[Federal Register Volume 74, Number 148 (Tuesday, August 4, 2009)]
[Rules and Regulations]
[Pages 38686-38714]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-18447]



[[Page 38685]]

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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

  Federal Register / Vol. 74, No. 148 / Tuesday, August 4, 2009 / Rules 
and Regulations  

[[Page 38686]]


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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

[[Page 38687]]

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.

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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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[[Page 38689]]

    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

[[Page 38690]]

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

[[Page 38691]]

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.

[[Page 38692]]

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.

[[Page 38693]]

    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.

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

[[Page 38694]]

    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).

[[Page 38695]]

    [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

[[Page 38696]]

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

[[Page 38697]]

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

[[Page 38698]]

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

[[Page 38699]]

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.''
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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

[[Page 38700]]

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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

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

[[Page 38701]]

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

[[Page 38702]]

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 
mercury concentrations have been shown to be proportional to the number 
of amalgam restorations and/or surfaces in the mouth.
    FDA is aware that, in autopsy studies, mercury has been found to 
accumulate in the brain. However, it is difficult to draw conclusions 
from autopsy studies regarding a potential association between exposure 
to dental amalgam and adverse health outcomes without information 
concerning the individual's lifetime history of exposure to mercury 
from fish and other environmental sources. Similarly, even in cases 
attempting to find an association, meaningful conclusions could not be 
drawn between neurodegenerative disorders, the number of dental 
amalgams, and the amount of accumulated mercury, because it is possible 
that damaged neuronal cells in patients with neurodegenerative 
disorders are able to accumulate more mercury than healthy cells (Ref. 
70).
    In response to the comments noting that mercury passes through both 
the umbilical cord, FDA agrees that mercury vapor has the ability to 
cross the placental barrier. As discussed in detail in section I.A., 
FDA found that 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. Moreover, FDA also reviewed several well-
conducted studies designed to assess high-level mercury vapor exposure 
on developmental effects in pregnant animals and their offspring. In 
one study no effects were observed on peripheral, somatosensory, 
auditory, or visual neurological functions in offspring of rats exposed 
to mercury vapor prenatally (Ref. 48). 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) (Ref. 44). More details are provided in section 
I.A.
    (Comment) One comment stated that mercury in dental amalgam is more 
toxic than mercury in fish.
    (Response) The form of mercury in dental amalgam (mercury vapor) is 
different from the form of mercury in fish (methylmercury). These two 
types of mercury differ in terms of kinetic behavior, mechanism of 
action, exposure routes, and tissue targets. For the purpose of 
classifying dental amalgam, FDA is addressing only the form of mercury 
in that device. As discussed in detail above, FDA disagrees that the 
levels of mercury released from dental amalgam are unsafe.
    (Comment) A few comments stated that toxic/allergic reactions to 
mercury in dental amalgam may produce autoimmune conditions such as 
lichen planus lesions, eczema, pustulosis, and dermatitis, and often 
play a role in the pathogenesis of periodontal disease.
    (Response) After reviewing 23 case studies and several 
epidemiological studies in the Addendum to the White Paper and 
conclusions from other reviews, FDA concluded that various 
dermatological conditions or lesions of the skin, mouth, and tongue 
were attributed to direct or indirect contact with dental amalgam, and 
may have been related to a pre-existing hypersensitivity or allergy to 
mercury and/or other metals. To help ensure that the device is not used 
in patients who are allergic to mercury, FDA is recommending that the 
labeling of the device contain a warning that the device contains 
mercury and a contraindication against use in persons with a known 
allergy to mercury.
    FDA disagrees that the mercury from dental amalgam plays a role in 
the pathogenesis of periodontal disease. Based on its review of the 
scientific literature on this subject (Refs. 71-75), FDA has concluded 
that the mercury in dental amalgam is not an etiological or aggravating 
agent for the initiation, propagation, or aggravation of any form of 
periodontitis.
    (Comment) Several comments suggested that the mercury in dental 
amalgam causes or contributes to chronic neurological or 
neurodegenerative diseases, such as Alzheimer's disease, Parkinson's 
disease, and autism.
    (Response) FDA discusses in detail in section I.A the available 
clinical information related to these diseases and its conclusions. In 
addition to the studies discussed in section I.A., and explained in the 
White Paper and Addendum reports (Refs. 10, 11), no evidence of 
neurodegenerative diseases have been reported in occupational cohorts 
exposed to much higher levels of mercury vapor in the workplace 
compared to the low levels in non-occupational groups with exposure 
from amalgams.
    (Comment) One comment claimed that dental amalgam may cause kidney 
damage in children, as evidenced by a recent clinical trial (New 
England) (Ref. 46) that showed that children with amalgam restorations 
had higher levels of microalbuminuria (protein in urine), which is a 
marker of kidney injury, than children with non-amalgam restorations.
    (Response) FDA disagrees with this comment. FDA reviewed the New 
England trial (Ref. 46) in the Addendum to the White Paper and 
concluded 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). However, in another children's prospective trial 
(Casa Pia), 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) (see also section I.A).

D. Patient Information

    (Comment) Several comments stated that FDA should require dentists 
to inform their patients that dental

[[Page 38703]]

amalgam contains mercury, and to advise them of the risks and benefits 
of the device, as well as the various restoration choices available to 
them. Many comments expressed concern that the labeling information 
would be provided only to dentists and not to patients. Several 
comments suggested that informed consent should be obtained from 
patients before they are treated with the device.
    (Response) As a preliminary matter, FDA believes the comments that 
suggested that ``informed consent'' be obtained before patients receive 
dental amalgam were not using the term as it is used in 21 CFR part 50, 
which applies to the protection of human subjects in clinical 
investigations (for example, investigations of devices that have not 
been cleared or approved for marketing). Rather, these comments appear 
to be concerned about ensuring that patients are informed about the 
risks, benefits, and alternatives to dental amalgam.
    FDA recognizes that selection of an appropriate restorative 
material for an individual patient, and hence an appropriate treatment 
plan, is a complex matter that requires the expertise of the dental 
professional. In selecting the appropriate restorative material for an 
individual patient, the dentist routinely considers many factors, such 
as the patient's oral health, the material properties of the various 
options, and the patient's medical history, including whether the 
patient has a known allergy to mercury.
    FDA believes that the recommended labeling statements in the 
special controls guidance document will provide dentists with important 
information that will improve their understanding of the devices and 
help them make appropriate treatment decisions with their patients. In 
addition, FDA notes that dental amalgam is a prescription device and, 
therefore, patients cannot receive the device without the involvement 
of a learned intermediary, the dental professional. Based on the 
reasons described above, FDA has concluded that it is not necessary to 
require that dentists provide this information to patients in order to 
provide reasonable assurance of the safety and effectiveness of the 
device.

E. Alternative Materials

    Several comments were submitted in response to FDA's request for 
information on the relative costs and replacement lives of dental 
amalgam and alternative materials, particularly composite resins.
    (Comment) With respect to cost, one comment stated that composites 
cost 46 percent more than equivalent amalgam restorations and are more 
likely to fail, resulting in the need for crowns on large surfaces. 
Another comment stated that alternative materials cost 20 percent more 
than amalgam restorations. One commenter stated that data from 2007 
indicate that the average fee submitted to insurance companies for one 
to four or more surfaces of dental amalgam ranged from $107 to $186, 
while the average submitted fee for composite resins ranged from $135 
to $242 for the same surfaces. One comment stated that amalgam remains 
the best choice for deeper carious lesions of the posterior teeth and 
for patients seeking effective, lower cost dentistry.
    (Response) FDA agrees that, in general, composite resin 
restorations are more costly than dental amalgam restorations.
    (Comment) FDA received conflicting comments on the durability of 
composite resins versus dental amalgam. Some comments stated that 
composite resins are inferior to amalgam with respect to durability, 
stiffness, wear resistance, marginal stability, and service life, and 
that they must be replaced more frequently. One comment stated that 
amalgam fillings can last for 35 years, while composites need to be 
replaced every 5 years. In contrast, other comments stated that amalgam 
is inferior to composites. For example, one comment stated that 
amalgam-filled teeth have a tendency to crack more frequently than 
composite-filled teeth, inevitably leading to more expensive 
restorations, such as crowns. The commenter stated further that 
composite resins better preserve the structural integrity of the tooth 
because they do not expand and because less natural tooth structure is 
removed in preparation for their placement. Other comments stated that 
the service lives of composite resins and dental amalgam are 
equivalent. One comment stated that the process for placing composite 
restorations is technique-sensitive and, if done properly, a composite 
restoration can last as long as an amalgam restoration.
    (Response) FDA believes that the durability of dental restorations 
is dependent on many factors related to material properties, the type 
and size of the restoration, the dentist's skill, and patient use. 
According to the literature, the two primary reasons dental 
restorations fail are secondary caries (as the result of marginal 
leakage) and fracture. Studies have shown higher secondary caries rates 
for composite resins, but equivalent fracture rates for composite and 
amalgam restorations (Ref. 76).

