United States
Environmental Protection
1=1 m m Agency
EPA/690/R-16/012F
Final
9-02-2016
Provisional Peer-Reviewed Toxicity Values for
Rubidium Compounds
(CASRN 7440-17-7, Rubidium)
(CASRN 7791-11-9, Rubidium Chloride)
(CASRN 1310-82-3, Rubidium Hydroxide)
(CASRN 7790-29-6, Rubidium Iodide)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGERS
Puttappa R. Dodmane, BVSc&AH, MVSc, PhD
National Center for Environmental Assessment, Cincinnati, OH
Scott C. Wesselkamper, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWER
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this PPRTV assessment should be directed to the EPA Office
of Research and Development's National Center for Environmental Assessment, Superfund
Health Risk Technical Support Center (513-569-7300).
li
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	6
HUMAN STUDIES	14
Oral Exposures	14
Inhalation Exposures	17
ANIMAL STUDIES	17
Oral Exposure	17
Inhalation Exposures	21
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	21
Tests Evaluating Genotoxicity and/or Mutagenicity	21
Other Supporting Human Studies	21
Supporting Animal Toxicity Studies	21
Metabolism/Toxicokinetic Studies	23
Mode-of-Action/Mechanistic Studies	23
DERIVATION 01 PROVISIONAL VALUES	24
DERIVATION OF ORAL REFERENCE DOSES	24
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	26
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	26
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	27
Derivation of a Provisional Oral Slope Factor (p-OSF)	27
Derivation of a Provisional Inhalation Unit Risk (p-IUR)	27
APPENDIX A. SCREENING PROVISIONAL VALUES	28
APPENDIX B. REFERENCES	32
in
Rubidium Compounds

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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere

Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute

Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD

Number
QSAR
quantitative structure-activity
CBI
covalent binding index

relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day

known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase

known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
RUBIDIUM CHLORIDE (CASRN 7791-11-9)
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 Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
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.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse 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 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. Environmental Protection Agency (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 EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Rubidium (Rb; atomic symbol) is a metallic element that has two naturally occurring
isotopes: 85Rb (72.15%) and the radioactive 87Rb (27.85%). There are no minerals in which
rubidium is the primary element; however, it is found naturally within the Earth's crust in trace
amounts in the rock-forming silicate minerals, such as potassium feldspars and micas. These
minerals must be chemically reduced to produce pure rubidium metal (Wagner. 2011).
Rubidium metal is used in atomic clocks and global positioning systems (GPS) as an atomic
resonance frequency standard (Wagner. 2011). The radioactive decay of 87Rb to 87Sr (half-life of
4.9 x 1010 years), resulting in the emission of a negative beta particle, is used in radiometric
dating of some rocks and minerals (Wagner, 2011). Rubidium metal is also used as a reagent in
making zeolite catalysts and in photoelectric cells. Additionally, it can be used as an
intermediate for preparing rubidium salts (O'Neil. 2006).
Rubidium is a soft, ductile, silvery-white metal, which, due to its low melting point of
39°C, may also be a liquid at higher ambient temperatures (Wagner. 2011). Rubidium metal
reacts violently with water in an exothermic reaction that produces hydrogen gas. If this reaction
occurs in the presence of oxygen or air, a spontaneous explosion will result (Wagner. 2011). In
addition, rubidium ignites in oxygen, burning with a characteristic red-violet flame (O'Neil.
2006). The U.S. Department of Transportation (DOT) classification code for shipping rubidium
is Label 4.3 Dangerous When Wet (Wagner. 2011).
Rubidium chloride, rubidium hydroxide, and rubidium iodide are water soluble. These
compounds have several established therapeutic applications. For example, rubidium chloride
has been used as an antidepressant (O'Neil. 2006) and rubidium iodide has been used as an
iodine source for the treatment of goiter (Wagner. 2011). Rubidium compounds are also used in
scientific research. For instance, rubidium hydroxide and rubidium chloride are catalysts used in
chemical syntheses (O'Neil. 2006).
Rubidium chloride, rubidium hydroxide, and rubidium iodide are all solids at room
temperature. Because these compounds are hygroscopic (i.e., absorb water from air), they are
generally stored and shipped in tightly sealed containers (Wagner, 2011). Rubidium iodide will
discolor when exposed to light or air (O'Neil. 2006) and emit toxic vapors when heated (Wagner.
2011). As salts (rubidium chloride and rubidium iodide) or alkali (rubidium hydroxide) will
exist as ions in the environment and, therefore, are not expected to volatilize from either water or
soil. However, due to their high water solubility, they are expected to leach readily from soil to
groundwater. The empirical formulas for rubidium chloride, rubidium hydroxide, and rubidium
iodide are RbCl, Rb(OH), and Rbl, respectively (see Figure 1). A table of physicochemical
properties for rubidium and selected rubidium compounds for which any toxicity data could be
located is provided below (see Table 1).
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Rb CI
A
Rb+ I
c
Figure 1. Structures of Rubidium Salts and Alkali:
(A) rubidium chloride, (B) rubidium hydroxide, and (C) rubidium iodide
Table 1. Physicochemical Properties of Rubidium, Rubidium Chloride, Rubidium
Hydroxide, and Rubidium Iodide
Property
(unit)
Rubidium
7440-17-7
Rubidium Chloride
7791-11-9
Rubidium Hydroxide
1310-82-3
Rubidium Iodide
7790-29-6
Physical state
Soft, ductile,
silvery-white solid, but
can be a liquid at
higher ambient
temperatures3
White crystalline
powderb
Grayish-white
deliquescent massb
White crystals or
crystalline powder that
discolors on exposure
to air or lightb
Boiling point
(°C)
689a
l,390a
ND
l,300a
Melting point
(°C)
39a
715a
30 la
642a
Density
(g/cm3)
1.522 (solid, 18°C),
1.472 (liquid, 39°C)a
2.76b
3.203b
3.55b
Vapor pressure
(mm Hg at
25°C)
ND
ND
ND
ND
Solubility in
water
Reacts violently3
139 g/100 mL at 100°C;
77 g/100 mL at 0°Ca
180 g/100 mL at 15°Ca
163 g/100 mL at 25°C;
152 g/100 mL at 15°Ca
Relative vapor
density
(air = 1)
ND
ND
ND
ND
Atomic/
molecular
weight (g/mol)
85.4678b
120.92b
102.48b
212.37b
a Wagner (201D.
hO'N'eil (2006).
ND = no data.
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A summary of available toxicity values for rubidium and selected rubidium compounds
from U.S. EPA and other agencies/organizations is provided in Table 2.
Table 2. Summary of Available Toxicity Values for Rubidium, Rubidium Chloride,
Rubidium Hydroxide, and Rubidium Iodide
Source3
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2016)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012)
ATSDR
NV
NA
ATSDR (2016)
IPCS
NV
NA
IPCS (2016):WHO (2016)
Cal/EPA
NV
NA
Cal/EPA (2014); Cal/EPA (2016a): Cal/EPA (2016b)
OSHA
NV
NA
OSHA (2006); OSHA (2011)
NIOSH
NV
NA
NIOSH (2016)
ACGIH
NV
NA
ACGIH (2015)
Cancer
IRIS
NV
NA
U.S. EPA (2016)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2015)
Cal/EPA
NV
NA
Cal/EPA (2011): Cal/EPA (2016a): Cal/EPA (2016b)
ACGIH
NV
NA
ACGIH (2015)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
NA = not applicable; NV = not available.
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Literature searches were conducted in July 2013 and June 2016 for studies relevant to the
derivation of provisional toxicity values for rubidium (CASRN 7440-17-7). The searches
included the following rubidium compounds: rubidium chloride (CASRN 7791-11-9), rubidium
hydroxide (CASRN 1310-82-3), rubidium nitrate (CASRN 13126-12-0), dirubidium dichromate
(CASRN 13446-73-6), rubidium fluoride (CASRN 13446-74-7), rubidium dichloride
(CASRN 39356-55-3), rubidium carbonate (CASRN 584-09-8), rubidium sulfate
(CASRN 7488-54-2), rubidium hydrogen sulfate (CASRN 15587-72-1), and rubidium iodide
(CASRN 7790-29-6). Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. The following databases were
searched: PubMed, ToxLine (including TSCATS1), and Web of Science. The following
databases were searched outside of HERO for health-related values: ACGIH, ATSDR, Cal/EPA,
U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA Office of Water (OW), U.S. EPA
TSCATS2/TSCATS8e, NIOSH, NTP, and OSHA.
