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EC number: 233-135-0 | CAS number: 10043-01-3
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Neurotoxicity
Administrative data
Description of key information
Orale exposure:
The results of the study of Al Moutaery 2000, clearly indicate that the neurological function and recovery rate following SCI are significantly impaired in rats exposed to aluminum sulphate at 250 mg/kg/bw day (LOAEL).
Inhalation exposure:
No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 38.6 mg /m3 for 6 months (Steinhagen et al. 1978).
Dermal exposure:
No studies were located regarding neurological effects in humans after acute- or intermediate-duration dermal exposure to various forms of
aluminum.
For dermal exposure we taken that:
-the average weight of rats is 190g (180-200g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.019 kg
corrected dermal LOAEL= oral LOAEL
250 mg/kg bw/day 0.019 kg =
LOAELrat 4.75 mg/kg bw/day
Key value for chemical safety assessment
Effect on neurotoxicity: via oral route
Link to relevant study records
- Endpoint:
- neurotoxicity: chronic oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Reliable without restrictions. Well-presented study, with relevant measurement of chemical concentrations
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 424 (Neurotoxicity Study in Rodents)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Adult male Sprague–Dawley rats weighing 180 to 200 g were housed in a temperature-controlled room and maintained in a 12- hour light/dark cycle. Standard laboratory animal food and aluminum- dosed drinking water were freely available throughout the study.
Four treatment groups (eight rats each) were treated with 0%, 0.25%, 0.50%, and 1% of aluminum sulfate (Al2[SO4]3 _ 18 H2O) in drinking water, respectively, for 30 days before being subjected to SCI. - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- Animals and Drugs
Adult male Sprague–Dawley rats weighing 180 to 200 g were housed in a temperature-controlled room and maintained in a 12- hour light/dark cycle. Standard laboratory animal food and aluminum- dosed drinking water were freely available throughout the study. Four treatment groups (eight rats each) were treated with 0%, 0.25%, 0.50%, and 1% of aluminum sulfate (Al2[SO4]3 _ 18 H2O) in drinking water, respectively, for 30 days before being subjected to SCI.
These doses are equivalent to 0 mg, 375 mg, 750 mg, and 1500 mg of aluminum per day consumed by humans weighing 70 kg and are similar to the amounts usually present in antacids ingested by people with peptic disorders.
Recently, we observed that administration of 0.25 to 1% of aluminum sulfate in drinking water produced a several-fold increase in serum aluminum levels in rats. All the experiments in the present study were undertaken according to the guidelines provided by the Research and Ethical Committee of Armed Forces Hospital, Riyadh, Saudi Arabia.
Spinal Cord Injury
After 30 days of aluminum treatment, the animals were subjected to spinal trauma according to the method described by Nystrom and Berglund
The animals received an anesthetic of chloral hydrate (400 mg/kg subcutaneously) and a T7–8 laminectomy was performed, leaving the dura intac.A slightly curved rectangular compression plate (2.2 x 5 mm) loaded with a weight of 35 g was gently placed over the exposed spinal cord for 5 minutes. The wound was closed in layers, and the animal was allowed to recover from anesthesia. Animals in the control group underwent the same surgical procedure but without receiving any compression injury (sham treatment). All the animals received intramuscular injection of gentamicin (2 mg/kg) daily for 3 days after surgery. The bladder was pressed manually twice a day to avoid urinary complications - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
of 0%, 0.25%, 0.5% and 1%,
Basis:
nominal in water - No. of animals per sex per dose:
- 34
- Control animals:
- yes
- Observations and clinical examinations performed and frequency:
- After 30 days of aluminum treatment, the animals were subjected to spinal cord trauma. Laminectomy was performed at T7-8 in anesthetized rats, followed by placement of a compression plate (2.2 x 5 mm) loaded with a 35-g weight over the exposed spinal cord for 5 minutes.
Control animals underwent the same surgical procedure, but the compression injury was not induced (sham). Postoperative neurological function was assessed using the inclined-plane test and by obtaining a modified Tarlov score and vocal/sensory score daily for 10 days.