F. Need for Public Hearings

    (Comment) FDA received many comments on the proposed rule in 2002 
requesting the agency to hold a public hearing or advisory committee 
meeting on dental amalgam, noting that dental amalgam had not been 
discussed in an FDA public meeting since 1994. Many comments requested 
that individual consumers, consumer advocacy organizations, and 
scientists and health professionals opposed to the use of dental 
amalgam be included in such a meeting.
    (Response) FDA believes the concerns expressed by these comments 
were addressed in 2006 when FDA held a joint meeting of the Dental 
Products Panel and the Peripheral and Central Nervous Drugs Advisory 
Committee. One of the principal purposes of that meeting was to provide 
a transparent, public forum where all parties might share information. 
The panelists at the meeting were selected from a wide range of 
disciplines and interests, including neurology, dentistry, toxicology, 
statistics, epidemiology, and consumer advocacy. The 2006 meeting 
included an opportunity for the public to provide presentations, and a 
docket was opened to permit additional information to be submitted to 
the agency (Docket No. FDA-2008-N-0163). The 2006 Panel listened to 
presentations from more than 50 members of the public and FDA's 
presentation of its White Paper. At the conclusion of the meeting, the 
2006 Panel provided individual and panel recommendations to the agency.

G. Accusations of FDA Bias

    (Comment) Several comments accused FDA of being biased in this 
rulemaking in support of the continued use of dental amalgam. The 
comments stated that the agency is too closely aligned with the 
interests of professional dental organizations and, as a result, has 
unfairly discounted evidence regarding the health risks presented by 
dental amalgam.
    (Response) FDA disagrees with the comments suggesting that it has 
been biased in its approach to regulating these devices. This final 
rule and the special controls guidance document reflect FDA's careful 
and impartial consideration of all the comments and information it has 
received, the scientific information and safety assessments discussed 
previously, the White Paper and Addendum reports, and the adverse event 
reports submitted regarding these devices.
    FDA has been proactive in obtaining as much information as 
practicable

[[Page 38704]]

regarding the safety of these devices. As described previously, FDA has 
undertaken or supported several safety assessments since the early 
1990s regarding dental amalgam. In 2006, in an effort to ensure a 
transparent, public forum for discussion, FDA convened a joint 
committee of panelists with diverse backgrounds, including neurology 
and toxicology experts, to consider FDA's most recent review of the 
scientific literature related to dental amalgam (the White Paper) as 
well as presentations from members of the public. In response to the 
recommendations of the 2006 Panel, FDA updated its White Paper in the 
Addendum report.
    (Comment) Some comments suggested that FDA did not consider the 
report on mercury by the Agency for Toxic Substances and Disease 
Registry, and that FDA ignored the toxicological and adverse health 
effects identified in Toxicological Profiles for Mercury, which was 
published by the U.S. Department of Health and Human Services.
    (Response) FDA disagrees with the comments. FDA reviewed and 
evaluated both of these reports in preparing the White Paper (Ref. 10).

H. Preemption

    (Comment) FDA received several comments requesting the agency to 
explain the preemptive effect of this rule on state requirements 
involving dental amalgam and on the tort liability of dentists.
    (Response) FDA has imposed a special control to address the risks 
of exposure to mercury, toxicity and adverse tissue reaction, corrosion 
and mechanical failure, and improper use presented by these devices. 
This special control creates ``requirements'' for the manufacturer's 
labeling and other aspects of dental amalgam devices under 21 U.S.C. 
360k, even though product sponsors have some flexibility in how they 
meet those requirements. Papike v. Tambrands, Inc., 107 F.3d 737, 740-
42 (9th Cir. 1997). With respect to the tort liability of dentists, the 
special control in this rule requires manufacturers to properly inform 
dentists about dental amalgam in the labeling, but does not impose any 
requirements on dentists. Dental amalgam is a prescription device, and 
properly informed dentists will be able to make the most appropriate 
treatment decisions for their patients, taking individual concerns into 
account. FDA does not intend to regulate the practice of dentistry. 
State consumer protection laws that concern the practice of dentistry, 
not manufacturer labeling, are therefore not implicated by this final 
rule. See Cal. Bus. & Prof. Code Sec. Sec.  1648.10-1648.20 (requiring 
dentists to provide factual information to patients about dental 
amalgam); Maine (32 M.R.S. Sec.  1094-C) (same); N.H. R.S.A. Sec.  317-
A:38 (same); N.Y. C.L.S. E.C.L. Sec.  27-0926 (precluding dentists from 
using mercury in dentistry unless it is encapsulated for environmental 
reasons).

I. Environmental Concerns

    (Comment) Many comments stated that dental amalgam should not be 
used because it is a toxic metal that pollutes the environment and 
frequently referenced concerns related to water and air pollution. 
Several comments stated, in general, that FDA has never prepared an 
Environmental Assessment for dental amalgam and should do so 
considering mercury is a bioaccumulative toxicant. One comment 
specifically addressed FDA requirements under the National 
Environmental Policy Act of 1969 (NEPA). The comment stated that FDA 
has a statutory duty to prepare an Environmental Impact Statement (EIS) 
or, at a minimum, an Environmental Assessment (EA) before promulgating 
any final action relating to the classification of dental amalgam, 
reclassification of mercury or the issuance of a special control. 
Moreover, the comment characterized the categorical exclusion in 21 CFR 
25.34(b) as being ``overbroad'' and seemed to fault FDA for not finding 
extraordinary circumstances in the context of this rulemaking. The 
comment cited to Louisiana v. Lee, 758 F.2d 1081 (5th Cir. 1985), cert. 
denied, 475 U.S. 1044 (1986) as support for its assertion that an FDA 
action to classify or reclassify dental mercury devices does not 
perpetuate the status quo and has significant effects. The comment 
suggests that FDA must evaluate the continued introduction of mercury 
into the environment attributable to dental devices.
    (Response) Under the National Environmental Policy Act of 1969 
(NEPA), all Federal agencies must assess the environmental impact of 
any ``major Federal action'' they take (42 U.S.C. 4332(C)). A 
regulation to classify or reclassify a device constitutes a major 
Federal action under NEPA (see 40 CFR 1508.18). The Council on 
Environmental Quality (CEQ) is responsible for overseeing Federal 
efforts to comply with NEPA and issued regulations on procedural 
requirements of NEPA (40 CFR Parts 1500-1508). CEQ directs Federal 
agencies to adopt procedures, as necessary, to supplement the CEQ 
regulations (40 CFR 1507.3). FDA promulgated its supplemental NEPA 
regulations in 21 CFR Part 25.
    For major Federal actions ``significantly affecting the quality of 
the human environment,'' an agency must prepare an Environmental Impact 
Statement (EIS) (see id.; 40 CFR 1501.4; 21 CFR 25.22). If the action 
``may'' have such a significant environmental effect, an agency must 
prepare an Environmental Assessment (EA) to provide sufficient evidence 
and analysis for the agency to determine whether to prepare an EIS or a 
finding of no significant impact (FONSI) (40 CFR 1501.3; 21 CFR 25.20).
    However, agencies can establish categorical exclusions for 
categories of actions that do not individually or cumulatively have a 
significant effect on the human environment and for which, therefore, 
neither an EA nor an EIS is required (see 40 CFR 1508.4). FDA 
promulgated such an exclusion, under 21 CFR 25.34(b), for agency 
actions that classify or reclassify a device and that may include the 
establishment of a special control, if the action will not result in 
increases in the existing levels of use of the device or changes in the 
intended use of the device or its substitutes. FDA considered the 
application of this categorical exclusion to its classification/
reclassification decision in this final rule, and to the establishment 
of the special control for mercury, amalgam alloy, and dental amalgam. 
(Ref. 77) Consistent with its NEPA obligations, the agency considered 
whether there were any extraordinary circumstances that would preclude 
its reliance on this categorical exclusion for this final rule (agency 
procedures must ``provide for extraordinary circumstances in which a 
normally excluded action may have a significant environmental effect'' 
(40 CFR 1508.4; see also 21 CFR 25.21)). The agency determined that the 
action it is taking in this final rule is appropriately categorically 
excluded under 21 CFR 25.34(b).
    These comments reflect a misunderstanding of the action FDA is 
taking in this final rule and it obligations under NEPA for such 
action. The comments presume that FDA has a general obligation under 
NEPA, in the context of promulgating this final rule, to assess the 
impacts of mercury on the environment and the effects of any continued 
introduction of mercury attributable to dental devices. FDA disagrees 
with such a presumption, particularly where there is ``no reasonably 
close causal relationship'' between the actions in the final rule and 
such general impacts. DOT v. Public Citizen, 541 U.S. 752, 767 (2004)

[[Page 38705]]