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Of the rubidium compounds evaluated, only rubidium chloride provided useful toxicity
information for the potential derivation of provisional toxicity values. Tables 3 A and 3B provide
an overview of the relevant databases for rubidium chloride and include all potentially relevant
repeated dose short-term-, subchronic-, and chronic-duration studies. Principal studies are
identified in bold. Reference can be made to details provided in Tables 3A and 3B. The phrase
"statistical significance," used throughout the document, indicates ap-walue of < 0.05 unless
otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Human
1. Oral (mg/kg-d)
Short-term
0 M/31 F, capsule, up to
3 wk
2.6-10.3
(Average doses:
Wk 1 = 5.3,
Wk 2 = 5.8,
Wk 3 = 5.6)
Weight gain (8/31),
diarrhea (7/31),
nausea/vomiting
(2/31), confusion
(4/31), excitement/
agitation (4/31),
polyuria (2/31),
adverse reaction
(2/31)
NDr
NDr
5.3
Placidi et al. (1988)
PR; PS
No control group; only
16 people completed
3 wk of treatment;
hematology and serum
chemistry results were
not made available.
Short-term
0 M/10 F, capsule, 15 d
5.1
None
5.1
NDr
NDr
Tuoni et al. (1987)
PR;
Serum chemistry related
to kidney function and
kidney function test data
available; serum
chemistry related to
liver or other organ
function was not
available.
Short-term
2 M/18 F, 60 d
5.1, 10.3
Skin rashes and
diarrhea, described as
"slight adverse
effects"
NDr
NDr
5.1
Torta et al. (1993)
PR;
Written in Italian;
marked antidepressant
effect
Short-term
15 subjects (sex not
reported), 3 wk
7.7
None
7.7
NDr
NDr
Brundusino and
Cairoli (1996)
PR;
Written in Italian; "lack
of side effects"
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Short-term
0 M/2 F subjects, solution,
administered
intermittently over 35- or
44-d period
Unspecified amounts
of a 50 g/L solution
administered
None
NDr
NDr
NDr
Paschalis et al.
(1978)
PR;
Hematology, serum
chemistry or
histopathological
analysis of any organ
were not performed;
"no severe effects"
Short-term
4 subjects (sex not
reported), solution,
(1 patient intermittently
for 86 d)
14.3 or 21.4 (single
dose)
1 patient administered
a total of 32.4 g over
86 d intermittently
(5.4 mg/kg-d)
Minimal or moderate
increase in proportion
of lower frequency
signals in EEG,
transient decrease in
pulse rate
NDr
NDr
NDr
Fieve et al. (1971)
PR;
Only blood and urine
electrolyte analysis
performed; no adverse
effects reported

Short-term
5 subjects (sex not
reported), 15-86 d
Unspecified amount
None
NDr
NDr
NDr
Fieve and Meltzer
(1974); Fieve et al.
PR;
No serum chemistry or
hematology is available;
"no immediate or
long-term effects"
(1973)
Short-term
15 subjects (sex
unspecified), up to 80 d
Unspecified amount
None
NDr
NDr
NDr
Meltzer and Fieve
(1975)
PR;
No serum chemistry or
hematology is available;
"no immediate or
long-term effects"
2. Inhalation (mg/m3)
ND
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Animal
1. Oral (mg/kg-d)
Short-term
3-4 M/3-4 F, Beagle dog,
capsules, 30 d
0 (n = 3), 48 (« = 3),
145 (« = 4)
Gastrointestinal
irritation, emesis,
colonic congestion
NDr
NDr
48
Stolk (1974)
PR;
Hematology, serum
chemistry present;
histology data not made
available;
apparent portal-of-entry
effects
Short-term
10-20 M/0 F,
Swiss-Webster mouse,
drinking water, 3 wk
0, 299, 597, 896
Convulsive seizures
in response to sound
stimuli, and death
299
NDr
597
(PEL)
Alexander and
Meltzer (1975)
PR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
only clinical signs and
audiogenic convulsions
were recorded.
Short-term
10 M/0 F, Swiss-Webster
mouse, drinking water,
3 wk
0, 896
Convulsive seizures
NDr
NDr
896
(PEL)
Alexander et al.
PR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
only clinical signs and
audiogenic convulsions
were recorded.
(1980)
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Short-term
10 M/0 F, S-D rat,
drinking water, 10 d
0, 167
Decreased saliva flow
rate from
submandibular gland,
increased saliva
concentrations of
protein, Ca2+ and
increased activity in
NAG
NDr
NDr
167
Abdollahi et al.
(1998)
PR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
biological significance
of effects is unclear.
Short-term
10 M/0 F, Swiss mouse,
drinking water, 10 d
0, 747, 1,494
Decrease in duration
of
phenobarbital-induced
sleep
NDr
NDr
747
Allain et al. (1974)
NPR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
biological significance
of effect is unclear.
Short-term
5-8 M/0 F, S-D rat,
drinking water, 4 wk
0, 834
Increased general
motor activity and
brain stem levels of
cAMP
NDr
NDr
834
Chow and Cornish
(1979)
NPR;
Hematology, serum
chemistry, or
histopathology of any
tissue was not
performed;
biological significance
of effects is unclear.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Subchronic
10 M/10 F, Wistar rat,
gavage, 30 d
0, 500, 1,000, 2,000
Death (dose- and
time-dependent),
decreased RBC count
(qualitatively), and
decreased hemoglobin
in females; slightly
congested liver,
bronchitis or
bronchopneumonia
with thickened
alveolar walls and
cellular infiltration in
males; mild kidney
congestion in both
sexes
NDr
NDr
500
(PEL)
Tomizawa et al.
(1974) as
summarized in Stolk
(1974)
PR;
Comprehensive study
with hematology,
clinical chemistry, and
histopathology.
However, actual data
were not presented.
Subchronic
10 or 60 M/0 F, S-D rat,
drinking water, varying
durations (up to 8 wk)
0, 167, 333, 500
Convulsive seizures
in response to sound
stimuli, and death
167
NDr
333
(PEL)
Alexander and
Meltzer (1975)
PR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
only clinical signs and
audiogenic convulsions
were recorded.
Subchronic
Up to 60 M/0 F (numbers
per group unspecified),
Wistar rat, drinking water,
8 wk
0, 176, 353, 529
None (no convulsions
or death in this strain
of rats)
529
NDr
NDr
Alexander and
Meltzer (1975)
PR;
No hematology, serum
chemistry, or
histopathology of any
tissue were performed;
only clinical signs and
audiogenic convulsions
were recorded.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Rubidium Chloride
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Notes0; Comments
Subchronic
2 M/2 F, rat (strain
unspecified), diet, up to
300 d
0, 14.1, 141,282, 423,
564
Death, convulsions,
decreased
body-weight gain
141
NDr
282
(FEL)
Glendenine et al.
PR;
No histopathology,
hematology, or serum
chemistry were
performed;
Na+ and K+ were
restricted in the diet
which confounded the
interpretation of the
results.
(1956)
2. Inhalation (mg/m3)
ND
"Category (treatment/exposure duration, unless otherwise noted): Short-term = repeated exposure for >24 hours <30 days (U.S. EPA. 20021:
long-term (subchronic) = repeated exposure for >30 days <10% lifespan for humans (more than 30 days up to approximately 90 days in typically used laboratory animal
species) (U.S. EPA. 20021: chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal
species) (U.S. EPA. 2002).
bDosimetry: Oral doses are expressed as ADD (mg/kg-day).
°Notes: PR = peer reviewed; NPR = not peer reviewed; PS = principal study.
ADD = adjusted daily dose; cAMP = cyclic adenosine monophosphate; EEG = electroencephalogram; F = female(s); FEL = frank effect level; M = male(s);
NAG = 7V-acetyl-P-D-glucosaminidase; ND = no data; NDr = not determined; RBC = red blood cell; S-D = Sprague-Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for Rubidium Chloride
Category
Number of Male/Female, Strain,
Species, Study Type, Study
Duration
Dosimetry
Critical Effects NOAEL
BMDL/BMCL
LOAEL
Reference
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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HUMAN STUDIES
Oral Exposures
Short-Term-Duration Studies
Limited clinical trials have been conducted of orally administered rubidium chloride as
an antidepressant (see Table 3A). No severe side effects were observed in any of these studies.
The trials, conducted in the United States (Meltzer and Fieve, 1975; Fieve and Meltzer, 1974;
Fieve et al.. 1973; Fieve et aL 1971). Italy (Brundusino and Cairoli. 1996; Torta et aL 1993;
Placidi et al.. 1988; Tuoni et aL. 1987). and the United Kingdom (Paschalis et aL. 1978).
administered oral doses ranging from about 180-1,000 mg/day for 15-86 days to small numbers
of patients with various types of depression in hospital settings. Brief reviews of the trials
conducted before 1988 were prepared by Williams et al. (1987) and Placidi et al. (1988). All of
the reports noted that oral treatment with rubidium chloride was without severe side effects.