Electrophysiological changes were assessed using corticomotor evoked potentials, whereas pathological changes were assessed by light microscop. The level of vitamin E in the spinal cord was measured as an index of antioxidan defense. - Specific biochemical examinations:
- Analysis of a-Tocopherol in Spinal Cord Tissue
The level of a-tocopherol (vitamin E) in spinal cord tissue was analyzed using high-performance liquid chromatography according to the method described by Dexter, et al.19 The injured site of the spinal cord (a 50-mg sample) was homogenized in a tube containing 1 ml of Tris buffer (50 mM, pH 7.6) and 3 ml of 1.5% ethanolic pyrogallol. The homogenate was incubated at 70°C in a water bath for 5 minutes, 150 ul of 10 M potassium hydroxide was added to each tube, and additional incubation (70°C) occurred for 30 minutes. The mixture was cooled in an ice bath to room temperature and extracted with 2 ml of hexane. The organic layer was separated after centrifugation, and the aqueous homogenate was further extracted with another 2 ml of hexane. The two hexane extracts were combined and evaporated in nitrogen and stored at -70°C for future analysis. The high-performance liquid chromatography instrument (Waters Associates Inc., Medford, MA) consisted of a solvent delivery pump (Model 510), autoinjector (Model 712), UV-Visible detector (Model 481), and integrator (Model 740). The column used was Bondapak C-18, 3.9 x 150 mm (Waters Associates, Inc.), made of stainless steel. The mobile phase consisted of 95% chromatography- grade methanol in deionized water. The flow rate of the mobile phase was adjusted to 1.5 ml/minute, and the absorbance was measured at 280 nm following a 60-ul injection. The level of vitamin E was calculated using a calibration curve. - Neurobehavioural examinations performed and frequency:
- Behavioral Studies
Neurological function following SCI was assessed daily for 10 days by obtaining a modified Tarlov score,70 a Rivlin and Tator angled-plane score,60 and a vocal/sensory score.10 A modified Tarlov score was used to assess the hindlimb function as follows: 0 = total paraplegia of hindlimbs; 1 = no spontaneous movement but responds to hindlimb pinch; 2 = spontaneous movement; 3 = able to support weight but not able to walk; 4 = walks with gross deficit; 5 = walks with mild deficit on broad flat surface; 6 = able to walk on broad, flat surface and support weight on a 1.8-cm-wide ledge; and 7 = walks on ledge. The angled-plane test consisted of measuring the maximum angle at which an animal can support its weight on an inclined board measured in degrees (0–90°). The board was covered with a rubber mat consisting of 1-mm-high ridges.
The animals were placed transversely on the inclined plane, and the highest angle the animal maintained for 5 seconds was recorded and described as the “capacity angle.” For every test session three separate measurements were made, and the mean score was determined. The sensory/vocal score was measured by administering a noxious stimulus (pinching with a toothed forceps) to the hindlimb of the animals.10 The response of the hindlimb to stimulus was graded as follows: 0 = no response; 1 = withdrawal from pinch without vocalization; 2 = vocalization without withdrawal; and 3 = vocalization and withdrawal.
For biochemical and histological studies, eight additional animals from each group were killed at 4 hours, 24 hours, 5 days, and 10 days post-SCI. All the behavioral, biochemical, and histological tests were performed in blinded fashion. - Sacrifice and (histo)pathology:
- Histological Examination
The rats were anesthetized with ether, and intracardiac perfusion was performed with isotonic saline followed by 10% neutral buffered formalin. After perfusion, the injured portion of the spinal cord was removed, embedded in paraffin, and 6-um sections were cut and stained with hematoxylin and eosin. The slides were viewed under a light microscope to study the structural changes. - Other examinations:
- Electrophysiological Monitoring
Corticomotor evoked potentials were measured using an electromyography system (MS92; Medelec, England) in which the active disc electrode was placed epidurally over the right motor cortex area, whereas the reference needle electrode was placed over the nasion of the anesthetized (400-mg/kg chloral hydrate) rat.
A grounding electrode was placed into the skin of the back. Two needle electrodes were placed into the lateral muscle mass of the left hindlimb and foot pad, respectively, to apply electrical stimulation. Transcortical stimulation was achieved by applying a constant square wave pulse of 0.1 msec in duration at 1 Hz at an intensity of 50 V (the stimulus was amplified and filtered in the range of 10–500 Hz). The time base was set at 50 msec. - Statistics:
- Statistical Analysis
Data were examined using analysis of variance followed by Dunnett’s multiple-range test for comparing different treatment groups. A p value of <0.05 was considered significant. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Compression of spinal cord produced transient paraparesis in which a maximum motor deficit occurred at Day 1 following SCI and resolved over a period of 10 days.
- Behaviour (functional findings):
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- effects observed, treatment-related
- Other effects:
- not examined
- Details on results:
- Tarlov Score
There was no significant postoperative change in Tarlov score in sham-treated animals compared with preoperative score). A highly significant decrease in Tarlov score was observed on Day 1 following SCI, which gradually recovered over a period of 10 days. Administration of aluminum significantly and dose dependently deteriorated the recovery rate following SCI.
Sensory and Vocal Score
There was a significant decrease in the sensory/vocal score at 24 hours (Day 1) postinjury, which recovered to preinjury level on Day 5 (Fig. 1 center). Treatment of rats with a low dose (0.25%) of aluminum failed to produce any effect on SCI-induced deterioration of sensory/vocal score, whereas medium and high doses significantly and dose dependently delayed the recovery of sensory/vocal scores following SCI.
