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Key value for chemical safety assessment

Effects on fertility

Additional information

Data describing potential effects on fertility are not available for anhydrous aluminium chloride. However, there are three studies assessing the toxicity to fertility of other soluble aluminium salts, namely aluminium chloride, basic (CAS 1327-41-9), aluminium chloride hexahydrate (CAS 7784-13-6), and aluminium sulfate (CAS 10043 -01 -3). Aluminium chloride hexahydrate is a hydrolysis product of anhydrous aluminium chloride in aqueous solution (see chapter 7.5 of the IUCLID). Basic aluminium chloride and anhydrous aluminium chloride can be expected to form the same dissociation products in aquaeous solution as anhydrous aluminium chloride and to have the same systemic effects in the body. 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 sulfate. In fact, ECHA has agreed that "a joint assessment of AC, ACH and AS is justified based on read-across" (SEV-D-2114385103 -55 -01/F).

Therefore, read-across from aluminium chloride hexahydrate, basic aluminium chloride and aluminium sulfate was considered appropriate to cover the endpoint of toxicity to reproduction for anhydrous aluminium chloride in accordance with section 1.5 in REACH Annex XI.

In a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test according to OECD guideline 422, aluminium chloride basic was administered by daily oral gavage to male and female rats at dose levels of 40, 200 or 1000 mg/kg bw/day, corresponding to 3.6, 18 and 90 mg/kg bw/day of elemental aluminium (NOTOX, 2007). Males were exposed for 28 days, i.e. 2 weeks prior to mating, during mating, and up to termintation. Females were exposed for 37 to 53 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 3 days of lactation. No reproduction, breeding and developmental toxicity was observed for treatment up to 1000 mg/kg bw/day, which was therefore defined as the definitive reproduction, breeding and developmental NOAEL.

Dixon et al. (1979) reported about the assessment of environmental factors affecting male fertility. Male rats were offered aluminium chloride hexahydrate in the drinking water corresponding to concentrations of 5, 50 or 500 mg Al3+/l up to 90 days prior to breeding (study duration: 160 days). The inclusion of aluminium chloride hexahydrate in the drinking water of young adult male rats at levels as high as 4476 mg/l (corresponding to 500 mg Al3 +/l) for a period up to 90 days did not result in any compound-induced abnormalities in the reproductive capacity of the males measured by histopathologic evaluation, plasma gonadotropin levels and serial mating of the males to untreated virgin females over a 70-day post-treatment period.

In a GLP-compliant 2 -generation reproduction toxicity study according to OECD TG 416 (Hirata-Koizumi, 2011), continuous drinking of AS-contained water for two generations did not result in changes in copulation, fertility or gestation indices, pre-coital or gestation length, the number of implantations or pups delivered, or the incidence of pups with malformations or variations. In addition, adverse effects were not found in estrous cyclicity or sperm parameters, and the histopathology of reproductive tissues in male and female parental animals. The most prominent effect of AS administered via drinking water was decreased water consumption, likely the cause for the associated decreased food consumption and body weight gain in parental animals. Male and female F1 pups and female F2 pups in the 3000ppm group had a lower body weight on PND 21 while no difference was found in the birth weight. This, too, was most likely secondary to maternal dehydration and corresponding reduced nursing capacity. Also, several changes in organ weights were observed in pups. However, no histopathological correlates were detected, and the changes were not considered adverse.Vaginal opening was slightly delayed in F1 females in the 3000ppm group while no compound-related changes were found in the other developmental landmarks, including male preputial separation, and other hormone-dependent events, including estrous cyclicity and AGD, were also not changed in AS-treated groups. In conclusion, the study gives no indication of Al-related toxicity to reproduction or development.

Based on the information available for basic aluminium chloride, aluminium chloride hexahydrate and aluminium sulfate, effects on fertility are not expected for anhydrous aluminium chloride.