However, the most comprehensive trial (Placidi et aL. 1988). which included the largest number
of patients (n = 31) at doses ranging from 2.6-10.3 mg/kg-day (180-720 mg/day) and used a
standardized survey on treatment-related symptoms, reported several symptoms that led to
downward dosage adjustment or termination of treatment. These symptoms included weight
gain (in 8/31 patients), diarrhea (7/31), nausea/vomiting (2/31), polyuria (2/31), confusion (4/31),
and excitement/agitation (4/31). In a related study, biomarkers of kidney dysfunction were not
changed in 10 patients receiving oral doses of 5.1 mg/kg-day (360 mg/day) rubidium chloride for
15 days (Tuoni et aL. 1987).
Placidi ei al. (1988)
The clinical trial conducted by Placidi et al. (1988) included the largest number of
patients of any of the identified studies (31 women who had been treated with antidepressive
therapies in the past). Patients were examined using standardized psychometric tests before and
after 3 weeks of daily dosing with one to four capsules containing 180 mg rubidium chloride
each. The trial was conducted without blinding, and treatment was preceded by a 1-week period
without pharmacological therapy. The average doses were 5.3, 5.8, and 5.6 mg/kg-day (370,
407, and 390 mg/day)1 in Weeks 1, 2, and 3, respectively. Information about side effects was
collected using standardized surveys on a weekly basis or when dosage was changed. In
addition, blood was collected before and after treatment for determining plasma rubidium
concentration, blood cell counts, and aspartate aminotransferase (AST; formerly called serum
glutamic-oxaloacetic transaminase [SGOT]), blood urea nitrogen (BUN), glucose, y-glutamyl
transferase (GGT), alkaline phosphatase (ALP), bilirubin, and electrolytes. Among these blood
endpoints, the report only mentioned results for plasma rubidium concentrations, which ranged
between 0.15 and 0.37 mEq/L (mmol/L) and did not correlate with clinical improvement. The
mean duration of treatment was 14.3 days, as only 52% of the patients received the complete
schedule of treatment. Premature terminations were due to adverse reaction (n = 2), inefficacy
(n = 7), mania (n= 1), and patient requests for termination due to significant improvement
(n = 5). By Week 2, about two-thirds of patients showed statistically significant clinical
improvement in the standardized psychometric measures. Reported symptoms (n = number of
patients reporting) that led to downward dosage adjustment or interruption of treatment were
1 Adult human standard body weight of 70 kg was used for all dosimetric conversions in human studies throughout
unless study-specific body weights were reported. Doses were calculated as follows: reported dose
(mg/day) standard body weight (70 kg) = single, average daily, or average weekly dose (mg/kg-day). Sample
calculations presented using weekly dose data from Placidi et al. (1988): 370 mg/day ^ 70 kg = 5.3 mg/kg-day;
407 mg/day ^ 70 kg = 5.8 mg/kg-day; 390 mg/day ^ 70 kg = 5.6 mg/kg-day.
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weight gain (n = 8), diarrhea (n = 7), nausea/vomiting (// = 2), polyuria (// = 2), confusion
(n = 4), and excitement/agitation (n = 4). It is not clear from the Placidi et al. (1988) study report
whether each individual was administered the same dose throughout the study or what the
individual average daily doses of rubidium chloride were for each patient. Only the weekly
average daily doses (ADDs) consumed by all the remaining subjects (at least 16 patients) in
Weeks 1, 2, and 3 were reported. The Week 1 ADD of 5.3 mg/kg-day is identified as the
lowest-observed-adverse-effect level (LOAEL) because it was the lowest ADD reported where
patients exhibited adverse effects such as diarrhea, vomiting/nausea, body-weight gain,
excitation/agitation, confusion, and polyuria. A no-observed-adverse-effect level (NOAEL)
could not be identified.
Tuoni et al. (1987)
Measures of kidney function were within normal ranges after 10 women with bipolar
emotional disturbances received 5.1 mg/kg-day (360 mg/day)1 rubidium chloride for 15 days
(Tuoni et al, 1987). This study appears to have been conducted at the same institution as the
Placidi et al. (1988) clinical trial. Kidney function was the focus because it is a side effect from
repeated treatment for bipolar emotional disturbances with lithium, a Group 1A alkali metal like
rubidium. One week prior to the start of rubidium chloride treatment, patients received no
pharmacological therapies. The following endpoints were examined, before and after treatment:
urea clearance, creatinine clearance, uric acid clearance, plasma and urinary electrolytes, BUN,
and urinary levels of a-glucuronidase, A-acetyl-P-D-glucosaminidase (NAG), muramidase, and
GGT. Mean values of these endpoints (before and after treatment) were reported to be within
normal ranges. No statistically significant adverse changes were found for any of the endpoints
after treatment. A NOAEL of 5.1 mg/kg-day is identified based on the absence of any adverse
side effects. No LOAEL is identified.
Torta et al. (1993)
An English language abstract reported "slight adverse effects" in the form of diarrhea and
skin rashes among 20 depressed patients (18 females and 2 males) who were given oral doses of
5.1 or 10.3 mg/kg-day (360 or 720 mg/day)1 rubidium chloride for 60 days (Torta et al, 1993).
The treatment was reported to elicit a "marked and rapid antidepressive action." The full report
of this trial is in Italian and was not translated for this assessment. A LOAEL of 5.1 mg/kg-day
(the lowest dose tested) is identified based on skin rashes and diarrhea, described as "slight
adverse effects," and no NOAEL is identified.
Bmndusino and Cairoli (1996)
A "lack of side effects" and "therapeutic efficacy" were reported in the English language
abstract of a trial in which oral doses of 7.7 mg/kg-day (540 mg/day)1 rubidium chloride were
given to 15 depressed patients for 3 weeks (Brundusino and Cairoli, 1996). The full report of
this study is in Italian, and was not translated for this assessment. A NOAEL of 7.7 mg/kg-day
is identified based on "lack of side effects." No LOAEL can be identified because only one dose
was tested.
Paschalis et al. (1978)
No "severe side effects" were noted in a trial of two female patients with chronic bipolar
emotional disturbance who received unspecified volumes of a solution containing 50 g/L
(410 mmol/L) rubidium chloride intermittently over a 35- or 44-day period, achieving peak
rubidium erythrocyte concentrations of 9.4 and 10.5 mmol/L, respectively
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(Paschalis et aL 1978). In these patients, rubidium chloride treatment was associated with
positive changes in mood and prolongation of mania periods. Three other chronic bipolar
patients received an unspecified volume of the same rubidium chloride solution once each,
without experiencing changes in mood. No severe side effects were reported by these patients.
No NOAEL or LOAEL can be identified because no adverse effects were reported at any of the
doses tested.
Fieveetal. (1971); Fieve andMeltzer (1974); Fieveetal. (1973); Meltzer andFieve
(1975)
Oral doses of 8.2 or 12.4 mmol (~1 or 1.5 g)2 rubidium chloride (given as single dose of
8.2 mmol or split into two doses of 4.1 or 6.2 mmol given 4 hours apart; resulting adjusted daily
doses are 14.3 or 21.4 mg/kg-day)3 were reported to produce a minimal or moderate increase in
the proportion of lower frequency signals in electroencephalographs, a transient decrease in
pulse rate, and no detectable changes in clinical state in four volunteer subjects, including two
patients hospitalized with depression and two normal subjects (Fieve et aL, 1971). One of the
depressed patients was given unspecified oral doses of rubidium chloride intermittently for
86 days for a cumulative administered dose of 268 mEq (32.4 g)4. No adverse side effects were
reported or observed during the treatment period and during 4 months after treatment. No
"meaningful gross therapeutic effects" were reported by the patient, and no changes were
observed in the frequency or duration of manic and depressive cycles. Plasma concentrations of
rubidium were determined at numerous times during treatment. The maximum concentration,
about 0.16 mEq/L, was measured on Day 75 (Meltzer and Fieve. 1975; Fieve and Meltzer. 1974;
Fieveetal. 1973).
No "immediate or long-term side effects" were observed in five hospitalized depression
patients given oral doses of rubidium chloride intermittently for 15 to 86 days, achieving plasma
rubidium concentrations as high as 0.35 mEq/L (Fieve and Meltzer. 1974; Fieve et al.. 1973).