Inclined-Plane Capacity Angle
Spinal compression produced a maximum deterioration of the rat’s ability to walk on an inclined plane on Day 1 postinjury; this was followed by a gradual recovery over a period of 10 days. A low dose (0.25%) of aluminum failed to affect SCI-induced deterioration of capacity angle, whereas medium and high doses significantly and dose dependently slowed the recovery of the animal’s ability to walk on the inclined plane.
Vitamin E Levels
A significant depletion of vitamin E was found in spinal cord tissue obtained in rats on Days 1 and 5 postinjury . Pretreatment with aluminum produced no change in vitamin E level in noninjured animals; however, aluminum dose dependently potentiated SCI-induced depletion
of vitamin E in spinal cord.
Electrophysiological Monitoring
There was a significant reduction in the amplitude of CMEP activity following SCI at 4 hours and 24 hours, and this recovered to normal on Day 10 postinjury . There was no significant difference in the amplitude of CMEP between SCI-alone group and SCI combined with aluminum-treated groups at 4 or 24 hours postinjury. However, on Day 10 the level of CMEP amplitude in aluminum and SCI-treated groups was significantly lower when compared with the SCI alone–treated group. On the other hand, SCI significantly increased the latency of the evoked potential at 4 hours and 24 hours, which partially recovered over a period of 10 days Treatment of animals with aluminum significantly potentiated the SCI-induced increase in the latency of evoked potentials.
Histological Examination
Spinal cord sections obtained in sham-operated animals appeared normal. The spinal cord sections obtained from injured animals showed focal demyelination of white matter in the posterior column of spinal cord and focal loss of neurons in the gray matter. Foci of granularity and vacuolation were demonstrated in the white matter. Administration of aluminum produced more severe degenerative changes in the spinal cord following SCI . - Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 0.25% of aluminium sulphate corresponds to 2500 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 2500 ppm is equavalent to 125 mg/kg bw per day (2500x 0.050).
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 0.5% of aluminium sulphate corresponds to 5000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 5000 ppm is equavalent to 250 mg/kg bw per day (5000x 0.050).
- Sex:
- male
- Basis for effect level:
- other: overall effects Significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Dose descriptor:
- LOAEL
- Effect level:
- 500 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 1% of aluminium sulphate corresponds to 10000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 10000 ppm is equavalent to 500 mg/kg bw per day (10000x 0.050).
- Sex:
- male
- Basis for effect level:
- other: overall effects: Significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Conclusions:
- The results of this study clearly indicate that the neurological function and recovery rate following SCI are significantly impaired in rats exposed to aluminum sulphate at 250 mg/kg/bw day (LOAEL).
- Executive summary:
Adult male Sprague-Dawley rats classified into different groups were given aluminum sulfate-dosed drinking water in the concentrations of 0%, 0.25%, 0.5% and 1%,respectively. After 30 days of aluminum treatment, the animals were subjected to spinal cord trauma. Laminectomy was performed at T7-8 inanesthetized rats, followed by placement of a compression plate (2.2 x 5 mm) loaded with a 35-g weight over the exposed spinal cord for 5 minutes.Control animals underwent the same surgical procedure, but the compression injury was not induced (sham). Postoperative neurological function was assessed using the inclined-plane test and by obtaining a modified Tarlov score and vocal/sensory score daily for 10 days. Electrophysiological changes were assessed using corticomotor evoked potentials, whereas pathological changes were assessed by light microscopy. The level of vitamin E in the spinal cord was measured as an index of antioxidan defense.
The behavioral, biochemical, and histological analyses were performed in a blinded fashion. Analysis of results obtained in the behavioral studies revealed that the compression of spinal cord produced transient paraparesis in which a maximum motor deficit occurred at Day 1 following SCI and resolved over a period of 10 days.
Administration of aluminum significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
Reference
0.25% of aluminium sulphate corresponds to 2500 ppm (mg/l).1 ppm in the diet of rat (old)is equavalent to 0.050mg/kg bw per day. Consequently2500 ppm is equavalent to125mg/kg bw per day (2500x 0.050).
0.5% of aluminium sulphate corresponds to 5000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to0.050 mg/kg bw per day. Consequently 5000 ppm is equavalent to 250 mg/kg bw per day (5000x0.050).
1% of aluminium sulphate corresponds to 10000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to0.050 mg/kg bw per day. Consequently 10000 ppm is equavalent to 500 mg/kg bw per day (10000x0.050).
