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EC number: 231-208-1
CAS number: 7446-70-0
large number of in vitro and in vivo genotoxicity studies is available
for anhydrous and basic aluminium chloride as well as for aluminium
chloride hexahydrate; however, many of these show major deficiencies
with regard to study design or experimental details and were disregarded
after careful reviewing. These studies were, nonetheless, included in
the dossier and are listed in the following paragraphs:
a bacterial reverse mutation assay using S. typhimurium strains TA 98,
100, 1535, 1537, 1538 and the E. coli WP2 uvrA strain. Test
concentrations used were between 20 - 5000 ug/plate. A positive result
was reported for two out of six bacterial strains (S. typhimurium TA 100
and 98) with and without metabolic activation. However, the reliability
of the study is considered to be low since the results were not reported
in the form of a comprehensive study and only two replicates per
concentration were tested, which significantly decreases the statistical
power of the assay. Furthermore, only single plates were used for
the vehicle control group, no positive control data and no historical
control data were reported, and finally, the positive response was very
and was not confirmed in a second experiment.
Therefore, the study was disregarded.
et al. (2007)
reported an in vitro mammalian chromosome aberration assay. Cultured
human lymphocytes were treated with 5, 10, 15 and 25 uM aluminum
chloride during the G1, G1/S, S (pulses of 1 and 6 h), and G2 phases of
the cell cycle. No data are available about metabolic activation. All
tested concentrations were cytotoxic, far beyond the range recommended
in OECD guideline 473, and reduced significantly the mitotic index in
all phases of cell cycle. The results are therefore considered
unsuitable to assess a chromosome aberration potential of the test
compound, and the study was assigned a Klimisch rating of 3 and
et al. (2006)
conducted an in vitro comet assay to analyze the level of DNA damage in
human peripheral blood lymphocytes treated with aluminium chloride
hexahydrate (CAS 7784-13-6) and the impact of Al on the repair of DNA
damage induced by ionizing radiation. Cells were treated with different
doses of aluminium chloride (1, 2, 5, 10, and 25 µg/mL) for 72 h.
Results indicated that Al induces DNA damage in a dose-dependent manner,
however, at the dose of 25 µg/mL the level of damage declined. This
decline was accompanied by a high level of apoptosis indicating
selective elimination of damaged cells. Under the test conditions,
aluminum chloride was considered to induce DNA damage in human
peripheral blood lymphocytes by the authors. However, this study was
conducted in non-GLP conditions and without standard methodology.
Cytotoxicity was indirectly measured by apoptosis. The increase in DNA
damage and apoptotic cells (cytotoxicity) was well correlated which
means that the DNA damage seen could simply be a side-effect of
cytotoxicity. Moreover, cells were exposed continuously for 72 h,
therefore only toxicity-induced cell-cycle delay may have been observed.
Also, no positive control was used. Therefore, the study was
et al. (2010) performed
an in vivo micronucleus assay with aluminium chloride
hexahydrate. Rats were orally administered the test substance at 34
mg/kg bw/day for 30 days. A control group and 2 additional groups were
also included: propolis at 50 mg/kg bw/day, and aluminium chloride (34
mg/kg bw/day) plus propolis (50 mg/kg bw/day). At the end of the
experiment, rats were sacrificed and hepatocytes were isolated for
counting the number of micronucleated hepatocytes. In addition, the
levels of serum enzymes and histological alterations in liver were
chloride induced a statistically significant increase in the numbers of
micronucleated hepatocytes whereas propolis did not. Simultaneous
administration of propolis attenuated the increased numbers of
micronucleated hepatocytes induced by aluminium chloride. A
significant increase in ALP, AST, ALT and LDH and induced
histopathological changes in the liver were observed in the group
treated with aluminium chloride.On the
contrary, treatment with propolis alone did not cause any adverse effect
on above parameters. Moreover, simultaneous treatment with propolis
significantly modulated the toxic effects of aluminium
the test conditions, repeated oral administration of aluminium chloride
was reported to induce a statistically significant increase in the
number of micronucleated hepatocytes. However, this study was diregarded
because of the following main limitations: Significant damage in the
liver was reported (increase in levels of serum enzymes and histological
alterations in liver) whereas in a GLP OECD guideline 422 study on AlCl
basic (CAS 1327-41-9), no liver damage and reduced ALP activity were
observed up to 1000 mg/kg/day. This discrepancy undermines the results
found in this study. Also, the liver cannot be used as a target tissue
for the micronucleus assay in adult rats: in this study, 8-weeks old
adult rats have been treated for 30 days which means they were 12-weeks
old at termination. This is too old for an appropriate micronucleus test
in liver because hepatocytes divide too slowly at this age.