No "mood changes" were noted in four of these patients showing maximum plasma
concentrations of about 0.28 mEq/L in 40 days of treatment, 0.35 mEq/L in 23 days of treatment,
0.3 mEq/L in 20 days of treatment, or 0.1 mEq/L in 44 days of treatment (Fieve and Meltzer,
1974). One patient with a maximum plasma concentration of about 0.3 mEq/L showed recovery
from depression (i.e., positive changes in mood) within about 15 days of treatment (Fieve and
Meltzer. 1974). In a later report of this clinical trial, a total of 15 patients with bipolar
disturbances were treated with rubidium chloride, achieving maximum plasma rubidium
concentrations as high as 0.4 mEq/L (Meltzer and Fieve. 1975). Three patients experienced
marked increase in mood, two experienced slight increase in mood, five experienced no change
in mood, and one experienced a decrease in mood. Four patients did not meet the criteria of
retaining at least 200 mEq and achieving greater than or equal to 0.25 mEq/L of rubidium in
plasma. No NOAEL or LOAEL can be identified because no adverse effects were reported at
any of the doses tested.
2Sample calculation: 8.2 mmol x 120.92 mg/mmol = 992 mg = ~1 g.
3Sample calculations: 1 g/day (or 1,000 mg/day) ^ 70 kg = 14.3 mg/kg-day;
1.5 g/day (or 1,500 mg/day) ^ 70 kg = 21.4 mg/kg-day.
4Sample calculation: 268 mEq = 268 mmol; 268 mmol x 120.92 mg/mmol = 32,406 mg = 32.4 g.
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Inhalation Exposures
No studies examining possible associations between health effects in humans and
repeated inhalation exposure to rubidium have been identified.
ANIMAL STUDIES
Oral Exposure
Short-Term-Duration Studies
Stolk (1974)
Preliminary results were reported from a study in which groups of Beagles were given
encapsulated doses of rubidium chloride for 30 days: three control dogs; three dogs given
0.4 mEq/kg-day (-48 mg/kg-day); and four dogs given 1.2 mEq/kg (-145 mg/kg-day)5. Results
from necropsy, hematology, and blood chemistry were presented, but histology of tissues was
not completed when the report was prepared. No follow-up report of this study was located in
the literature search for this assessment. Evidence presented for gastrointestinal irritation was
frequent emesis after dose administration in 1/3 low-dose and 2/4 high-dose dogs, and
generalized congestion of the colonic mucosa was noted in 2/3 low-dose and 4/4 high-dose dogs.
Necropsy showed no gross effects in the kidney, liver, or heart in exposed dogs. No
exposure-related changes were found in red blood cell (RBC) or white blood cell (WBC) counts,
hemoglobin, hematocrit, or blood chemistry variables (calcium, inorganic phosphate, glucose,
creatinine, BUN, uric acid, cholesterol, total protein, albumin, and total bilirubin). The lowest
dose tested of 48 mg/kg-day appears to be a LOAEL for gross signs of gastrointestinal tract
irritation without changes in hematological or blood chemistry variables. The small number of
dogs per group and the lack of histological examination limit the reliability of this LOAEL
determination. A NOAEL cannot be identified.
Alexander et al. (1980); Alexander andMeltzer (1975)
Repeated exposure of mice to high concentrations of rubidium chloride in drinking water
has been shown to increase the incidence of animals susceptible to audiogenic seizures
( Alexander et aL 1980; Alexander and Meltzer. 1975). These studies were conducted because
earlier studies noted that some rats receiving repeated oral doses of rubidium chloride had
convulsive seizures induced by the noise from the release of compressed air.
In the Alexander et al. (1980) study, male Swiss-Webster mice (10 per group) were
treated with 0 or 896 mg/kg-day6 (0.03 Eq/L) rubidium chloride in drinking water for 3 weeks.
About 45% of exposed mice exhibited convulsive seizures when stimulated with sound signals
of 22 kHz and 74 dbA (40% in one group and 50% in another group) (Alexander et al.. 1980).
In the same study, male Swiss-Webster mice (10 per group, except 20 in high-dose
group) were exposed to 0, 299, 597, or 896 mg/kg-day6 (0, 0.01, 0.02, or 0.03 Eq/L) rubidium
chloride in drinking water for 3 weeks. Incidences of audiogenic-convulsive seizures were 2/10
in the 597-mg/kg-day dose group and 7/20 in the 896-mg/kg-day dose group ( Alexander and
Nleltzer. 1975).
5Sample calculation for converting mEq/kg-day to mg/kg-day throughout: 0.4 mEq/kg-day = 0.4 mmol/kg-day;
0.4 mmol/kg-day x 120.92 mg/mmol = 48 mg/kg-day.
' An estimated dose of 896 mg/kg-day is calculated using U.S. EPA (1988) reference values for body weight
(0.0316 kg) and water consumption (0.0078 L/day) for subchronically exposed male mice (B6C3Fi) as follows:
0.03 Eq/L = 0.03 mol/L x 120.92 g/mol = 3.63 g/L x 1,000 mg/g x0.0078 L/day 0.0316 kg = 896 mg/kg-day.
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The available data indicate that rubidium-induced susceptibility to audiogenic seizures is
a high-dose phenomenon. In these mouse studies, a LOAEL (also a frank effect level [FEL]) of
597 mg/kg-day is identified for audiogenic convulsive seizures. A corresponding NOAEL of
299 mg/kg-day is also identified.
Abdollahi et al. (1998)
Exposure of male Sprague-Dawley (S-D) rats to 167 mg/kg-day rubidium chloride in
drinking water (1,200 mg/L [-0.01 Eq/L]) for 10 days caused decreased saliva flow rate from
submandibular glands, increased saliva concentrations of protein and Ca2+, and increased activity
of NAG in saliva, compared with control rats (Abdollahi et al.. 1998). Saliva was collected from
anesthetized (60 mg/kg pentobarbital, intraperitoneal [i.p.]) exposed and control rats fitted with
cannulas in both submandibular ducts. Secretion was stimulated by pilocarpine (6 mg/kg, i.p.),
which reportedly does not stimulate secretion of NAG.
Attain et al. (1974)
Reduced pentobarbital-induced sleeping time was observed in male Swiss mice
(10 mice/dose group) exposed to 747 or 1,494 mg/kg-day (0.025 or 0.05 M [or Eq/L])7 rubidium
chloride in drinking water for up to 10 days, compared with controls given drinking water with
equimolar concentrations of sodium chloride. Following 10 days of exposure, duration of
phenobarbital-induced sleep was decreased by 34 and 60% in low- and high-dose mice,
respectively, compared with controls. In high-dose mice, the decreases were dependent on
duration of exposure: 9, 24, and 60% decrease in sleep duration after 2, 5, and 10 days of
exposure, respectively. In mice exposed to 1,494 mg/kg-day (0.05 M) rubidium chloride for
10 days, the mean cerebral concentrations of pentobarbital 8, 16, or 24 minutes after
pentobarbital injection were not statistically significantly different from control values, providing
evidence that rubidium chloride did not influence the metabolism of pentobarbital. From the
results, the study authors proposed that rubidium chloride may have similar pharmacological
properties to amphetamine.
Chow and Cornish (1979)
Increased general motor activity and brainstem levels of cyclic adenosine monophosphate
(cAMP) were found in groups of 5-8 male S-D rats provided 834 mg/kg-day rubidium chloride
(0.05 M [~6 g/L]) in drinking water for 4 weeks compared with control rats. This dose is
identified as a LOAEL, and no NOAEL is identified. No additional study details were provided.
Subchronic-Duration Studies
Tomizawa et al. (1974), as cited by Stolk (1974)
Groups of Wistar rats (10/sex/dose) were given daily gavage doses of 0, 500, 1,000, or
2,000 mg/kg-day rubidium chloride in water (0, 4.13, 8.26, or 16.5 mEq/kg-day) for up to
30 days. Deaths occurred in 2 males and 2 females between Days 18 and 30 in the
500-mg/kg-day group, 4 males and 5 females between Days 15 and 30 in the 1,000-mg/kg-day
group, and 10 males and 9 females between Days 10 and 25 in the 2,000-mg/kg-day group. The
rats died while crouching quietly with lowered spontaneous motor activity. Hematological
findings were reported qualitatively as decreased RBC counts in males and females in all
exposed groups and decreased hemoglobin levels in females in all exposed groups, with no
changes in hematocrit, relative to control values. No exposure-related changes in blood
7Note that for rubidium chloride, 1 M = 1 Eq/L because the valence state = 1.
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chemistry endpoints (Na+ and K+, glucose, creatinine, BUN, total protein, SGOT, alanine
aminotransferase [ALT; formerly called serum glutamic pyruvic transaminase, or SGPT], and
ALP) were found. Changes in urinalysis endpoints from control values were also reported
qualitatively: decreased urine volume in low- and middle-dose males at 2 weeks and middle-dose
females at 2-4 weeks, and increased urine levels of Na+ and K+ in males and females in the
1,000- and 2,000-mg/kg-day groups, generally at Weeks 1-4. Necropsy findings were reported
qualitatively (without incidence data) as congestive edema of the lung, pneumonitis, pulmonary
abscess formation, and cloudy swelling of the kidney in exposed animals, and pneumonitis in
one control rat.