(rejecting a ``but for'' causal relationship as sufficient to require 
agency environmental review under NEPA) (citation omitted)). The 
comments ignore the scope of the action FDA is taking in this final 
rule and the categorical exclusion that applies to it.
    Specifically, FDA is classifying dental amalgam into class II, 
reclassifying mercury from class I to class II, and designating a 
special control to support the class II classifications of dental 
amalgam, mercury, and amalgam alloy (currently classified as class II). 
The action is being taken to establish sufficient regulatory controls 
that will provide reasonable assurance of the safety and effectiveness 
of these devices. This action does not constitute a decision to permit 
any individual's particular use of any of these devices in the market. 
It simply provides a classification regulation establishing sufficient 
regulatory controls that will provide reasonable assurance of safety 
and effectiveness as to the particular class of these devices. The 
introduction into interstate commerce of amalgam alloy, mercury, or 
dental amalgam requires FDA clearance under section 510(k) of the act 
(21 U.S.C. 360(k)). An FDA decision to clear a device under section 
510(k) of the act would be a ``major Federal action'' (as defined in 40 
CFR 1508.18) and would be independent of FDA's action in this final 
rule. Thus, FDA would evaluate, independent of this final rule, its 
obligations under NEPA for a decision to clear a particular use of 
amalgam alloy, mercury, or dental amalgam in the context of a 510(k) 
submission. Such a decision is not before the agency in this final 
rule. Manufacturers currently or intending to market amalgam alloy, 
mercury, or dental amalgam are expected to comply with the requirements 
of special controls and address the issues of safety and effectiveness 
identified in the special controls guidance, either by following the 
recommendations in the guidance or by some other means that provides 
equivalent assurances of safety and effectiveness, on or before 
effective date of rule (see the DATES section of this document).
    Further, the reference in the comment to Louisiana v. Lee is 
misplaced. In that case, the court vacated a lower court's judgment and 
remanded the case for more careful review to ascertain whether an 
environmental assessment and finding of no significant impact by the 
United States Army Corps of Engineers was reasonable. 758 F.2d 1081 at 
1086. To the extent the comment likens the issuance of permits that 
would allow for continued dredging of the Louisiana Gulf Coast area to 
a decision on a classification, the comparison is not on point. As 
previously stated, this final rule does not constitute a decision on a 
particular submission to ``permit'' any particular introduction into 
the environment of any of these devices.
    FDA appropriately focuses its environmental review in this final 
rule on its action to classify, reclassify, and establish a special 
control for amalgam alloy, mercury, and dental amalgam. FDA disagrees, 
as one comment asserts, that FDA is required to prepare an 
environmental assessment or an environmental impact statement under 
NEPA for this final rule. FDA has evaluated the application of the 
existing categorical exclusion in 21 CFR 25.34(b) to the actions it is 
taking in this final rule and concludes, based on the reasons set forth 
below, that it is proper to rely on that categorical exclusion for this 
final rule.
    In 1985, FDA finalized a categorical exclusion in 21 CFR 
25.24(e)(2) for the ``classification or reclassification of a device 
under Part 860'' (50 FR 16635 at 16661; April 26, 1985). FDA identified 
this as a class of actions that would not result in the production or 
distribution of any substance, and therefore, would not result in the 
introduction of any substance into the environment. (44 FR 71742 at 
71745; December 11, 1979). In other words, changing the classification 
of a device from, e.g., class I to class II, would not, by itself, 
result in the introduction of any substance into the environment. 
Therefore, such an action would not normally require the preparation of 
an environmental assessment (44 FR 71742 at 71745; December 11, 1979). 
In 2005, FDA expanded the categorical exclusion for the classification 
and reclassification of devices to include, within its scope, an action 
that establishes special controls, if such action will not result in 
increases in the existing levels of use of the device or changes in the 
intended use of the device or its substitutes (70 FR 69276; November 
15, 2005). Thus, FDA would evaluate the application of the categorical 
exclusion for classification and reclassification decisions that 
include the establishment of special controls on a case-by-case basis 
to determine whether its action would result in increases in the 
existing levels of use or changes to the intended use of the device or 
its substitutes. FDA does not consider such a categorical exclusion to 
be ``overbroad'' as one comment asserts.
    FDA has determined that its action to classify dental amalgam, 
reclassify dental mercury, and to establish a special control are all 
within the scope of the categorical exclusion in 21 CFR 25.34(b). This 
final rule reclassifies mercury from the lower risk class I to the 
higher risk class II and classifies dental amalgam as class II. The 
final rule does not change the requirements in place prior to this 
final rule and that remain in effect after this final rule publishes, 
e.g., premarket review and general controls. The change in 
classification alone does not result in the introduction of any 
substance into the environment, does not increase the existing levels 
of use, and does not change the intended use of these devices or their 
substitutes (Ref. 77).
    In addition, FDA undertook a careful review of the special control 
designated by this final rule to determine whether the special control 
would increase the existing levels of use or change the intended use of 
amalgam alloy, mercury, and dental amalgam or their substitutes. (Ref. 
77) FDA has determined that the labeling recommendations in the special 
controls guidance imposed by the final rule would not result in 
increases in the existing levels of use of the devices or changes in 
the intended use of the devices or their substitutes. (Ref. 77) The 
labeling statements should help ensure that dentists are more fully 
informed regarding the devices. We have no basis to suggest or expect 
that the labeling recommendations would result in any increase in use 
of these devices or changes in the intended use of the devices or their 
substitutes.
    Further, FDA has determined that testing recommendations would not 
result in increases in the existing levels of use of the devices or 
changes in the intended use of the devices or their substitutes. (Ref. 
77) None of the tests require additional specimens of dental amalgam, 
amalgam alloy, or mercury. The test for mercury requires only visual 
inspection, which can be performed using current inventory, i.e., 
without the need for any additional mercury for the test. The tests for 
dental amalgam and amalgam alloy, required by the final rule and that 
were not routinely performed prior to the final rule, would require 
approximately 2.2 grams per product, which can be obtained from 
material used for a previous non-destructive test already routinely 
performed or from inventory needed for all testing. To the extent a 
manufacturer elects to procure additional product for the test, the 
amount is not significant. (Ref. 77) Moreover, the possibility a 
manufacturer would even elect to procure additional material for such 
tests is speculative. FDA found that its

[[Page 38706]]

action in this final rule to classify dental amalgam into class II, 
reclassify mercury from class I to class II, and to establish a special 
control for dental amalgam, mercury, and amalgam alloy does not 
significantly affect the quality of the human environment and that 
there are no extraordinary circumstances (Ref. 77). (See also, Utah 
Envtl. Cong. v. Bosworth, 443 F.3d 732 (10th Cir. 2006) (stating an 
extraordinary circumstance exists ``only where a proposed action `may 
have a significant environmental effect.' '') (citations omitted)). 
Based on FDA's review, it concludes that this final rule is 
appropriately categorically excluded under 21 CFR 25.34(b), and 
therefore, does not require an environmental assessment or an 
environmental impact statement.
    (Comment) Some comments suggested that dental amalgam manufacturers 
should provide an environmental impact statement to prove that dental 
amalgams are environmentally safe.
    (Response) Under 21 CFR 25.40, FDA generally requires an applicant 
to prepare an environmental assessment for any action that is not 
categorically excluded. FDA would determine, for each 510(k) submission 
the agency may receive, what environmental documents may be necessary 
to comply with the agency's obligations under NEPA.

IV. Environmental Impact

    The agency has considered the environmental effects of this final 
rule and has determined under categorical exclusion 21 CFR 25.34(b) 
that this action is of a type that does not individually or 
cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required (Ref. 77).

V. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order 
12866 directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes this 
final rule is a not an economically significant regulatory action under 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because of the relatively minor direct costs to 
entities attributable to this final rule, the agency certifies that the 
final rule will not have a significant economic impact on a substantial 
number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandates that may result in the expenditure by 
State, local, and Tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $133 million, using the most current (2008) Implicit 
Price Deflator of the Gross Domestic Product. FDA does not expect this 
final rule to result in a 1-year expenditure that could exceed this 
amount.

B. Summary of Economic Impacts

    The final rule classifies dental amalgam into class II, 
reclassifies mercury from class I to class II, and designates a special 
control to support the class II classifications of these two devices, 
as well as the current class II classification of amalgam alloy. 
Today's action classifies the three devices 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,'' which includes labeling recommendations as well as 
quality control procedures.
    Conforming to the special control will require few additional 
resources at the manufacturing stage as well as costs to FDA for 
administering the final regulation. Some dentists may consider the 
information-for-use statement, along with many other factors, when 
making treatment decisions for their patients. A small number of 
dentists may use dental amalgam for some patients for whom they may not 
have used the device previously, and decide not to use the device for 
other patients for whom they may have used the device. However, any 
change away from use of dental amalgam is likely to result in negative 
public health outcomes (delayed dental treatments or increased costs of 
treatment). While there would be a decrease in mercury exposure, there 
is no evidence that there would be any reduction in adverse affects 
associated with mercury. Conversely, any change towards use of dental 
amalgam is likely to result in positive public health outcomes or 
decreased costs of treatment.

