S-EPA
United States
Environmental Protection
Agency
EPA/690/R-23/004F I June 2023 i FINAL
Provisional Peer-Reviewed Toxicity Values for
Aluminum Phosphate Salts
(multiple CASRNs)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
-------
A United States
Environmental Protection
%#UI JTT,Agency
EPA/690/R-23/004F
June 2023
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Aluminum Phosphate Salts
(multiple CASRNs)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
SCIENTIFIC TECHNICAL LEAD
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Daniel D. Petersen, MS, PhD, DABT, ATS, ERT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Laura M. Carlson, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
PRIMARY EXTERNAL REVIEW
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
in
Aluminum phosphate salts
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVS 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 11
2.1. HUMAN STUDIES 18
2.1.1. Oral Exposures 18
2.1.2. Inhalation Exposures 18
2.2. ANIMAL STUDIES 18
2.2.1. Oral Exposures 18
2.2.2. Inhalation Exposures 31
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 31
2.3.1. Genotoxi city 36
2.3.2. Other Animal Studies 36
2.3.3. Absorption, Distribution, Metabolism, and Excretion (ADME) Studies 38
3. DERIVATION 01 PROVISIONAL VALUES 40
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES 40
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS 40
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 41
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 41
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 42
APPENDIX A. DATA TABLES 68
APPENDIX B. SCREENING NONCANCER PROVISIONAL VALUES 43
APPENDIX C. REFERENCES 68
iv
Aluminum phosphate salts
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
N-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NO A F.I.
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODADJ
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
glutathione-S'-transfcrase
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV assessment.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ALUMINUM PHOSPHATE SALTS (MULTIPLE CASRNS)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund program. PPRTVs are derived after a review of the relevant
scientific literature using established U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing
toxicologically relevant human-health effects. Questions regarding nomination of chemicals for
update can be sent to the appropriate U.S. EPA eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment
was written with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP),
the QAPP titled Program Quality Assurance Project Plan (PQAPP) for the Provisional
Peer-Reviewed Toxicity Values (PPRTVs) and Related Assessments/Documents
(L-CPAD-0032718-QP), and the PPRTV assessment development contractor QAPP titled
Quality Assurance Project Plan—Preparation of Provisional Toxicity Value (PTV) Documents
(L-CPAD-0031971-QP). As part of the QA system, a quality product review is done prior to
management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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DISCLAIMERS
The PPRTV document provides toxicity values and information about the toxicologically
relevant effects of the chemical and the evidence on which the value is based, including the
strengths and limitations of the data. All users are advised to review the information provided in
this document to ensure that the PPRTV assessment used is appropriate for the types of
exposures and circumstances at the site in question and the risk management decision that would
be supported by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
This document addresses the available data on the toxicity of aluminum phosphate salts.
Aluminum phosphate salts are considered separately in this document from other inorganic
phosphates (monovalent, divalent, and ammonium phosphates) because it is expected that the
presence of aluminum would influence the chemistry, toxicokinetics, and/or toxicity of these
salts relative to the other classes of inorganic phosphates. Specifically, the aluminum ions are
expected to exert toxic effects that are independent of the phosphate moiety, which would
confound the hazard identification for the other inorganic phosphates. The reader is referred to
the PPRTV assessments for sodium/potassium salts of inorganic phosphates (U.S. EPA. 202Id),
calcium salts of inorganic phosphates (U.S. EPA. 2021c). and ammonium phosphates (U.S. EPA.
2021b) for assessments of these inorganic phosphate salts, as well as the PPRTV assessment for
aluminum (U.S. EPA. 2006).
Aluminum phosphate salts are inorganic salts composed of a phosphate anion and an
aluminum cation. Aluminum phosphate (AIPO4, CASRN 7784-30-7) is a highly insoluble and
unreactive compound consisting of aluminum (Al3+) and phosphate (PO43 ) in a 1:1 ratio. Other
complexes of aluminum phosphate, with varying ratios of aluminum and phosphoric acid groups
(i.e., 3:1) and mixed sodium aluminum phosphates (SALPs), are also included in this assessment
(see Table 1). These chemicals all contain aluminum (CASRN 7429-90-5). Aluminum is a
metallic element with an atomic number of 13 and is a member of the post-transition metal
series. Aluminum is the most abundant metallic element in the Earth's crust and is the most
widely used nonferrous metal. Aluminum-containing compounds are widely distributed in rocks,
soils, water, air, and food. In the environment and biological systems, aluminum is not found in
the elemental form because of its chemical reactivity. Al3+ readily forms complexes with ligands,
such as phosphates and metaphosphates, where phosphoric acid moieties form a cyclic (ring)
structure, to counter the +3 charge.
Phosphorus (P) is most commonly found in nature in its pentavalent form in combination
with oxygen, as phosphate (PO43 ). Phosphorus is an essential constituent of all living organisms,
and is ubiquitous in most plant and animal tissues. Condensed (pyro-, meta-, and other)
polyphosphates are formed when two or more orthophosphate molecules condense into a single
molecule. Pyrophosphates refer to compounds with two condensed orthophosphates, and higher
number polymers are termed polyphosphates, sometimes preceded by a prefix indicating the
number (e.g., tri- and tetrapolyphosphates have three and four condensed phosphates,
respectively). The term "metaphosphates" is used when phosphoric acid moieties form a cyclic
(ring) structure. Inorganic phosphates (both ortho- and condensed phosphate anions) can be
grouped into four classes based on their cations: monovalent (sodium, potassium, and hydrogen),
divalent (calcium and magnesium), ammonium, and aluminum. The phosphoric acids have been
grouped with the other monovalent cations based on valence state.
Aluminum phosphate occurs naturally as minerals such as berlinite (AIPO4) or variscite
(aluminum phosphate dihydrate [A1P04-2H20]) (Sellrodter et at.. 2012). Aluminum phosphates
are produced by combining alkali metal phosphates and solutions of aluminum salts or aluminum
hydroxide with phosphoric acid (Gilmour. 2019). Aluminum phosphates are used in ceramics,
cosmetics, paints, and varnishes and in paper and pulp industries (ATSDR. 2008). Human
exposure to aluminum phosphates is expected based on their characterization as generally
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Aluminum phosphate salts
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EPA/690/R-23/004F
recognized as safe (GRAS) for use as food additives, antacids, and as vaccine adjuvants by the
U.S. Food and Drug Administration (FDA. 1975). Basic and acidic mixed SALPs are used in
food applications, as emulsifying agents in pasteurized processed cheese, and as leavening agents
in cereal foods, self-rising flour, prepared cake mixes, pancakes, waffles, and refrigerated or
frozen dough or batter products (ATSDR. 2008). SALPs are food additives classified by the
FDA as GRAS as a multiple-purpose food substance when used in accordance with good
manufacturing practice under Chapter 21 of the Code of Federal Regulations (FDA. 2020b). The
commercial product, Levair®, is an acidic form of SALP used as a leavening agent in food
products and contains approximately 8% aluminum (Hicks et at.. 1987). Levn Lite® is another
acidic SALP that is used as a heat-triggered leavening agent in frozen foods and baking products
(percentage aluminum unknown). Kasal™ and Kasal™II are dibasic forms of sodium phosphate
containing approximately 6 and 13% aluminum, respectively. Kasal™ and Kasal™II are used in
the production of cheese products (Hicks et at.. 1987).
In 1974, the FDA announced that antacids containing aluminum compounds are GRAS
for over-the-counter sale (FDA. 1975). The FDA has established a maximum daily dose of 8 g of
aluminum phosphate gel for use as an antacid (FDA. 2020a). In general, antacids function by
limiting the acid within the gastrointestinal tract from reaching the duodenum by neutralizing the
acid present in the stomach. Available information on aluminum-containing antacids applies
mostly to aluminum hydroxide gel, which is reported to function by the aluminum binding with
dietary phosphorus and impairing gastrointestinal absorption of phosphorus (Spencer and
Lender. 1979). The mechanism of acid neutralization is expected to vary for each salt (Salisbury
and Terrell. 2020).
The FDA has also licensed aluminum salts (aluminum hydroxide, aluminum phosphate,
and potassium aluminum sulfate) to be used as an adjuvant in many vaccines (ATSDR. 2008).
Aluminum salt adjuvants form an insoluble depot that slowly releases the antigen, which
stimulates an antibody response. Clinical studies have demonstrated that aluminum enhances the
antigenicity of certain vaccines (Bavlor et at.. 2002). The amount of aluminum permitted within
an individual dose of a biological product cannot exceed 0.85 mg if determined by assay, or
1.14 mg if determined by calculation on the basis of the amount of aluminum compound added
(FDA. 2020b). Aluminum adjuvants have been associated with severe local reactions in some
people (ATSDR, 2008; Bavlor et at., 2002).
The empirical formulas for several aluminum and mixed SALPs are shown in Table 1.
Table 1 also summarizes available information on the physicochemical properties of these
compounds; limited information is available for most of them. Several of these compounds
(CASRNs 13776-88-0, 13939-25-8, 13530-50-2, and 7785-88-8) are listed in the U.S. EPA's
2019 Toxic Substance and Chemical Act (TSCA) public inventory (U.S. EPA. 202 le). and
several (CASRNs 7784-30-7, 13776-88-0, 13939-25-8, 13530-50-2, 7785-88-8, and 15136-87-5)
are registered or preregistered in Europe's Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH) program (ECHA, 2019a, b, c, d, e, f). Repeated-dose toxicity
information in the European Chemicals Agency (ECHA) is based on an analogue (read-across)
approach using available data on oral exposures to SALPs, along with available supporting
information. This approach was based on the common functional groups of the Al3+ cation and
the PO43 anion, the likelihood of these common breakdown products, and similarities in
solubilities.
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EPA/690/R-23/004F
Table 1. Identity, Molecular Weight, and Physicochemical Properties of Aluminum Phosphates and Mixed Sodium
Aluminum Phosphates Considered in this Assessment3
Compound [synonym]
CASRN
Molecular
Formulab
MW
(g/mol)b
MW Ratio
P:Compoundc
Physical
State
Melting
Point
(°C)
Density
(g/cm3 at
25°C)
Solubility in Water
Phosphoric acid, aluminum salt (1:1)
[aluminum phosphate]
7784-30-7
A104P
121.951
0.25399
White
crystals'1
l,500d
2.566d
Insoluble in water;d
slightly soluble at low pH
Metaphosphoric acid (HP03), aluminum salt (3:1)
[aluminum metaphosphate]
13776-88-0
AIO9P3
263.894
0.35212
White
powder1
l,527d
NV
Insoluble in w ater1
Triphosphoric acid, aluminum salt (1:1)
[aluminum triphosphate]
13939-25-8
AIH2O10P3
281.909
0.32962
NV
NV
NV
Insoluble in water6
Phosphoric acid, aluminum salt (3:1)
[monoaluminum phosphate; aluminum
dihydrogen phosphate]
13530-50-2
AlHsOizPs
317.939
0.29226
White
powder'
NV
NV
Soluble in unbuffered water
(294 g Al/L at pH 2 at
20°C); low solubility in
buffered water (5,535.5 |ig
Al/L at pH 6; 6.293 ng
Al/L at pH 8)s
Phosphoric acid, aluminum sodium salt (8:3:1),
tetrahydrate
[sodium aluminum phosphate tetrahydrate
(SALP)]
10305-76-7
AlsIfeNaOssP 8
949.864
0.26087
NV
NV
NV
Insoluble in water11
Phosphoric acid, aluminum sodium salt (8:2:3)
[sodium aluminum phosphate anhydrous (basic
SALP)]
10279-59-1
AI2H15Na3C>32P8
897.81
0.27600
White
powder1
NV
NV
Sparingly soluble in water1
Phosphoric acid, aluminum sodium salt (1:?:?)
[sodium aluminum phosphate acidic (acidic
SALP)]
7785-88-8
Mixture of
AlsHzzNaCbePg
and
AI2H15Na3C>32P8
NA
NA
White
powder1
NV
NV
Insoluble in w ater1
5
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Table 1. Identity, Molecular Weight, and Physicochemical Properties of Aluminum Phosphates and Mixed Sodium
Aluminum Phosphates Considered in this Assessment3
Compound [synonym]
CASRN
Molecular
Formulab
MW
(g/mol)b
MW Ratio
P:Compoundc
Physical
State
Melting
Point
(°C)
Density
(g/cm3 at
25°C)
Solubility in Water
Phosphoric acid, aluminum sodium salt (8:3:1)
[trialuminum sodium
tetra-decahydrogenoctaorthophosphate]
15136-87-5
Al3Hi4Na032P8
877.804
0.28229
NV
NV
NV
Insoluble in water1
aOctanol-water partition coefficient, Henry's law constant, soil adsorption coefficient (Koc), atmospheric OH rate constant, and atmospheric half-life are not applicable to
aluminum phosphates.
' Data were extracted from the U.S. EPA CompTox Chemicals Dashboard: aluminum phosphate salts, multiple CASRNs; https://comptox.epa.gov/dashboard: accessed
December 18, 2019. Data presented are experimental averages unless otherwise noted (U.S. EPA. 202131.
°MW of P = 30.974 g/mol (NUM. 2021b).
dLarraftaga et at (2016).
'ITU A (2019a).
'U.S. EPA (2015).
8 EC HA (2019c).
hEU (2012).
'IQM (2003).
MW = molecular weight; NA = not applicable; NV = not available; P = phosphorus; SALP = sodium aluminum phosphate; U.S. EPA = U.S. Environmental Protection
Agency.
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As shown in Table 1, aluminum phosphate salts are largely insoluble in water and
sparingly soluble under acidic conditions (Schrodtcr et al.. 2012; ATSDR. 2008). Free aluminum
(Al3+) forms an insoluble salt with phosphate (AIPO4; A1P04-2H20) within the pH range of
5-6 (ATSDR. 2008). Aluminum tris(aluminum dihydrogen phosphate) (CASRN 13530-50-2)
demonstrated high solubility in unbuffered water, where the final pH value of the solution was 2
(HCHA. 2019c). The pH of the water decreased with increased loading of the aluminum
tris(dihydrogen phosphate) test substance. However, in buffered solutions at pH 6 and 8, this
compound demonstrated low solubility. Under acidic conditions, like those found in parts of the
digestive system, Al3+ is expected to be the dominant species (Martin. 1986). However, due to
the low solubility of aluminum phosphates at biological pHs, the "free" aluminum ions occur in
very low concentrations (ATSDR. 2008). Although bioavailability appears to generally parallel
water solubility, data are insufficient to fully inform this extrapolation (ATSDR. 2008).
Bioavailability in the human body is a function of the chemical form that occurs in the
gastrointestinal tract (i.e., forming of complexes with dietary ligands). By comparison to other
aluminum salts (i.e., aluminum hydroxide), aluminum phosphates have a lower tendency to be
solubilized in the presence of dietary acids and a lower tendency to form absorbable complexes
(Berthon and Davde. 1992).
A summary of available toxicity values for aluminum phosphates from the U.S. EPA and
other agencies/organizations is provided in Table 2.
Table 2. Summary of Available Toxicity Values Relevant to Aluminum
Phosphates (Multiple CASRNs)
Source (parameter)ab
Value (applicability)
Notes
Reference0
Noncancer
IRIS
NV
NA
U.S. EPA (2019)
PPRTV
(RfD,
chronic)
Aluminum
1 mg Al/kg-d
Based on a LOAEL of
100 mg Al/kg-d for
minimal neurotoxicity
in the offspring of mice.
U.S. EPA (2006)
HEAST
NV
NA
U.S. EPA
(2011b)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR
(MRL, oral
intermediate)
Aluminum
1 mg Al/kg-d
Based on a NOAEL of
26 mg Al/kg-d for
neurodevelopmental
effects in mice.
ATSDR (2019);
ATSDR (2008)
ATSDR
(MRL, oral
chronic)
Aluminum
1 mg Al/kg-d
Based on decreases in
forelimb and hindlimb
grip strength and
thermal sensitivity in a
chronic study in mice.
ATSDR (2019);
ATSDR (2008)
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Table 2. Summary of Available Toxicity Values Relevant to Aluminum
Phosphates (Multiple CASRNs)
Source (parameter)ab
Value (applicability)
Notes
Reference0
IOM (UL)
Phosphate
Children: 3,000 mg P/d
Adults <70 yr: 4,000 mg P/d
Adults >70 yr: 3,000 mg P/d
Pregnant women: 3,500 mg P/d
Lactating women: 4,000 mg P/d
The maximum level of
daily P intake that is
likely to pose no risk of
toxicologically relevant
effects. The UL
represents total intake
from food, water, and
supplements.
IOM (1997)
WHO
(MIDI)
Phosphate
70 mg P/kg body weight
Maximum intake of P
across all sources; based
on nephrocalcinosis in
rats.
IPCS (2019):
WHO (1982)
CalEPA
NV
NA
CalEPA (2019):
CalEPA (2001)
OSHA
NV
NA
OSHA (2018a):
OSHA (2018b):
OSHA (2018c)
NIOSH
NV
NA
NIOSH (2018)
ACGIH
(TLV-TWA,
respirable
particulate
matter)
Aluminum metal and
insoluble compounds
1 mg/m3
Based on
pneumoconiosis, lower
respiratory tract
irritation, and
neurotoxicity.
ACGIH (2018):
ACGIH (2008)
DOE (PAC)
Aluminum phosphate
(CASRN 7784-30-7)
PAC-1: 14 mg/m3
PAC-2: 200 mg/m3
PAC-3: 1,200 mg/m3
PAC-1 based on
MW-adjusted insoluble
aluminum
(CASRN 7429-90-5)
TLV-TWA, PAC-2
based on TEEL-3, and
PAC-3 based on rat oral
LDLo.
DOE (2018)
DOE (PAC)
Aluminum
tris(dihydrogen
phosphate)
(CASRN 13530-50-2)
PAC-1: 3 mg/m3
PAC-2: 33 mg/m3
PAC-3: 200 mg/m3
PAC-1 based on
insoluble aluminum
(CASRN 7429-90-5)
TLV-TWA, PAC-2
based on TEEL-1, and
PAC-3 based on
TEEL-2.
DOE (2018)
USAPHC
(air-MEG)
Aluminum phosphate
(CASRN 7784-30-7)
1-h critical: 500 mg/m3
1-h marginal: 500 mg/m3
1-h negligible: 100 mg/m3
Based on TEELs.
U.S. APHC
(2013)
USAPHC
(air-MEG)
Aluminum phosphate
solution
(CASRN 13530-50-2)
1-h critical: 300 mg/m3
1-h marginal: 60 mg/m3
1-h negligible: 60 mg/m3
Based on TEELs.
U.S. APHC
(2013)
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Table 2. Summary of Available Toxicity Values Relevant to Aluminum
Phosphates (Multiple CASRNs)
Source (parameter)ab
Value (applicability)
Notes
Reference0
Cancer
IRIS
NV
NA
U.S. EPA (2019)
HEAST
NV
NA
U.S. EPA
(2011b)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2019)
CalFPA
NV
NA
CalEPA (2019)
ACGIH
(WOE)
Aluminum metal and
insoluble compounds
A4: Not classifiable as a human
carcinogen
Based on no evidence
that aluminum
compounds are
carcinogenic except on
implantation in animals,
a route of exposure that
is not relevant to
occupational exposure.
ACGIH (2018);
ACGIH (2008)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency;
DOE = U.S. Department of Energy; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer;
IOM = Institute of Medicine; IRIS = Integrated Risk Information System; NIOSH = National Institute for
Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health
Administration; PPRTV = Provisional Peer-Reviewed Toxicity Value; USAPHC = U.S. Army Public Health
Command; WHO = World Health Organization.
Parameters: LOAEL = lowest-observed-adverse-effect level; MEG = military exposure guideline;
MRL = minimum risk level; MTDI = maximum tolerable daily intake; NOAEL = no-observed-adverse-effect
level; PAC = protective action criteria; RfD = reference dose; TEEL = temporary emergency exposure limit;
TLV = threshold limit value; TWA = time-weighted average; UL = tolerable upper intake level; WOE = weight of
evidence.
°Reference date is the publication date for the database and not the date the source was accessed.
A1 = aluminum; LDLo = lowest reported lethal dose; MW = molecular weight; NA = not applicable; NV = not
available; P = phosphorus.
Literature searches were conducted in April-June 2019 and updated most recently in
January 2023 for studies relevant to the derivation of provisional toxicity values for the
eight aluminum phosphate compounds shown in Table 1 above: aluminum phosphate
(CASRN 7784-30-7), aluminum metaphosphate (CASRN 13776-88-0), aluminum triphosphate
(CASRN 13939-25-8), monoaluminum phosphate (CASRN 13530-50-2), sodium aluminum
phosphate tetrahydrate (SALP, CASRN 10305-76-7), sodium aluminum phosphate anhydrous
(basic SALP, CASRN 10279-59-1), sodium aluminum phosphate acidic (acidic SALP,
CASRN 7785-88-8), and trialuminum sodium tetra decahydrogenoctaorthophosphate
(CASRN 15136-87-5). Searches were conducted using the U.S. EPA's Health and
Environmental Research Online (HERO) database of scientific literature. HERO searches the
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following databases: PubMed, TOXLINE1 (including TSCATS1), Scopus, and Web of Science.
The following resources were searched outside of HERO for health-related values: American
Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and
Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense
Technical Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of
Chemicals (ECETOC), European Chemicals Agency (ECHA), the U.S. EPA Chemical Data
Access Tool (CDAT), the U.S. EPA ChemView, the U.S. EPA Integrated Risk Information
System (IRIS), the U.S. EPA Health Effects Assessment Summary Tables (HEAST), the
U.S. EPA Office of Water (OW), International Agency for Research on Cancer (IARC), the
U.S. EPA TSCATS2/TSCATS8e, the U.S. EPA High Production Volume (HPV), Chemicals via
International Programme on Chemical Safety (IPCS) INCHEM, Japan Existing Chemical Data
Base (JECDB), Organisation for Economic Co-operation and Development (OECD) Screening
Information Data Sets (SIDS), OECD International Uniform Chemical Information Database
(IUCLID), OECD HPV, National Institute for Occupational Safety and Health (NIOSH),
National Toxicology Program (NTP), Occupational Safety and Health Administration (OSHA),
and World Health Organization (WHO).
'TOXLINE content was migrated to PubMed (https://www.nlm.nih.gov/databases/download/toxlinesubset.html'):
therefore, it was not included in the literature search update from March 2022.
Aluminum phosphate salts
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer evidence
bases, respectively, for aluminum phosphate salts and include all potentially relevant
repeated-dose short-term, subchronic, and chronic studies, as well as reproductive and
developmental toxicity studies. The phrase "statistical significance" and term "significant," used
throughout the document, indicate ap-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Data for Aluminum Phosphate Salts (Multiple CASRNs)
Number of Male/Female, Strain,
Species, Exposure Route,
Reference
Category3
Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Short-term
25 M/0 F, Sprague Dawley, rat,
0, 2,436
No toxicologically relevant effects in
2,471
NDr
Hicks et al.
PR
oral in feed (corn oil vehicle), 28 d
(Kasal™),
males.
(1987)
0, 558, 2,471
Reported analytical concentrations:
(Kasal™II)
0, 30,000 (Kasal™), 7,000, or
30,000 ppm (Kasal™II)
Subchronic
15 M/15 F, albino, rat (strain NR),
0, 172.66,
No toxicologically relevant effects in
1,803.11 (M)*
NDr (M)*
Anonymous
NPR,
oral in feed, 90 d
562.74,
males.
(1972) as cited in
SS
1,803.11 (M)
NDr (F)*
205.62 (F)*
ECHA (1972e)
Reported analytical concentrations:
Dose-related increase in incidence
(Limited study
0,0.3, 1.0, or 3.0% Kasal™
0, 205.62,
and severity of nephrocalcinosis in
details are
701.32,
females; increased relative kidney
available: FDA
2,113.79 (F)
weight in high-dose females.
(1975) reported
that the study was
performed by
IBT.*)
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Table 3A. Summary of Potentially Relevant Data for Aluminum Phosphate Salts (Multiple CASRNs)
Category3
Number of Male/Female, Strain,
Species, Exposure Route,
Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
15 M/15 F, albino, rat (strain NR),
oral in feed, 90 d
Reported analytical concentrations:
0, 0.3, 1.0, or 3.0% Levair®
0, 182.57,
594.65,
1,909.53 (M)
0, 210.09,
693.99,
1,988.42 (F)
No toxicologically relevant effects in
males.
Dose-related increase in incidence of
nephrocalcinosis in females.
1,909.53 (M)*
NDr (F)*
NDr (M)*
210.09 (F)*
Anonymous
(1972) as cited in
ECHA (1972D
(Limited study
details are
available: FDA
(1975) reported
that the study was
performed by
IBT.*)
NPR,
SS
Subchronic
15 M/15 F, albino, rat (strain NR),
oral in feed, 90 d
Reported analytical concentrations:
0,0.3, 1.0, or 3.0% Levn Lite®
0, 155.36,
545.64,
1,796.95 (M)
0, 181.18,
701.65,
2,070.10 (F)
No toxicologically relevant effects in
males.
Dose-related increase in incidence of
nephrocalcinosis in females;
increased relative kidney weight in
high-dose females.
1,796.95 (M)*
NDr (F)*
NDr (M)*
181.18(F)*
Anonymous
(1972) as cited in
ECHA f 1972c)
(Limited study
details are
available: FDA
(1975) reported
that the study was
performed by
IBT.*)
NPR,
SS
Subchronic
15 F, albino, rat (strain NR), oral in
feed, 90 d
Reported analytical concentrations:
0, 300, or 1,000 ppm Levn Lite®
0, 18.1,70.17,
(F)
Decreased absolute kidney weight by
23 and 24% in low- and high-dose
females, respectively. Decreased
relative kidney weight by 6% in both
treated groups.
NDr (F)*
NDr (F)*
Anonymous
(1972) as cited in
ECHA (1973)
(Limited study
details are
available.)
NPR,
SS
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Table 3A. Summary of Potentially Relevant Data for Aluminum Phosphate Salts (Multiple CASRNs)
Category3
Number of Male/Female, Strain,
Species, Exposure Route,
Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
4 M/4 F, beagle, dog, oral in feed,
90 d
Reported analytical concentrations:
0,0.3, 1.0, or3.0%Kasal™
0, 94.23,
322.88,
1,107.12 (M)
0, 129.31,
492.77,
1,433.56 (F)
Renal tubular concretions of
moderate severity observed in
2/4 males and 1/4 females at the high
dose.
322.88 (M)*
492.77 (F)*
1,107.12 (M)*
1,433.56 (F)*
Anonymous
(1972) as cited in
ECHA (1972a)
(Limited study
details are
available: FDA
(1975) reported
that the study was
performed by
IBT.*)
NPR,
SS
Subchronic
4 M/4 F, beagle, dog, oral in feed,
90 d
Reported analytical concentrations:
0, 0.3, 1.0, or3.0%LevnLite®
M: 0, 94.55,
345.21,
1,038.77
F: 0, 118.66,
511.06,
1,460.76
No toxicologically relevant effects
were observed in either sex.
