UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: September 30, 2007

MEMORANDUM

SUBJECT:	Sodium Fluoride Risk Assessment for the Reregistration
Eligibility Decision (RED) Document.  PC Code: 075202  (active). Case
No.  3132

		Regulatory Action:  Reregistration Eligibility Decision (RED) (Phase
I)

FROM:	Timothy F. McMahon, Ph.D.

		Senior Toxicologist

		Antimicrobials Division (AD) (7510P)

		And

		Jonathan Chen, Ph.D., Toxicologist

		Timothy Leighton, Exposure/Risk Assessor

		Richard Petrie, Agronomist

		A. Najm Shamim, Ph.D. Chemist

	            Antimicrobials Division (AD) (7510P)

TO:		Sanyvette Williams, D.V.M, Chemical Review Manager

		And

		Mark Hartman, Branch Chief

		Regulatory Management Branch II

		Antimicrobials Division (7510P)

Attached is the Risk Assessment for Sodium Fluoride The disciplinary
science chapters are also included as attachments and are listed on the
following pages.

Supporting chapters discussed in this Risk assessment and are included
as Appendices:

 Occupational and Residential/Bystander Assessment of the Antimicrobial
Use (Remedial Wood Treatment) of Sodium Fluoride for the Reregistration
Eligibility Decision (RED) Document. Timothy Leighton, Environmental
Scientist, August 2007.

Sodium Fluoride Product Chemistry  Chapter  for the Reregistration
Eligibility Decision Document (RED).  A. N. Shamim, August 2007.

Ecological Hazard and Environmental Risk Assessment Chapter for Sodium
Fluoride

RED.  Richard C. Petrie, July 2007.

Toxicology Chapter for Sodium Fluoride RED.    Timothy F.  McMahon,
August 2007.

Environmental Fate Science Chapter for Sodium Fluoride RED.  A. Najm.
Shamim.   August 2007.

Sodium Fluoride- Incident Report Summary.    Jonathan Chen, Ph.D.
August 2007.

TABLE OF CONTENTS

1.0	EXECUTIVE
SUMMARY………………………………………………………
………………..4

2.0	PHYSICAL AND CHEMICAL
PROPERTIES....……………………………………………..8

3.0	HAZARD
CHARACTERIZATION……………………………………….………
…………....9

   	 3.1	HAZARD
PROFILE………………………………………………………
……………..9

    	 3.2	FQPA
CONSIDERATIONS…………………………………………………
…………..9

   	 3.3	DOSE-RESPONSE
ASSESSMENT..............................................................
.................. 10

     	 3.4	ENDOCRINE
DISRUPTION……………………………………………………
…........12

.

4.0	EXPOSURE ASSESSMENT AND
CHARACTERIZATION………………………………........13

     	 4.1	SUMMARY OF REGISTERED
USES....................................................................
.........13

    	 4.2	DIETARY EXPOSURE AND
RISK....................................................................
.............13

     	 4.3	DRINKING WATER EXPOSURES AND
RISKS...................................................... ....13

    	 4.4	RESIDENTIAL EXPOSURES/RISK
PATHWAYS........................................................ 13

5.0	AGGREGATE RISK ASSESSMENT AND
CHARACTERIZATION………………………14

6.0	CUMULATIVE EXPOSURE AND
RISK……………………………………………………...14

7.0	OCCUPATIONAL EXPOSURE
ASSESSMENT……………………………………………...14

     	 7.1	SUMMARY OF REGISTERED
USES....................................................................
........ 14

     	 7.1.1	PRE-DRILLED HOLE
TREATMENTS………………............................................
.......16

 7.1.2	GROUNDLINE
TREATMENTS……........................................................
......................17

     	 7.2	APPLICATION RATES AND AMOUNT
HANDLED...................................................17

	7.3	EXPOSURE AND RISK
ESTIMATES…………………………………………………18

	7.4	DATA
LIMITATIONS/UNCERTAINTIES………………………………………
…….20

8.0
ENVIRONMENTALRISKS.……………………………………………..
..................................20

    	 8.1	ECOLOGICAL
HAZARD..................................................................
..............................20

    	 8.2	ENVIRONMENTAL FATE
ASSESSMENT..............................................................
.....26

    	 8.3	ENVIRONMENTAL EXPOSURE AND ECOLOGICAL RISK
ASSESSMENT..........26

    	 8.4	ENDANGERED SPECIES
CONSIDERATIONS..........................................................
..26

9.0	INDCIDENT
REPORTS………………………………………………………
………………...27

10.0
REFERENCES..............................................................
.................................................................30

11.0	APPENDIX
A.……………………………………………………………
……………………....39

1.0	EXECUTIVE SUMMARY

Hazard Characterization

	Sodium fluoride is registered for commercial use only as a wood
preservative for utility poles and railroad ties.  Sodium fluoride
products are used as supplemental wood treatments and are not intended
for primary wood preservative or pressure treated wood preservation.

Sodium Fluoride is an inorganic substance which does not undergo
hydrolysis typically like an organic compound. Sodium fluoride is water
soluble and dissociates in water.

The acute toxicity database for sodium fluoride is considered complete.
Sodium fluoride has a high order of toxicity via the oral route of
exposure (Toxicity Category II) and a moderate order of toxicity via the
dermal and inhalation routes of exposure (Toxicity Category III).
Primary eye irritation studies classify sodium fluoride as corrosive
(Toxicity Category I) whereas dermal irritation studies classify sodium
fluoride as a mild or slight irritant (Toxicity Category IV). Sodium
fluoride is not a dermal sensitizer.  Sodium fluoride does not appear to
be a primary developmental or reproductive toxicant based on the
available animal studies. Further data are needed in the neurotoxic and
endocrine effects of sodium fluoride.  Positive mutagenicity results
have been reported in mouse lymphoma assays, in chromosome aberration
assays, in unscheduled DNA synthesis assays, and in in vitro sister
chromatid exchange assays. Sodium fluoride has been classified as a
“Group D” (not classifiable as to carcinogenicity). The recent
conclusion of the 2006 National Academy of Sciences report supports this
classification, where the report concluded that

 “on the basis of the committee’s collective consideration of data
from humans, genotoxicity assays, and studies of mechanism of action in
cell systems…the evidence on the potential of fluoride to initiate or
promote cancers, particularly of the bone, is tentative and mixed.”

The database for metabolism consists of one study from the open
literature. In a study by Hall et al. 1977, 6 adult male New Zealand
rabbits were administered sodium fluoride in the diet (15 ppm), water (1
ppm), and  in a single oral dose injected (0.5 mg/kg ) directly into
stomach through nasal catheter. Urine excretion following oral
administration of sodium fluoride was 5 and 13% for 60 and 600 minutes,
respectively.  Under steady state conditions approximately 15% of
fluoride ingested in food and water was absorbed by the animals. 15% was
excreted in urine and 85% of ingested fluoride was removed via fecal
excretion.

Dose-Response Assessment

	For acute and chronic dietary risk assessments, no appropriate
endpoints were identified that represent a single dose effect.  Hence
these risk assessments are not required.

	For short-term (1-30 days) dermal risk assessment, a LOAEL of 20
mg/kg/day was selected based on based on significant reductions in body
weight gain and suppressed spontaneous motor activity in an oral
subchronic toxicity study in the rat. An uncertainty factor of 300 is
assigned (10x inter-species extrapolation, 10x intra-species variation,
3x for use of LOAEL) in this case.

	For intermediate-term (30 days-6 months) dermal risk assessment, a
NOAEL of 1.5 mg/kg/day was selected based on histopathology observed in
bone with degeneration in tibias and femurs of animals in a 6-month oral
toxicity study in the mouse. An uncertainty factor of 100 is applied
(10x inter-species extrapolation, 10x intra-species variation) in this
case.

For long-term (> 6months) dermal risk assessment, a LOAEL of 1.3
mg/kg/day was selected based on dentine dysplasia in males and females,
and ameloblast degeneration in males in a 2 year chronic
toxicity/carcinogenicity study in the rat. An uncertainty factor of 100
is assigned (10x inter-species extrapolation, 10x intra-species
variation) in this case.

For short-term (1-30 days) inhalation risk assessment, a LOAEL of 20
mg/kg/day was selected based on significant reductions in body weight
gain and suppressed spontaneous motor activity at a dose of 20
mg/kg/day, in an oral subchronic toxicity in the rat. An uncertainty
factor of 300 is assigned (10x inter-species extrapolation, 10x
intra-species variation, 3x for use of a LOAEL).

	For intermediate-term (30 days-6 months) inhalation risk assessment, a
NOAEL of 1.5 mg/kg/day was selected based on histopathology observed in
bone with degeneration in tibias and femurs of animals, in a 6-month
oral toxicity study in the mouse. An uncertainty factor of 100 is
assigned (10x inter-species extrapolation, 10x intra-species variation,
10x route extrapolation).

For long-term (> 6months) inhalation risk assessment, a LOAEL of 1.3
mg/kg/day was selected based on dentine dysplasia in males and females,
and ameloblast degeneration in males in a 2 year chronic
toxicity/carcinogenicity study in the rat. An uncertainty factor of 300
is assigned (10x inter-species extrapolation, 10x intra-species
variation, 3x for use of a LOAEL) in this case.

FQPA Considerations

	FQPA considerations are not applicable to sodium fluoride.  There are
no food use tolerances for this chemical and indirect food contact is
not expected from the current uses of this chemical.

Dietary Exposure and Risk

There are no antimicrobial uses for sodium fluoride which involve
dietary exposure, and thus a dietary exposure and risk assessment are
not needed for the antimicrobial uses of this chemical.

Drinking Water Exposure and Risk

The antimicrobial uses of sodium fluoride are not expected to pose a
hazard to ground water or surface water. Therefore, a drinking water
exposure and risk assessment is not needed.

Residential Post-application Exposure and Risk

Potential bystander risks to the remedial wood treatment uses of sodium
fluoride were assessed. The potential bystander inhalation exposure to
sodium fluoride is minimized by the extremely low vapor pressure. The
potential for dermal exposure to bystanders (i.e., children playing in
the vicinity of treated poles) is minimized by the enclosure of the
application site (i.e., capping of pre-drilled holes and groundline
applications covered with dirt).

Aggregate Exposure and Risk

	An aggregate risk assessment is not required for sodium fluoride.
Residential exposures  are assumed to be minimal as noted above from the
antimicrobial uses of  sodium fluoride.

Occupational Exposure

	The occupational and potential bystander risks to the remedial wood
treatment uses of sodium fluoride were assessed. The remedial wood
treatment is used to treat poles, crossties, structural timbers such as
bridge pilings and posts, etc., against decay producing fungi. Based on
label directions, two distinct application types were assessed including
predrilled hole treatments as well as groundline treatments. The
pre-drilled hole treatments are applied with pre-packaged insert
products and also mechanical pressure pumps. Exposure to the
pre-packaged insert products is expected to be negligible and is not
assessed quantitatively.  PPE should be required for these products to
mitigate potential exposure for leaks, etc.   The inhalation risks for
the pre-drilled hole spray applications using the mechanical pressure
pumps are not of concern.  However, dermal risks are triggered for this
application scenario for the treatment of distribution and transmission
poles.  Additionally, all of the dermal MOEs are below the target MOE
for the groundline brush-on treatments (MOEs less then or equal to 1).
The brush-on treatment also represents the high-end exposures for the
trowel-on and impregnated wraps.  Inhalation exposure is expected to be
minimal for the groundline treatments because of the viscosity of the
product as well as its low vapor pressure.

Ecological/Environmental Risk

	Sodium fluoride is registered for commercial use only as a wood
preservative for utility poles and railroad ties.  Sodium fluoride
products are used as supplemental wood treatments and are not intended
for primary wood preservative or pressure treated wood preservation.

	Sodium fluoride can be rolled or brushed onto an external wood surface
typically 3 inches above and 18 inches below the ground surface.  The
application is then wrapped with a water proof bandage.  Another method
of application is by drilling holes into the timber and inserting sodium
fluoride rods that contain pellets or tablets into the drilled holes.
The holes are then sealed with a plug or putty filler.

	Sodium fluoride is an inorganic substance which does not undergo
hydrolysis but is water soluble and dissociates in water to sodium and
fluoride ions.  Fluoride ions undergo hydrolysis to form hydrogen
fluoride acid and hydroxide ions which can shift the pH to alkaline.
Sodium fluoride does not adversely affect soil biomass, microflora and
macro invertebrates, and is not expected to be bio-accumulative.  A
field monitoring study of sodium fluoride treated poles found that
sodium fluoride ions occasionally exceed background levels and do not
migrate outward from treated poles more than 10 cm or for more than 50
cm deep.  Elevated levels returned to background by the end of the 18
month study.  Sodium fluoride is not expected to pose a hazard to
groundwater or surface waters.

	Sodium fluoride use as a wood preservative is not expected to pose an
adverse risk to terrestrial or aquatic animals or plants based on
current use patterns unless a spill were to occur. The use of water
proof wraps and sealed injections should serve to greatly reduce
environmental exposure.

