[Federal Register: August 4, 2009 (Volume 74, Number 148)]
[Rules and Regulations]
[Page 38685-38714]
[DOCID:fr04au09-15]

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Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 872

Dental Devices: Classification of Dental Amalgam, Reclassification of
Dental Mercury, Designation of Special Controls for Dental Amalgam,
Mercury, and Amalgam Alloy; Final Rule

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 872

[Docket No. FDA-2008-N-0163; Formerly Docket No. 2001N-0067]
RIN 0910-AG21

Dental Devices: Classification of Dental Amalgam,
Reclassification of Dental Mercury, Designation of Special Controls for
Dental Amalgam, Mercury, and Amalgam Alloy

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
classifying dental amalgam into class II, reclassifying dental mercury
from class I to class II, and designating a special control to support
the class II classifications of these two devices, as well as the
current class II classification of amalgam alloy. The three devices are
now classified in a single regulation. The special control for the
devices is a guidance document entitled, ``Class II Special Controls
Guidance Document: Dental Amalgam, Mercury, and Amalgam Alloy.'' This
action is being taken to establish sufficient regulatory controls to
provide reasonable assurance of the safety and effectiveness of these
devices. Elsewhere in this issue of the Federal Register, FDA is
announcing the availability of the guidance document that will serve as
the special control for the devices.

DATES: This rule is effective November 2, 2009.

FOR FURTHER INFORMATION CONTACT: Michael E. Adjodha, Food and Drug
Administration, Center for Devices and Radiological Health, 10903 New
Hampshire Ave., Bldg. 66, rm. 2606, Silver Spring, MD 20993-0002, 301-
796-6276.

SUPPLEMENTARY INFORMATION:

I. Background
    A. Overview
    1. Review of Scientific Evidence
    a. Evidence Related to the Population Age Six and Older
    i. Air Monitoring Standards for Elemental Mercury Vapor
    ii. Biological Monitoring Standards for Urine Mercury
    iii. Clinical Studies
    b. Evidence Related to Special Populations
    i. Potentially Sensitive Subpopulations (Developing Fetuses,
Breastfed Infants, and Children Under Age Six)
    ii. Dental Professionals
    iii. Individuals with Mercury Allergies
    2. Rationale for Special Controls
    a. Risk of Exposure to Mercury
    i. Specific Labeling Recommendations
    ii. Information for Use Recommendation
    iii. Performance Test Recommendation
    b. Risk of Allergic Response Including Adverse Tissue Reaction
    i. Specific Labeling Recommendations
    ii. Performance Test Recommendation
    c. Risk of Mercury Contamination
    d. Risk of Mechanical Failure
    i. Specific Labeling Recommendation
    ii. Performance Test Recommendation
    e. Risk of Corrosion
    i. Specific Labeling Recommendation
    ii. Performance Test Recommendation
    f. Risk of Improper Use
    B. Statutory Authority
    C. Regulatory History of the Devices
    1. Regulatory Status
    2. Proposed Rule
    3. Scientific Information, Safety Assessments, and Adverse Event
Reports Regarding Dental Amalgam
    a. Information and Assessments Discussed in the Proposed Rule
    b. Information and Assessments That Have Become Available Since
Publication of the Proposed Rule
    i. Life Sciences Research Office (LSRO) Report
    ii. White Paper and Addendum Scientific Reviews
    c. Adverse Event Reports
II. Development of the Final Rule
III. Comments and FDA's Responses
    A. Classification
    B. Banning
    C. Mercury Content and Toxicity
    D. Patient Information
    E. Alternative Materials
    F. Need for Public Hearings
    G. Accusations of FDA Bias
    H. Preemption
    I. Environmental Concerns
IV. Environmental Impact
V. Analysis of Impacts
    A. Introduction
    B. Summary of Economic Impacts
    C. Objective and Need of the Final Rule
    D. Risk
    E. Baseline in the Absence of the Final Rule
    F. The Final Rule
    G. Costs of the Final Rule
    1. Manufacturing Costs
    a. Testing Costs
    b. Labeling Costs Associated With the Final Rule
    c. Increased Manufacturing Costs
    2. Costs of FDA Regulatory Oversight
    3. Total Costs
    H. Potential Public Health Effects of the Final Rule
    I. Alternatives to the Final Rule
    1. No New Regulatory Action
    2. Class II But With Other Special Controls
    3. Reclassification to Class III
    4. Ban the Use of Mercury in Dental Restorations
    J. Regulatory Flexibility Analysis
VI. Federalism
VII. The Paperwork Reduction Act of 1995
VIII. References

I. Background

    The following section provides an overview of the final rule,
applicable statutory authority for classifying devices, the regulatory
history of these dental devices, scientific information and safety
assessments involving the devices, and the development of this rule.

A. Overview

    Dental amalgam is a metallic restorative material that is used for
direct filling of carious lesions or structural defects in teeth. It is
a combination of mercury (liquid) and amalgam alloy (powder), which is
composed primarily of silver, tin, and copper.
    As discussed in detail in this preamble, this final rule
classifying dental amalgam reflects FDA's careful consideration of the
valid scientific evidence related to dental amalgam's benefits, which
include its effectiveness as a restorative material, strength, and
durability, and its potential risks, which include those related to the
release of low levels of mercury vapor. FDA is required by statute to
classify devices (21 U.S.C. 360c). This final rule classifies the
device ``dental amalgam'' into class II and reclassifies the device
``dental mercury'' (hereinafter ``mercury'') from class I to class II.
Importantly, the rule also establishes special controls for dental
amalgam, mercury, and amalgam alloy (mercury and amalgam alloy are
combined to form dental amalgam). Special controls are established to
provide a reasonable assurance of safety and effectiveness for class II
devices and are in addition to the general controls already applicable
to any device.\1\ This rule designates a special controls guidance
document with performance data and labeling recommendations as the
special controls for dental amalgam.
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    \1\ General controls are specifically identified in the statute
and include requirements such as adverse event reporting and good
manufacturing practices. General controls are applicable to any
class of device. Special controls are controls identified and
designated by the Agency as controls in addition to the general
controls that apply to a specific device to address the specific
risks to health of that device.
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    The Agency has determined that class II with special controls is
the appropriate classification for dental amalgam after evaluating the
valid scientific evidence related to dental amalgam, including
comprehensive reviews of the scientific literature and safety
assessments. Based on its review of this scientific evidence, FDA made
the two findings it is required by law to make when classifying a
device (21 CFR

860.7(d)(1)): First, FDA found that, when subject to the general
controls of the act and the designated special control, the probable
benefits to health from the use of the device for its intended use and
conditions for use, when accompanied by adequate directions and
warnings against unsafe use, outweigh any probable risks. Second, FDA
found that, when subject to the general controls of the act and the
designated special control, the scientific evidence adequately
demonstrates the absence of unreasonable risk of illness or injury
associated with the intended use of dental amalgam.
    In developing this final rule, FDA reviewed scientific evidence and
also considered the classification recommendation of the Dental
Products Panel (Ref. 1), which concluded that there are no major risks
associated with encapsulated dental amalgam, when used as directed, but
recognized there is a small population of patients who may experience
allergic hypersensitive reactions to the materials in the device. The
Panel also noted that improper use exposes dental professionals to
risks associated with mercury toxicity, with improper storage,
trituration, and handling contributing to this risk.
    As part of its assessment, FDA considered the important public
health benefits of dental amalgam and the advantages it presents as a
restorative material.
    Dental amalgam has been used since the 1890s.\2\ Millions of
patients have received dental amalgam restorations to treat dental
caries.\3\
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    \2\ Earlier prototypes were available beginning in the 1830s.
    \3\ Over 50 million dental amalgam restorations are placed per
year in the United States (Ref. 2).
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    A dentist's decision concerning the use of a particular restorative
material is complex, involving factors related to the tooth, the
patient, the clinician and the properties of the restorative materials.
The dentist must, among other considerations, take into account the
patient's age, caries history, oral hygiene, ability to maintain a dry
field, degree of tooth destruction and the necessity to perform a
procedure quickly and efficiently due to a patient's ability to
cooperate. Specific clinical situations may limit the restoration
options. Dental amalgam provides advantages in that it may be placed
quickly in a wet field while providing high strength, durability,
longevity, and marginal integrity, features that may help prevent
recurrent decay. Dental amalgams are typically used:
     In stress-bearing areas and in small to moderate sized
cavities in posterior teeth;
     In teeth with severe destruction;
     As a foundation for cast-metal, metal-ceramic and ceramic
restorations;
     When a patient's commitment to oral hygiene is poor; and/
or
     When moisture control is problematic.
    Dental amalgam may provide benefits over other dental restorative
materials because amalgam fillings offer a broad range of applicability
in clinical situations, ease of use and relative insensitivity to
variations in handling technique and oral conditions (Refs. 3-7).
    FDA also considered the potential risks of dental amalgam. Dental
amalgam is a combination of elemental mercury (liquid) and amalgam
alloy (powder), which is composed primarily of silver, tin, and copper.
FDA's assessment focused on the risks associated with the presence of
mercury in the device.
    Mercury is a toxic metal that exists naturally in several forms in
the environment: Elemental metallic mercury, inorganic mercury (ionic
salt forms), and methylmercury (Ref 70, Ref. 69). Elemental metallic
mercury is highly volatile and releases mercury vapor. This form of
mercury has a well-studied toxicity profile and its toxicity is
dependent on dose and exposure conditions. The toxicokinetics and
adverse effects associated with mercury vapor are different from those
associated with methylmercury. These differences include route of
exposure (mercury vapor is inhaled while methylmercury is ingested),
percent of dose that is absorbed (80% in the case of mercury vapor; 95%
in the case of methylmercury), and toxicity profiles (Ref. 69, Ref.
70).
    Dental amalgam releases low levels of mercury vapor, with higher
amounts released with mastication and gum chewing (Ref. 3). Higher
levels of exposure to elemental mercury vapor are also associated with
placement and removal of dental amalgams. For example, urinary mercury
concentrations in 43 children ages 5 to 7 years before and after
amalgam placement (1-4 teeth filled) were 3.04  1.42 [mu]g
Hg/L (2.34 [mu]g Hg/g Cr) and 4.20  1.60 [mu]g Hg/L (3.23
[mu]g Hg/g Cr), respectively (Ref. 8). Removal of amalgams resulted in
an increase in urinary mercury; values were 1.8  1.2 [mu]g
Hg/L (1.4 [mu]g Hg/g Cr) before removal compared to 2.8
2.1 [mu]g Hg/L (2.2 [mu]g/g Cr) at 10 days post-removal (Ref. 9).
    After inhalation, approximately 70-80% of a mercury vapor dose is
absorbed by the lung, enters the systemic circulation, distributes to
several organ systems in varying amounts, and excretion occurs
generally via the urinary route (Ref. 70). Because of its high lipid
solubility, mercury vapor readily diffuses into erythrocytes and is
oxidized by the catalase-hydrogen peroxide complex to divalent mercuric
ion (Hg2+) (Ref. 70). Despite this rapid oxidation and
intracellular localization, a fraction of the elemental mercury dose
crosses the blood-brain barrier. Once inside cells, mercury vapor is
also oxidized to mercuric ions (Hg\2+\) that are unable to diffuse back
across the cell membrane (Ref. 70). The mercuric ion is believed to be
the proximate toxic species responsible for the adverse health effects
of inhaled mercury vapor. The mercuric ion has a biological half-life
of two months (Ref. 69, Ref. 70).
    While mercury toxicity has been demonstrated in a variety of organ
systems in laboratory studies, the central nervous system (CNS) and the
kidneys are both target organs sensitive to mercury vapor (Ref. 69).
    The first signs of mercury vapor toxicity at high doses are subtle
effects on the nervous system, such as changes in nerve conduction,
slight tremor, abnormalities in electroencephalography (EEG) patterns,
and changes in motor functions, cognitive functions, and behavior.
(Ref. 69, Ref. 70). With progressively higher exposures, these effects
become more pronounced and include prominent tremor, ataxia
(incoordination), memory loss, psychological distress, irritability,
excitability, depression, and gingivitis (inflammation of the gums)
(Refs. 69, 70).
    Mercury also accumulates in the kidneys. Adverse renal effects can
range from reversible proteinuria (protein in the urine) to
irreversible nephrotic syndrome, depending on the degree of exposure to
mercury vapor (Ref. 69, Ref. 70).
    In addition to crossing the blood-brain barrier, mercury vapor has
been shown in animal studies to cross the placenta and reach the fetal
brain (Ref. 48, Ref. 44) is also able to cross the placenta and reach
the fetal brain. Inorganic mercury, most likely in the form of
Hg2+, is found in breast milk after maternal exposure to
mercury vapor and, therefore, may be present in breastfed infants (Ref.
55). Because maternal exposure to mercury vapor from dental amalgam may
lead to prenatal and postnatal exposure of offspring, FDA considered
the potential health effects of dental amalgam on developing fetuses
and breastfed infants.