C. Objective and Need of the Final Rule

    The purpose of this final rule is to classify dental amalgam, 
reclassify mercury, and designate a special control to support the 
class II classification of dental amalgam, mercury, and amalgam alloy 
as required by section 513 of the act. The special control for the 
device is a guidance document with composition and performance data, 
biocompatibility, and labeling recommendations. One of the labeling 
recommendations is the following information for use:

    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.\33\ 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.\34\ Mercury 
vapor concentrations are highest immediately after placement and 
removal of dental amalgam but decline thereafter.
---------------------------------------------------------------------------

    \33\ 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.
    \34\ 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.\35\
---------------------------------------------------------------------------

    \35\ 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

[[Page 38707]]

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.\36\ Exceeding these 
levels does not necessarily mean that any adverse effects will 
occur.
---------------------------------------------------------------------------

    \36\ 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 guidance also recommends that the labeling of dental amalgam 
and mercury devices include warnings about potential exposure to 
mercury, including: ``WARNING: CONTAINS MERCURY'' and ``harmful if 
vapors are inhaled.'' The labeling recommendations also include the 
following contraindication: ``Do not use in persons with a known 
mercury allergy.'' In addition, the special controls guidance document 
includes recommendations regarding composition and performance data, 
and biocompatibility testing.
    The need for this regulation stems from the current poor 
distribution of accurate information about exposure to mercury (Hg) 
through dental amalgam. The special control imposed by this final rule 
will ensure that dentists are reminded that dental amalgam contains 
mercury, and will provide them with FDA's assessment of the most 
current, best available information regarding use of the device in 
various patient groups.

D. Risk

    Mercury poisoning is a disease caused by exposure to mercury or its 
compounds. The most common exposure is to organic mercury through fish 
consumption. Elemental mercury may be inhaled or absorbed through the 
skin and is used for dental restorations as amalgam. Toxic effects of 
mercury, depending on the level of exposure, include damage to the 
brain, kidneys, and lungs, with symptoms that include sensory 
impairment, disturbed sensation, and lack of coordination. Elemental 
mercury is primarily associated with neurologic toxicity (Ref. 78), 
although most cases do not have any noticeable physiological effects. 
Table 2 of this document shows reported elemental mercury exposures and 
treatments for 2005-2007.

                                               Table 1--Elemental Mercury Exposures and Treatment Outcomes
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                            Number of                                                        Moderate
                  Year                      reported     Number  seeking    No adverse     Minor adverse      adverse      Major adverse       Death
                                            exposures        treatment        outcome         outcome         outcome         outcome
--------------------------------------------------------------------------------------------------------------------------------------------------------
2005...................................           2,786            909            747              99              55               6               2
2006...................................           2,336            854            767              66              20               1               0
2007...................................           2,319            672            576              55              38               3               0
                                        ----------------------------------------------------------------------------------------------------------------
    Total..............................           7,441          2,435          2,090             220             113              10               2
Percentage.............................  ..............            100.0           85.83            9.03            4.64            0.41            0.08
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: American Association of Poison Control Centers (Refs. 79, 80, and 81).

    Dental amalgam has not been shown to cause mercury poisoning and no 
data show a causal effect of dental amalgam for any adverse health 
effects (except in a small number of patients with a known allergy to 
mercury). Dental amalgam does contain mercury, although in quantities 
much smaller than those associated with the adverse outcomes summarized 
in table 2 of this document.
    Dental amalgam has been used to restore decayed teeth since the 
1890s in the United States, although early prototypes were available 
from the 1830s. Amalgam is an alloy that is about 50% mercury (usually 
combined with silver, tin, or copper) and is one of several potential 
materials used to treat dental caries. Over the last 15 years (1993-
2008), we estimate that approximately 900 million restorations have 
been performed using dental amalgam, although the annual number of all 
restorations, as well as amalgam restorations, has been decreasing (see 
Section V.E). According to Delta Dental Insurance (Ref. 82), the 
typical amalgam restoration has 1.8 surfaces (a ``surface'' is a 
measure of exposed surface of the restoration). Research has indicated 
that each surface of an amalgam restoration releases approximately 
0.534 [mu]g Hg/day (Ref. 83). With a baseline of 900 million amalgams 
and 1.8 surfaces per amalgam, we estimate 865 million [mu]g Hg/day were 
released by amalgams (900 million amalgams x 1.8 surfaces per amalgam x 
0.534 [mu]g Hg/day per surface) during 2008.
    We are unable to estimate possible changes in exposure to mercury 
that may result from this rule. Dentists may use dental amalgam for 
some patients for whom they may not have used the device previously, 
and decide not to use the device for other patients for whom they may 
have used the device. However, any change away from use of dental 
amalgam is likely to result in negative public health outcomes (delayed 
dental treatments or increased costs of treatment); while there would 
be a decrease in mercury exposure,

[[Page 38708]]

there is no evidence that there would be any reduction in adverse 
effects associated with mercury. Conversely, any change toward use of 
dental amalgam is likely to result in positive public health outcomes 
(fewer delayed dental treatments or decreased costs of treatment).

E. Baseline in the Absence of the Final Rule

    During 2008, there were an estimated 154.1 million dental 
restorations in the United States (Ref. 84). This number represents a 
decrease of almost 12 million restorations from 2005, with the decrease 
associated with better dental care. We assume that recent trends to 
reduce the use of dental amalgam as a restorative material will 
continue as patients and dentists take advantage of improved 
alternative materials for restorative and cosmetic purposes. Table 2 of 
this document shows projected annual restorations and annual amalgam 
restorations expected for the 15-year evaluation period.

                                                      Table 2--Projected Annual Dental Restorations
                                                                      [In millions]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                       Total U.S.
                         Evaluation year                               population         Total restoration   Amalgam restorations   Other restorations
--------------------------------------------------------------------------------------------------------------------------------------------------------
2009............................................................                 307.2                 149.0                  50.5                  98.5
2010............................................................                 310.2                 145.0                  49.0                  96.0
2011............................................................                 313.2                 141.0                  47.6                  93.5
2012............................................................                 316.3                 137.2                  46.2                  91.0
2013............................................................                 319.3                 133.4                  44.8                  88.5
2014............................................................                 322.4                 129.7                  43.5                  86.2
2015............................................................                 325.5                 126.1                  42.2                  83.9
2016............................................................                 328.7                 122.6                  41.0                  81.6
2017............................................................                 331.8                 119.1                  39.8                  79.4
2018............................................................                 335.0                 115.8                  38.6                  77.2
2019............................................................                 338.2                 112.5                  37.5                  75.0
2020............................................................                 341.4                 109.4                  36.4                  72.9
2021............................................................                 344.6                 106.3                  35.4                  70.9
2022............................................................                 347.8                 103.3                  34.4                  68.9
2023............................................................                 351.0                 100.3                  33.4                  67.0
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The population of the United States is projected to increase at an 
annual rate of about 0.9 percent over this period and dental 
restorations as a whole, as well as amalgam restorations, are expected 
to decrease by about 1.9 percent per year. This projection is based on 
the expected age distribution of the population as reported by the 
Census Bureau and historical rates of restorations by age-cohort. For 
example, the population between the ages of 0-4 was about 20.3 million 
in 2005, during which year 3,339,000 restorations were conducted for 
this age cohort, for an average of 0.16 restorations per capita. The 
Census Bureau projected that there will be about 20.9 million in the 
population aged 0-4 in 2009. Using the per capita rate of restorations, 
we expect there to be 3,344,000 restorations for this age group. The 
distributions of restoration by material and by age groups were summed 
for each year to result in the estimates shown in table 2 of this 
document.
    As an approximation of the total number of patients in specific 
populations who might be expected to be more vulnerable to mercury 
(pregnant women and their fetuses, children under the age of six, 
including those who are breastfed), we use the total number of pregnant 
and lactating women and children under six as the targeted or special 
populations in this analysis. According to the Agency for Toxic 
Substances and Disease Registry (Ref. 85), very young children are more 
sensitive to mercury than adults. Mercury in a mother's body can pass 
to the fetus and may accumulate there (Ref. 85), and a nursing infant 
may be exposed to inorganic mercury through breast milk. Because of 
these sensitivities, we projected dental amalgam restorations for 
children under the age of 6, as well as for pregnant and lactating 
females ages 15-44 based on reporting from the American Dental 
Association (ADA) and projections from the Bureau of Census. The number 
of pregnant women was obtained from the National Center of Health 
Statistics for 2004 (Ref. 86). The rate of pregnancy among women 
between the ages of 15 and 44 for 2004 (0.1036) was used to project 
future annual pregnancies. Approximately two-thirds of all live births 
breast feed at least once (Ref. 87). Therefore, we have estimated that 
two-thirds of the previous years' live births account for lactating 
women. The number of children under the age of 6 was obtained from 
Census projections. We could not obtain information on the potential 
number of other affected sub-populations but believe they could 
reasonably be accounted for in these projections, which include 
practically all the affected persons. Table 3 of this document shows 
these projections.