Histopathology was also reported qualitatively without incidence data for all lesions.
Histologic evaluation of spleen, pituitary gland, thymus, adrenal glands, pancreas, testis, and
ovary were reported to be "benign," whereas adverse changes were described for the liver, lung,
heart, and kidney in exposed groups compared with control groups. Histopathology in the
500-mg/kg-day group was described as consisting of slightly congested liver, bronchitis or
bronchopneumonia with thickened alveolar walls and cellular infiltration in all male rats (but not
females), and mild kidney congestion without major alterations in glomeruli or tubules. In the
1,000-mg/kg-day group, histopathology was described as: degeneration of liver cells without
necrosis: endocardial thrombus with mild degeneration of the heart muscle and neutrophilic
infiltration in two dead animals: congestive pulmonary edema with exudative cells and
yellowish-brown pigmentation, which was prominent in dead animals; and markedly
degenerated or destructed renal tubules in animals of both sexes, especially noted in dead
animals. Histopathology in the 2,000-mg/kg-day group was described as: degeneration of liver
cells without necrosis, myocardial degeneration and inflammatory cell infiltration in one animal,
severe congestive pulmonary edema with hemorrhage and pneumonitis, especially in animals
with marked kidney lesions; and markedly degenerated or destructed renal tubules in animals of
both sexes, especially noted in dead animals.
The lowest dose (500 mg/kg-day) in this 30-day study appears to be a FEL with
premature deaths occurring in 20% of the rats. At higher dose levels (1,000 and
2,000 mg/kg-day), greater percentages of rats had premature deaths, with marked
histopathological changes in the lungs and kidneys. Decreased RBC counts and hemoglobin
were reported for all exposed groups, but further details were not available. A NOAEL is not
identified.
Alexander andMeltzer (1975)
As in mice, repeated exposure of rats to high concentrations of rubidium chloride in
drinking water has been shown to increase the incidence of animals susceptible to audiogenic
seizures ( Alexander et aL 1980; Alexander and Meltzer, 1975).
In a study by Alexander and Meltzer (1975). male S-D rats were exposed to 0 (10 rats),
167 (10 rats), 333 (10 rats), or 500 mg/kg-day (60 rats) (0, 0.01, 0.02, or 0.03 Eq/L, respectively)
rubidium chloride in drinking water for up to 8 weeks. Upon stimulation with sound signals of
22 kHz and 74 dbA, the incidence of convulsive seizures was 1/10 (treatment terminated on
Day 56) and 17/60 (treatment terminated on Day 31) in animals treated with 333 or
500 mg/kg-day rubidium chloride, respectively. Deaths were observed only in 4/60 rats treated
with 500 mg/kg-day and none in 333-mg/kg-day treated rats. No audiogenic effects were
observed in rats treated with 167 mg/kg-day.
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In the same study by Alexander and Meltzer (1975). male Wistar rats (up to 60 per
group) were exposed to 0, 176, 353, or 529 mg/kg-day rubidium chloride in drinking water for
up to 8 weeks. Unlike the S-D rats, no convulsions or deaths were observed in the Wistar rats.
The rate of development of this susceptibility to sound was dose-related, and less
rubidium chloride was needed to induce susceptibility if dietary levels of potassium and
magnesium were deficient (Alexander and Meltzer. 1975). Variability between S-D and Wistar
rat strains was also evident. At similar doses, Wistar rats did not show convulsive behavior in
any of the doses when exposed for up to 8 weeks. Tissue rubidium levels were not significantly
different in audiosensitive and audioresistant rats exposed to rubidium chloride (Alexander and
Meltzer. 1975). The available data indicate that rubidium-induced susceptibility to audiogenic
seizures is a high-dose phenomenon. In these rat studies, a LOAEL (also an FEL) of
333 mg/kg-day is identified for audiogenic convulsive seizures. A corresponding NOAEL of
167 mg/kg-day is also identified.
Glendenine et al. (1956)
To test whether rubidium is an essential element, rats were treated with varying levels of
Rb, Na+, and K+. Four rats per group (two females and two males) were fed diets containing 0,
0.01, 0.1, 0.2, 0.3, or 0.4% rubidium with constant K+ and Na+ levels in feed (equivalent to 0,
14.1, 141, 282, 423, or 564 mg/kg-day8 of rubidium chloride, respectively) in the absence or
presence of 0.2% sodium (added as sodium chloride) in a synthetic custom basal diet for up to
300 days. Body weight was recorded on Days 10, 20, 40, 80, and 120 of treatment. Rubidium
chloride at 282 mg/kg-day and higher doses decreased survival time. Excitement from handling
caused convulsions, often leading to death. Postmortem findings were not conclusive. Lungs,
heart, liver, kidney, and brain were weighed and preserved for analysis. A dose of
282 mg/kg-day rubidium chloride appears to be the lowest dose that caused death, and is thus
identified as a FEL, and 141 mg/kg-day appears to be a NOAEL. The reduction in body weight
was present in the 282-, 423-, and 564-mg/kg-day dose groups beginning on Day 40. Body
weight was reduced compared to controls in the 141-mg/kg-day dose group beginning on
Day 80. Conversely, rats treated with 14.1 mg/kg-day exhibited increased body weight
compared to controls from Days 40-120. However, because there are only four rats per group
(two per sex), the biological relevance of the changes in body weight following rubidium
chloride exposure is unclear. One of the major shortcomings of this study is that the synthetic
diet has half the content of Na+ and K+ (compared to laboratory chow from the same study), and
lower levels of Na+ and K+ have been shown to enhance the effects of rubidium. Therefore, the
interpretation of the effects observed in this study may be confounded by the reduced levels of
Na+ and K+.
Mannisto andSaarnivaara (1976); Saarnivaara and Mannisto (1976)
These studies examined counteraction of the antinociception effects (i.e., pain
diminishment in a hot plate test) of antipsychotic drugs and narcotic analgesic drugs in male
mice exposed to 247 mg/kg-day rubidium chloride in drinking water (as 1 g/L [-0.008 Eq/L]) for
up to 21 days (Mannisto and Saarnivaara. 1976; Saarnivaara and Mannisto. 1976). However, the
8Rubidium chloride consists of 70.68% of Rb element. Rat (Fischer 344) rat default food intake factor default for
subchronic duration study is 0.1. Dosimetry calculation:0.01% rubidium in feed = 0.01/0.7068 = 141 ppmof
rubidium chloride; 141 ppm x 0.1 [waterfood intake factor calculated using average Fischer 344 rat body weight
(BW) and average water food intake according to U.S. EPA (1988)1 = 14.1 mg/kg day.
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reports had apparent errors in tables reporting the results, discrepancies between results in the
tables and conclusions in the text, and inconsistencies of effects with duration of exposure to
rubidium chloride and across drugs of the same class. These reports were considered to be
unreliable sources of information for the purposes of identifying health hazards from subchronic
or chronic durations of exposure to rubidium and deriving provisional reference doses (p-RfDs)
for rubidium chloride.
Inhalation Exposures
No studies have been identified examining any toxicologically pertinent endpoints
following inhalation exposure of laboratory animals to rubidium or rubidium compounds.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tests Evaluating Genotoxicity and/or Mutagenicity
Rubidium chloride did not induce deoxyribonucleic acid (DNA) damage in the rec assay
with Bacillus subtilis (Kanematsu et aL 1980). Other tests of rubidium genotoxicity in
short-term in vitro or in vivo tests have not been identified.
Other Supporting Human Studies
Severe dermatitis of the face, eyelids, and periorbital areas occurred in a 70-year-old man
following 5 months of treatment with ophthalmic preparations containing rubidium chloride for
the treatment of cataracts (Camel i et aL 1990). Skin patch tests with a 1% rubidium chloride
solution were strongly positive for this subject, whereas patch testing with 10% rubidium
chloride in 20 healthy human subjects produced negative results. Other supporting human
studies identifying possible adverse effects of rubidium chloride have not been identified.
Supporting Animal Toxicity Studies
Reported acute oral lethality values for rubidium compounds in rats are median lethal
dose (LD50) values of 586 mg/kg for rubidium hydroxide and 4,708 mg/kg for rubidium iodide
(Johnson et aL 1975; Johnson et aL 1972). The LD50 values for rubidium chloride are
4,440 mg/kg in rats and 3,800 mg/kg in mice (ChemlDplus, 2016).
A number of studies of animals parenterally exposed for short time periods to rubidium
chloride reported changes in behavior and associated endpoints. Observations of
rubidium-induced changes in general activity include the following.
