Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 512 mg/kg bw/day
Additional information

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic (Al(OH)1.3Cl1.7) by oral gavage to male and female Wistar rats at dose levels of 40, 200 or 1000 mg /kg bw/d (equivalent to 3.6, 18 or 90 mg Al3+/kg bw/day)

. 10 animals/sex/group were used. Males were exposed for 28 days, females between 37 -53 days, i.e. during 2 weeks prior to mating, during mating, during postcoitum, and during at least 3 days of lactation. Litter was not exposed. There were no treatment-related effects found regarding to mortality, clinical signs, functional observations, histopathology, organ weigths, reproduction, breeding data and pup development. No reproduction, breeding and developmental toxicity was observed for treatment up to 1000 mg/kg bw/day. Based on these results, the No Observed Adverse Effect Level for maternal and developmental toxicity including the fertility was established to be 1000 mg/kg bw/day for Aluminium chloride basic which corresponded to 90 mg Al/kg bw/day. This study conducted on Aluminium chloride basic is relevant for Aluminium ammonium (bis)sulfate. In fact, following ingestion Aluminium chloride basic is dissociated into the aluminium (Al3+) and the chloride (Cl-) in the acidic aqueous conditions of the gut such as the stomach. Therefore, as for Aluminium ammonium (bis)sulfate (see § 7.1), the toxicity of Aluminium chloride basic should mainly result from the aluminium ion (Al3 +) considering systemic effects and differences in toxicity are likely due to variation in bioavailability due to differences in the form of the ingested compound and dietary constituents. Consequently it is possible to predict the absence of effect on fertility with Aluminium ammonium (bis)sulfate by reading across from the reproductive toxicity result on Aluminium chloride basic.

Finally, under the test conditions of this study, the NOAEL for the fertility is determined at 90 mg Al3+/kg bw/day which corresponds to 1512 mg/kg bw/day of Aluminium ammonium (bis)sulfate (using the molecular mass of 906.6 g/mol).


Short description of key information:
- Combined repeated dose / reproductive screening study (OECD 422): study performed on Aluminium chloride basic relevant for Aluminium ammonium (bis)sulfate in a read-across approach based on Aluminium (Al3+) toxicity (K, Reliability 2).

Effects on developmental toxicity

Description of key information
- Combined repeated dose / reproductive screening study (OECD 422): study performed on Aluminium chloride basic relevant for Aluminium ammonium (bis)sulfate in a read-across approach based on Aluminium  (Al3+)  toxicity (K, Reliability 2)
- Combined OECD426/OECD452: study conducted on Aluminium citrate relevant for Aluminium ammonium (bis)sulfate in a worst case read-across approach based on Aluminium (Al3+) toxicity (K, Reliability 2)
Additional information

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic (AlCl3) by oral gavage to male and female Wistar rats at dose levels of 40, 200 or 1000 mg /kg bw/d corresponding to 3.6, 18, 90 mg Al3+/kg bw/day . 10 animals/sex/group were used. Males were exposed for 28 days, females between 37 -53 days, i.e. during 2 weeks prior to mating, during mating, during postcoitum, and during at least 3 days of lactation. Litter was not exposed.There were no treatment-related effects found regarding to mortality, clinical signs, functional observations, histopathology, organ weigths, reproduction, breeding data and pup development. No reproduction, breeding and developmental toxicity was observed for treatment up to 1000 mg/kg bw/day.Based on these results, the No Observed Adverse Effect Level for maternal and developmental toxicity including the fertility was established to be 1000 mg/kg bw/day for Aluminium chloride basic which corresponded to 202 mg Al/kg bw/day.This study conducted on Aluminium chloride basic is relevant for Aluminium ammonium (bis)sulfate. In fact, following ingestion Aluminium chloride basic is dissociated into the aluminium (Al3+) and the chloride (Cl-) in the acidic aqueous conditions of the gut such as the stomach.Therefore, as for Aluminium ammonium (bis)sulfate (see § 7.1), the toxicity of Aluminium chloride basic should mainly result from the aluminium ion (Al3 +) considering systemic effects and differences in toxicity are likely due to variation in bioavailability due to differences in the form of the ingested compound and dietary constituents. Consequently, the absence of effect on the development with Aluminium ammonium (bis)sulfate is predictable from the absence of effect on the development with Aluminium chloride basic.

Finally, under the test conditions of this study, the NOAEL for fertility is determined at 90 mg Al3+/kg bw/day which corresponds to 1512 mg/kg bw/day of Aluminium ammonium (bis)sulfate (using the molecular mass of 906.6 g/mol).

The second study was designed “to develop data on the potential functional and morphological hazards to the nervous system that may arise from pre-and post-natal exposure to aluminium citrate”. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions of aluminium citrate at 3 dosage levels (nominal - 30, 100 and 300 mg Al3+/kg bw/day. Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L) or plain water (control group). The Al-citrate and Na-citrate were administered to dams ad libitum via drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at the same levels as their dams. Pups were assigned to one of four cohorts (80 males, 80 females): a pre-weaning cohort that was sacrificed at PND 23, and cohorts that were sacrificed at PND 64, PND120 and PND 364.