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LOAEL
- 250 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Effect on neurotoxicity: via inhalation route
Link to relevant study records
- Endpoint:
- neurotoxicity: chronic inhalation
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Reliable with restrictions.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 424 (Neurotoxicity Study in Rodents)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Route of administration:
- inhalation: dust
- Vehicle:
- other: Wright dust feed mechanism
- Details on exposure:
- Groups of rats and guinea pigs were exposed, by inhalation, to 0.25, 2.5, and 25 mg/m3 of aluminum chlorhydrate (ACH) for six months to study the effects of a common component of antiperspirants. Similar groups of animals of both species exposed to clean air served as controls. The ACH was generated as a particulate dust using a Wright dust feed mechanism. After six months of exposure, animals were sacrificed.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 6 months
- Frequency of treatment:
- 5 day/ week, 6 hours/day
- Remarks:
- Doses / Concentrations:
0.25, 2.5, and 25 mg/m3 of aluminum chlorhydrate (ACH)
Basis:
actual ingested - No. of animals per sex per dose:
- na
- Control animals:
- yes
- Observations and clinical examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule:5 day/ week, 6 hours/day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:5 day/ week, 6 hours/day
BODY WEIGHT: Yes
- Time schedule for examinations:5 day/ week, 6 hours/day
OPHTHALMOSCOPIC EXAMINATION: No - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreases in body weight were seen in rats exposed to 25 mgAl/m3 of ACH.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 38.6 mg /m3 for 6 months
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 38.6 mg /m3 for 6 months
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Other effects:
- not examined
- Details on results:
- No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 6.1 mg Al/m3 as aluminum chlorhydrate for 6 months.
Decreases in body weight were seen in rats exposed to 25 mgAl/m3 of ACH. Marked increases in lung weights and significant increases in lung to body weight ratios were seen in rats and guinea pigs exposed to 25 mg/m3 of ACH. The lungs of all rats and guinea pigs showed significant dose-related increases in aluminum accumulation when exposed to either 0.25, 2.5, or 25 mgAl/m3 of ACH. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris. - Dose descriptor:
- NOAEL
- Effect level:
- 38.6 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 38.6 mg /m3 for 6 months
- Remarks on result:
- other: Generation: maternal (migrated information)
- Conclusions:
- No brain weight or histological changes were observed in Fischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 38.6 mg /m3 for 6 months
- Executive summary:
Groups of rats and guinea pigs were exposed, by inhalation, to 0.25, 2.5, and 25 mgAl/m3 of aluminum chlorhydrate (ACH) for six months to study the effects of a common component of antiperspirants. Similar groups of animals of both species exposed to clean air served as controls. The ACH was generated as a particulate dust using a Wright dust feed mechanism. After six months of exposure, animals were sacrificed. Decreases in body weight were seen in rats exposed to 25 mg/m3 of ACH. Marked increases in lung weights and significant increases in lung to body weight ratios were seen in rats and guinea pigs exposed to 25 mg/m3 of ACH. The lungs of all rats and guinea pigs showed significant dose-related increases in aluminum accumulation when exposed to either 0.25, 2.5, or 25 mg/m3 of ACH. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 38.6 mg/m³
- Study duration:
- chronic
- Species:
- rat
Effect on neurotoxicity: via dermal route
Link to relevant study records
- Endpoint:
- neurotoxicity: chronic oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Reliable without restrictions. Well-presented study, with relevant measurement of chemical concentrations
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 424 (Neurotoxicity Study in Rodents)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Adult male Sprague–Dawley rats weighing 180 to 200 g were housed in a temperature-controlled room and maintained in a 12- hour light/dark cycle. Standard laboratory animal food and aluminum- dosed drinking water were freely available throughout the study.
Four treatment groups (eight rats each) were treated with 0%, 0.25%, 0.50%, and 1% of aluminum sulfate (Al2[SO4]3 _ 18 H2O) in drinking water, respectively, for 30 days before being subjected to SCI. - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- Animals and Drugs
Adult male Sprague–Dawley rats weighing 180 to 200 g were housed in a temperature-controlled room and maintained in a 12- hour light/dark cycle. Standard laboratory animal food and aluminum- dosed drinking water were freely available throughout the study. Four treatment groups (eight rats each) were treated with 0%, 0.25%, 0.50%, and 1% of aluminum sulfate (Al2[SO4]3 _ 18 H2O) in drinking water, respectively, for 30 days before being subjected to SCI.
These doses are equivalent to 0 mg, 375 mg, 750 mg, and 1500 mg of aluminum per day consumed by humans weighing 70 kg and are similar to the amounts usually present in antacids ingested by people with peptic disorders.
Recently, we observed that administration of 0.25 to 1% of aluminum sulfate in drinking water produced a several-fold increase in serum aluminum levels in rats. All the experiments in the present study were undertaken according to the guidelines provided by the Research and Ethical Committee of Armed Forces Hospital, Riyadh, Saudi Arabia.