•	Increased low frequency changes in electroencephalograms and increased locomotor
activity in monkeys following intravenous (i.v.) injection with 2 mEq of rubidium
chloride. In another experiment, monkeys were given oranges injected with
increasing concentrations of rubidium chloride up to the point where the monkeys
refused to eat them. One monkey retreated instantly after consuming 4 mmol. A
second monkey, originally aggressive, became hyperactive and more aggressive after
consuming increasing once-a-week doses of 0.5, 1.0, 2.0, 4.0 mmol rubidium and
trace amounts in the fifth week. The monkeys that were administered rubidium
chloride in oranges orally showed none of the toxic effects noted after i.v. injection
(Nlelt/.er et aL 1969).
•	Increased shock-elicited aggressive behaviors in rats given single i.p. injections of 0.3
or 0.6 mEq/kg rubidium chloride, compared with rats given 6 mEq/kg potassium
chloride (Stolk et aL 1971).
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•	Increased motor activity in rats given 14 daily i.p. injections of 3 mEq/kg rubidium
chloride, compared with rats given injections with 3 mEq/kg sodium chloride
(Acobettro et al.. 1979).
•	Increased rearing activity in rats over a period of 6 hours after i.p. administration of 3
or 6 mEq/kg BW rubidium chloride (Ribas et al. 1979). This report also noted that
statistically significant elevations of serotonin concentrations were found in the
hypothalamus of rats given daily i.p injections of 1 mEq/kg body weight (BW)
rubidium chloride for 14 days, but not in rats given three or six daily injections.
•	Decreased immobility times in forced swimming test (FST) and tail suspension test
(TST) in male NMRI mice tested 60 minutes after i.p. administration of 30 mg/kg
rubidium chloride (FST) and 30 and 50 mg/kg (TST). No effects were observed at
10 mg/kg. In a time-course evaluation, decreased immobility time in FST was also
observed 30 minutes and 120 minutes after i.p. administration of 30 mg/kg rubidium
chloride, but only 30 minutes after administration for TST. In separate i.p
experiments, noneffective doses of L-NAME (10 mg/kg) and aminoguanidine
(50 mg/kg), coadministered with 30 mg/kg rubidium choride, reversed decreased
immobility time in FST and TST, while 7-nitroindazole (25 mg/kg) could not prevent
decreased immobility time. Conversely, coadministration of a noneffective
L-arginine dose (750 mg/kg) with 10 mg/kg rubidium chloride decreased immobility
time in FST and TST (Kordia/.v et al.. 2015) (Kordjazy et al., 2015).
Other studies found equivocal or no evidence for rubidium-induced general activity in
animals.
•	Spontaneous locomotor activities were not statistically elevated in male ddY mice
given single or 16 repeated (every other day) subcutaneous doses of 50, 150, or
450 mg/kg rubidium, compared with sodium chloride controls (Furukawa and
Tokuda. 1976).
•	Mice that were repeatedly injected subcutaneously with 150 mg/kg rubidium chloride
showed greater activity in response to methamphetamine than sodium chloride
controls, but this apparent potentiation of methamphetamine-induced increased
activity was not as pronounced with the higher dose of rubidium chloride, 450 mg/kg
(Furukawa and Tokuda. 1976).
•	No exposure-related effects on immobility time in a forced swimming test were found
in male Wistar rats following single or repeated (once daily for 14 days) i.p.
injections of 1 or 3 mEq/kg rubidium chloride (Sueihara et al. 1989).
•	S-D rats administered 10 mmol of rubidium chloride plus potassium chloride or
20 mmol of potassium chloride only in drinking water for three generations did not
show adverse effects compared to control animals, except that the rats in the group
receiving rubidium plus potassium were more excitable (Nleltzer and Lieberman,
1971).
Wistar rats administered 30 mg/100 g BW-day of rubidium chloride by i.p. injection for
21 days showed degenerative changes in the morphology of liver cells including hypertrophy of
hepatocytes with condensed picnotic nuclei, and increased mitochondrial glutamate oxaloacetate
transaminase (GOT) levels in the serum. In the kidneys, rubidium chloride treatment caused
detachment of the glomerulus from the Bowman's capsule as well as degeneration of the
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glomerulus. The activities of both cholinesterase and inorganic pyrophosphatase in the brain
were decreased significantly compared to control (Chatteriee et al.. 1979). Additionally, isolated
rat kidneys perfused with 3 or 6 mEq/L rubidium for an unspecified period of time developed
tubular dilations, degeneration, and necrosis, similar in severity to that produced in kidneys
perfused with 3 mEq/L lithium (Bertelli et al.. 1985).
Metabolism/Toxicokinetic Studies
As reviewed by Williams et al. (1987). orally ingested rubidium chloride is rapidly and
completely absorbed by the gastrointestinal tract. It is expected to distribute widely to tissues
throughout the body and be excreted predominantly through the kidneys (Williams et al.. 1987).
On a biochemical and physiological basis, rubidium is considered to resemble potassium;
whereas, lithium (another Group 1A alkali metal) is considered to resemble sodium (Williams et
al.. 1987). Following administration of single oral doses of rubidium chloride (180 mg) to
human subjects, peak rubidium concentrations in RBCs were reached within about 3 hours and
maintained for 24 hours (del Vecchio et al.. 1979). In contrast, peak plasma concentrations were
attained within about 60-90 minutes and declined through 24 hours after dose administration
(del Vecchio et al.. 1979). Paschal is et al. (1978) reported similar blood kinetics in a few
patients given oral doses of rubidium chloride at an unspecified level. More than 90% of
rubidium in whole blood is contained in RBCs, and rubidium concentrations in RBCs are
typically 20- to 30-fold higher than plasma concentrations (Williams and Leggett 1987).
Monitoring of urinary excretion of rubidium in human subjects following oral administration of
single doses of rubidium chloride ranging from about 500-1,000 mg found fairly long
whole-body half-times of 21-55 days (Fieve et al.. 1971). Usuda et al. (2014) reported a
recovery of 8-10.5% rubidium in the urine of rats 24 hours after administration of single dose of
rubidium as an acetate, bromide, carbonate, chloride, or fluoride. Observed differences in liver
and kidney toxicity were attributable to the type of anion rather than rubidium itself (Usuda et
al.. 2014).
Mode-of-Action/Mechanistic Studies
As reviewed by Williams et al. (1987), the use of rubidium as an antidepressant was
suggested by findings indicating that rubidium has biological effects opposite to those of lithium,
an agent used to treat patients with bipolar emotional disturbances (i.e., manic depression).
Description of a few of these findings follows.
•	Rubidium chloride increased shock-induced aggressive behaviors in rats (Stolk et al..
1971). while lithium decreased shock-induced aggressive behaviors in rats (Sheard.
1970).
•	Rubidium increased the release and turnover of brain stem norepinephrine (Stolk et
al.. 1970). while lithium decreased the release of norepinephrine from brain neurons
(Schanberg et al.. 1967).
•	Rubidium increased electroencephalogram frequency in monkeys (Meltzer et al..
1969), while lithium slowed el ectroencephal ogram s in manic and nonmanic patients
(Mayfield and Brown. 1966).
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of noncancer and cancer reference values,
respectively, for rubidium chloride. IRIS data are indicated in the table, if available.
Table 4. Summary of Noncancer Reference Values for
Rubidium Chloride (CASRN 7791-11-9)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Screening
subchronic p-RfD
(mg/kg-d)
Human/F
Adverse side effects (weight
gain, diarrhea,
nausea/vomiting, polyuria,
confusion, and
excitement/agitation)
5 x icr3
LOAEL
5.3
1,000
Placidi et al.
(1988)
Chronic p-RfD
(mg/kg-d)
Not derived due to inadequate data
Subchronic
p-RfC (mg/m3)
Not derived due to inadequate data
Chronic p-RfC
(mg/m3)
Not derived due to inadequate data
F = female(s); LOAEL = lowest-observed-adverse-effect level; p-RfC = provisional reference concentration;
p-RfD = provisional reference dose; POD = point of departure; UFC = composite uncertainty factor.
Table 5 Summary of Cancer Values for Rubidium Chloride (CASRN 7791-11-9)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
Not derived due to inadequate data
p-IUR (mg/m3)-1
Not derived due to inadequate data
p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
Human and animal data are not completely adequate, and the lack of a comprehensive
database does not provide a suitable basis for deriving a p-RfD for rubidium chloride. The
specific associated shortcomings are listed below. However, hazards from rubidium chloride
exposure have been identified in human and animal studies. Therefore, a screening subchronic
p-RfD was derived (see Appendix A).
The available human studies are small clinical trials designed to test the efficacy of
rubidium chloride for treating depression in a few patients. The studies' shortcomings are as
follows.
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•	The trials with the greatest number of subjects were those by Placid! et al. (1988) with
3 1 patients and Tort a et al. (1993) with 20 patients, but neither study had an untreated
control group for comparison.
