# Dental Devices: Classification of Dental Amalgam, Reclassification of Dental Mercury, Designation of Special Controls for Dental Amalgam, Mercury, and Amalgam Alloy > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3AE9-18447 ## Record - **Collection:** Federal Register - **Document type:** Rule - **Published:** August 4, 2009 - **Citation:** 74 FR 38686 ## Text 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. 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. 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. The Agency has determined that class II with special controls is the appropriate classification for dental amalgam after evaluating the valid scientific evidence related to dental amalgam, including comprehensive reviews of the scientific literature and safety assessments. Based on its review of this scientific evidence, FDA made the two findings it is required by law to make when classifying a device (21 CFR 860.7(d)(1)): First, FDA found that, when subject to the general controls of the act and the designated special control, the probable benefits to health from the use of the device for its intended use and conditions for use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks. Second, FDA found that, when subject to the general controls of the act and the designated special control, the scientific evidence adequately demonstrates the absence of unreasonable risk of illness or injury associated with the intended use of dental amalgam. In developing this final rule, FDA reviewed scientific evidence and also considered the classification recommendation of the Dental Products Panel (Ref. 1), which concluded that there are no major risks associated with encapsulated dental amalgam, when used as directed, but recognized there is a small population of patients who may experience allergic hypersensitive reactions to the materials in the device. The Panel also noted that improper use exposes dental professionals to risks associated with mercury toxicity, with improper storage, trituration, and handling contributing to this risk. As part of its assessment, FDA considered the important public health benefits of dental amalgam and the advantages it presents as a restorative material. Dental amalgam has been used since the 1890s. 2 Millions of patients have received dental amalgam restorations to treat dental caries. 3 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). 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 μg Hg/L (2.34 μg Hg/g Cr) and 4.20 ± 1.60 μg Hg/L (3.23 μg Hg/g Cr), respectively (Ref. 8). Removal of amalgams resulted in an increase in urinary mercury; values were 1.8 ± 1.2 μg Hg/L (1.4 μg Hg/g Cr) before removal compared to 2.8 ± 2.1 μg Hg/L (2.2 μg/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 (Hg 2+ ) (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 Hg 2+ , is found in breast milk after maternal exposure to mercury vapor and, therefore, may be present in breastfed infants (Ref. 55). Because maternal exposure to mercury vapor from dental amalgam may lead to prenatal and postnatal exposure of offspring, FDA considered the potential health effects of dental amalgam on developing fetuses and breastfed infants. 1. Review of Scientific Evidence As already noted, this rule and the special controls guidance reflect FDA's evaluation of the valid scientific evidence related to the use of dental amalgam in the population age six and older and in potentially sensitive subpopulations (developing fetuses, breastfed infants, and children under age six). The White Paper (Ref. 10) and Addendum (Ref. 11) referenced in this rule include more details regarding FDA's examination. 4 These documents are included as references and are available on FDA's Web site. 4 FDA decided to conduct this comprehensive review of the literature and prepare the Addendum rather than revise the White Paper. 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. 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) 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 μg/m 3 . The Environmental Protection Agency (EPA) has established a Reference Concentration (RfC) 8 for elemental mercury vapor at 0.3 μg/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 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 μmol/mol creatinine (Cr) (approximately 20.1 μg/g Cr; 26.1 μg/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 μg/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). 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 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. At these ventilation rates, chronic exposure at the level of the MRL would result in an estimated dose of mercury vapor of 3.2 μg/day in the average adult, 1.5 μg/day in the average five-year-old child, and 1.2 μg/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 μg/day in the average adult, 2.3 μg/day in the average five-year-old child, and 1.7 μg/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 μg/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 μg/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 μg/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 μg/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 μg/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 μg/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 μg/day) or the RfC (6 μg/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. 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 . 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 μg 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 μg Hg/g Cr (Refs. 25-28). 13 Given that 50 μg 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 μg Hg/g Cr. This urinary mercury concentration is associated with chronic occupational exposure of a healthy worker to an air concentration of 25 μg Hg/m 3 . 