                                            Table 3--Projected Amalgam Restorations for Specific Populations
                                                                      [In millions]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                          Total amalgam
                                                  Number of      Total children     Total amalgam   Total amalgam in  Total amalgam in   restorations in
               Evaluation year                  pregnant and      under the age     restorations      pregnant and    children under 6   sensitive sub-
                                               lactating women        of 6                           lactating women                       populations
--------------------------------------------------------------------------------------------------------------------------------------------------------
2009........................................              9.22              25.1              50.5               1.8               2.6               4.4
2010........................................              9.23              25.3              49.0               1.8               2.5               4.3
2011........................................              9.27              25.5              47.6               1.7               2.5               4.2
2012........................................              9.29              25.7              46.2               1.6               2.4               4.0
2013........................................              9.32              26.0              44.8               1.6               2.3               3.9

[[Page 38709]]

 
2014........................................              9.37              26.2              43.5               1.5               2.3               3.8
2015........................................              9.41              26.4              42.2               1.5               2.2               3.7
2016........................................              9.44              26.7              41.0               1.4               2.1               3.5
2017........................................              9.49              26.9              39.8               1.4               2.1               3.5
2018........................................              9.55              27.1              38.6               1.3               2.0               3.3
2019........................................              9.62              27.2              37.5               1.3               2.0               3.3
2020........................................              9.70              27.4              36.4               1.3               1.9               3.2
2021........................................              9.78              27.6              35.4               1.2               1.8               3.0
2022........................................              9.93              27.7              34.4               1.2               1.8               3.0
2023........................................             10.04              27.9              33.4               1.2               1.7               2.9
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Because the annual use of dental amalgam for restorations is 
expected to continue to decrease, the exposures of these sub-
populations to amalgam are also expected to decrease along with 
exposures in the population age six and older. We model the expected 
contribution per day of amalgam for the evaluation period in table 4 of 
this document. These projections are based on the decreasing number of 
amalgam restorations expected as replacements. During the period 1993-
2008, according to data supplied by the ADA, approximately 60 million 
annual restorations used amalgam for a total of 900 million current 
amalgam restorations in place. In the absence of the final rule, we 
project only 50.5 million new amalgam restorations during 2009, down 
from 60 million from 1993, resulting in only 890.5 million amalgam 
restorations for the entire population (900 million restorations in 
place + 50.5 new restorations during year 1 - 60 million restorations 
from 1993). Therefore, the daily potential exposure to mercury vapor 
originating from dental amalgam is expected to decrease gradually in 
the absence of the final rule.

  Table 4--Projected Total [mu]g Hg per Day From Dental Amalgam in the
                        Absence of the Final Rule
                              [In millions]
------------------------------------------------------------------------
                                                                  Micro-
                                                                  grams
                                       Number of     Number of   ([mu]g)
          Evaluation year               amalgam       annual        of
                                     restorations     amalgam    mercury
                                       in place    restorations    (Hg)
                                                                 per day
------------------------------------------------------------------------
2009...............................      890.5          50.5         856
2010...............................      879.5          49.0         845
2011...............................      867.1          47.6         833
2012...............................      853.3          46.2         820
2013...............................      838.1          44.8         806
2014...............................      821.6          43.5         790
2015...............................      803.8          42.2         772
2016...............................      784.8          41.0         754
2017...............................      764.6          39.8         735
2018...............................      743.2          38.6         714
2019...............................      720.7          37.5         693
2020...............................      697.1          36.4         670
2021...............................      672.5          35.4         646
2022...............................      646.9          34.4         622
2023...............................      620.3          33.4         596
------------------------------------------------------------------------

    Table 4 of this document includes estimates of projected levels of 
mercury per day associated with the expected number of amalgams in 
place. Each amalgam is assumed to have 1.8 surfaces and release 0.534 
[mu]g Hg per day per surface.

F. The Final Rule

    This final rule will classify dental amalgam as class II, 
reclassify mercury from class I to class II, and designate a special 
control to support the class II classifications of these class II 
devices, as well as the current class II classification of amalgam 
alloy. All three devices will now be classified in a single regulation. 
Under Class II, these devices will be subject to a special control. In 
this case, we are designating as the special control a guidance 
document (with composition and performance data, biocompatibility 
testing, and labeling recommendations). The guidance document provides 
for some increased testing requirements that will ensure the 
composition of the amalgam as well as labeling recommendations. 
Specific additional tests in the guidance document include particle 
size distribution assays and corrosion testing that are not typically 
currently conducted by manufacturers. The labeling recommendations 
include a warning that dental amalgam contains mercury and provide 
information for use explaining that, although there are 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, the estimated 
concentration of mercury in breastmilk attributable to dental amalgam 
exposure is low and is an order of magnitude below the EPA protective 
reference dose for oral exposure to inorganic mercury. The estimated 
daily dose of mercury in children under age 6 with dental amalgams is 
also low and at or below the ATSDR and EPA protective reference levels.

G. Costs of the Final Rule

    FDA is required by statute to classify devices (21 U.S.C. 360c). 
This final rule classifies dental amalgam into Class II and 
reclassifies 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).
    The costs of the final rule are the costs of complying with and 
administrating the special control (including testing and labeling 
costs, and FDA administration costs).
    The special controls guidance referenced in this final rule 
recommends that dental amalgam, mercury, and amalgam alloy be subject 
to periodic assays to demonstrate physical properties. Two of these 
assays are not routinely conducted and, consequently, would constitute 
additional expenses. In addition, the

[[Page 38710]]

special controls guidance recommends that the labeling state that the 
device contains mercury, that it should not be used in persons with a 
known allergy to mercury, and that data are limited regarding long term 
outcomes in certain populations. These labeling revisions are also 
additional requirements for manufacturers.
1. Manufacturing Costs
a. Testing Costs
    FDA records indicate the final rule will affect 50 separate 
products manufactured by 16 companies. These companies are classified 
in the Dental Equipment and Supplies Industry (NAICS 339114) by the 
Census of Manufacturers (NAICS is the North American Industry 
Classification System).
    The special controls guidance document that is part of this final 
rule includes two recommended quality control assays that are not 
routinely conducted by manufacturers. These assays are particle size 
distribution testing and corrosion products identification. While some 
of the 16 manufacturers may use in-house laboratories to conduct these 
tests, if additional equipment is needed they are more likely to use 
contract laboratories. Discussions with contract laboratories showed 
that estimated costs for conducting assays of these types ranged 
between $35 and $150 per test with a typical test costing approximately 
$75.
    It is unclear how frequently these tests would be conducted. The 
current guidance recommends that tests be conducted once before 
marketing. However, we expect manufacturers to test each of their 50 
marketed products at least once per year to ensure product quality. 
Therefore, the expected annual cost of conducting these additional 
tests equals $7,500 per year (50 products times 2 tests times $75).
b. Labeling Costs Associated With the Final Rule
    The recommended labeling controls included in this final rule will 
result in enhanced labeling for dental amalgam devices. Specifically, 
the guidance recommends that the labeling for this product state that 
the device contains mercury, that it should not be used in persons with 
a known allergy to mercury, and that current scientific evidence 
indicates there is no connection between the device and adverse events 
in the population age six and older. The label also informs dentists 
that the clinical data are limited regarding long term outcomes in 
certain patients who might be expected to be more sensitive to the 
effects of mercury.
    We expect that each of the 50 products currently marketed will 
develop a new label that includes this information. The cost of 
developing new artwork, label design, regulatory review, production, 
and application was estimated based on a labeling cost model developed 
by the Eastern Research Group (Ref. 88) and updated to 2008. Overall, 
the cost of developing a new label using these guidelines is estimated 
to be approximately $2,000 per label. Each of the 50 products marketed 
by 16 manufacturers is expected to have a revised label due to this 
requirement and result in a total one-time labeling cost of $100,000 
(50 products times $2,000).
c. Increased Manufacturing Costs
    The total increased manufacturing costs of this final rule are 
$107,500 in the first evaluation year and $7,500 per year thereafter. 
The present value over 15 years is $186,600 (3 percent discount rate) 
or $161,800 (7 percent discount rate).
2. Costs of FDA Regulatory Oversight
    Although FDA currently regulates dental amalgam, the 
reclassification from this final rule is likely to increase oversight. 
Label review will likely be more rigorous and inspections will entail 
review of more testing data. Any reviews of marketing applications will 
be more rigorous and there are likely to be increases in the number of 
marketing applications submitted for review (although we have not 
estimated any such increase). In addition, FDA can anticipate 
additional interest in these products, which will probably require 
resources to respond to consumer and media requests for information. 
These activities are not likely to consume more than 30 minutes of 
full-time equivalent (FTEs) per product per year, or approximately 26 
hours of resources. The estimated cost of an FDA FTE is approximately 
$130,000 per year, or about $64.75 per hour. (This estimate includes 
salary, benefits, overhead, and support). Therefore, the increased use 
of FDA resources due to the final rule is only approximately $1,700 per 
year (26 hours times $64.75). The present values of 15 years of this 
cost equal $20,300 (using 3 percent annual discount rate) and $15,500 
(using 7 percent annual discount rate).
3. Total Costs
    Table 5 of this document shows the estimated present value of costs 
and the annualized costs of the final rule by type. Testing costs and 
the costs of FDA administration are annual recurring costs. While the 
present values of these costs differ by discount rate, the annualized 
costs are not affected by discount rates.