Spinal Cord Injury
After 30 days of aluminum treatment, the animals were subjected to spinal trauma according to the method described by Nystrom and Berglund
The animals received an anesthetic of chloral hydrate (400 mg/kg subcutaneously) and a T7–8 laminectomy was performed, leaving the dura intac.A slightly curved rectangular compression plate (2.2 x 5 mm) loaded with a weight of 35 g was gently placed over the exposed spinal cord for 5 minutes. The wound was closed in layers, and the animal was allowed to recover from anesthesia. Animals in the control group underwent the same surgical procedure but without receiving any compression injury (sham treatment). All the animals received intramuscular injection of gentamicin (2 mg/kg) daily for 3 days after surgery. The bladder was pressed manually twice a day to avoid urinary complications - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
of 0%, 0.25%, 0.5% and 1%,
Basis:
nominal in water - No. of animals per sex per dose:
- 34
- Control animals:
- yes
- Observations and clinical examinations performed and frequency:
- After 30 days of aluminum treatment, the animals were subjected to spinal cord trauma. Laminectomy was performed at T7-8 in anesthetized rats, followed by placement of a compression plate (2.2 x 5 mm) loaded with a 35-g weight over the exposed spinal cord for 5 minutes.
Control animals underwent the same surgical procedure, but the compression injury was not induced (sham). Postoperative neurological function was assessed using the inclined-plane test and by obtaining a modified Tarlov score and vocal/sensory score daily for 10 days.
Electrophysiological changes were assessed using corticomotor evoked potentials, whereas pathological changes were assessed by light microscop. The level of vitamin E in the spinal cord was measured as an index of antioxidan defense. - Specific biochemical examinations:
- Analysis of a-Tocopherol in Spinal Cord Tissue
The level of a-tocopherol (vitamin E) in spinal cord tissue was analyzed using high-performance liquid chromatography according to the method described by Dexter, et al.19 The injured site of the spinal cord (a 50-mg sample) was homogenized in a tube containing 1 ml of Tris buffer (50 mM, pH 7.6) and 3 ml of 1.5% ethanolic pyrogallol. The homogenate was incubated at 70°C in a water bath for 5 minutes, 150 ul of 10 M potassium hydroxide was added to each tube, and additional incubation (70°C) occurred for 30 minutes. The mixture was cooled in an ice bath to room temperature and extracted with 2 ml of hexane. The organic layer was separated after centrifugation, and the aqueous homogenate was further extracted with another 2 ml of hexane. The two hexane extracts were combined and evaporated in nitrogen and stored at -70°C for future analysis. The high-performance liquid chromatography instrument (Waters Associates Inc., Medford, MA) consisted of a solvent delivery pump (Model 510), autoinjector (Model 712), UV-Visible detector (Model 481), and integrator (Model 740). The column used was Bondapak C-18, 3.9 x 150 mm (Waters Associates, Inc.), made of stainless steel. The mobile phase consisted of 95% chromatography- grade methanol in deionized water. The flow rate of the mobile phase was adjusted to 1.5 ml/minute, and the absorbance was measured at 280 nm following a 60-ul injection. The level of vitamin E was calculated using a calibration curve. - Neurobehavioural examinations performed and frequency:
- Behavioral Studies
Neurological function following SCI was assessed daily for 10 days by obtaining a modified Tarlov score,70 a Rivlin and Tator angled-plane score,60 and a vocal/sensory score.10 A modified Tarlov score was used to assess the hindlimb function as follows: 0 = total paraplegia of hindlimbs; 1 = no spontaneous movement but responds to hindlimb pinch; 2 = spontaneous movement; 3 = able to support weight but not able to walk; 4 = walks with gross deficit; 5 = walks with mild deficit on broad flat surface; 6 = able to walk on broad, flat surface and support weight on a 1.8-cm-wide ledge; and 7 = walks on ledge. The angled-plane test consisted of measuring the maximum angle at which an animal can support its weight on an inclined board measured in degrees (0–90°). The board was covered with a rubber mat consisting of 1-mm-high ridges.
The animals were placed transversely on the inclined plane, and the highest angle the animal maintained for 5 seconds was recorded and described as the “capacity angle.” For every test session three separate measurements were made, and the mean score was determined. The sensory/vocal score was measured by administering a noxious stimulus (pinching with a toothed forceps) to the hindlimb of the animals.10 The response of the hindlimb to stimulus was graded as follows: 0 = no response; 1 = withdrawal from pinch without vocalization; 2 = vocalization without withdrawal; and 3 = vocalization and withdrawal.
For biochemical and histological studies, eight additional animals from each group were killed at 4 hours, 24 hours, 5 days, and 10 days post-SCI. All the behavioral, biochemical, and histological tests were performed in blinded fashion. - Sacrifice and (histo)pathology:
- Histological Examination
The rats were anesthetized with ether, and intracardiac perfusion was performed with isotonic saline followed by 10% neutral buffered formalin. After perfusion, the injured portion of the spinal cord was removed, embedded in paraffin, and 6-um sections were cut and stained with hematoxylin and eosin. The slides were viewed under a light microscope to study the structural changes. - Other examinations:
- Electrophysiological Monitoring
Corticomotor evoked potentials were measured using an electromyography system (MS92; Medelec, England) in which the active disc electrode was placed epidurally over the right motor cortex area, whereas the reference needle electrode was placed over the nasion of the anesthetized (400-mg/kg chloral hydrate) rat.