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 μg Hg/g Cr in adults (Refs. 29, 30) and 0.5-2 μg 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 μg 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 μg Hg/g Cr. In a study of 550 adults, aged 30-49, urinary mercury concentrations ranged from 0.75-2.9 μg 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 μg Hg/g Cr, and 1.3 percent of the participants had urinary mercury concentrations over 12 μg Hg/g Cr (Ref. 30). A urinary mercury concentration of 1.9 μg 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 μg Hg/g Cr. Studies have also assessed urinary mercury concentrations in amalgam-bearing children age six or older. Two prospective studies assessed urinary mercury concentrations in children age six and older after placement of dental amalgam restorations. In a seven-year study of children ages eight to ten at baseline, the highest average urinary mercury concentration reported during the study period was 3.2 μg 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 μg 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 μg Hg/g Cr. Children from the composite restoration-only group averaged 0.6 μg 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 μg Hg/g Cr) compared to those without amalgams (0.436 μg 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 μg Hg/g Cr] or higher, but not when the average [urinary mercury] concentration has been lower than 10 nmol/mmol Cr [17.7 μg Hg/g Cr].” In another study, 38 chloralkali workers with average urinary mercury concentration of 9 μg Hg/g Cr were compared with non-exposed controls (average urinary mercury concentration 2 μg/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 μg Hg/g creatinine (Ref. 24). However, occupational studies published since 1996 report that increases in urinary levels of early biomarkers predictive of renal injury have been observed at urinary mercury concentrations of 16-28 μg Hg/g creatinine. In a study of chloralkali workers exposed to mercury vapor for 13 years (mean urinary mercury concentrations of 16.5 μg/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 μg Hg/g Cr. In another study, 38 chloralkali workers with average urinary mercury concentration of 9 μg Hg/g Cr were compared with non-exposed controls (average urinary mercury concentration 2 μg 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 μg Hg/m 3 (maximum 600 μg/m 3 ), no significant differences in stillborn or miscarriage rates were observed between exposed and unexposed subjects (Ref. 50). The mercury vapor concentrations to which these workers were exposed were over an order of magnitude higher than those associated with dental amalgam. Studies in Amalgam Bearers Very few well-controlled animal studies or human epidemiological studies have evaluated the potential effect of low-level mercury vapor exposure on fetal development, especially at exposures experienced by dental amalgam bearers. In one retrospective study (Ref. 51), no association was found between the number of amalgam fillings in women and low birth weight of their babies. However, there is limited clinical information concerning the effects of prenatal exposure from maternal sources of mercury vapor at relevant concentrations. Although the data are limited, FDA concludes that the existing data do not suggest that fetuses are at risk for adverse health effects due to maternal exposure to mercury vapors from dental amalgam. As described earlier in this document, maternal exposures are likely to increase temporarily when new dental amalgams are inserted or existing dental amalgam restorations are removed. Breastfed Infants Mercury present in the mother's body is transmitted to her infant through breast milk. Maternal exposure to elemental mercury vapor would be expected to affect the concentration of inorganic mercury in breast milk. The EPA has set a Reference Dose (RfD) 15 for oral exposure to inorganic mercury at 0.3 μg 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 μg 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 μg Hg/day. For a 5 kg infant, the daily exposure to inorganic mercury from breastfeeding would be 0.015 μg 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 μg/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 μg Hg/L (~0.7 to 2.3 μg 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 μg Hg/L (~0.8 μg Hg/g Cr) to greater than 50 μg Hg/L (~38μg 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 μg Hg/L (0.7 μg Hg/g Cr) before chelation; 9.1 ± 6.9 μg Hg/L (7 μg Hg/g Cr) after chelation. Subtle but statistically significant associations were demonstrated for recent exposure (pre-chelation) and measures of mood, motor function and cognition, and mercury body burden (post-chelation) was associated with symptoms, mood, and motor function. Chelation of mercury in dental professionals suggests that the mercury body burden in this population of workers is much greater than indicated solely by pre-chelation urinary mercury levels. Another study (Ref. 58) 230 dentists (data pooled from six previous studies) had urinary mercury concentrations ranging from less than 1 μg Hg/L (~0.8 μg Hg/g Cr) to greater than 50 μg Hg/L (~38 μg Hg/g Cr); 50% subjects had urine concentrations less than 3 μg Hg/L (~2 μg Hg/g Cr) and 30% had concentration greater than 20 μg Hg/L (~15 μg Hg/g Cr). Dentists stratified into three urine mercury concentration groups: Less than 1 μg Hg/L (~0.8 μg Hg/g Cr), 1-20 μg Hg/L (~0.8-15 μg Hg/g Cr) and greater than 20 μg Hg/L (~15 μg 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 μg/L, ~2.6 μg/g Cr) and 233 hygienists (average exposure of 15 years; average amalgam surfaces = 12; urine mercury = 1.98 ± 2.29 μg/L, ~1.48 μg/g Cr) for neurological effects. No effects were observed on verbal intelligence and reaction time. Significant correlations with urine mercury concentrations were found on 9 measures in dentists and 8 measures in hygienists, including visual discrimination, hand steadiness, finger tapping and trail making tests. A weakness of the study was that no non-mercury-exposed dental professionals were studied; therefore, the effect of exposure to other chemicals in the workplace (gases, organic solvents) cannot be ruled out. Nor was a non-dental workplace control group studied, which would have been informative about effects of the dental work environment in general. FDA concludes that existing data indicate that dental professionals are generally not at risk for mercury toxicity except when dental amalgams are improperly