                            Table 5--Present Value and Annualized Costs of Final Rule
----------------------------------------------------------------------------------------------------------------
                                                                                    Annualized      Annualized
                                                   Present value   Present value    value at  3     value at  7
                                                   at 3 percent    at 7 percent       percent         percent
----------------------------------------------------------------------------------------------------------------
Labeling Cost...................................        $100,000        $100,000          $8,400         $10,100
Testing Cost....................................          89,500          68,300           7,500           7,500
Cost of FDA Administration......................          20,300          15,500           1,700           1,700
                                                 ---------------------------------------------------------------
    Total Cost..................................         209,800         183,800          17,600          19,300
----------------------------------------------------------------------------------------------------------------

H. Potential Public Health Effects of the Final Rule

    The recommended information for use statement will provide dentists 
with current information to help them make treatment decisions for 
their patients. We expect that dentists will consider that information, 
along with other factors, when making treatment decisions for their 
patients. Dentists may use dental amalgam for some patients for whom 
they may not have used the device previously, and decide not to use the 
device for other patients for whom they may have used the device. 
However, any change away from use of dental amalgam is likely to result 
in negative public health outcomes (delayed dental treatments or 
increased costs of treatment); while there would be a decrease in 
mercury exposure, there is no evidence that there would be any 
reduction in adverse effects associated with mercury. Conversely,

[[Page 38711]]

any change toward use of dental amalgam is likely to result in positive 
public health outcomes (fewer delayed dental treatments or decreased 
costs of treatment).

I. Alternatives to the Final Rule

    The principal regulatory alternatives considered were as follows: 
(1) No new regulatory action, (2) Class II but with other special 
controls, (3) reclassification to Class III, and (4) ban the use of 
mercury in dental restorations.
1. No New Regulatory Action
    No new regulatory action is the projected baseline we use to 
estimate the effects of the other options. By definition, there are no 
costs or public health effects associated with the baseline.
2. Class II But With Other Special Controls
    This alternative would retain Class II but calls for different 
special controls. While deciding the type of special controls best 
suited for this device, we considered many different options. For 
example, we considered a labeling requirement that would require 
dentists to inform patients of the presence of mercury in dental 
amalgam and discuss treatment options and a special controls guidance 
document with labeling recommendations. Whatever the special controls 
in this alternative, the result would be that patients would get direct 
information that would include the presence of mercury in amalgam. The 
costs of this alternative would include the opportunity costs both 
dentists and patients of discussing treatment options, costs of 
alternative restorative materials, potentially delayed or deferred 
treatments, the cost of periodic testing by manufacturers, and the cost 
of FDA administration. There would be an expected reduction in mercury 
exposure and some potential reduction in anxiety for patients who would 
choose alternative materials with this information and after 
consultation with dentists. The costs and effects of this alternative 
are shown in table 6 of this document.

                      Table 6--Present Value and Annualized Effects of Alternative Labeling
----------------------------------------------------------------------------------------------------------------
                                                                          Annualized value--  Annualized value--
                                   Present value--3%   Present value--7%          3%                  7%
----------------------------------------------------------------------------------------------------------------
Costs (In millions).............  $2,433 to $6,563..  $1,932 to $4,948..  $208 to $550......  $212 to $543.
Reduced Mercury Exposures (in     0 to 153.2........  0 to 109.5........  0 to 12.8.........  0 to 12.0.
 million of [mu]g Hg per day).
Delayed Dental Treatments.......  0 to 990,000......  0 to 813,000......  0 to 83,000.......  0 to 89,000.
----------------------------------------------------------------------------------------------------------------

    The ranges shown in Table 6 show the uncertainty of how patients 
and dentists may be expected to react to information and differences in 
the durability of alternative materials. The estimates and ranges shown 
in table 6 include the effects of the higher costs of alternative 
materials, ranges of expected useful life of alternative materials, 
opportunity costs of dentists providing counseling, opportunity costs 
of patients, different durations of counseling, different expected 
reactions by patients to the information that amalgam contains mercury 
(based on market response of tuna consumers), and ranges of estimates 
of price elasticities of demand for dental services. The ranges are 
shown to address a wide range of potential alternative special controls 
that we did not select.
3. Reclassification to Class III
    Class III classification of these products would require that 
manufacturers obtain premarket approval for dental amalgam, mercury, 
and amalgam alloy. The most likely effect of this alternative would be 
that marketers would choose to withdraw their products from the market 
rather than incur the costs and resources necessary to collect safety 
and effectiveness data to support premarket approval applications. The 
effects of this regulatory alternative are probably equivalent to a ban 
on the use of mercury in restorations and should be equal to the 
estimated impacts discussed for Alternative 4.
4. Ban the Use of Mercury in Dental Restorations
    Another alternative is to ban dental amalgam. The ban would not 
give consumers a choice with respect to the use of dental amalgam. All 
consumers would be forced to use alternative materials or defer 
treatment for dental caries. The costs and effects of a ban are shown 
in tables 7 and 8 of this document. While the estimated number of 
delayed dental caries treatments that may result from a ban are not 
included in table 7, we consider them to represent negative public 
health effects. Any delay in dental treatment would likely lead to 
further deterioration and patient discomfort. However, there are no 
empirical data to suggest how long a delay in treatment would typify 
the response to a ban or what the social costs of delayed (or avoided) 
dental treatment would be. This negative public health outcome should 
be considered an additional non-quantified cost. The annualized public 
health effects appear equal for both discount rates due to rounding to 
the nearest hundred thousand. The difference in annualized treatment 
delays shown in Table 6 is a reflection of the differing responses to 
prices and alternative special controls. The totality of a potential 
ban removes most of the variability of response to regulation and 
reduces differences arising from different discount rates.

                                             Table 7--Costs of a Ban
                                                  [In millions]
----------------------------------------------------------------------------------------------------------------
                                                  Present value-- Present value--   Annualized      Annualized
                                                        3%              7%           value--3%       value--7%
----------------------------------------------------------------------------------------------------------------
Total costs assuming durable alternative               $33,224.0       $25,867.0        $3,784.2        $2,840.2
 material.......................................
Total costs assuming alternative materials have         63,953.8        44,714.7         5,359.3         4,909.7
 ten-year replacement life......................
----------------------------------------------------------------------------------------------------------------


[[Page 38712]]


                                Table 8--Potential Public Health Effects of a Ban
----------------------------------------------------------------------------------------------------------------
                                                  Present value-- Present value--   Annualized      Annualized
                                                        3%              7%           value--3%       value--7%
----------------------------------------------------------------------------------------------------------------
Reduced Mercury Exposure........................          *688.6          *525.5           *57.7           *57.7
Delayed Caries Treatments (in millions).........            27.1            21.0             2.3             2.3
----------------------------------------------------------------------------------------------------------------
* Million [mu]g Hg per day.

J. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because of the relatively minor costs to 
manufacturing entities attributable to this final rule, the agency 
believes that the final rule will not have a significant economic 
impact on a substantial number of small manufacturing entities.
    FDA records indicate the final rule will affect 50 separate 
products manufactured by 16 domestic companies. These companies are 
classified in the Dental Equipment and Supplies Industry (NAICS 339114) 
by the Census of Manufacturers. The affected industry (NAICS 339114; 
Dental Equipment and Supplies) is typified by small entities. Only 
about 35 of the approximately 875 establishments in the entire industry 
employ more than 100 workers. According to the Small Business 
Administration Size Standards, any entity with fewer than 500 employees 
is considered small in this industry. We therefore conclude that the 
manufacturing 16 companies affected by this final rule will be small 
businesses. The formal costs per company, however, are relatively 
small. The annualized costs of developing new required and recommended 
labeling and conducting additional assays to ensure product quality are 
not significant for a substantial number of small entities. The 
annualized costs per firm, $750 using a 3-percent discount rate or $865 
using a 7-percent discount rate, are not significant. (These annualized 
costs are based on an average of 3.125 products per company). The 
average value of shipments for establishments in this industry with 
fewer than five employees was $244,100 according the Census of 
Manufacturers. The annualized costs of the final rule represent less 
than 0.5% of the annual value of shipments. We certify that there will 
not be a significant economic impact on a substantial number of small 
entities.

VI. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe * * * a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.'' Federal law includes an express preemption provision 
that preempts certain state requirements ``different from or in 
addition to'' certain Federal requirements applicable to devices. 21 
U.S.C. 360k; Medtronic v. Lohr, 518 U.S. 470 (1996); Riegel v. 
Medtronic, 128 S. Ct. 999 (2008).
    In this rulemaking, FDA has determined that general controls by 
themselves are insufficient to provide reasonable assurance of the 
safety and effectiveness of these devices, and that there is sufficient 
information to establish special controls to provide such assurance. 
FDA has therefore imposed special controls to address the risks of 
exposure to mercury, allergic reaction including adverse tissue 
reaction, contamination, mechanical failure, corrosion, and improper 
use. These special controls create ``requirements'' for specific 
medical devices under 21 U.S.C. 360k, even though product sponsors have 
some flexibility in how they meet those requirements. Papike v. 
Tambrands, Inc., 107 F.3d 737, 740-42 (9th Cir. 1997).
    The preemptive effects are the result of existing law set forth in 
the statute as interpreted in decisions of the United States Supreme 
Court. FDA therefore has not sought separate comment on the preemptive 
effect of this action because it is not seeking independently to 
preempt state law beyond the effects of 21 U.S.C. 360k or existing case 
law.