1. Review of Scientific Evidence
    As already noted, this rule and the special controls guidance
reflect FDA's evaluation of the valid scientific evidence related to
the use of dental amalgam in the population age six and older and in
potentially sensitive subpopulations (developing fetuses, breastfed
infants, and children under age six). The White Paper (Ref. 10) and
Addendum (Ref. 11) referenced in this rule include more details
regarding FDA's examination.\4\ These documents are included as
references and are available on FDA's Web site.
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    \4\ FDA decided to conduct this comprehensive review of the
literature and prepare the Addendum rather than revise the White
Paper.
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    In developing the White Paper and Addendum, FDA drew from the
expertise of other groups \5\ that had previously conducted reviews
related to the potential health effects of dental amalgam. FDA's
approach was to build upon these reviews, rather than to duplicate the
work other groups had already undertaken. FDA reviewed more than 200
scientific articles, published from 1997 to 2008, on the potential
health effects of dental amalgam. In addition to considering these
studies, FDA also considered information and assessments reviewed in
the proposed rule, and other risk assessments developed since the
publication of the proposed rule, including the 2004 Life Sciences
Research Office (LSRO) Report (Ref. 13).\6\ In an effort to determine
if any very recent articles would have an impact on FDA's analysis, a
literature search was conducted for 2008--July 2009 (even though FDA
had already reviewed studies published through October 2008). Three
databases (PubMed, Biosis, and Embase) were searched with key words,
such as mercury, toxicity, mercury vapor, adverse effect, dental, etc.
Several studies from this search had already been reviewed in the FDA
Addendum to the White Paper. After review of the total of 70 abstracts
from the search, FDA determined that no studies have been published in
2008-2009 that would change FDA conclusions about the health effects of
dental amalgam.
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    \5\ These groups included the U.S. Public Health Service and the
Environmental Health Policy Committee's Working Group on Dental
Amalgam (Refs. 3, 12).
    \6\ The LSRO report examined studies published from 1996 through
2003. In conducting its review, LSRO engaged an independent panel of
academic experts in the fields of immunotoxicology, immunology, and
allergy; neurobehavioral toxicology and neurodevelopment;
pediatrics; developmental and reproductive toxicology;
toxicokinetics and modeling; occupational health and epidemiology;
pathology; and general toxicology. (Ref. 13)
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    FDA also considered the fact that dental amalgam is a commonly used
device with a low frequency of adverse events reported to the Agency.
FDA received 141 adverse event reports related to dental amalgam from
1988 to 2008. It is estimated that over one billion amalgam
restorations were placed during this time period. The majority of the
dental amalgam adverse event reports submitted to FDA were anecdotal,
lacked specific details, and were often reported years after placement
of the restoration, making it difficult for the Agency to perform a
causal analysis.
    An overview of the available evidence and FDA's conclusions
follows.
a. Evidence Related to the Population Age Six and Older
i. Air Monitoring Standards for Elemental Mercury Vapor
    The Agency for Toxic Substance and Disease Registry (ATSDR) has
established a Minimal Risk Level (MRL) \7\ for elemental mercury vapor
at 0.2 [mu]g/m\3\. The Environmental Protection Agency (EPA) has
established a Reference Concentration (RfC) \8\ for elemental mercury
vapor at 0.3 [mu]g/m\3\. These reference values were derived using a
standard risk assessment approach employing uncertainty factors,
including an uncertainty factor to account for variability in
sensitivity of the human population. They are considered to represent
chronic or lifetime inhalation exposures that are free from adverse
health outcomes and protective of human health for all individuals,
including potentially sensitive populations such as children prenatally
or postnatally exposed to mercury vapor (Refs. 14, 15).\9\
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    \7\ ATSDR defines a Minimal Risk Level (MRL) as follows: ``An
MRL is an estimate of the daily human exposure to a hazardous
substance that is likely to be without appreciable risk of adverse
noncancer health effects over a specified duration of exposure. * *
* [MRLs] are set below levels that, based on current information,
might cause adverse health effects in the people most sensitive to
such substance induced effects'' (http://www.atsdr.cdc.gov/mrls/).
    \8\ EPA defines a Reference Concentration (RfC) as follows: ``An
estimate (with uncertainty spanning perhaps an order of magnitude)
of a continuous inhalation exposure to the human population
(including sensitive subgroups) that is likely to be without an
appreciable risk of deleterious effects during a lifetime. It can be
derived from a NOAEL [No Observed Adverse Event Level], LOAEL
[Lowest Observed Adverse Event Level], or benchmark concentration,
with uncertainty factors generally applied to reflect limitations of
the data used'' (http://www.epa.gov/ncea/iris/help_gloss.htm#r).
    \9\ After considering a large body of literature, ATSDR derived
the MRL for elemental mercury from a study of 26 workers exposed to
low levels of mercury (0.026 mg/m\3\) in three industrial settings
for an average of 15.3 years (range 1-41 years) (Ref. 16). Urinary
mercury concentrations for this study averaged 11.3 [mu]mol/mol
creatinine (Cr) (approximately 20.1 [mu]g/g Cr; 26.1 [mu]g/L urine).
Continuous exposure was taken into account by converting workplace
exposures of 8 hr/day-5 days/week into exposures of 24 hr/day-7
days/week. Uncertainty factors (UFs) were used in deriving the MRL
included variability in sensitivity to mercury within the human
population (UF = 10) and the use of a lowest observed adverse effect
level (LOAEL)--in this study, increased average velocity of
naturally occurring hand tremors--instead of a no observed adverse
effect level (NOAEL). In deriving the MRL, the ATSDR applied a less
conservative uncertainty factor for the LOAEL (UF = 3), an approach
commonly used when the endpoint is determined to be a less serious
effect. In total, an uncertainty factor of 30 was applied.
Application of the exposure conversions and uncertainty factors
yielded a tolerable mercury vapor intake concentration of 0.2 [mu]g/
m\3\ for chronic inhalation exposure. The derivation of the ATSDR
MRL for chronic exposure to mercury vapor also considered supporting
evidence from several more recent studies that showed effect levels
and adverse outcomes similar to those reported in Fawer et al. (Ref.
16), including Ngim et al. (Ref. 17) and Piikivi and Tolonen (Ref.
18). (See ATSDR, Ref. 14) EPA derived its RfC for chronic inhalation
exposure to mercury vapor using the same occupational exposure study
(Fawer et al., Ref. 16) and supporting studies (including Ngim et
al. (Ref. 17) and Piikivi and Tolonen, (Ref. 18) used by ATSDR in
deriving the MRL for chronic mercury vapor exposure (Ref. 15). EPA
conducts periodic screening level reviews for chemicals and in 2002
decided that the RfC for mercury vapor would remain unchanged (Ref.
15).
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    Using widely accepted values for the respiratory rate and tidal
volume in individuals at various ages, the following ventilation rates
were calculated: 16.2 m\3\/day for the average adult; 7.6 m\3\/day for
the average five-year-old child; and 5.8 m\3\/day for the average one-
year-old child.\10\
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    \10\ These ventilation rates were calculated as follows, using
standard physiological parameters from several sources and handbooks
(Refs. 19 and 20) Adult: The tidal volume per kilogram body weight
in adults is 10.7 mL/kg. The weight of the average adult is 70 kg.
Given these two values, the tidal volume of the average adult is 750
mL. The respiratory rate of the average adult is 12-15 breaths/
minute. At a rate of 15 breaths/minute, the average adult would have
a respiratory minute volume of 11.25 L/min. Given that there are
1,440 minutes/day and 1 m\3\/1000 L, this would result in a
ventilation rate of 16.2 m\3\/day. Five-year-old child: The tidal
volume per kilogram body weight in five-year-old children is 10.7
mL/kg. The weight of the average five-year-old child is 20 kg. Given
these two values, the tidal volume of the average five-year-old
child is 217 mL. The respiratory rate of the average five-year-old
child is 21-25 breaths/minute. At a rate of 25 breaths/minute, the
average five-year-old child would have a respiratory minute volume
of 5.3 L/min. Given that there are 1440 minutes/day and 1 m\3\/1000
L, this would result in a ventilation rate of 7.6 m\3\/day. One-
year-old child: The tidal volume per kilogram body weight in one-
year-old children is 10 mL/kg. The weight of the average one-year-
old child is 10 kg. Given these two values, the tidal volume of the
average one-year-old child is 100 mL. The respiratory rate of the
average one-year-old child is 40 breaths/minute. At a rate of 40
breaths/minute, the average one-year-old child would have a
respiratory minute volume of 4 L/min. Given that there are 1440
minutes/day and 1 m\3\/1000 L, this would result in a ventilation
rate of 5.8 m\3\/day.

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    At these ventilation rates, chronic exposure at the level of the
MRL would result in an estimated dose of mercury vapor of 3.2 [mu]g/day
in the average adult, 1.5 [mu]g/day in the average five-year-old child,
and 1.2 [mu]g/day in the average one-year-old child. Chronic exposure
at the level of the RfC would result in an estimated dose of mercury
vapor of 4.9 [mu]g/day in the average adult, 2.3 [mu]g/day in the
average five-year-old child, and 1.7 [mu]g/day in the average one-year-
old child.
    ATSDR assumes a slightly higher ventilation rate of 20 m\3\/day for
the average adult (Ref. 14). At this ventilation rate, chronic exposure
at the level of the MRL would result in an estimated dose of elemental
mercury vapor of 4 [mu]g/day in the average adult. Chronic exposure at
the level of the RfC would result in an estimated dose of elemental
mercury vapor of 6 [mu]g/day in the average adult.
    The U.S. Public Health Service (PHS) reviewed several studies
estimating the daily dose of elemental mercury from dental amalgam
(Ref. 3). In some of the studies, investigators measured the mercury
concentration of intraoral and exhaled air in small populations of
individuals with and without amalgams. In these studies, estimates of
the daily dose of mercury from dental amalgams ranged from 1-29 [mu]g/
day. However, the reliability of these studies is questionable.
Problems have been cited with the instruments used to measure mercury
vapor in the oral cavity. Questions have also been raised about whether
the small size of the oral cavity is appropriate for accurately
measuring vapor concentrations, and about how to control for variable
factors such as the dilution of vapor with inhaled air within the oral
cavity and inhalation/exhalation rates, analytical quality control, and
differences in sampling methodology (Ref. 20). According to PHS, the
best estimates of daily intake of mercury from dental amalgam
restorations have come from measurements of mercury in blood among
subjects with and without amalgam restorations, and subjects before and
after amalgams were removed. For adults, these estimates range from 1-5
[mu]g/day.
    The World Health Organization (WHO) also reviewed several studies
estimating the daily dose of elemental mercury from dental amalgam
(Ref. 21). WHO found that values generally in the range of 1-5 [mu]g/
day were estimated in the U.S. adult population, which is consistent
with the PHS determination. WHO noted three studies that made higher
estimates of the daily dose. The highest estimate that WHO reports was
a dose of 12 [mu]g/day, for middle-aged individuals with approximately
30 amalgam surfaces (Ref. 22).
    According to these estimates, the daily dose of mercury from dental
amalgam is generally expected to be in the same range as the daily dose
that would result from chronic exposure at the level of the MRL (4
[mu]g/day) or the RfC (6 [mu]g/day) in adults. Moreover, exceeding
these protective reference levels does not necessarily mean that any
adverse effects will occur (Refs. 14-15). FDA assumes that the daily
dose from amalgam in children under six years old is below those in
adults since children under six years old have fewer and smaller teeth
and lower ventilation rates as compared to adults.
    Given that the MRL and the RfC were derived to be protective and
are set below air mercury concentrations associated with observed
adverse health effects,\11\ chronic exposure at these levels would not
generally be expected to produce such effects. Chronic exposure to air
mercury concentrations several times higher than the MRL and the RfC
would also generally not be expected to result in adverse effects,
because of the conservative approach of incorporating uncertainty
factors in the derivation of these reference levels.\12\ Moreover, both
the MRL and the RfC assume lifetime chronic exposure. FDA has taken a
conservative approach by applying these reference levels to children,
who have experienced less than a full lifetime of exposure.
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    \11\ As described in Footnote 9, ATSDR used a total uncertainty
factor of 30 to derive the MRL.
    \12\ As discussed by EPA in their Staff Paper on Risk Assessment
Principles and Practices, ``EPA risk assessments tend towards
protecting public and environmental health by preferring an approach
that does not underestimate risk in the face of uncertainty and
variability. In other words, EPA seeks to adequately protect public
and environmental health by ensuring that risk is not likely to be
underestimated.'' See EPA 2004, An Examination of EPA Risk
Assessment Principles and Practices, EPA/100/B-04/001 available at:
http://www.epa.gov/osa/pdfs/ratf-final.pdf.
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ii. Biological Monitoring Standards for Urine Mercury
Occupational Studies
    Several studies have assessed the risk of adverse health effects in
workers occupationally exposed to high doses of mercury vapor. Strong
correlations have been found between daily, time-weighted air
concentrations, adverse health outcomes, and urinary mercury levels in
workers (Refs. 14, 21).
    Based on a number of occupational studies, the American Conference
of Government Industrial Hygienists (ACGIH) has determined that the
biological threshold for preclinical changes for central nervous system
and kidney effects is 50 [mu]g Hg/g Cr (Ref. 24).\13\ However,
occupational studies published since 1996 report that increases in
urinary levels of early biomarkers predictive of renal injury have been
observed at urinary mercury concentrations of 16-28 [mu]g Hg/g Cr
(Refs. 25-28).
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    \13\ Given that 50 [mu]g Hg/g Cr is the threshold urinary
mercury concentration associated with preclinical nervous and renal
system effects, ACGIH recommends that the urinary mercury
concentration of occupationally exposed individuals not exceed 35
[mu]g Hg/g Cr. This urinary mercury concentration is associated with
chronic occupational exposure of a healthy worker to an air
concentration of 25 [mu]g Hg/m\3\.
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Studies of Amalgam Bearers
    Studies of large cohorts indicate that urinary mercury
concentrations in individuals without dental amalgam restorations are
approximately 0.5-0.6 [mu]g Hg/g Cr in adults (Refs. 29, 30) and 0.5-2
[mu]g Hg/g Cr in children, aged 6-17 (Refs. 31, 32).
    Studies of adults with dental amalgam restorations have found a
positive correlation between the number of dental amalgam restorations
in the mouth and urinary mercury concentration. In a study of 1,626
women, aged 16-49, urinary mercury concentrations ranged from 0.83-1.25
[mu]g Hg/g Cr (Ref. 29). The average urinary mercury concentration for
the 75 percent of the women who had 12 amalgam surfaces or less was
reported to be 0.81 [mu]g Hg/g Cr. In a study of 550 adults, aged 30-
49, urinary mercury concentrations ranged from 0.75-2.9 [mu]g Hg/g Cr
in individuals with 1-46 amalgam surfaces (Ref. 33). In one study of
1,127 men, aged 40-78, with dental amalgam restorations, 47 percent of
the participants had a urinary mercury concentration less than 1.5
[mu]g Hg/g Cr, and 1.3 percent of the participants had urinary mercury
concentrations over 12 [mu]g Hg/g Cr (Ref. 30). A urinary mercury
concentration of 1.9 [mu]g Hg/g Cr was reported for men with
approximately 20 amalgam surfaces. Based on the study's analysis, an
individual with 60 amalgam surfaces would be expected to have a urinary
mercury concentration of 4-5 [mu]g Hg/g Cr.
    Studies have also assessed urinary mercury concentrations in
amalgam-bearing children age six or older. Two prospective studies
assessed urinary mercury concentrations in children age six and older
after placement of dental amalgam restorations. In a seven-year study
of children ages eight to ten at