1,038.77 (M)*
1,460.76 (F)*
NDr (M)*
NDr (F)*
Anonymous
(1972) as cited in
ECHA (1972d)
(Limited study
details are
available: FDA
(1975) reported
that the study was
performed by
IBT.*)
NPR,
SS
Subchronic
6 M/6 F, beagle, dog, oral in feed
(corn oil vehicle), 6 mo
Reported analytical concentrations:
0, 0.3, 1.0, or 3.0% Levair®
0, 118, 317,
1,034 (M)
0, 112, 361,
1,087 (F)
No toxicologically relevant effects
were observed in either sex.
1,034 (M)
1,087 (F)
NDr
Katz et al. (1984)
(GLP-compliant,
OECD 422
guideline study.)
PR
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Table 3A. Summary of Potentially Relevant Data for Aluminum Phosphate Salts (Multiple CASRNs)
Category3
Number of Male/Female, Strain,
Species, Exposure Route,
Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
4 M/4 F, beagle, dog, oral in feed
(corn oil vehicle), 6 mo
Reported analytical concentrations:
0, 3,000, 10,000, or 30,000 ppm
Kasal™
0, 112, 390,
1,143 (M)
0, 106, 323,
1,251 (F)
High-dose males experienced sharp
decreases in food consumption and
body weight near the end of the
study, presumably reflecting an
unexplained problem with the food,
health, or handling of the animals in
that group at that time.
Disregarding effects likely secondary
to the abrupt decrease in food
consumption, the high dose is
tentatively identified as a LOAEL in
males for mild liver (hepatocyte
vacuolation and hypertrophy) and
kidney (tubular-glomerulonephritis)
lesions of uncertain relation to the
drop in food consumption and body
weight.
No toxicologically relevant effects in
females.
390 (M)
1,251 (F)
1,143 (M)
NDr(F)
Pettersen et al.
(1990).
Anonymous
(1987) as cited in
ECHA (1987)
PR
Reproductive/
Developmental
10 breeding pairs/group,
Crj:CD(SD)IGS, rat, gavage, 46 d
beginning 14 d prior to mating (M),
14 d prior to mating to PND 4 (F)
Reported analytical concentrations:
0, 100, 300, or 1,000 mg/kg-d
triphosphoric acid aluminum salt
(K-Fresh 100P)
0, 100, 300,
1,000
Parental: No toxicologically relevant
effects.
Pups: No toxicologically relevant
effects.
1,000
NDr
Anonymous
(2002) as cited in
ECHA (2002d)
(GLP-compliant,
OECD 422
guideline study.)
NPR,
SS
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Table 3A. Summary of Potentially Relevant Data for Aluminum Phosphate Salts (Multiple CASRNs)
Category3
Number of Male/Female, Strain,
Species, Exposure Route,
Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
2. Inhalation (mg/m3)
ND
aDuration categories are defined as follows: acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated
exposure for >30 days <10% life span for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% life span for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021.
bDosimetry: doses are presented as ADDs (mg/kg-day) for oral noncancer effects.
°Notes: NPR = not peer reviewed; PR = peer reviewed; SS = available only as reported in secondary source.
*These effect levels are tentative and for comparative purposes only. The reported data are not considered by the U.S. EPA to be a suitable basis for quantitative
evaluation. There is low confidence in this study, due to demonstrated poor reliability of the performing laboratory (IBT) and limitations of the available secondary
source (see Section 2.2.1 for details).
ADD = adjusted daily dose; F = female(s); GLP = Good Laboratory Practice; IBT = Industrial Bio-Test Laboratories, Inc.; Kasal™ = basic SALP containing
approximately 6% aluminum; Kasal™II = basic SALP containing 13% aluminum; Levair® = an acidic SALP from Staffer Chemical Company; Levn Lite® = an acidic
SALP formulation from Monsanto Company (Solutia Inc.); LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not determined;
NOAEL = no-observed-adverse-effect level; NR = not reported; OECD = Organisation for Economic Co-operation and Development; PND = postnatal day;
SALP = sodium aluminum phosphate; U.S. EPA = U.S. Environmental Protection Agency.
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Table 3B. Summary of Potentially Relevant Cancer Data for Aluminum Phosphate Salts (Multiple CASRNs)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
Reference
(comments)
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
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2.1. HUMAN STUDIES
2.1.1. Oral Exposures
Data in humans following oral exposure to aluminum phosphate come from a single
study that evaluated the safety of aluminum phosphate gel (as an antacid treatment) in the
short-term treatment of duodenal ulcer (Parents et al.. 1995). In this study, 153 patients with
endoscopically proven active duodenal ulcer received 11 g of aluminum phosphate gel 5 times
daily for 6 weeks. At the end of treatment, 74 out of 113 patients (65%) who completed the study
showed ulcer healing, although constipation was reported as a side effect of the treatment.
2.1.2. Inhalation Exposures
No studies of humans exposed to aluminum phosphate salts by inhalation have been
identified in the literature searches or secondary sources reviewed.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures
Short-Term Studies
Hicks et al. (1987)
A 28-day repeated-dose study in rats was performed by Hicks et al. (1987). This study
evaluated the effects of dietary exposure to two separate samples of commercial food-grade basic
SALP, Kasal™ (contains approximately 6% aluminum as reported by the study authors) and
Kasal™II (contains approximately 13% aluminum as reported by the study authors).
Forty-eight-day-old male Sprague Dawley rats (25/group) were fed basal diets (Purina certified
rat chow no. 5002) or diets containing nominal concentrations of 30,000 ppm Kasal™ or 7,000
or 30,000 ppm Kasal™II for 28 days. Measured dietary concentrations were within 5% of
nominal. Reported average daily doses of Kasal™ were 0 or 2,436 mg/kg-day. Reported average
daily doses of Kasal™II were 0, 558, or 2,471 mg/kg-day. A fifth group of animals serving as a
positive control was similarly dosed with 14,470 ppm (1,139 mg/kg-day) of aluminum
hydroxide. A corn oil (0.5% weight) vehicle was used for all diet preparations. Animals were
observed twice daily for clinical signs, behavior (details not specified), and mortality. General
physical examinations were performed weekly. Food consumption and body weights were
measured for 10 rats/group and water consumption was measured for 5 rats/group, weekly.
After 28 days of treatment, 15 rats/group were sacrificed. At sacrifice, blood from five
rats/group was collected for hematology (hematocrit, hemoglobin concentration, erythrocyte
count, total and differential leucocyte count, and platelet count) and serum chemistry (alanine
aminotransferase [ALT], alkaline phosphatase [ALP], blood urea nitrogen [BUN], creatinine,
phosphorus, sodium, chloride, and potassium) measurements. Brain, liver, kidneys, and testes
from sacrificed animals were weighed. Tissues from select organs (not specified) were fixed for
histological analysis (five per group). Femurs from five animals/group were analyzed for
aluminum concentration. The remaining rats from all groups were placed on basal diets for a
2-month (five per group) or 5-month (five per group) recovery period. Femurs from these
animals were collected for aluminum analysis. No gross or microscopic examinations were
performed on recovery animals. The Dunnett's test was used to identify significant changes in
body weights, food consumption, hematology, clinical chemistry parameters, and organ weights.
The Mann-Whitney U-Test was used on nonparametric data. The Mantel-Haenszel test was used
to identify trends in incidence data, followed by %2 analysis or Fisher's exact test. Data were
considered significant atp< 0.05.
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Data for several endpoints (clinical signs, body weights, food and water consumption,
hematology, organ weights, and gross examinations) were not provided in the published report,
and were therefore not available for independent review. Clinical signs, including abrasions,
scabs, and sporadic incidences of chromorhinorrhea, chromodacryorrhea, hair loss, and
dehydration were reported to occur similarly across all groups. There were no apparent changes
in body weights or in food or water consumption throughout treatment or during the recovery
periods. Hematological endpoints were reported to be similar across all groups. Serum chemistry
measurements were reported, and statistically significant increases in plasma sodium levels were
observed in all treatment groups (including animals treated with aluminum hydroxide), compared
with controls (see Table B-l). However, the magnitudes of change in serum sodium levels
compared to controls were small (2-4%) and values fell within the range of historical control
values. A significant 16% increase compared to controls in absolute kidney weight was reported
by the study authors in the 558 mg/kg-day group (low-dose Kasal™II), but there were no
increases in relative kidney weight at this dose or any significant changes at the higher dose (data
not provided).
The study authors reported no gross pathology findings at autopsy related to treatment.
No significantly increased incidences of microscopic lesions were observed, although the
number of animals examined was small (n = 5) (see Table B-2). Mild to moderate focal
myocardial degeneration was observed in one to three rats in all groups, including controls.
Observed renal lesions in all groups included focal cystic changes, pelvic dilation, membranous
glomerulonephropathy, hyaline-droplet degeneration of proximal tubes, hyperplasia of pelvic
transitional epithelium, and focal lymphocytic inflammation. Two control rats and one rat treated
with 2,436 mg/kg-day of Kasal™ exhibited moderate degeneration of the testicular seminiferous
tubules. Aluminum concentrations in the femur did not appreciably change from controls in any
treatment group, including aluminum hydroxide, and was at or below the limit of detection in
several animals.
A no-observed-adverse-effect level (NOAEL) of 2,471 mg/kg-day, the highest dose, was
determined based on the lack of treatment-related effects in male Sprague Dawley rats
administered Kasal™ or Kasal™II (basic SALP) in the diet for 28 days.
Subchronic Studies
Industrial Bio-Test Laboratories Studies
As described by FDA (1975). Industrial Bio-Test Laboratories, Inc. (1BT) evaluated three
commercial SALP products for two separate producers in a series of studies performed in rats
and dogs. IBT has been identified by OECD as an unreliable source of laboratory data.2 In
addition, descriptions of study findings are based on a limited summary from a secondary source.
2In its manual for assessment of HPV chemicals, OECD (2019) noted that 618 of 867 nonacute toxicity studies
conducted by IBT (including subacute, subchronic, carcinogenicity, reproductive toxicity, genotoxicity, and
neurotoxicity studies) were found to be invalid during a post hoc audit program conducted by the U.S. EPA and the
Canadian Health and Welfare Department. OECD (2019) outlines specific criteria for using data generated by IBT
and recommends rejecting a study when either a regulatory or internal (IBT) audit revealed problems impacting the
reliability of the findings or when the findings of unaudited studies are inconsistent with data collected later by
reputable laboratories. OECD (2019) recommends that studies that have not been audited should be used with
caution and only as weak evidence if supported by later data from reputable laboratories.
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The studies are described here because they constitute much of the available database for
aluminum phosphate salts. There is, however, low confidence in the reported results.
In 1972, 90-day feeding studies in rats and dogs were performed evaluating the effects of
oral exposure to Kasal™ (basic SALP) and Levair® (an acidic SALP from Stauffer Chemical
Company) and Levn Lite® (an acidic SALP formulation from Monsanto Company [Solutia
Inc.]). Full study reports are not available, but there are study summaries in ECHA that
correspond to the 90-day dietary rat study of Kasal™, Levair®, and Levn Lite® [Anonymous
(1972) studies as cited in ECHA (1972c. 1972e. 197201 and to the 90-day dietary dog study of
Kasal™ and Levn Lite® [Anonymous (1972) studies as cited in ECHA (1972a. 1972d)l. No
study summary was located corresponding to the 90-day dietary study of Levair® in dogs. For
the rats, the summaries in ECHA share the same methodological details and matching control
data, suggesting that only a single negative control group was used. It was, therefore, presumed
that the three commercial SALP products were evaluated as a single study in rats. Similarly for
the dogs, the summaries in ECHA share the same methodological details and matching control
data, suggesting that only a single negative control group was used, and exposures to both
Kasal™ and Levn Lite® were evaluated as a single study in dogs.
For the purposes of this assessment, the studies are summarized below for rats first and
then for dogs. Methodological details, which apply to exposures for all the commercial
formulations evaluated, are presented first, followed by the results for each of the formulations
tested in sequence.
Industrial Bio-Test Laboratories. Inc. 90-Day Feeding Study in Rats
The doses selected for the 90-day feeding study in rats appear to have been based on the
results of a 30-day pilot study summarized in ECHA [Anonymous (1972) as cited in ECHA
(1972b VI. In this dose range-finding study, groups of commercially obtained albino rats
(5/sex/dose, strain and age not specified) were fed ad libitum diets that contained 0 (plain diet),
1.0, 3.0, 5.0, or 7.0% nominal concentrations of the three test materials, Kasal™, Levair®, or
Levn Lite® (each separately), for 30 days. Details of the composition and purity of the test
materials were not provided. For the pilot study, rats were only evaluated for changes in body
weights and food consumption. Body weights of each animal were measured on the first day of
the test and weekly thereafter. Food consumption data were collected weekly. Weekly body
weight and food consumption data were not provided in the study summary, but a table
summarizing the mean 30-day weight gains and food consumptions was provided. In brief,
depressions in weight gains and food intake were noted in groups fed diets containing 5.0 or
7.0% nominal concentrations of Levair®, Kasal™, and Levn Lite®. Based on the results of this
study, dietary levels of 0.3, 1.0, and 3.0% were selected for the 90-day rat study.
The 90-day study predated (1972) established OECD guidelines and Good Laboratory
Practices (GLP). Groups of commercially obtained albino rats (15/sex/dose, strain and age not
specified) were fed continuous diets that contained no test material (plain diet), or 0.3, 1.0, or 3%
of Kasal™, Levair®, or Levn Lite® for 90 days [Anonymous (1972) studies as cited in ECHA
(1972c. 1972e. 197201. Doses (as noted below) of each commercial product were reported in the
individual ECHA summaries, calculated using the mean of the weekly body weight and food
consumption data. The purity of Levair® [NaAbHi4(P04)8 4H2O] was reported to be 99.9%;
details of the composition and purity of the other two test materials were not provided. Animals
were observed daily for clinical signs. Body weights (all animals) and food consumption
20
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(5/sex/group) were recorded weekly. The methodology ("Examinations") sections in the ECHA
summaries for Kasal™ and Levair® simply noted that hematology, clinical chemistry,
urinalysis, gross pathology, and histopathology were performed, without providing additional
details. The study summary for the Levn Lite® study indicated that hematology (hematocrit,
erythrocyte count, hemoglobin, and total and differential leukocyte counts), limited clinical
chemistry (BUN, fasted glucose, ALP, and ALT), and urine endpoints (glucose, albumin,
microscopic elements, pH, and specific gravity) were measured in 10 control and 10 high-dose
males and females on Study Days 45 and 84. All surviving rats were sacrificed at the end of the
90-day feeding period. Animals were grossly examined at sacrifice. Organ weight measurements
were limited to the liver, kidneys, spleen, gonads, heart, and brain of each rat.
The Levn Lite® summary stated that the microscopic examination of tissues was
performed for 10 rats/sex from the control and high-dose group on esophagus, stomach, small
intestine, cecum, colon, liver, kidneys, spleen, pancreas, urinary bladder, pituitary gland, adrenal
gland, testes, seminal vesicle, ovary, bone marrow, thyroid gland, parathyroid gland, salivary
gland, prostate gland, heart, aorta, lung, lymph nodes, skeletal muscle, peripheral nerve, bone
(femur), spinal cord, uterus, trachea, eye, optic nerve, and brain. Results (for all formulations),
however, were provided for all dose groups and indicated that there were 15 female rats
evaluated from the low-dose groups (10 rats/sex for other dose groups). The endpoints that were
analyzed statistically are unclear. Except for organ weight data, no statistical analysis was
included in the available data tables. Organ-weight data were analyzed for variance using
analysis of variance (ANOVA) followed by Mests to identify statistical significance. Measures
of variance (e.g., standard deviation [SD] or standard error [SE]) were not included in any of the
data tables. For clarity, results for each commercial product are reported separately below.
However, the data tables in Appendix B include values for all three formulations for a given
endpoint to facilitate comparisons across the three SALP products.
Kasal™
Doses of Kasal™ were reported as 0, 172.66, 562.74, and 1,803.11 mg/kg-day for male
rats and 0, 205.62, 701.32, and 2,113.79 mg/kg-day for female rats [Anonymous (1972) as cited
in ECHA (1972e)1. No animals in the Kasal™ treatment groups died. Details of cage-side
observations were not included in the available summary. It was reported that no effects on body
weights, body-weight gain, or food consumption were seen; data for these endpoints were not
available for independent review. Mean values without measures of variance were provided for
hematological, clinical chemistry, and urinalysis endpoints in control and high-dose groups.
Hematology measurements showed 15, 18, and 120% increases in neutrophil, monocyte, and
eosinophil cell counts, respectively, in high-dose males compared with controls (see Table B-3).
Changes in females included 10-11% decreases in neutrophils and eosinophils and a 30%
increase in monocytes. No measures of variance or statistical analyses were provided; therefore,
the significance of these changes is unclear. Several animals in all groups, including controls,
were reported to have chronic murine pneumonia, and/or chronic tracheitis, indicating that
animals in this study were potentially in poor general health. The available study summary
indicated that no serum biochemistry effects were observed, although again, no measures of
variance or statistical analyses were provided. The data showed a 21% decrease in ALP in
high-dose male rats and a 42% increase in ALP and 14% increase in BUN in high-dose female
rats, compared with controls (see Table B-4). No notable changes in the urine endpoints
examined were observed.
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The only statistically significant organ weight change in males treated with Kasal™
compared to controls was a 15% increase in absolute liver weight in the lowest dose group
(see Table B-5). Relative liver-to-body and liver-to-brain weights were increased at this dose by
10-11% (not a statistically significant increase), but not at higher doses. In female rats, a
statistically nonsignificant 12% increase in absolute kidney weight, compared with controls, and
statistically significant increases of 16 and 14% in kidney weights relative to body and brain
weight, respectively, were seen in the high-dose group. No changes in kidney weights were
observed in the lower dose groups. Absolute and relative liver weights were significantly
increased 16-23% in the low-dose females, but not in the higher dose groups. The study
summary did not include all histological data, but rather presented limited data for the lesions
that were observed, most notably a dose-related increase in the incidence of microconcretions in
the renal tubules (nephrocalcinosis) of female rats. The data table presented in the study
summary does not specifically note incidence of this lesion within controls. However, the
conclusion section stated that these microconcretions were absent in the control animals. Thus,
the incidences of microconcretions in female rats fed diets containing Kasal™ were 0/10, 4/15,
3/10, and 8/10 in the control, low-, mid-, and high-dose groups, respectively (see Table B-6).
The severity of these lesions increased from minimal in the low-dose animals to mild in the
mid- and high-dose animals. Similar lesions were not observed in male rats. Focal interstitial
nephritis occurred in 2/10 high-dose males but was not observed in females. Other kidney
lesions, including tubular nephrosis, chronic nephritis, and focal lymphoid infiltration, occurred
at low incidences in a non-dose-related manner. Non-neoplastic findings in other organs did not
appear to be treatment-related (i.e., incidences of chronic pneumonia and tracheitis in several
animals, including controls).
As noted above, there is low confidence in this study, based on availability only as a
limited summary from a secondary source and demonstrated poor reliability of the performing
laboratory (IBT). For this reason, the reported data are not considered by the U.S. EPA to be a
suitable basis for quantitative evaluation. Tentative effect levels are identified here for
comparative purposes only. In female rats, the low dose of 205.62 mg Kasal™/kg-day is
tentatively identified as a lowest-observed-adverse-effect level (LOAEL), based on the
dose-related increase of microconcretions in the renal tubules, and a NOAEL was not
determined. For male rats, the high dose of 1,803.11 mg Kasal™/kg-day is tentatively identified
as a NOAEL, based on the lack of toxicologically relevant treatment-related effects following
dietary exposure to Kasal™ for 90 days, and no LOAEL was determined.
Levair®
Doses of Levair® were reported as 0, 182.57, 594.65, and 1,909.53 mg/kg-day for male
rats and 0, 210.09, 693.99, and 1,988.42 mg/kg-day for female rats [Anonymous (1972) as cited
in ECHA (1972f)1. Four animals treated with Levair® died (sex and treatment groups were not
specified). All deaths were attributed to trauma incurred during collection of blood samples. It
was reported that no unexpected behavioral changes occurred and there were no effects on body
weights, body-weight gain, or food consumption; data for these endpoints were not available for
independent review. There was a 24% increase in monocytes in high-dose males and a 50%
increase in monocytes in high-dose females, compared with controls (see Table B-3), but the
significance of these changes is unclear, as variance data were not shown and statistical analyses
were not performed. Other hematological changes were unremarkable. Compared to controls,
high-dose females exhibited a 58% increase in ALP activity (see Table B-4), but again, the
significance of this change is uncertain without statistical analysis or variance data. No serum
22
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chemistry changes in males and no changes in urinalysis parameters in either sex were observed,
and there were no noteworthy organ weight changes (see Tables B-4 and B-5). Microconcretions
in renal tubules were observed in 3/15, 7/10, and 7/10 females in the low-, mid-, and high-dose
groups, respectively (see Table B-6). The severity of these lesions was minimal in all dose
groups. Incidences in the control group were not reported in the data table provided in the study
summary, but the conclusion text stated that microconcretions were absent in the control
animals. Focal interstitial nephritis occurred in 2/10 high-dose females, and single incidences of
focal lymphoid infiltration and chronic nephritis were observed in low-dose females. A single
incidence of focal interstitial nephritis was observed in high-dose males. Similar to control
animals and those dosed with Kasal™, several animals in the Levair® groups also exhibited
signs of chronic pneumonia and tracheitis, unrelated to treatment.
This study is considered by the U.S. EPA to be unsuitable as a basis for quantitative
evaluation due to availability only as a limited summary from a secondary source and poor
reliability of the performing laboratory (IBT). Tentative effect levels are identified here for
comparative purposes only. A tentative LOAEL of 210.09 mg/kg-day (lowest dose tested) was
determined for female rats based on the dose-related increase of microconcretions in the renal
tubules. A NOAEL could not be determined for female rats. For male rats, a tentative NOAEL of
1,909.53 mg/kg-day was determined based on the lack of toxicologically relevant
treatment-related effects following dietary exposure to Levair® for 90 days.
Levn Lite®
Doses of Levn Lite® were reported as 0, 155.36, 545.64, and 1,796.95 mg/kg-day for
male rats and 0, 181.18, 701.65, and 2,070.10 mg/kg-day for female rats [Anonymous (1972) as
cited in ECHA (1972cYl. Three animals (sex and dose group not reported) treated with Levn
Lite® died. Similar to the mortalities in the Levair® groups, the deaths were attributed to trauma
incurred during collection of blood samples. It was reported that no unexpected behavioral
reactions occurred. Weekly body weight and food consumption data were not reported, but the
90-day average total weight gains and total food consumption were reported (see Table B-7).
Total body-weight gain of treated male rats was higher than controls by 17, 5, and 5% in the
low-, mid-, and high-dose groups, respectively. Low-dose males exhibited similar food
consumption rates compared to controls, while slight decreases (<10%) were seen in the
mid- and high-dose groups. Unlike the male rats, total body-weight gain was decreased in female
rats compared to the control group by 10, 13, and 18% in the low-, mid-, and high-dose groups,
respectively. This was accompanied by slight decreases in food consumption compared to the
control group of 8, 8, and 1%, respectively. Although final body weights were not reported, the
study summary noted that no statistical differences were found between treated and control rats
based on final body weights or total weight gains for either sex.
The available ECHA summary reported that no treatment-related effects were observed
based on hematology, clinical chemistry, urinalysis, organ weights, or gross pathological
findings in rats dosed with Levn Lite®. Mean values of these data without measures of variance
or statistical analysis were provided in the summary. Independent review of the magnitudes of
change show similar increases in neutrophil (24%), monocyte (24%), and eosinophil (100%)
counts in high-dose male rats as those observed for males treated with Kasal™ and Levair®
(see Table B-3). Eosinophil levels in females were decreased 78%, compared with controls; all
other changes in females were <10% in magnitude. The largest serum chemistry changes were a
19%) increase and a 25% decrease in serum ALT in high-dose male and female rats, respectively,
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compared with controls (see Table B-4). Compared to controls, relative kidney-to-body weight in
female rats was statistically significantly increased in high-dose females by 10% (see Table B-5).
In addition, relative kidney-to-brain weight was increased by 9% and absolute kidney weight was
increased by 5% in this group, compared to controls. Statistically significant weight changes in
other organs included a 14% increase in relative testes-to-body weight and a 9% decrease in
brain-to-body weight measures in low-dose male rats, compared with controls, and a 7%
decrease in absolute brain weight in mid-dose females. Similar to females treated with Kasal™
and Levair®, there was a dose-related increase in the incidences of microconcretions in renal
tubules in female rats, but not males, treated with Levn Lite® (see Table B-6). The incidences
were 4/15, 5/10, and 9/10 in the low-, mid-, and high-dose groups, respectively. The severity of
these lesions was minimal in the low- and high-dose females and mild in the mid-dose females.
Incidences in the control group were not reported in the data table provided in the study
summary, but the conclusion text stated that microconcretions were absent in the control
animals. Incidence of kidney focal lymphoid infiltration (5/10) in the mid-dose group was also
significant. There was one case of hydronephrosis at the low dose. Non-neoplastic findings in
other organs did not appear to be related to treatment.
This study is considered by the U.S. EPA to be unsuitable as a basis for quantitative
evaluation due to availability only as a limited summary from a secondary source and poor
reliability of the performing laboratory (IBT). Tentative effect levels are identified here for
comparative purposes only. A tentative LOAEL of 181.18 mg Levn Lite®/kg-day (lowest dose
tested) was determined for female rats based on the dose-related increase of microconcretions in
the renal tubules. A NOAEL could not be determined for female rats. For male rats, a tentative
NOAEL of 1,796.95 mg/kg-day was determined based on the lack of toxicologically relevant
treatment-related effects following dietary exposure to Levn Lite® for 90 days.
FDA (1975) reported that, in 1973 and 1974, IBT conducted 90-day feeding studies in
female rats with Kasal™, Levair®, and Levn Lite® in follow-up to the 90-day feeding studies
conducted in 1972 (described in above). These follow-up tests apparently evaluated exposures at
lower dose levels than the previous studies, but focused primarily on assessing changes in body
and kidney weights. FDA (1975) reported that female rats fed diets containing 300 and
1,000 ppm Kasal™ and Levair® for 90 days exhibited a higher incidence of microconcretions in
renal tubules when compared with controls. These studies were not available. A summary of the
study conducted using Levn Lite® was available in ECHA [Anonymous (1973) as cited in
ECHA (1973)1. although the ECHA summary indicated that histopathology was not evaluated.