Endangered Species

This preliminary analysis indicates that current sodium fluoride wood
treatment uses are not likely to enter the environment in sufficient
quantities to adversely affect terrestrial or aquatic species, however,
an endangered species effects determination will not be made at this
time.

Incident Reports

	There are only limited incidents associated with acute exposure to
sodium fluoride used in wood preservatives.  All the symptoms are
classified as either minor or moderate.  Historically, there are some
fatal incidents associated with oral exposure to sodium fluoride, but
this occurred at much higher concentrations.

Chronic fluoride intake has been shown to decrease the prevalence of
dental caries. However, high levels of fluoride exposure, especially by
the oral route, can cause dental fluorosis and can result in an
increased prevalence of bone fractures in the elderly or skeletal
fluorosis (ATSDR, 2003).

2.0	PHYSICAL AND CHEMICAL PROPERTIES

Table 2.1 Chemical Identity of Sodium Fluoride

Parameter	Sodium Fluoride

PC Chemical Code	075202

CAS Number	7681-49-4

Molecular Formula	NaF

Chemical Name	Sodium Fluoride

Synonyms	Chemifluoro, Dentafluoro, Villiaumite

Structure	Na-F

Table 2.2 Physical/Chemical Properties for Sodium Fluoride

 Parameter	Sodium Fluoride

Molecular Weight	42.00

Melting Point	993 o C

Boiling Point	1704 o C

Solubility	Water: 4.10 g/100 ml; at 15°C,

4.3 g/ 100 ml at 25 o C.

Alcohol: Insoluble

Vapor Pressure	5.43 x 10-26 mm Hg (25 o C)1

Log Kow	-0.77 1

Henry law Constant	5.04 x 10-33 atm m3/mole1

Bulk Density	37 in3/lb (95% technical grade)

Density	2.55 g/cm3

pH	Slightly Alkaline

1 The values have been taken form the US EPA’s EPI Suite Modeling
Program, developed by OPPT

3.0	HAZARD CHARACTERIZATION

	3.1	Hazard Profile

Acute Toxicity

Adequacy of database for Acute Toxicity: The acute toxicity database for
sodium fluoride is considered complete. For the technical grade active
ingredient, sodium fluoride has a high order of toxicity via the oral
route of exposure (Toxicity Category II) and a moderate order of
toxicity via the dermal and inhalation routes of exposure (Toxicity
Category III). Primary eye irritation studies classify sodium fluoride
as corrosive (Toxicity Category I) whereas dermal irritation studies
classify sodium fluoride as a mild or slight irritant (Toxicity Category
IV). Sodium fluoride is not a dermal sensitizer. The acute toxicity data
for sodium fluoride is summarized below in Table 3.1.

Table 3.1. Acute toxicity data for sodium fluoride technical a.i.

Guideline Number	Study Type/Test substance (% a.i.)	MRID Number/

Citation	Results	Toxicity Category

870.1100

(§81-1)

Acute Oral – Rat

Purity 95.6% - Sodium Fluoride

43778501

LD50 (combined) = 105 (93-119 CL)

Male LD50 = 120 mg/kg

Female LD50 = 89 mg/kg

II

870.1200

(§81-2)

Acute Dermal – Rat

Purity 95.6% - Sodium Fluoride

43778502

LD50 > 2000 mg/kg

III

870.1300

(§81-3)

Acute Inhalation - Rat

Purity 95.6% - Sodium Fluoride

43778503

LC50 = 1.00 mg/L

III

870.2400

(§81-4)

Primary Eye Irritation - Rabbit

Purity 95.6% - Sodium Fluoride

43778504

Severely irritating to unwashed eyes

II

870.2500

(§81-5)

Primary Dermal Irritation- Rabbit

purity 95.6% – Sodium Fluoride

43778505

Slightly Irritating

IV

870.2600

(§81-6)

	Dermal Sensitization - Guinea pig

purity 95.6 % - Sodium Fluoride

43778506

Buehler: Not a skin sensitizer

No

870.2600

(§81-6)

	Dermal Sensitization - Guinea pig

purity not reported

40866801

Not a dermal sensitizer

No

3.2	FQPA Considerations

	FQPA considerations are not applicable to sodium fluoride.  There are
no food use tolerances for this chemical and indirect food contact is
not expected from the current uses of this chemical.

3.3	Dose-Response Assessment

Summary of toxicology endpoint selection for sodium fluoride. Table 3.2

Table 3.2. Sodium Fluoride for Use in Human Risk Assessment

Exposure

Scenario	Dose (mg/kg/day) used in risk assessment

UF	Special FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Dietary Risk Assessments

Acute Dietary

(general population and females 13-49)

	No appropriate endpoints were identified that represent a single dose
effect.

Therefore, this risk assessment is not required.

Chronic Dietary

	No appropriate endpoints were identified that represent a single dose
effect.

    Therefore, this risk assessment is not required.

Non-Dietary Risk Assessments

Short -Term Dermal

(1 - 30 Days)

LOAEL = 20 mg/kg/day

Target MOE=300 (10x inter-species extrapolation, 10x intra-species
variation, 3x for use of LOAEL)

Oral Subchronic Toxicity – Rat (Sodium Fluoride)

LOAEL = 20 mg/kg/day, based on significant reductions in body weight
gain and suppressed spontaneous motor activity.

Intermediate -Term Dermal

(30 Days- 6 months)

NOAEL = 1.5 mg/kg/day

Target MOE=100 (10x inter-species extrapolation, 10x intra-species
variation)

6-month NTP oral toxicity study-mouse

LOAEL = 7.5 mg/kg/day based on  histopathology observed in bone with
degeneration in tibias and femurs of animals

Long-Term Dermal (> 6 months)

LOAEL = 1.3 mg/kg/day

TARGET MOE = 300 (10x inter-species extrapolation, 10x intra-species
variation and 3x for use of  LOAEL)

2-year NTP chronic toxicity/carcinogenicity study in rats

LOAEL = 1.3 mg/kg/day, based on   dentine dysplasia in males and
females, and ameloblast degeneration in males

Short-term Inhalation

(1-30 days)

LOAEL = 20 mg/kg/day

Target MOE=300 (10x inter-species extrapolation, 10x intra-species
variation, 3x for use of LOAEL)

Note: 10x route extrapolation for confirmatory inhalation study.

Oral Subchronic Toxicity – Rat (Sodium Fluoride)

LOAEL = 20 mg/kg/day, based on significant reductions in body weight
gain and suppressed spontaneous motor activity.

Intermediate-term Inhalation

NOAEL = 1.5 mg/kg/day

Target MOE=100 (10x inter-species extrapolation, 10x intra-species
variation)

Note: 10x route extrapolation for confirmatory inhalation study.

6-month NTP oral toxicity study-mouse

LOAEL = 7.5 mg/kg/day based on  histopathology observed in bone with
degeneration in tibias and femurs of animals

Long-term Inhalation

LOAEL = 1.3 mg/kg/day

TARGET MOE =300 (10x inter-species extrapolation, 10x intra-species
variation, 3x for use of LOAEL)

Note:  10x route extrapolation for confirmatory inhalation study.

2-year NTP chronic toxicity/carcinogenicity study in rats

LOAEL = 1.3 mg/kg/day, based on   dentine dysplasia in males and
females, and ameloblast degeneration in males

Cancer

Sodium fluoride has been classified as a “Group D” (not classifiable
as to carcinogenicity). This conclusion is consistent with the recent
report by the National Academy of Sciences which concluded that ‘the
evidence on the potential of fluoride to initiate or promote cancers,
particularly of the bone, is tentative and mixed.’

3.3.2	Dermal Absorption

There are no dermal absorption studies for sodium fluoride. Thus, dermal
absorption is conservatively assumed to be 100%.

3.3.3	Classification of Carcinogenic Potential

	Sodium fluoride has been classified as a “Group D” (inadequate
evidence of carcinogenicity).  This conclusion is consistent with the
recent report by the National Academy of Sciences which concluded that
‘the evidence on the potential of fluoride to initiate or promote
cancers, particularly of the bone, is tentative and mixed.’

3.4	Endocrine Disruption

	EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA),
as amended by the Food Quality Protection Act (FQPA), to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other endocrine effects as the Administrator may designate.”
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system.
EPA also adopted EDSTAC’s recommendation that EPA include evaluations
of potential effects in wildlife.  For pesticides, EPA will use FIFRA
and, to the extent that effects in wildlife may help determine whether a
substance may have an effect in humans, FFDCA authority to require the
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, sodium fluoride may be
subject to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1	Summary of Registered Antimicrobial Uses

	 Sodium fluoride is used as a remedial wood treatment for the
protection against decay producing fungi.  Table 7.1 summarizes the
various sodium fluoride label parameters used in this assessment
including EPA Reg. No., percent active ingredient, signal word, personal
protective equipment, and use directions/application methods.
Application techniques include a product-specific dispenser,
grease/caulking guns, pressurized sprayers, preservative cartridges,
brush-on and/or trowel-on applications.  The personal protective
equipment (PPE) listed on the label range from a minimum protection of
goggles to a maximum protection of goggles, gloves, and respirators.
Label PPE should be reviewed for accuracy and consistency.

     4.2 Dietary Exposure and Risk

There are no antimicrobial uses for sodium fluoride which involve
dietary exposure, and thus a dietary exposure and risk assessment are
not needed for the antimicrobial uses of this chemical.

	4.3 Drinking Water Exposure and Risk

The antimicrobial uses of sodium fluoride are not expected to pose a
hazard to ground water or surface water. Therefore, a drinking water
exposure and risk assessment is not needed.

	4.4	Residential Exposure/Risk Pathway

In general, remedial wood treatment for poles and beams on bridges do
not occur in high traffic areas for bystanders.  However, distribution
poles are numerous and often located in people’s front yards.  The
vapor pressure of sodium fluoride is negligible (i.e., 5.43 x 10-26 mmHg
at 25 C), and therefore, no vapor will be released in the vicinity of
treated poles.  Additionally, label directions to cap treated holes
after application will minimize any potential for dermal contact.
Likewise, groundline treatments are also covered (i.e., brush-on and
wrap treatments are below the groundline and then covered with dirt) and
will minimize potential dermal contact to children playing in areas of
treated poles.

5.0	AGGREGATE RISK ASSESSMENT AND CHARACTERIZATION

	In order for a pesticide registration to continue, it must be shown
“that there is reasonable certainty that no harm will result from
aggregate exposure to pesticide chemical residue, including all
anticipated dietary exposures and other exposures for which there are
reliable information.” Aggregate exposure is the total exposure to a
single chemical (or its residues) that may occur from dietary (i.e.,
food and drinking water), residential, and other non-occupational
sources, and from all known or plausible exposure routes (oral, dermal,
and inhalation).

An aggregate risk assessment was not performed for sodium fluoride.
There are no dietary exposures from the antimicrobial uses of sodium
fluoride, and residential exposures are assumed to be minimal.

6.0	CUMULATIVE EXPOSURE AND RISK

Risks summarized in this document are those that result only from the
antimicrobial uses of sodium fluoride. The Food Quality Protection Act
(FQPA) requires that the Agency consider “available information”
concerning the cumulative effects of a particular pesticide’s residues
and “other substances that have a common mechanism of toxicity.” The
reason for consideration of other substances is due to the possibility
that low-level exposures to multiple chemical substances that cause a
common toxic effect by a common toxic mechanism could lead to the same
adverse health effect as would a higher level of exposure to any of the
substances individually. Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding for
sodium fluoride. For information regarding EPA’s efforts to determine
which chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released
by EPA’s Office of Pesticide Programs concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/_"
http://www.epa.gov/pesticides/cumulative/ .

7.0	OCCUPATIONAL EXPOSURE ASSESSMENT

		7.1		Summary of Registered Uses

		Sodium fluoride is used as a remedial wood treatment for the
protection against decay producing fungi. Table 7.1 summarizes the
various sodium fluoride label parameters used in this assessment
including EPA Reg. No., percent active ingredient, signal word, personal
protective equipment, and use directions/application methods.
Application techniques include a product-specific dispenser,
grease/caulking guns, pressurized sprayers, preservative cartridges,
brush-on and/or trowel-on applications.  The personal protective
equipment (PPE) listed on the label range from a minimum protection of
goggles to a maximum protection of goggles, gloves, and respirators.
Label PPE should be reviewed for accuracy and consistency.

Table 7.1.  Summary of Sodium Fluoride Labels.

EPA Reg No.	% ai	Signal Word	PPE	Label Directions

(e.g., application techniques, rates,etc)

3008-58	97.5	Danger	Respirator, goggles	Includes a non pesticide
statement

75340-2

	54.92	Warning	Gloves	TIE-GARD dispenser; grease gun; pressurized
applicator; Apply to drilled holes to “fill” and cap; Used on rail
road ties and structural timbers such as bridge pilings and posts.

75341-6	92.6	Danger	Gloves	FLURODS (i.e., preservative cartridges, solid
sticks) placed into drilled holes and capped.  For treating poles,
posts, timbers, crossties, etc.  Rate:  39.2 grams/cubic foot wood.

75341-4	70.6	Danger	Gloves, goggles	PoleWrap.  Groundline treatment.
Dig 20 inches around pole, wrap down to 18 inches below groundline to 2
inches above groundline and cover with dirt.