VII. The Paperwork Reduction Act of 1995

    This final rule refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in 21 CFR part 801 have been approved under 
control number 0910-0485; the collections of information in 21 CFR part 
807 subpart E have been approved under OMB control number 0910-0120; 
the collections of information in 21 CFR part 50 have been approved 
under OMB control number 0910-0130; and the collections of information 
in 21 CFR 820 have been approved under OMB control number 0910-0073.

VIII. References

1. Transcript from Meeting of the Food and Drug Administration 
Dental Products (Advisory) Panel, December 3, 1993, and transcript 
from Meeting of the Food and Drug Administration Dental Products 
(Advisory) Panel, June 29, 1994.
2. Beazoglu, T. et al., Economic Impact of Regulating the Use of 
Amalgam Restorations, Public Health Reports, September-October 2007, 
Volume 122.
3. 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.
4. Update Statement by the U.S. Public Health Service on the Safety 
of Dental Amalgam, September 1, 1995.
5. Review and Analysis of the Literature on the Potential Adverse 
Health Effects of Dental Amalgam, Life Sciences Research Office, 
July 2004.
6. The Safety of Dental Amalgam and Alternative Dental Restoration 
Materials for Patients and Users--Preliminary Report, Scientific 
Committee on Emerging and Newly Identified Health Risks (SCENIHR), 
European Commission, Health and Consumer Protection DG, 2007.
7. Bernardo, M. et al., ``Survival and Reasons for Failure of 
Amalgam Versus Composite Posterior Restorations Placed in a 
Randomized Clinical Trial,'' Journal of the American Dental 
Association, Vol. 138, pp. 775-783, June 2007.
8. Khordi-Mood M., et al., ``Urinary mercury excretion following 
amalgam filling in children,'' Journal of Toxicology, Clinical 
Toxicology, Vol. 39 (7), pp. 701-705, 2001.
9. Berglund, A. et al., ``Mercury vapor release from dental amalgam 
in patients with symptoms allegedly caused by amalgam fillings,'' 
European Journal of Oral Science, Vol. 104, pp. 56-63, 1996.
10. FDA Update/Review of Potential Adverse Health Risks Associated 
with Exposure to Mercury in Dental Amalgam, National Center for 
Toxicological Research, Food and Drug Administration, August 2006. 
(FDA Draft White Paper)

[[Page 38713]]

11. Addendum to FDA Draft White Paper, Addendum Review in Response 
to Advisory Panel Comments and Recommendations, July 2009. (The 2006 
Draft White Paper and the 2009 Addendum constitute the final White 
Paper.)
12. Dental Amalgam and Alternative Restorative Materials: An Update 
Report to the Environmental Health Policy Committee, September 1997.
13. Review and Analysis of the Literature on the Potential Adverse 
Health Effects of Dental Amalgam, Life Sciences Research Office, 
July 2004.
14. 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.
15. United States Environmental Protection Agency (EPA), 
``Integrated Risk Information System (IRIS) Screening-Level 
literature Review''--Mercury, elemental, 2002.
16. Fawer R.F. et al., ``Measurement of hand tremor induced by 
industrial exposure to metallic mercury,'' British Journal of 
Industrial Medicine, Vol. 40, pp. 204-208, 1983.
17. Ngim C.H. et al., ``Chronic neurobehavioral effects of elemental 
mercury in dentists,'' British Journal of Industrial Medicine, Vol. 
49, pp. 782-790, 1992.
18. Piikivi L. et al., ``EEG findings in chlor-alkali workers 
subjected to low long term exposure to mercury vapour,'' British 
Journal of Industrial Medicine, 1989; 46:30-35.
19. Pinkerton KE, Joad JP (2006) ``Influence of air pollution on 
respiratory health during perinatal development,'' Clin Exp 
Pharmacol Physiol 33:269-272.
20. ICRP (1994), ``Human respiratory tract model for radiological 
protection,'' (Ann Int Comm Rad Protect, Vol. 24).
21. World Health Organization, ``Inorganic Mercury,'' Environmental 
Health Criteria Document 118, Geneva, Switzerland, 1991.
22. World Health Organization, ``Elemental Mercury and Inorganic 
Mercury Compounds: Human health effects,'' Concise International 
Chemical Assessment Document (CICAD) 50, Geneva, Switzerland, 2003.
23. Skare, I. et al., ``Human exposure to mercury and silver 
released from dental amalgam restorations,'' Archive of 
Environmental Health, Vol. 49, pp. 384-394, 1994.
24. American Conference of Governmental Industrial Hygienists, 
``Mercury, All forms except alkyl,'' Chemical Substances, 7th 
Edition, pp. 1-13, ACGIH, Cincinnati, OH 2001.
25. Ellingsen, D.G. et al., ``Renal and immunologic markers for 
chloralkali workers with low exposure to mercury vapor,'' Scand. J. 
Work Environ. Health, Vol. 26, pp. 427-435, 2000.
26. Roels, H.A. et al., ``Usefulness of biomarkers of exposure to 
inorganic mercury, lead, or cadmium in controlling occupational and 
environmental risks of nephrotoxicity,'' Renal Failure, Vol. 21, pp. 
251-262, 1999.
27. Boogaard, P.J. et al., ``Effects of exposure to elemental 
mercury on the nervous system and the kidneys of workers producing 
natural gas,'' Archives of Environmental Health, Vol. 51, pp. 108-
115, 1996.
28. Mandic, L. et al., ``Change in the iso-enzyme profiles of 
urinary N-acetyl-[beta]-D-glucosoaminidase in workers exposed to 
mercury,'' Toxicol. Ind. Health, Vol. 18, pp. 207-214, 2002.
29. Dye et al., ``Urinary mercury concentrations associated with 
dental restorations in adult women aged 16-49 years: United States, 
1999-2000,'' Occupational and Environmental Medicine, Vol. 62, pp. 
368-375, 2005.
30. Kingman, A. et al., ``Mercury concentrations in urine and whole 
blood associated with amalgam exposure in a U.S. military 
population,'' Journal of Dental Research, Vol. 77, pp. 461-471, 
1998.
31. 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, 2006.
32. Bellinger, D.C. et al., ``A Dose-Effect Analysis of Children's 
Exposure to Dental Amalgam and Neuropsychological Function: The New 
England Children's Amalgam Trial,'' Journal of the American Dental 
Association, Vol. 138, 1210-1216, 2007.
33. Factor-Litvak, P. et al., ``Mercury derived from dental amalgams 
and neuropsychologic function,'' Environmental Health Perspectives, 
Vol. 111, pp. 719-723, 2003.
34. 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, 1775-1783, 
2006.
35. Bast-Pettersen R. et al., ``A neurobehavioral study of 
chloralkali workers after the cessation of exposure to mercury 
vapor,'' Neurotoxicology, Vol. 26(3), pp. 427-437, 2005.
36. Camerino, D. et al., ``Evaluation of the neurotoxic and 
nephrotoxic effects following long-term exposure to metallic mercury 
in employed at a chlorine/sodium-hydroxide plant,'' Med. Lav, Vol. 
93, pp. 238-250, 2002
37. Kingman, A. et al., ``Amalgam exposure and neurological 
function,'' Neurotoxicology, Vol. 26, pp. 241-255, 2005.
38. Saxe S.R. et al., ``Alzheimer's disease, dental amalgam, and 
mercury,'' Journal of the American Dental Association, Vol. 130, pp. 
191-199, 1999
39. Fung F. et al., ``Neurotoxicity of mercury in dental amalgam,'' 
Journal of the American Medical Association, Vol. 296 (12), pp. 
1462-1463, 2006
40. 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, 2008.
41. Barregard, L. et al., ``Tissue levels of mercury determined in a 
deceased worker after occupational exposure,'' International 
Archives Occupational Environmental Health, Vol. 72, pp. 169-173, 
1999.
42. Maas, C. et al., ``Study on the significance of mercury 
accumulation in the brain from dental amalgam fillings through 
direct mouth-nose-brain transport,'' Zentralbl. Hyg. Umweltmed, Vol. 
198, pp. 275-291, 1996.
43. Davis, B.J. et al., ``Mercury Vapor and Female Reproductive 
Toxicity,'' Toxicological Sciences, Vol. 59, pp. 291-296, 2001.
44. Morgan, D.L. et al., ``Disposition of Inhaled Mercury Vapor in 
Pregnant Rats: Maternal Toxicity and Effects on Developmental 
Outcome,'' Toxicological Sciences, Vol. 66, pp. 261-273, 2002.
45. Efskind J. et al., ``Renal function of chloralkali workers after 
the cessation of exposure to mercury vapor,'' Scand. J. Work. 
Environ. Health, Vol. 32 (3), pp. 241-249, 2006
46. 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, 2008.
47. 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.
48. Herr, D.W. et al., ``Evaluation of Sensory Evoked Potentials in 
Long Evans Rats Gestationally Exposed to Mercury Vapor,'' 
Toxicological Sciences, Vol. 82, pp. 193-206, 2004.
49. Lindbohm, M.L. et al., ``Occupational exposure in dentistry and 
miscarriage,'' Occupational Environmental Medicine, Vol. 64 (2), pp. 
127-133, 2007.
50. Elghany, N.A. et al., ``Occupational exposure to inorganic 
mercury vapour and reproductive outcomes,'' Occupational Medicine, 
Vol. 47 (6), pp. 333-336. 1997.
51. Hujoel, P.P. et al., ``Mercury exposure from dental filling 
placement during pregnancy and low birth weight risk,'' American 
Journal of Epidemiology, Vol. 161(8), pp. 734-740, 2005.
52. United States Environmental Protection Agency (EPA), 
``Integrated Risk Information System (IRIS) Screening-Level 
literature Review''--Mercuric chloride, 2002.
53. Drexler, H. et al., ``The mercury concentration in breast milk 
resulting from amalgam fillings and dietary habits,'' Environmental 
Research, Vol. 77, pp. 124-129, 1998.
54. Drasch, G. et al., ``Mercury in human colostrum and early breast 
milk. Its dependence on dental amalgam and other factors,'' J. Trace 
Elem. Med. Biol., Vol. 12, pp. 23-27, 1998.
55. Oskarsson A. et al., ``Total and inorganic mercury in breast 
milk in relation to fish