Female albino rats (15/group; strain not specified) were fed diets containing 0 (plain diet), 300,
or 1,000 ppm Levn Lite® ad libitum for 90 days. Animals were monitored daily for abnormal
reactions and mortality. Rats were weighed on the first day of the test and monthly thereafter.
The study summary indicated that food consumption was not monitored. Rats surviving to the
end of the 90-day exposure period were sacrificed and examined grossly. Kidneys were removed
and weighed. Statistical analysis was conducted on absolute and relative kidney weights as
ANOVA followed by a Student's /-test. Five deaths not attributed to treatment were reported to
have occurred during the study. No abnormal behaviors were observed. There were no
significant differences between treated rats and control rats in final body weights, body-weight
gains, kidney weights, or gross pathological observations. Although not statistically significant,
absolute kidney weights were reduced by 23 and 24% compared to controls in the 300 and
1,000 ppm groups, respectively. Relative kidney weights of treated rats in both dose groups were
reduced by 6% from controls. These magnitude changes were larger than seen in the previously
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described 90-day rat study for Levn Lite®. The ECHA summary indicated that histopathology
was not examined, so it is not clear if these changes in kidney weights were accompanied by
microscopic changes.
FDA (1975) also reported that IBT conducted separate histologic evaluations of the
kidney tissues of both rats and dogs fed Kasal™, Levair®, or Levn Lite®, but these reports are
not available. FDA (1975) did not describe the pathology results in any detail but noted that
microconcretions were not observed in dogs fed Kasal™, which contradicts the findings of
microconcretions in renal tubules observed in the 90-day dog study summarized below.
Industrial Bio-Test Laboratories. Inc. 90-Day Feeding Study in Dogs
The 90-day dog study predated (1972) established OECD guidelines and GLP
[Anonymous (1972) studies as cited in ECHA (1972a. 1972d)l. Beagle dogs (4/sex/dose), age
unknown, were fed diets ad libitum containing 0 (plain diet), 0.3, 1.0, or 3% Kasal™ (basic
SALP) or Levn Lite® (acidic SALP) for 90 days. Daily intake doses (as noted below) of each
commercial product were reported in the individual study summaries, calculated using the mean
of the weekly body weight and food consumption data (excluding the 5th week from the
mid-dose female group due to illegible figures in the report). Animals were monitored daily for
mortality and clinical signs of toxicity. Body weights were recorded prior to study initiation and
weekly thereafter. Food consumption was calculated weekly. Blood and urine were collected at
the beginning of the study and on Study Days 42 and 84 for hematological (total and differential
leucocyte counts, erythrocyte counts, hemoglobin, and hematocrit) and clinical chemistry (BUN,
glucose, ALP, ALT, and aspartate aminotransferase [AST]) measurements, and for urinalysis. At
sacrifice, all major tissues and organs were examined grossly. Liver, kidneys, heart, brain,
spleen, gonads, adrenal glands, thyroid gland, and pituitary organs were weighed. Histological
analysis was performed on an unreported number of tissues (based on the results that were
presented in the study summary, examined tissues at least included kidneys, liver, lungs,
prostate, spleen, heart, uterus, ovaries, pancreas, mesenteric lymph node, gonads, and spinal
cord). Body weight, food consumption, and limited histological findings on select tissues were
the only quantitative data provided in the available summaries; measures of variance and details
on statistical analysis were not provided in the study summaries.
Kasal™
Daily intakes were reported to be equivalent to 0, 94.23, 322.88, and 1,107.12 mg/kg-day
for male dogs and 0, 129.31, 492.77, and 1,433.56 mg/kg-day for female dogs fed diets
containing Kasal™ for 90 days [Anonymous (1972) as cited in ECHA (1972a)1. All dogs treated
with Kasal™ survived until the end of the study, and no clinical signs related to treatment were
reported. Quantitative data tables of mean body weight at week 0, overall weight gain, and mean
food consumed weekly without measures of variance were available for independent review. No
treatment-related effects on body weight or food consumption were found.
Hematological, clinical chemistry, and urine endpoints were reported to be unaffected by
treatment, although the data were not provided. Similarly, no quantitative organ weight data were
provided; the study summary reported that no effects were observed. Gross pathology findings
were described as those attributed to spontaneous disease. Based on histopathological
examinations, the animals (including controls) appeared to be in poor general health. Chronic
interstitial pneumonia was observed in at least two male and female animals in every treatment
group, including controls; liver congestion was also observed in every group. One low-dose
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female and one mid-dose female had bronchopneumonia. Histological data were selectively
reported in tabular format. The study summary indicated that all tissues and organs not
mentioned in the tables were histologically normal. Incidences of tubular concretions of
moderate severity were reported in 2/4 males and 1/4 females fed the high-dose diet
(see Table B-8). These concretions were described as unusually large and more numerous than
those typically observed in untreated dogs. The conclusion section of the study summary noted
that a few other calcified microconcretions present in the lumen of renal tubules located at the
corticomedullary junction and/or medulla of the kidney were attributed to normally occurring
disease. One low-dose male and one high-dose male also presented minimal or slight focal
lymphoid infiltration. Findings in other organs were unremarkable.
This study is considered by the U.S. EPA to be unsuitable as a basis for quantitative
evaluation due to availability only as a limited summary from a secondary source and poor
reliability of the performing laboratory (IBT). Tentative effect levels are identified here for
comparative purposes only. The highest dose tested was identified as the tentative LOAEL
(1,107.12 mg Kasal™/kg-day for males and 1,433.56 mg Kasal™/kg-day for females) based on
the occurrence of microconcretions of moderate severity in the renal tubules of male and female
dogs. The mid-dose was tentatively identified as the NOAEL (322.88 mg Kasal™/kg-day for
males and 492.77 mg Kasal™/kg-day for females).
Levn Lite®
Daily intakes were reported to be equivalent to 0, 94.55, 345.21, and 1,038.77 mg/kg-day
for male dogs and 0, 118.66, 511.06, and 1,460.76 mg/kg-day for female dogs fed diets
containing Levn Lite® for 90 days [Anonymous (1972) as cited in ECHA (1972d)1. There were
no deaths reported in dogs dosed with Levn Lite®. No clinical signs related to treatment were
described. Like Kasal™, body weight and food consumption data were presented as means in the
absence of measures of variance, and no statistical analyses were provided in the study summary.
No treatment-related effects on body weight or food consumption were found.
Hematological, clinical chemistry, urinalysis, and organ weight data were not available
for independent review, but it was reported that no effects were observed for any of these
endpoints. Gross pathology findings were attributed to spontaneous disease. Consistent with
observations in controls, chronic interstitial pneumonia and congestion in the liver were
identified in animals from all dose groups. No renal tubular concretions were observed in dogs
treated with Levn Lite® (see Table B-8). The only observed effect in the kidney was minimal to
slight congestion in a single mid-dose male. Findings in other organs were unremarkable.
This study is considered by the U.S. EPA to be unsuitable as a basis for quantitative
evaluation due to availability only as a limited summary from a secondary source and poor
reliability of the performing laboratory (IBT). Tentative effect levels are identified here for
comparative purposes only. Tentative NOAEL values of 1,038.77 and 1,460.76 mg/kg-day for
males and females, respectively (the highest dose), were determined based on the lack of
treatment-related effects in beagle dogs administered Levn Lite® in the diet for 90 days.
Katzetal. (1984)
In a GLP-compliant, OECD 422 guideline study, beagle dogs (6/sex/group),
approximately 7-9 months of age, were exposed to daily diets containing 0, 0.3, 1.0, or 3.0%
Levair® in corn oil vehicle (1% w/w) for 6 months (Katz et at., 1984). These diets were
26
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equivalent to reported mean intakes of 0, 118, 317, and 1,034 mg/kg-day of acidic SALP in
males and 0, 112, 361, and 1,087 mg/kg-day in females, based on body weight and food
consumption data. The basal diet was analyzed for appropriate nutrients and contaminants, but
results were not reported. Throughout the study, animals were observed twice daily for mortality
and clinical signs. Body weights were recorded weekly, and food consumption was recorded
daily. Animals were subjected to ophthalmological examinations both prior to study initiation
and at termination. Hematology, clinical chemistry, and urinalysis were described as being done
in accordance with the U.S. EPA (1978) standards. Prothrombin, activated partial thromboplastin
times, and serum levels of inorganic phosphorus were also measured. At 2-month intervals, fecal
samples were tested for occult blood. At necropsy, heart, liver, kidneys, gonads, prostate,
pituitary, thyroid, adrenals, and brain weights were recorded. Microscopic analysis was
performed on these and 25 additional tissues (not specified), and on any significant gross lesions.
Data were analyzed by one-way ANOVA and Dunnett's Mests. Data were considered significant
atp < 0.05.
No mortalities were reported. Clinical signs were described as not related to treatment.
Food consumption was reduced throughout much of the study in the treated dogs, significantly
so in females at various times, but not necessarily in relation to dose (see Table B-9). It was
reported that mean body weights of all groups, presumably including controls, increased 5-18%
over the course of the study and that reductions in body weights observed in all groups at the end
of the study (Week 27) were due to pretermination tests and increased handling. No statistically
significant differences in mean body weights were found between male or female test groups and
their respective controls at any time during the study (data not shown). The report indicated that
no toxicologically relevant changes in ocular, hematological, or clinical chemistry endpoints
were observed and that all values remained within the expected range for animals of this age and
strain (data not shown). There were no urinalysis changes, abnormal fecal occult blood results, or
significant organ weight changes in treated groups, compared with controls (data not shown). No
abnormal gross or microscopic changes were reported (data not shown). None of these data other
than food consumption were available for independent review.
NOAELs of 1,034 and 1,087 mg Levair®/kg-day for males and females, respectively (the
highest dose), are determined based on the lack of treatment-related effects in beagle dogs
administered Levair® in the diet for 6 months.
Fetter sen etal. (1990); Anonymous (1987) as cited in ECHA (1987)
The toxicity of Kasal™ in beagle dogs following dietary exposure for 26 weeks was
investigated by Pettcrsen et al. (1990). Additional study details that were not available in the
published report were presented in a study summary in ECHA [Anonymous (1987) as cited in
ECHA (1987)1. Groups of beagle dogs (4/sex/dose) were fed diets containing nominal
concentrations of 0, 3,000, 10,000, or 30,000 ppm Kasal™ in 0.5% w/w corn oil for 26 weeks.
Measured Kasal™ consumption was 0, 112, 390, or 1,143 mg/kg-day for males and 0, 106, 323,
or 1,251 mg/kg-day for females. Diet was analyzed for aluminum content (3-4, 10, 22-27, and
75-80 mg/kg-day in the control, low-, mid- and high-dose groups, respectively), but not for
phosphate or calcium. Animals were observed at least twice daily for clinical signs of toxicity
and mortality. Food consumption was recorded 2-3 times/week and body weights were
determined weekly. Ophthalmoscopic examinations were done prior to study initiation and at
termination. Urine and fecal samples were collected overnight using metabolism cages prior to
study initiation and at termination. Fasting blood samples were collected from all animals prior
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to initiation and at sacrifice for hematological (hematocrit, hemoglobin, erythrocyte count, total
and differential leukocyte count, and platelet count) and clinical chemistry (BUN, creatinine,
sodium, potassium, chloride, phosphorus, ALT, AST, ALP, y-glutamyl transferase [GGT],
sorbitol dehydrogenase [SDH], total bilirubin, total protein, albumin, globulin, glucose, calcium,
cholesterol, and triglyceride) analysis. Heart, liver, kidneys, ovaries, testes, thyroid, adrenals, and
brain were weighed at necropsy. More than 35 tissues were fixed for microscopic examination.
Aluminum concentrations in trabecular bone and brain samples were determined using an atomic
absorption spectrophotometer. Body weights, food consumption, clinical laboratory test values,
and tissue aluminum concentration data were analyzed by one-way ANOVA followed by
appropriate post-hoc tests, including the Neuman-Keuls test. Data were considered significant at
p < 0.05.
Data available for independent review were limited to the aluminum concentrations
measured in bone and brain (Pettersen et al.. 1990); the remaining results were reported in text
only (including the ECHA summary). No mortalities were observed. Clinical signs were not
discussed in the published paper, but ECHA reported erythema of the gums in one male and two
females in both the low- and mid-dose groups. A sharp, transient, statistically significant
decrease in food consumption during Study Week 24 was reported in male dogs at
1,143 mg/kg-day (presumably reflecting an unexplained problem with the food, health, or
handling of the animals in that group at that time), leading to a precipitous decrease in body
weights during Weeks 24-25 in that group (data not shown). The published report stated that
there was no effect on food intake or body weight in females. Additional information provided in
ECHA were terminal body weights of 85, 89, and 81% of controls in males and 93, 94, and 83%
of controls in females in the low-, mid-, and high-dose groups, respectively, with the body
weights in high-dose females consistently lower than controls throughout the study. This
information is difficult to interpret, however, in the absence of data on body weights at study
initiation and body-weight gains during the study. The published paper reported that there were
no treatment-related effects on hematology, serum chemistry, or urinalysis endpoints, without
presenting any data. The ECHA summary reported some sporadic serum chemistry changes,
including a 22% decrease in serum creatine and a 3% decrease in sodium in high-dose males at
termination, and a 5% decrease in serum calcium and 25% decrease in phosphorus at 14 weeks
in females at 323 and 1,251 mg/kg-day, respectively.
The only organ weight change reported in the published paper was a decrease in testes
weight in high-dose males. The ECHA summary reported this as a statistically significant 31 %
decrease in absolute testes weight, with no change in relative testes weight and suggested that the
decrease in absolute testes weight reflected the reduction in body weight observed in this group.
ECHA also reported that relative kidney weights were significantly increased (magnitude not
reported) in this group but that absolute kidney weights did not differ significantly from controls.
This, too, may reflect the decrease in body weight in this group. No organ weight changes were
observed in females. Pathology observations indicated that 2/4 high-dose males had reduced
testes sizes compared to controls, with moderate seminiferous tubule germinal epithelial cell
degeneration and atrophy, consistent with the decreases in absolute testes and body weight in this
group. Other pathology findings in high-dose males were mild to moderate hepatocyte
vacuolation and hypertrophy and mild bile stasis with bile canaliculi (3/4 males) in the liver and
very mild (2/4) to mild (2/4) tubular-glomerulonephritis in the kidney. It is unclear to what extent
the liver and kidney findings may reflect the abrupt decrease in body weight at Week 24 in this
group. There were no reported findings in low- or mid-dose males. Tubular-glomerulonephritis
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EPA/690/R-23/004F
was observed in 1/4 control males. Necropsy results and microscopic findings in females were
not described in the study report, but the ECHA summary noted that treated females did not
exhibit any significant treatment-related pathological changes. Trabecular bone concentrations of
aluminum did not differ significantly from controls in males or females at any dose. Brain
aluminum concentrations were significantly increased (-60%) only in high-dose females.
Observations in high-dose males included precipitous decreases in food consumption and
body weight near the end of the study, presumably reflecting an unexplained problem with the
food, health, or handling of the animals in that group at that time. Decreased group mean
absolute testes weight and testicular atrophy in 2/4 dogs from this group likely reflect the abrupt
decrease in body weight, as does an observed increase in relative kidney weight. Mild liver
(hepatocyte vacuolation and hypertrophy) and kidney (tubular-glomerulonephritis) lesions in this
group may or may not have been secondary to the plunge in body weight. The researchers
reported no effects in the low- or mid-dose males or in female dogs at any dose. These results
suggest that for male dogs, the mid dose of 390 mg/kg-day is a clear NOAEL for Kasal™
administered continuously in the diet for 26 weeks. It is less clear how to interpret findings in
males at the high dose, but for this assessment, the high dose of 1,143 mg/kg-day is tentatively
considered a LOAEL based on mild liver and kidney effects. For females, the high dose of
1,251 mg/kg-day is a NOAEL.
Reproductive/Developmental Studies
Anonymous (2002a) as cited in ECHA (2002d. 2002e)
An unpublished, GLP-compliant, OECD guideline 422 repeated-dose toxicity study with
a reproductive/developmental screening test that is summarized in ECHA [Anonymous (2002) as
cited in ECHA (2002d)l evaluated the effects of orally administered triphosphoric acid
aluminum salt (1:1) (tradename K-Fresh 100P) in rats. Commercially available Crj:CD(SD)IGS
rats (10/sex/dose) were dosed with 0 (vehicle), 100, 300, or 1,000 mg/kg-day triphosphoric acid
aluminum salt (94.7% pure) dissolved in 0.5% carmellose sodium in purified water (vehicle) via
gavage. Males were dosed for 46 days, beginning 14 days prior to mating. Females were dosed
from 14 days prior to mating, then throughout mating, gestation, delivery, and up to postnatal
day (PND) 4. Doses were selected based on a 14-day preliminary study in rats that reported no
observed effects at the highest dose of 1,000 mg/kg-day. Exposure doses were prepared weekly
and were analytically verified by comparing absorbance to standard solutions. Animals were
observed 4 times daily for mortality, external appearance, and behavior. Detailed clinical
observations were not made. Body weights were measured prior to study initiation and on
Days 1, 2, 5, 7, 10, and 14, and weekly thereafter. Food consumption was monitored daily, and
water consumption was evaluated on Days 43-44 of administration. Blood was collected
(5/sex/dose) on the day following the last dosing for hematological and clinical chemistry
measurements. Urine was collected on Days 43-44 for urinalysis (males only). The study did not
include neurobehavioral analysis. At sacrifice, all parental animals were subject to macroscopic
examination and reproductive organs were weighed. Gross and histological analysis was
performed on >40 tissues from animals in all dosing groups, with special attention to
reproductive organs, and on any gross findings.
Sperm parameters were not included in the study. Female estrous cyclicity was monitored
10 days prior to dosing through copulation. Reproductive parameters (copulation, corpora lutea,
implantation sites/indices, gestation, delivery) were monitored. Litter examinations included the
number of surviving offspring, viability through PND 4, sex, external appearance, body weights
29
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(at birth, and on PNDs 1 and 4), and body-weight gain. Offspring were sacrificed on PND 4, and
pups were grossly examined. Bartlett's test was used for statistical analysis of body weight/
body-weight gain, growth rate, feed consumption, urinalysis, hematology and clinical chemistry,
and organ weights, and for reproductive and developmental parameters. ANOVA was applied in
cases of equal variance, followed by Dunnett's test. The Kruskal-Wallis test was applied for data
sets of unequal variance; when no significance was found, a Mann-Whitney U-test was applied.
The litter was used as the experimental unit for determination of the live birth index, sex ratio,
viability index, and pup body weights. Incidence data were analyzed using a multiple-sample x2
test followed by a two-sample x2 test. When mismatches occurred, a Fisher's exact test was used.
A value ofp< 0.05 was considered significant. Minimal quantitative data were provided in the
summary available for review.
All parental animals survived to the end of the study. Clinical signs were limited to a
swollen abdomen and soiling of perioral fur in one high-dose male on the day of autopsy and a
subcutaneous mass first observed on gestation day (GD) 13 in one female from the
300 mg/kg-day group. Body weights and body-weight gains in treated males and females were
comparable to controls (data not provided). A reduction in food consumption observed in males
was transient and not dose-related. Food consumption in treated females was comparable to
controls. Mean corpuscular volume was significantly low in females at 1,000 mg/kg-day. There
were no other hematological changes in females, and no significant hematological effects in
males. High-dose females exhibited significantly reduced levels of total protein and calcium,
compared with controls, but the magnitudes of the reported decreases were not reported, and the
data were not shown. Calcium was also significantly reduced in females at 100 mg/kg-day, but
not at 300 mg/kg-day. At 1,000 mg/kg-day, a decrease in urine pH was observed in males, and
was attributed to the low pH of the test material. Absolute and relative spleen weights were
reported to be significantly reduced, compared with controls, in females in the 100 and
1,000 mg/kg-day groups (magnitudes not reported and data not shown); no differences were
observed in the 300 mg/kg-day group. No significant organ weight changes were reported in
males. At necropsy, several individual macroscopic findings were reported across dose groups,
but incidences were low, sporadic, and not statistically significant. Deformity of the liver with
multi-focal yellowish-white spots was observed in one low-dose male, and atrophy of the
bilateral testes and epididymides was observed in one mid-dose male and one high-dose male;
this high-dose male failed to establish a pregnancy in a paired female. There were no
dose-related or significant macroscopic changes in females. Histopathological lesions were also
low in incidence and sporadic. Histological examinations identified severe atrophy of the testes
with decreased sperm in one high-dose male that did not establish a pregnancy in a paired
female. Atrophy of the testes was also observed in two control and four mid-dose males, but with
lesser severity. In another high-dose male that failed to establish pregnancy in a paired female,
mild myocardial degeneration was observed. Single incidences of dilated cerebral ventricles and
extramedullary hematopoiesis in the spleen were observed in females at 1,000 and
300 mg/kg-day, respectively. Localized necrosis of the liver and atrophy of the thymus were
described as being sporadic in females at 1,000 mg/kg-day. One female that did not become
pregnant had vaginal closure/inflammation in the uterus horn.
The estrous cycles in females were not affected by treatment. Copulation, gestation, and
nursing indices were comparable across groups. One mid-dose female that did not give birth by
GD 25 had two dead and five live fetuses when sacrificed, and another mid-dose female
delivered seven dead fetuses. The gestation index at 300 mg/kg-day was 90%, compared to
30
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EPA/690/R-23/004F
100% in all other groups. The gestation index decrease did not display a relationship to dose. As
surviving fetuses were present in the uterus and no comparable effect was observed in the higher
dose group, this effect is not considered as adverse but rather incidental. The fertility index of the
high-dose group was decreased (significance not specified) due to infertility in 1/10 males with
severe testes atrophy and 1/10 females with vaginal closure and inflammation of the uterine
horn. Pregnancy rates, however, were reported to fall within the range of historical data. There
were no dose-related changes in corpora lutea, number of implantations, implantation and
delivery indices, or total number of offspring.
Limited data on offspring parameters were provided. No toxicologically relevant effects
in offspring were described. The live birth, survival, and viability indices were reported to be
comparable across all groups. The few neonatal deaths noted occurred with equal incidence to
controls. There were no notable clinical signs, body weight or body-weight changes, or gross
findings in offspring.
A maternal and reproductive/developmental NOAEL of 1,000 mg/kg-day (the highest
dose tested) is identified; a LOAEL could not be determined.
2.2.2. Inhalation Exposures
No studies of animals exposed to aluminum phosphate salts by inhalation have been
identified in the literature searches or secondary sources reviewed.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4 provides an overview of genotoxicity studies of aluminum phosphate salts.
31
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Table 4. Summary of Genotoxicity Data for Aluminum Phosphates
Endpoint
Test Substance
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Aluminum
dihydrogen
tripolyphosphate
Salmonella
typhimurium TA1535,
TA1537, TA98, TA100
0, 313,625, 1,250,
2,500, 5,000 (ig/plate
Preincubation assay. No evidence of
mutagenicity in any of the strains
tested, with or without rat liver S9
activation. Precipitation occurred at
>1,250 ng/plate without S9 and
>625 ng/plate with S9. No cytotoxicity
was observed; tests were done to
recommended limit concentrations.
The positive controls gave expected
results.
Anonymous (2002) as cited in
ECHA (2002b)
Mutation
Aluminum
orthophosphate
S. typhimurium
TA1535, TA1537,
TA98, TA100
0, 50, 150, 500,
1,500, 5,000 (ig/plate
Preincubation assay. No evidence of
mutagenicity with or without rat liver
S9 activation. Precipitation was
observed at 5,000 (ig/plate without
metabolic activation. No cytotoxicity
was observed; tests were done to
recommended limit concentrations.
The positive controls gave expected
results.
Anonymous (2010) as cited in
ECHA (2010e)
Mutation
Aluminum
metaphosphate
S. typhimurium
TA1535, TA1537,
TA98, TA100
0, 313,625, 1,250,
2,500, 5,000 (ig/plate
In both preincubation and plate
incorporation assays, there was no
evidence of mutagenicity with or
without rat liver S9 activation. Slight
precipitation at all concentrations. No
cytotoxicity was observed; tests were
done to recommended limit
concentrations. The positive controls
gave expected results.
Anonymous (2015) as cited in
ECHA (2015b)
32
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Table 4. Summary of Genotoxicity Data for Aluminum Phosphates
Endpoint
Test Substance
Test System
Doses /
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Mutation
Aluminum
dihydrogen
tripolyphosphate
Escherichia coli WP2
uvrA pKM 101
0, 313,625, 1,250,
2,500, 5,000 (ig/plate
Preincubation assay. No evidence of
mutagenicity with or without rat liver
S9 activation. Precipitation occurred at
>1,250 ng/plate without S9 and
>625 ng/plate with S9. No cytotoxicity
was observed; tests were done to
recommended limit concentrations.
The positive controls gave expected
results.
Anonymous (2002) as cited in
ECHA (2002b)
Mutation
Aluminum
orthophosphate
E. coli WP2 uvrA
0, 50, 150, 500,
1,500, 5,000 (ig/plate
Preincubation assay. No evidence of
mutagenicity with or without rat liver
S9 activation. Precipitation was
observed at 5,000 (ig/plate without
metabolic activation. No cytotoxicity
was observed; tests were done to
recommended limit concentrations.
The positive controls gave expected
results.
Anonymous (2010) as cited in
ECHA (2010c)
Mutation
Aluminum
metaphosphate
E. coli WP2 uvrA
0, 313,625, 1,250,
2,500, 5,000 (ig/plate
In both preincubation and plate
incorporation assays, there was no
evidence of mutagenicity with or
without rat liver S9 activation. Slight
precipitation occurred at all
concentrations. No cytotoxicity was
observed; tests were done to
recommended limit concentrations.
The positive controls gave expected
results.
Anonymous (2015) as cited in
ECHA (2015b)
DNA repair
(rec assay)
Aluminum phosphate
Bacillus subtilis H17
(Rec+, org-, try-) and
M45 (Rec-, arg-,
try-)
0.05 mL of
0.005-0.5 M
NA
No evidence of recombination repair
function in plates exposed for 24 h at
4°C and then at 37°C overnight.
Kanematsu et al. (1980)
33
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Table 4. Summary of Genotoxicity Data for Aluminum Phosphates
Endpoint
Test Substance
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in mammalian cells—in vitro
Mutation
Aluminum
orthophosphate
Mouse lymphoma
L5178Y cells
0, and six
concentrations
ranging from 20 to
320 iig/mL
The test material did not induce
statistically significant increases in
mutant frequency after incubation for
4 h with rat liver S9 activation or after
24 h without metabolic activation.
Precipitation occurred at >20 |ig/mL.
No cytotoxicity was observed. The
positive controls gave expected results.