75341-5	44.4	Danger	Goggles	Used in combination with copper naphthenate.
 Brush-on, trowel-on, grease gun.  1/16th of an inch rate 18 inches
below and 3 inches above groundline and covered with a wrap.  Also used
in drilled holes applied by a grease gun and capped (paste density 12
lbs/gallon).

75341-12	8.39	Danger	Gloves, goggles, respirator, and respirator when
spraying for continued or prolonged use or frequent use	Used in
combination with copper naphthenate.  Mix 1 gallon of product with 1.5
gallons of water.  Apply using air or mechanical pressure pump into
prepared opening (assume pre-drilled).  Rate:  1 gallon of treatment
solution per cubic foot of wood.

75341-13	44.42	Warning	Goggles, face shield or safety glasses,
protective clothing, and chemical resistant-gloves	Used in combination
with copper naphthenate.  Brush-on, trowel-on, grease gun.  1/16th of an
inch rate 18 inches below and 3 inches above groundline and covered with
a wrap.  Also used in drilled holes applied by a grease gun and capped.

Chemical-specific exposure data were not submitted to support the
remedial wood applications. Therefore, AD developed a screening-level
assessment using surrogate data to determine the potential risks
associated with remedial wood treatment. Based on the label review
listed in Table 7.1 above, there are two basic remedial applications:
(1) applying product into pre-drilled holes; and (2) applying product
around the circumference of poles at or below the groundline. Each
remedial application can be applied using various techniques. Surrogate
exposure data are not available for all application techniques specified
on the label. Representative exposure scenarios (i.e., application
techniques) are used to represent the potential worker short-,
intermediate, and in some cases long-term durations of inhalation and
dermal exposures. Table 7.2 presents the representative exposure
scenarios used to assess the labeled remedial wood treatment uses.

Table 7.2.  Representative Exposure Scenarios for Remedial Wood
Treatments.

Remedial Applications	High-end Exposure Scenarios	Application Techniques
Represented by the High-end Exposure Scenario

Pre-drilled holes	Closed systems (PPE mitigation)	TIE GARD dispenser for
rail ties; FLURODS (solid sticks)

	Sprays	Grease/caulking gun; air or mechanical pressure pump

Groundline	Brush-on	Brush; Trowel; PoleWrap (dry wrap)

7.1.1	Pre-Drilled Hole Treatments

TIE-GARD and FLURODS:

TIE-GARD and FLURODS are sodium fluoride products that are inserted into
pre-drilled holes and capped are expected to result in minimal
inhalation and dermal handler exposure because the products are
engineered to be closed systems.  The FLURODS are solid sticks that are
placed in the pre-drilled holes.  TIE-GARD is a gel product containing
sodium fluoride.  The automated rail tie use is packaged in 30 gallon
PVC closed head drums.  It is applied from high capacity rubber track
machinery that rides on railroads and automatically injects the gel
product into rail ties.  Any potential for exposure from leaks/spills
from these products (i.e., TIE GARD and FLURODS) is believed to be best
mitigated by the label requirement of PPE such as chemical resistant
gloves, goggles, long pants, and long sleeved-shirts.  Therefore, the
handler risks to pre-packaged products are not quantified.

Spray/Injection Applications:

Although EPA does not have a specific surrogate exposure scenario for
injection of pesticides into wooden poles, similar exposure data for
hand-held application equipment exist.  The spray application is
believed to represent the high end of exposure to the grease gun.  The
exposure data for hand-held applications that are available to EPA
include data from the Pesticide Handlers Exposure Database (PHED) and
the Outdoor Residential Exposure Task Force (ORETF).  The data available
from these sources are for garden hose-end sprayers, low pressure
hand-wands, backpack sprayers, high pressure handwands, and rod shank
termiticide applications.  The most representative data available for an
injection-type hand-held devise is the rod shank termiticide application
from PHED.  Other equipment types are not believed to be as
representative because each one involves a spray and the injection into
the pole will minimize spray.

The rod shank termiticide injection data in PHED are used to develop a
screening-level assessment for the pole use.  The dermal unit exposure
(UE) for combined liquid pour and termiticide injection is based on 17
replicates with the test subjects wearing a single layer of clothing and
chemical resistant gloves with AB grades (i.e., guideline
recommendations for analytical quality).  The dermal UE is 0.36 mg/lb
ai.  The inhalation UE is based on the same 17 replicates and the grades
are also AB.  The inhalation UE is 0.0022 mg/lb ai.  Although not all of
the labels currently specify the use of chemical resistant gloves (e.g.,
EPA Reg. No. 75341-5), the “gloved” clothing scenario is the only
one available to assess risks.

		7.1.2	Groundline Treatments

Groundline treatments consist of brush and trowel-on applications as
well as impregnated wraps around poles. Once applied, the pole treatment
is covered with dirt.  The most representative surrogate exposure data
available to assess the high-end of the exposure potential are for
painting with a paint brush. The product is expected to have a much
higher viscosity then paint. Because of the high viscosity and low vapor
pressure, inhalation exposure is expected to be minimal. Dermal unit
exposure values for paint brush applications from PHED were used (single
layer of clothing). The dermal unit exposure is 24 mg/lb a.i. for the
painting scenario for a test subject wearing long pants, long-sleeved
shirt, and chemical resistant gloves.

	7.2	Application Rates and Amounts Handled

Label directions indicate that sodium fluoride is applied into poles,
timbers, etc, via four different formulations; paste, bandage or wrap,
liquid and solid rods. The application for these formulations is very
different from each other due to the physical properties and percentage
of sodium fluoride present in each formulation. Typically paste
formulations are applied by brush-on application around the groundline
area of pole and then wrapped with a protective barrier before being
backfilled with dirt. The dry impregnated wrap is applied around the
groundline portion of the pole. Liquid formulations are normally applied
to internal voids through means of pressurized injection and rods are
applied by drilling application holes, inserting the rods into the holes
and then plugging them.

Labeled application rates for pastes are to apply by brush to a
thickness of 1/16th inch.  The dry wrap is applied by cutting the wrap
to match the circumference of the pole. Liquid application instructions
include filling application holes to refusal and more specific
instructions such as 1 gallon of diluted solution per cubic foot of
wood.  However, label directions are not provided to determine neither
the number of holes per pole nor the number of cubic feet per pole to be
treated with sodium fluoride. Therefore, for this assessment 1 cubic
foot of wood per pole is assumed to be treated for the spray/injection
application.

Specific amounts of sodium fluoride applied by workers daily are not
available.  Therefore, in addition to the number of cubic feet treated
per pole, the number of poles treated per day (i.e., pre-drilled
treatments, not groundline applications) with sodium fluoride was also
estimated.

The amount of paste applied to each pole for groundline treatments is
estimated to be 0.167 gallons/pole for distribution poles and 0.255
gallons per transmission pole (i.e., 21 inch wide treatment x up to 34
inch circumference for distribution poles and 50 inches for transmission
poles x 1/16 inch thickness of product treatment).

Distribution Poles - the smaller diameter wooden distribution poles
(~140 million distribution poles in service) are treated at a high end
rate of ~24 per day (for short-term duration).  Workers treat these
types of poles as their main work function, treating 5 days per week, on
a yearly basis (i.e., 250 days/year).  This scenario is represented by
the short-, intermediate- and long-term exposure durations.

Transmission Poles -  the larger wooden transmission poles are treated
at a rate of 30 per day. Workers treat these types of poles as their
main work function, treating 5 days per week, on a yearly basis (i.e.,
250 days/year).  This scenario is represented by the short-,
intermediate- and long-term exposure durations.

7.3	Exposure and Risk Estimates

	Table 7.3 presents the potential dermal and inhalation short-,
intermediate-, and long-term exposures and risks for the remedial pole
treatment uses of sodium fluoride.   The exposure and risks to handlers
of the TIE-GARD product used in the automated rail tie treatment system
and the solid stick FLURODS are expected to be minimal and are not
quantified.

For the spray applications into pre-drilled holes for the transmission
poles, the inhalation (all durations) and short-term dermal risks are
not of concern.  However, the short-, intermediate- and long-term dermal
risks for the transmission poles are of concern.  The short-,
intermediate- and long-term dermal MOEs are 280, 21 and 18,
respectively, with a target MOE of 300 for short-term and 100 for
intermediate-term.

All of the dermal MOEs are below the target MOE for the groundline
brush-on treatments (MOEs less then or equal to 1).  The brush-on
treatment also represents the high-end exposures for the trowel-on and
impregnated wraps.  Inhalation exposure is expected to be minimal for
the groundline treatments because of the viscosity of the product as
well as its low vapor pressure

Table 7.3.  Dermal and Inhalation Exposure and Risks for Remedial
Applications of Sodium Fluoride to Poles.

 Application

 	Dermal UE

(mg/lb a.i)	Inhalation UE

(mg/lb a.i)	Rate

(gal/pole)	Rate

(lb a.i/gal)

# poles	Dermal dose

(mg/kg/day)	Inhalation dose

(mg/kg/day)	Dermal MOEs	Inhalation MOEs

ST (300)	IT (100)	LT (300)	ST (300)	IT (100)	LT (300)

Spray (Distribution Poles)

 	0.36	0.0022	1	0.47	24	0.058	0.00035	350	26	22	56,000	4200	3700

	Spray (Transmission Poles)

 	0.36	0.0022	1	0.47	30	0.073	0.00044	280	21	18	45,000	3400	2900

	Brush-on (Distribution Poles)

 	24	NA	0.225	5.33	24	5.17	NA	4	NA	NA	NA

	Brush-on (Transmission Poles)

 	24	NA	0.368	5.33	30	20.2	NA	1	NA	NA	NA

UE are from PHED for termiticide MLAP, liquid pour, rod shank injection

Dermal UE is single layer of clothing and chemical resistant gloves.

Treatment solution for spray from EPA Reg. No. 75341-12 (i.e., 1 gal
product x 8.34 lb/gal x 8.39% a.i / 1.5 gallons water = 0.47 lb a.i/gal
treatment solution)

Brush-on rate EPA Reg No 75341-5 is 44.4% a.i; density of 12lb/gal =
5.33lb a.i./gallon

# poles =  registrant estimate during the reregistration phase 1 error
comment period (Distribution is 24 poles per day and transmission is 30
poles per day

Dermal (mkd) = Dermal UE x rate x # poles x 1/70kg

Inhalation dose (mkd) = Inhalation UE x rate x #poles x 1/70kg

MOE ST Dermal & inhalation = LOAEL 20 mkd / dose;  UF = 300

MOE IT Dermal & Inhalation = NOAEL 1.5 mkd / dose; UF = 100

MOE LT Dermal & Inhalation = LOAEL 1.3 mkd / dose; UF = 300

NA = Not applicable (e.g., short-term (ST) MOEs are only applicable for
the high treatment frequency of poles).

ST = short-term; IT = intermediate-term; LT = long-term.

7.4	Data Limitations/Uncertainties

EPA has used the best available surrogate exposure data from PHED and
CMA to develop a screening-level assessment for the handlers of sodium
fluoride. The following uncertainties should be considered by the
regulatory risk managers during the decision making process:

Unit exposures are not available for the scenarios that are prescribed
for remedial pole injection.  Nonetheless, the data from PHED for
combined mixing/loading/injecting a liquid termiticide is a reasonable
surrogate for the pole treatment as the label for the remedial wood
treatment indicates to apply a spray into predrilled holes with an air
or mechanical pressure pump. The PHED termiticide scenario is considered
to be of “high confidence” (i.e., 17 replicates of Grade AB data –
indicating the analytical portion of the study meets EPA exposure test
guidelines).

Sodium fluoride is used to treat both poles and timbers. The assessment
for the remedial wood treatments is based on applications to
distribution and transmission poles as representative of all the
remedial treatments. Although it is unknown how many timbers in a bridge
or other structure are treated, the pole use is believed to be
representative of the high end use.

 The use information for the remedial pole treatments is based on the
registrant’s response during the error comment period.  The
individuals contacted have experience in these operations and their
estimates are believed to be the best available without undertaking a
statistical survey of the uses.

8.0	ENVIRONMENTAL RISKS

8.1	Ecological Hazard

	8.1.1	Toxicity to Terrestrial Animals

		<IP_ADDRESS>   Birds, Acute

	In order to establish the toxicity of sodium fluoride to avian species,
the Agency requires an acute oral toxicity study using the technical
grade active ingredient (TGAI).  The preferred test species is either
mallard duck (a waterfowl) or bobwhite quail (an upland game bird).  The
results of one acute oral toxicity study submitted for sodium fluoride
are provided in the following table (Table 8.1).

Table 8.1.  Acute Oral Toxicity of Sodium Fluoride to Birds

Species

Chemical,

% Active Ingredient

(a.i.)

Tested

Endpoint

(mg/kg)

Toxicity Category

Satisfies Guidelines/

Comments

Reference

(MRID No.)