baseline, the highest average urinary mercury concentration reported
during the study period was 3.2 [mu]g Hg/g Cr (Ref. 31); this level
occurred during the second year of the follow-up and progressively
declined through year seven. The subjects had an average total of 19
amalgam surfaces at the end of the study period. In a five-year study
of children ages six to ten at baseline, average urinary mercury
concentrations were 0.9 [mu]g Hg/g Cr (range 0.1-5.7) five years after
dental amalgam placement (Ref. 34). The subjects had an average total
of 12 amalgam surfaces at the end of the study period. The highest
outlier in this study had a reported urinary mercury concentration of
10.5 [mu]g Hg/g Cr. Children from the composite restoration-only group
averaged 0.6 [mu]g Hg/g Cr (range 0.1-2.9). In a study of 60 children
aged 4-8 years (Ref. 89), those with amalgam restorations had higher
urinary mercury concentrations (1.4 [mu]g Hg/g Cr) compared to those
without amalgams (0.436 [mu]g Hg/g Cr).
    The urinary mercury concentrations generally observed in adults and
children age six and older with dental amalgam restorations is
approximately one order of magnitude less than the threshold levels
associated with preclinical neurological and renal health effects in
persons occupationally exposed to mercury vapor. Reported high outliers
in adults and children age six and older are also below this threshold
level.
    FDA has concluded that exposures to mercury vapor from dental
amalgam do not put individuals age six and older at risk for mercury-
associated adverse health effects.
iii. Clinical Studies
    In order to assess potential health effects of mercury exposure
from dental amalgam in the population age six and older, FDA reviewed
studies evaluating neurological and renal outcomes. Studies of persons
occupationally exposed to mercury vapor are also helpful for assessing
risks of potential toxicity in the population age six and older from
exposure to mercury vapors released from dental amalgams because
occupationally-exposed individuals are exposed to higher mercury levels
than those associated with dental amalgams.
Neurological Effects
Occupational Studies
    In a study of chloralkali workers and age-matched controls
evaluated twice at five years apart, no correlations were found between
multiple neurobehavioral (motor and cognitive) and tremor tests and
mercury vapor exposure (Ref. 35). Performance on only one test, the
Digital Symbol Test, showed improvement when subjects were tested five
years later after exposure ceased suggesting that these individuals
experienced some neurological toxicity while still being exposed to
mercury at the time of the initial testing. Those subjects who
demonstrated improvement had the highest inorganic mercury blood
concentrations.\14\
---------------------------------------------------------------------------

    \14\ The authors noted that ``[w]hen summarizing the available
evidence, one could suggest that long-term neurobehavioral effects
on a group basis may occur when the average [urinary mercury]
concentration has been in the range of 30-40 nmol/mmol Cr [53.1-70.8
[mu]g Hg/g Cr] or higher, but not when the average [urinary mercury]
concentration has been lower than 10 nmol/mmol Cr [17.7 [mu]g Hg/g
Cr].''
---------------------------------------------------------------------------

    In another study, 38 chloralkali workers with average urinary
mercury concentration of 9 [mu]g Hg/g Cr were compared with non-exposed
controls (average urinary mercury concentration 2 [mu]g/g Cr (Ref.
36)). No differences in results of multiple neurobehaviorial tests were
observed between the two groups.
Studies of Amalgam Bearers
    Studies have shown a lack of association between amalgam exposure
and neuropsychological and neurobehavioral deficits. In a retrospective
study of 550 adults, no significant associations between
neuropsychological function and indices of cumulative amalgam exposure
over many years were found (Ref. 33). In a report evaluating 1,127 men
(Ref. 37), no effects on tremor, coordination, gait, strength,
sensation, muscle stretch, or peripheral neuropathy were associated
with amalgam exposure.
    It has been suggested that exposure to mercury vapor from dental
amalgam may be linked to various neurological or neurodegenerative
diseases, such as Parkinson's disease, Alzheimer's disease, multiple
sclerosis, amyotrophic lateral sclerosis, and autism. There is a
paucity of studies that evaluate a link between dental amalgam and
these conditions.
    In one study, regional brain levels of mercury were determined at
autopsy in subjects with Alzheimer's disease and controls (Ref. 38).
Brain mercury levels did not correlate with the number of amalgams and
there were no differences between the Alzheimer's disease and control
groups with respect to number of amalgams. In another study, the mean
number of dental amalgam surfaces and urinary mercury concentrations
for Alzheimer's disease patients were not different from those of
control patients (Ref. 39). In a study of aging and Alzheimer's disease
evaluating 129 Catholic nuns, aged 75-102, no effect of dental amalgam
number and surfaces was observed for eight tests of cognitive function
(Ref. 38). These findings do not support the hypothesis that mercury
from dental amalgam plays a role in the pathogenesis of Alzheimer's
disease.
    Several reports of results from prospective clinical studies of
dental amalgam numbers (Refs. 31, 32, 34, and 40) found no neurological
deficits in children who first received dental amalgam restorations at
ages six to ten and were followed for five or seven years.
    FDA concludes that the existing data support a finding that
exposures to mercury vapor at levels associated with dental amalgams do
not result in neurological deficits, tremors, peripheral neuropathies,
or Alzheimer's Disease in the population age six and older. Although
the existing clinical data on purported links between dental amalgam
and other neurological or neurodegenerative diseases, such as
Parkinson's Disease are limited, FDA concludes that, in light of the
air monitoring and biological monitoring evidence described above,
there is information from which to determine that general and special
controls are sufficient to provide a reasonable assurance of safety and
effectiveness.
Renal Effects
    The kidneys accumulate the highest organ concentration of mercury
(as Hg \2+\) following exposure to mercury vapor. The concentration of
mercury in the kidney has been associated with the number of dental
amalgams (Refs. 41, 42).
Animal Studies
    Renal mercury concentrations increased in proportion to increasing
mercury vapor exposure concentrations in rats (Refs. 43, 44). Pregnant
rats exposed to high concentrations of mercury vapor through gestation
exhibited increases in two biomarkers of renal injury at gestation day
15, but no changes were observed for three other biomarkers at any time
evaluated during gestation (Ref. 44).
Occupational Studies
    Numerous occupational studies of mercury vapor exposure indicate
that effects on the kidney begin to manifest when urinary mercury
concentrations reach or exceed 50 [mu]g Hg/g creatinine (Ref. 24).
However, occupational studies published since 1996 report that
increases in urinary levels of early

biomarkers predictive of renal injury have been observed at urinary
mercury concentrations of 16-28 [mu]g Hg/g creatinine. In a study of
chloralkali workers exposed to mercury vapor for 13 years (mean urinary
mercury concentrations of 16.5 [mu]g/g Cr), no significant differences
in urinary biomarkers of renal function were found between the exposed
and non-exposed groups (Ref. 45). Urinary biomarkers of renal function
may be reversible upon cessation of exposure at the levels of exposure
in this study. In several occupational studies of exposed workers
(Refs. 25-28), increases in urinary N-acetylglucosamindase (NAG), a
preclinical renal biomarker, were correlated with urinary mercury
concentrations of 16-28 [mu]g Hg/g Cr. In another study, 38 chloralkali
workers with average urinary mercury concentration of 9 [mu]g Hg/g Cr
were compared with non-exposed controls (average urinary mercury
concentration 2 [mu]g Hg/g Cr (Ref. 36)). No differences in renal
expression as measured by multiple preclinical urinary biomarkers were
observed between the two groups.
Studies of Amalgam Bearers
    Two prospective amalgam trials in children age six and older
demonstrated that kidney injury is not associated with exposure to
dental amalgam. In the New England trial (Ref. 46) groups of children
had amalgam or composite restorations placed at ages 6-8 and were
followed for 5 years. Results showed that, although microalbuminuria
levels were higher in the amalgam treatment group, the levels of three
other biomarkers of kidney injury were not different between the
amalgam versus composite restoration groups. The authors of the study
noted that they were unable to determine whether the increase in
microalbuminuria was related to treatment or may have occurred by
chance, since albuminuria may be caused by strenuous physical exercise,
urinary tract infections, or other conditions with fever, or be related
to orthostatic proteinuria (Ref. 46). In another children's prospective
trial (Casa Pia), groups of children had amalgam or composite
restorations placed at ages 6-10 and were followed for 7 years. There
were no differences between the amalgam and composite groups with
respect to the urinary excretion of microalbumin or albumin (Ref. 31),
a biomarker of renal glomerular injury, and GST-alpha and GST-pi, two
biomarkers of renal proximal and distal tubule injury, respectively
(Ref. 47).
    FDA concludes that the data from these studies support a finding
that exposures to mercury vapor at levels associated with dental
amalgams do not result in renal damage in the population age six and
older. The conclusions from studies of amalgam mercury exposure and
neurological and renal endpoints are supported by independent
investigations by other scientific bodies, such as the European
Commission's Scientific Committee on Emerging and Newly Identified
Health Risks (SCENIHR), which stated in 2007 that ``no risks of adverse
systemic effects exist and the current use of dental amalgam does not
pose a risk of systemic disease'' (Ref. 6).
    In light of the evidence from air monitoring, biological
monitoring, and clinical studies, FDA concludes that exposures to
mercury vapor from dental amalgam are not associated with adverse
health effects in the population age six and older.
b. Evidence Related to Special Populations
i. Potentially Sensitive Subpopulations (Developing Fetuses, Breastfed
Infants, and Children Under Age Six)
Fetal Development
    Elemental mercury is transported through the placenta, which
results in fetal exposure with the potential for subsequent
developmental toxicity in offspring.
Animal Studies
    FDA reviewed several well-conducted studies designed to assess
high-level mercury vapor exposure on developmental effects in pregnant
animals and their offspring. High levels of maternal mercury vapor
exposure were associated with the accumulation of mercury in fetal
tissues. In one study (Ref. 48), no effects were observed on
peripheral, somatosensory, auditory, or visual neurological functions
in offspring of rats exposed to mercury vapor prenatally. In another
study, prenatal exposure of pregnant rats was associated with adverse
effects on fetal development only in cases where maternal exposure to
mercury vapor was so high that it became toxic to the mother (leading
to decreased maternal body weight, which can directly alter fetal
development) (Ref. 44). The 2004 Life Sciences Research Office (LSRO)
Report (Ref. 13) reviewed several studies of exposure of pregnant
squirrel monkeys to high concentrations of mercury vapor. Although
mercury accumulated in brain tissues in utero, only modest effects were
observed on learning, motor function, and adaptive behaviors. In all of
the aforementioned studies, maternal mercury vapor exposures were
considerably higher than those estimated for individuals with dental
amalgam restorations.
Occupational Studies
    Very few available studies have evaluated the effects of elemental
mercury exposure on pregnancy outcomes in humans. Although mercury has
the ability to cross the placental barrier, the limited human data do
not demonstrate an association between exposure to the mercury in
dental amalgam and adverse reproductive outcomes such as low birth
weight babies or increased rates of miscarriage. In a retrospective
study (Ref. 49), no strong association or clear dose-response
relationship between occupational exposure to chemical agents or
restorative materials and the risk of miscarriage was observed. A
slight but non-significant increase in risk was found for exposure to
some acrylate compounds, mercury amalgam, solvents and disinfectants
leading the authors to conclude that they could not rule out the
possibility of a slightly increased risk of miscarriage among exposed
dental workers. In a study of female factory workers exposed to a
median concentration of 90 [mu]g Hg/m\3\ (maximum 600 [mu]g/m\3\), no
significant differences in stillborn or miscarriage rates were observed
between exposed and unexposed subjects (Ref. 50). The mercury vapor
concentrations to which these workers were exposed were over an order
of magnitude higher than those associated with dental amalgam.
Studies in Amalgam Bearers
    Very few well-controlled animal studies or human epidemiological
studies have evaluated the potential effect of low-level mercury vapor
exposure on fetal development, especially at exposures experienced by
dental amalgam bearers. In one retrospective study (Ref. 51), no
association was found between the number of amalgam fillings in women
and low birth weight of their babies. However, there is limited
clinical information concerning the effects of prenatal exposure from
maternal sources of mercury vapor at relevant concentrations.
    Although the data are limited, FDA concludes that the existing data
do not suggest that fetuses are at risk for adverse health effects due
to maternal exposure to mercury vapors from dental amalgam. As
described earlier in this document, maternal exposures are likely to
increase temporarily when new dental amalgams are inserted or existing
dental amalgam restorations are removed.