Anonymous (2010) as cited in
ECHA (2010g)
Mutation
Aluminum
metaphosphate
Mouse lymphoma
L5178Y cells
0.00032, 0.0016,
0.008, 0.04, 0.2, 1,
5 mg/mL
No significant increases in mutation
frequencies after 3- or 4-h incubations
with test material either with or
without metabolic activation. Slight
precipitation occurred at all
concentrations tested. No cytotoxicity
reported. The positive controls gave
expected results.
Anonymous (2015) as cited in
ECHA (2015a)
CA
Aluminum
dihydrogen
tripolyphosphate
Chinese hamster
CHL/IU cells
Without metabolic
activation: 0, 6.25,
12.5, 25, 50,
100 (ig/mL
With metabolic
activation: 0, 250,
500, 1,000, 1,500,
2,000 (ig/mL
0, 1,600, 1,800, and
2,000 (ig/mL with
metabolic activation
(confirmation study)
+/-
No increases in cells with structural or
numerical CAs following treatment for
6 h in absence of metabolic activation.
With activation, increased incidences
of cells with structural, but not
numerical, aberrations were observed
at 2,000 |ig/mL. However,
dose-related increases in cytotoxicity
were reported at >50 ng/mL without
metabolic activation and
>1,000 |ig/mL with metabolic
activation along with a decrease in pH.
The positive controls gave expected
results.
Anonymous (2002) as cited in
ECHA (2002c)
34
Aluminum phosphate salts
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Table 4. Summary of Genotoxicity Data for Aluminum Phosphates
Endpoint
Test Substance
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
CA
Aluminum
orthophosphate
Primary human
lymphocytes
0, 20, 40, 80, 160,
320, 480 ng/mL
Negative for CAs following exposure
for 4 h with and without S9 metabolic
activation or for 24 h without S9
activation. Precipitation occurred at
>20 iig/mL at the end of the 4-h
exposure and at >320 ng/mL at
harvest. In the 24-h exposure group,
precipitation occurred at >40 |ig/mL.
The positive controls gave expected
results.
Anonymous (2010) as cited in
ECHA (2010f)
MN
Aluminum
metaphosphate
Primary human
peripheral lymphocytes
0,0.3162, 1.0,3.162,
10.0 (ig/mL
No increases in the frequency of cells
with MN with or without metabolic
activation following 4- or 24-h
exposures. Precipitation occurred at
10.0 |ig/mL with and without
metabolic activation. No cytotoxicity
was observed. The positive controls
gave expected results.
Anonymous (2016) as cited in
ECHA (2016)
a+ = positive; ± = weakly positive; - = negative; +/- = equivocal.
CA = chromosomal aberration; DNA = deoxyribonucleic acid; MN = micronuclei.
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2.3.1. Genotoxicity
The genotoxicity of aluminum phosphate has been evaluated in a limited number of in
vitro studies (see Table 4 for more details). Data indicate that in bacteria, the aluminum
phosphate compounds, aluminum dihydrogen tripolyphosphate, aluminum orthophosphate, and
aluminum metaphosphate, are not mutagenic in Salmonella typhimurium strains TA1535,
TA1537, TA98, or TA100 or in Escherichia coli WP2 uvrA, either in the presence or absence of
activation [Anonymous (2015) as cited in ECHA (2015b); Anonymous (2010) as cited in ECHA
(2010c); Anonymous (2010) as cited in ECHA (2010e); Anonymous (2002) as cited in ECHA
(2002b)1. There were also no mutations observed in mouse lymphoma cells under any of the
conditions tested [Anonymous (2015) as cited in ECHA (2015a); Anonymous (2010) as cited in
ECHA (2010g)l. Aluminum phosphates did not induce clastogenic effects in vitro. No increases
in the frequency of chromosomal aberrations (CAs) in Chinese hamster CHL/IU cells or in
human lymphocytes with or without metabolic activation [Anonymous (2010) as cited in ECHA
(201 Of); Anonymous (2002) as cited in ECHA (2002c)"I. and no increases in micronuclei (MN)
in human peripheral lymphocytes, were observed [Anonymous (2016) as cited in ECHA (2016)1.
Finally, in Bacillus subtilis, there was no evidence of deoxyribonucleic acid (DNA) repair
following exposure to aluminum phosphate (Kanematsu et al.. 1980).
2.3.2. Other Animal Studies
Schaeffer et al. (1928) fed groups of 40 mice (20/sex; strain not specified) bread with
aluminum phosphate (2.07 g of aluminum for 1,000 g of bread; type of phosphate not specified)
or bread of similar composition but raised with alum baking powder (4.1 g of aluminum for
1,000 g of bread) for 4 months. At the end of the 4-month exposure, the mice from both groups
exhibited paracellular necrosis of the superficial epithelium of the stomach and of the tops of
certain intestinal villi. None of the mice fed bread leavened with yeast demonstrated this lesion.
The mice evaluated in this study were coupled and allowed to reproduce. The groups of mice fed
bread leavened with aluminum phosphate or alum baking powder produced fewer offspring
(193 and 71, respectively) than mice fed bread with yeast (300 offspring). In a follow-up
experiment by the same researchers, four groups of 10 couples of mice were fed bread with yeast
plus 4% physiological saline mixture, bread with yeast plus 13% saline mixture, bread with
alum-phosphate baking powder (4.4% of aluminum) plus 4% saline mixture, or bread with
alum-phosphate baking powder (1.3%) for 4 months. Mice fed the bread containing 4.4%
aluminum as alum-phosphate baking powder experienced increased mortality of offspring during
the first week of life (23% mortality rate compared to 10% mortality rate in mice fed bread
without alum-phosphate baking powder) and decreased number of offspring. The ovaries of
these animals contained a large number of atretic follicles and were greatly reduced in size.
Aluminum phosphate salts exhibit low acute lethal potential based on unpublished data in
secondary sources. The oral median lethal dose (LDso) values determined in rats were
>2,000 mg/kg for aluminum orthophosphate, aluminum dihydrogen triphosphate, and
triphosphoric acid aluminum salt (1:1); no clinical signs or body-weight changes were noted
[Anonymous (2013) as cited in ECHA (2013); Anonymous (2012) as cited in ECHA (2012a);
Anonymous (2010) as cited in ECHA (2010a); Anonymous (2002) as cited in ECHA (2002a)"I.
In a review, Weiner et al. (2001) reported the following oral LDso values for rats: >1,000 mg/kg
for monoaluminum phosphate (MALP), >4,640 mg/kg for aluminum metaphosphate (ALMP),
and 5,580 mg/kg for SALP, as well as a dermal LDso of >4,640 mg/kg for both MALP and
ALMP, citing unpublished studies by Stauffer and Solutia.
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Acute inhalation toxicity data for several aluminum phosphate compounds were
summarized in ECHA. An inhalation median lethal concentration (LCso) of >5.1 mg/L was
reported for Wistar rats exposed to a monobasic aluminum phosphate (compound reported as
FFB716) in powder form, nose-only for 4 hours. Although all animals in this study survived
exposure, principal clinical signs observed during the first 11 days of recovery included hunched
posture, ruffled fur, labored breathing, breathing noises, and salivation. Transient body-weight
loss was also noted in all animals during the first day following exposure; normal body weight
development was observed after test Day 4. No significant necropsy findings were reported.
Similar inhalation studies on aluminum dihydrogen triphosphate and ALMP reported
LCso values of >3.46 mg/L for Wistar rats and >2.17 mg/L for Sprague Dawley rats,
respectively. These reported LC50 concentrations represented the maximum technically
achievable concentration under the conditions of the study. No mortalities were observed in
either study. Rats exposed to aluminum dihydrogen triphosphate exhibited increased respiratory
rate, hunched posture, and piloerection for several days following exposure, but appeared normal
by Days 6 and 7 postexposure for males and females, respectively. Slight decreases in body
weights were observed during the first 4 days post exposure, but normal body-weight gain was
observed in all animals thereafter. No macroscopic findings were observed during necropsy.
The review by Weiner et al. (2001) reported that MA LP and ALMP were nonirritating
and slightly irritating, respectively, when applied to the skin of rabbits in 4-hour tests under
occlusive conditions, citing unpublished studies by Stauffer. MALP was also reported to be
mildly to moderately irritating when applied to rabbit skin for 24 hours as a 47% H3PO4 solution,
citing the unpublished studies by Albright and Wilson. No further details were provided.
Additional skin irritation results were summarized in ECHA [Anonymous (2014) as cited in
ECHA (2014b); Anonymous (2010) as cited in ECHA (2010d)1. ALMP was not irritating when
applied to rabbit skin under semi-occlusive conditions for 4 hours. Aluminum orthophosphate
and aluminum dihydrogen triphosphate were nonirritating when applied to reconstructed human
epidermis.
A broad range of eye irritation responses have been found within the class of aluminum
phosphates. As reported in the review by Weiner et al. (2001). ALMP was found to be
nonirritating in rabbits, whereas studies of MALP reported results ranging from slightly irritating
to severely irritating, citing unpublished studies by Stauffer and by Albright and Wilson.
Similarly, records within ECHA [Anonymous (2014) as cited in ECHA (2014a); Anonymous
(2012) as cited in ECHA (2012b); Anonymous (2010) as cited in ECHA (2010b)1 summarized
eye irritation studies in rabbits that classified ALMP as nonirritating, aluminum orthophosphate
as mildly irritating, aluminum dihydrogen triphosphate as irritating, and MALP as corrosive.
A study conducted by de Chambrun et al. (2014) performed in vivo and in vitro
experiments with various aluminum compounds, including aluminum phosphate, to evaluate the
potential effects of aluminum on the development or potentiation of inflammatory bowel disease.
In the in vivo study, aluminum phosphate diluted in phosphate buffer saline (PBS) was
administered to groups of C57BL6 mice (14 males/group) via gavage daily for 4 weeks (31 days)
at a reported concentration of 1.5 mg aluminum element/kg-day, or 17.8 mg aluminum
phosphate as determined for this review. No significant effects on body weights or macroscopic
or microscopic changes in colonic tissues were observed in mice treated with aluminum
phosphate compared with controls. However, in mice with induced colitis, aluminum phosphate
37
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EPA/690/R-23/004F
was found to increase the intensity and duration of macroscopic and histologic intestinal
inflammation. Induction of inflammation was evaluated in vitro using human colon epithelial
cell lines, HT-29 and Caco-2. Cells were incubated with 0, 10, 50, or 100 |ig/mL aluminum
phosphate for 3 hours. Dose-dependent increases in the expression of cytokines, IL-8 and ILip,
that were significant at 50 |ag/m L suggest a pro-inflammatory effect. In vitro, the formation of
granuloma-like cell aggregates in primary human peripheral blood mononuclear cells (PBMCs)
can be used as a model to mimic early host immune responses (Je et al.. 2016). To study the
potential early immune responses to aluminum phosphate, PBMCs were left untreated or
incubated for 4 days with increasing concentrations of aluminum phosphate (up to 100 |ag/m L
aluminum element). In the absence of bacteria, granuloma counts increased in a dose-related
manner, and were visible at a dose as low as 5 ng of aluminum element/mL.
2.3.3. Absorption, Distribution, Metabolism, and Excretion (ADME) Studies
Limited data on the absorption and distribution of aluminum following exposures to
SALPs are available. A separate body of data evaluating the use of aluminum phosphates as
adjuvants for vaccines, including toxicokinetic data following injection routes of exposure, is
available (ATSDR. 2008; Bavlor et al.. 2002) and not reviewed here.
Absorption
Data on the absorption of aluminum phosphates are primarily limited to studies testing
the effects of aluminum chemical forms on the bioavailability of aluminum as summarized in
several reviews (Younes et al.. 2018; Willhite et al.. 2014; Greger. 1993). Early studies were
impeded by the lack of suitable radioisotopes (Yokel et al.. 2005). and to date, estimates of oral
aluminum absorption have primarily been based only on levels detected either in serum or in
urine, often from a single collection point, or a limited number of collection points, and without
taking possible retention into account. The general consensus is that the bioavailability of oral
aluminum from aluminum phosphates and their salts is low, foremost due to the insoluble nature
of aluminum phosphates. In a human study, poor absorption was inferred when no increases in
plasma aluminum levels were observed in a single measurement taken on the final day for six
volunteers who ingested 2.2 g of aluminum phosphate in divided doses between meals for 3 days
(Kaehnv et al .. 1977). In the same study, detection of aluminum in daily urine samples was
regarded as an indication that some absorption through the gastrointestinal tract did occur, but no
accurate estimates of bioavailability were made. In rodents, serum levels of aluminum in rats fed
biscuits containing 1 or 2% of the leavening agent, [26Al]-acidic SALP (acidic SALP) averaged
0.11 and 0.13%, respectively, with maximum concentrations measured at 4.2 and 6 hours post
consumption (Yokel and Florence. 2006). In a similar study, aluminum bioavailability when
[26Al]-basic SALP was delivered to rats at concentrations of 1.5 and 3% in a processed cheese
was -0.1 and 0.3%, respectively; the time to maximum serum [26A1] concentration ('/max) was
8-9 hours (Yokel et al.. 2008). Some studies suggest that the chemical form (e.g., aluminum
phosphate vs. aluminum citrate), pH of the gastrointestinal tract, and consumption of other foods
may alter acidity or contain ligands that impact absorption (Younes et al.. 2018; Greger et al..
1997; Berthon and Davde. 1992; Davde et al.. 1990). but consistent data supporting these
hypotheses are lacking (de Chambrun et al.. 2014; Yokel and McNamara. 2001; Owen et al..
1994; Yokel and McNamara. 1988; Kaehnv et al.. 1977).
No data on absorption of aluminum phosphate salts via inhalation or dermal routes were
identified.
38
Aluminum phosphate salts
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Distribution
Since aluminum is known to accumulate in bone. Hicks et al. (1987) designed a study to
measure aluminum concentrations in the femurs of male Sprague Dawley rats administered basic
SALP in the diet for 28 days. Aluminum concentrations measured in the femurs of control rats
ranged from below the level of detection to 0.3 ppm. Aluminum concentrations in rats fed diets
containing basic SALP as Kasal™ or Kasal™II were not quantifiable (detectable levels that were
below the limits of quantification). Thus, this study found no significant deposition of aluminum
in bone of rats fed diets with either basic SALP formulation.
In beagle dogs fed Kasal™ for 26 weeks, the aluminum concentrations in trabecular bone
of treated dogs were unchanged from controls lYPettersen et al.. 1990); Anonymous (1987) as
cited in IX'HA (1987)1. In female brains, but not male brains, aluminum concentrations were
increased 1.6 times over controls in animals dosed with 30,000 ppm, but the levels were low
(0.129 ppm). In another study in guinea pigs, animals were fed sponge cake diets containing
SALP (only aluminum concentrations were reported), with or without orange juice (citrate), for
3 weeks (Owen et al.. 1994). Compared with animals on control chow diets, aluminum contents
in the femurs of animals eating sponge cake were significantly higher. No aluminum was
detected in brain tissue, and compared to controls, aluminum levels in the kidney were only
significantly increased in the group that received both sponge cake and orange juice. Less than
1% of ingested aluminum was found in the soluble fraction of the upper intestinal tract.
Metabolism
No data on the metabolism of aluminum phosphate salts have been identified.
Excretion
The primary route of elimination is expected to be through urine, with bile as a
secondary, minor route (Younes et al.. 2018; Yokel et al.. 2008; Greger et al.. 1997; Kaehnv et
al.. 1977).
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Aluminum phosphate salts
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES
The database for aluminum phosphate salts (multiple CASRNs) is inadequate to support
derivation of subchronic or chronic provisional oral reference values. Repeated-dose oral toxicity
studies were identified for acidic and basic SALPs, including a 28-day dietary study in male
Sprague Davvley rats with Kasal™ (Hicks et al.. 1987). 90-day dietary studies in male and
female albino rats with Kasal™, Levair®, and Levn Lite® [Anonymous (1972) studies as cited
in ECHA (1972c. 1972e. 197201. 90-day dietary studies in male and female beagle dogs with
Kasal™ and Levair® [Anonymous (1972) as cited in ECHA (1972a. 1972d)l. and 6-month
dietary studies in male and female beagle dogs with Levair® (Katz et al.. 1984) and Kasal™
[(Pettersen et al.. 1990); Anonymous (1987) as cited in ECHA (1987)1. There is also a
reproductive/developmental gavage study in Sprague Dawley rats with triphosphoric acid
aluminum salt [Anonymous (2002) as cited in ECHA (2002d)l. No repeated-dose oral toxicity
studies were identified for other forms of aluminum phosphate salts.
Limitations of these studies are significant. Several of the studies are available only as
selectively described submissions to the ECHA database. Information in all such cases was
insufficient to support independent review and evaluation of the study. In addition, the 90-day rat
and dog studies [Anonymous (1972) as cited in ECHA (1972c. 1972e. 197201 were reported by
FDA (1975) to have been conducted by IBT, a laboratory found by OECD to be unreliable,
further lowering confidence in these results. Although the 6-month dog studies were published,
few of the data are shown, again providing limited basis for independent study evaluation. None
of the studies provided any information on phosphate or calcium content of the baseline diets fed
to the animals. Dietary phosphate data are necessary to ensure that the total phosphate dose can
be accurately characterized, and dietary calcium data are needed to evaluate potential effects of
altered calcium:phosphate ratio, which is an important determinant of phosphate toxicity. For
observed health outcomes to be reliably attributed to changes in phosphate, calcium levels need
to be constant across control and exposure groups.
As a result of the limitations of the available oral toxicity data for aluminum phosphates,
subchronic and chronic provisional reference doses (p-RfDs) were not derived directly. Instead,
subchronic and chronic screening p-RfDs are derived in Appendix A using an alternative
analogue approach. Based on the overall analogue approach presented in Appendix A, aluminum
was selected as the most appropriate analogue for aluminum phosphate salts for deriving a
subchronic and chronic screening p-RfD.
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS
There are no suitable human or animal data available to derive subchronic or chronic
provisional reference concentrations (p-RfCs) for aluminum phosphate salts (multiple CASRNs).
An alternative analogue approach was considered but not employed due to lack of relevant
inhalation toxicity values for the candidate analogues and extremely limited inhalation data for
aluminum phosphate salts (see Appendix A for more details).
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3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
The noncancer provisional reference values for aluminum phosphate salts are
summarized in Table 5.
Table 5. Summary of Noncancer Reference Values for Aluminum
Phosphate Salts (Multiple CASRNs)
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Subchronic
screening
p-RfD
(mg/kg-d)
Mouse/
M, F
Neurobehavioral
effects (shorter
latency to fall in wire
suspension test [M],
impaired performance
in water maze [F])
3 x 10-1
NOAEL
26
(based on
analogue
POD)a
100
Golub and
Germann
(2001) as cited
in ATSDR
(2008)
Chronic
screening
p-RfD
(mg/kg-d)
Mouse/
M, F
Neurobehavioral
effects (shorter
latency to fall in wire
suspension test [M],
impaired performance
in water maze [F])
3 x 10-1
NOAEL
26
(based on
analogue
POD)a
100
Golub and
Germann
(2001) as cited
in ATSDR
(2008)
Subchronic
p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
aBased on aluminum assessment (ATSDR 2008).
F = female(s); M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; UFC = composite
uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 6 identifies the cancer weight-of-evidence (WOE) descriptor for aluminum
phosphate salts (multiple CASRNs). No human or animal studies evaluating cancer endpoints are
available for any of the chemicals. Limited genotoxicity assays (see Table 4) for aluminum
dihydrogen tripolyphosphate, aluminum orthophosphate, and aluminum metaphosphate have
reported negative results. Under the U.S. EPA (2005) cancer guidelines, the available data are
inadequate for an assessment of human carcinogenic potential, and the cancer WOE descriptor
for aluminum phosphate salts is "Inadequate Information to Assess the Carcinogenic Potential'
(for both oral and inhalation routes of exposure).
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Table 6. Cancer WOE Descriptor for Aluminum Phosphate Salts
(Multiple CASRNs)
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation, or
both)
Comments
"Carcinogenic to Humans"
NS
NA
There are no human carcinogenicity data
identified to support this descriptor.
"Likely to Be Carcinogenic to
Humans "
NS
NA
There are no human or animal
carcinogenicity studies identified to
support this descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no human or animal
carcinogenicity studies identified to
support this descriptor.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
This descriptor is selected due to the lack
of any information on carcinogenicity of
aluminum phosphate salts.
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
No evidence of noncarcinogenicity is
available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Due to a lack of carcinogenicity data, derivation of cancer risk estimates is precluded
(see Table 7).
Table 7. Summary of Cancer Risk Estimates for Aluminum Phosphate Salts
(Multiple CASRNs)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Risk Estimate Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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APPENDIX A. NONCANCER SCREENING PROVISIONAL VALUES
Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity
Value (PPRTV) assessment, it is inappropriate to derive provisional toxicity values for
aluminum phosphate salts. However, some information is available for this chemical, which
although insufficient to support derivation of a provisional toxicity value under current
guidelines, may be of limited use to risk assessors. In such cases, the Center for Public Health
and Environmental Assessment (CPHEA) summarizes available information in an appendix and
develops a "screening value." Appendices receive the same level of internal and external
scientific peer review as the provisional reference values to ensure their appropriateness within
the limitations detailed in the document. Users of screening toxicity values in an appendix to a
PPRTV assessment should understand that there could be more uncertainty associated with
deriving an appendix screening toxicity value than for a value presented in the body of the
assessment. Questions or concerns about the appropriate use of screening values should be
directed to the CPHEA.
APPLICATION OF AN ALTERNATIVE ANALOGUE APPROACH (METHODS)
The analogue approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for analogue analysis are presented in Wang et al. (2012);
Lizarraga et al. (2023). Three types of potential analogues (structural, metabolic, and toxicity-
like) are identified to facilitate the final analogue chemical selection. The analogue approach
may or may not be route-specific or applicable to multiple routes of exposure. All information
was considered together as part of the final weight-of-evidence (WOE) approach to select the
most suitable analogue both toxi col ogically and chemically.
An expanded analogue identification approach was developed to collect a more
comprehensive set of candidate analogues for the compounds undergoing the U.S.
Environmental Protection Agency (U.S. EPA) PPRTV screening-level assessment. As described
below, this method includes application of a variety of tools and methods for identifying
candidate analogues that are similar to the target chemical based on chemical structure and key
features; metabolic relationships; or related toxic effects and mechanisms of action.
To identify structurally-related compounds, an initial pool of analogues is identified using
automated tools, including ChemlDplus3 (NI.M. 202 la), CompTox Chemicals Dashboard (U.S.
HP A. 202 la), and the Organisation for Economic Co-operation and Development (OECD)
Quantitative Structure-Activity Relationship (QSAR) Toolbox (OECD. 2021). Additional
analogues identified as ChemlDplus-related substances, parent, salts, and mixtures, and
CompTox-related substances are considered. CompTox Generalized Read-Across (GenRA)
analogues are collected using the methods available on the publicly available GenRA Beta
version, which may include Morgan fingerprints, Torsion fingerprints, ToxPrints and ToxCast,
Tox21, and ToxRef data. For compounds that have very few analogues identified by structure
similarity using a similarity threshold of 0.8 or 80%, substructure searches in the QSAR Toolbox
may be performed, or similarity searches may be rerun using a reduced similarity threshold
3The National Library of Medicine (NLM) retired ChemlDPlus in December 2022.
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(e.g., 70 or 60%). The compiled list of candidate analogues is batch run through the CompTox
Chemicals Dashboard where QSAR-ready simplified molecular-input line-entry system
(SMILES) notations are collected and toxicity data availability is determined (e.g., from the
Agency for Toxic Substances and Disease Registry [ATSDR], Office of Environmental Health
Hazard Assessment [OEHHA), California Environmental Protection Agency [CalEPA], the
U.S. EPA Integrated Risk Information System [IRIS], PPRTVs). The batch output information is
then uploaded into the Chemical Assessment Clustering Engine (ChemACE) (U.S. EPA. 2011a).
which clusters the chemicals based on chemical fragments and displays the toxicity data
availability for each candidate. The ChemACE output is reviewed by an experienced chemist,
who narrows the list of structural analogues based on known or expected structure-toxicity
relationships, reactivity, and known or expected metabolic pathways.
Toxicokinetic studies tagged as potentially relevant supplemental material during
screening were used to identify metabolic analogues (metabolites and metabolic precursors).
Metabolites were also identified from the two OECD QSAR Toolbox metabolism simulators (in
vivo rat metabolism simulator and rat liver S9 metabolism simulator). Targeted PubMed
searches were conducted to identify metabolic precursors and other compounds that share any of
the observed or predicted metabolites identified for the target chemical. Metabolic analogues are
then added to the pool of candidate analogues and toxicity data availability is determined
(e.g., from ATSDR, OEHHA, CalEPA, the U.S. EPA IRIS, PPRTV assessments).
In vivo toxicity data for the target chemical (if available) are evaluated to determine
whether characteristic toxicity associated with a particular mechanism of toxicity was observed
(e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation). In addition, in vitro
mechanistic data tagged as potentially relevant supplemental material during screening or
obtained from tools including GenRA, ToxCast/Tox21, and Comparative Toxicogenomics
Database (CTD) (CTD, 2022; Davis et at., 2021) were evaluated for this purpose. Data from
CompTox Chemicals Dashboard ToxCast/Tox21 are collected to determine bioactivity of the
target chemical in in vitro assays that may indicate potential mechanism(s) of action. The
GenRA option within the Dashboard also offers an option to search for analogues based on
similarities in activity in ToxCast/Tox21 in vitro assays. Using the ToxCast/Tox21 bioactivity
data, nearest neighbors identified with similarity indices of >0.5 may be considered potential
candidate analogues. The CTD (CTD, 2022; Davis et at., 2021) is searched to identify
compounds with gene interactions similar to interactions induced by the target chemical;
compounds with gene interactions similar to the target chemical (with a similarity index >0.5)
may be considered potential candidate analogues. These compounds are then added to the pool
of candidate analogues, and toxicity data availability is determined (e.g., from ATSDR, OEHHA,
CalEPA, the U.S. EPA IRIS, PPRTV assessments).
The application of a variety of different tools and methods to identify candidate
analogues serves to minimize the limitations of any individual tool with respect to the pool of
chemicals included, chemical fragments considered, and methods for assessing similarity.
Further, the inclusion of techniques to identify analogues based on metabolism and toxicity or
bioactivity expands the pool of candidates beyond those based exclusively on structural
similarity. The specific tools described above are used for the expanded analogue searches were
selected because they are publicly available, supported by U.S. and OECD agencies, updated
regularly, and widely used.
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Analogue Search Results for Aluminum Phosphates
Because aluminum phosphates are composed entirely of inorganic components, potential
structural analogues are limited to its component functional groups (i.e., the aluminum cation and
inorganic phosphate anion), and there are no metabolic analogues.