Bobwhite quail

(Colinus virginianus)

	Sodium

Fluoride

95%	LD50 = > 387

NOAEL =  45

	Moderately toxic

Yes (core)

43611501

	This acceptable acute oral toxicity study on the bobwhite quail
indicates that sodium fluoride is moderately toxic on an acute oral
basis. The guideline requirement OPPTS 850.2100 is satisfied.

	<IP_ADDRESS>	   Birds, Subacute

	A subacute dietary study using the TGAI may be required on a
case-by-case basis depending on the results of lower-tier ecological
studies and pertinent environmental fate characteristics in order to
establish the toxicity of a chemical to avian species.  The
preferred-test species are the mallard duck and bobwhite quail.  The
results of subacute dietary toxicity studies for sodium fluoride are
provided in the following table (Table 8.2).

Species

Chemical,

% Active Ingredient

(a.i.)

Tested

Endpoint

(ppm)

Toxicity Category

Satisfies Guidelines/

Comments

Reference

(MRID No.)

Bobwhite quail

(Colinus virginianus)	Sodium

Fluoride

95%

LC50 (diet) = >5620

NOAEC = 1000

	Practically

nontoxic	Yes (core)

-	8-day test duration

	43593102

Mallard duck

(Anas platyrhynchos)	Sodium

Fluoride

95%

LC50 (diet) = >5620

NOAEC = 5620

	Practically

nontoxic	Yes (core)

-	8-day test duration

	43593101

Table 8.2.  Subacute Oral Toxicity of Sodium Fluoride to Birds

	Sodium fluoride is practically nontoxic to avian species through
subacute dietary exposure. These studies fulfill guideline requirements
OPPTS 850.2200 (Bobwhite quail and Mallard duck).

<IP_ADDRESS>   Mammals, Acute and Chronic Toxicity

Wild mammal testing is not required by the Agency.  In most cases, rat
toxicity values obtained from studies conducted to support data
requirements for human health risk assessments substitute for wild
mammal testing.  Refer to the human toxicology chapter for mammalian
toxicity data.

		<IP_ADDRESS>.   Non-target Insects

Honeybees should not be exposed to sodium fluoride wood treatments due
to the requirement to wrap the treated area with a waterproof barrier or
the requirement to inject sodium fluoride into the wood and then seal
the bore hole.  Beehives should not be constructed from or treated with
sodium fluoride.  The product label(s) must state:  “Sodium fluoride
must not be used to treat wood intended for construction or maintenance
of beehives.”  Otherwise, the following bee toxicity and honey residue
studies are required:  850.3020, 850.3030 and 860.1500.

8.1.2	Toxicity to Aquatic Animals

			<IP_ADDRESS>   Freshwater Fish, Acute

	In order to establish the acute toxicity of sodium fluoride to
freshwater fish, the Agency requires a freshwater fish toxicity studies
using the TGAI.  Preferred test species are rainbow trout (a cold water
fish) and bluegill sunfish (a warm water fish).  The results of two
freshwater fish acute studies submitted for sodium fluoride are
presented in Table 8.3.

 Table 8.3.  Acute Toxicity of Sodium Fluoride to Freshwater Fish

Species

Chemical,

% Active Ingredient

(a.i.)

Tested

Endpoint

(mg/L)

Toxicity Category

Satisfies Guidelines/

Comments

Reference

(MRID No.)

Bluegill Sunfish (Lepomis macrochirus)

Sodium fluoride

   95%

LC50 = 830

NOAEC = 350

Practically nontoxic

Yes (core)

-	96-hr test duration

-	static renewal test system

	43648201

Rainbow Trout (Oncorhynchus mykiss)

Sodium fluoride

   95%

LC50 = 317

NOAEC = < 26

Practically nontoxic

Yes (core)

-	96-hr test duration

-	static test system

	43648202

	Freshwater acute toxicity tests indicate that sodium fluoride is
practically nontoxic to fish on an acute basis.  Study 43648201 fulfills
the guideline requirement for the warm water species and study 43648202
fulfills the guideline requirement for the cold water fish species under
OPPTS 850.1075.

<IP_ADDRESS>   Freshwater Invertebrates, Acute

The Agency requires a freshwater aquatic invertebrate study using the
TGAI to establish the acute toxicity to freshwater invertebrates.  The
preferred test species is Daphnia magna.  The result of one study
submitted for sodium fluoride is provided in the following table (Table
8.4).

Table 8.4.  Acute Toxicity of Sodium Fluoride to Freshwater
Invertebrates

Species

Chemical,

% Active Ingredient

(a.i.)

Tested

Endpoint

(mg/L)

Toxicity Category

Satisfies Guidelines/

Comments

Reference

(MRID No.)

Waterflea (Daphnia magna)

Sodium Fluoride

95%

EC50 = > 120

NOAEC = 120

Practically nontoxic

Yes (core)

-	48-hr test duration

-	static test system

43648203

	The results of 43648203 indicate that sodium fluoride is practically
nontoxic to freshwater invertebrates.  This study fulfills guideline
requirement OPPTS 850.1010.

		<IP_ADDRESS>   Estuarine and Marine Organisms, Acute

	Acute toxicity testing with estuarine and marine organisms using the
TGAI is required when the end-use product is intended for direct
application to the marine/estuarine environment or effluent containing
the active ingredient is expected to reach this environment.  The
preferred fish test species is the sheepshead minnow.  The preferred
invertebrate test species are mysid shrimp and eastern oysters.  Sodium
fluoride is not expected to reach the estuarine or marine environment,
therefore, studies OPPTS 850.1075, OPPTS 850.1035, and OPPTS 850.1025
are not required for the current wood treatment use patterns.

			<IP_ADDRESS>   Aquatic Organisms, Chronic

	Chronic toxicity tests (fish early life stage and aquatic invertebrate
life cycle) are required for pesticides when certain conditions of use
and environmental fate apply.  The preferred freshwater fish test
species is the fathead minnow.  The preferred freshwater invertebrate is
Daphnia magna. Sodium fluoride is not expected to present a chronic
aquatic toxicity concern, therefore, studies OPPTS 850.1300 and OPPTS
850.1400 are not required for the current wood treatment use patterns.

		8.1.3	Toxicity to Plants

	Non-target plant phytotoxicity tests are required for pesticides when
certain conditions of use and environmental fate apply. Tests are
conducted with one species of aquatic vascular plant (Lemna gibba) and
four species of algae: (1) freshwater green alga, Selenastrum
capricornutum, (2) marine diatom, Skeletonema costatum, (3) freshwater
diatom, Navicula pelliculosa, and (4) bluegreen cyanobacteria, Anabaena
flos-aquae. The rooted aquatic macrophyte rice (Oryza sativa) is also
tested in seedling emergence and vegetative vigor tests.

Current sodium fluoride wood treatment use patterns are not expected to
result in surface water or spray drift residues of sufficiently large
quantities to adversely affect terrestrial or aquatic plant species.
Therefore, non-target plant toxicity studies 850.4225, 850.4400, and
850.5400 are not required for the current wood treatment use patterns.

8.1.4	RISK QUOTIENTS

	Risk characterization integrates the results of the exposure and
ecotoxicity data to evaluate the likelihood of adverse ecological
effects.  The means of this integration is called the quotient method.
Risk quotients (RQs) are calculated by dividing exposure estimates by
acute and chronic ecotoxicity values.

RQ =   EXPOSURE/TOXICITY

RQs are then compared to OPP's levels of concern (LOCs).  These LOCs are
used by OPP to analyze potential risk to nontarget organisms and the
need to consider regulatory action.  The criteria indicate that a
pesticide used as directed has the potential to cause adverse effects on
nontarget organisms.  LOCs currently address the following risk
presumption categories: (1) acute -- potential for acute risk to
non-target organisms which may warrant regulatory action in addition to
restricted use classification, (2) acute restricted use -- the potential
for acute risk to non-target organisms, but may be mitigated through
restricted use classification, (3) acute endangered species - endangered
species may be adversely affected by use, (4) chronic risk - the
potential for chronic risk may warrant regulatory action, endangered
species may potentially be affected through chronic exposure, (5)
non-endangered plant risk – potential for effects in non-target
plants, and (6) endangered plant risk – potential for effects in
endangered plants.   Currently, OPP does not perform assessments for
chronic risk to plants, acute or chronic risks to nontarget insects, or
chronic risk from granular/bait formulations to birds or mammals.

The ecotoxicity test values (measurement endpoints) used in the acute
and chronic risk quotients are derived from required studies.  Examples
of ecotoxicity values derived from short-term laboratory studies that
assess acute effects are: (1) LC50 (fish and birds), (2) LD50 (birds and
mammals), (3) EC50 (aquatic plants and aquatic invertebrates) and (4)
EC25 (terrestrial plants).  Examples of toxicity test effect levels
derived from the results of long-term laboratory studies that assess
chronic effects are: (1) LOAEC (birds, fish, and aquatic invertebrates),
and (2) NOAEC (birds, fish and aquatic invertebrates). For birds and
mammals, the NOAEC generally is used as the ecotoxicity test value in
assessing chronic effects, although other values may be used when
justified. However, the NOAEC is used if the measurement endpoint is
production of offspring or survival.

Risk presumptions and the corresponding RQs and LOCs are tabulated below
in Table 8.5.

Table 8.5. Risk Presumption Categories

Risk Presumption for Terrestrial Animals

LOC

  Acute: Potential for acute risk for all non-target organisms

>0.5

  Acute Restricted Use: Potential for acute risk for all non-target
organisms, but may be mitigated through restricted use classification

>0.2

  Acute Endangered Species: endangered species may be adversely affected
by use

>0.1

  Chronic Risk: potential for chronic risk may warrant regulatory action

>1

Risk Presumption for Aquatic Organisms

LOC

  Acute: Potential for acute risk for all non-target organisms

>0.5

  Acute Restricted Use: Potential for acute risk for all non-target
organisms, but may be mitigated through restricted use classification

>0.1

  Acute Endangered Species: endangered species may be adversely affected
by use

>0.05

  Chronic Risk: potential for chronic risk may warrant regulatory action

>1

Risk Presumption for Terrestrial and Aquatic Plants

LOC

  Potential for risk for all non-endangered and endangered plants

>1

	8.2	Environmental Fate Assessment

Sodium fluoride is an organic substance which does not undergo
hydrolysis but is water soluble and dissociates in water to sodium and
fluoride ions.  Fluoride ions undergo hydrolysis to form hydrogen
fluoride acid and hydroxide ions which can shift the pH to alkaline.
Sodium fluoride does not adversely affect soil biomass, microflora and
macro invertebrates, and is not expected to be bio-accumulative.  A
field monitoring study of sodium fluoride treated poles found that
sodium fluoride ions occasionally exceed background levels and do not
migrate outward from treated poles more than 10 cm or for more than 50
cm deep.  Elevated levels returned to background by the end of the 18
month study.  Sodium fluoride is not expected to pose a hazard to
groundwater or surface waters. (Refer to the Environmental Fate Science
Chapter for greater detail.)

8.3	Environmental Exposure and Ecological Risk Assessment

An environmental risk assessment was not conducted for sodium fluoride
wood treatment uses because precautions are taken to prevent release
into the terrestrial or aquatic environment. Some exposure to
woodpeckers and wood boring insects may occur, however, sodium fluoride
is practically nontoxic to avian and aquatic species tested.  Any
incidental exposure is not expected to be toxic to non-target species.

8.4	Endangered Species Considerations

Section 7 of the Endangered Species Act, 16 U.S.C. Section 1536(a)(2),
requires all federal agencies to consult with the National Marine
Fisheries Service (NMFS) for marine and anadromous listed species, or
the United States Fish and Wildlife Services (FWS) for listed wildlife
and freshwater organisms, if they are proposing an "action" that may
affect listed species or their designated habitat.  Each federal agency
is required under the Act to insure that any action they authorize,
fund, or carry out is not likely to jeopardize the continued existence
of a listed species or result in the destruction or adverse modification
of designated critical habitat.  To jeopardize the continued existence
of a listed species means "to engage in an action that reasonably would
be expected, directly or indirectly, to reduce appreciably the
likelihood of both the survival and recovery of a listed species in the
wild by reducing the reproduction, numbers, or distribution of the
species." 50 C.F.R. ( 402.02.

To facilitate compliance with the requirements of the Endangered Species
Act subsection (a) (2) the Environmental Protection Agency, Office of
Pesticide Programs has established procedures to evaluate whether a
proposed registration action may directly or indirectly reduce
appreciably the likelihood of both the survival and recovery of a listed
species in the wild by reducing the reproduction, numbers, or
distribution of any listed species (U.S. EPA 2004).  After the
Agency’s screening-level risk assessment is performed, if any of the
Agency’s Listed Species LOC Criteria are exceeded for either direct or
indirect effects, a determination is made to identify if any listed or
candidate species may co-occur in the area of the proposed pesticide
use.  If determined that listed or candidate species may be present in
the proposed use areas, further biological assessment is undertaken.
The extent to which listed species may be at risk then determines the
need for the development of a more comprehensive consultation package as
required by the Endangered Species Act.

This preliminary analysis indicates that current sodium fluoride wood
treatment uses are not likely to enter the environment in sufficient
quantities to adversely affect terrestrial or aquatic species, however,
an endangered species effects determination will not be made at this
time.

