Aluminium trilactate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Twenty-six week toxicity study with KASAL (basic sodium aluminum phosphate) in beagle dogs

Author:

Pettersen JC et al.

Year:

1990

Bibliographic source:

Environmental Geochemistry and Health Volume 12, Numbers 1-2, 121-123

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

yes

Remarks:

duration of treatment extended to 180 days

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

7785-88-8 (KASAL (basic sodium aluminium phosphate); autogenous mixture of alkaline sodium aluminum phosphate and dibasic sodium phosphate)

IUPAC Name:

7785-88-8 (KASAL (basic sodium aluminium phosphate); autogenous mixture of alkaline sodium aluminum phosphate and dibasic sodium phosphate)

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): KASAL (basic sodium aluminium phosphate); autogenous mixture of alkaline sodium aluminum
phosphate and dibasic sodium phosphate
- Molecular formula (if other than submission substance): Na8Al2(OH)2PO4)4 + 30% NaH2PO4
- Physical state: solid
- Analytical purity: no data

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Marshall Research Animals (North Rose, NY)
- Age at study initiation: 20 to 22 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individually in stainless steel cages, exercised weekly
- Diet (e.g. ad libitum): Purina Certified Canine Diet #5007 + basic sodium aluminium phosphate + small amount of Mazola corn oil (0.5% w/w); 400 g of blended diet containing basic sodium aluminium phosphate was provided to each dog in a 3-hour feeding period
- Water (e.g. ad libitum): no data
- Acclimation period: ca. 5 weeks

ENVIRONMENTAL CONDITIONS
no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

Four-hundred grams of blended diet containing basic sodium aluminium phosphate was provided to each dog in a 3-hour feeding period.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test diets were blended biweekly and stored at room temperature. The concentration and homogeneity of basic sodium aluminium phosphate in each of the blended diets were determined monthly by analysis of aluminum content using atomic absorption spectrophotometry.

Duration of treatment / exposure:

26 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
106, 323, 1251 mg basic Sodium aluminium phosphate/kg bw/d (females)
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
112, 390, 1143 mg basic Sodium aluminium phosphate/kg bw/d (males)
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
3, 10, 22, 80 mg Al/kg bw/d (females)
Basis:
actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:
4, 10, 27, 75 mg Al/kg bw/d (males)
Basis:
actual ingested

Doses / concentrations 5

Remarks:

Doses / Concentrations:
0, 3000, 10000 or 30000 p.p.m. basic Sodium aluminium phosphate
Basis:
nominal in diet

No. of animals per sex per dose:

4

Control animals:

yes, plain diet

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes :

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Basic sodium aluminium phosphate consumption was calculated from each animal's weekly food consumption and body weight. Aluminium consumption was calculated from each animal's weekly food consumption, body weight as well as the mean aluminum concentrations calculated for basal and blended diet.

FOOD EFFICIENCY: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Blood samples were collected for clinical laboratory analyses from all animals prior to study initiation, near midpoint and at termination. The
dogs were fasted for at least 16 hours prior to sample collection. Blood samples were collected from the jugular vein in the morning. Hematocrit, haemoglobin concentration, erythrocyte count, leukocyte count (total and differential), and platelet count were determined.

CLINICAL CHEMISTRY: Yes
- Blood samples were collected for clinical laboratory analyses from all animals prior to study initiation, near midpoint and at termination. The
dogs were fasted for at least 16 hours prior to sample collection. Blood samples were collected from the jugular vein in the morning. Serum chemistry measurements included blood urea nitrogen, creatinine, sodium, potassium, chloride, phosphorus, alanine aminotransferase, aspartate
aminotransferase, alkaline phosphatase, gamma glutamyl transferase, sorbitol dehydrogenase, total bilirubin, total protein, albumin, globulin, glucose, calcium, cholesterol, and triglyceride.

URINANALYSIS: Yes
- Urine samples were collected for clinical laboratory analyses from all animals prior to study initiation and at termination. Urine samples were collected overnight using metabolism cages.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- FECALANALYSIS: Yes
-- Faecal samples were collected for clinical laboratory analyses from all animals prior to study initiation and at termination. Faecal samples were collected overnight using metabolism cages.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- Organs weighed at necropsy included heart, liver, kidneys, ovaries, testes, thyroid, adrenals, and brain. Specimens from all major organs (not mentioned in detail) were fixed by immersion in 10% neutral buffered formalin or 2.5% buffered glutaraldehyde and processed for light microscopic examination.

Other examinations:

- Bone aluminium analysis: The aluminum concentration of trabecular bone and brain specimens were determined. Trabecular bone specimens were obtained from the fight and left femurs and brain specimens from the frontal cortex. Tissue samples were prepared for aluminum analysis in a Class 10-100 clean room. The samples were digested with NBS (National Bureau of Standards Purified Reagent) nitric acid. Aluminum in the resulting solution was determined with a Perkin-Elmer 5000 (Norwalk, CT) atomic absorption spectrophotometer equipped with a graphite furnace and Zeeman background correction system. Limits of detection and quantitation of tissue aluminum concentrations were calculated as described by Long and Winefordner (1983) and the American Chemical Society's Committee on Environmental Improvement (1980). The limit of detection for a sample was the lowest concentration measured that was statistically different from the blank sample concentration. In a similar manner, the limit of quantitation was also calculated from the blank analysis data that assured that the measured value was a precise number. For ,these studies, concentration values for aluminum below the detection limit were reported as not detected, values between the limit of detection and the limit of quantitation could not be precisely measured and were therefore reported as a range, and values that exceeded the limit of quantitation were assigned numerical values. Tissue aluminum concentrations were analyzed statistically by a one-way analysis of variance followed by Neuman-Keuls tests. Statistical significance was accepted at p<0.05.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Findings were limited to high dose males.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Findings were limited to high dose males. For actual ingested doses see section "Doses/concentrations"

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Findings were limited to high dose males.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Findings were limited to high dose males.