Available toxicity and mechanistic data for aluminum phosphates were evaluated to
determine whether these data would suggest candidate analogues. The GenRA option within the
U.S. EPA CompTox Chemicals Dashboard offers an option to search for analogues based on
similarities in activity in in vitro assays in ToxCast/Tox21; however, for the aluminum phosphate
salts, the GenRA module returned an error message (based on insufficient data). No bioactivity
data were available for aluminum phosphate compounds in the dashboard. The CTD did not have
any entries for aluminum phosphates.
The available oral toxicity data for aluminum phosphates, described in the main PPRTV
assessment text above, were reviewed to determine whether there were in vivo toxicity data
suggesting specific, characteristic toxicity (e.g., inhibition of oxidative phosphorylation) that
could be used to identify candidate analogues. The kidney has been identified as a target of
aluminum phosphates-induced toxicity after oral exposure. Limited oral toxicity data in animals
identified renal nephrocalcinosis and increased kidney weight in animals administered mixed
sodium aluminum phosphates [Anonymous (1972) as cited in ECHA (1972a. 1972c. 1972e.
197201. However, none of the effects identified in the limited in vivo studies suggested a
characteristic or unique toxicity that could be used to suggest candidate analogues other than
those identified based on structure.
Assessments are available for both aluminum and inorganic phosphate compounds. The
PPRTV assessment for aluminum (U.S. EPA. 2006) and the ATSDR Toxicological Profile for
Aluminum (ATSDR. 2008) both used studies of aluminum salts to derive oral toxicity values for
aluminum that were meant to be generally applicable to aluminum compounds. Aluminum, as
represented by oral toxicity values from U.S. EPA (2006) and ATSDR (2008). is therefore a
candidate structural analogue for aluminum phosphates by oral exposure. Although the U.S. EPA
(2006) also derived a chronic provisional reference concentration (p-RfC) for aluminum, it was
based on inhalation of uncharacterized aluminum fumes and dusts by foundry workers. Without
more specific exposure information (e.g., compounds, particle sizes), it is not possible to make
the quantitative comparisons between inhalation of analogue and aluminum phosphates that form
the basis for the alternative analogue approach.
For inorganic phosphates, PPRTV assessments for monovalent (sodium and potassium)
salts of inorganic phosphates (U.S. EPA. 202 Id) and divalent (calcium) salts of inorganic
phosphates (U.S. EPA, 2021c) were identified. A PPRTV assessment for ammonium phosphates
(U.S. EPA. 2021b) was not considered, because ammonium (as a dissociation product) is not
expected to behave (chemically or toxicologically) in the same manner as metal ions. In addition,
the screening toxicity value derived for ammonium phosphates is based on an effect (submucosal
stomach inflammation) associated with the ammonium moiety of the compound. The sodium and
potassium salts of inorganic phosphates and calcium salts of inorganic phosphates, which were
assessed by U.S. EPA (2021c, 202Id), are candidate structural analogues for aluminum
phosphates by oral exposure. Although IRIS lists a chronic RfC for phosphoric acid, it is based
45
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on data for obscurant smoke aerosol combustion products of a 95% red phosphorus/5% butyl
rubber mixture and is not relevant to the current assessment.
In summary, the two key structural components of aluminum phosphates, aluminum, and
inorganic phosphate, are identified as candidate structural analogues with applicable oral toxicity
values but no relevant inhalation toxicity values. No potential metabolic or toxicity/mechanistic
analogues were identified. Due to the lack of candidate analogues with inhalation toxicity values,
the alternative analogue approach was performed only for oral exposure.
Structural/Physicochemical Properties Similarity Comparisons
Although information pertaining to the physicochemical properties of aluminum
phosphates and its candidate analogues is sparse, water solubility data are available
(see Table A-l). Water solubility data are important for evaluating the candidate analogues
because water solubility is a key determinant of bioavailability, which is discussed in the
"Metabolic/Toxicokinetic Similarity Comparison" section below.
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Table A-l. Water Solubility of Aluminum Phosphates and Candidate Analogues3
Solubility
Aluminum Phosphates
Aluminum Salts
Sodium and Potassium Phosphate Salts
Calcium Phosphate Salts
Very soluble
• Aluminum nitrate
• Monosodium phosphate (949 g/L)
(U.S. EPA. 202Id)
• Monopotassium phosphate
• Disodium phosphate
• Trisodium phosphate
• Dipotassium phosphate
• Tripotassium phosphate
• Tetrapotassium pyrophosphate
• Potassium tripolyphosphate
• Sodium acid pyrophosphate
• Tetrasodium pyrophosphate
• Sodium tripolyphosphate
• Sodium trimetaphosphate
Soluble
• Aluminum lactate (4.67 g/L)
(littD://www.vcclab.ore/lab/alo2Ds/)
• Aluminum sulfate
• Aluminum chlorohydrate
• Sodium polyphosphate
• Sodium hexametaphosphate
Moderate
solubility
• Dicalcium phosphate
(153 mg/L) (U.S. EPA. 2021c)
• Monocalcium phosphate
Slightly or
sparingly
soluble
• Monoaluminum phosphate
• Sodium aluminum phosphate
anhydrous (basic SALP)
• Aluminum fluoride
• Aluminum potassium sulfate
• Tricalcium phosphate
<20 mg/L (U.S. EPA. 2021c)
Insoluble or
negligible
solubility
• Aluminum phosphate
• Aluminum metaphosphate
• Aluminum triphosphate
• Sodium aluminum phosphate
tetrahydrate (SALP)
• Sodium aluminum phosphate
acidic (acidic SALP)
• Aluminum hydroxide
• Aluminum carbonate
• Calcium pyrophosphate
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Table A-l. Water Solubility of Aluminum Phosphates and Candidate Analogues3
Solubility
Aluminum Phosphates
Aluminum Salts
Sodium and Potassium Phosphate Salts
Calcium Phosphate Salts
Soluble at low
pH
• Monoaluminum phosphate
• Aluminum phosphate
(slightly)
• Aluminum hydroxide
• Aluminum carbonate
• Aluminum fluoride (sparingly)
• Monocalcium phosphate
• Dicalcium phosphate (moderate)
• Calcium pyrophosphate
(slightly)
aAssignment of aluminum salts, sodium and potassium salts of inorganic phosphates, and calcium salts of inorganic phosphates to solubility categories was based on
qualitative or quantitative data provided in existing assessments (U.S. EPA. 2021c. d; ATSDR. 2008: U.S. EPA. 20061. For quantitative data, the following criteria were
used (mg/L): >10,000 = very soluble, >1,000-10,000 = soluble, >100-10,000 = moderately soluble, >0.1-100 = slightly soluble, and <0.1 = negligible solubility.
Bold indicates that data for the compound were used to derive a toxicity value.
SALP = sodium aluminum phosphate.
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The target compounds, aluminum phosphates, are slightly soluble or insoluble in water.
Although the solubility of some aluminum phosphates is increased at low pH
(e.g., monoaluminum phosphate), solubility at biological pH remains low (Sellrodter et al.. 2012;
AT SDR. 2008).
Aluminum salts, which form the basis for the ATSDR assessment for aluminum and
compounds (ATSDR. 2008) and the PPRTV assessment for aluminum (U.S. EPA. 2006). range
from insoluble to very soluble in water and are expected to exhibit increased solubility under
acidic conditions. As shown in Table A-l, aluminum salts are at least as soluble as aluminum
phosphate salts. Aluminum lactate, the compound used to derive toxicity values for aluminum
and compounds, is freely soluble in water.
With respect to inorganic phosphates, sodium and potassium salts of inorganic
phosphates are soluble in water (U.S. EPA. 202Id). Monosodium phosphate (MSP), the
compound used to derive toxicity values for sodium and potassium phosphate salts, exhibits
moderate solubility in water. Calcium phosphate salts are less water-soluble than sodium and
potassium phosphate salts. The water solubility of calcium phosphate salts ranges from
practically insoluble to moderately soluble. The solubility of calcium phosphate salts is enhanced
in acidic conditions relative to neutral or basic solutions (U.S. EPA. 2021c). The calcium
phosphate salts used to derive the toxicity value, dicalcium phosphate (DCP) and tricalcium
phosphate (TCP), are slightly soluble in water (U.S. EPA. 2021c).
Solubility data suggest that aluminum salts, sodium and potassium salts of inorganic
phosphates, and calcium salts of inorganic phosphates are suitable analogues for aluminum
phosphates because these compounds are as soluble as, or more soluble than, aluminum
phosphates. Based on solubility considerations alone, aluminum and sodium and potassium
phosphate salts are more health-protective choices than calcium phosphate salts because the
water solubility of these compounds (i.e., the compounds used to derive toxicity values) is higher
than that of calcium phosphate salts.
Metabolic/Toxicokinetic Similarity Comparisons
Candidate analogues for aluminum phosphates have oral toxicity values, but no
inhalation toxicity values that are relevant to this assessment. Thus, comparison of toxicokinetic
data for aluminum phosphates and candidate analogues will focus on the oral route of exposure.
In addition, since toxicity is partly a function of the amount of the compound that reaches the
target, the focus will be the absorption and bioavailability of the aluminum and phosphate
moieties from aluminum phosphates and the candidate analogues. There are no data to indicate
that aluminum phosphates or candidate analogues (as inorganic compounds) are substantially
metabolized. Absorption, distribution, metabolism, and excretion (ADME) data for aluminum
phosphates and candidate analogues are presented in Table A-2 and discussed below.
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Table A-2. Comparison of ADME Data for Aluminum Phosphates and Candidate Analogues3
Aluminum Phosphates
(target)b
Aluminum and Compounds
(aluminum moiety)
Sodium and Potassium Phosphate Salts
(phosphate moiety)
Calcium Phosphate Salts
(phosphate moiety)
Absorption
• Poor absorption of aluminum from
aluminum phosphates (0.1-0.3% based
on studies in rats)
• Absorption and bioavailability
influenced by chemical form, pH,
ingestion of other ligands.
• Bioavailability of aluminum low;
aluminum phosphates sparingly soluble
or insoluble.
• Aluminum is poorly absorbed (ranging
from 0.1 to 5% based on studies in
humans and animals).
• Absorption and bioavailability can vary
substantially (as much as 10-fold)
based on chemical form, pH, caloric
state, and/or ingestion of other ligands.
• Ligands enhance absorption by
forming absorbable complexes
(e.g., carboxylic acids) or reduce
absorption by forming insoluble
compounds.
• Bioavailability expected to parallel
water solubility (excluding other
factors).
• Moderate to high absorption.
• Bioavailability expected to parallel water
solubility.
• Bioavailability depends on amount of
co-ingested calcium, also food source
(animal or plant).
• Low to moderate absorption.
• Reduced absorption owing to the
interaction of free phosphorus and
calcium in the intestine.
• Bioavailability expected to parallel
water solubility.
Distribution
• Low amounts of bioavailable
aluminum distributed throughout body.
• Little to no evidence for aluminum
deposition in bone (based on studies in
rodents and dogs).
• Bioavailable aluminum distributed
throughout body (e.g., bone, brain,
kidney).
• Evidence for aluminum deposition to
bone (based on animal studies).
• Phosphate distributed throughout the
body.
• Phosphate distributed throughout the
body.
Metabolism
ND
ND
ND
ND
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Table A-2. Comparison of ADME Data for Aluminum Phosphates and Candidate Analogues3
Aluminum Phosphates
(target)b
Aluminum and Compounds
(aluminum moiety)
Sodium and Potassium Phosphate Salts
(phosphate moiety)
Calcium Phosphate Salts
(phosphate moiety)
Excretion
• Aluminum excreted primarily in the
urine; also in bile.
• Aluminum excreted primarily in the
urine; also in bile.
• Phosphate excreted in both the urine and
feces.
• Phosphate excreted in both the urine
and feces.
• Urinary excretion of phosphate can
be reduced due to the interaction of
phosphate and calcium in the kidney.
'Data for aluminum salts, sodium and potassium salts of inorganic phosphates, and calcium salts of inorganic compounds are from existing assessments (U.S. EPA.
2021c. d; ATSDR. 2008: U.S. EPA. 20061.
bADME data were only available for the aluminum moiety from aluminum phosphates.
ADME = absorption, distribution, metabolism, and excretion; ND = no data.
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Data on the absorption of aluminum phosphates are limited to the aluminum moiety. The
aluminum moiety of aluminum phosphates is poorly absorbed (about 0.1-0.3% based on studies
in rats). The bioavailability of aluminum from aluminum phosphates is low owing to their
limited solubility (Younes et al.. 2018; Willhite et al.. 2014; Greger. 1993). Absorption is
influenced by chemical form, pH of the gastrointestinal tract (higher solubility at low pH), and
the consumption of other foods (e.g., that alter acidity) (Younes et al .. 2018; Greger et al.. 1997;
Bert lion and Davde. 1992; Davde et al.. 1990). The small amounts of free aluminum that are
generated at low pH in the stomach can complex with its original anion (forming largely
insoluble compounds) or other dietary constituents. Free aluminum that reaches the higher pH
environment of the intestine predominantly leads to the formation of insoluble aluminum
hydroxide (ATSDR. 2008). Low amounts of absorbed aluminum are distributed throughout the
body. However, there is little to no evidence for the deposition of aluminum from aluminum
phosphates in bone, a tissue in which aluminum is known to accumulate.
For aluminum salts other than aluminum phosphates, data indicate that the aluminum
moiety is poorly absorbed via the oral route of exposure (albeit not as poorly as the aluminum
moiety from aluminum phosphates). Absorption of aluminum from aluminum salts is estimated
to range from 0.1 to 5% based on studies in humans and animals (ATSDR. 2008; U.S. EPA.
2006). As is the case for aluminum phosphates, the absorption and bioavailability of aluminum
varies based on the chemical form administered, pH, caloric status, and/or the presence of
ligands. Ligands can enhance absorption by forming absorbable complexes (e.g., carboxylic
acids) or reduce absorption by forming insoluble compounds (ATSDR. 2008; U.S. EPA. 2006).
Excluding these other factors, the bioavailability of the aluminum moiety from aluminum
phosphates is expected to parallel water solubility (ATSDR, 2008); therefore, the aluminum
moiety from other aluminum salts is likely more bioavailable than the aluminum moiety from
aluminum phosphates. Bioavailable aluminum is distributed throughout the body (e.g., bone,
brain, kidney). There is evidence from animal studies that levels of aluminum in bone are
increased after administration of other aluminum salts (including aluminum lactate) (ATSDR.
2008).
Data for inorganic phosphates (sodium and potassium phosphate salts and calcium
phosphate salts) indicate that inorganic phosphate is readily absorbed from the gastrointestinal
tract. Calcium phosphate salts are more soluble at low pH (e.g., the stomach); neutralization of
the pH in the intestines leads to reductions in solubility and absorption of phosphate (U.S. EPA.
2021c). For sodium, potassium, and calcium phosphate salts, absorption of the phosphate moiety
depends on the amount of calcium present, because calcium and phosphate bind in the intestine,
leading to decreased phosphate absorption (U.S. EPA. 2021c. d). In general, the bioavailability
of phosphate from sodium and potassium phosphate salts (including MSP) and calcium
phosphate salts (including DCP and TCP) is expected to be higher than that from aluminum
phosphates because they are more soluble. Further, because bioavailability is expected to parallel
water solubility, the bioavailability of the phosphate moiety is expected to be higher from
sodium and potassium phosphate salts than calcium phosphate salts (U.S. EPA. 2021c. d).
Toxicokinetic data suggest that aluminum (from aluminum salts) is a suitable analogue
for aluminum phosphates because the aluminum moiety from other aluminum salts is expected to
be absorbed at least as much or more than the aluminum moiety from aluminum phosphates.
Similarly, the phosphate moiety from sodium and potassium phosphate salts and calcium
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phosphate salts is expected to be more absorbed and more bioavailable than the phosphate
moiety from aluminum phosphates (with sodium and potassium phosphate salts having a greater
expected absorption and bioavailability of the phosphate moiety than calcium phosphate salts).
Therefore, the available metabolism data suggest that aluminum and phosphate salts are
plausible metabolic analogues for the target.
Toxicodynamic Similarity Comparisons
Table A-3 summarizes available oral toxicity values for the candidate analogues of
aluminum phosphates. No inhalation toxicity values relevant to this assessment were identified
for the candidate analogues. The database considered suitable for the derivation of subchronic
and chronic toxicity values for aluminum phosphates and candidate analogues (e.g., studies of an
appropriate duration and including information on the baseline diet) consists predominantly of
oral toxicity studies in animals. Table A-4 shows the lowest lowest-observed-adverse-effect
levels (LOAELs) or highest no-observed-adverse-effect levels (NOAELs) for the target organ or
systems which served as the basis for the derivation of subchronic or chronic toxicity values for
the candidate analogues.
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Table A-3. Comparison of Available Oral Toxicity Data for Aluminum Phosphates and Candidate Analogues
Chemical
Aluminum Phosphates3
(target)
Aluminum (and compounds)
Sodium and Potassium
Phosphate Salts
Calcium Phosphate Salts
CASRN
Multiple
Multiple
Multiple
Multiple
Subchronic oral toxicity values
POD
ND
26 mg Al/kg-d (as aluminum lactate)
120 mg P/kg-d (as monosodium
phosphate)
240 mg DCP or TCP/kg-d
(48-50 mg P/kg-d)b
POD type
ND
NOAEL
LOAEL
NOAEL
Subchronic UFC and MF
(component uncertainty
factors)
ND
100 (10 forUFA, 10 forUFH); MF of 0.3
30
30
Subchronic p-RfD/MRL
ND
1 mg Al/kg-d
4 mg P/kg-d
8 mg DCP or TCP/kg-d
(1.6-1.8 mgP/kg-d)°
Critical effects
ND
Neurobehavioral effects (impaired
performance in water maze [F], shorter
latency to fall in wire suspension test [M])
Nephrocalcinosis
No treatment-related effects
Species
ND
Mouse
Rabbit
Rat
Duration
ND
During gestation, lactation, and
PNDs 21-35
8 wk
28 d or during premating,
mating, gestation, and
lactation
Route (method)
ND
Oral (diet)
Oral (diet)
Oral (gavage)
Source
NA
Golub and Germann (2001) as cited in
ATSDR (2008)
U.S. EPA (202Id): Ritskes-
Hoitinea et al. (2004)
NIER (2007, 2009, 2010) as
cited in U.S. EPA (2021c)
Chronic oral toxicity values
POD
ND
100 mg Al/kg-d (as aluminum lactate)
120 mg P/kg-d (as monosodium
phosphate)
ND
POD type
ND
LOAEL
LOAEL
ND
Subchronic UFC and MF
(component uncertainty
factors)
ND
100 (10 forUFA, 3 for
UFh, 3 for UFl)
300 (10 forUFA,
10 for UFh, 3 for
UFl); MFd of 0.3
100
ND
54
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Table A-3. Comparison of Available Oral Toxicity Data for Aluminum Phosphates and Candidate Analogues
Chemical
Aluminum Phosphates3
(target)
Aluminum (and compounds)
Sodium and Potassium
Phosphate Salts
Calcium Phosphate Salts
Chronic p-RfD/MRL
ND
1 mg Al/kg-d
1 mg P/kg-d
ND
Critical effects
ND
Neurobehavioral
effects (changes in
forelimb and hindlimb
strength, increased
foot splay)
Neurobehavioral
effects (reductions
in forelimb and
hindlimb strength
and thermal
sensitivity)
Nephrocalcinosis
ND
Species
ND
Mouse
Rabbit
ND
Duration
ND
During gestation and
lactation and/or
maturity
Conception to
24 mo
8 wk
ND
Route (method)
ND
Oral (diet)
Oral (diet)
ND
Source
NA
U.S. EPA (2006);
Golubetal. (1995):
Golub and
Germann (2001) as
cited in ATSDR
(2008)
U.S. EPA (202Id): (Ritskes-
Hoitinea et al.. 2004)
NA
Donald et al. (1989)
aNo toxicity values were derived for aluminum phosphates due to limitations associated with the available database (data that could not be independently verified,
inadequate information on the content of baseline diets, studies conducted by a laboratory OECD deemed unreliable, and small sample sizes).
bDoses in mg P/kg-day calculated based on the following molecular weights (in g/mol): P = 30.974, DCP = 136.056, and TCP = 310.174.
°Screening-level value.
dA modifying factor of 0.3 was used by ATSDR to account for the higher bioavailability of the aluminum lactate used in the principal study, as compared to
the bioavailability of aluminum in the human diet and drinking water.
DCP = dicalcium phosphate; F = female(s); LOAEL = lowest-observed-adverse-effect level; M = male(s); MF = modifying factor; MRL = minimal risk level; NA = not
applicable; ND = no data; NOAEL = no-observed-adverse-effect level; OECD = Organisation for Economic Co-operation and Development; P = phosphorus;
PND = postnatal day; POD = point of departure; p-RfD = provisional reference dose; TCP = tricalcium phosphate, UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor
55
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Table A-4. Comparison of Effects Following Oral Exposure to Aluminum Phosphates and Candidate Analogues
Target
Organ/System
Aluminum Phosphates
(target)
Aluminum and Compounds
Sodium and Potassium
Phosphate Salts
Calcium Phosphate Salts
Effect (species)ab
Body weight
NOAEL = 2,471 mg basic
SALP/kg-d (320 mg Al/kg-d°); diet
for 28 d (rat IMI). Hicks et al.
(1987)
>130 mg Al/kg-d as aluminum lactate
•I Body-weight gain; diet for 6 wk
(mouse [Golub et al. (1989) as cited
in U.S. EPA (2006)1. rat)
>980 mg P/kg-day as MKP
1 Body weight; diet for 8 wk (rat),
Huttunen et al. (2007) as cited in
U.S. EPA (202Id)
NOAEL = 1,000 mg DCP or
TCP/kg-d (200-230 mg P/kg-dc);
gavage for 28 d or during premating,
mating, gestation, and until LD 4
(rat), NIER (2007) as cited in U.S.
EPA (2021c)
Kidney
>694 mg basic or acidic SALPs/kg-d
(>56 mg Al/kg-d°)
Nephrocalcinosis; diet for 90 d (rat
IFI. ECHA (1972e): doa)1
NOAEL = 284 mg Al/kg-d as
aluminum nitrate; drinking water for
100 d (rat), Domingo et al. (1987) as
>290 mg P/kg-d as MSP dihydrate
Nephrocalcinosis; diet for 4 or
8 wk (rat IFI: rabbit IMI). Ritskes-
Hoitinea et al. (2004)
NOAEL = 1,000 mg DCP or
TCP/kg-d (200-230 mg P/kg-dc);
gavage for 28 d or during premating,
mating, gestation, and until LD 4
(rat), NIER (2007) as cited in U.S.
EPA (2021c)
Neurological
ND
>130 mg Al/kg-d as aluminum lactate
1 Motor activity; diet for 6 wk
(mouse [Golub et al. (1989) as cited
in U.S. EPA (2006)1. rat)
NOAEL = 1,100 mg P/kg-d as
MKP; diet for 14 wk (rat),
Abuduli et al. (2016) as cited in
U.S. EPA (202Id)
NOAEL = 1,000 mg DCP or
TCP/kg-d (200-230 mg P/kg-dc);
gavage for 28 d or during premating,
mating, gestation, and until LD 4
(rat), NIER (2007) as cited in U.S.
EPA (2021c)
Reproductive
NOAEL = 1,000 mg triphosphoric
acid aluminum salt/kg-d (96 mg
Al/kg-d or 330 mg P/kg-d°); gavage
during premating, mating, gestation,
and until LD 4 (rat), Anonymous
(2002) as cited ECHA (2002d)
155 mg Al/kg-d as aluminum lactate
Altered gestational length; diet from
GD 1 to LD 21 (mouse). Donald et al.
(1989)
ND
NOAEL = 1,000 mg DCP or
TCP/kg-d (200-230 mg P/kg-dc);
gavage during premating, mating,
gestation, and until LD 4 (rat), NIER
(2007) as cited in U.S. EPA (2021c)
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Table A-4. Comparison of Effects Following Oral Exposure to Aluminum Phosphates and Candidate Analogues
Target
Organ/System
Aluminum Phosphates
(target)
Aluminum and Compounds
Sodium and Potassium
Phosphate Salts
Calcium Phosphate Salts
Developmental
NOAEL = 1,000 mg triphosphoric
acid aluminum salt/kg-d (96 mg
Al/kg-d or 330 mg P/kg-d°); gavage
during premating, mating, gestation,
and until LD 4 (rat), Anonymous
(2002) as cited in ECHA (2002d)
>100 mg Al/kg-d as aluminum lactate
Neurobehavioral effects; diet during
gestation and lactation and/or
maturity or conception to 24 mo
(mouse, rat). Golub etal. (1995)
ND
NOAEL = 1,000 mg DCP or
TCP/kg-d (200-230 mg P/kg-dc);
gavage during premating, mating,
gestation, and until LD 4 (rat, mouse
rabbit). NIER (2007) as cited in U.S.
EPA (2021c)
aLowest LOAEL or highest NOAEL for effects on the target organ/system; > indicates that other effects were reported at doses equal to or greater than the lowest
LOAEL.
bLists all species in which effects on the target organ/system were observed. The lowest LOAEL corresponds to the first species listed.
Doses in mg P/kg-day or mg Al/kg-day were calculated based on the following molecular weights (in g/mol): A1 = 26.9815, P = 30.974, DCP = 136.056,
TCP = 310.174, and triphosphoric acid aluminum salt = 281.909. Basic SALPs were provided only as trade names (e.g., Kasal™, Kasal™II). Kasal™ is a mixture of
alkaline sodium aluminum phosphate and dibasic sodium phosphate. The A1 content (6-13%) of these basic SALPs was provided in the study report (doses in mg
Al/kg-day could be estimated); however, P content was not provided and could not be reliably determined (doses in mg P/kg-day could not be estimated).
dLOAELs for kidney effects in rats were identified only tentatively. LOAELs are for comparison purposes only; the reported data are not considered a suitable
comparison for quantitative evaluation. There is low confidence in these studies, due to demonstrated poor reliability of the performing laboratory (IBT) and limitations
of the available secondary source.
t = increased; j = decreased; A1 = aluminum; DCP = dicalcium phosphate; DKP = dipotassium phosphate; F = female(s); GD = gestation day; IBT = Industrial Bio-Test
Laboratories, Inc.; LD = lactation day; LOAEL = lowest-observed-adverse-effect level; M = male(s); MKP = monopotassium phosphate; MSP = monosodium
phosphate; ND = not determined; NOAEL = no-observed-adverse-effect level; P = phosphorus; SALP = sodium aluminum phosphate; SHMP = sodium
hexametaphosphate; TCP = tricalcium phosphate.
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The limitations of the available data for aluminum phosphates described in the main
PPRTV assessment text include studies that did not provide data or were available only from
secondary sources (precluding independent review), limited presentation of data (studies in
dogs), and/or absent information on the phosphate and/or calcium content of the baseline diets.