In a study by Geyikoglu et
al. (2012), rats
were intraperitoneally administered basic aluminium chloride at 5 mg/kg
bw/day for 10 weeks. Control group was treated with sodium chloride
under similar test conditions. At the end of the experiment, rats were
sacrificed and hepatocytes (HEP) were isolated for counting the number
of micronucleated hepatocytes (MNHEPs). In addition, haematological,
biochemical parameters and histological alterations in liver and kidney
were investigated. In the study, aluminium
chloride induced a statistically significant increase in the numbers of
micronucleated hepatocytes. In
addition,the enzymatic activities of
ALP, AST, ALT and LDH, and the levels of urea and uric acid
significantly increased. RBC, WBC, PLT, Hb and Ht revealed significant
decreases in the Al treated group compared to the control. Furthermore,
severe pathological damages were established in both liver and kidneys
of Al treated rats. The
study basically showed the same limitations as the Turkez study and was
disregarded for the same reasons.
et al. (1972) performed an in vivo bone marrow chromosomal
aberration test, mice were applied basic aluminium chloride intraperitoneally
dose-levels of 0.01, 0.05 and 0.1 M. Bone marrow cells of specimens at
0.1 M were fixed at 1, 2, 4, 8, 12, 16, 20, 24, 48 and 72 h after the
injection while those of 0.01 and 0.05 M series were fixed at 20 h only
after the injection. Four mice were used for each fixation interval.
Specimens injected with distilled water and their bone marrow fixed at
the corresponding intervals served as controls. Sodium citrate-acetic
acid alcohol - air drying - Giemsa staining methodology was followed for
the preparations of bone marrow cells. The
data of the treated series showed that the chromatid type breaks, gaps
and constrictions were regular in occurrence while the chromosome type
break was very rare. In the 0.1 M series, the aberration types would not
show regularity in their increase or decrease at different fixation
intervals. The data of 8 and 48 h were disregarded because of the
inadequate figures; the frequency of total aberration remained more or
less the same at different intervals between 4 and 72 h. Tissue fixed at
one hour after the treatment had also a good number of chromosomal
effect of AlCl3 on bone marrow chromosomes of mice was, therefore,
non-delayed type and it continued without much change even at 72 h. In
the combined data of 0.1 M series among the different types of
aberration, the frequency per cell was found to be the highest for the
chromatid type (0.1) and lowest for the chromosome type break (0.0024).
The frequency of gaps and constrictions (0.0775) was close to that of
the chromatid type. Treatment
of 0.01, 0.05 and 0.1 M solutions of AlCl3 and the tissues fixed at 20 h
revealed that the frequencies of total aberrations were 12, 20 and 26 %;
the chromatid type breaks were 4.5 and 13.5 % and the gaps and
constriction were 4, 6.7 and 9.5 %, respectively. Thus the values of the
aberration frequency were not proportional to the different molar
solutions used. However, the use of higher concentration of AlCl3, no
doubt, increased the aberration frequency to some extent.
the test conditions, AlCl3 was considered to induce chromosomal
aberrations at higher concentrations. However, this study suffers from
many limitations: the early sampling times (just several hours after
exposure) are unappropriate: it is biologically unrelevant to search for
chromosome aberrations only few hours after administration. Also, the
OECD guideline 475 recommends the analysis of at least 100 cells/animal
: in this study, there were supposed to be 4 mice per group and 200
cells per group, therefore potentially only 50 cells analysed per
animal, but in some cases even 200 cells could not be analysed, which
suggests a serious problem with the quality and number of metaphases
studied. Moreover, the volume administered intraperitoneally was 3.3
mL/100 g bodyweight which clearly exceeds the recommended limit volume
of 2 mL/100 g bodyweight. In addition, there was no time-related change
in aberration frequency which undermines the isolated increases
observed. On top of that, cytotoxicity was not assessed and no positive
control was used. The study was therefore disregarded.
A micronucleus test in Swiss mice was performed by Paz et al, 2017,
in which aluminium chloride was administered to male and female Swiss
mice orally at doses of 49, 98 and 161 mg/kg bw. Negative (distilled
water) and positive (CPA) control groups were included as well. 24 h
after administration, the animals were killed, bone marrow slides were
prepared and evaluated for micronucleus frequency. Histopathological
analysis was performed on livers, kidneys and stomachs, and the weight
of these organs was determined.
The authors report a significant increase in the number of MN in all
treated groups. Furthermore, the authors state that animals in all
treated groups were "found to have histopathological alterations in the
tissue integrity of their stomachs, kidneys and most of all their
The study has several severe deficiencies making it unreliable:
Positive control results were originally not reported and only delivered
upon request, and no historical control data are reported. The rationale
for selecting the applied dose levels (fractions of a published LD50) is
not in line with the OECD TG, which requires testing of a defined MTD.