A grounding electrode was placed into the skin of the back. Two needle electrodes were placed into the lateral muscle mass of the left hindlimb and foot pad, respectively, to apply electrical stimulation. Transcortical stimulation was achieved by applying a constant square wave pulse of 0.1 msec in duration at 1 Hz at an intensity of 50 V (the stimulus was amplified and filtered in the range of 10–500 Hz). The time base was set at 50 msec. - Statistics:
- Statistical Analysis
Data were examined using analysis of variance followed by Dunnett’s multiple-range test for comparing different treatment groups. A p value of <0.05 was considered significant. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Compression of spinal cord produced transient paraparesis in which a maximum motor deficit occurred at Day 1 following SCI and resolved over a period of 10 days.
- Behaviour (functional findings):
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- effects observed, treatment-related
- Other effects:
- not examined
- Details on results:
- Tarlov Score
There was no significant postoperative change in Tarlov score in sham-treated animals compared with preoperative score). A highly significant decrease in Tarlov score was observed on Day 1 following SCI, which gradually recovered over a period of 10 days. Administration of aluminum significantly and dose dependently deteriorated the recovery rate following SCI.
Sensory and Vocal Score
There was a significant decrease in the sensory/vocal score at 24 hours (Day 1) postinjury, which recovered to preinjury level on Day 5 (Fig. 1 center). Treatment of rats with a low dose (0.25%) of aluminum failed to produce any effect on SCI-induced deterioration of sensory/vocal score, whereas medium and high doses significantly and dose dependently delayed the recovery of sensory/vocal scores following SCI.
Inclined-Plane Capacity Angle
Spinal compression produced a maximum deterioration of the rat’s ability to walk on an inclined plane on Day 1 postinjury; this was followed by a gradual recovery over a period of 10 days. A low dose (0.25%) of aluminum failed to affect SCI-induced deterioration of capacity angle, whereas medium and high doses significantly and dose dependently slowed the recovery of the animal’s ability to walk on the inclined plane.
Vitamin E Levels
A significant depletion of vitamin E was found in spinal cord tissue obtained in rats on Days 1 and 5 postinjury . Pretreatment with aluminum produced no change in vitamin E level in noninjured animals; however, aluminum dose dependently potentiated SCI-induced depletion
of vitamin E in spinal cord.
Electrophysiological Monitoring
There was a significant reduction in the amplitude of CMEP activity following SCI at 4 hours and 24 hours, and this recovered to normal on Day 10 postinjury . There was no significant difference in the amplitude of CMEP between SCI-alone group and SCI combined with aluminum-treated groups at 4 or 24 hours postinjury. However, on Day 10 the level of CMEP amplitude in aluminum and SCI-treated groups was significantly lower when compared with the SCI alone–treated group. On the other hand, SCI significantly increased the latency of the evoked potential at 4 hours and 24 hours, which partially recovered over a period of 10 days Treatment of animals with aluminum significantly potentiated the SCI-induced increase in the latency of evoked potentials.
Histological Examination
Spinal cord sections obtained in sham-operated animals appeared normal. The spinal cord sections obtained from injured animals showed focal demyelination of white matter in the posterior column of spinal cord and focal loss of neurons in the gray matter. Foci of granularity and vacuolation were demonstrated in the white matter. Administration of aluminum produced more severe degenerative changes in the spinal cord following SCI . - Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 0.25% of aluminium sulphate corresponds to 2500 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 2500 ppm is equavalent to 125 mg/kg bw per day (2500x 0.050).
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 0.5% of aluminium sulphate corresponds to 5000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 5000 ppm is equavalent to 250 mg/kg bw per day (5000x 0.050).
- Sex:
- male
- Basis for effect level:
- other: overall effects Significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Dose descriptor:
- LOAEL
- Effect level:
- 500 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- 1% of aluminium sulphate corresponds to 10000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to 0.050 mg/kg bw per day. Consequently 10000 ppm is equavalent to 500 mg/kg bw per day (10000x 0.050).
- Sex:
- male
- Basis for effect level:
- other: overall effects: Significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
- Remarks on result:
- other: Generation: other: - Adult male Sprague–Dawley rats (migrated information)
- Conclusions:
- The results of this study clearly indicate that the neurological function and recovery rate following SCI are significantly impaired in rats exposed to aluminum sulphate at 250 mg/kg/bw day (LOAEL).
- Executive summary:
Adult male Sprague-Dawley rats classified into different groups were given aluminum sulfate-dosed drinking water in the concentrations of 0%, 0.25%, 0.5% and 1%,respectively. After 30 days of aluminum treatment, the animals were subjected to spinal cord trauma. Laminectomy was performed at T7-8 inanesthetized rats, followed by placement of a compression plate (2.2 x 5 mm) loaded with a 35-g weight over the exposed spinal cord for 5 minutes.Control animals underwent the same surgical procedure, but the compression injury was not induced (sham). Postoperative neurological function was assessed using the inclined-plane test and by obtaining a modified Tarlov score and vocal/sensory score daily for 10 days. Electrophysiological changes were assessed using corticomotor evoked potentials, whereas pathological changes were assessed by light microscopy. The level of vitamin E in the spinal cord was measured as an index of antioxidan defense.