•	Durations of exposure were mostly on the order of 2-3 weeks. The trial reported by
Tort a et al. (1993) treated 20 patients with rubidium chloride for 60 days, and
reported "slight adverse effects" similar to those reported in the Placid! et al. (1988)
study. However, the full report of this trial is in Italian and was not translated for this
assessment. Moreover, the half-life of rubidium in humans in more than 20 days
[21-55 days; Fieve et al. (1971)1. which means approximately 80-100 days
(4-5 half-lives) would be required to reach a steady state (Ito, 2011). The duration of
2-3 weeks or 60 days of rubidium treatment in the available human studies is not
long enough for rubidium to reach steady-state levels in the body, and may not be
long enough to capture all of the effects of rubidium chloride following longer
duration exposure.
•	Many of the studies did not report clinical chemistry or hematological data to assess
effects on different organs and tissue (e.g., liver, kidney, and blood). They mainly
mentioned self-reported or clinically observed side effects (weight gain, diarrhea,
nausea/vomiting, skin rash, or polyuria) that were noted in the trials (Torta et al..
1993; Placidi et al.. 1988).
•	A clinical trial (with 10 patients) reported by Tuoni et al. (1987) included objective
tests for possible side effects, specifically biomarkers for kidney dysfunction. No
effects on these endpoints were found.
A number of studies of animals given oral doses of rubidium chloride for 10-30 days,
and one study in rats exposed for 12—300 days (Glendenine et al. 1956) are available, but these
are not useful for the purposes of deriving a p-RfD for several reasons that are detailed below.
•	The most comprehensive study is a 30-day gavage rat toxicity study with an adequate
design (e.g., control and three dose groups, and 10 rats/sex/group) and a relatively
comprehensive set of toxicity endpoints (e.g., hematology, blood chemistry,
urinalysis, and histopathology). However, the lowest dose level, 500 mg/kg-day,
caused early mortality in 20% of the low-dose animals (Tomizawa et al.. 1974 as
cited bv Stolk. 1974). A FEL is not a suitable basis for p-RfD derivation. The
qualitatively reported hematological and histological findings indicate that the
toxicity targets were RBCs, lungs, and kidneys, but it is unknown if these targets
would be affected at nonfatal doses.
•	A study of Beagles orally exposed for 30 days to encapsulated rubidium chloride at
two nonfatal dose levels included necropsy, hematology, and blood chemistry
endpoints, but results of histological examinations are not available and exposure
groups only contained 3-4 dogs (Stolk. 1974). Both low and high doses induced
gross signs of gastrointestinal tract irritation without changes in hematological or
blood chemistry variables. This study, however, is not a suitable basis for developing
a p-RfD, because of the small number of dogs per group and the lack of histological
examination of a comprehensive set of tissues.
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•	The subchronic-duration oral exposure study in rats by Glendening et al. (1956).
which examined rubidium chloride exposure for 12-300 days, had inadequate study
design (e.g., only four rats per group, controls were not included in an experiment to
study reproductive outcomes). Rubidium toxicity is variable in relation to the amount
of sodium and/or potassium present in the body or administered to rats (Glendening et
al., 1956). In this study, rubidium chloride effects were demonstrated with restricted
sodium and potassium intake (with 0.2% sodium and 0.29% potassium in diet)
confounding the effects observed.
•	Other available animal studies involving ten 30-day oral exposures are inadequate to
serve as a principal study for a p-RfD because they were focused on limited endpoints
and did not include more general assessment of toxicity (Abdollahi et al.. 1998;
Alexander et al.. 1980; Chow and Cornish. 1979; Alexander and Nlelt/.er. 1975;
Allain et al.. 1974).
•	Induction of frank effects such as convulsive seizures necessitates a comprehensive
neurotoxicity study, which is missing in the current database.
•	Although animal studies were relatively more comprehensive than human studies, the
lowest dose used in animal studies (Stolk. 1974) was at least nine times higher than
the lowest dose that induced effects in human subjects. Hence, animal studies were
not useful to derive a p-RfD.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Suitable data for deriving subchronic or chronic p-RfCs for rubidium or rubidium
compounds have not been identified.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 6 identifies the cancer WOE descriptor for rubidium.
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Table 6. Cancer WOE Descriptor for Rubidium and Rubidium Compounds
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
No human data are available.
"Likely to Be Carcinogenic to
Humans "
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No adequate chronic-duration animal
cancer bioassays are available. No
studies are available assessing the
carcinogenic potential of rubidium or
rubidium compounds in humans or
animals following oral or inhalation
exposure.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
No evidence of noncarcinogenicity is
available. No adequate chronic-duration
animal cancer bioassays are available.
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of a Provisional Oral Slope Factor (p-OSF)
Not derived due to inadequate data.
Derivation of a Provisional Inhalation Unit Risk (p-IUR)
Not derived due to inadequate data.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main provisional peer-reviewed toxicity value (PPRTV)
document, it is inappropriate to derive provisional toxicity values for rubidium chloride.
However, 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 Superfund Health Risk Technical Support Center 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 PPRTV documents 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 is considerably more
uncertainty associated with the derivation of 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 Superfund Health Risk Technical Support Center.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of a Screening Subchronic Provisional Reference Dose (p-RfD)
Placidi et al. (19881 a peer-reviewed, short-term-duration study in human patients, is
selected as the principal study to derive a screening subchronic p-RfD for rubidium chloride.
Limitations
Including Placidi et al. (1988). each of the human studies in the database had limitations
with respect to design, duration of treatment, outcomes observed, and dosing. Specifically,
Placidi et al. (1988) did not include a control/placebo group for comparison, had only
16/31 patients remaining by the end of the third week, and used subjects who were treated
chronically with a variety of antidepressants until 1 week before the start of the rubidium
chloride treatment.
Justification for the study
Placidi et al. (1988) had the most number of patients (n = 31 females) in the study and
they were exposed to rubidium chloride up to 3 weeks. Only the study by Torta et al. (1993) had
a longer exposure duration (60 days) and similar exposure doses, but the detailed study report
was not available for review. Neither of these studies are comprehensive. Lower doses of
rubidium chloride were tested in Placidi et al. (1988) as well as all other human studies when
compared to the animal studies. Although the rat study by Tomizawa et al. (1974) as
summarized in Stolk (1974) and the dog study by Stolk (1974) were more comprehensive studies
than Placidi et al. (1988). a true no-observed-adverse-effect level (NOAEL) could not be
established in these animal studies as all the doses tested produced adverse and frank effects.
Based on this information from the database, the Placidi et al. (1988) study in humans was
selected to derive a screening subchronic p-RfD.
Justification of adverse effects
Adverse effects such as diarrhea, body-weight gain, vomiting/nausea,
excitation/agitation, confusion, and polyuria (Placidi et al.. 1988) were considered as critical
effects to derive points of departure (PODs). Taken together, all the human studies describe
rubidium chloride treatment-related outcomes as producing no adverse effects (Tuoni et al..
1987; Fieve et al.. 1971) or lack of side effects (Brundusino and Cairoli, 1996), no severe
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adverse effects (Paschalis et aL 1978; Meltzer and Fieve. 1975; Fieve and Nleltzer. 1974; Fieve
et al., 1973). or adverse effects (Torta et aL. 1993; Placidi et aL. 1988). Gastrointestinal effects
such as vomiting, nausea, and diarrhea in humans were reported by both Placidi et aL (1988) and
Torta et aL (1993). Dogs treated with rubidium chloride also exhibited gastrointestinal irritation,
emesis, and colonic congestion (Stolk. 1974) concurring with gastrointestinal effects observed in
humans.
The POD for derivation of the screening sub chronic p-RfD from Placidi et al. (1988) is a
lowest-observed-adverse-effect level (LOAEL) of 5.3 mg/kg-day for adverse effects such as
diarrhea, vomiting/nausea, body-weight gain, excitation/agitation, confusion, and polyuria in
human patients. This POD represents the Week 1 average daily dose of 5.3 mg/kg-day, which
was the lowest average daily dose (ADD) reported where patients exhibited the aforementioned
adverse effects in the Placidi et al. (1988) study. The screening subchronic p-RfD is derived as
follows:
Screening Subchronic p-RfD = LOAEL UFc
= 5.3 mg/kg-day ^ 1,000
= 5 x 10 3 mg/kg-day
Table A-l summarizes the uncertainty factors for the screening subchronic p-RfD for
rubidium chloride.
Table A-l. Uncertainty Factors for the Screening Subchronic p-RfD for
Rubidium Chloride
UF
Value
Justification
UFa
1
A UFa of 1 is applied because a human study is selected as the principal study.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of rubidium chloride in humans.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The database
lacks a proper long-term exposure study, as well as reproductive and developmental toxicity studies in
either humans or animals. Additionally, convulsive seizures is one of the common hazards identified
in animal studies necessitating a need for a neurotoxicity study in the database.
