2	95.22	2.61	7.634
Mn	1.4832	54.94	0.2700	9.9	MnCl2	125.84	3.40	9.945
					HCl	36.46	1.3	3.80

There is some indication that MnCl2 (NOAEL/C unspecified) and AlCl3 (NOAEL = 444.8 mg/Kg bw) have some potential to act as reproductive/developmental toxicants. Nervertheless the data basis is to weak to date for a clear judgment on the classification of the test substance for this endpoint. When more detailed data are available for these ingredients on the respective endpoints a reassessment should be conducted.

In the meantime it is assumed that the risk for reproductive/developmental toxicity is sufficiently covered by the strict threshold values that are based on repeated dose toxicity.

The summary is based on the data presented below.

Detailed data:

- toxicity to reproduction:

FeCl2:

It is considered that based on the following points, a weight-of-evidence approach can be taken for reproductive and developmental endpoints, rather than proposing to conduct further, new experimental animal tests to fulfil the Annex requirements:

the ubiquitous nature of iron in the environment;

the fact that iron is an essential element;

- iron plays an important role in biological processes, with iron homeostasis being under strict control;

- iron has been given to pregnant women for many years without an effect on pregnancy outcome;

- available experimental animal data have not revealed any adverse effects on reproduction parameters and development.

From the weight-of-evidence approach the following conclusion can be reached:

Results from recent guideline oral screening studies performed on ferrous chloride gave NOAELs for reproductive and developmental effects of =500 mg/kg body weight/day (no adverse effects were observed), respectively.

human data:

In humans, iron supplementation of about 5.8 to 11.7 mg/kg bw/day (for a 60kg individual) is routinely prescribed throughout pregnancy with no adverse effects on pregnancy outcome. Evidence of adverse effects on male testes has only been observed at acutely toxic, overload doses, at which some of the experimental animals died (EVM 2003, see chapter 7.10.3)

MnCl2:

Due to a delay in the correspondance between the registrant of this test substance and the Manganese Consortium, no first hand animal data is available.

In the ACGIH document "Manganese, Elemental and Inorganic Compounds ambigous data are presented. While animal data suggests no significant reproductive or developmental toxicity potential of manganes compounds, human data is indicative for effects on the male reproductive system. This aspect needs reassessment when MnCl2 specific data is available.

AlCl3:

For AlCl3 Beekhuijzen 2007 is the key study. In a combined repeated dose / reproductive screening study (OECD 422), administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d) was studied. As chloride, hydroxide and sulfate are anions that are essential for cellular life and are found in living cells in high abundance their effect on toxicity is regarded negligible. In addition basic aluminium chloride will be transferred into aluminium chloride when passing the stomach. Therefore results for this test item can be read across to aluminium trichloride (AlCl3). This study revealed no maternal toxicity at any dose and no reproductive, breeding or developmental toxicity at any dose from two weeks prior to mating to at least 3 days of lactation (females). Therefore, a NOAEL for maternal local and systemic toxicity of 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+) was established. For reproductive and developmental toxicity the NOAEL was 1000 mg/kg bw /d (equivalent to 90 mg/kg/d Al3+ = 444.8 mg/kg bw AlCl3).

In addition a study using aluminium citrate was conducted to analyse the effect of aluminium on neurotoxicity in the offspring after oral dosing in a developmental neurotoxicity study. See Semple 2010 in chapter 7.9.1. A NOAEL of 30 mg/Kg bw Al(III) was determined based on effects in fore- and hind-limb grip strength and other parameters. In addition a delayed sexual maturation was seen in the high dose animals, but as a comparable effect was seen in the sodium citrate control group, this effect cannot be clearly assigned to Al(III). Generally these findings are of less relevance as the complexation with citrate increases the aluminium uptake drastically as compared to aluminium chloride.

HCl:

Hydrochloric acid is irritant or corrosive, depending on concentration, and its toxicity is related to site-of-contact effects. In contact with water it dissociates completely to give eventually hydronium and chloride ions, both normal constituents in the body of all mammalian species, and no systemic toxicity is expected.

In a fully compliant 90-d whole-body inhalation toxicity study carried out in two strains of rats and one strain of mice (Dudek B. R., 1984), decreased body weight associated to a decrease in food consumption was noted at the highest concentration (ca. 47 ppm, equivalent to approx. 37.5 mg/m3) in mice only. The animals experienced severe clinical signs again related to the corrosiveness of hydrogen chloride but notwithstanding the severe health status impairment, no abnormality at haematology or clinical chemistry was detected. Histopathological examination at terminal sacrifice failed to show any abnormality in major organs and tissues, including reproductive organs, and only changes in site-of-contact tissues/organs (lips and/or anterior portion of nasal airflow passage) were detected both in the two strains of rats and in mice.

In an inhalation carcinogenicity study in rats (Sellakumar A.R., et al., 1985) in which animals were exposed to 10 ppm HCl for 6 hours/day, 5 days/week up to 128 weeks histopathology revealed changes only at the site-of contact (i.e. increased incidence of hyperplasia of the larynx and trachea) but no abnormality was detected in major organs including reproductive ones. Moreover, no increase in any kind of tumours, compared to control animals was found.

Since hydrogen chloride dissociates entirely in aqueous media, the foetus will be exposed only to hydrogen and chloride ions (both of which are physiological electrolytes). While it is possible that an excess of hydrogen ions might alter pH sufficiently to affect the foetus, the results of Pavlova (1976) suggest such findings are in practice inseparable from maternal toxicity.

As a High Production Volume (HPV) chemical, hydrochloric acid has been subjected to the evaluation for identifying those materials for which further action (hazard identification or risk management measures) is considered necessary. The SIDS Initial Assessment Report (SIAR) developed under this programme for hydrogen chloride was discussed at SIAM No. 15 held in Boston 22 to 25 October 2002 at which it was agreed that, based on data presented, the chemical was of low priority for further work (OECD, 2002). Based the local nature of the toxic effects of hydrogen chloride and on animal welfare grounds, a two-generation toxicity study is not considered necessary.

Effects on developmental toxicity

Description of key information

- developmental toxicity/teratogenicity: database insufficient, not sufficient for classification

Additional information

For the summary on reproductive/developmental toxicity, please see above under "fertility".

FeCl2:

See above under fertility.

MnCl2:

See above under fertility.

AlCl3:

See above under fertility.

HCl:

See above under fertility.

In addition in an inhalation study of unclear reliability (Pavlova 1976), groups of female Wistar rats were exposed once for 1 hour to HCl at the CL50concentrations of 450 mg/m³ either on day 9 of pregnancy or 12 days before mating. Animals were allowed to litter and progeny was observed up to 3 months of age. Tests reflecting the state of lungs (respiration rate, blood oxygen saturation, vital staining of lung tissue), liver (Quick-Pytel test) and kidney (diuresis, chlorides, protein) were performed in mothers as well as in the progeny. Young animals were challenged under hypoxic conditions and also re-exposed to HCl at 1/10 CL50 (52mg/m³). Relative organ weights were also determined in both mothers and progeny.

As the study was carried out at an extremely high dose, it is considered that effects observed in progeny were due to maternal toxicity and that the study did not demonstrate any increased sensitivity of foetuses compared to the mothers.

Toxicity to reproduction: other studies

Additional information

No information is available.

Justification for classification or non-classification

Based on the assessment of the reproductive/developmental toxicity stated above the test substance is not to be classified for this endpoint.