Breastfed Infants
    Mercury present in the mother's body is transmitted to her infant
through breast milk. Maternal exposure to elemental mercury vapor would
be expected to affect the concentration of inorganic mercury in breast
milk.
    The EPA has set a Reference Dose (RfD) \15\ for oral exposure to
inorganic mercury at 0.3 [mu]g Hg/kg/day (Ref. 52). This value
represents the daily exposure to inorganic mercury that is likely to be
without an appreciable risk of deleterious health effects during a
lifetime. Reference values are derived to be protective against adverse
health effects in sensitive subpopulations, such as developing fetuses
and children.
---------------------------------------------------------------------------

    \15\ EPA defines a Reference Dose (RfD) as follows: ``An
estimate (with uncertainty spanning perhaps an order of magnitude)
of a daily oral exposure to the human population (including
sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. It can be derived
from a NOAEL [no observed adverse effect level], LOAEL [lowest
observed adverse effect level], or benchmark dose, with uncertainty
factors generally applied to reflect limitations of the data used''
(http://www.epa.gov/ncea/iris/help_gloss.htm#r).
---------------------------------------------------------------------------

    Seven studies reviewed in the 2004 Life Sciences Research Office
Report evaluated concentrations of total mercury in breast milk. In
some of the reviewed studies, the number of amalgams correlated with
the concentration of total mercury in breast milk (Refs. 53, 54, 55).
However, the LSRO report concluded from its review that inorganic
mercury absorption through breast milk is not a significant source of
mercury exposure to infants (Ref. 13).
    One study (Ref. 56) determined the concentration of breast milk
mercury attributable to dental amalgam. In this study, the
concentration of mercury in subjects with dental amalgam restorations
was subtracted from the level in subjects without dental amalgam
restorations. The level of mercury attributable to amalgam was 0.09
[mu]g Hg/L (Addendum, p. 13). A standard value used in risk assessment
for daily breast milk consumption is 0.85 L/day. Based on this value,
the typical daily dose of inorganic mercury from breastfeeding in an
individual with dental amalgam restorations would be 0.075 [mu]g Hg/
day. For a 5 kg infant, the daily exposure to inorganic mercury from
breastfeeding would be 0.015 [mu]g Hg/kg/day.
    The estimated concentration of mercury in breast milk attributable
to dental amalgam exposure is low and is an order of magnitude below
the health-based exposure reference value for oral exposure to
inorganic mercury established to protect the health of adults and
children.
    FDA concludes that the existing data support a finding that infants
are not at risk for adverse health effects from the breast milk of
women exposed to mercury vapors from dental amalgams.
Children Under Six Years of Age \16\
---------------------------------------------------------------------------

    \16\ Table 4 of this final rule (section V), ``Projected Amalgam
Restorations for Specific Populations'' projects for 2009 that total
amalgam in children under age 6 will be 2.6 million.
---------------------------------------------------------------------------

    No clinical studies have evaluated the effects of mercury vapor
exposure from dental amalgam in children under six years of age. FDA
assumes that the daily dose of mercury from amalgams in children less
than six years old would not be higher than the estimated daily dose
for adults (1-5 [mu]g/day). FDA expects that the daily dose in children
will be lower than the estimated dose for adults since children less
than six have fewer and smaller teeth and lower ventilation rates, as
compared to adults. The MRL and the RfC are derived using a
conservative approach by applying uncertainty factors, and therefore
are protective against adverse health effects, in populations including
potentially sensitive subpopulations such as young children. Therefore,
chronic exposure at these or slightly higher levels would not generally
be expected to produce adverse health effects, suggesting that these
children are not at risk for adverse health effects from mercury vapor
released from dental amalgams.
Summary
    Based on comparisons between the expected daily dose in these
potentially sensitive subpopulations and the MRL and RfC, the exposure
estimated from breast milk in breastfed infants, and clinical studies,
we would not expect to see any adverse health effects in these
subpopulations from mercury vapors released from dental amalgam.
However, the data regarding risk in these subpopulations is not as
robust as in adults due to the absence of measured urinary mercury
concentrations and limited clinical data in these subpopulations.
ii. Dental Professionals
    Dentists and their staff may be exposed to mercury vapor in the
workplace during the preparation, placement, and removal of dental
amalgams. As noted by the Dental Products Panel, improper use of dental
amalgam exposes dental professionals to risks associated with mercury
toxicity. Improper storage, trituration, and handling contribute to
this risk (Ref. 1).
    Dental professionals are generally exposed to lower levels of
mercury vapor than those that have been reported in industrial
settings, and they have urinary mercury concentrations approaching
those observed in non-occupationally-exposed populations.
    Several studies, primarily from one laboratory group, provide the
most information about the potential health effects of low-level
mercury exposure among dental professionals. In four of these studies,
mean urinary mercury concentrations in dentists and hygienists ranged
from 0.9 to 3 [mu]g Hg/L (~0.7 to 2.3 [mu]g Hg/g Cr) and were
associated with some neurobehavioral effects. In a fourth study which
pooled results from six earlier studies, urine mercury concentrations
ranged from less than 1 [mu]g Hg/L (~0.8 [mu]g Hg/g Cr) to greater than
50 [mu]g Hg/L (~38[mu]g Hg/g Cr). A significant weakness of these
studies was that no non-mercury-exposed dental professionals were
evaluated; therefore, the effect of exposure to other chemicals in the
workplace (gases, organic solvents) cannot be ruled out. Nor was a non-
dental workplace control group studied, which would have been
informative about effects of the dental work environment in general.
The neurobehavioral measures reported in several studies of dentist/
dental assistant populations as being significantly correlated with
mercury exposure (urine mercury levels) have not been shown in some
cases to be similarly affected in other occupationally-exposed groups
where urinary mercury concentrations were much higher (e.g.,
chloralkali workers) than in the dental professional cohorts.
    In one study (Ref. 57), 34 dentists and 15 hygienists exposed to
mercury vapor in the workplace (mean number of amalgams placed was
16.1) were chelated to allow assessment of recent mercury exposure
(pre-chelation) and body burden from longer-term exposures (post-
chelation). Mean urinary mercury concentrations for each group were:
0.9  0.5 [mu]g Hg/L (0.7 [mu]g Hg/g Cr) before chelation;
9.1  6.9 [mu]g Hg/L (7 [mu]g Hg/g Cr) after chelation.
Subtle but statistically significant associations were demonstrated for
recent exposure (pre-chelation) and measures of mood, motor function
and cognition, and mercury body burden (post-chelation) was associated
with symptoms, mood, and motor function. Chelation of mercury in dental
professionals suggests that the mercury body burden in this population
of workers is much greater than indicated solely by pre-chelation
urinary mercury levels.

    Another study (Ref. 58) 230 dentists (data pooled from six previous
studies) had urinary mercury concentrations ranging from less than 1
[mu]g Hg/L (~0.8 [mu]g Hg/g Cr) to greater than 50 [mu]g Hg/L (~38
[mu]g Hg/g Cr); 50% subjects had urine concentrations less than 3 [mu]g
Hg/L (~2 [mu]g Hg/g Cr) and 30% had concentration greater than 20 [mu]g
Hg/L (~15 [mu]g Hg/g Cr). Dentists stratified into three urine mercury
concentration groups: Less than 1 [mu]g Hg/L (~0.8 [mu]g Hg/g Cr), 1-20
[mu]g Hg/L (~0.8-15 [mu]g Hg/g Cr) and greater than 20 [mu]g Hg/L (~15
[mu]g Hg/g Cr). An association of urine mercury concentrations to a
hand steadiness test was highly significant; however, associations with
motor function tests were not significant.
    Two studies (Refs. 59, 60) evaluated 194 dentists (average exposure
of 26 years; average amalgam surfaces = 16; urine mercury = 3.32  4.87 [mu]g/L, ~2.6 [mu]g/g Cr) and 233 hygienists (average
exposure of 15 years; average amalgam surfaces = 12; urine mercury =
1.98  2.29 [mu]g/L, ~1.48 [mu]g/g Cr) for neurological
effects. No effects were observed on verbal intelligence and reaction
time. Significant correlations with urine mercury concentrations were
found on 9 measures in dentists and 8 measures in hygienists, including
visual discrimination, hand steadiness, finger tapping and trail making
tests. A weakness of the study was that no non-mercury-exposed dental
professionals were studied; therefore, the effect of exposure to other
chemicals in the workplace (gases, organic solvents) cannot be ruled
out. Nor was a non-dental workplace control group studied, which would
have been informative about effects of the dental work environment in
general.
    FDA concludes that existing data indicate that dental professionals
are generally not at risk for mercury toxicity except when dental
amalgams are improperly used, stored, triturated, or handled.
iii. Individuals With Mercury Allergies
    Some individuals are hypersensitive or allergic to mercury and/or
other metals. FDA reviewed several epidemiological and case studies
related to the effects of mercury vapor exposure from dental amalgam on
allergic individuals.
    According to some of the studies that were reviewed, some patients
develop adverse tissue reactions such as dermatological conditions or
lesions of the skin, mouth, and tongue as a result of exposure to
dental amalgam (Ref. 61, 62). In mercury-allergic individuals, clinical
improvements were reported after dental amalgam restorations were
removed. Other studies reported that dental amalgam may exacerbate pre-
existing autoimmune disease in mercury-allergic individuals (Refs. 63,
64). After dental amalgam restorations were removed, the health status
of these patients reportedly improved.
    FDA concludes that existing data indicate that certain individuals
with a pre-existing hypersensitivity or allergy to mercury may be at
risk for adverse health effects from mercury vapor released from dental
amalgam.
2. Rationale for Special Controls
    In light of the above information, FDA has identified the following
as the potential risks to health associated with the use of dental
amalgam devices, requiring the establishment of special controls: (1)
Exposure to mercury; (2) allergic response including adverse tissue
reaction; (3) contamination; (4) mechanical failure; (5) corrosion; and
(6) improper use. FDA is establishing a special controls guidance
document that includes recommendations to address these risks as
follows.
a. Risk of Exposure to Mercury
    As discussed above, dental amalgam releases mercury vapor and is
associated with a risk of human exposure to this vapor. The special
controls to address this risk are recommendations for: (i) Specific
labeling, (ii) an information for use statement, and (iii) a
performance test for mercury vapor release.
i. Specific Labeling Recommendation
    The special controls guidance recommends the following specific
labeling:
     WARNING: CONTAINS MERCURY.
     Warning: May be harmful if vapors are inhaled.
     Precaution: Use with adequate ventilation.
     Precaution: Store in a cool, well ventilated place.
     Contains [ ]% mercury by weight.
    The recommended warning about the presence of mercury in a dental
amalgam device and the recommended disclosure of mercury content by
weight will alert dental professionals of the potential for exposure to
mercury vapor and will remind them of the need for protective measures,
such as the use of gloves when handling the device. The recommended
precautions about the need for adequate ventilation and the need to
store in a cool, well ventilated place will encourage professionals to
ensure there is adequate ventilation when in proximity to the device
and to use a vacuum pump and adequate ventilation during placement of
dental amalgams to minimize the amount of mercury vapor that they or
their patients may inhale.
ii. Information for Use Recommendation
    Dental amalgam has been and remains one of the most commonly used
restorative materials in dentistry. In the recent past the use of
dental amalgam has gradually declined due to the improved properties of
composite resin materials. Although amalgam has been used successfully
for many years, the risks associated with this device have been
controversial. Some scientists, professional groups, clinicians and
patient advocacy groups have expressed concern about the potential
hazards to health arising from mercury vapor release from amalgam
restorations. Other groups of scientists, clinicians, and professional
organizations have disagreed with these concerns. These opposing
viewpoints were voiced at the 2006 FDA joint panel meeting (Ref. 66).
    In order for dentists to make appropriate treatment decisions with
their patients, it is important to provide information to help dentists
understand the complexities of the science related to dental amalgam
and its mercury content.
    FDA recommends the inclusion of an ``information for use''
statement in dental amalgam labeling as a special control:

    Dental amalgam has been demonstrated to be an effective
restorative material that has benefits in terms of strength,
marginal integrity, suitability for large occlusal surfaces, and
durability.\17\ Dental amalgam also releases low levels of mercury
vapor, a chemical that at high exposure levels is well-documented to
cause neurological and renal adverse health effects.\18\ Mercury
vapor concentrations are highest immediately after placement and
removal of dental amalgam but decline thereafter.
---------------------------------------------------------------------------

    \17\ Dental Amalgam: A Scientific Review and Recommended Public
Health Service Strategy for Research, Education and Regulation;
Public Health Service, U.S. Department of Health and Human Services,
January 1993.
    \18\ Liu, J. et al., ``Toxic effects of metals,'' Casarett &
Doull's Toxicology: The Basic Science of Poisons, Chapter 23, pp.
931-979, McGraw-Hill Medical, New York, New York, 2008.
    Clarkson, T.W. et al., ``The Toxicology of Mercury and Its
Chemical Compounds,'' Critical Reviews in Toxicology, Vol. 36, pp.
609-662, 2006.
---------------------------------------------------------------------------

    Clinical studies have not established a causal link between
dental amalgam and adverse health effects in adults and children age
six and older. In addition, two clinical trials in children aged six
and older did not find neurological or renal injury associated with
amalgam use.\19\
---------------------------------------------------------------------------

    \19\ De Rouen, T. et al., ``Neurobehavioral Effects of Dental
Amalgam in Children, A Randomized Clinical Trial,'' Journal of the
American Medical Association, Vol. 295, 1784-1792, No. 15, April,
19, 2006.
    Bellinger, D.C. et al., ``Neuropsychological and Renal Effects
of Dental Amalgam in Children: A Randomized Clinical Trial,''
Journal of the American Medical Association, Vol. 295, No. 15, April
19, 2006, 1775-1783, 2006.
    Barregard, L. et al., ``Renal Effects of Dental Amalgam in
Children: The New England Children's Amalgam Trial,'' Environmental
Health Perspectives, Volume 116, 394-399, No. 3, March 2008.
    Woods, J.S. et al., ``Biomarkers of Kidney Integrity in Children
and Adolescents with Dental Amalgam Mercury Exposure: Findings from
the Casa Pia Children's Amalgam Trial,'' Environmental Research,
Vol. 108, pp. 393-399, 2008.
    Lauterbach, M. et al., ``Neurological Outcomes in Children with
and Without Amalgam-Related Mercury Exposure: Seven Years of
Longitudinal Observations in a Randomized Trial,'' Journal of the
American Dental Association, Vol. 139, 138-145, February 2008.

---------------------------------------------------------------------------

    The developing neurological systems in fetuses and young
children may be more sensitive to the neurotoxic effects of mercury
vapor. Very limited to no clinical information is available
regarding long-term health outcomes in pregnant women and their
developing fetuses, and children under the age of six, including
infants who are breastfed.
    The Agency for Toxic Substances and Disease Registry's (ATSDR)
and the Environmental Protection Agency (EPA) have established
levels of exposure for mercury vapor that are intended to be highly
protective against adverse health effects, including for sensitive
subpopulations such as pregnant women and their developing fetuses,
breastfed infants, and children under age six.\20\ Exceeding these
levels does not necessarily mean that any adverse effects will
occur.
---------------------------------------------------------------------------

    \20\ Agency for Toxic Substances and Disease Registry (ATSDR)
and Research Triangle Institute, Toxicological profile for mercury,
U.S. Dept. of Health and Human Services, Public Health Service,
Atlanta, Georgia, 1999.
    United States Environmental Protection Agency (EPA),
``Integrated Risk Information System (IRIS) Screening-Level
literature Review''--Mercury, elemental, 2002.
---------------------------------------------------------------------------

    FDA has found that scientific studies using the most reliable
methods have shown that dental amalgam exposes adults to amounts of
elemental mercury vapor below or approximately equivalent to the
protective levels of exposure identified by ATSDR and EPA. Based on
these findings and the clinical data, FDA has concluded that
exposures to mercury vapor from dental amalgam do not put
individuals age six and older at risk for mercury-associated adverse
health effects.
    Taking into account factors such as the number and size of teeth
and respiratory volumes and rates, FDA estimates that the estimated
daily dose of mercury in children under age six with dental amalgams
is lower than the estimated daily adult dose. The exposures to
children would therefore be lower than the protective levels of
exposure identified by ATSDR and EPA.
    In addition, the estimated concentration of mercury in breast
milk attributable to dental amalgam is an order of magnitude below
the EPA protective reference dose for oral exposure to inorganic
mercury. FDA has concluded that the existing data support a finding
that infants are not at risk for adverse health effects from the
breast milk of women exposed to mercury vapors from dental
amalgam.''

The purpose of this labeling recommendation is address potential
misunderstandings about the risk of exposure to mercury from the device
and to help dental professionals plan appropriate treatment
recommendations for their patients by providing them with FDA's
assessment of the most current, best available evidence regarding
potential risks to health from mercury vapor released from dental
amalgams.
iii. Performance Test Recommendation
    The special controls guidance recommends a performance test to
determine the amount of mercury vapor released by a dental amalgam
device during corrosion (ng/cm\2\ in 4 hrs).
    Dental amalgam releases the highest levels of mercury vapor when it
corrodes (Ref. 65). By measuring the amount of mercury vapor released
during corrosion, the recommended performance test will quantify the
highest levels of vapor release that can be expected from a dental
amalgam device. The results of this test will enable FDA, through a
premarket notification (510(k)) submission, to determine if these
levels are acceptable and are comparable to legally marketed
devices.\21\
---------------------------------------------------------------------------

    \21\ Dental amalgam devices currently on the market must also be
in conformance with the special controls guidance.
---------------------------------------------------------------------------

b. Risk of Allergic Response Including Adverse Tissue Reaction
    Dental amalgam is associated with a risk of adverse tissue
reaction, particularly in individuals with a mercury allergy, who may
experience additional allergic reactions. The special controls to
address this risk are recommendations for: (i) Specific labeling and
(ii) a performance test for biocompatibility.
i. Specific Labeling Recommendation
    The special controls guidance recommends the following specific
labeling:
    [mshbox] Contraindication: Do not use in persons with a known
mercury allergy.
    The recommended contraindication is designed to prevent exposure
and resultant adverse tissue reactions in allergic individuals.
ii. Performance Test Recommendation
    The special controls guidance recommends a performance test to
assess the biocompatibility of a dental amalgam device. Specifically,
the guidance recommends that devices be tested in conformance with the
following consensus standard: ``ISO 7405:1997(E), Dentistry--
Preclinical evaluation of biocompatibility of medical devices used in
dentistry--Test methods for dental materials.''
    Biocompatibility refers to the appropriate interaction between the
device and the human body, and the minimization of risk of rejection or
toxicity. Conformance to the recommended consensus standard will
minimize the potential of a dental amalgam device to cause toxic or
injurious effects by ensuring that the device will have the appropriate
biological response for its intended use.
c. Risk of Mercury Contamination
    When the mercury used to form dental amalgam is contaminated with
impurities, such as oil, water, or other foreign matter, the amalgam
may not harden properly. This may cause the device to be less
effective. The special control to address this risk is a recommendation
for a quality control test.
    The special controls guidance recommends a quality control test for
the production of dental amalgam devices. Specifically, the guidance
recommends that devices be tested in conformance with the ISO
24234:2004(E) consensus standard. This standard includes quality
control procedures for mercury, setting specific guidelines for
visually inspecting mercury during production and observing its pouring
characteristics. Among other things, this standard describes what
visual signs indicate that a mercury sample is contaminated and
therefore unsuitable for dental amalgam.
    The recommended quality control test will ensure that the mercury
used in dental amalgam devices is free from contamination.
d. Risk of Mechanical Failure
    If a dental amalgam device is not sufficiently strong, it will not
be able to withstand the force of regular chewing. As a result, it may
fracture and require replacement. The special controls to address the
risk of mechanical failure are recommendations for (i) specific
labeling and (ii) a performance test.
i. Specific Labeling Recommendation
    The special controls guidance recommends the following specific
labeling:
    [squarf] Compressive strength (MPa) @ 24 hrs.
    [squarf] Dimensional change during hardening (%).
    [squarf] Trituration time (s).

    [squarf] Working time (min).
    The recommended labeling will ensure that dental professionals are
aware of the key physical properties of a dental amalgam device. This
information will be useful in helping the professional decide if the
device is suitable for an intended application.
ii. Performance Test Recommendation
    The special controls guidance recommends that dental amalgam
devices be tested in conformance with the ISO 24234:2004(E) performance
standard. This standard calls for evaluation of the following physical
properties:
    [squarf] Complete chemical composition.
    [squarf] Compressive strength (MPa) @ 1 hr.
    [squarf] Compressive strength (MPa) @ 24 hrs.
    [squarf] Maximum creep (%).
    [squarf] Dimensional change during hardening (%).
    [squarf] Particle size distribution ([mu]) and shape, i.e.,
spherical, irregular, etc.
    [squarf] Trituration time (s).
    [squarf] Working time (min).
    The recommended performance test will evaluate key physical
properties of dental amalgam devices that could affect their function.
Analysis of these properties will enable FDA, through a premarket
notification (510(k)) submission, to determine if a device has physical
properties that are acceptable and are comparable to legally marketed
devices.
e. Risk of Corrosion
    Dental amalgam devices may corrode under certain conditions,
including when they are placed in direct contact with other metals. If
a dental amalgam device corrodes, it will lose its strength and will
need to be replaced. Corrosion also increases the amount of mercury
vapor a dental amalgam device releases. The special controls to address
the risk of corrosion are recommendations for: (i) Specific labeling
and (ii) a performance test for corrosion potential.
i. Specific Labeling Recommendation
    The special controls guidance recommends the following specific
labeling:
    [squarf] Precaution: Do not place the device in direct contact with
other types of metals.
    This labeling precaution recommendation will alert dental
professionals of a potential material incompatibility between dental
amalgam and other metal restoratives that may be present in the mouth,
such as stainless steel, titanium, base metal alloys, and noble metal
alloys. It will help ensure that a dental amalgam device is not placed
in contact with a metal that will cause the device to corrode.
ii. Performance Test Recommendation
    The special controls guidance recommends that dental amalgam
devices be tested to assess their corrosion potential. Specifically,
the guidance recommends that dental amalgam devices be tested in
conformance with the ISO 24234:2004(E) performance standard. This
standard calls for an evaluation of corrosion byproducts, identifying
the type and amount of substances leached from the device when
corrosion occurs.
    The recommended performance test will provide information about
what chemical products could be expected to be leached if the device
were to corrode. This information will enable FDA, through a premarket
notification (510(k)) submission, to determine if the device is
acceptable and is comparable to legally marketed devices.
f. Risk of Improper Use
    ``Improper use'' of a device can result from misuse of the device.
The special controls to address the risk of improper use are
recommendations for specific labeling.
    The special controls guidance recommends the following specific
labeling:
    [squarf] Contraindication: Do not use in persons with a known
mercury allergy.
    [squarf] Precaution: Single-use only.
    The recommended labeling contraindiation will alert dental
professionals of situations in which the use of a dental amalgam device
is not recommended, such as in patients with a known mercury allergy.
The recommended labeling precaution will inform dental professionals
that a dental amalgam device is not intended to be reused.