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: There were no mortalities during the study. No data on clinical signs.

BODY WEIGHT AND WEIGHT GAIN and FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): There was a sharp, transient decrease of food consumption and a concomitant decrease of body weight in high-dose males. No effect on food consumption and body weight was observed in females. For actual ingested dose see section "Doses/concentrations"

FOOD EFFICIENCY: not examined

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): no data

OPHTHALMOSCOPIC EXAMINATION: no data

HAEMATOLOGY, CLINICAL CHEMISTRY and URINALYSIS: No treatment-related effects on serum chemistry, haematology or urinalysis were observed.

NEUROBEHAVIOUR: not examined

ORGAN WEIGHTS and HISTOPATHOLOGY: NON-NEOPLASTIC: Findings were limited to a decrease in testes weight in high dose males and microscopic changes which included mild to moderate hepatocyte vacuolation accompanied by hepatocyte hypertrophy and mild bile stasis involving bile
cannuliculi (three of four animals). Two high-dose males had moderate seminiferous tubule germinal epithelial cell degeneration and atrophy. Changes in both organs were probably a consequence of the large body weight effect observed in these animals. Other changes included very mild to mild tubular-glomerularnephritis in high-dose males.

GROSS PATHOLOGY: no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable): not examined

HISTORICAL CONTROL DATA (if applicable): not relevant

OTHER FINDINGS
- Individual animal tissue aluminum concentrations were determined in triplicate. To provide for a conservative method and aid in statistical analysis, individual mean values were calculated by using the highest possible aluminum concentration for each determination (i.e., detection limit, limit of quantitation or actual value). These individual mean values were utilized for calculation of group mean values and for statistical analysis. Using this approach, group mean trabecular bone aluminum concentrations in males or females fed basic sodium aluminium phosphate were not significantly different from control.Similarly, brain aluminum concentrations were comparable among control and KASAL-treated males. In contrast, brain aluminum concentrations were significantly increased (p<0.05, values were 1.6 times greater than control), in high-dose (30,000 p.p.m.) females relative to control while no effect was apparent at lower KASAL dose levels.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

27 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Aluminium

Sex:

male

Basis for effect level:

other: overal effects

2

Dose descriptor:

LOAEL

Effect level:

75 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Aluminium

Sex:

male

Basis for effect level:

other: reduced body weights and food consumption with accompanying histopathological findings in liver, testes, and kidneys

3

Dose descriptor:

NOAEL

Effect level:

80 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Aluminium

Sex:

female

Basis for effect level:

other: overall effects / highest dose tested

4

Dose descriptor:

NOAEL

Effect level:

390 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

basic Sodium aluminium phosphate

Sex:

male

Basis for effect level:

other: overall effects / dose corresponds to 10.000 ppm basic Sodium aluminium phosphate in diet

5

Dose descriptor:

LOAEL

Effect level:

1 143 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

basic Sodium aluminium phosphate

Sex:

male

Basis for effect level:

other: reduced body weights and food consumption with accompanying histopathological findings in liver, testes, and kidneys / dose corresponds to 30.000 ppm basic Sodium aluminium phosphate in diet

6

Dose descriptor:

NOAEL

Effect level:

1 251 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

basic Sodium aluminium phosphate

Sex:

female

Basis for effect level:

other: overall effects / highest dose tested corresponding to 30.000 ppm basic Sodium aluminium phosphate in diet

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In this study, dietary administration of basic Sodium aluminium phosphate, to beagle dogs for 26 weeks resulted in decreased food consumption, decreased body and testis weight and histopathological changes in liver, testes and kidney of male dogs after 75 mg Al/kg bw/d. No effects were seen in females. The NOAEL was 390 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 27 mg Al/kg bw/d in male beagle dogs. The NOAEL in female beagle dogs was the highest dose tested of 1251 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 80 mg Al/kg bw/d.

Executive summary:

In a repeated dose toxicity study comparable to OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents), male and female Beagle dogs were exposed basic Sodium aluminium phosphate at dose levels of 0, 3000, 10000 and 30000 ppm in their diets. Based on Aluminium measurements, food consumption and body weights, the male animals received 0, 112, 390 and 1143 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 4, 10, 27 and 75 mg Al/kg bw/d and the female animals 0, 106, 323 and 1251 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 3, 10, 22 and 80 mg Al/kg bw/d. In deviation to the guideline mentioned, study duration was 26 weeks and not 13 weeks. In-life observation findings were limited to a sharp, transient decrease of food consumption and a concomitant decrease of body weight in high-dose males. No effect on food consumption and body weight was observed in females. No treatment-related effects on serum chemistry, haematology or urinalysis were observed. No animal died during the study. Postmortem observations findings were limited to a decrease in testes weight in high-dose males and microscopic changes which included mild to moderate hepatocyte vacuolation accompanied by hepatocyte hypertrophy and mild bile stasis involving bile cannuliculi (three of four animals). Two high-dose males had moderate seminiferous tubule germinal epithelial cell degeneration and atrophy. According to discussion of the study authors, changes in both organs were probably a consequence of the large body weight effect observed in these animals. Other changes included very mild to mild tubular-glomerularnephritis in high-dose males. The NOAEL was 390 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 27 mg Al/kg bw/d in male beagle dogs. The NOAEL in female beagle dogs was the highest dose tested of 1251 mg basic Sodium aluminium phosphate/kg bw/d, corresponding to 80 mg Al/kg bw/d.