The behavioral, biochemical, and histological analyses were performed in a blinded fashion. Analysis of results obtained in the behavioral studies revealed that the compression of spinal cord produced transient paraparesis in which a maximum motor deficit occurred at Day 1 following SCI and resolved over a period of 10 days.
Administration of aluminum significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats.
Reference
0.25% of aluminium sulphate corresponds to 2500 ppm (mg/l).1 ppm in the diet of rat (old)is equavalent to 0.050mg/kg bw per day. Consequently2500 ppm is equavalent to125mg/kg bw per day (2500x 0.050).
0.5% of aluminium sulphate corresponds to 5000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to0.050 mg/kg bw per day. Consequently 5000 ppm is equavalent to 250 mg/kg bw per day (5000x0.050).
1% of aluminium sulphate corresponds to 10000 ppm (mg/l).1 ppm in the diet of rat (old) is equavalent to0.050 mg/kg bw per day. Consequently 10000 ppm is equavalent to 500 mg/kg bw per day (10000x0.050).
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LOAEL
- 4.75 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Additional information
Orale exposure:
LABORATORY ANIMALS: Neurotoxicity/.Pregnant mice were injectedintraperitoneally with 200 mg/kg aluminum-sulfate or saline from days 10 to13 of gestation inclusive. A second group of pregnant mice was givenaluminum-sulfate at 750 milligrams/liter as their sole drinking water fromdays ten to 17 of gestation inclusive. Offspring were sacrificed at agesranging from 3 to 44 weeks for determination of choline-acetyltransferaseactivity. For behavioral and developmental studies, pups were crossfostered on postnatal day one. Pups were tested for slow righting, cliffaversion, forelimb grasping, pole grasping, climbing on a wire mesh, andeye opening. At 10 weeks, male mice were tested in an eight arm radialmaze. At 22 weeks, adult activity tested were carried out. The cholinergicsystem, as evaluated by the activity of choline-acetyltransferase, wasaffected differentially in different regions of the brain and still showedsignificant effects in the adult. Differences between the intraperitonealand oral series in the magnitude of effect seen in the regions of thebrain probably reflect differences in the effective level of exposure.
Growth rate and psychomotor maturation in the preweaning mouse wereaffected in the intraperitoneal series only, showing a marked postnatal maternal effect. [Clayton RM et al; Life Sci 51 (25): 1921-1928 (1992
/LABORATORY ANIMALS: Neurotoxicity/:Male, 1 day old white-leghorn-chicks were fed 200 or 400mg/kg aluminum-sulfate (10043013) for 15 days. Cerebral hemispheres were analyzed 24 hours after the last feeding. Cerebral hemisphere tissue homogenates prepared from 1 and 56 day old chicks were incubated with various concentrations of aluminum-sulfate to examine the effects of Al on lipid peroxidation in-vitro. The thiobarbituric-acid (TBA) assay was used to estimate tissue peroxidation. Tissue homogenates from 56 day old animals produced more TBA reactive substances than did homogenates from 1 day old animals. Al dependent peroxidation was only seen using 100 micrograms (microg) of Al in 1 day old chicks and 500microg Al in 56 day old chicks. Peroxidation was evident within 15 minutes of incubation and peaked at 30 minutes. Formation of TBA reactive substances using 1 millimolar Al showed a positive linear relationship with the protein concentration after 30 minutes of incubation. No changes in the body weights, brain weights, heights, endogenous levels of TBA reactive substances, free sulfhydryl levels, or brain protein content were seen in animals which ingested Al for 15 days. [Chainy GBN et al; Bull Environ Contam Toxicol 50 (1): 85-91 (1993)]
/LABORATORY ANIMALS: Neurotoxicity/ Oral administration of Al3+ to rats and chickens fed aluminum sulfate was believed to bind to ferritin and thus secondarily free more cellular Fe2+; such increased activity enhanced membrane lipid peroxidation activity, particularly in the brain. Such phenomena were believed to be related aluminum neurotoxicity. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V2 377
/LABORATORY ANIMALS: Neurotoxicity/ We exposed male albino rats for 35 days to aluminum sulfate by gavage. ... Aluminum levels were high in brain specimens of the treated groups comparing to the control and it was dose-dependent. Marked increase in glutamate and glutamine levels was noticed while GABA level was significantly decreased.The most pronounced changes in brain tissue included spongioform changes in the neurons specially those of hippocampus, nuclear deformity, and neurofibrillary degeneration, similar to neurofibrillary tangles in Alzheimer's disease. [El-Rahman SS; Pharmacol Res 47 (3): 189-194 (2003)]