B. Statutory Authority

    FDA regulates devices, including dental devices, under the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301 et seq.), and the
act's implementing regulations (parts 800 through 898 (21 CFR parts 800
through 898)). The Medical Device Amendments of 1976 (Pub. L. 94-295)
amended the act to add premarket review authority and other authorities
related to devices. Section 513 of the act (21 U.S.C. 360c) established
three categories (classes) of devices, depending on the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three categories of devices are class I devices,
which are subject to general controls; class II devices, which are
subject to general and ``special'' controls; and class III devices, for
which premarket approval applications generally must be submitted.
    General controls include requirements for registration, listing,
adverse event reporting, and good manufacturing practice (section
513(a)(1)(A) of the act). Special controls are controls that, in
addition to general controls, are applicable to a class II device to
help provide reasonable assurance of that device's safety and
effectiveness (section 513(a)(1)(B) of the act). Under the 1976
amendments, class II devices were defined as devices for which there
was insufficient information to show that general controls themselves
would provide reasonable assurance of safety and effectiveness, but for
which there was sufficient information to establish performance
standards to provide such assurance. The Safe Medical Devices Act of
1990 (SMDA) (Pub. L. 101-629) broadened the definition of class II
devices to mean those devices for which the general controls by
themselves are insufficient to provide reasonable assurance of safety
and effectiveness, but for which there is sufficient information to
establish special controls to provide such assurance, including
performance standards, postmarket surveillance, patient registries,
development and dissemination of guidelines, recommendations, and any
other appropriate actions the agency deems necessary (section
513(a)(1)(B) of the act). The premarket approval requirements specify
data and information that must be provided to FDA to obtain approval of
a class III device (section 515 of the act (21 U.S.C. 360e)).
    Devices that were in commercial distribution before the enactment
of the Medical Device Amendments of 1976 (May 28, 1976) are commonly
referred to as ``preamendments devices.'' Under section 513 of the act,
FDA classifies preamendments devices according to the following steps:
(1) FDA receives a recommendation from a device classification panel
(an FDA advisory committee); (2) FDA publishes the panel's
recommendation for comment, along with a proposed regulation
classifying the device; and (3) FDA publishes a final regulation. FDA
has classified most preamendments devices under these procedures.
    Section 513(e) of the act governs reclassification of preamendments
devices. This section provides that FDA may reclassify a device by
rulemaking based upon ``new information.'' FDA may initiate
reclassification under section 513(e) or an interested person

may petition FDA to reclassify a preamendments device. The term ``new
information,'' as used in section 513(e) of the act, includes
information developed as a result of a reevaluation of the data before
the agency when the device was originally classified, as well as
information not presented, not available, or not developed at that
time. (See, e.g., Holland Rantos v. United States Department of Health,
Education, and Welfare, 587 F.2d 1173, 1174 n.1 (DC Cir. 1978); Upjohn
v. Finch, 422 F.2d 944 (6th Cir. 1970); Bell v. Goddard, 366 F.2d 177
(7th Cir. 1966)).
    Reevaluation of the data previously before the agency is an
appropriate basis for subsequent regulatory action where the
reevaluation is made in light of newly available regulatory authority
(see Bell v. Goddard, supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762
F. Supp. 382, 389-91 (D.D.C. 1991)), or in light of changes in
``medical science.'' (See Upjohn v. Finch, supra, 422 F.2d at 951).
Whether data before the agency are past or new data, the ``new
information'' to support reclassification under section 513(e) must be
``valid scientific evidence,'' as defined in section 513(a)(3) of the
act (21 U.S.C. 360c(a)(3)) and 21 CFR 860.7(c)(2). (See, e.g., General
Medical Co. v. FDA, 770 F.2d 214 (DC Cir. 1985); Contact Lens Assoc. v.
FDA, 766 F.2d 592 (DC Cir.), cert. denied, 474 U.S. 1062 (1985)).
    FDA relies upon ``valid scientific evidence'' in the classification
process to determine the level of regulation for devices (Sec.  860.7).
For the purpose of reclassification, the valid scientific evidence upon
which the agency relies must be publicly available. Publicly available
information excludes trade secret and/or confidential commercial
information, e.g., the contents of a pending premarket approval
application (PMA). (See section 520(c) of the act (21 U.S.C. 360j(c)).

C. Regulatory History of the Devices

1. Regulatory Status
    Dental amalgam \22\ is a metallic restorative material that has
been used for direct filling of carious lesions or structural defects
in teeth since the 1890s.\23\ It is a combination of two devices,
mercury \24\ (liquid) and amalgam alloy (powder), which is composed
primarily of silver, tin, and copper. At the time FDA proposed to
classify mercury and amalgam alloy, the devices were most commonly
marketed individually in tablet/sachet or bulk form to be prepared by
mixing the two devices in a dentist's office, although the devices were
also available in an already combined predosed, encapsulated form.
Since the mid-1980s, the device has been marketed most frequently in
the predosed, encapsulated form.
---------------------------------------------------------------------------

    \22\ ``Dental amalgam,'' as it is referred to in this final
rule, is a device that is a combination of two component devices,
mercury and amalgam alloy.
    \23\ Earlier prototypes were available from the 1830s.
    \24\ FDA is no longer using the term ``dental mercury,'' but
instead is using ``mercury,'' to more accurately reflect the fact
that the mercury used in dental amalgam is elemental mercury.
---------------------------------------------------------------------------

    FDA classified mercury and amalgam alloy separately in accordance
with the classification procedures for preamendments devices. In 1980,
FDA published a proposed rule to classify amalgam alloy into class II,
based on the recommendation of a device classification panel (Dec. 30,
1980, 45 FR 85979), and finalized the classification of amalgam alloy
into class II in the Federal Register of August 12, 1987 (52 FR 30099).
Although FDA proposed classifying mercury into class II, in the Federal
Register of August 12, 1987 (52 FR 30089) FDA issued a final rule
classifying mercury into class I. FDA explained that it believed that
the general controls of the act, particularly the requirement that the
device bear adequate directions for use, were sufficient to provide
reasonable assurance of the safety and effectiveness of the device and
to address the risk of rare allergic reactions among patients as well
as the risk of toxicity among dental health professionals.
    FDA did not classify dental amalgam at the time it classified its
two components, mercury and amalgam alloy. However, in accordance with
its customary practice regarding regulation of devices composed of two
or more devices, FDA has regulated the predosed, encapsulated form of
dental amalgam in accordance with the requirements applicable to its
component with the highest classification, i.e., amalgam alloy.
Accordingly, dental amalgam devices entering the market have been
regulated as class II devices under 21 CFR 872.3050, amalgam alloy.
2. Proposed Rule
    In the Federal Register of February 20, 2002 (67 FR 7620), FDA
published a proposed rule entitled ``Dental Devices: Classification of
Dental Amalgam and Reclassification of Dental Mercury; Issuance of
Special Controls for Amalgam Alloy.'' The proposed rule was based on
the recommendation of the device advisory panel, information submitted
in citizen petitions requesting the agency to take various actions with
respect to the devices, a substantial amount of scientific data, and
the results of several government safety assessments related to the
devices (Refs. 3, 4, 12).
    The Dental Products Panel \25\ (the Panel) unanimously recommended
that FDA classify dental amalgam in its encapsulated form into class II
(Ref. 1). The Panel concluded that there are no major risks associated
with encapsulated dental amalgam, when used as directed, but recognized
there is a small population of patients who may experience allergic
hypersensitive reactions to the materials in the device. The Panel also
noted that improper use of the device exposes professionals to risks
associated with mercury toxicity. To address these risks, the Panel
recommended that the device be subject to voluntary performance
standards, voluntary testing guidelines, and requirements that the
device be used only on the written or oral authorization of a licensed
practitioner, and only by persons with training or expertise in its
use.
---------------------------------------------------------------------------

    \25\ A panel of FDA's Center for Devices and Radiological Health
Medical Devices Advisory Committee.
---------------------------------------------------------------------------

    The proposed rule included the following actions: (1) Classify
encapsulated dental amalgam into class II (special controls); (2) amend
the class II classification for amalgam alloy by designating special
controls; and (3) reclassify mercury from class I (general controls) to
class II (special controls). In the 2002 proposed rule, FDA identified
risks to health associated with the use of dental amalgam, mercury, and
amalgam alloy that it believed required the imposition of special
controls that, in conjunction with the general controls of the act,
would provide reasonable assurance of the safety and effectiveness of
the device. The risks identified were mercury toxicity associated with
the improper use of dental amalgam and allergic reactions in a small
subpopulation of individuals. To mitigate these risks, FDA proposed a
labeling guidance and compliance with recognized consensus standards as
special controls for these devices. FDA proposed that all three devices
be subject to the same special control guidance document, ``Special
Control Guidance Document on Encapsulated Amalgam, Amalgam Alloy, and
Dental Mercury Labeling,'' dated February 20, 2002, as well as the
following consensus standards, as relevant: (1) International Standards
Organization (ISO) 1559:1995 Dental Materials-Alloys for Dental
Amalgam, and (2) American National Standards Institute/American Dental
Association (ANSI/ADA) Specification

No. 6-1987 for Dental Mercury. The comment period on the proposed rule
was reopened on July 17, 2002 (67 FR 46941), and again on April 28,
2008 (73 FR 22877), to permit additional opportunities for public
comment (Docket No. FDA-2008-N-0163).
3. Scientific Information, Safety Assessments, and Adverse Event
Reports Regarding Dental Amalgam
a. Information and Assessments Discussed in the Proposed Rule
    Before issuing the proposed rule, FDA carefully examined extensive
information related to the safety and effectiveness of dental amalgam.
This information included a comprehensive safety assessment of dental
amalgam performed by the U.S. Public Health Service (PHS), U.S.
government research related to dental amalgam, studies and other
information submitted in citizen petitions to the agency, several
national and international comprehensive reviews of scientific
information about the risks and benefits of the device, comprehensive
safety assessments of dental products that contain mercury by
international health organizations and foreign countries, and the
scientific literature reviewed by the Panel. See 67 FR 7621-7625 (Feb.
20, 2002).
b. Information and Assessments That Have Become Available Since
Publication of the Proposed Rule
i. Life Sciences Research Office (LSRO) Report
    In 2004, the Trans-agency Working Group on the Health Effects of
Dental Amalgam completed a comprehensive review of approximately 300
peer-reviewed studies of dental amalgam and mercury vapor published
from 1996 through 2003 (LSRO report) (Ref. 13). The project was
completed under contract by Life Sciences Research Office, Inc. (LSRO),
and was funded by the National Institutes of Health (NIH), in
cooperation with FDA, the Centers for Disease Control and Prevention
(CDC), and the Office of the Chief Dental Officer of the Public Health
Service. In conducting the review, LSRO engaged an independent panel of
experts from academia in the fields of immunotoxicology, immunology,
and allergy; neurobehavioral toxicology and neurodevelopment;
pediatrics; developmental and reproductive toxicology; toxicokinetics
and modeling; occupational health and epidemiology; pathology; and
general toxicology. The LSRO report concluded that there is little
evidence to support claims of a causal relationship between mercury
fillings and human health problems, such as kidney or cognitive
dysfunction; neurodegenerative disease, specifically Alzheimer's
disease or Parkinson's disease; or autoimmune disease (Refs. 13, 67).
The report also identified important data gaps, including whether low-
level mercury vapor results in neurotoxicity, whether low-level in
utero exposure to mercury vapor affects the developing brain, and
whether occupational exposure to mercury vapor affects reproductive
and/or pregnancy outcomes.
ii. White Paper and Addendum Scientific Reviews
    In an effort to assess whether peer-reviewed literature published
since FDA's 1997 safety assessment of dental amalgam (Ref. 12)
presented new information on the potential health risks of dental
amalgam, FDA's National Center for Toxicological Research (NCTR)
prepared a White Paper review (Ref. 10). Rather than duplicate previous
extensive reviews of the scientific literature by U.S. government
agencies and international organizations, NCTR chose to build on the
previous reviews and conducted an in-depth evaluation of 34 primary
research articles that were chosen for their scientific merit,
relevance, and potential to provide the most significant current
information regarding the potential health risks associated with
exposure to mercury in dental amalgam. The conclusion in the draft
White Paper was that the peer-reviewed scientific information published
since 1997 was consistent with FDA's previous assessment that, except
for persons with rare allergic or hypersensitivity reactions,
individuals with dental amalgam restorations do not experience adverse
effects from the device.
    On September 6 and 7, 2006, FDA presented the findings of the White
Paper in draft to a joint meeting of the Dental Products Panel and the
Peripheral and Central Nervous System Drugs Advisory Committee (the
2006 Panel). At that time, FDA also opened a docket related to the
meeting to facilitate public submission of information regarding the
potential health risks of mercury in dental amalgam (Docket No. FDA-
2006-N-0543 (formerly 2006N-0352)).
    The 2006 Panel heard from numerous public speakers, and then
deliberated and made recommendations on a series of questions FDA had
posed on its draft White Paper (Ref. 66). The committee concluded that
FDA's draft White Paper had significant limitations, such as the fact
that the literature search used a single database (PubMed), the Paper
did not satisfactorily explain how the scientific references were
chosen,\26\ and it failed to identify significant gaps in the
scientific knowledge, particularly with respect to exposure limits and
possible health risks for sensitive subpopulations. The majority of the
2006 Panel voted that it could not find the conclusions of the draft
White Paper to be ``reasonable'' in light of these limitations. In
their closing comments, the panelists provided individual
recommendations, including the individual (not consensus)
recommendations that FDA consider labeling requirements related to the
use of dental amalgam in pregnant women and small children, that
manufacturers be required to provide information to patients to ensure
that they understand that the devices contain mercury, and that the
Federal government (public health agencies) research the effects of
dental amalgam mercury on reproductive health and developing fetuses.
---------------------------------------------------------------------------