Effects on developmental toxicity

Additional information

To assess the potential developmental toxicity of anhydrous aluminium chloride, five different studies were evaluated. Three of these studies were conducted with aluminium chloride (Bernuzzi et al., 1989; Misawa and Shigeta, 1993; Zhang et al. 2013), one was performed with aluminium citrate (ToxTest, 2007), and one was performed with aluminium lactate (Yokel, 1985). A comparative bioavailability study with different Al-26-labeled salts (ToxTest, 2010; discussed in chapter 7.1 of the IUCLID) showed comparably low bioavailabilities of aluminium citrate, sulphate, chloride, nitrate and hydroxide in most tissues when applied to rats by gavage at a dose level of 30 mg Al/kg bw/day for 7 or 14 days. Significant differences between control and treated animals only existed for bone and kidney, where aluminium citrate treatment caused the highest differences. Concentrations of aluminium in these tissues for other treatments were much lower by comparison. Since aluminium citrate tended to result in higher Al concentrations than aluminium chloride in several tissues in the bioavailability study, it can be anticipated to represent a "worst case" in relation to aluminium chloride. In light of this, the developmental neurotoxicity study conducted with aluminium citrate was considered acceptable for read-across to cover the endpoint of developmental toxicity for anhydrous aluminium chloride. As aluminium lactate is a soluble aluminium salt, read-across from the study by Yokel is also considered appropriate.

The study by Misawa and Shigeta (1993) examining the effects of prenatal aluminium chloride treatment on development and behavior in the rat was disregarded. Animals were given single doses (gavage) of 900 or 1800 mg/kg on day 15 of pregnancy (study duration: until postnatal day 28). Significant differences were observed between the aluminum-treated offspring and controls in terms of body weight, timing of pinna detachment and eye opening, and appearances of auditory startle. The only statistically significant difference between treated and control pups regarding behavior was more rearings in the open field test observed in female pups treated with 1800 mg/kg treated females. These results are considered unreliable as the group size of maternal animals was only 3-4 and, in the case of the dams treated with 1800 mg/kg bw/day, was further diminished by mortality (2 out of 3 dams died immediately after dosing).

The study by Zhang et al. (2013) was designed to observe the effects of subchronic Al exposure on the spatial memory, hippocampus ultrastructure and late phase long-term potentiation (L-LTP) in rats. Neonatal rats were exposed to Al by parental lactation from parturition to weaning for 3 weeks and then fed with the distilled water containing 0, 0.2%, 0.4% and 0.6% aluminium chloride (AlCl3), respectively, from weaning to postnatal 3 months. Levels of Al in blood and hippocampus were quantitated, Morris water maze test was performed to study spatial memory, the induction and maintenance of late phase long-term potentiation (L-LTP) in the area of Schaffer collateral-CA1 synpase was recorded by extracellular microelectrode recording technology in the hippocampus. Hippocampus was collected for transmission electron microscopy observation. The results showed that the Al concentrations in blood and hippocampus of Al-exposed rats were higher than those of the control rats. The authors reported an impairment of spatial memory in the Morris water maze test in pups treated with Al for 3 months. The authors also observed pathological neuronal and synaptic ultrastructure changes and impaired L-LTP of hippocampus and concluded that these effects could have been the morphological and electrophysiological basis, respectively, for damaged spatial memory.

The study provides basic information, but it has limitations. It is a non-GLP and non-guideline study, water intake was not reported (which precludes exact determination of the amount of test substance taken up per kg body weight), and the Morris water maze test was the only parameter assessed in the context of memory and learning. Furthermore, the electrophysiological measurements that were conducted are considered unsuitable for the evaluation a potential developmental neurotoxicity of aluminium chloride in a regulatory context. The study as a whole is therefore, although not disregarded, assigned less relevance than the studies described below.