[[Page 38714]]

consumption and amalgam in lactating women,'' Archives of 
Environmental Health, Vol. 51 (3), pp. 234-241, 1996.
56. Vimy M.J. et al., ``Mercury from maternal ``silver'' tooth 
fillings in sheep and human breast milk: A source of neonatal 
exposure,'' Biol. Trace Elem. Res., Vol. 56 (2), pp. 143-152, 1997.
57. Echeverria, D. et al., ``Neurobehavioral effects from exposure 
to dental amalgam Hg\0\: new distinctions between recent exposure 
and Hg body burden,'' The FASEB Journal, Vol. 12, pp. 971-980, 1998.
58. Bittner, A.C., et al., ``Behavioral effects of low-level 
exposure to Hg\0\ among dental professionals: a cross-study 
evaluation of psychomotor effects,'' Neurotoxicology and Teratology, 
Vol. 20 (4), pp. 429-439, 1998.
59. Echeverria, D. et al., ``Chronic low-level mercury exposure, 
BDNF polymorphism, and associations with cognitive and motor 
function,'' Neurotoxicology and Teratology, Vol. 27, pp. 781-796, 
2005.
60. Echeverria, D. et al., ``The association between a genetic 
polymorphism of coproporphyrinogen oxidase, dental mercury exposure 
and neurobehavioral response in humans,'' Neurotoxicology and 
Teratology, Vol. 28, pp. 39-48, 2006.
61. Kanerva L. et al., ``A multicenter study of patch test reactions 
with dental screening series,'' Amer. J. Contact. Dermat, Vol. 12 
(2), pp. 83-87, 2001.
62. Laeijendecker R. et al., ``Oral lichen planus and allergy to 
dental amalgam restorations,'' Archives of Dermatology, Vol. 140 
(12), pp. 1434-1438, 2004.
63. Prochazkova J. et al., ``The beneficial effect of amalgam 
replacement on health in patients with autoimmunity.'' Neuro. 
Endocrinol. Lett., Vol. 25 (3), pp. 211-218, 2004.
64. Yaqob A. et al., ``Metal-specific lymphocyte reactivity is 
downregulated after dental metal replacement,'' Neuro. Endocrinol. 
Lett., Vol. 27 (1-2), pp. 189-197, 2006.
65. Dodes, J., ``The amalgam controversy,'' Journal of the American 
Dental Association, Vol. 132, pp. 348-356, 2001.
66. Transcript from Joint Meeting of Dental Products Panel and 
Central Nervous System Drugs Advisory Committee, September 6 and 7, 
2006.
67. Brownawell, A.M. et al., ``The Potential Adverse Health Effects 
of Dental Amalgam,'' Toxicological Reviews, 24(1):1-10, 2005.
68. Woods, J.S. et al., ``The Association between Genetic 
Polymorphisms of Coproporphyrinogen Oxidase and an Atypical 
Porphyrinogenic Response to Mercury Exposure in Humans,'' Toxicology 
and Applied Pharmacology, Vol. 206, pp. 113-120, 2005.
69. 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.
70. Clarkson, T.W. et al., ``The Toxicology of Mercury and Its 
Chemical Compounds,'' Critical Reviews in Toxicology, Vol. 36, pp. 
609-662, 2006.
71. McCullough, M.J. et al., ``Local Adverse Effects of Amalgam 
Restorations,'' International Dental Journal, Vol. 58, pp. 3-9, 
2008.
72. Prochazkova, J.J. et al., ``HLA-Association in Patients with 
Intolerance to Mercury and other Metals in Dental Materials,'' 
Disease Markers, Vol. 16, pp. 135-138, 2000.
73. Henriksson, E. et al., ``Healing of Lichenoid Reactions 
Following Removal of Amalgam. A Clinical Follow-Up,'' Journal of 
Clinical Periodontology, Vol. 22, pp. 287-94, 1995.
74. Swartzendruber, D.E., ``The Possible Relationship Between 
Mercury from Dental Amalgam and Diseases. I: Effects within the Oral 
Cavity,'' Medical Hypotheses, Vol. 41, pp. 31-34, 1993.
75. Siblerud, R.L., ``The Relationship Between Mercury from Dental 
Amalgam and Oral Cavity Health,'' Annals of Dentistry, Vol. 49, pp. 
6-10, 1990.
76. Bernardo, M. et al., ``Survival and Reasons for Failure of 
Amalgam Versus Composite Posterior Restorations Placed in a 
Randomized Clinical Trial,'' Journal of the American Dental 
Association, Vol. 138, pp. 775-783, June 2007.
77. Review of the Agency's Analysis of its NEPA obligations for the 
Classification of Dental Amalgam, Reclassification of Dental 
Mercury, Designation of Special Controls for Dental Amalgam, 
Mercury, and Amalgam Alloy, July 2009.
78. Diner, B.M. et al., ``Mercury Toxicity''; http://emedicine.medscape.com/article/819872-overview; December 11, 2007.
79. Lai, M.W. et al., ``2005 Annual Report of the American 
Association of Poison Control Center's National Poisoning and 
Exposure Database,'' Clinical Toxicology, Vol. 44:8, pp. 803-932, 
2006.
80. Bronstein, A.C. et al., ``2006 Annual Report of the American 
Association of Poison Control Center's National Poisoning Data 
System,'' Clinical Toxicology, Vol. 45:8, pp. 815-917, 2007.
81. Bronstein, A.C. et al., ``2007 Annual Report of the American 
Association of Poison Control Center's National Poisoning Data 
System,'' Clinical Toxicology, Vol. 46:10, pp. 927-1057, 2008.
82. Delta Dental Plans Association, Comment 0169, Docket No. FDA-
2008-N-0163; July 24, 2008.
83. Jones, D.W., ``Exposure and Absorption and the Crucial Question 
of Limits for Mercury,'' Journal of Canadian Dental Association, 
Vol. 65, pp. 788-792, 1999.
84. American Dental Association, ``Survey of Dental Practice--Dental 
Services,'' 2006.
85. U.S. Agency for Toxic Substances and Disease Registry, ``ToxFAQs 
for Mercury,'' U.S. Department of Health and Human Services, April 
1999.
86. Ventura, S.J. et al.; Estimated Pregnancy Rates by Outcome for 
the United States, 1990-2004; National Vital Statistics Reports; 
April 14, 2008; 56:15:1-28.
87. American Academy of Pediatrics; Breastfeeding and the Use of 
Human Milk; Pediatrics 2005; 115; 496-506.
88. Eastern Research Group; ``Preliminary Estimates: Labeling and 
Related Testing Costs for Medical Glove Manufacturers,'' Memorandum, 
January 18, 1999.
89. Levy, M. et al., ``Childhood urine mercury excretion: Dental 
amalgam and fish consumption as exposure factors,'' Environmental 
Research, Vol. 64, pp. 283-290, 2004.

List of Subjects in 21 CFR Part 872

    Medical devices.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
872 is amended as follows:

PART 872--DENTAL DEVICES

0
1. The authority citation for 21 CFR part 872 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.


Sec.  872.3050  [Removed]

0
2. Remove Sec.  872.3050.
0
3. Add Sec.  872.3070 to subpart D to read as follows:


Sec.  872.3070  Dental amalgam, mercury, and amalgam alloy.

    (a) Identification. Dental amalgam is a device that consists of a 
combination of elemental mercury, supplied as a liquid in bulk, sachet, 
or predosed capsule form, and amalgam alloy composed primarily of 
silver, tin, and copper, supplied as a powder in bulk, tablet, or 
predosed capsule form, for the direct filling of carious lesions or 
structural defects in teeth. This device also includes the individual 
component devices, mercury and amalgam alloy, when intended to be 
combined with each other to form dental amalgam.
    (b) Classification. Class II (special controls). The special 
control for this device is FDA's ``Class II Special Controls Guidance 
Document: Dental Amalgam, Mercury, and Amalgam Alloy.'' See Sec.  
872.1(e) for the availability of this guidance document.

    Dated: July 28, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-18447 Filed 7-29-09; 4:15 pm]
BILLING CODE P