Existing studies of acidic and basic sodium aluminum phosphates (SALPs) are not considered
suitable for quantitative evaluation owing to demonstrated poor reliability of the performing
laboratory and limitations of the available secondary source (see footnote in Table A-4). The
available data for aluminum phosphates identified nephrocalcinosis as a sensitive toxicological
effect (see Table A-4). The same effect was identified for sodium and potassium phosphate salts
but not for the aluminum salts, suggesting that the observed renal toxicity is likely mediated by
the phosphate moiety. There is no evidence for effects attributed to aluminum; however, none of
the studies included a neurotoxicity evaluation. This is identified as a data gap.
Data for other aluminum salts were adequate to evaluate aluminum toxicity following
oral exposure. The database contains five subchronic studies (rats and mice), four developmental
studies in mice, and one multi-generation reproductive study in mice. The most sensitive
toxicological effects identified were neurotoxicity and developmental effects;
neurodevelopmental effects were the critical effects for the derivation of toxicity values
(ATSDR. 2008; U.S. EPA. 2006). These effects were observed consistently in rats and mice.
With respect to the inorganic phosphates, reliable toxicity data for sodium and potassium
phosphate salts (i.e., studies that identified calcium and phosphate levels in the baseline diet)
identified a LOAEL for nephrocalcinosis (the critical effect); this effect was observed in
short-term and subchronic studies of rats and rabbits. Toxicity studies (mostly unpublished) for
calcium phosphate salts included a 28-day repeated-dose study, a reproductive/developmental
screening test, a combined repeated-dose with reproductive/developmental toxicity study, and
developmental toxicity studies, none of which reported any treatment-related effects. A
screening-level toxicity value was derived for calcium phosphate salts based on the absence of
effects.
The available toxicity data are sparse, limiting the conclusions that can be drawn based
on these data. The most sensitive effects associated with exposure to aluminum salts
(neurotoxicity and neurodevelopmental toxicity) were not observed in studies of aluminum
phosphates. This might reflect low uptake and bioavailability of the aluminum moiety from
aluminum phosphates. However, it may also be due to database limitations for aluminum
phosphates, including the lack of available studies of appropriate design to identify these types of
effects and the poor quality of many of the existing studies. The most sensitive effect identified
for sodium and potassium phosphate salts is nephrocalcinosis, which was also the only effect
observed in studies of aluminum phosphate, suggesting that the phosphate moiety is responsible
for the effect. No treatment-related effects, including nephrocalcinosis, were seen in studies of
calcium phosphate salts. This likely reflects the lower uptake and bioavailability of calcium
phosphate salts relative to the sodium and potassium phosphate salts.
Weight-of-Evidence Approach
A tiered WOE approach as described in Wang et al. (2012) and Lizarraga et al. (2023)
was used to select the overall best analogue chemical. The approach focuses on identifying a
preferred candidate for three types of analogues: structural analogues, toxicokinetic or metabolic
analogues, and toxicity-like analogues. Selection of the overall best analogue chemical is then
58
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based on all of the information from the three analogue types, and the following considerations
used in a WOE approach: (1) lines of evidence from the U.S. EPA assessments are preferred;
(2) biological and toxicokinetic data are preferred over the structural similarity comparisons;
(3) lines of evidence that indicate pertinence to humans are preferred; (4) chronic studies are
preferred over subchronic studies when selecting an analogue for a chronic value; (5) chemicals
with more conservative/health-protective toxicity values may be favored; and (6) if there are no
clear indications as to the best analogue chemical based on the other considerations, then the
candidate analogue with the most structural similarity may be preferred.
Water solubility data indicate that aluminum phosphates are less soluble than other
aluminum salts (including aluminum lactate, which serves as the basis for the toxicity values for
aluminum) and also less soluble than sodium and potassium phosphate salts (including MSP,
used to derive the toxicity values for these compounds) and calcium phosphate salts (including
DCP and TCP, used to derive the toxicity values for these compounds). Toxicokinetic data
suggest that absorption from the gastrointestinal tract and bioavailability parallel water solubility.
Therefore, the aluminum moiety from aluminum phosphates is expected to be less bioavailable
than the aluminum moiety from other aluminum salts, and the phosphate moiety from aluminum
phosphates is expected to be less bioavailable than the phosphate moiety from sodium and
potassium phosphate salts, and to a lesser extent, calcium phosphate salts. Data from animal
studies detected little to no accumulation of aluminum in bone following administration of
aluminum phosphates; however, aluminum was found in the bone of animals administered other
aluminum salts (including aluminum lactate). This indicates that aluminum (from aluminum
salts) and sodium and potassium phosphate salts and calcium phosphate salts are all
appropriately conservative analogues for aluminum phosphates based on physicochemical
properties and toxicokinetics (with aluminum and/or sodium and potassium phosphate salts
being more protective choices than calcium phosphate salts).
The available toxicity data provide limited additional information to evaluate the
suitability of the candidate analogues. No effects of aluminum (e.g., neurotoxicity,
neurodevelopmental toxicity) were observed in studies of aluminum phosphates, possibly
reflecting low uptake and bioavailability of the aluminum moiety from aluminum phosphates.
However, this is also possibly due to limitations of the database for aluminum phosphates (lack
of studies designed to identify neurotoxic effects and poor study quality). Nephrocalcinosis was
the only effect observed following exposure to aluminum phosphates and is the most sensitive
effect for sodium and potassium phosphate salts. This commonality in the toxicologically
relevant effect suggests that the phosphate moiety is responsible for the effect. In contrast, no
effects were observed in studies of calcium phosphate salts at doses much higher than that of
sodium and potassium phosphate salts causing nephrocalcinosis, likely reflecting the lower
uptake and bioavailability of calcium phosphate salts relative to the sodium and potassium
phosphate salts, and suggesting that calcium phosphate salts would be a less suitable analogue
for aluminum phosphate.
Taken together, the water solubility, bioavailability, and toxicity data indicate that
aluminum (from aluminum salts) and sodium and potassium phosphate salts are the most suitable
analogues for aluminum phosphates. Although there are toxicity data that indicate that
nephrocalcinosis, likely mediated by the phosphate moiety, was observed following aluminum
phosphate exposure (and no effects attributed to aluminum), the available database for aluminum
phosphates does not adequately evaluate the neurological/neurodevelopmental endpoints
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associated with aluminum toxicity; this deficiency is considered a data gap. To adequately
protect against all of the potential effects mediated by both the aluminum moiety and the
phosphate moiety of aluminum phosphates (and given the data gaps for neurotoxic and
developmental effects), the candidate analogue with the most conservative toxicity value is
selected as the most suitable analogue. The intermediate minimum risk level (MRL)/chronic
provisional reference dose (p-RfD) value of 1 mg Al/kg-day for aluminum compounds (ATSDR.
2008) is lower than the sub chronic p-RfD value of 4 mg P/kg-day for sodium and potassium
phosphate salts (U.S. HP A. 202 Id). However, aluminum phosphate compounds typically contain
more phosphate than aluminum. The molar ratio of aluminum to inorganic phosphate is between
1:1 and 1:3 for most of the included aluminum phosphate salts (and did not exceed 1:4 for any
compound; see Table A-5). Comparing the toxicity values on a molar basis (i.e., 1 mg Al/kg-day
equivalent mol of aluminum to 4 mg P/kg-day equivalent mol of phosphorus) yields a ratio of
1:3.5 aluminum:phosphorus (calculated using molecular weights for aluminum and phosphorus
of 26.982 and 30.974 g/mol, respectively), higher than all but one of the included aluminum
phosphate compounds (AhHisNasCtePs, with ratio of 1:4)). Thus, using aluminum as an
analogue will be more protective. For example, the reference dose (RfD) of 1 mg Al/kg-day is
equivalent to 11.8 mg AlH60i2P3/kg-day (with aluminum to inorganic phosphate molar ratio of
1:3), and the RfD of 4 mg P/kg-day is equivalent to 13.7 mg AlH60i2P3/kg-day.4 Therefore,
selection of aluminum as the analogue is expected to be protective for aluminum phosphate salts
collectively, both for effects of aluminum and effects of inorganic phosphate. Aluminum (from
aluminum salts) is identified as the most appropriate analogue for aluminum phosphates for the
subchronic RfD. Although the chronic RfD of sodium and potassium phosphate salts is 1 mg
P/kg-day (U.S. HP A. 202 Id), which is equivalent to 3.4 mg AlHe.OnP^/kg-day, considering a
much higher water solubility (869 g/L) of the sodium phosphate used to derive the RfD for
sodium and potassium phosphate salts (U.S. HP A. 202 Id) than that of the aluminum lactate
(4.67 g/L) used to derive the RfD for aluminum compounds, the POD based on aluminum
compounds is still expected to be protective for chronic exposure to aluminum phosphate.
Table A-5. Aluminum: Phosphate Molar Ratio of Aluminum Phosphates
and Mixed Sodium Aluminum Phosphates
Compound [synonym]
CASRN
Molecular Formula3
Molar Ratio A1:P
Phosphoric acid, aluminum salt (1:1)
[aluminum phosphate]
7784-30-7
AIO4P
1:1
Metaphosphoric acid (HPO3), aluminum salt (3:1)
[aluminum metaphosphate]
13776-88-0
AIO9P3
1:3
Triphosphoric acid, aluminum salt (1:1)
[aluminum triphosphate]
13939-25-8
AIH2O10P3
1:3
Phosphoric acid, aluminum salt (3:1)
[monoaluminum phosphate; aluminum
dihydrogenphosphate]
13530-50-2
AlHsOizPs
1:3
41 mg Al/kg-day = 317.939 (AIH6O12P3) - 26.981(A1) = 11.8 mg AlHsO^Ps/kg-day.
4 mg P/kg-day = 4 x [317.939 (AIH6O12P3) - (30.974 x 3) (P)] = 13.7 mg AlHsO^Ps/kg-day.
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Table A-5. Aluminum: Phosphate Molar Ratio of Aluminum Phosphates
and Mixed Sodium Aluminum Phosphates
Compound [synonym]
CASRN
Molecular Formula3
Molar Ratio A1:P
Phosphoric acid, aluminum sodium salt (8:3:1),
tetrahydrate
[sodium aluminum phosphate tetrahydrate (SALP)]
10305-76-7
AlsHzzNaCbePs
3:8
Phosphoric acid, aluminum sodium salt (8:2:3)
[sodium aluminum phosphate anhydrous (basic
SALP)]
10279-59-1
AI2H15Na3032P 8
1:4
Phosphoric acid, aluminum sodium salt (1:?:?)
[sodium aluminum phosphate acidic (acidic SALP)]
7785-88-8
Mixture of
Al3H22Na036P8 and
AI2H15Na3C>32P8
NA
Phosphoric acid, aluminum sodium salt (8:3:1)
[trialuminum sodium
tetra- decahydrogenoctaorthophosphate]
15136-87-5
Al3Hi4Na032P8
3:8
aU.S. EPA (2021a).
NA = not applicable; SALP = sodium aluminum phosphate.
ORAL NONCANCER TOXICITY VALUES
Derivation of a Subchronic Screening Provisional Reference Dose
Based on the overall analogue approach presented in this PPRTV assessment, aluminum
was selected as the analogue for aluminum phosphates for derivation of subchronic and chronic
screening p-RfDs. The study used for the U.S. EPA subchronic screening p-RfD value for
aluminum phosphates is a developmental toxicity study of aluminum lactate in mice [Golub and
Germann (2001) as cited in ATSDR (2008)]5. ATSDR (2008) provided the following summary:
Groups of pregnant Swiss Webster mice were exposed to 0, 100, 500, or
1,000 mgAl/kg diet on gestational days 0-21 and during lactation until day 21.
On postnatal day (PND) 21, one male and one female pup from each litter were
placed on the same diet as the dam. The offspring were exposed until PND 35.
The composition of the diet was modifiedfrom the National Research Council's
recommendations; the investigators noted that the nutrients were reduced to
correspond to the usual intake of these nutrients by young women. The average
daily intakes of phosphorus, calcium, magnesium, iron, and zinc in women aged
18-24 years are 83, 56, 71, 69, and 67% of the recommended dietary allowance
(RDA); these per cents were used to modify the recommended dietary intake for
the mice used in this study. Doses of26, 130, and 260 mg Al/kg/day are
calculated by averaging reported estimated doses of 10, 50, and 100 mg Al/kg/day
for adults (i.e., at beginning ofpregnancy) and 42, 210, and 420 mg Al/kg/day
maximal intake during lactation. The doses at lactation were calculated using
doses estimated in previous studies with similar exposure protocols performed by
5Golub MS, Germann SL. 2001. Long-term consequences of developmental exposure to aluminum in a suboptimal
diet for growth and behavior of Swiss Webster mice. Neurotoxicol Teratol 23(4):365-372. (as cited in ATSDR.
20081
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the same group of investigators (Golub et al. 1995). At 3 months of age, the
females were testedfor neurotoxicity using the Morris water maze. At 5 months of
age, males were testedfor motor activity andfunction using rotarod, grip
strength, wire suspension, mesh pole descent, and beam traversal tests.
No alterations in pregnancy weight gain or pup birth weights were
observed. At PND 21, significant decreases in pup body weights were observed at
130 and 260 mg Al/kg/day. No information on maternal weight gain during
lactation was reported; however, the investigators noted that the decrease in pup
weight was not associated with reduced maternal food intake. At PND 35, the
decrease in body weight was statistically significant at 260 mg Al/kg/day. On
PND 90, female mice in the 260 mg Al/kg/day group weighed 15% less than
controls. Decreases in heart and kidney weights were observed at 260 mg
Al/kg/day in the females. Also, increases in absolute brain weight were observed
in females at 26 mg Al/kg/day and relative brain weights were observed at 26 or
260 mg Al/kg/day, but not at 130 mg Al/kg/day. In the males, significant decreases
in body weight were observed at 130 (10%) and 260 (18%) mg Al/kg/day at
5 months; an increase in food intake was also observed at these doses. In the
Morris maze (tested at 3 months in females), fewer animals in the 260 mg
Al/kg/day group had escape latencies of <60 seconds during sessions 13
(learning phase) and a relocation of the visible cues resulted in increased
latencies at 130 and 260 mg Al/kg/day. Body weight did not correlate with latency
to find the platform or with the distribution of quadrant times. The investigators
concluded that controls used salient and/or nonsalient cues, 26 and 130 mg
Al/kg/day animals used both cues, but had difficulty using only one cue, and
260 mg Al/kg/day animals only used the salient cues. In the males tested at
5 months, a significant decrease in hindlimb grip strength was observed at
260 mg Al/kg/day, an increase in the number of rotations on the rotor od as
observed at 260 mg Al/kg/day, and a shorter latency to fall in the wire suspension
test was observed at 130 and 260 mg Al/kg/day. The investigators noted that there
were significant correlations between body weight and grip strength and number
of rotations. When hindlimb grip strength was statistically adjustedfor body
weight, the aluminum-exposed mice were no longer significantly different from
controls; the number of rotations was still significantly different from control
after adjustment for body weight.
The NOAEL of 26 mg Al/kg-day was selected as the point of departure (POD) for
aluminum based on neurobehavioral effects; namely a shorter latency to fall from the wire in
males (wire suspension test) and increased latency to locate the platform following cue
relocation in females (Morris water maze) at 130 mg Al/kg-day (LOAEL). Benchmark dose
(BMD) modeling with Benchmark Dose Software (BMDS; version 3.2) could not be conducted
for latency to fall from the wire because the measure of variance provided in the study
(i.e., standard error of the mean [SEM] or standard deviation [SD]) was not specified. Data for
the change in latency to find the platform were modeled using 1 SD from controls as the
benchmark response (BMR). The constant variance linear model provided an adequate fit to the
data; however, the BMD and the 95% benchmark dose lower confidence limit (BMDL) were
higher than the LOAEL for latency to fall (and were therefore not considered appropriate for use
as the POD). Human equivalent doses (HEDs) were not calculated.
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The intermediate MRL (analogous to a subchronic p-RfD) of 1 mg Al/kg-day was
derived from the NOAEL of 26 mg Al/kg-day using a composite uncertainty factor (UFc) of 100,
reflecting 10-fold uncertainty factors for interspecies extrapolation (UFa) and intraspecies
variability (UFii). ATSDR (2008) also applied a modifying factor (MF) of 0.3:
... to account for possible differences in the bioavailability of the aluminum
lactate used in the Golub and Germann (2001) study and the bioavailability of
aluminum from drinking water and a typical U.S. diet.
No studies were identified that estimated the bioavailability of aluminum
lactate following long-term dietary exposure; however, a bioavailability of 0.63%
was estimated in rabbits receiving a single dose of aluminum lactate (Yokel and
McNamara 1988). Yokel andMcNamara (2001) and Powell and Thompson
(1993) suggested that the bioavailability of aluminum from the typical U.S. diet
was 0.1%; the bioavailability of aluminum from drinking water ranges from
0.07 to 0.39% (Hohl et al. 1994; Priest et al. 1998; Stauber et al. 1999;
Steinhausen et al. 2004). These data suggest that aluminum lactate has a higher
bioavailability than aluminum compounds typically found in drinking water or the
diet.
Wang et al. (2012) indicated that the uncertainty factors typically applied in deriving a
toxicity value for the chemical of concern are the same as those applied to the analogue unless
additional information is available. ATSDR methodology did not include application of a
database uncertainty factor (UFd), so none was assigned in deriving the intermediate oral MRL
for aluminum. Because in the Golub and Germann (2001) as cited in ATSDR (2008) study, the
animals were not only exposed to the aluminum during gestation, but also during lactation,), an
HED for the POD of 26 mg/kg-day was not calculated for the current assessment for aluminum
phosphates, consistent with the U.S. EPA guidelines (U.S. HP A. 2011c). A UFc of 100 was
applied based on a 10-fold UFa and 10-fold UFh. A UFd of 1 was used because the database for
aluminum compounds includes multiple studies identifying neurotoxicity and
neurodevelopmental toxicity as sensitive effects in rodents. Although no studies of aluminum
phosphates specifically evaluated neurological endpoints, an increase in this uncertainty factor
was not considered necessary because the aluminum moiety from aluminum phosphates
(insoluble in water or slightly soluble at low pH, see Table 1) is expected to be less bioavailable
than the aluminum moiety from other aluminum salts (i.e., aluminum lactate used as the basis for
analogue POD is soluble in water and its bioavailability is higher than most of the aluminum
compounds typically found in drinking water or diet).
Subchronic Screening p-RfD = Analogue POD ^ UFc
= 26 mg Al/kg-day -M00
= 3 x 10"1 mg Al/kg-day
Table A-6 summarizes the uncertainty factors for the subchronic screening p-RfD for
aluminum phosphates.
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Table A-6. Uncertainty Factors for the Subchronic Screening p-RfD for
Aluminum Phosphates (Multiple CASRNs)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans when no cross-species dosimetric adjustment (HED calculation) is performed.
UFd
1
A UFd of 1 is applied because neurotoxicity and neurodevelopmental toxicity are well-documented
effects of aluminum compounds in studies of rats and mice following oral exposure. Although none
of the identified studies of aluminum phosphates specifically evaluated neurological endpoints, an
increase in this uncertainty factor was not considered necessary, because the aluminum moiety from
aluminum phosphates is expected to be less bioavailable than the aluminum moiety from other
aluminum salts, which mitigates some of the concern for completeness of the database. In addition,
the POD based on aluminum toxicity is more conservative than the POD based on phosphate.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of aluminum phosphates in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the analogue POD is a NOAEL.
UFS
1
A UFS of 1 is applied because among the available subchronic and developmental studies, a
developmental study is selected as the principal study, and it will be protective against subchronic
systemic toxicity.
UFC
100
Composite UF = UFA x UFH x UFD x UFL x UFS.
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level;
NOAEL= no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty
factor; UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Chronic Screening Provisional Reference Dose
The POD for the subchronic screening p-RfD is also used for derivation of the chronic
screening p-RfD. This POD is further supported by co-principal studies used for the U.S. EPA
screening chronic p-RfD value for aluminum phosphates, which are developmental toxicity
studies of aluminum lactate in mice [Donald et al. (1989) and Golub et al. (1995) as cited in U.S.
EPA (2006)16-7. The PPRTV assessment for aluminum provided the following summary of
Donald et al. (1989) as cited in U.S. EPA (2006):
Groups of 16 pregnant Swiss-Webster mice were fed 25 (control group),
500 or 1000 mgAl/kg diet as aluminum lactate throughout gestation and lactation
(Donald et al., 1989). The control diet was fed to pups that were selectedfor
post-weaning neurobehavioral assessment. Reported maternal doses were 5,
100 and200 mgAl/kg bw-day at the beginning of pregnancy and 10.5, 210 and
420 mgAl/kg bw-day near the end of lactation. No mice were exposed to lactate
6Donald, J.M., M.S. Golub, M.E. Gershwin and C.L. Keen. 1989. Neurobehavioral effects in offspring of mice given
excess aluminum in diet during gestation and lactation. Neurotoxicol. Teratol. 11:345-351. (as cited in U.S. EPA.
20061
7Golub, M.S., B. Han, C.L. Keen, M.E. Gershwin and R.P. Tarara. 1995. Behavioral performance of Swiss-Webster
mice exposed to excess dietary aluminum during development or during development and as adults. Toxicol. Appl.
Pharmacol. 133:64-72. (as cited in U.S. EPA. 20061
64
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alone. There were no treatment-related changes in maternal survival, body weight
(measured on GD 0 and 16 andPDs [postnatal days] 0, 5, 10, 15 and 20), food
intake, toxic signs or neurobehavior (evaluated after pups were weaned at PD 21
using the same test battery used for the pups and described below), or on litter
size or postnatal growth and development in pups as assessed by body weight,
toxic signs on PDs 0-55, and by crown-rump length on PDs 0 and 20.
Neurobehavioral maturation was tested in two pups per litter on PDs 8-18 with a
12-item test battery (fore- and hindlimb grasp, fore- and hindpaw placement on
sticks of 2 widths, vibrissa placing, visual placing, auditory and air puff startle,
eye opening and screen grasp, cling and climb). A neurobehavioral test battery
was administered to six pups per litter at age 25 days (4 days postweaning) or
39 days (fore- and hindlimb grip strengths, temperature sensitivity of tail,
negative geotaxis, startle reflex to air puff and auditory stimuli) or age 21 and
35 days (foot splay). The pre-weaning neurobehavioral testing showed that a
significant (p = 0.007) number of pups in the high dose group had impaired
vertical screen climb performance. The postweaning neurobehavioral assessment
showed significantly (p < 0.05) altered performance on several tests. These
included decreased forelimb grip strength at age 39 days in the low dose group,
increased hindlimb grip strength at age 25 days in both low and high dose
groups, increased foot splay distance at age 21 days in both low and high dose
groups and at age 35 days in the low dose group, and increased forelimb grip
strength at age 25 days and decreased thermal sensitivity at age 25 and 39 days
in the high dose group. There were no treatment-related changes in
concentrations of Al in pup liver or bone (brain tissue was not analyzed).
The study by Golub et al. (1995) as cited in U.S. EPA (2006) was considered an
extension of the study by Donald et al. (1989) as cited in U.S. EPA (2006):
...pregnant female Swiss-Webster mice were exposed continuously to a
semi-purified diet containing 7 (control), 500 or 1000 mg Al/kg from the time of
conception, through pregnancy and lactation (Golub et al., 1995). At weaning,
pups were exposed to the same Al diet as their mothers (500 or 1000 mg Al/kg)
until they were 150-170 days of age or were switched to the control diet (7 mg
Al/kg) for the same time period. Based on reported dosages in previous studies by
the same investigators, estimated daily dosages for mice exposed to 1000 mg
Al/kg diet were as follows: 200 mg/kg-day in pregnant mice, 420 mg/kg-day in
lactating mice and 130 mg/kg-day in offspring (Golub et al., 1994); doses for the
mice exposed to 500 mg Al/kg diet were assumed to be approximately half of that
of mice fed 1000 mg Al/kg, or 100 mg/kg-day in pregnant mice, 210 mg/kg-day in
lactating mice and 65 mg/kg-day in offspring. Compared to the control diet, the
Al diet had no effect on dam weight, gestation length, litter size, pup weight,
offspring growth or organ weights. Operant conditioning (nose poke) of offspring
for delayed spatial alternation or discrimination reversal tasks was initiated at
50 days of age and continued 5 days/week for a total of 35 sessions. A
neurobehavioral test battery was conducted when the offspring were
150-170 days of age (forelimb and hindlimb grip strength, temperature
sensitivity, negative geotaxis, air puff and auditory startle response). Maternal
and pre-weaning exposure to 500 mg Al/kg significantly affected (p < 0.05)
65
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operant training in the offspring, but not performance after training in delayed
spatial alternation or discrimination reversal tasks (i.e., decreased number of
training sessions to achieve the training criteria). This exposure also significantly
decreasedforelimb and hindlimb grip strength and puff startle response
(p < 0.05). Pre-weaning and combined pre- and post-weaning exposure to
1000 mg Al/kg-day significantly increased (p < 0.05) incidence of cagemate
aggression at the time behavioral testing. No effects were observed on auditory
startle response, temperature sensitivity or negative geotaxis in offspring.
Histopathological examination of the brain and spinal cord revealed no
treatment-related changes. Thus, the LOAEL for combined maternal and
pre-weaning exposure on neurobehavioral effects in mice would approximate to
100 mg Al/kg-day (estimated daily maternal dosage).
The LOAEL of 100 mg Al/kg-day was selected as the POD for aluminum based on
neurobehavioral effects (decreased forelimb strength, increased hindlimb grip strength, and
increased hindlimb foot splay distance) in the PPRTV assessment. It was noted in the PPRTV
assessment for aluminum (U.S. EPA. 2006) that the LOAEL was considered minimal because
postweaning neurobehavioral effects were marginal; the toxicological significance of increased
(rather than decreased) hindlimb strength is uncertain, and two of the effects (increased hindlimb
strength and increased foot splay) were observed only transiently (i.e., did not persist 2 weeks
after cessation of exposure).
The LOAEL of 100 mg Al/kg-day based on U.S. EPA (2006) is further supported by
A I'SDR (2008). In addition to the chronic p-RfD for aluminum developed by U.S. EPA (2006).
there is a chronic oral MRL for aluminum from ATS PR (2008). The chronic MRL is also based
on a LOAEL of 100 mg Al/kg-day for neurobehavioral effects (reductions in forelimb strength,
hindlimb strength, and thermal sensitivity) in mice exposed to aluminum as aluminum lactate
from conception until 24 months of age [Golub et al. (2000) as cited in ATS PR (2008)1. BMP
modeling could not be performed for these data because the study used only one aluminum dose
group. Using the LOAEL of 100 mg Al/kg-day and applying a UFc of 300 (10-fold for UFa,
10-fold for UFh, and 3-fold for LOAEL-to-NOAEL uncertainty factor [UFl]) and a MF of
0.3 (owing to the same concerns about bioavailability noted for the subchronic p-RfP) results in
a chronic MRL of 1 mg Al/kg-day (equal to the value of the chronic p-RfP derived by U.S. EPA
(2006).