 

Endpoints and observations in the dams included water consumption, body weight, a Functional Observational Battery (FOB), morbidity and mortality. Endpoints were assessed in both female and male pups that targeted behavioral ontogeny (motor activity, T-maze, auditory startle, the Functional Observational Battery (FOB) with domains targeting autonomic function, activity, neuromuscular function, sensimotor function, and physiological function), cognitive function (Morris swim maze), brain weight, clinical chemistry, haematology, tissue/blood levels of aluminium and neuropathology at the different dose levels and time points PND 23, 64, 120 and 364.

 

Statistical analyses were undertaken according to intention-to-treat, with appropriate consideration of multiple testing issues and, through the study design, also the unit of analysis. Censored analyses using survival analysis (Fixed Effects Partial Likelihood) were required for the grip strength measurements due to an equipment-defined maximum value. Females and males were analysed separately.

The results from this study are informative for developmental and neurotoxic effects due to prenatal and chronic postnatal exposure of rats to high doses of aluminium (30 mg Al/kg bw/day, 100 mg Al/kg bw/day and 300 mg Al/kg bw/day). As the F1 generation was dosed during the whole post-weaning period, it is difficult to differentiate between developmental or direct toxicity after weaning, however. This does not affect the formal reliability of the study.

 

The results in the Day 364 cohort show a clear, consistent effect on post-weaning body weight in the high dose Al-citrate group in both male and female pups. An effect of Na-citrate was observed in the female pups. Urinary tract pathology was observed in high dose rats, more frequently in the males. The results showed no evidence of an effect on memory or learning. Fairly consistent results were observed for the critical effect, fore- and hind-limb grip strength, and this was supported by the following less consistently observed effects also observed in the mid-dose (100 mg Al/kg bw/day) group: urinary tract lesions at necropsy (4 males, 1 female); body weight (mid-dose males weighed less than controls in the Day 120 cohort); defecation (more boluses produced by females in the mid-dose group compared with the controls); urination (mid-dose males produced more urine pools that controls); tail pinch (mid-dose females displayed more exaggerated responses); foot splay (mid-dose females had significantly narrower foot splay than the controls); the albumin/globulin ratio (Day 64 mid-dose males had a greater mean ratio than the controls). No treatment-related differences in FOB characteristics were observed in the neonatal and juvenile pups (see details § 7.9.1). A LOAEL of 100 mg Al/kg bw/day for aluminium repeated dose toxicity is assigned based on this study.

 

Delayed sexual maturation, measured as delayed vaginal opening in females and delayed preputial separation in males, was observed in the high dose Al-citrate group of this study. The same effect, although somewhat less pronounced, was also seen in the sodium citrate control group. Based on the observed upward deviations from the target dose in the Al citrate groups and the data on water consumption seen in the first weeks after weaning, it is possible that both in the pre- and post-weaning stage, the animals in the Al citrate groups received considerably more citrate than the sodium citrate control group. Moreover, the calculated Al dose during the immediate post-weaning period was more than twice the target dose, which may have contributed to post-natal systemic toxicity due to exposure to the test substance. Given that effects were seen in both the Al-citrate high-dose group and the NA-citrate group, no Al-based LOAEL/NOAEL can be suggested based on the sexual maturation results in this study.

 

Body weight differences at end-of-weaning, relative to controls, occurred in the high-dose Al-citrate group as well as in the sodium citrate group and are considered to be treatment-related but the role of Al is unclear. The relative differences between the high-dose Al-citrate group and the sodium citrate group may be related to differences in liquid consumption.

This study by oral conducted on Aluminium citrate is relevant for Aluminium ammonium (bis)sulfate since both soluble salts are completly dissociated into the aluminium (Al3+) and citrate or ammonium and sulfate in the acidic aqueous conditions of the gut such as the stomach (see section § 7.1). However, the bioavailability of Aluminium varies mainly due to differences in the form of the ingested compound and dietary constituents (i.e.the kinds and amounts of ligands in the stomach with which absorbable Aluminium species can be formed). Although the range of fractional absorption is low compared to many other chemicals, Aluminium uptake can significantly increase following oral exposure depending on conditions, including the presence of certain dietary components such as citrate. Therefore, the oral administration of aluminium citrate, as the most soluble Aluminium species studied in man, is considered as the worst-case for Aluminium bioavailability by comparison with the bioavailability of Aluminium from Aluminium ammonium (bis)sulfate (dissociated in Aluminium sulfate) by oral route (see §7.1).

Consequently it is possible to predict the effect on development with Aluminium ammonium (bis)sulfate by reading across from the developmental toxicity result on Aluminium citrate which is considered as a worst case for the Aluminium bioavailability. The NOEL for the development of the Aluminium ammonium (bis)sulfate was calculated at 1680 mg/kg bw/day (using 906.6 g/mol). This NOEL based on a one-year combined chronic study/developmental study was considered instead of the NOAEL of 1512 mg/kg bw/day based on the screening reproductive/developmental study, considering the long-term duration. Under the test conditions, Aluminium ammonium (bis)sulfate is not classified for the toxicity to the development.

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available.

Self classification:

Aluminium ammonium (bis)sulphate l is not classified for the toxicity to reproduction according to the CLP regulation and according to the criteria of the Annex VI of the Directive 67/548/EC.