9.0	INCIDENT REPORTS

The Agency reviewed the following information for human poisoning
incidents related to sodium fluoride use: (1) OPP Incident Data System
(IDS) – The Office of Pesticides Programs (OPP) Incident Data System
contains reports of incidents from various sources, including
registrants, other federal and state health and environmental agencies
and individual consumers, submitted to OPP since 1992; (2) California
Department of Pesticide Regulation (1982-2004) - The California
Department of Pesticide Regulation pesticide poisoning surveillance
program consists of reports from physicians of illness suspected of
being related to pesticide exposure since 1982. (3) National Pesticide
Information Center (NPIC) – NPIC is a toll-free information service
supported by OPP that provides a ranking of the top 200 active
ingredients for which telephone calls were received during calendar
years 1984-1991. (4) National Poison Control Centers (PCC) (1993-1996).
(5) Incident Reports / Epidemiological Studies Published in Scientific
Literature

	Between 1993 and 2003 there were 5 reported incidents in the American
Association of Poison Control Centers Toxic Exposure Surveillance System
(TESS). From 1993-1998 two cases involving oral exposure were reported
with patients exhibiting symptoms such as blurred visions, chest and
abdominal pain as a result of the exposure. These were considered to be
moderate effects and were not life-threatening and the patients have
returned to a pre-exposure state of well-being with no residual
disability or disfigurement. From 1999-2003, three cases (two involving
oral exposure and one involving aerosol inhalation exposure) were
reported. For oral exposure, vomiting was the primary reported symptom
while nausea and headache were the primary reported symptoms for
inhalation exposure. These three cases were classified as minor effects
as symptoms resolved rapidly and subjects returned to a pre-exposure
state of well being with no residual disability or disfigurement.

	The California Department of Pesticide Regulation has one reported
incident involving sodium fluoride where a worker applying wood
preservative to the base of a telephone pole, got some on his cheek.
While wiping it off with his sleeve, he rubbed it into his left eye.  He
flushed the eye with a portable kit. The reported symptoms included
pain, burning sensation, and marked conjunctival infection in the left
eye. However, creosote and potassium dichromate may also have been
involved in this incident.

	There are some concerns associated with sodium fluoride exposure
reported in the public literature.

Acute Effects

Direct contact with fluoride can result in tissue damage. At high
concentrations, fluoride can cause irritation and damage to the
respiratory tract, stomach, and skin following inhalation, oral, and
dermal exposure, respectively (ATSDR, 2003).  Dermal irritation and
contact urticaria have been reported from dermal contact of sodium
fluoride (Camarasa et al., 1993).

There are incidences associated with sodium fluoride through acute oral
ingestion (Abukurah et al. 1972; Hayes, 1975; Eichler et al., 1982). As
summarized by Dreisbach (1987), through oral exposure, soluble fluoride
salts may cause salivation, nausea and vomiting, diarrhea, and abdominal
pain. Later, weakness, tremors, shallow respiration, carpopedal spasm,
and convulsions occur. Death is by respiratory paralysis. If death does
not occur immediately, jaundice and oliguria may appear. Experience with
oral fluoride supplements used to prevent tooth decay has been
reassuring; no adverse effects occur unless enormous amounts are
ingested. A variety of metabolic disorders may occur including
hypocalcemia, hypomagnesemia, metabolic and/or respiratory acidosis and
sometimes hyperkalemia, may also occur in acute fluoride poisoning
(Gosselin, et al., 1984).

llation. For example, a plasma fluoride level of 2,000 μg/L was
reported in a case of severe oral poisoning with 53 g fluoride as sodium
fluoride (Abukurah et al. 1972).  The noticed cardiac symptoms may be
associated with the metabolic disorder resulted from acute fluoride
exposure.

Chronic Effects

Fluoride intake has been shown to decrease the prevalence of dental
caries.  However, chronic exposure to high levels of fluoride,
especially through the oral route, can cause dental fluorosis and can
result in an increased prevalence of bone fractures in the elderly or
skeletal fluorosis (ATSDR, 2003).

Numerous epidemiological studies have examined the issue of a connection
between fluoridated water and heart disease. There are studies
indicating no significant differences between areas with different
fluoride levels in mortality due to coronary disease, angina, and other
heart disease (Leone et al. 1954; Heasman and Martin 1962).  Although
one study demonstrated a positive relationship between heart disease and
water fluoridation (Hagan et al. 1954), this study was criticized for
not properly age-adjusting the sample population  (Jansen and Thomson,
1974).  Other studies have suggested fluoridation can decrease the
incidence of cardiovascular disease (Bernstein et al. 1966; Luoma 1980;
and Taves, 1978).

Numerous epidemiological studies have examined the issue of a connection
between fluoridated water and cancer. Most studies have not found
significant increases in cancer mortality (Erickson 1978; Hoover et al.
1976; Rogot et al. 1978; Taves 1977) or site-specific cancer incidence
(Freni and Gaylor 1992; Gelberg et al. 1995; Hoover et al. 1976; Mahoney
et al. 1991; McGuire et al. 1991). However, a couple of studies have
reported significant fluoridation-related increases in cancer mortality.
 In order to address the cancer concern,  the National Toxicology
Program (NTP) conducted two chronic oral bioassays of fluoride
administered as sodium fluoride (0, 25, 100, or175 ppm) in drinking
water for 103 weeks, using F344/N rats and B6C3F1 mice (NTP, 1990). The
estimated total fluoride intake (including fluoride in both water and
diet) of control, low-, medium-, and high-dose male rats was 0.2, 0.8,
2.5, and 4.1 mg/kg/day, respectively. Similarly, the high doses for
female rats, male mice, and female mice were 4.5, 8.1, and 9.1
mg/kg/day, respectively. The study found osteosarcomas in the bone of
1/50 male rats in the mid-dose group and 3/80 of the high dose male
rats. An additional high-dose male had an extra skeletal osteosarcoma in
subcutaneous tissue. Osteosarcomas were observed in one low-dose male
mouse, one low-dose female mouse, and one control female mouse. There
was also one osteoma in a control female mouse. No osteosarcomas were
observed at mid- or high-dose levels in female rats or male or female
mice.

In 1996, the EPA’s Office of Prevention, Pesticides, and Toxic
Substances classified sodium aluminofluoride (cryolite) as a “Group
D” carcinogen (not classifiable as to carcinogenicity), citing the
National Toxicology Program’s carcinogenicity study of sodium fluoride
(NTP, 1990). More recently, the National Academy of Sciences (NAS, 2006)
at the request of the EPA conducted a review of the toxicologic,
epidemiologic, and clinical data on fluoride since the 1993 NAS report.
With respect to carcinogenicity, the 2006 NAS report concluded that
“on the basis of the committee’s collective consideration of data
from humans, genotoxicity assays, and studies of mechanism of action in
cell systems…the evidence on the potential of fluoride to initiate or
promote cancers, particularly of the bone, is tentative and mixed.”
This recent conclusion is consistent with the past conclusion of OPPTS
regarding carcinogenic potential of fluoride.

10.0	REFERENCES

Toxicology References

MRID						CITATION

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40928204	Naas, D. (1988). Primary Irritation Study in Albino Rats with
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43778504	Wnorowski, G. (1995). Primary Eye Irritation (in Rabbits):
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43778505	Wnorowski, G. (1995). Primary Skin Irritation (in Rabbits):
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43778506	Wnorowski, G. (1995). Dermal Sensitization Test-Buehler Method
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after In Vivo Treatment with Sodium Fluoride. Mutation Res 170:85-92.

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Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
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Tsutsui T, et al.  (1984). Sodium Fluoride-Induced Morphological and
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Tsutsui, T., N. Suzuki, et al.  (1984). Cytotoxicity, Chromosome
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Environmental Fate References

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                                                     Unpublished study
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65p.

43648202 		Collins, M.  1995.  “Osmose Sodium Fluoride CTM—Acute
Toxicity to Rainbow Trout (Oncorhynchus mykiss) Under Static-Renewal
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43648201 		Collins, M.  1995.  “Osmose Sodium Fluoride CTM—Acute
Toxicity to Bluegill sunfish (Lepomis macrochirus) Under Static-Renewal
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Supporting Documents

Committee on Fluoride in Drinking Water, National Research Council.
Fluoride in Drinking Water: A Scientific Review of EPA’s Standards.
The National Academies Press. Last accessed on July 30, 2007.
HYPERLINK "http://www.nap.edu/catalog.php?record_id=11571%23toc"
http://www.nap.edu/catalog.php?record_id=11571#toc

APPENDIX A

Toxicity Profile for Sodium Fluoride

Table 5.  Subchronic, Chronic, and other Toxicity Profiles for Sodium
Fluoride

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number (Year)/

Citation/

Classification/ Doses	Results

870.3100 (§ 82-1)

90-Day oral toxicity in rodents

Purity: 99%

Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
Publication No. 91-2848, December 1990, Pgs. 1-477.

Acceptable

Guideline

10 F344/N rats/sex/dose administered sodium fluoride at doses of 0, 10,
30, 100, or 300 ppm for 6 months

NOAEL = 30 ppm

LOAEL = 100 ppm, based on the presence of hyperplasia in the glandular
stomach

There were no treatment-related effects on mortality.
Treatment-related effects were noted in 300-ppm treated rats including
clinical observations of dental fluorosis (chalk white appearance of
teeth, overgrowth of upper incisors, occlusal surface of the lower
incisor worn to the gum, unusual wear pattern of incisors) and rough
hair coat, decreased food and water consumption, and

reductions in mean body weight and body weight change.

Measurement of fluoride content revealed a dose-dependent increase in
fluoride concentration in bone and urine, while elevated levels of
fluoride in plasma were only observed in 300-ppm treated rats.

r stomach was observed in rats treated with ≥100 ppm.  Diffuse
hyperplasia of the mucosal epithelium of the glandular stomach was noted
in 5/10 males and 2/10 females treated with 100 ppm, and in 10/10 males
and 9/10 females treated with 300 ppm.  This effect was accompanied by
minimal individual cell necrosis (apoptosis) in the pyloric region in
300-ppm treated rats, and by evidence of acute inflammation in several
males at 300 ppm.  Focal basal cell hyperplasia of the stratified
squamous epithelium was located adjacent to the limiting ridge in nearly
all 300-ppm treated rats.   Microscopic evidence of the effects of the
test article on the incisors included focal or multifocal degeneration
of the enamel organ in 300-ppm males (5/10), localized in the maturation
zone near the apical end of the tooth.

870.3100 (§ 82-1)

90-Day oral toxicity in rodents

Purity: 99%

Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
Publication No. 91-2848, December 1990, Pgs. 1-477.

Acceptable

Guideline

8-12 B6C3F1 mice/sex/dose administered deionized water at doses of 0,
10, 50, 100, 200, 300 or 600 ppm for 6 months

NOAEL = 50 ppm in female mice, and could not be determined in males
based on the observation of increased osteoid of the tibia in 5/10 males
dosed at 50 ppm.

LOAEL = 50 ppm in male mice and 100 ppm in female mice based on
histopathology observed in bone.

Premature deaths, including sacrifice due to moribundity, occurred at
300 ppm (1 male) and 600 ppm (4 males and 9 females) dose levels.
Clinical signs of thin appearance, hunched posture and weakness were
observed in several of the decedents prior to premature sacrifice.
Clinical signs in surviving animals included chalky white incisors
(≥100 ppm) and chipped teeth (≥300 ppm).  The effects on the
incisors correlated with microscopic findings, which included focal or
multifocal degeneration of the enamel organ. Mean body weight was
significantly decreased in 600-ppm treated males and in 200- and 300-ppm
treated females.  Mean body weight gain was significantly decreased in
≥200-ppm males and in 200- and 300-ppm females.  These parameters were
also decreased in the 600-ppm females, but did not reach statistical
significance, likely due to the reduced number of animals in this group
as a result of premature deaths.  Food consumption in 600-ppm males was
approximately 77% of controls.  Food consumption in the other treatment
groups and water consumption in all treatment groups were within 20% of
control values.

There was a dose-dependent increase in fluoride content in bone and
urine.  Due to the pooling of plasma samples for sufficient volume for
analysis, meaningful statistical analyses in this fluid could not be
performed.  The data indicate that there was generally a dose-dependent
increase in fluoride concentration in the plasma.

a) in ≥300-ppm treated mice.

Non-Guideline

Oral Subchronic (Rodent)

Purity  not reported

Bohatyrewicz, A. (1999). Effects of Fluoride on Mechanical Properties of
Femoral Bone in Growing Rats. Fluoride 32:47-54.

Open Literature

10 female 6-week-old Wistar rats/group administered NaF at levels of 0,
8, 30, and 60 mg of fluoride/L in drinking water for 6 weeks.

Femoral bones from each rat were assayed for bending strength

High fluoride intake (30 and 60 mg/L) significantly decrease bone
quality of the femoral shaft and neck of young rats.

NaF administered in lower concentrations (8 mg/L) significantly
increases the strength of the femoral neck from the control.