Clinical signs or body weights were not reported, which makes an
evaluation of whether the MTD has been met or exceeded impossible. The
test substance identity is unclear (indicated as "aluminium chloride
hexahydrate" with CAS no 7446-70-0, but that CAS no. identifies
anhydrous aluminium chloride and not the hexahydrate).
Most importantly, the reported histopathological findings are
implausible: The animals were killed and their organs prepared for
further examinations 24 hours after test substance administration. It is
highly unlikely that the observed histopathological changes would
manifest themselves within the extremely short period of 24 hours.
Histopathology was not performed or not reported for the negative
control group, so it is not possible to compare the treated and
untreated groups. All in all, it is very likely that the observed
effects are not related to test substance exposure but were present in
all animals (from treated and control groups) already before substance
administration. Furthermore, the microscopic alterations are not in line
with the results of available high-quality studies, such as the combined
28-day repeated dose toxicity study and reproduction/developmental
toxicity screening test of aluminium chlorid basic in rats (NOTOX, 2007;
see IUCLID section 7.5): None of the histopathological changes observed
by Paz et al. were seen in the NOTOX study from 2007, despite the fact
the animals in this study were repeatedly treated with much higher
aluminium doses for a much longer time.
All in all, the study is considered unreliable for the above-mentioned
reasons and is disregarded.
assess the genotoxic potential of aluminium chloride, several valid in
vitro and two valid in vivo genotoxicity studies, partly
conducted with other aluminium salts as supporting substances, were
evaluated in a weight-of-evidence approach.
The studies cited in IUCLID chapter 7.1.1 (ToxTest 2010; Priest 2010)
demonstrate very similar systemic bioavailabilities of a number of
aluminium compounds, including aluminium chloride and aluminium
hydroxide. It has been postulated that especially those aluminium
compounds that are water soluble will behave very similarly regarding
bioavailability. Consequently, ECHA has agreed that "a joint assessment
of AC, ACH and AS is justified based on read-across" (SEV-D-2114385103
-55 -01/F) and has performed substance evaluation of these three
water-soluble aluminium salts jointly.
read-across from aluminium hydroxide, basic aluminium chloride and dialuminium
chloride pentahydroxide (which is also a soluble aluminium salt)
appropriate to cover the endpoint of genotoxicity for anhydrous
aluminium chloride in accordance with section 1.5 in REACH Annex XI.
valid Ames assay conducted in accordance with GLP and OECD guideline 471
was performed by BASF (BASF, 2015) and gave no indication of
mutagenicity of anhydrous aluminium chlorid in S. typhimurium TA 98,
100, 1535, 1537, 1538 and the E. coli WP2 uvrA strain with and without
et al. (1982)
reported limited information from an in vitro mammalian cell gene
mutation assay. Mouse lymphoma L5178Y cells were used. The test
concentrations were 570, 580, 590, 600, 620 and 625 ug/ml. Anhydrous
aluminium chloride was found to be non-mutagenic with and without
aluminium chloride was tested in a GLP-compliant in vitro micronucleus
assay conducted according to OECD guideline 487 (NOTOX, 2010).
The results of the study gave no indication of a clastogenic or
aneugenic potential of the test substance.
aluminium chloride was also tested in a GLP-compliant in vitro mammalian
gene mutation assay (mouse lymphoma assay) conducted according to OECD
guideline 476 (NOTOX,
A mutagenic potential was not identified in this study.
Villarini et al. (2017) assessed the early effects of co-exposure
to 50 Hz ELF-MF (extremely low frequency magnetic fields) and
non-cytotoxic doses of Aluminum chloride (AlCl3) on DNA damage by comet
assay in SH-SY5Y and SK-N-BE-2 human neuroblastoma (NB) cells. Although
the study was not specified as GLP-compliant, it is well documented and
was performed according to a peer reviewed protocol developed during the
International Workshop on Genotoxicity Test Procedures. The study gave
no indication of DNA damage by aluminium chloride.
hydroxide, a compound related to aluminium chloride, was tested in a
GLP-compliant in vivo micronucleus assay conducted according to
OECD guideline 474 (Covance, 2010). The test substance did not
induce micronuclei in the polychromatic erythrocytes of the bone marrow
of male rats treated up to 2000 mg/kg/day (the maximum recommended dose
for this study).
The potential of dialuminium chloride pentahydroxide to cause
micronuclei in vivo was evaluated in a GLP-compliant in vivo
micronucleus assay conducted according to OECD TG 474 (Stammberger,
1999) in mice treated
up to 2000 mg/kg/day (the maximum recommended dose for this study).
The substance did not cause an increase in the the number of
polychromatic erythrocytes containing micronuclei. Systemic
bioavailability of the administered test substance was demonstrated by
clinical signs (reduced spontaneous activity).
of the available studies considered valid and reliable gave an
indication of a genotoxic potential of anhydrous aluminium chloride.
By means of the data available concerning genetic toxicity, a
classification of the test substance is not warranted.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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