These LOAELs of 100 mg Al/kg-day based on minimal neurobehavior toxicity identified
in mice exposed to aluminum for up to 24 months [Ponald et al. (1989) as cited in U.S. EPA
(2006)1; Golub et al. (2000) as cited in ATS PR (2008)1 is consistent with the NOAEL of 26 mg
Al/kg-day and LOAEL of 130 mg Al/kg-day based on similar toxicity identified in mice exposed
to aluminum from gestation to postnatal day (PND) 35 [Golub and Germann (2001) as cited in
( A'I'SPR. 2008)1. indicating that there were likely no significant increases in severity of
neurobehavioral toxicity when exposure duration increases.
Therefore, the chronic p-RfP for aluminum phosphate was derived using the NOAEL of
26 mg Al/kg-day using a UFc of 100 based on a 10-fold UFa and a 10-fold UFh. A UFd was not
used because limitations in the database (e.g., lack of chronic data) were considered not to
increase uncertainty in the RfP. (U.S. EPA. 2006). Wang et al. (2012) indicated that the
uncertainty factors typically applied in deriving a toxicity value for the chemical of concern are
66
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EPA/690/R-23/004F
the same as those applied to the analogue unless additional information is available. As discussed
in the section on subchronic RfD derivation above, although neurological endpoints were not
evaluated in studies of aluminum phosphates, an increase in UFd was not considered necessary
because the aluminum moiety from aluminum phosphates is expected to be less bioavailable than
the aluminum moiety from other aluminum salts.
Chronic Screening p-RfD = Analogue POD UFc
= 26 mg Al/kg-day -MOO
= 3 x 10"1 mg Al/kg-day
Table A-7 summarizes the uncertainty factors for the chronic screening p-RfD for
aluminum phosphates.
Table A-7. Uncertainty Factors for the Chronic Screening p-RfD for
Aluminum Phosphates (Multiple CASRNs)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans when no cross-species dosimetric adjustment (HED calculation) is performed.
UFd
1
A UFd of 1 is applied because neurotoxicity and neurodevelopmental toxicity are well-documented
effects of aluminum compounds in studies of rats and mice following oral exposure. Although none
of the identified studies of aluminum phosphates specifically evaluated neurological endpoints, an
increase in this UF was not considered necessary, because the aluminum moiety from aluminum
phosphates is expected to be less bioavailable than the aluminum moiety from other aluminum salts,
which mitigates some of the concern for completeness of the database. In addition, the POD based on
aluminum toxicity is more conservative than the POD based on phosphate.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of aluminum phosphates in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the analogue POD is a NOAEL.
UFS
1
A UFS of 1 is applied because among the available subchronic, chronic, and developmental studies, a
developmental study is selected as the principal study, and the severity of observed toxic effects
doesn't appear to increase when exposure duration increases. Thus, it will be protective against
chronic systemic toxicity.
UFC
100
Composite UF = UFA x UFH x UFD x UFL x UFS.
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; POD = point of departure;
p-RfD = provisional reference dose; UF = uncertainty factor; UFA = interspecies uncertainty factor;
UFc = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFl = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
67
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APPENDIX B. DATA TABLES
Table B-l. Serum Chemistry of Male Sprague Dawley Rats Orally
Administered Sodium Aluminum Phosphates in the Diet for 28 Days3
Endpoint
(units)
Dose Group, mg/kg-db
Control
(0)
Al(OH)s
(1,139)
Kasal™
(2,436)
Kasal™II
(558)
Kasal™II
(2,471)
BUN (mg/dL)
17 ± 2c-d
19 ± 2 (+12%)
22 ± 5 (+29%)
16 + 2 (-6%)
19 + 2 (+12%)
Creatinine (mg/dL)
0.4 ±0.1
0.4 ± 0.1 (+0%)
0.4 ± 0.2 (+0%)
0.5 + 0.1 (+25%)
0.7 + 0.2 (+75%)
ALP (IU/L)
103 ±3
102 ± 21 (-1%)
106 ± 15 (+3%)
101 + 12 (-2%)
112+14 (+9%)
ALT (IU/L)
41 ± 1
31 ±9 (-24%)
40 ± 19 (-2%)
44 + 16 (+7%)
45 + 7 (+10%)
Phosphorus
10.2 ± 1.5
10 ± 1.8 (-2%)
11.7 ±3 (+15%)
9.7+ 1.3 (-5%)
10.9 + 1.4 (+7%)
Sodium (mEq/L)
145 ±2
148 ± 1* (+2%)
149 ± 2* (+3%)
149 ± 1** (+3%)
151 ± 1** (+4%)
Potassium (mEq/L)
5.3 ±0.8
5.3 ± 0.3 (+0%)
6.1 + 0.3 (+15%)
5.8 + 0.8 (+9%)
5.3 + 0.6 (+0%)
Chloride (mEq/L)
105 ± 1
106 ± 1 (+1%)
108 + 3 (+3%)
106 + 2 (+1%)
105 + 2 (+0%)
aHicks et al. (1987).
bDoses correspond to 14,470 ppm Al(OH)3, 30,000 ppm Kasal™, 7,000 ppm Kasal™II, and 30,000 ppm Kasal™II
in the diet, respectively.
Data are means ± SD; n = 5 animals/treatment group.
dValue in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Dunnett's test (p < 0.05), as reported by the study authors.
**Significantly different from control by Dunnett's test (p < 0.01), as reported by the study authors.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; BUN = blood urea nitrogen; SD = standard
deviation.
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Table B-2. Histopathologic Findings in Male Sprague Dawley Rats Orally
Administered Sodium Aluminum Phosphates in the Diet for 28 Days3
Dose (mg/kg-d)b
Control
Al(OH)3
Kasal™
Kasal™II
Kasal™II
Endpoint
(0)
(1,139)
(2,436)
(558)
(2,471)
Heart
Zenker's degeneration2-3
2/5 (40%)°
1/5 (20%)
3/5 (60%)
2/5 (40%)
2/5 (40%)
Lymphocytic inflammation2
1/5 (20%)
NR
NR
1/5 (20%)
1/5 (20%)
Liver
Necrosis1
NR
NR
NR
1/5 (20%)
NR
Kidneys
Cyst0
NR
1/5 (20%)
NR
1/5 (20%)
NR
Cystic change3
1/5 (20%)
NR
NR
NR
NR
Dilation2-3
NR
1/5 (20%)
2/5 (40%)
1/5 (20%)
1/5 (20%)
Dilation with atrophy2
NR
NR
NR
NR
1/5 (20%)
Glomerulonephropathyd-2
NR
NR
NR
NR
1/5 (20%)
Hyaline droplets2-3
NR
3/5 (60%)
NR
2/5 (40%)
NR
Hyperplasia2
1/5 (20%)
NR
2/5 (40%)
1/5 (20%)
1/5 (20%)
Lymphocytic inflammation2-3
1/5 (20%)
NR
NR
NR
1/5 (20%)
Testes
Calcification2
1/5 (20%)
NR
NR
NR
NR
Atrophic degeneration2-3
2/5 (40%)
NR
1/5 (20%)
NR
NR
Edema3
NR
NR
1/5 (20%)
NR
NR
licks et al. (1987).
bDoses correspond to 14,470 ppm Al(OH)3, 30,000 ppm Kasal™, 7,000 ppm Kasal™II, and 30,000 ppm Kasal™II
in diet, respectively.
°Values denote number of animals showing changes/total number of animals examined (% incidence). Statistical
analysis results were not reported.
dReferred to as "membranous glomerulonephropathy" in the study text.
°No grade applicable for endpoint.
Severity of endpoint graded as "slight."
2Severity of endpoint graded as "mild."
2 'Severity of endpoint graded as "mild to moderate."
3Severity of endpoint graded as "moderate."
NR = not reported.
69
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Table B-3. Hematology Results in Male and Female Albino Rats Orally
Administered Sodium Aluminum Phosphates in the Diet for 90 Days3
Endpoint
Males: Dose (mg/kg-d)b
Control
(0)
Kasal™
(1,803.11)
Levair®
(1,909.53)
Levn Lite®
(1,796.95)
Leucocytes (thousands/mm3)
15.9od-e
16 (+1%)
13.4 (-16%)
14.2 (-11%)
Erythrocytes (millions/mm3)
8.08
7.98 (-1%)
8.05 (-0%)
8.23 (+2%)
Hemoglobin (g/100 mL)
15.9
15.7 (-1%)
15.8 (-1%)
16.2 (+2%)
Hematocrit (%)
40.5
39.6 (-2%)
40.1 (-1%)
41 (+1%)
Lymphocytes (cells/100)
86.7
84.1 (-3%)
85.8 (-1%)
83.1 (-4%)
Neutrophils (cells/100)
11.1
12.8 (+15%)
11.5 (+4%)
13.8 (+24%)
Monocytes (cells/100)
1.7
2 (+18%)
2.1 (+24%)
2.1 (+24%)
Eosinophils (cells/100)
0.5
1.1 (+120%)
0.6 (+20%)
1 (+100%)
Basophils (cells/100)
0
0 (+0%)
0 (+0%)
0 (+0%)
Endpoint
Females: Dose (mg/kg-d)
Control
(0)
Kasal™
(2,113.79)
Levair®
(1,988.42)
Levn Lite®
(2,070.10)
Leucocytes (thousands/mm3)
9.9
9.4 (-5%)
8.6 (-13%)
9.2 (-7%)
Erythrocytes (millions/mm3)
7.52
7.59 (+1%)
7.46 (-1%)
7.77 (+3%)
Hemoglobin (g/100 mL)
15.7
15.8 (+1%)
15.6 (-1%)
15.7 (+0%)
Hematocrit (%)
37.9
39.2 (+3%)
38.3 (+1%)
39.3 (+4%)
Lymphocytes (cells/100)
85.5
86.6 (+1%)
84.3 (-1%)
87.1 (+2%)
Neutrophils (cells/100)
12.6
11.3 (-10%)
13.6 (+8%)
11.7 (-7%)
Monocytes (cells/100)
1
1.3 (+30%)
1.5 (+50%)
1 (+0%)
Eosinophils (cells/100)
0.9
0.8 (-11%)
0.6 (-33%)
0.2 (-78%)
Basophils (cells/100)
0
0 (+0%)
0 (+0%)
0 (+0%)
"Anonymous (1972) as cited in ECHA (1972c): Anonymous (1972) as cited inECHA (1972e); Anonymous (1972)
as cited in ECHA (1972:0.
bDoses are equivalent to 3% of the test substances in the diets of male and female rats; measurements were not
performed in low- or mid-dose groups.
Data represent means; measurement of variance was not provided by the study authors; n= 10 animals/sex/dose.
Statistical analysis results were not reported.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
eData from Study Day 84.
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Table B-4. Serum Biochemistry and Select Urinalysis Results in Male and
Female Albino Rats Orally Administered Sodium Aluminum Phosphates in
the Diet for 90 Days3
Endpoint
Males: Dose (mg/kg-d)b
Control
(0)
Kasal™
(1,803.11)
Levair®
(1,909.53)
Levn Lite®
(1,796.95)
ALP (King-Armstrong units)
24c'd'e
19 (-21%)
22 (-8%)
23 (-4%)
ALT (Dade units)
27
27 (+0%)
29 (+7%)
32 (+19%)
BUN (mg%)
15
15 (+0%)
NDr
14 (-7%)
Fasted glucose (mg%)
141
131 (-7%)
NDr
153 (+9%)
Urine pH
6.8
7.4 (+9%)
6.4 (-6%)
6.8 (+0%)
Urine specific gravity
1.039
1.043 (+0%)
1.049 (+1%)
1.053 (+1%)
Endpoint
Females: Dose (mg/kg-d)
Control
(0)
Kasal™
(2,113.79)
Levair®
(1,988.42)
Levn Lite®
(2,070.10)
ALP (King-Armstrong units)
12
17 (+42%)
19 (+58%)
12 (+0%)
ALT (Dade units)
28
25 (-11%)
29 (+4%)
21 (-25%)
BUN (mg%)
14
16 (+14%)
NDr
14 (+0%)
Fasted glucose (mg%)
137
128 (-7%)
NDr
143 (+4%)
Urine pH
6.8
7 (+3%)
6.4 (-6%)
6.6 (-3%)
Urine specific gravity
1.036
1.03 (-1%)
1.03 (-1%)
1.032 (-0%)
"Anonymous (1972) as cited in ECHA (1972c): Anonymous (1972) as cited inECHA (1972e); Anonymous (1972)
as cited in ECHA (1972:0.
bDoses are equivalent to 3% of the test substances in the diets of male and female rats; measurements were not
performed in low or mid-dose groups.
Data represent means; measurement of variance was not provided by the study authors; n= 10 animals/sex/dose.
Statistical analysis results were not reported.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
"Data from Study Day 84.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; BUN = blood urea nitrogen; NDr = not determined.
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Table B-5. Select Organ Weights in Albino Rats Orally Administered
Sodium Aluminum Phosphates in the Diet for 90 Days3
Endpoints
Kasal™ Males: Dose (mg/kg-d)
0
172.66
562.74
1,803.11
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
3.666
0.7019
1.8015
3.755 (+2%)
0.6899 (-2%)
1.7692 (-2%)
3.937 (+7%)
0.7082 (+1%)
1.8755 (+4%)
3.971 (+8%)
0.7308 (+4%)
1.8971 (+5%)
Liver
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
18.14
3.479
8.8872
20.853* (+15%)
3.8236 (+10%)
9.8207 (+11%)
19.431 (+7%)
3.4787 (-0%)
9.2459 (+4%)
18.462 (+2%)
3.3903 (-3%)
8.8323 (-1%)
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
Kasal™ Females: Dose (mg/kg-d)
0
205.62
701.32
2,113.79
2.117
0.6798
1.0695
2.184 (+3%)
0.7212 (+6%)
1.1753 (+10%)
1.993 (-6%)
0.6865 (+1%)
1.0274 (-4%)
2.375 (+12%)
0.7916* (+16%)
1.2197* (+14%)
Liver
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
10.064
3.2526
5.0896
11.633* (+16%)
3.8286** (+18%)
6.2497** (+23%)
9.325 (-7%)
3.2024 (-2%)
4.8121 (-5%)
9.485 (-6%)
3.1562 (-3%)
4.8732 (-4%)
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
Levair® Males: Dose (mg/kg-d)
0
182.57
594.65
1,909.53
3.666
0.7019
1.8015
3.699 (+1%)
0.7104 (+1%)
1.8193 (+1%)
3.636 (-1%)
0.6722 (-4%)
1.7239 (-4%)
3.886 (+6%)
0.723 (+3%)
1.8586 (+3%)
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
Levair® Females: Dose (mg/kg-d)
0
210.09
693.99
1,988.42
2.117
0.6798
1.0695
2.048 (-3%)
0.6596 (-3%)
1.0902 (+2%)
2.157 (+2%)
0.6984 (+3%)
1.109 (+4%)
2.104 (-1%)
0.7153 (+5%)
1.0908 (+2%)
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
Levn Lite® Males: Dose (mg/kg-d)b
0
155.36
545.64
1,796.95
3.666c'd,e
0.7019
1.8015
3.713 (+1%)
0.6364 (-9%)
1.7939 (-0%)
3.739 (+2%)
0.693 (-1%)
1.8148 (+1%)
3.644 (-1%)
0.6812 (-3%)
1.7462 (-3%)
72
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Table B-5. Select Organ Weights in Albino Rats Orally Administered
Sodium Aluminum Phosphates in the Diet for 90 Days3
Kidney
Absolute (g)
Relative to body weight (g/lOOg)
Relative to brain weight (g/g)
Levn Lite® Females: Dose (mg/kg-d)
0
181.18
701.65
2,070.10
2.117
0.6798
1.0695
2.134 (+1%)
0.6686 (-2%)
1.1141 (+4%)
2.067 (-2%)
0.6688 (-2%)
1.1259 (+5%)
2.227 (+5%)
0.7468* (+10%)
1.1639 (+9%)
"Anonymous (1972) as cited in ECHA (1972c): Anonymous (1972) as cited inECHA (1972e); Anonymous (1972)
as cited in ECHA (1972:0.
bDoses are equivalent to dietary concentrations of 0.3, 1.0, and 3%, respectively, for all groups.
Data represent means; measurement of variance was not provided by the study authors; n= 15 animals/sex/dose in
all studies.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
eThe same control data were reported for each compound.
* Statistically different from control (p < 0.05); statistical test not reported by the study authors.
**Statistically different from control (p < 0.01); statistical test not reported by the study authors.
73
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Table B-6. Select Non-neoplastic Lesions of the Kidney in Albino Rats
Orally Administered Sodium Aluminum Phosphates in the Diet for 90 Days3
Kasal™ Males: Dose (mg/kg-d)
Endpoints
0
172.66
562.74
1,803.11
Kidney
Focal lymphoid infiltration
Nephrocalcinosis
Chronic nephritis
Tubular nephrosis
Focal interstitial nephritis
3/10 (30%)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
1/10 (10%)
1/10 (10%)
NR
NR
NR
NR
NR
2/10 (20%)
Kasal™ Females: Dose (mg/kg-d)
Kidney
Focal lymphoid infiltration
Nephrocalcinosis
Chronic nephritis
Tubular nephrosis
Focal interstitial nephritis
0
205.62
701.32
2,113.79
NR
0/10
NR
NR
NR
1/15 (7%)
4/15 (27%)
2/15 (13%)f
NR
NR
2/10 (20%)
3/10 (30%)f
NR
NR
NR
1/10 (10%)
8/10** (80%)f
NR
NR
NR
Levair® Males: Dose (mg/kg-d)
Kidney
Focal lymphoid infiltration
Nephrocalcinosis
Chronic nephritis
Tubular nephrosis
Focal interstitial nephritis
0
182.57
594.65
1,909.53
3/10 (30%)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
1/10 (10%)
NR
NR
NR
NR
NR
1/10 (10%)
Levair® Females: Dose (mg/kg-d)
Kidney
Focal lymphoid infiltration
Nephrocalcinosis
Chronic nephritis
Tubular nephrosis
Focal interstitial nephritis
0
210.09
693.99
1,988.42
NR
NR
NR
NR
NR
1/15 (7%)f
3/15 (20%)
1/15 (7%)
NR
NR
NR
7/10** (70%)
NR
NR
NR
NR
7/10** (70%)
NR
NR
2/10 (20%)
Levn Lite® Males: Dose (mg/kg-d)b
Kidney
Focal lymphoid infiltration
Nephrocalcinosisc
Hydronephrosis
0
155.36
545.64
1,796.95
3/10 (30%)d,e
NR
NR
NR
NR
NR
NR
NR
NR
1/10 (10%)
NR
NR
74
Aluminum phosphate salts
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EPA/690/R-23/004F
Table B-6. Select Non-neoplastic Lesions of the Kidney in Albino Rats
Orally Administered Sodium Aluminum Phosphates in the Diet for 90 Days3
Kidney
Focal lymphoid infiltration
Nephrocalcinosis
Hydronephrosis
Levn Lite® Females: Dose (mg/kg-d)
0
181.18
701.65
2,070.10
NR
NR
NR
1/15 (7%)f
4/15 (27%)
1/15 (7%)
5/10* (50%)f
5/10* (50%)f
NR
1/10 (10%)
9/10** (90%)
NR
"Anonymous (1972) as cited in ECHA (1972c): Anonymous (1972) as cited inECHA (1972e); Anonymous (1972)
as cited in ECHA (1972:0.
bDoses are equivalent to dietary concentrations of 0.3, 1.0, and 3%, respectively, for all groups.
"Nephrocalcinosis referred to as "microconcretions" or "microconcentrations" in study tables; however,
"nephrocalcinosis" was referenced in multiple locations in study texts.
dValues denote number of animals showing changes/total number of animals (% incidence).
"Number of animals examined (n) = 10 for all males and for mid- and high-dose females; n= 15 for low-dose
females.
Severity scored as mild; all other incidences reported were considered minimal to slight.
* Statistically different from control (p < 0.05) by Fischer's exact test (two-tailed) performed for this review. For
statistical analysis, control incidences that were not reported were considered to be 0/10.
**Statistically different from control (p < 0.01) by Fischer's exact test (two-tailed) performed for this review. For
statistical analysis, control incidences that were not reported were considered to be 0/10.
NR = not reported; available data tables presented selected results only.
Table B-7. Body-Weight Gain and Food Consumption in Albino Rats Orally
Administered Sodium Aluminum Phosphates in the Diet for 90 Days3
Endpoints
Levn Lite® Males: Dose (mg/kg-d)b
0
155.36
545.64
1,796.95
Total body-weight gain (g/rat)
337c,d
395 (+17%)
355 (+5%)
355 (+5%)
Total food consumption (g/rat)
2,296
2,318 (+1%)
2,127 (-7%)
2,194 (-4%)
Endpoints
Levn Lite® Females: Dose (mg/kg-d)
0
181.18
701.65
2,070.10
Total body-weight gain (g/rat)
181
162 (-10%)
157 (-13%)
148 (-18%)
Total food consumption (g/rat)
1,705
1,566 (-8%)
1,570 (-8%)
1,680 (-1%)
"Anonymous (1972) as cited in ECHA (1972d).
bDoses are equivalent to dietary concentrations of 0.3, 1.0, and 3%, respectively.
Data represent means; measurement of variance was not provided by the study authors, n = 15/group for
body-weight gain and n = 5/group for food consumption. Statistical analysis results were not reported.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
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Table B-8. Select Histopathologic Changes in the Kidneys of Beagle Dogs
Orally Administered Sodium Aluminum Phosphates
in the Diet for 90 Days3
Kasal™ Males: Dose (mg/kg-d)
Endpoints
0
94.23
322.88
1,107.12
Kidneys
NR
NR
NR
NR
Congestion
NR
NR
NR
2/4 (50%)
Tubular concretions
NR
NR
NR
NR
(total)Minimal or slight
NR
NR
NR
NR
Mild
NR
NR
NR
2/4 (50%)
Moderate
NR
1/4 (25%)
NR
1/4 (25%)
Focal lymphoid infiltration (total)
NR
1/4 (25%)
NR
1/4 (25%)
Minimal or slight
Kasal™ Females: Dose (mg/kg-d)
Kidneys
0
129.31
492.77
1,433.56
Congestion
NR
NR
NR
NR
Tubular concretions (total)
NR
NR
NR
1/4 (25%)
Minimal or slight
NR
NR
NR
NR
Mild
NR
NR
NR
NR
Moderate
NR
NR
NR
1/4 (25%)
Focal lymphoid infiltration
NR
NR
NR
NR
Levn Lite® Males: Dose (mg/kg-d)b
Kidneys
0
94.55
345.21
1,038.77
Congestion
NR°
NR
NR
NR
Tubular concretions
NR
NR
NR
NR
Focal lymphoid infiltration
NR
NR
NR
NR
Levn Lite® Females: Dose (mg/kg-d)
Kidneys
0
118.66
511.06
1,460.76
Congestion (total)
NR
NR
1/4 (25%)
NR
Minimal or slight
NR
NR
1/4 (25%)
NR
Tubular concretions
NR
NR
NR
NR
Focal lymphoid infiltration
NR
NR
NR
NR
"Anonymous (1972) as cited in ECHA (1972a): Anonymous (1972) as cited in ECHA (1972d).
bDoses are equivalent to dietary concentrations of 0.3, 1.0, and 3%, respectively.
°Values denote number of animals showing changes/total number of animals (% incidence). Statistical analysis
results were not reported.
NR = not reported.
76
Aluminum phosphate salts
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Table B-9. Food Consumption in Beagle Dogs Orally Exposed to Sodium
Aluminum Phosphates in the Diet for 6 Months3
Time point
Males: Dose (mg/kg-d)b
0
118
317
1,034
Week 1
230 ± 54c,d
257 ± 67 (+12%)
239 ± 50 (+4%)
186 ± 57 (-19%)
Week 4
345 ± 64
359 ± 105 (+4%)
285 ± 62 (-17%)
303 ± 70 (-12%)
Week 8
355 ±61
345 ± 94 (-3%)
325 ± 87 (-8%)
334 ± 77 (-6%)
Week 12
385 ±83
373 ±31 (-3%)
303 ± 49 (-21%)
332 ± 30 (-14%)
Week 16
405 ± 80
394 ± 99 (-3%)
319 ± 101 (-21%)
331 ±70 (-18%)
Week 20
420 ± 88
361 ± 100 (-14%)
302 ± 73 (-28%)
328 ± 42 (-22%)
Week 24
403 ± 70
344 ± 53 (-15%)
299 ± 90 (-26%)
331 ±74 (-18%)
Week 27
352 ±78
322 ± 62 (-9%)
277 ± 68 (-21%)
316 ±62 (-10%)
Time point
Females: Dose (mg/kg-d)
0
112
361
1,087
Week 1
220 ± 20
232 ± 24 (+5%)
241 ± 57 (+10%)
236 ± 66 (+7%)
Week 4
330 ±37
277 ± 28* (-16%)
284 ± 46 (-14%)
273 ± 22* (-17%)
Week 8
364 ± 75
294 ± 43* (-19%)
278 ± 34* (-24%)
266 ± 18* (-27%)
Week 12
355 ±91
303 ±31 (-15%)
286 ± 49 (-19%)
290 ± 30 (-18%)
Week 16
334 ±68
279 ± 44 (-16%)
261 ± 61 (-22%)
273 ± 24 (-18%)
Week 20
344 ± 83
262 ± 26* (-24%)
280 ± 35 (-19%)
277 ± 30 (-19%)
Week 24
340 ± 56
273 ± 26* (-20%)
265 ± 29* (-22%)
248 ± 19* (-27%)
Week 27
274 ± 82
232 ± 29 (-15%)
223 ± 84 (-19%)
218 ± 14 (-20%)
aKatz et at (1984).
bDoses are equivalent to dietary concentrations of 0.3, 1.0, and 3%, respectively.
Data are means ± SD; n = 6 animals/sex/dose; food consumption reported as g/day.
dValue in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Dunnett's test (p < 0.05), as reported by the study authors.
SD = standard deviation
77
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APPENDIX C. REFERENCES
ACGIH. (2008). Aluminum metal and insoluble compounds. In Documentation of the threshold
limit values and biological exposure indices (7th ed.). Cincinnati, OH.
ACGIH. (2018). 2018 TLVs and BEIs: based on the documentation of the threshold limit values
for chemical substances and physical agents & biological exposure indices. Cincinnati,
OH.