    \26\ Appendix A of the draft White Paper did list the inclusion
and exclusion criteria for identification of relevant studies.
---------------------------------------------------------------------------

    In response to the deliberations and recommendations of the 2006
Panel, FDA conducted a more comprehensive review of the scientific
literature in an Addendum to the White Paper (Ref. 11). In total, more
than 200 scientific articles, including 33 case studies, were
considered in the White Paper and its Addendum.\27\
---------------------------------------------------------------------------

    \27\ FDA decided to conduct this comprehensive review of the
literature and prepare the Addendum rather than revise the White
Paper. FDA finalized the White Paper with the addition of the
Addendum.
---------------------------------------------------------------------------

    The conclusions of the Addendum generally confirmed the conclusions
of the White Paper and previous assessments by other organizations and
agencies regarding the potential health risks presented by the presence
of mercury in dental amalgam. More specifically, the articles and case
studies reviewed in the Addendum to the White Paper were consistent
with the conclusion in earlier government safety assessments (Refs. 3,
4, 12) that exposures to mercury vapor from dental amalgam are not
associated with adverse health effects in the population age six and
older (see also section I.A.). As discussed in the Addendum, FDA also
concluded that prospective clinical studies of dental amalgam published
to date (Refs. 31, 32, 34, 40, 46, 47, 68) found no neurological
deficits in children who first received dental amalgam restorations at
ages six to ten and were followed for five or seven years. FDA
concluded, however, that the clinical data are limited regarding
certain subpopulations (pregnant

women and their developing fetuses, and children under the age of six,
including breastfed infants).
c. Adverse Event Reports
    As part of FDA's effort to determine the appropriate regulatory
controls to provide reasonable assurance of the safety and
effectiveness of dental amalgam, FDA reviewed all adverse event reports
submitted to MedWatch for dental amalgam devices through 2008. The
review identified 141 reports, dating back to 1988, including 102
reports of injuries, 12 reports of malfunctions, 26 miscellaneous
complaints, and 1 misreported death.\28\ The large majority of the
injury reports were submitted voluntarily by individual patients. The
malfunction reports were submitted primarily by health professionals
and two reports were submitted by manufacturers.
---------------------------------------------------------------------------

    \28\ The death report appears to have been misclassified because
it was self reported (an actual death had not occurred). This report
attributes symptoms of joint pain, neurological spasms, a
compromised immune system, and a variety of other physical symptoms
to dental amalgam.
---------------------------------------------------------------------------

    The malfunction reports described problems with encapsulated
amalgam such as product shrinkage, inaccurate powder to liquid ratios,
and capsule leaking. There were also some reports of mercury spills as
a result of mixing (triturating) amalgam capsules.
    The injury reports described a wide array of conditions and
symptoms that individual patients believed to be caused by their dental
amalgam fillings. The conditions and symptoms reported included
fatigue, headaches, joint pain, brain ``fog,'' depression, neuropathy,
rheumatoid arthritis, hypothyroidism, visual impairments, hearing loss,
allergies, kidney damage, attention deficit disorder, irritable bowel
syndrome, seizures, abnormal menstrual cycle, weight loss, and
developmental problems, such as autism, attention deficit hyperactivity
disorder, and unidentified congenital defects. Several reporters stated
that they experienced relief from their symptoms when their amalgam
fillings were removed, while others stated that their symptoms did not
appear until after their fillings were removed.
    The great majority of the adverse event reports submitted to FDA
regarding dental amalgam are anecdotal and lack specific details, such
as when symptoms first appeared, how they progressed, and what may have
caused onset or relief of certain symptoms. In addition, the reports
frequently were not made until years after the events occurred. Because
of these factors, FDA is unable to assess the relationship of the
reported adverse effects with the device. FDA notes, however, that the
number of adverse event reports it has received regarding dental
amalgam is quite low in light of the device's long history of use in
tens of millions of dental restorations in the United States each
year.\29\
---------------------------------------------------------------------------

    \29\ FDA estimates that dental amalgam has been used in
approximately one billion restorations between 1988 and 2008.
---------------------------------------------------------------------------

II. Development of the Final Rule

    In developing this final rule, FDA considered the comments and
information submitted in response to the proposed rule, the scientific
reviews, studies, and safety assessments described above, and its
analysis of the adverse event reports submitted. The final rule and the
special controls guidance document are consistent with the proposed
regulation, although they reflect several changes made in response to
the comments and information received. As proposed, the final rule
classifies dental amalgam into class II, reclassifies mercury from
class I to class II, and designates a special control for dental
amalgam, mercury, and amalgam alloy. However, the final rule classifies
the three devices together in a single regulation and uses the term
``mercury'' instead of ``dental mercury.''
    The special controls guidance document specifically revises the
draft special controls guidance document as follows:
     Includes recommendations related to the updated relevant
consensus standards, rather than designating these standards as
separate special controls.
     Includes recommendations regarding device composition,
performance data, warnings, and labeling precautions.
     Recommends a contraindication against use in persons with
a known mercury allergy.
     Recommends that the labeling include an information for
use (IFU) statement.
     Updates recommendations regarding performance testing to
be included in 510(k) submissions to include strength, creep,
dimensional change, particle shape and distribution, corrosion
products, and amount of mercury vapor released.
     Replaces the recommendation that each ingredient of the
device be listed in the labeling with the recommendation that the
primary ingredients be listed, and that the labeling state that the
device contains mercury.
     Replaces the recommendation that the labeling warn that
the device contains zinc with the recommendation that the labeling warn
that the device contains mercury. FDA believes that the effects of zinc
on the expansion of dental amalgam are well understood and that a
warning that the device contains zinc is not necessary to provide a
reasonable assurance of the safety and effectiveness of the device. In
contrast, as discussed in section I.A., FDA recommends that the device
bear a warning that the device contains mercury because FDA believes
such a warning is necessary to provide a reasonable assurance of safety
and effectiveness because of the potential risks to health of exposure
to mercury and toxicity and adverse tissue reaction.
     Deletes recommendations regarding packaging and handling
because FDA has concluded that these recommendations are not necessary
to provide a reasonable assurance of the safety and effectiveness of
the device.
    In this final rule, FDA is designating a special controls guidance
document (described in section I.A.) that, along with the general
controls under the act, will provide reasonable assurance of the safety
and effectiveness of the device. Elsewhere in this issue of the Federal
Register, FDA is announcing the availability of the special controls
guidance. Following the effective date of this final rule, any firm
submitting a 510(k) premarket notification for dental amalgam, as well
as any firm currently marketing the device, must address the risks to
health identified in the special controls guidance document. Firms
marketing or intending to market mercury or amalgam alloy must address
the risks to health identified in the special controls guidance
document that apply to those devices.
    When a guidance document is established as a special control by
rulemaking, manufacturers are required to address the issues identified
in the guidance, either by following the recommendations in the
guidance or by some other means that provides equivalent assurances of
safety and effectiveness. If a manufacturer proposes to use a means
other than the recommendations set forth in the special controls
guidance, it is required to demonstrate that the alternative means
provides equivalent assurances of safety and effectiveness.

III. Comments and FDA's Responses

    As stated previously, in addition to the comment period provided
when the proposed rule was issued in 2002, FDA reopened the comment
period on the rule in July 2002 and again in April 2008. Altogether,
FDA received more than 1,400 comments on the proposed

rule and the draft special controls guidance document. The commenters
included consumers, health professionals, industry, academia, State and
Federal agencies, professional societies, and organizations. Because of
the intertwined nature of the documents and the significant duplication
of comments, FDA is summarizing and responding to the comments it
received on both the proposed rule and the draft special controls
guidance document in this preamble.\30\
---------------------------------------------------------------------------

    \30\ FDA also received more than 1,800 comments to the docket
for the 2006 Panel meeting on dental amalgam (Docket No. 2006N-
0352), which had been established to permit persons to comment and
provide information on the issues and questions raised at the
meeting. FDA reviewed and considered those comments in finalizing
this regulation.
---------------------------------------------------------------------------

    In the 2008 Federal Register notice reopening the comment period on
the proposed rule, FDA requested comments supported by empirical data
and scientific evidence on specific topics relating to the
classification of the devices and the special controls that should
apply to them if they were classified into class II. FDA requested
comments on whether the proposed special controls (materials and
labeling) would provide reasonable assurance of the safety and
effectiveness of the devices if they were placed in class II, and on
whether the proposed special controls guidance document should be
revised in light of the recommendations and discussions of the 2006
Panel. FDA also sought information related to the agency's analysis of
the benefits and costs of the various regulatory options for
classifying the devices, including the number of annual procedures in
which the devices are used, trends in the use of various restorative
devices, information regarding alternatives to dental amalgam, how
labeling describing the risks in certain populations might affect
demand, how such risks should be communicated, information regarding
the current level of mercury to which patients and professionals are
exposed, and whether that exposure might be reduced by using
alternatives to dental amalgam.

A. Classification

    (Comment) FDA received many comments regarding the appropriate
classification of these devices. The comments generally did not
distinguish among dental amalgam, mercury, and amalgam alloy, treating
them as one device, dental amalgam. Many comments urged the agency to
classify the device into class III (premarket approval), frequently
stating safety concerns. For example, some commentators urged the
agency to classify dental amalgam into class III because, as a class
III device, ``[it would be] presumed as unsafe and needing to be proven
safe before general use can be allowed'' and that ``it should be placed
in class III where manufacturers are forced to prove that it is safe,
not the class II where it can continue to be grandfathered.'' Others
believed the device should be classified into class II because there is
sufficient information to establish special controls for the device
that would provide reasonable assurance of its safety and
effectiveness. One comment stated that special controls were
unnecessary because it believed that the general controls of the act
are sufficient to provide reasonable assurance of the safety and
effectiveness of the device.
    (Response) FDA has determined that class II with a designated
special controls guidance document will provide a reasonable assurance
of safety and effectiveness for dental amalgam. In reaching this
determination, FDA made the findings required by Sec.  860.7(d)(1)
that, first, when subject to the general controls of the act and the
designated special control, and when accompanied by warnings against
unsafe use in individuals who are allergic to mercury, the probable
benefits to health from use of the device outweigh any probable risks.
Second, FDA has determined that, when subject to the general controls
of the act and the designated special control, valid scientific
evidence demonstrates the absence of unreasonable risk of illness or
injury associated with the use of the device for its intended uses and
conditions of use.
    FDA classifies devices in accordance with the statutory criteria in
section 513 of the act. As provided in section 513, class I devices are
devices for which the general controls of the act are sufficient to
provide reasonable assurance of safety and effectiveness. Class II
devices are devices for which general controls are not sufficient to
provide reasonable assurance of safety and effectiveness, but for which
there is sufficient information to establish special controls that,
along with the general controls of the act, will provide such
assurance. Class III devices are devices for which premarket approval
is necessary to provide reasonable assurance of safety and
effectiveness.
    As stated above, FDA relies on valid scientific evidence in making
determinations regarding classification. Valid scientific evidence is
defined as ``evidence from well-controlled investigations, partially
controlled studies, studies and objective trials without matched
controls, well-documented case histories conducted by qualified
experts, and reports of significant human experience with a marketed
device, from which it can fairly and responsibly be concluded by
qualified experts that there is reasonable assurance of the safety and
effectiveness of a device under its conditions of use.'' Sec.
860.7(c)(2). Consistent with the regulation, FDA does not rely on
isolated case reports, random experience, reports lacking sufficient
details to permit scientific evaluation, or unsubstantiated opinions.
The valid scientific evidence to support classification of a device may
vary according to, among other things, the existence and adequacy of
warnings and restrictions, and the extent of experience with use of the
device. Sec.  860.7(c)(2).
    The standard for determining whether there is reasonable assurance
that a device is safe is described in Sec.  860.7(d)(1).\31\ According
to that section, ``[t]here is reasonable assurance that a device is
safe when it can be determined, based on valid scientific evidence,
that the probable benefits to health from use of the device for its
intended uses and conditions of use, when accompanied by adequate
directions and warnings against unsafe use, outweigh any probable
risks. The valid scientific evidence used to determine the safety of a
device shall adequately demonstrate the absence of unreasonable risk of
illness or injury associated with the use of the device for its
intended uses and conditions of use.''
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    \31\ There is no question regarding the effectiveness of the
device. It is undisputed that the device has been used effectively
in millions of dental restorations over 100 years.
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    In determining the appropriate classification of dental amalgam,
FDA has relied on valid scientific evidence, including, as described in
detail in section I.A., several comprehensive reviews of the scientific
literature and safety assessments, air monitoring standards for mercury
vapor, biological monitoring standards for urine mercury, and clinical
studies. Based on its review of this information, FDA concludes that
exposures to mercury vapor from dental amalgam are not associated with
adverse health effects in the population age six and older. With
respect to potentially sensitive populations, i.e., fetuses, breastfed
infants, and children under six years of age, FDA would not expect to
see any adverse health effects in these subpopulations from mercury
vapors released from dental amalgam, although clinical data are
limited. These conclusions are supported by

