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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)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
504 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic by oral gavage to male and female Wistar rats at dose levels of 20, 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 (because of developmental toxicity purpose of study). Detailed clinical signs, body weight, food consumption, water consumption (subjective appraisal), haematology, clinical chemistry, neurobehaviour and gross and histopathology were studied.

Based on these results, the overall NOAEL for female rats was established to be >1000 mg/kg bw/day. For males the NOAEL was established to be 1000 mg/kg bw/day for systemic toxicity which corresponded to 90 mg Al/kg bw/day. This study conducted on Aluminium chloride basic is relevant for Aluminium ammonium (bis)sulfate for systemic effect only. 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. However, the local effects induced by chloride are not intended following the Aluminium ammonium (bis) sulfate ingestion.

Consequently it is possible to predict the absence of effect with Aluminium ammonium (bis)sulfate by reading across from the short term repeated dose toxicty result on Aluminium chloride basic. Finally, a NOAEL of 3400 mg/kg bw/day could be extrapolated for the Aluminium ammonium (bis)sulfate.

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 Al/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 damsad libitumvia 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 combined 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 offspring were dosed during the whole post-weaning period, it is difficult to differentiate between developmental or direct toxicity after weaning, however. Urinary tract pathology was observed in rats in the high dose group, more frequently and more severe in the males. The study showed no evidence of an effect of Al-citrate on memory or learning but a more consistent effect was observed in endpoints in the neuromuscular domain.

 

The ambiguity as to the critical period of exposure and the time-varying water consumption complicate the derivation of a point-of-departure from this study. A LOAEL of 100 mg Al/kg bw/day for aluminium toxicity is assigned. The critical effect was a deficit in fore- and hind-limb grip strength in the mid-dose group, supported by evidence of dose response and less consistently observed effects in the mid-dose animals: 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 than controls); tail pinch (mid-dose females displayed more exaggerated responses); foot-splay (mid-dose females had significantly narrower foot-splay than the controls); and the albumin/globulin ratio (Day 64 mid-dose males had a greater mean ratio than the controls).

Finally, the effects for the offspring were described in the Table following:

Effect levels

Endpoint

Generation

Sex

Effect level

Based on

Basis for effect level / Remarks

LOAEL

F1

female/male

100 mg Al/kg bw/day

test mat.

Neuromuscular effects, hindlimb grip strenght, forelimb grip strenght

NOAEL

F1

female/male

30 mg Al/kg bw/day

test mat.

Neuromuscular effects

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. 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 (via Aluminium sulfate) by oral route (see §7.1).

Consequently it is possible to predict the effect following chronic exposure to Aluminium ammonium (bis)sulfate by reading across from the repeated dose toxicty result on Aluminium citrate which is considered as a worst case for the Aluminium bioavailability. The NOAEL for the Aluminium ammonium (bis)sulfate was calculated at 504 mg/kg bw/day (using 906.6 g/mol). Under the test conditions, Aluminium ammonium (bis)sulfate is not classified for the chronic toxicity by oral route.

Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: other

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available by oral and dermal route , by inhalation

Self classification:

Aluminium ammonium (bis)sulphate is not classified for the chronic toxicity by oral and dermal route , by inhalation

according to the CLP Regulation and according to the criteria of the Annex VI to the Directive 67/548/EEC.