Non-Guideline

Oral Subchronic (Rodent)

Purity  not reported

Paul, V. et al. (1998). Effects of Sodium Fluoride on Locomotor Behavior
and a Few Biochemical Parameters in rats. Environmental Toxicol and
Pharmacol 6:187-191.

Open literature

10 female Wistar rats/dose administered Sodium Fluoride via oral
intubation at dose levels of 20 or 40 mg/kg/day for 60 days.

Subchronic Toxicity:

NOAEL < 20 mg/kg/day (lowest dose tested)

LOAEL ≤ 20 mg/kg/day based on significant reductions in body weight
gain and suppressed spontaneous motor activity.

There were significant dose-dependant decreases of 17 and 30% for food
intake and 14 and 37% for body weight gain at the 20 and 40 mg/kg/day
dose levels, respectively. Total protein concentrations in serum
(low-dose, 13%; high-dose, 38%), liver (low-dose, 22%; high-dose, 42%),
and skeletal muscle (low-dose, 15%; high-dose, 31%) were also
significantly reduced in a dose-related manner in animals treated with
sodium fluoride.

Spontaneous motor activity was suppressed in a dose-dependant manner
with decreases of 15 and 29% at the 20 and 40 mg/kg/day dose levels,
respectively. However, motor co-ordination was not altered in treated
animals. Total blood cholinesterase activity was reduced at the low- and
high-dose, although there was no evidence of change in
acetyl-cholinesterase activity of the cerebral cortex, brain stem, or
cerebellum.

Food intake reductions may account for the decrease in protein
concentration of a direct deleterious action of fluoride on protein
metabolism can also play a role in depleting protein in sensitive
tissues. Thus, a decreased food intake together with a depletion of
protein in soft tissues accounted for an inhibition of body growth in
sodium fluoride-treated animals. Sodium fluoride deprived skeletal
muscle of total protein and suppressed blood cholinesterase activity;
although, these effects are unlikely to have a deteriorating action on
neuromuscular function. However, similar sodium fluoride doses can
produce neurobehavioral deficit resulting in an inhibition of
spontaneously occurring locomotor activity.

Non-Guideline

Oral Subchronic (Rodent)

Purity  not reported

Pillai et al. (1988). Effect of Subacute Dosage of Fluoride on Male
Mice. Toxicology Letters 44:21-29.

Open Literature

5 Male Swiss albino mice administered 5.2 mg F/kg/day for 35 days.

NOAEL ≤ 5.2 mg/kg/day (lowest dose tested)

LOAEL ≤ 5.2 mg/kg/day, based on significant decreases in body weight
gain, and food and water consumption.

There were significant changes in hematological analyses with decreases
in red blood cells, lymphocytes, hemoglobin, albumin, total protein,
cholesterol, glucose, and alkaline phosphatase. Statistically
significant increases were observed in white blood cells, monocytes,
basophils, and eosinophils. Food and water consumption was significantly
decreased in treated animals compared to controls. There were
significant treatment-related decreases from controls in body weight
gain of sodium fluoride-treated mice after day 19 of the treatment
period. A significant relationship between food and water consumption
and the body weight was observed in the controls, but not in the treated
animals.

Significant increases in fluoride content were measured in the kidneys,
stomach, brain, liver, and intestines of the sodium-fluoride-treated
animals when compared to the controls. The increases were 3.5- and 1.5
fold greater than control in the kidneys and stomach, respectively,
while the brain, intestines, and liver exhibited 2-fold increases over
control. There was no evidence of sperm abnormalities following
treatment with sodium fluoride.

Non-Guideline

Oral Subchronic (Rodent)

Purity: 99%

Chinoy and Patel. (2001). Effects of Sodium Fluoride and Aluminum
Chloride on Ovary and Uterus of Mice and Their Reversal by Some
Antidotes. Fluoride 1:9-20.

Open Literature

20 Adult female albino mice administered 10 mg/kg/day NaF for 30 days.

Significant decline of ovarian protein and 3-beta- and
17-beta-hydroxysteroid dehydrogenase activities, which could be related
to increased cholesterol levels in the ovary suggesting altered
steroidogenesis.

Special Study

Subchronic (subcutaneous injection) Toxicity

Purity  not reported	Shahshi et al. (1994). Effect of Long-term
Administration of Fluoride on Levels of Protein, Free Amino Acids and
RNA in Rabbit Brain. Fluoride 27.3:155-159.

Open Literature

Albino rabbits administered sodium fluoride via subcutaneous injection
for 100 days at 0, 5, 10, 20, and 50 mg/kg/day.

12 animals/group

Fluoride treated rabbits showed a significant decline in soluble, basic,
and total protein and free amino acid levels. RNA content rapidly
decreased, except in male rabbits treated with 5 and 10 mg/kg/day sodium
fluoride.

Decreased body weight gain in the 20 and 50 mg/kg/day groups.

Some animals in the 10, 20, and 50 mg/kg/day groups showed paralysis by
day 35. No rabbits in the 50 mg/kg/day group survived the experiment.

870.3700a

Developmental

Toxicity (Rodent)

Purity > 99%

Bates et al. (1994). Final report on the developmental toxicity of
sodium fluoride

(Cas No. 7681-49-4) in Sprague-Dawley rats. RTI, RTP NC, for NTP
(PB95-110193).

Open Literature

Administered ad libitum in deionized/filtered drinking water to
Sprague-Dawley-derived rats (26/group) on

Gestation days 6-15 at levels 0, 50, 150, or 300 ppm. Rats killed on
gestation by day 20 and examined.

Feed contained 12.4 ppm.

Maternal toxicity:

NOAEL = 18 mg/kg/day

LOAEL = 27 mg/kg/day, based on reduced maternal body weight.

There were no treatment-related clinical signs, increases in mortality
(100% survival), or decreases in body weight in rats dosed with sodium
fluoride. The maternal body weight gain during

the first two days of exposure (GD 6 to 8) was significantly reduced
(55%) at 300 ppm (27 mg/kg/day) relative to controls. The mean maternal
body weight gain and water consumption during the treatment period was,
also, significantly reduced, possibly due to a decrease in palatability.

Reproductive toxicity:

NOAEL ≥ 27 mg/kg/day (highest dose tested)

LOAEL > 27 mg/kg/day ( not established)

There were no treatment-related effects on mean live fetal body weight
/litter, and the number of live fetuses. A dose-related increase in the
percent of litters with one or more externally malformed fetuses, the
percent of externally malformed fetuses/litter, and the percent of
skeletally malformed fetuses/litter occurred however was not
statistically significant.

870.3700a

Developmental

Toxicity (Rodent)

Purity  not reported

Collins, T et al. (1995). Developmental Toxicity of Sodium Fluoride in
Rats. Fd Chem Toxicol 33:951-960.

Open Literature

Female (CD:CRL: CD-BR, VAF+) rats were given drinking water containing

0, 10, 25, 100, 175, or 250 ppm Fluoride (0, 1.4, 3.9, 15.6, 24.7, or
25.1 mg/kg bw)

34, 35, 33, 33, 33, 35 female rats for each dose

Caesarean sections were performed on gestation day 20.

Maternal Toxicity:

NOAEL = 175 ppm (24.7 mg/kg/day)

LOAEL = 250 ppm (25.1 mg/kg/day), based on significant reductions in
body weight gain, and food and water consumption.

There were no incidences of maternal mortality, changes in behavior,
clinical signs, or mottled teeth in dams treated with sodium fluoride.
In the 100

ppm dose group, there was 1 female rat that exhibited multiple,
apparently random, clinical findings (exudate from the eye and nose, and
overgrown teeth) that was not associated with treatment. The 250 ppm
dose group experienced significant decreases in food and water
consumption, and body weight gain that were 7, 30 and 11 % respectively,
less than controls. A significant reduction (10.7%) from control, in
fluid consumption was observed in animals treated with 175 ppm sodium
fluoride; however, there were no other treatment-related changes found
at this dose level.

Reproductive toxicity:

NOAEL ≥ 250 ppm (25.1 mg/kg/day; highest dose tested)

LOAEL > 250 ppm (25.1 mg/kg/day; not established)

The pregnancy rate was greater than 90% for all groups. There was a
significant decrease in the mean number of corpora lutea/female in dams
of the 250 ppm dose group; however, because number of corpora lutea is
determined at birth, this decrease is considered to be random. There
were no significant changes in reproductive parameters in treated
animals when compared to controls.

Developmental toxicity:

NOAEL ≥ 250 ppm (25.1 mg/kg/day; highest dose tested)

LOAEL > 250 ppm (25.1 mg/kg/day; not established)

There were no treatment-related effects in fetal body weight, litter
sizes, or viable fetuses. Several external variations were observed in
control and treated animas; however, there were no significant increases
in the number of fetuses with at least 1, 2 or 3 variations, or in the
number of litters with fetal sternebral variations. There was no
evidence of teratogenicity observed in the rats following administration
of phenol.

870.3700a

Developmental

Toxicity (Rodent)

Purity > 99%

Heindel, J. et al. (1996). Developmental Toxicity Evaluation of Sodium
Fluoride Administered to Rats and Rabbits in Drinking Water. Fund
Applied Toxicol 30:162-177.

Open Literature

Administered ad libitum in deionized/filtered drinking water to
Sprague-Dawley rats (26/group) on gestation days 6-15 at levels 0, 50,
150, or 300 ppm (0, 6.6, 18.3, or 27.1 mg/kg/day, respectively).  Rats
killed on gestation day 20 and examined.

Feed contained 15.6 ppm.

Maternal toxicity:

NOAEL = 18.3 mg/kg/day

LOAEL = 27.1 mg/kg/day, based on reduced maternal body weight gain

There were no treatment-related clinical signs, increases in mortality
(100% survival), or decreases in body weights in rabbits dosed with
sodium fluoride at the low- and mid-dose.  The maternal body weight gain
of the high dose group on GD 6-8 was 56% less than the controls.  During
the treatment period, as a whole, there was not a significant difference
in mean body weight gain; however, a decreasing trend that approached
statistical significance was observed.  The water consumption during the

treatment period was significantly reduced at the high-dose.  The food
consumption was decreased at the high-dose during GD 8-10, but was
normal thereafter.

Reproductive toxicity:

NOAEL >= 27.1 mg/kg/day (highest dose tested)

LOAEL > 27.1 mg/kg/day (not established).

There were no changes in reproductive parameters in treated animals when
compared to controls.

Developmental toxicity:

NOAEL >= 27.1 mg/kg/day (highest dose tested)

LOAEL > 27.1 mg/kg/day (not established)

There were no treatment-related effects on mean live fetal body
weight/litter, live fetal number, and prevalence of malformations.

870.3700b

Developmental

Toxicity (Non- Rodent)

Purity > 99%

Heindel, J. et al. (1996). Developmental Toxicity Evaluation of Sodium
Fluoride Administered to Rats and Rabbits in Drinking Water. Fund
Applied Toxicol 30:162-177.

Open Literature

Administered ad libitum in deionized/filtered drinking water to New
Zealand White rabbits (26/group) on gestation days (6-19 at levels of 0,
50, 150, or 300 ppm. Rats killed on gestation day 30 and examined.

Feed contained 15.6 ppm

Maternal toxicity:

NOAEL = 18 mg/kg/day

LOAEL = 29 mg/kg/day, based on reduced maternal body weight gain.

There were no treatment-related clinical signs, increases in mortality
(100% survival), or decreases in body weights in rabbits dosed with
sodium fluoride at the low- and mid-dose. The high-dose (400 ppm) group,
during GD 6 to 8, experienced a mean weight loss of 112 grams versus a
mean weight gain of 14 grams for the control. During the GD 10 to 12,
the 400 ppm group recovered with a mean weight gain of 71 grams versus
22 grams for the control. During the treatment period, as whole, there
was not a significant difference in mean body weight gain. The water
consumption during the treatment period was significantly reduced,
possibly due to a decrease in palatability. The food consumption was
decreased during the first four days of treatment, but was normal
thereafter.

Reproductive toxicity:

NOAEL ≥ 29 mg/kg/day (highest dose tested)

LOAEL > 29 mg/kg/day (not established)

There were no changes in reproductive parameters in treated animals when
compared to controls.

Developmental toxicity:

NOAEL ≥ 29 mg/kg/day (highest dose tested)

LOAEL > 29 mg/kg/day (not established)

There were no treatment-related effects in mean live fetal body
weight/litter, live fetal number, and prevalence of malformations.

Non-guideline Developmental

Toxicity (Rodent)

Purity not reported

Elbetieha, A et al. (2000). Fertility Effects of Sodium Fluoride in Male
Mice. Fluoride 33:128-134.

Open Literature

80 sexually mature Swiss mice exposed to 0, 100,

200, 300 ppm NaF via drinking water for 4 weeks (0, 12.35, 21.80, 39.19
mg/kg/day) and 10 weeks (0, 8.85, 15.64, 27.25 mg/kg/day) (10
mice/group/exposure period)

Males mated after exposure periods to untreated female mice

2/10 and 3/10 mice died during 10 week exposure at 100 and 300 ppm,
respectively.

200 and 300 ppm for 4 weeks caused significant increase in the relative
weights of preputial glands. Mice tested for ten weeks showed no
significant increase in any reproductive organ.