Bernuzzi et al. (1989) reported about developmental alterations in offspring of female rats orally treated with aluminium chloride or lactate during gestation in a non-guideline study. Rats were offered daily dietary concentrations of 100, 300 or 400 mg Al/kg bw/day as chloride salt from day 1-21 of gestation (study duration: 41 days). No effect of treatment on litter size was detected, but strongly increased mortality appeared during the first week in the groups treated with 300 and 400 mg/kg bw/day. Weight was transitorily delayed, but the reversal of this effect could be attributed to the decrease of litter size. The neuromotor maturation of surviving pups treated with the two aluminium salts showed an impairment during the first 2 weeks of postnatal life with regard to righting reflex, grasping reflex (300 and 400 mg Al/kg bw group), negative geotaxis and locomotor coordination (400 mg Al/kg bw group only). None of these effects were observed at doses that did not show maternal toxicity as well (decreased body weight gain). The NOAELs for maternal toxicity and fetotoxicity were found to be 100 mg/kg bw/day.

The developmental and neurobehavioural toxicological effects of orally administered aluminum citrate in rats in utero through to 1 year of age was evaluated in a GLP-compliant study conducted according to OECD guideline 426 (extended exposure period of offspring consistent with OECD guideline 452) (ToxTest, 2010). The Al citrate dosing solutions were administered in the drinking water of pregnant dams to deliver target dosages of 30, 100 and 300 mg/kg body weight elemental Al. A Na citrate control group was concurrently treated with a concentration that was the molar equivalent of the high dose Al citrate solution.

After delivery, litters were culled to 4 males and 4 females each, and 20 litters were randomly selected and retained from the available total number of litters per treatment group. From each culled litter, one male and one female were randomly assigned to one of 4 milestone groups designated by age at sacrifice to undergo neurobehavioural testing, neuro-histopathological examination and tissue metal analysis: postnatal days 23 (immediately post-weaning), 64, 120 and 364. Weaned rat pups were administered the same treatments as the dams until sacrifice.

No relevant maternal effects were observed.

For the rat pups, the actual dosages were one third to one half of target for most of the 1 year lifespan, due to lower than expected fluid consumption. In the neurobehavioral tests, the strongest effect was in the neuromuscular domain, with dose-related reductions in fore- and hind-limb grip strength and in the females, foot splay, because they were detected at the mid dose level as well as at the high dose. However, these effects are attributable to the lower body weights of the individual rats in this test. The individual data are not available, and neither are historical control data. Therefore, the neuromuscular effects cannot unequivocally ascribed to treatment with Al3+. The

se effects formed the basis for the assignment of 100 mg Al/kg Body weight as the conservative LOAEL for this study. The highest dose also produced substantial physiological (urinary tract, growth rate, maturation rate, hematological and clinical chemical) adverse effects, and concentrations of Al in blood, femur, liver and some CNS tissues were significantly higher than controls. However, there was no evidence of an effect on learning and memory in this study based on maze and habituation tests.

There was no evidence of Al-related pathology beyond the urinary and gastrointestinal tracts, with no Al-related neuropathology observed.

Subcutaneous injection of aluminium lactate at 2.7 or 10.8 mg Al/kg or higher on gestation days 2 -27 led to body weight loss and (at 10.8 mg/kg) to mortality in pregnant rabbits, which is indicative of excessive maternal toxicity (Yokel, 1985). The offspring of the 10.8 mg/kg group showed significantly increased postnatal mortality. Decreased body weight gain and impairment in a conditioned reflex test was also observed, but the findings were not consistent and only in part statistically significant. Since the findings were restricted to maternally toxic doses, they are not considered to represent a specific developmental toxicity. The NOAEL for maternal toxicity in this study is 0.7 mg Al/kg, the NOAEL for developmental toxicity is 2.7 mg Al/kg.

In conclusion, the combined OECD 426/452 study (ToxTest, 2010) is considered to provide the most reliable data to evaluate the developmental toxicity of anhydrous aluminium chloride: It was conducted with aluminium citrate as a read-across substance, but firstly, aluminium citrate is considered to represent a "worst case" with regard to bioavailability as compared to aluminium chloride, and secondly, it was performed in compliance with GLP and OECD guidelines. Consequently, the study includes a full guideline-compliant FOB, in contrast to the other studies described above. As the offspring were dosed during the whole post-weaning period, it is difficult to differentiate between developmental or direct toxicity after weaning, however.

Justification for classification or non-classification

Taking into account the whole of the available information, a classification is not considered warranted.