independent investigations by other scientific bodies, such as the
European Commission's Scientific Committee on Emerging and Newly
Identified Health Risks (SCENIHR), which stated in 2007 (Ref. 6) that
``no risks of adverse systemic effects exist and the current use of
dental amalgam does not pose a risk of systemic disease.''
    Consistent with the regulation defining valid scientific evidence,
in determining the appropriate classification of dental amalgam, FDA
has considered the device's long history of use in tens of millions of
procedures in the United States each year, as well as the information
available regarding that use. FDA has also considered the adequacy of
warnings and the fact that the device is a prescription device and,
therefore, available to patients only with the involvement of a health
care provider. Finally, FDA has considered the probable benefits to
health from use of the device, such as its strength, marginal
integrity, suitability for large occlusal surfaces, durability, ease of
placement, and low failure and complication rates.
    FDA recognizes that dental amalgam releases low levels of mercury,
and that there are scientific data showing mercury vapor, at high
enough exposures, to be a neurotoxicant and nephrotoxicant. FDA also
recognizes that certain individuals are allergic to mercury. In
addition, there is very limited to no clinical information available
regarding long-term health outcomes in pregnant women and their
developing fetuses, and children under the age of six, including
infants who are breastfed. FDA believes that, in order to provide
reasonable assurance of the safety of dental amalgam, it is important
that dentists are informed that the device contains mercury, that it is
contraindicated against use in persons with a known allergy to mercury,
and that the labeling include an information for use statement
discussing the benefits, risks, and scientific study information.
    FDA has concluded that general controls alone are not sufficient to
address the identified risks to health presented by dental amalgam and
thus provide reasonable assurance of its safety and effectiveness. FDA
has also determined that premarket approval is not necessary to provide
such assurance because there is sufficient information to establish
special controls that, in conjunction with the general controls under
the act, will provide reasonable assurance of the safety and
effectiveness of the device. Specifically, FDA has concluded that the
recommendations in the special controls guidance document, including
the recommended labeling statements, along with the general controls of
the act, are sufficient to provide a reasonable assurance of the safety
and effectiveness of the device.
    In accordance with Sec.  860.7(d)(1), FDA has also concluded that,
when subject to the general controls of the act and the designated
special control, and when accompanied by warnings against unsafe use in
individuals who are allergic to mercury, the probable benefits to
health from use of the device outweigh any probable risks. Finally, FDA
has determined that, when subject to the general controls of the act
and the designated special control, valid scientific evidence
demonstrates the absence of unreasonable risk of illness or injury
associated with the use of the device for its intended uses and
conditions of use.
    (Comment) Some comments were opposed to ``FDA reclassifying
mercury-encapsulated amalgam dental fillings as a class II,'' stating
that ``FDA is moving quickly to approve mercury.''
    (Response) These comments reflect a misunderstanding of the device
classification process. Mercury, amalgam alloy, and dental amalgam are
legally marketed preamendments devices. As explained above,
preamendments devices are subject to specific classification
procedures. In 1987, FDA classified mercury and amalgam alloy through
notice and comment rulemaking, as required by the statute. Although FDA
did not classify dental amalgam (the combination of those two devices)
at that time, the device has been regulated in accordance with the
requirements applicable to its component with the highest
classification, i.e., amalgam alloy. In 2002, the agency issued a
proposed rule to classify dental amalgam. Consistent with that proposed
rule, FDA is now classifying the device into class II subject to a
special control that, along with the general controls under the act,
will provide reasonable assurance of its safety and effectiveness.
Thus, this rule does not constitute an ``approval'' for marketing, but
rather establishes additional regulatory controls for the device.
    (Comment) One comment stated that dental amalgam should be
regulated as a class III device because it is an implant.
    (Response) FDA disagrees with the comment. As explained in the
Federal Register of December 30, 1980 (45 FR 85962 at 85964), FDA does
not consider restorative materials placed in the teeth, such as dental
amalgam, to be implants.\32\ Moreover, even if the devices were
considered to be implants, FDA would not be required to classify them
into class III. In accordance with section 513(d)(2)(B) of the act (21
U.S.C. 360c(d)(2)(B)) and 21 CFR 860.93, an implant may be classified
into class I or class II if FDA determines that premarket approval is
not necessary to provide reasonable assurance of its safety and
effectiveness. As stated above, FDA has made this determination with
respect to dental amalgam.
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    \32\ The classification panel identified a dental implant as ``a
device that is surgically placed into, or in opposition to, the
maxilla or mandible and which protrudes through the mucosa of the
oral cavity'' (45 FR 85964). Dental restorative materials such as
amalgam do not protrude through the mucosa of the oral cavity and,
therefore, are not considered implants.
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B. Banning

    (Comment) Some comments stated that dental amalgam should be banned
because it is poisonous and not safe for use in dentistry. Other
comments requested that dental amalgam be banned for children 18 and
under, women of childbearing age, pregnant women, nursing mothers, and
persons with compromised immune systems and kidney problems. Some
comments suggested that FDA employ the ``precautionary principle''
adopted by other countries to protect these populations. In contrast,
other comments noted that no scientific study or assessment has found a
causal link between dental amalgam and adverse health effects in either
the general population or in any sensitive subpopulation, and that the
device has been used safely for many years in millions of dental
restorations.
    (Response) As discussed in detail above, FDA disagrees that the
levels of mercury released from dental amalgam contribute to adverse
health outcomes or is unsafe for use in dentistry when used with
appropriate occupational health controls for dental offices. FDA
recognizes that certain countries, e.g., Norway, Sweden, and Denmark,
have banned dental amalgam, adopting a ``precautionary principle''
approach (taking preventive action despite uncertainty regarding the
need for such action). However, FDA regulates devices, like dental
amalgam, in accordance with the requirements of the act. As explained
above, in accordance with the statutory criteria for classifying
devices, FDA has concluded that there is sufficient information from
which to establish special controls that, along with the general
controls of the act, will provide reasonable assurance of the

safety and effectiveness of the device. Specifically, FDA has
determined that the risks to health presented by dental amalgam can be
addressed through the general controls of the act in conjunction with
the recommendations in the special controls guidance document. Because
of this determination, FDA disagrees with comments suggesting that the
device should be banned.

C. Mercury Content and Toxicity

    (Comment) One comment stated that the labeling of the device should
disclose the fact that it contains mercury, citing to a recent poll
showing that 76 percent of Americans do not know that the primary
component of amalgam fillings is mercury. Another comment stated that
the amount of mercury vapor released from dental amalgam also should be
disclosed.
    (Response) FDA agrees that the labeling of the device should
disclose the fact that it contains mercury. Accordingly, the special
controls guidance recommends that the labeling include a warning that
the device contains mercury and disclose the total mercury content (%
by mass). FDA has concluded that labeling disclosing the amount of
mercury vapor released from the device would not provide useful
information because the mercury vapor released in a clinical setting
varies among patients and is dependent on several variables, such as
age and wear of the restoration, as well as the diet and chewing habits
of the patient. FDA believes, however, the recommended warning about
the presence of mercury in a dental amalgam device and the recommended
disclosure of mercury content by weight will alert dental professionals
of the potential for exposure to mercury vapor and will remind them of
the need for protective measures, such as the use of gloves when
handling the device. The recommended precaution about the need for
adequate ventilation will encourage professionals to use a vacuum pump
and adequate ventilation during placement of dental amalgams to
minimize the amount of mercury vapor that they or their patients may
inhale. Moreover, FDA is recommending that, to establish substantial
equivalence to a legally marketed device in a 510(k) premarket
notification, manufacturers conduct a test showing that the amount of
mercury vapor released due to corrosion is acceptable when evaluated
using an FDA-recognized standard or an equivalent method of evaluating
the amount of mercury vapor released due to corrosion.
    (Comment) Several comments were submitted in response to FDA's
request for information on the current level of exposure to the mercury
in dental amalgam for patients and dental professionals. One comment
stated that dental amalgams release 0.53 micrograms of mercury per
surface per day, resulting in an uptake into the blood stream of 0.081
micrograms of mercury per surface per day, well below the World Health
Organization (WHO) Acceptable Daily Intake (ADI) levels of 40
micrograms/day or 300 micrograms/day for demonstrable health effects to
the most sensitive individual. Another comment stated that dental
amalgam fillings release 4 to 22 micrograms/cm\2\ per day, that those
amounts are increased further by galvanism, heat, or chewing, and that
data show an average of 60 micrograms of mercury are excreted daily in
the feces of the average patient with amalgam fillings. Another comment
stated that the average urinary mercury concentrations in children (age
six and older) with amalgam fillings range from 0.1 to 5.7 micrograms/
gram creatinine, as compared to 0.1 to 2.9 micrograms/gram creatinine
for children with composite fillings. Another comment stated that
health screenings of dental professionals from 1997-2007 found an
average urinary mercury concentration of approximately 2.5 micrograms/L
and that this level is within the range of the urinary mercury
concentration found in individuals who are not exposed to mercury in
their occupations. Finally, one comment stated that there are 0.2
micrograms of mercury in the breathing zone of dentists during
placement and removal of amalgam.
    (Response) FDA agrees with the comments that the current level of
exposure to mercury in dental amalgam, for patients with restorations
and dental professionals exposed occupationally, is below the accepted
threshold levels for the most subtle health effects and is consistent
with the conclusions of previous safety assessments (Refs. 3, 6, 12,
13) that the mercury in dental amalgam does not present a risk to
health for the population age six and older. While the fact that dental
amalgam releases mercury vapor has been known for a long time, it is
difficult to make accurate estimates of the amount of mercury released
from amalgam and subsequent absorption of mercury in the body using an
air monitoring approach. These difficulties account for the disparate
range of values reported in the literature, some of which are noted in
the comment above. Because of the difficulties noted in determining a
robust estimate of daily dose of mercury resulting from monitoring of
mercury vapor in the oral cavity, as discussed in section I.A., FDA is
primarily relying on a consensus estimate of 1-5 [mu]g/day for adults
(Refs. 3, 22).
    FDA also recognizes that good dental hygiene practices, such as the
use of vacuum pumps and chair-side traps, have greatly reduced the
level of mercury to which dental professionals are exposed.
Nevertheless, because dental amalgam releases mercury vapor and is
associated with a risk of human exposure to this vapor, and because
some individuals have a known allergy to mercury, FDA is recommending
that the labeling warn that the device contains mercury, contain a
precaution that it should be used with proper ventilation, and include
a contraindication against use in persons with a known allergy to
mercury.
    (Comment) A few comments stated that dental amalgam fillings
contribute to the majority of the mercury body burden in the general
population and that urinary mercury concentrations are not measures of
mercury body burden, but rather represent a combination of the amount
of mercury to which an individual has been exposed and his or her
ability to excrete mercury. The comments added that 90 percent of
mercury is excreted from the body through the fecal route, and that low
urinary mercury concentrations are not an accurate predictor of mercury
exposure. Some comments stated that data obtained from autopsies
demonstrate that high mercury levels are present in the brain and
kidneys, despite dental amalgam mercury exposure levels being below
safety limits. A few comments noted that mercury passes through both
the umbilical cord and the blood/brain barrier.
    (Response) FDA recognizes that dental amalgam contributes to the
majority of the body burden of mercury for many people not
occupationally exposed to mercury (Ref. 22). FDA recognizes that urine
and feces are major routes of mercury excretion, but also recognizes
that which excretion route predominates is dependent on the mercury
species. The ``90% mercury excreted by the fecal route'' relates to
excretion of organic methylmercury, and this high percent is not the
case for inorganic forms of mercury, where the urinary route
predominates, especially in the case of chronic mercury vapor exposure
(Refs. 14, 69, 70). The amount of mercury excreted into feces is not a
well-accepted index of exposure to elemental mercury vapor. Further,
the

correlation of fecal mercury levels, mercury vapor exposure, and
adverse health effects has not been reliably established, as has been
shown for urinary mercury concentrations. Fecal mercury concentrations
might increase during removal of dental amalgams due to swallowing
amalgam particles. Fecal levels might also be elevated from dietary
exposure to methylmercury, which undergoes extensive enterohepatic
recycling between the GI tract and liver biliary excretion system.
    FDA disagrees with the comment that urinary mercury concentrations
are not accurate measures of inorganic mercury, including mercury
vapor, exposure. In fact, FDA and other public health agencies, such as
ATSDR (Ref. 14), and WHO (Refs. 21, 22), consider urinary mercury
concentrations to be the most accurate and widely used biomarker for
assessing the absorbed dose that results from chronic mercury vapor
exposure. For example, in a number of occupational studies, strong
correlations have been found between daily, time-weighted air
concentrations (which are considerably higher than exposures to dental
amalgam mercury) and urinary mercury concentrations in workers (Refs.
14, 21). In studies evaluating dental amalgam mercury exposure, urinary