/LABORATORY ANIMALS: Neurotoxicity/ ... Adult male Sprague-Dawley rats classified into different groups were given aluminum sulfate-dosed drinking water in the concentrations of 0%, 0.25%, 0.5% and 1%, respectively. After 30 days of aluminum treatment, the animals were subjected to spinal cord trauma. Laminectomy was performed at T7-8 in anesthetized rats, followed by placement of a compression plate (2.2 x 5 mm) loaded with a 35-g weight over the exposed spinal cord for 5 minutes. Control animals underwent the same surgical procedure, but the compression injury was not induced (sham). Postoperative neurological function was assessed using the inclined-plane test and by obtaining a modified Tarlov score and vocal/sensory score daily for 10 days. Electrophysiological changes were assessed using corticomotor evoked potentials, whereas pathological changes were assessed by light microscopy. The level of vitamin E in the spinal cord was measured as an index of antioxidant defense. The behavioral, biochemical, and histological analyses were performed in a blinded fashion. Analysis of results obtained in the behavioral studies revealed that the compression of spinal cord produced transient paraparesis in which a maximum motor deficit occurred at Day 1 following SCI and resolved over a period of 10 days. Administration of aluminum significantly impaired the recovery following SCI. Analysis of the results of the biochemical, electrophysiological, and histopathological studies also confirmed the deleterious effects of aluminum on recovery from SCI in rats. [Al Moutaery K et al; J Neurosurg 93 (2 Suppl): 276-282 (2000)]
/LABORATORY ANIMALS: Neurotoxicity/ Administration of aluminum sulfate in the drinking water of male Sprague-Dawley rats for thirty days resulted in an impairment of both consolidation and extinction of a passive avoidance task. No impairment of performance was observed on an active avoidance task, radial arm maze or open field activity measure. Biochemical analysis indicated a slight (less than 10%) but significant increase in hippocampal muscarinic receptor number after aluminum treatment as determined by tritiated quinuclidinyl benzilate (3H-QNB) binding. No changes were found in choline acetyltransferase (ChAT) activity, phosphoinositide hydrolysis, 3H-QNB binding in the cortex or tritiated pirenzepine (3H-PZ) binding in the hippocampus or cortex. These results indicate that cholinergic degeneration was not the cause of the observed cognitive impairments. [Connor DJ et al; Pharmacol Biochem Behav 31 (2): 467-474 (1988)]
Dermal exposure:
No studies were located regarding neurological effects in humans after acute- or intermediate-durationdermal exposure to various forms of aluminum.
Graves et al. (1990) examined the association betweenAlzheimer’s disease and the use of aluminum-containing antiperspirants in a case-control study using130 matched pairs. The Alzheimer’s disease was clinically diagnosed at two geriatric psychiatric centers;the controls were friends or nonblood relatives of the Alzheimer patients. Information on lifetime use ofantiperspirants/deodorant was collected via a telephone interview with the subject’s spouse. Noassociation was found between Alzheimer’s disease and antiperspirant/deodorant use, regardless ofaluminum content (odds ratio of 1.2; 95% confidence interval of 0.6–2.4). When only users of aluminumcontainingantiperspirants/deodorants were examined, the adjusted odds ratio was 1.6 (95% confidenceinterval of 1.04–2.4). A trend (p=0.03) toward a higher risk ofAlzheimer’s with increasing use ofaluminum-containing antiperspirants/ deodorants was also found.
Inhalation exposure:
No brain weight or histological changes were observed inFischer 344 rats or Hartley guinea pigs exposed by inhalation to up to 6.1 mg Al/m3 as aluminumchlorhydrate for 6 months (Steinhagen et al. 1978).
Groups of rats and guinea pigs were exposed, by inhalation, to 0.25, 2.5, and 25 mg/m3 of aluminum chlorhydrate (ACH) for six months to study the effects of a common component of antiperspirants. Similar groups of animals of both species exposed to clean air served as controls. The ACH was generated as a particulate dust using a Wright dust feed mechanism. After six months of exposure, animals were sacrificed. Decreases in body weight were seen in rats exposed to 25 mg/m3 of ACH. Marked increases in lung weights and significant increases in lung to body weight ratios were seen in rats and guinea pigs exposed to 25 mg/m3 of ACH. The lungs of all rats and guinea pigs showed significant dose-related increases in aluminum accumulation when exposed to either 0.25, 2.5, or 25 mg/m3 of ACH. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.
Justification for selection of effect on neurotoxicity via dermal route endpoint:
For dermal exposure we taken that:
-the average weight of rats is 190g (180-200g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.019 kg
corrected dermal LOAEL= oral LOAEL
250 mg/kg bw/day 0.019 kg =
LOAELrat 4.75 mg/kg bw/day
Justification for classification or non-classification
There are conclusive but not suffcient data for the classification of substance Aluminium sulphate with regard to neurotoxicity.
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