Mice tested for 4 weeks ha d no effect on male fertility. 100, 200 and
300 ppm for 10 weeks caused a significant increase in resorptions, a
decrease in implantations and pregnancies in untreated females mated
with NaF treated males.

870.3800

Reproduction

Purity not reported

Collins, T et al. (2001). Developmental Toxicity of Sodium Fluoride
Measured During Multiple Generations. Fd Chem Toxicol 39:867-876.

Open Literature

Administered 0, 25, 100, 175, 250 mg of NaF in drinking water to (CD
CRL: CD-BR) rats continuously for three generations. Parental generation
(F0) was treated for ten weeks and mated within groups. On gestation day
20m caesarian sections were performed on 8 F0 females per group and
their litters (F1) observed. The remaining F0 females were allowed to
litter. Caesarian sections were performed on all of the F1 generation
females (36/group) and were
observed愠潬杮眠瑩桴楥⁲楬瑴牥⹳ഠഇ慍整湲污琠硯
捩瑩㩹

NOAEL ≥ 250 ppm (highest dose tested)

LOAEL > 250 ppm (not established)

There were no treatment-related effects on maternal mortality. A
significant decrease from control in fluid consumption (30%) was
observed at the 250 ppm dose level. There were no other changes in F0
maternal generation. There were significant decreases from control of 28
and 31% in fluid consumption in the F1 dams at the 175 and 250 ppm dose
levels, respectively. The decreases in fluid consumption corresponded
with decreased palatability of the solution. Food consumption was
significantly reduced (11%) in F1 dams when compared to control in the
175 ppm dose group. There was a 14% decrease from control in the body
weight gain of F1 females (dams) treated with 175 ppm. These reductions
at 175 ppm were considered random because of the lack of effect in the
150 pp, group. Gravid uterine weight measurements showed no doe-related
differences.

Reproductive toxicity:

NOAEL ≥ 250 ppm (highest dose tested)

LOAEL > 250 ppm (not established)

There were no treatment-related effects in the mean number of corpora
lutea, mean number of implantation sites, implantation efficiency, mean
number of viable fetuses, and average percentage of early and late
deaths per litter of dams.

Offspring toxicity:

NOAEL = 175 ppm

LOAEL = 250 ppm, based on decreased ossification of the hyoid bone.

Fetal body weight was not affected by treatment with sodium fluoride.
There was no evidence of toxicity in fetuses or pups of the F1
generation. Similarly, the F2 generation fetuses and pups were
unaffected by treatment with sodium fluoride with the exception of
decreased ossification of the hyoid bone in the F2 fetuses at the 175
(not significant) and 250 ppm (significant) dose groups.

870.3800

Reproduction

Purity not reported

Collins, T et al. (2001). Multigenerational Evaluation of Sodium
Fluoride in Rats. Food and Chemical Toxicology 39.6:601-13.

Open Literature

Rats administered 0, 25, 100, 175, or 250 ppm NaF in drinking water
throughout three generations.

The Maternal toxicity NOAEL is ≥ 250 ppm (highest dose tested). The
Maternal toxicity LOAEL > 250 ppm (not established).

Reproductive toxicity:

 NOAEL ≥ 250 ppm (highest dose tested).

LOAEL > 250 ppm (not established).

Rats were monitored daily during the 10 week growth period and only 2
animals died; 1 F0 male at 25 ppm and 1 F1 female of control dose
groups. There were no dose-related clinical effects observed. No
significant differences were observed in F0 female food consumption
while there was a 5% decrease (significant) reduction in F0 males at 250
ppm (in the first 7 weeks, and week 9 of the 10 week growth period). F1
females exhibited an overall decrease in food consumption but never
significantly different for control. Males of the F1 generation consumed
less food than controls but in a dose-related or significant manner.

Fluid consumption was significantly reduced from control levels in the
175 and 250 ppm dose groups with decreases of 11 and 20% for F0 females,
9 and 20% for F0 males, 19 and 29% for F1 females, and 15 and 25% for F1
males, respectively. F1 males in the 100 ppm dose group drank
significantly less (9%) than control animals. The decrease in fluid
consumption was attributed to a reduced palatability.

Weight gain of F0 females and males showed a significant negative linear
regression for the 10 weeks but only the individual weight gain of F0
males in 250 ppm dose group was statistically significantly less than
controls. There was a 6% reduction from 367.0 to 345.9 g in first
generation females treated with the high-dose (250 ppm) of sodium
fluoride.

F0 female mating indices (mating and fertility) were over 90% in all
groups, although these were slightly (but not significantly) decreased
at the 250 ppm sodium fluoride dose level. Similarly, F1 female mating
indices exceeded 90% with slight but not significant decreases in the 25
and 250 ppm groups; indicating a lack of compound-related effects. There
were no significant or dose-related effects observed in implantation and
reproductive

parameters of any generation.

Survival indices of the F2 generation (implantation, live-births, days
4, 7, 14, and 21 survival and lactation indices) were calculated for
both male and female offspring. Neither significant nor dose-related
effects were observed (data not shown in this study).

870.3800

Reproduction

Purity not reported

Messer et al. Influence of Fluoride Intake on Reproduction in Mice. J.
Nutr. 103:1319-1326.

Open Literature

Weaning female albino mice administered 0, 50, 100, and 200 ppm NaF via
drinking water to 58, 55, 50, and 50 animals, respectively.

Females mated and litters were normalized to 6 pups and a maximum of 4
litters were analyzed.

Second generation mice from control and 50 ppm groups (38 and 44
animals, respectively) were mated and followed the same parameters as
the parental group.

Maternal Toxicity:

Offspring toxicity: Retardation of growth in the 100 and 200 ppm F1
groups, with death in 50% of animals in the 200 ppm groups by 8 weeks of
age.

Reproductive toxicity: No litter production at the 200 ppm group and
only 9 litters at the 100 ppm over a ten-week period. 50 ppm group had
progressive decrease in litter production in both generations, but
considered insignificant differences.

Non-guideline Reproduction

Purity not reported

Araibi et al. (1989). The Effect of High Fluoride on the Reproductive
Performance of the Male Rat. J. Biol. Sc. Res. 20:19-20.

Open Literature

Male albino rats administered sodium fluoride in the diet for 60 days

15 mice/dose

100 or 200 ppm

Lesions on the teeth (mottling and erosion of enamel), a characteristic
commonly associated with sodium fluoride exposure, were observed in
animals at the end of the experiment. Males treated with sodium fluoride
seemed to show less interest toward females when compared to those
animals of the control group. The number of pregnant females were
decreased 10 and 40% from controls in groups treated with 100 and 200
ppm, respectively. High-dose animals exhibited significant reductions in
the number of pregnant females. The number of newborns produced by the
100 and 200 ppm dose groups were 30 and 57% (significant), respectively,
less than controls. There was a decrease in average litter size for both
dose levels, although neither reduction was significantly different from
controls.

Mean tubular diameters were significantly less than controls with 3 and
7% decreases in diameter for the 100 and 200 ppm dose levels,
respectively. There were 94 and 93% (significant) increases in
peritubular membrane thickness in the low- and high-dose groups,
respectively. Treatment of animals with 200 ppm sodium fluoride resulted
in significant decreases from control in percentage of seminiferous
tubules containing spermatozoa. There were decreases in mean
testosterone levels in the serum of treated animals with 29
(nonsignificant) and 71% (significant) reductions from controls observed
in the 100 and 200 ppm dose groups, respectively There was a decrease in
reproductive performance of male rats exposed to a high intake of sodium
fluoride in spite of the absence (until the end of the experiment) of
clinical signs in the teeth that are characteristic features of
fluorosis. The testes of 200 ppm sodium fluoride-treated rates exhibited
impairments of spermatogenesis based on changes in mean diameter of
seminiferous tubules, the thickness of peritubular membranes,
spermatozoa, and serum testosterone levels. The researchers suggested
that sodium fluoride appears to be antispermatogenic and the decrease in
testosterone may account for the decrease of mated females in sodium
fluoride-treated groups.

Non-guideline Reproduction

Purity not reported

Ream et al. (1983). Bone Morphology of Weaning Rats from Dams Subjected
to Fluoride. Cell Tissue Res 233:689-691.

Open Literature

0 or 150 ppm fluoride as NaF in drinking water administered to 12 female
Sprague-Dawley rats for 10 weeks prior to breeding and during 3
successive pregnancy and lactation periods.

Rebreeding periods commenced immediately following a 3 week lactation
period and all litters were normalized to 8 pups were sacrificed and
femur removed for analysis.

The amount of fluoride transferred to the offspring and incorporated
into the skeleton is not sufficient to cause a visible structural
alteration in the growth and development if the long bones.

Non-guideline Reproduction

Purity not reported

Shivarajashankara et al. (2002). Histological Changes in the Brain of
Young Fluoride-Intoxicated Rats. Fluoride 35:12-21.

Open Literature

0.5 (control), 30 or 100 ppm fluoride (as NaF) in drinking water
administered to female Wistar albino rats, respectively, during the last
(3rd) week of pregnancy and throughout the lactation period.

Litters exposed to same dose levels for up to ten weeks.

30 ppm fluoride did not show any notable alterations in brain histology,
whereas rats exposed to 100 ppm fluoride showed significant
neurodegenerative changes in the hippocampus, amygdale, motor cortex,
and cerebellum. Changes included decrease in size and number of neurons
in all regions, decrease in the number of Purkinje cells in the
cerebellum, and signs of chromatolysis and gliosis in the motor cortex.
These histological changes suggest a toxic effect of high-fluoride
intake during the early developing stages of life on the growth,
differentiation, and sub cellular organization of brain cells in rats.

Non-guideline Reproduction

Purity not reported

Trabelsi, M et al. (2001). Effect of Fluoride on Thyroid Function and
Cerebellar Development in Mice. Fluoride 34: 165-173.

Open Literature

0 or 500 mg/L NaF in drinking water to pregnant and lactating mice, from
the 15th day of pregnancy to the 14th day after delivery. Litter size
was reduced to 8 pups for the control and tested group.

Tested group pups showed 35% decrease in body weight, a 75% decrease in
the plasma free T4 level, a 27% decrease in cerebellar protein, and a
17% decrease in cerebral protein compared to the control.

(Graphs missing in study).

870.4100a

Chronic Toxicity

(Rodent)

Purity not reported

Varner, J.A. et al. (1998). Chronic Administration of Aluminum-Fluoride
and Sodium Fluoride to Rats in Drinking Water: Alterations in Neuronal

and Cerebrovascular Integrity. Brain Research 784:284-298.

Open Literature

Adult male Long-Evans rats received double deionized water (ddw) and 0.5
ppm Aluminum Fluoride, or ddw and 2.1 ppm NaF for 52 weeks.

7 animals/group

No differences were found between the body weights of rats in the
different treatment groups although more rats died in the aluminum
fluoride (5) ad the NaF group (3) than the control group (1). All levels
in samples of brain and kidney were higher in both the aluminum fluoride
and NaF groups relative to controls. The effects of the two treatments
on cerebrovascular and neuronal integrity were qualitatively and
quantitatively different. These alterations were greater in animals in
the aluminum fluoride group than in the NaF group and greater in the NaF
group than in controls.

Non-guideline Chronic Toxicity

(Rodent)

Purity not reported

Turner et al. (1995). Fluoride Reduced Bone Strength in Older Rats. J.
Dent Res. 74:1475-1481.

Open Literature

Four groups of 64 to 66 rats administered 0, 5, 15, or 50 ppm of
fluoride via drinking water for exposure periods of 3, 6, 12, or 18
months.

Femoral failure load was not significantly decreased in rats treated for
3 to 6 months , but was decreased as much as 23% in rats treated 12 to
18 months at 50 ppm fluoride.

870.4200a

Oncogenicity (Rat)

Purity not reported

Maurer et al. (1990). Two-Year Carcinogenicity Study of Sodium Fluoride
in Rats. J. Natl. Cancer Inst. 82:1118-1126.

Open Literature

Sprague-Dawley rats fed a diet containing 0, 4, 10, or 25 mg/kg/day NaF
added to a low-fluoride diet for up to 99 weeks

70 rats/group

There was no evidence of treatment-related incidence of carcinogenicity
in Sprague-Dawley rats administered dietary sodium fluoride in
concentrations up to 25 mg/kg/day for 2 years. All bone neoplasms
observed were considered to be incidental and spontaneous and not
related to sodium fluoride treatment, because of their low incidence and
random distribution. The incidence of preneoplastic and neoplastic
lesions at any site in rats of either sex was not altered by the
administration of sodium fluoride. Sodium fluoride was not carcinogenic
to rats within the confines of this study.

At study termination, diet consumption for the 25 mg/kg/day (group 5)
was significantly reduced when compared to the control (group 1), with
decreases of approximately 20 and 18% for males and females,
respectively. Body weight gain was significantly less than the control
for the 25 mg/kg/day dose group. Both male and female rats administered
the high-dose of sodium fluoride experienced decreases of roughly 25% in
mean body weight gain.