ATSDR. (2008). Toxicological profile for aluminum: Update, 2008.
https://www.atsdr.cdc. gov/ToxProfiies/tp.asp?id=191&tid=34
ATSDR. (2019). Toxic substances portal: Toxicological profiles. Atlanta, GA.
http://www.atsdr.cdc.gov/toxprofiles/index.asp
Bavlor. NW; Egan. W; Richman. P. (2002). Aluminum salts in vaccines—US perspective
[Review], Vaccine 20 Suppl 3: S18-S23. http://dx.doi.org/10.1016/SQ264-
410X702)00166-4
Berthon. G; Davde. S. (1992). Why aluminum phosphate is less toxic than aluminum hydroxide
[Review], J Am Coll Nutr 11: 340-348.
http://dx.doi.org/10.1080/Q7315724.1992.10718236
CalEPA. (2001). Public health goal for aluminum in drinking water. California: Office of
Environmental Health Hazard Assessment, https://oehha.ca.gov/water/public-health-
goal/public-health-goal-aluminum-drinking-water
CalEPA. (2019). OEHHA chemical database. Sacramento, CA: Office of Environmental Health
Hazard Assessment. Retrieved from https://oehha.ca.gov/chemicals
CTD. (2022). Comparative toxicogenomics database [Database]: MDI Biological Laboratory.
Retrieved from http://ctdbase.org/
Davis. AP; Grondin. CJ: Johnson. RJ; Sciakv. D; Wiegers. J; Wiegers. TC; Mattinglv. CJ.
(2021). The comparative toxicogenomics database (CTD): update 2021 [Database]: MDI
Biological Laboratory. NC State University. Retrieved from http://ctdbase.org/
Davde. S; Fitetta. M; Berthon. G. (1990). Aluminum speciation studies in biological fluids. Part
3. Quantitative investigation of aluminum-phosphate complexes and assessment of their
potential significance in vivo. J Inorg Biochem 38: 241-259.
http://dx.doi.org/10.1016/0162-0134(90)84016-1
de Chambrun, GP; Body-Matapet, M; Lrev-Wagner. I; Djouina, M; Deknuydt, F; Atrott, K;
Esquerre. N; Altare. F; Neut. C; Arricta. MC; Kanneganti. TP; Rogler. G; Cotombet. IF;
Cortot. A; Desreumaux. P; Vignal. C. (2014). Aluminum enhances inflammation and
decreases mucosal healing in experimental colitis in mice. Mucosal Immunol 7: 589-601.
http://dx.doi.org/10.1038/mi.2013.78
DOE. (2018). Table 2: Protective Action Criteria (PAC) Rev. 29a based on applicable 60-minute
AEGLs, ERPGs, or TEELs.
https://edms3.energv.gov/pac/docs/Revision 29A Tabte2.pdf
Donald. JM; Golub. MS; Gershwin. ME; Keen. CL. (1989). Neurobehavioral effects in offspring
of mice given excess aluminum in diet during gestation and lactation. Neurotoxicol
Teratol 11: 345-351.
ECHA. (1972a). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 001 key |
experimental result, https://echa.curopa.cu/rcgistration-dossicr - rcgistcrcd-
dossier/15100/7/6/2
78
Aluminum phosphate salts
-------
EPA/690/R-23/004F
ECHA. (1972b). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 005
supporting | experimental result. https://echa.europa.eu/regi stration-dossier/-/registered-
dossier/15100/7/6/2/?documentUUID=5b9572b9-1151-4ac0-9ec6-aab390d9e638
ECHA. (1972c). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 006
supporting | experimental result, https://echa.curopa.cu/rcgistration-dossier/-rcgistcrcd-
dossier/15100/7/6/2/? documentUUID=32810d64-47f4-45bl-883f-67dc5e83be4d
ECHA. (1972d). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 009
supporting | experimental result, https://echa.curopa.cu/rcgistration-dossier/-rcgistcrcd-
dossier/15100/7/6/2/?documentUUID=11449da0-44db-43e7-89cb-34c9d490dla9
ECHA. (1972c). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 01 1
supporting | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15100/7/6/2/?documentUUID=87860a98-f413-47ec-b9e9-3cf3204c7eb8
ECHA. (1972f). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 013
supporting | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15100/7/6/2/?documentUUID=b3e091eb-0653-49f6-b2e4-901403df023d
ECHA. (1973). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 008
supporting | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15 100/7/6/2/? documentUUID=98ab 1 e91 -c7a3-427t'-91 t'c-59t'd4bacc841
ECHA. (1987). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 012
supporting | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15100/7/6/2/?documentUUID=4950dc9f-46e7-4efe-8649-abb08b8b7394
ECHA. (2002a). Aluminium dihydrogen triphosphate: acute toxicity: oral: 002 supporting |
experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/14476/7/3/2/?documentUUID=dlc475bl-9abe-4277-8c83-6448e50c8155
ECHA. (2002b). Aluminium dihydrogen triphosphate: genetic toxicity: in vitro: 003 key |
experimental result, https://ccha.curopa.cu/cs/rcgistration-dossicr/- rcgistcrcd-
dossier/14476/7/7/2/?documentUUID=2dbl00c4-6d66-4c30-b664-2e5aa6a539e0
ECHA. (2002c). Aluminium dihydrogen triphosphate: mammalian cell chromosome aberration:
005 supporting | experimental result, https://echa.europa.eu/es/registration-dossier/-
/registered-dossier/14476/7/7/2/?documentUUID=e4610d4f-895c-47e0-a7b5-
d6c4 Ib2t'a719
ECHA. (2002d). Aluminium tris(dihydrogen phosphate): repeated dose toxicity: oral: 014
supporting | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15100/7/6/2/? documentUUID=2b26«6d-5e46-442d-be9a-6aafdaff5494
ECHA. (2002e). Aluminium tris(dihydrogen phosphate): Toxicity to reproduction: 002 weight of
evidence | experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15100/7/9/2/?documentUUID=18659f83-f84c-40c7-ac3d-0f7al3bla8ff
ECHA. (2010a). Aluminium orthophosphate: acute toxicity oral.
https://echa.europa.eu/regi stration-dossier/-/registered-dossier/l 5223/7/3/2
ECHA. (2010b). Aluminium orthophosphate: eye irritation: 001 weight of evidence |
experimental result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15223/7/4/3
ECHA. (2010c). Aluminium orthophosphate: genetic toxicity: in vitro: 001 key | experimental
result, https://ccha.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/15223/7/7/2/?documentUUID=3aa7688f-9b99-4bd6-a534-b227e9acab51
79
Aluminum phosphate salts
-------
EPA/690/R-23/004F
ECHA. (2010d). Aluminium orthophosphate: skin irritation/corrosion: 001 weight of evidence
experimental result. https://echa.europa.eu/regi stration-dossier/-/registered-
dossier/15223/7/4/2
ECHA. (2010e). Aluminium tris(dihydrogen phosphate): genetic toxicity: in vitro: 001 key |
experimental result. https://echa.europa.eu/regi stration-dossier/-/registered-
dossier/15100/7/7/2
ECHA. (201 Of). Aluminium tris(dihydrogen phosphate): genetic toxicity: in vitro: 002 key |
experimental result, https://echa.curopa.cu/es/registration-dossicr- registered-
dossier/ 15 1 OO/7/7/2'.'documentUUlI) c6ea2c78-5c0t-41 fd-8e 16-t'1 a7ddfc99af
ECHA. (2010g). Aluminium tris(dihydrogen phosphate): genetic toxicity: in vitro: 003 key |
experimental result, https://echa.curopa.cu/es/rcgistration-dossicr - rcgistcrcd-
dossier/15 100/7/7/2/? documentUUID=9cfa 1 e21 -752f-46c3 -93 ed-691617a 1 Obcc
ECHA. (2012a). Aluminium dihydrogen triphosphate: acute toxicity: oral: 001 key |
experimental result, https://echa.curopa.cu/rcgistration-dossicr/- rcgistcrcd-
dossier/14476/7/3/2
ECHA. (2012b). Aluminium dihydrogen triphosphate: eye irritation: 001 key | experimental
result, https://echa.europa.eu/registration-dossier/-/registered-dossier/14476/7/4/3
ECHA. (2013). Aluminium metaphosphate: acute toxicity: oral.
https://echa.europa.eu/regi stration-dossier/-/registered-dossier/5484/7/3/2
ECHA. (2014a). Aluminium metaphosphate: eye irritation, https://echa.curopa.eu/registration-
dossi cr-rcgi stcrcd-dossi er/5484/7/4/3
ECHA. (2014b). Aluminium metaphosphate: skin irritati on/corrosi on.
https://echa.europa.eu/regi stration-dossier/-/registered-dossier/5484/7/4/2
ECHA. (2015a). Aluminium metaphosphate: genetic toxicity: in vitro: 001 key | experimental
result, https://echa.europa.eu/registration-dossier/-/registered-dossier/5484/7/7/2
ECHA. (2015b). Aluminium metaphosphate: genetic toxicity: in vitro: 002 key | experimental
result. https://echa.europa.eu/es/registration-dossier/-/registered-
dossier/5484/7/7/2/?documentUUID=889f0a84-29bf-4c0a-92d4-76683f497e4f
ECHA. (2016). Aluminium metaphosphate: genetic toxicity: in vitro: 003 key | experimental
result. https://echa.curopa.cu/es rcgistration-dossicr/-/rcgistcrcd-
dossier/5484/7/7/2/?documentUUID=b53baea8-be8f-45be-a501-659edcf8e04d
ECHA. (2019a). Registration dossier: Aluminium dihydrogen triphosphate. CAS number:
13939-25-8. https://echa.curopa.cu/rcgistration-dossicr/- rcgistcrcd-dossicr/14476
ECHA. (2019b). Registration dossier: Aluminium orthophosphate: CAS number: 7784-30-7.
https://echa.curopa.cu/rcgistration-dossicr/-rcgistcrcd-dossicr/15223
ECHA. (2019c). Registration dossier: Aluminium tris(dihydrogen phosphate). CAS number:
13530-50-2. https://echa.curopa.cu/rcgistration-dossier/- rcgistcrcd-dossier/15 100
ECHA. (2019d). Registration dossier: Aluminum metaphosphate. CAS number: 13776-88-0.
https://echa.curopa.cu/rcgistration-dossier/-rcgistcrcd-dossier/5484
ECHA. (2019e). Substance information: Phosphoric acid, aluminium sodium salt.
https://echa.curopa.cu/substance-intbrmation/-substanccintb/100.029.173
ECHA. (2019f). Substance information: Trialuminium sodium
tetradecahydrogenoctaorthophosphate. https://echa.curopa.cu/substance-intbrmation -
/substanceinfo/100.035.619
80
Aluminum phosphate salts
-------
EPA/690/R-23/004F
EU. (2012). Regulations: Commission Regulation (EU) No 231/2012 of 9 March 2012: Laying
down specifications for food additives listed In Annexes II and III to regulation (EC) No
1333/2008 of the European Parliament and of the Council. Official Journal of the
European Union 22: 83/81-83/295.
FDA. (1975). Evaluation of the health aspects of aluminum compounds as food ingredients.
(FDA/BF-77/24). Bethesda, MD: Food and Drug Administration.
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchQuerv=PB262655
FDA. (2020a). Antacid products for over-the-counter (OTC) human use. Subpart A -General
provisions. Code of Federal Regulations. (21 CFR 331.11).
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=331
&showFR=l
FDA. (2020b). General biological products standards. Subpart B - general provisions. Code of
Federal Regulations. (21 CFR 610.15).
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm7fF610.15
Gilmour. RB. (2019). Phosphoric acids and phosphates. In Kirk-Othmer encyclopedia of
chemical technology. Hoboken, NJ: John Wiley & Sons, Inc.
http://dx.doi.org/10.1002/0471238961.16081519070118Q4.a01.pub3
Golub. MS; Han. B; Keen. CI.; Gershwin. ME; Tarara. RP. (1995). Behavioral performance of
Swiss Webster mice exposed to excess dietary aluminum during development or during
development and as adults. Toxicol Appl Pharmacol 133: 64-72.
http://dx.doi.Org/10.1006/taap.1995.l 127
Greger. JL. (1993). Aluminum metabolism [Review], Annu RevNutr 13: 43-63.
http://dx.doi.Org/10.l 146/annurev.nu. 13.070193.0003 55
Greger. JL; Sutherland. JE; Yokel. R. (1997). Aluminum exposure and metabolism [Review],
Crit Rev Clin Lab Sci 34: 439-474. http://dx.doi.org/10.3109/104083697090Q6422
Hicks. JS; Hackett. DS; Sprague. GL. (1987). Toxicity and aluminium concentration in bone
following dietary administration of two sodium aluminium phosphate formulations in
rats. Food Chem Toxicol 25: 533-538. http://dx.doi.org/10.1016/0278-6915(87)90205-5
IARC. (2019). Agents classified by the I ARC monographs. Lyon, France.
http://monographs.iarc.fr/ENG/Classification/List of Classifications.pdf
IOM. (1997). Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and
fluoride. Washington, DC: National Academy Press.
http://www.nap.edu/catalog.php7record id 5776
IOM. (2003). Sodium aluminum phosphate [acidic and basic]. In Food chemicals codex (5th
ed.). Washington, DC: National Academies Press.
https://www.nap.edu/catalog/10731/food-chemicals-codex-fifth-edition
IPCS. (2019). INCHEM: Chemical safety information from intergovernmental organizations
[Database], Geneva, Switzerland: World Health Organization, Canadian Centre for
Occupational Health and Safety. Inter-Organization Programme for the Sound
Management of Chemicals. Retrieved from http://www.inchem.org/
Je. S; Ouan. H; Na. Y; Cho. SN; Kim. BJ; Seok. SH. (2016). An in vitro model of granuloma-
like cell aggregates substantiates early host immune responses against Mycobacterium
massiliense infection. Biol Open 5: 1118-1127. http://dx.doi.org/10.1242/bio.019315
Kaehnv. WD; Hegg. AP; Alfrev. AC. (1977). Gastrointestinal absorption of aluminum from
aluminum-containing antacids. N Engl J Med 296: 1389-1390.
http://dx.doi.org/10.1056/NEJM197706162962407
81
Aluminum phosphate salts
-------
EPA/690/R-23/004F
Kanematsu- N; Hara. M; Kada. T. (1980). Rec assay and mutagenicity studies on metal
compounds. Mutat Res 77: 109-116. http://dx.doi.org/10.1016/0165-1218(80)90127-5
Katz. AC; Frank. DW; Sauerhoff. MW; Zwicker. GM; Freudenthai. RI. (1984). A 6-month
dietary toxicity study of acidic sodium aluminium phosphate in beagle dogs. Food Chem
Toxicol 22: 7-9. http://dx.doi.org/10.1016/0278-6915(84)90045-0
Larranaga. MP; Lewis. RJ; Lewis. RA. (2016). Hawley's condensed chemical dictionary (16th
ed.). Hoboken, NJ: John Wiley & Sons. http://dx.doi.org/10.10Q2/9781119312468
Lizarraga. LE; Suter. GW; Lambert. JC; Patlewicz. G; Zhao. JQ; Dean. JL; Kaiser. P. (2023).
Advancing the science of a read-across framework for evaluation of data-poor chemicals
incorporating systematic and new approach methods. Regul Toxicol Pharmacol 137:
105293. http://dx.doi.org/10.1016/i.vrtph.2022.105293
Martin. RB. (1986). The chemistry of aluminum as related to biology and medicine [Reviewl.
Clin Chem 32: 1797-1806.
NIOSH. (2018). NIOSH pocket guide to chemical hazards. Index of chemical abstracts service
registry numbers (CAS No.). Atlanta, GA. http://www.cdc.gov/niosh/npg/npgdcas.html
NLM. (2021a). Chem 1 Dpi us advanced. Available online at
https://chem.nlm.nih.gov/chemidplus/
NLM. (2021b). Hazardous substances data bank [Database], Bethesda, MD. Retrieved from
https://www.nlm.nih.gov/databases/download/hsdb.html
NTP. (2016). 14th Report on carcinogens. Research Triangle Park, NC.
https://ntp.niehs.nih.gov/pubhealth/roc/index-l.html
OECD. (2019). Manual for the assessment of chemicals, http://www.oecd.org/env/ehs/risk-
asscssmcnt, manualforthcasscssmcntofchcmicals.htm
OECD. (2021). The OECD QSAR toolbox [version 4.5], Retrieved from
http://www.oecd.org/chemicalsafetv/risk-assessment/oecd-qsar-toolbox.htm
OSHA. (2018a). Air contaminants: Occupational safety and health standards for shipyard
employment, Subpart Z, toxic and hazardous substances. (OSHA Standard 1915.1000).
Washington, DC: U.S. Department of Labor.
https://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p
id10286
OSHA. (2018b). Safety and health regulations for construction: Occupational health and
environmental controls: Gases, vapors, fumes, dusts, and mists: Appendix A. Available
online at https://www.osha.gov/laws-
regs/regulations/standardnumber/1926/1926.55AppA (accessed June 6, 2019).
OSHA. (2018c). Table Z-l: Limits for air contaminants. Occupational safety and health
standards, Subpart Z, toxic and hazardous substances. Available online at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p
id=9992 (accessed June 6, 2019).
Owen, LM; Crews, HM; Bishop, NJ; Massey, RC. (1994). Aluminium uptake from some foods
by guinea pigs and the characterization of aluminium in in vivo intestinal digesta by
SEC-ICP-MS. Food Chem Toxicol 32: 697-705. http://dx.doi.org/10.1016/SQ278-
6915(09)80002-1
Parente, F; Porro, GB; Canali. A; Bensi. G. (1995). Double-blind randomized, multicenter study
comparing aluminium phosphate gel with rantitidine in the short-term treatment of
duodenal ulcer. Hepatogastroenterology 42: 95-99.
82
Aluminum phosphate salts
-------
EPA/690/R-23/004F
Pettersen. JC; Hackett DS; Zwicker. GM; Sprague. GL. (1990). Twenty-six week toxicity study
with KASAL (basic sodium aluminum phosphate) in beagle dogs. Environ Geochem
Health 12: 121-123. http://dx.doi.org/10.1007/BF01734Q61
Ritskes-Hoitinga. J; Grooten. UNA; Wienk. KJH; Peters. M; I .emmens. AG; Bevnen. AC.
(2004). Lowering dietary phosphorus concentrations reduces kidney calcification, but
does not adversely affect growth, mineral metabolism, and bone development in growing
rabbits. Br JNutr 91: 367-376.
Salisbury. B; Terrell JM. (2020). Antacids. In StatPearls. Treasure Island, FL: StatPearls
Publishing. https://www.ncbi.nlm.nih.gov/books/NBK526049/
Schaeffer. G; Pontes. G; Le Breton. E; Oberling. C; Thivotte. L. (1928). The dangers of certain
mineral baking-powders based on alum, when used for human nutrition. J Hyg 28: 92-99.
http://dx.doi.org/10.1017/s002217240000943 8
Schrodter. K; Be nermann. G; Staffel. T; Wahl. F; Klein. T; Hofmann. T. (2012). Phosphoric acid
and phosphates. In B Elvers (Ed.), Ullmann's encyclopedia of industrial chemistry (7th
ed.). Hoboken, NJ: Wiley-VCH Verlag GmbH & Co.
Spencer. H; Lender. M. (1979). Adverse effects of aluminum-containing antacids on mineral
metabolism. Gastroenterology 76: 603-606.
U.S. APHC. (2013). Environmental health risk assessment and chemical exposure guidelines for
deployed military personnel. (Technical guide 230, 2013 revision). Aberdeen Proving
Ground, MD. https://phc.amedd.armv.mil/PHC%20Resource%20Librarv/TG230-
DeplovmentEHRA-and-MEGs-2013 -Revision.pdf
U.S. EPA. (1978). Proposed guidelines for registering pesticides in the United States; hazard
evaluation: humans and domestic animals. Fed Reg 43: 37335-37402.
U.S. EPA. (2002). A review of the reference dose and reference concentration processes [EPA
Report], (EPA630P02002F). Washington, DC.
https://www.epa.gov/sites/production/files/2014-12/documents/rfd-final.pdf
U.S. EPA. (2005). Guidelines for carcinogen risk assessment [EPA Report], (EPA630P0300IF).
Washington, DC. https://www.epa.gov/sites/production/files/2013-
09/documcnts cancer guidelines final 3-25-05.pdf
U.S. EPA. (2006). Provisional peer reviewed toxicity values for aluminum (CASRN 7429-90-5)
[EPA Report], Cincinnati, OH.
https://cfpub.epa.gov/ncea/pprtv/documents/Aluminum.pdf
U.S. EPA. (2011a). Chemical assessment clustering engine (ChemACE). Retrieved from
https://www.epa.gov/tsca-screening-tools/chemical-assessment-clustering-engine-
chemace
U.S. EPA. (2011b). Health effects assessment summary tables (HEAST) for superfund [EPA
Report], Washington, DC. https://epa-heast.ornl.gov/heast.php
U.S. EPA. (2011c). Recommended use of body weight 3/4 as the default method in derivation of
the oral reference dose. (EPA100R110001). Washington, DC.
https://www.epa.gov/sites/production/fiies/2013-09/documents/recommended-use-of-
bw34.pdf
U.S. HP A. (2015). ACToR: Aluminum phosphate (A1(H2P04)3) [Fact Sheet], Washington, DC.
https://actor.epa.gov actor chemical.xhtmr'casrn 13530-50-2
U.S. EPA. (2018). 2018 Edition of the drinking water standards and health advisories tables
[EPA Report], (EPA822F18001). Washington, DC: U.S. Environmental Protection
Agency, Office of Water, https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P100U7U8.txt
83
Aluminum phosphate salts
-------
EPA/690/R-23/004F
U.S. EPA. (2019). Integrated Risk Information System. IRIS Assessments [Database],
Washington, DC. Retrieved from http://www.epa.gov/iris/
U.S. EPA. (2021a). CompTox chemicals dashboard. Washington, DC. Retrieved from
https://comptox.epa.gov/dashboard
U.S. EPA. (2021b). Provisional peer-reviewed toxicity values for ammonium salts of inorganic
phosphates: Monoammonium phosphate (MAP) (CASRN 7722-76-1), diammonium
phosphate (DAP) (CASRN 7783-28-0) [EPA Report], (EPA/690/R-21/007F). Cincinnati,
OH: U.S. Environmental Protection Agency, Office of Research and Development,
Center for Public Health and Environmental Assessment.
https://cfpub. epa.gov/ncea/pprtv/recordisplav. cfm?deid=3 52926
U.S. EPA. (2021c). Provisional peer-re vie wed toxicity values for calcium salts of inorganic
phosphates (multiple CASRNs) [EPA Report], (EPA/690/R-21/009F). Cincinnati, OH:
U.S. Environmental Protection Agency, Office of Research and Development, Center for
Public Health and Environmental Assessment.
https://cfpub.epa.gov/si/si public record Report.cfm'MirHntrvkl 352930ŁI.abCPHHA
U.S. EPA. (202Id). Provisional peer-reviewed toxicity values for sodium and potassium salts of
inorganic phosphates (multiple CASRNs) [draft] [EPA Report],
U.S. EPA. (202le). TSCA chemical substance inventory. Download the non-confidential TSCA
inventory. Available online at https://www.epa.gov/tsca-inventorv/how-access-tsca-
inventorv
Wang. NC; Zhao. OJ: Wesselkampcr. SC; I .ambert. JC; Petersen. D; Hess-Wiison. JK. (2012).
Application of computational toxicological approaches in human health risk assessment.
I. A tiered surrogate approach. Regul Toxicol Pharmacol 63: 10-19.
http://dx.doi.Org/10.1016/i.vrtph.2012.02.006
Weiner. ML; Salminen. WF; I .arson. PR; Barter. RA; Kranetz. JL; Simon. GS. (2001).
Toxicological review of inorganic phosphates [Review], Food Chem Toxicol 39: 759-
786. http://dx.doi.org/10.1016/S0278-6915(01 )00028-X
WHO. (1982). Phosphoric acid and phosphate salts. In Toxicological evaluation of certain food
additives and contaminants. (WHO Food Additive Series 17). Geneva, Switzerland:
International Programme on Chemical Safety.
Willhite. ('('; Karvakina. NA; Yokel. RA; Yenugadhati. N; Wisniewski. I'M; Arnold. IM;
Momoli. F; Krewski. D. (2014). Systematic review of potential health risks posed by
pharmaceutical, occupational and consumer exposures to metallic and nanoscale
aluminum, aluminum oxides, aluminum hydroxide and its soluble salts [Review], Crit
Rev Toxicol 44 Suppl 4: 1-80. http://dx.doi.org/10.3109/10408444.2Q14.934439
Yokel. RA; Florence. RL. (2006). Aluminum bioavailability from the approved food additive
leavening agent acidic sodium aluminum phosphate, incorporated into a baked good, is
lower than from water. Toxicology 227: 86-93.
http://dx.doi.Org/10.1016/i.tox.2006.07.014
Yokel. RA; Hicks. CI,; Florence. RL. (2008). Aluminum bioavailability from basic sodium
aluminum phosphate, an approved food additive emulsifying agent, incorporated in
cheese. Food Chem Toxicol 46: 2261-2266. http://dx.doi.Org/10.1016/i.fct.2008.03.004
Yokel. R A; McNamara. PJ. (1988). Influence of renal impairment, chemical form, and serum
protein binding on intravenous and oral aluminum kinetics in the rabbit. Toxicol Appl
Pharmacol 95: 32-43.
84
Aluminum phosphate salts
-------
EPA/690/R-23/004F
Yokel RA; McNamara. PJ. (2001). Aluminium toxicokinetics: an updated mini review
[Review], Basic Clin Pharmacol Toxicol 88: 159-167. http://dx.doi.org/10.111 l/i.1600-
0773.2001.880401.x
Yokel RA; Urbas. AA; I .odder. RA; Setegue. JP; Florence. RL. (2005). Al-26-containing acidic
and basic sodium aluminum phosphate preparation and use in studies of oral aluminum
bioavailability from foods utilizing Al-26 as an aluminum tracer. Nucl Instrum Methods
Phys Res B 229: 471-478. http://dx.doi.Org/10.1016/i.nimb.2004.12.130
Younes. M; Aggett. P; Aguilar. F; Crebetti. R; Dusemund. B; Filipic. M; Frutos. MJ; Galtier. P;
Gott. D; Gundert-Remv. U; Kuhnle. GG; Lambre. C; Leblanc. JC; Littegaard. IT;
Moldeus. P; Mortensen. A; Oskarsson. A; Stankovic. I; Waatkens-Berendsen. I; Wright.
M. (2018). Re-evaluation of aluminium sulphates (E 520-523) and sodium aluminium
phosphate (E 541) as food additives. EFSA J 16: 5372.
http://dx.doi.Org/10.2903/i.efsa.2018.5372
85
Aluminum phosphate salts
------- |