UFl
10
A UFl of 10 is applied for LOAEL-to-NOAEL extrapolation because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because although the POD is based on a short-term-duration study, the severity
of adverse side effects in human subjects does not appear to increase following a longer treatment
duration (60 d) with an equivalent dose of rubidium chloride.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure.
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Derivation of a Screening Chronic Provisional Reference Dose (p-RfD)
Placidi et ai (1988) and other human studies were short-term-duration studies and are not
considered appropriate for deriving a screening chronic p-RfD. This is because the half-life of
rubidium in humans is 21-55 days (Fieve et al.. 19711 and approximately 80-100 days
(4-5 half-lives) is required to reach a steady state (Ito. 2011). Accordingly, the durations of
2-3 weeks or 60 days of rubidium exposure in the available human studies is not enough to
reach steady-state levels of rubidium in the body and may not be enough to capture all of the
effects of rubidium chloride following chronic-duration exposures. Furthermore, the Glendenine
et al. (1956) study in rats indicated that lower doses of rubidium chloride exposure takes a longer
time to develop toxicity, suggesting that severity of toxicity increases with an increase in
exposure duration. Hence, a screening chronic p-RfD was not derived from the available
short-term-duration studies.
Derivation of Screening Subchronic p-RfDs for Other Rubidium Compounds
The screening subchronic p-RfD derived for rubidium chloride is used as the basis for
calculating screening subchronic p-RfDs for additional rubidium compounds. Because the
toxicity of the various rubidium salts is expected to be due to rubidium itself, the toxicity of such
salts would be directly related to the fraction of the molecular weight contributed from rubidium.
Thus, based on molecular-weight adjustments to the screening subchronic p-RfD derived for
rubidium chloride (molecular weight = 120.92 g/mol) in this PPRTV assessment, the resulting
screening subchronic p-RfDs for other rubidium compounds are summarized in Table A-2 (see
calculations below).
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Screening Subchronic p-RfD Calculations for Rubidium Compounds9
Screening Subchronic p-RfD for Rubidium Hydroxide
= Screening Subchronic p-RfD for Rubidium Chloride
Rubidium Hydroxide ^ MW of Rubidium Chloride)
= 5 x 10~3 mg/kg-day x (102.48 g/mol 120.92 g/mol)
= 4 x 10"3 mg/kg-day
Screening Subchronic p-RfD for Rubidium Iodide
= Screening Subchronic p-RfD for Rubidium Chloride
Rubidium Iodide ^ MW of Rubidium Chloride)
= 5 x 10~3 mg/kg-day x (212.37 g/mol 120.92 g/mol)
= 9 x 10"3 mg/kg-day
Screening Subchronic p-RfD for Rubidium
= Screening Subchronic p-RfD for Rubidium Chloride
Rubidium Chloride)
= 5 x 10~3 mg/kg-day x (85.4678 g/mol 120.92 g/mol)
= 4 x 10"3 mg/kg-day
Table A-2. Molecular Weights and Screening Subchronic p-RfDs for
Rubidium Compounds
Compound
Fraction as Rubidium
(%)
Molecular Weight
(g/mol)
Screening Subchronic p-RfD
(mg/kg-d)
Rubidium Hydroxide
83.4
102.48
4 x 10-3
Rubidium Iodide
40.2
212.37
9 x 10-3
Rubidium
100
85.4678
4 x 10-3
X (MW of
x (MW of
x (MW of Rubidium MW of
9MW = molecular weight.
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APPENDIX B. REFERENCES
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of the rat submandibular gland. Toxic Subst Mech 17: 121-131.
ACGIH (American Conference of Governmental Industrial Hygienists). (2015). 2015 TLVs and
BEIs. Based on the documentation of the threshold limit values for chemical substances
and physical agents and biological exposure indices. Cincinnati, OH.
http://www.acgih.org/forms/store/ProductFormPublic/2015-tlvs-and-beis
Acobettro. RI; Ribas. B; Ortiz. T; Torres. IT. (1979). Role of monoamine oxidase isoenzymes in
rat motor activity after rubidium chloride treatment. Biochem Soc Trans 7: 534-536.
http://dx.doi.org/10.1042/bst007Q534
Alexander. GJ; Kopeloff. LM; Alexander. RB. (1980). Metrazol thresholds in inbred and non-
inbred audiosensitive mice. Neurotoxicology 2: 91-95.
Alexander. GJ: Meltzer. HL. (1975). Onset of audiogenic seizures in rodents after intake of near-
toxic doses of rubidium chloride. J Pharmacol Exp Ther 194: 480-487.
Allain. P; Leblonde. G: Diard. J: Premelca. A: Cailleux. A. (1974). [Influence of rubidium on
sleeping time induced by pentobarbital in mouse]. Arch Int Pharmacodyn Ther 211: 159-
164.
AT SDR (Agency for Toxic Substances and Disease Registry). (2016). Minimal risk levels
(MRLs). March 2016. Atlanta, GA: Agency for Toxic Substances and Disease Registry
(ATSDR). Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp
Bertelli. A: Giovannini. L; Romano. MR; Maltinti. G: DeH'Osso. L; Bertelli. AA. (1985).
Experimental comparative renal toxicity of lithium and rubidium. Drugs Exp Clin Res
11: 269-273.
Brundusino. AO: Cairoli. S. (1996). [The pharmacological action of rubidium chloride in
depression], Minerva Psichiatr 37: 45-49.
Cal/EPA (California Environmental Protection Agency). (201 1). Hot spots unit risk and cancer
potency values. Appendix A. Sacramento, CA: Office of Environmental Health Hazard
Assessment.
http://standards.nsf.org/apps/group public/download.php?document id= 19121
Cal/EPA (California Environmental Protection Agency). (2014). All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as of June 2014. Sacramento, CA: Office of
Health Hazard Assessment, http://www.oehha.ca.gov/air/allrels.html
Cal/EPA (California Environmental Protection Agency). (2016a). Chemicals known to the state
to cause cancer or reproductive toxicity July 15, 2016. (Proposition 65 list). Sacramento,
CA: California Environmental Protection Agency, Office of Environmental Health
Hazard Assessment, http://oehha.ca.gov/proposition-65/proposition-65-list
Cal/EPA (California Environmental Protection Agency). (2016b). OEHHA toxicity criteria
database [Database], Sacramento, CA: Office of Environmental Health Hazard
Assessment. Retrieved from http://www,oehha.ca. gov/tcdb/index.asp
Cameli, N; Bardazzi, F; Morelli. R; Tosti, A. (1990). Contact dermatitis from rubidium iodide in
eyedrops. Contact Derm 23: 377-378. http://dx.doi.Org/10.l 11 l/i.1600-
0536.1990.tb05182.x
Chatteriee. GC: Chatteriee. S: Chatteriee. K; Sahu. A: Bhattacharvva. A: Chakrabortv. D: Das.
PK. (1979). Studies on the protective effects of ascorbic acid in rubidium toxicity.
Toxicol Appl Pharmacol 51: 47-58.
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ChemlDplus. (2016). Rubidium iodide. Bethesda, MD: National Library of Medicine, National
Institutes of Health and Human Services. Retrieved from
http://www.chem.sis.nlm.nih.eov/chemidplus/name/rubidium%20iodide
Chow. CP; Cornish. HH. (1979). Possible mechanism of rubidium-induced hyperactivity in the
rat. Experientia 35: 1090-1091. http://dx.doi.org/10.1007/BF0194996Q
del Vecchio, M; Famiglietti, LA; Mai, M; Zizolfi, S; Borriello. R; Sciaudone, G. (1979). Kinetics
of lithium and rubidium after a single administration. Blood and plasma levels during 24
hours in human volunteers. Acta Neurol 1: 204-213.
Fieve. RR; Meltzer, H; Dunner. PL; Levitt M; Mendlewicz, J: Thomas, A. (1973). Rubidium:
Biochemical, behavioral, and metabolic studies in humans. Am J Psychiatry 130: 55-61.
Fieve. RR; Meltzer, FPL. (1974). Proceedings: Rubidium salts—toxic effects in humans and
clinical effects as an antidepressant drug. Psychopharmacol Bull 10: 38-50.
Fieve. RR; Meltzer. FPL; Taylor, RM. (1971). Rubidium chloride ingestion by volunteer subjects:
Initial experience. Psychopharmacology 20: 307-314.
http://dx.doi.org/10.1007/BF004Q3562
Furukawa, T; Tokuda, M. (1976). Effects of rubidium on behavioral responses to
methamphetamine and tetrabenazine. Jpn J Pharmacol 26: 395-402.
http://dx.doi.org/10.1254/iip.26.395
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