Clear evidence of fluoride toxicity was seen in the teeth, bones, and
stomach, the severity of which was related t dose and duration of
treatment. At sodium fluoride concentrations of 4 mg/kg/day or greater,
dental changes occurred including incisors malformations and fractures,
and enamel hypoplasia. Treatment-related bone effects, mostly skull,
were observed at concentrations of 10 mg/kg/day and greater, affected
bones were white, thick, and found to have roughened surfaces and
subperiostal hyperostosis. There was lack of bone marrow cavities in the
new bone. There was an increase in incidence and severity of chronic
inflammation of the gastric glandular mucosa in rats treated with sodium
fluoride doses at or above 10 mg/kg/day.

870.4200b

Oncogenicity (Mouse)

Purity = 99%

Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
Publication No. 91-2848, December 1990, Pgs. 1-477.

Acceptable

Guideline

100, 70, 70, or 100 B6C3F1 mice/sex administered sodium fluoride in the
drinking water at doses of 0, 25, 100, or 175 ppm (mice/sex) for 103
weeks.

(male: 0, 2.4, 9.6, or 16.7 mg/kg/day)

(female: 0, 2.8, 11.3, or 18.8 mg/kg/day)

Male:

NOAEL = 9.6 mg/kg/day

LOAEL = 16.7 mg/kg/day, based on the clinical chemistry changes in
alkaline phosphatase and serum phosphorus (males) at 66 weeks and bone
lesions (dentine dysplasia)

Female:

NOAEL = 11.3 mg/kg/day

LOAEL = 18.8 mg/kg/day, based on the clinical chemistry changes in
alkaline phosphatase and bone lesions (myelofibrosis)

There were no compound-related effects on mortality, body weight, food
consumption, water consumption, hematology, or organ weights.
Treatment-related clinical findings included a dose-dependent increase
in white discoloration of the teeth (27%, 39%, 80%, and 100% in males
and 19%, 43%, 84%, and 100% in females, from control to high dose,
respectively) which occurred as early as Day 74 in the high-dose animals
compared to Day 508 in the control animals.  Serum alkaline phosphatase
was significantly increased in high-dose females at 24 (29%) and 66
weeks (88%) and in high dose-males at 66 weeks (11%).  Serum phosphorus
levels were significantly decreased (13%) in high-dose males at 66
weeks.  There was a significant increase in incisor dentine dysplasia in
high-dose males (78% in controls versus 91% at the high dose).  There
was an increase in the incidence of myelofibrosis (femoral, humerus,
maxilla, and thoracic) in female mice at all doses.

870.4300

Chronic/Oncogenicity

(Rodent)

Purity = 99%

Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
Publication No. 91-2848, December 1990, Pgs. 1-477.

Acceptable

Guideline

100, 70, 70, or 100 F344/N rats/sex administered sodium fluoride in the
drinking water at doses of 0, 25, 100, or 175 ppm (mice/sex) for 103
weeks.

(male: 0, 1.3, 5.2, or 8.6 mg/kg/day)

(female: 0, 1.3, 5.5, or 9.5 mg/kg/day)

Three bone osteosarcomas were noted in high-dose males and one in a
mid-dose male, with none in controls.  A fourth osteosarcoma, not
originating in the bone, was observed in an additional high-dose male.
Dosing was considered adequate based on tooth deformities and
discoloration; dentine dysplasia and degeneration in the ameloblasts and
odontoblasts, bone osteosarcomas in males and osteosclerosis in females.
 Trend analyses revealed that, at the doses tested, there was a
significant treatment-related increase in the incidence of bone
osteosarcomas in males but the incidence was not significantly increased
in the high-dose males as compared to controls when comparisons were
made either within the animals scheduled for terminal sacrifice or all
animals (including the interim sacrifice and concurrent control
animals).  In those animals scheduled for terminal sacrifice,
statistical analysis of all organ osteosarcoma in dosed animals as
compared to controls also failed to show significance.  The study
authors failed to perform the statistical analysis all osteosarcoma
analysis among all animals. That analysis, done by the contractor, did
reveal a significant difference between the high dose and control
groups.  Due to the fact that bone osteosarcoma incidence of the
high-dose as compared to the control group was not significant, but
displayed a significant positive trend, the occurrence of these rare
tumors was considered equivocal evidence of carcinogenicity in male rats
by the study authors.  Such a conclusion was bolstered by the fact that
bone osteosarcomas were not observed in treated females or in the
parallel study in B6C3F1 mice (TR393).  However, with the significant
difference between high dose animals and controls in the all organ
osteosarcoma incidence analysis when all animals are considered, the
reviewer believes that the occurrence of osteosarcomas in the male rats
should have been considered some evidence, if not clear evidence, of the
carcinogenic activity of sodium fluoride.

NOAEL < 1.3 mg/kg/day (lowest dose tested)

LOAEL = 1.3 mg/kg/day, based on dentine dysplasia in males and females,
and ameloblast degeneration in males

Mortality, body weight, body weight gain, food consumption, water
consumption, hematology, and organ weights were not affected by exposure
to NaF.  Fluoride concentration increased with dose in blood (serum) at
Weeks 27 and 66, and bone and urine at Weeks 27, 66, and 105.  Analysis
of bone fluoride revealed an increase with dose and age.  Urinary
calcium was observed to be significantly increased in high-dose females.

Tooth discoloration (whitening and mottling) was noted in all treated
animals with attrition, deformity, and occasional malocclusions noted in
the high- and/or mid-dose males. Histopathology of the incisors noted
dentine dysplasia (all dosed animals), degeneration of the ameloblasts
(mid- and high-dose animals), and, to a lesser extent, degeneration of
the odontoblasts (principally dosed males).  Increases in the incidence
and severity of osteosclerosis of the long bones were noted in the
high-dose females (6/80 control; 18/81 high- dose, P=0.04).

870.5100

Bacterial reverse mutation test

Purity not reported

Gocke et al. (1981). Mutagenicity of Cosmetics Ingredients Licensed by
the European Communities.

Mutation Research 90.2:91-109.

Open Literature

5 Tester strains of Salmonella typhimurium in the presence and absence
of metabolic activation.

NEGATIVE

There was no evidence of induced mutant colonies over background
following administration of sodium fluoride in the presence or absence
of metabolic activation. The numbers of his+ revertants observed with
treatment were not significantly different from control with any of the
study concentrations of sodium fluoride. Sodium fluoride was not
mutagenic to any of the 5 Salmonella typhimurium bacterial strains in
the presence or absence of metabolic activation.

870.5100

Bacterial reverse mutation test

Purity not reported

Haworth et al. (1983). Salmonella Mutagenicity Test Results for 250
Chemicals. Env. Mutagenesis Supplement 1:3-142.

Open Literature

Incubation concentration up to 10 mg/plate

NEGATIVE

There was no evidence of induce mutant colonies over background.
Positive controls produced appropriate responses in corresponding
strains of the bacterial reverse mutagenesis test. S. typhimurium did
not show mutagenic activity in the presence or absence of metabolic
activation following administration of sodium fluoride.

870.5100

Bacterial reverse mutation test

Purity not reported

Li, Y., Dunipace, A., Stookey, G. (1987). Absence of Mutagenic and
Antimutagenic Activities of Fluoride in Ames Salmonella

Assays. Mutation Res 190:229-236.

Open Literature

Bacterial Tester Strains TA97a, TA98, TA100, TA102, and TA1535 (these 5
strains have a greater sensitivity) 0.44, 4.42, 44.2, 88.4m 221.1,
442.1, 1105.3, 2210.5, or 4421.0 µg/plate NaF. Cultures performed in
triplicate in the presence and absence of metabolic activation.

NEGATIVE

Sodium fluoride was not mutagenic in the Salmonella typhimurium
bacterial strains in the presence or absence of metabolic activation.

Toxic effects were first observed at concentrations ≥ 1100 µg/plate
in various strains. The strains ranged from the most sensitive to least
sensitive; 97a, 102, 100, 1535 and 98. The incorporation of metabolic
activation increased the number of revertants, but did not significantly
influence the toxic effects of sodium fluoride on the bacteria. There
was no evidence of induced mutant colonies over background following
administration of sodium fluoride in the presence or absence of
metabolic activation. The numbers of his+ revertants observed with the
treatment were not significantly different from control with any of the
study concentrations of sodium fluoride.

870.5100

Bacterial reverse mutation test

Purity not reported

Martin, G. et al. (1979). Lack of Cytogenic Effects in Mice or Mutations
in Salmonella Receiving Sodium Fluoride. Mutation Res 66:159-167.

Open Literature

Bacterial Tester Strains, Salmonella typhimurium TA 1535, TA 1537, TA
1538, TA 98, and TA 100 administered Sodium Fluoride.

0.1-500 µg/plate NaF

Incubation time not reported

NEGATIVE

There was no evidence of induce mutant colonies over background.
Positive controls produced appropriate responses in corresponding
strains of the bacterial reverse mutagenesis test. S. typhimurium did
not show mutagenic activity in the presence or absence of metabolic
activation following administration of sodium fluoride.

870.5100

Bacterial reverse mutation test

Purity = 99.99%

Tong et al. (1988). The Lack of Genotoxicity of Sodium Fluoride in a
Battery of Cellular Tests. Cell Biology and Toxicology 4.2:173-186.

Open Literature

Bacterial Tester Strains, Salmonella typhimurium TA 1535, TA 1537, TA
1538, TA 98, and TA 100 were incubated with sodium fluoride in the
presence or absence of metabolic activation.

10, 20, 40, 80, 160, or 320 µg/plate

NEGATIVE

Sodium fluoride was not mutagenic to any of the 5 Salmonella typhimurium
bacterial strains in the presence or absence of metabolic activation.

The higher doses (80-320 µg/plate) were slightly cytotoxic. However at
all doses there was no evidence of induced mutant colonies over
background following administration of sodium fluoride in the presence
or absence of metabolic activation. The numbers of his+ revertants
observed with treatment were not significantly different from control
with any of the study concentrations of sodium fluoride.

870.5100

Bacterial reverse mutation test

Purity not reported

Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No.
7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
National Toxicology Program, Technical Report Series No. 393, NIH
Publication No. 91-2848, December 1990, Pgs. 1-477.

Acceptable

Guideline

Strains TA98, TA100, TA1535, and TA1537 of S. typhimurium exposed to
sodium fluoride diluted in DMSO at concentrations of 0, 100, 333, 1000,
3333, and 10000 µg/plate in the presence and absence of mammalian
metabolic activation, hamster or rat S9, using a pre-incubation
procedure.

NEGATIVE

There was no clear evidence, or a concentration related positive
response, of induced mutant colonies over background.

870.5300

In Vitro mammalian cell gene mutation test

Purity = 99%

Caspary, W. et al. (1987). Mutagenic Activity of Fluorides in Mouse
Lymphoma Cells. Mutation Res 187:165-180

Open Literature

-S9 1-200, 300, 400, 500, 600, 0r 800 µg/mL

Trial 2-50, 100, 200, 300, 400, 500, or 600 µg/mL

+S9: Trial 1-100, 200, 300, 400, 500, or 600 µg/mL

Trial 2-50, 100, 200, 300, 400, 500 or 600 400, 500, or 600 µg/mL

Incubated for 4 hours with a 2-day expression period.

POSITIVE

Sodium fluoride was mutagenic in L5179Y mouse lymphoma cells in the
presence and absence of metabolic activation.

There was evidence of general toxicity in the 300-500 µg/mL sodium
fluoride concentration range and lethality usually occurred at higher
concentrations (600-800 µg/mL). In the absence of metabolic activation,
cytotoxicity was apparent at the 800 µg/mL sodium fluoride dose level
in Trial 1. Cytotoxicity was observed in the presence of metabolic
activation at 600 µg/mL.

There were significant increases in mutation frequency following
administration of sodium fluoride. Trial 1 (-S9) experienced 1.8-, 1.6-,
1.9-, and 2.9-fold increases at sodium fluoride concentrations of 300,
400, 500 and 600 µg/mL, respectively, while Trial 2 (-S9) exhibited a
1.6-fold increase at the 500 µg/mL dose. In the presence of metabolic
activation, 1.5-, 3.1-, and 3.6- fold increases in Trial 1 and 1.6-,
1.9-, and 2.3-fold increases in Trial 2 occurred at sodium fluoride 400,
500, and 600 µg/mL and 300, 400, and 500 µg/mL, respectively.

Sodium fluoride had a significant effect in gene mutations at the TK
locus, although the addition of metabolic activation ha no apparent
effect on either the toxicity or mutagenic activities of sodium
fluoride. The measured mutant colony size was predominantly small.

870.5300

In Vitro mammalian cell gene mutation test

Purity not reported.

Oberly et al. (1990). An Evaluation of the CHO/HGPRT Mutation Assay
Involving Suspension Cultures and Soft Agar Cloning: Results for 33
Chemicals. Environmental and Molecular Mutagenesis 16:260-271.

Open Literature

Chinese Hamster Ovary (CHO)/HGPRT+ cells, Strain K1-BH4 were exposed to
sodium fluoride for 9 days

250, 500, 600, 700, or 800 µg/mL in –S9

200, 400, 450, 500, 550, 600, or 700 µg/mL in +S9

NEGATIVE