used, stored, triturated, or handled. iii. Individuals With Mercury Allergies Some individuals are hypersensitive or allergic to mercury and/or other metals. FDA reviewed several epidemiological and case studies related to the effects of mercury vapor exposure from dental amalgam on allergic individuals. According to some of the studies that were reviewed, some patients develop adverse tissue reactions such as dermatological conditions or lesions of the skin, mouth, and tongue as a result of exposure to dental amalgam (Ref. 61, 62). In mercury-allergic individuals, clinical improvements were reported after dental amalgam restorations were removed. Other studies reported that dental amalgam may exacerbate pre-existing autoimmune disease in mercury-allergic individuals (Refs. 63, 64). After dental amalgam restorations were removed, the health status of these patients reportedly improved. FDA concludes that existing data indicate that certain individuals with a pre-existing hypersensitivity or allergy to mercury may be at risk for adverse health effects from mercury vapor released from dental amalgam. 2. Rationale for Special Controls In light of the above information, FDA has identified the following as the potential risks to health associated with the use of dental amalgam devices, requiring the establishment of special controls: (1) Exposure to mercury; (2) allergic response including adverse tissue reaction; (3) contamination; (4) mechanical failure; (5) corrosion; and (6) improper use. FDA is establishing a special controls guidance document that includes recommendations to address these risks as follows. a. Risk of Exposure to Mercury As discussed above, dental amalgam releases mercury vapor and is associated with a risk of human exposure to this vapor. The special controls to address this risk are recommendations for: (i) Specific labeling, (ii) an information for use statement, and (iii) a performance test for mercury vapor release. i. Specific Labeling Recommendation The special controls guidance recommends the following specific labeling: • WARNING: CONTAINS MERCURY. • Warning: May be harmful if vapors are inhaled. • Precaution: Use with adequate ventilation. • Precaution: Store in a cool, well ventilated place. • Contains [ ]% mercury by weight. The recommended warning about the presence of mercury in a dental amalgam device and the recommended disclosure of mercury content by weight will alert dental professionals of the potential for exposure to mercury vapor and will remind them of the need for protective measures, such as the use of gloves when handling the device. The recommended precautions about the need for adequate ventilation and the need to store in a cool, well ventilated place will encourage professionals to ensure there is adequate ventilation when in proximity to the device and to use a vacuum pump and adequate ventilation during placement of dental amalgams to minimize the amount of mercury vapor that they or their patients may inhale. ii. Information for Use Recommendation Dental amalgam has been and remains one of the most commonly used restorative materials in dentistry. In the recent past the use of dental amalgam has gradually declined due to the improved properties of composite resin materials. Although amalgam has been used successfully for many years, the risks associated with this device have been controversial. Some scientists, professional groups, clinicians and patient advocacy groups have expressed concern about the potential hazards to health arising from mercury vapor release from amalgam restorations. Other groups of scientists, clinicians, and professional organizations have disagreed with these concerns. These opposing viewpoints were voiced at the 2006 FDA joint panel meeting (Ref. 66). In order for dentists to make appropriate treatment decisions with their patients, it is important to provide information to help dentists understand the complexities of the science related to dental amalgam and its mercury content. FDA recommends the inclusion of an “information for use” statement in dental amalgam labeling as a special control: Dental amalgam has been demonstrated to be an effective restorative material that has benefits in terms of strength, marginal integrity, suitability for large occlusal surfaces, and durability. 17 Dental amalgam also releases low levels of mercury vapor, a chemical that at high exposure levels is well-documented to cause neurological and renal adverse health effects. 18 Mercury vapor concentrations are highest immediately after placement and removal of dental amalgam but decline thereafter. 17 Dental Amalgam: A Scientific Review and Recommended Public Health Service Strategy for Research, Education and Regulation; Public Health Service, U.S. Department of Health and Human Services, January 1993. 18 Liu, J. et al. , “Toxic effects of metals,” Casarett & Doull's Toxicology: The Basic Science of Poisons , Chapter 23, pp. 931-979, McGraw-Hill Medical, New York, New York, 2008. Clarkson, T.W. et al. , “The Toxicology of Mercury and Its Chemical Compounds,” Critical Reviews in Toxicology , Vol. 36, pp. 609-662, 2006. Clinical studies have not established a causal link between dental amalgam and adverse health effects in adults and children age six and older. In addition, two clinical trials in children aged six and older did not find neurological or renal injury associated with amalgam use. 19 19 De Rouen, T. et al. , “Neurobehavioral Effects of Dental Amalgam in Children, A Randomized Clinical Trial,” Journal of the American Medical Association , Vol. 295, 1784-1792, No. 15, April, 19, 2006. Bellinger, D.C. et al. , “Neuropsychological and Renal Effects of Dental Amalgam in Children: A Randomized Clinical Trial,” Journal of the American Medical Association , Vol. 295, No. 15, April 19, 2006, 1775-1783, 2006. Barregard, L. et al. , “Renal Effects of Dental Amalgam in Children: The New England Children's Amalgam Trial,” Environmental Health Perspectives , Volume 116, 394-399, No. 3, March 2008. Woods, J.S. et al. , “Biomarkers of Kidney Integrity in Children and Adolescents with Dental Amalgam Mercury Exposure: Findings from the Casa Pia Children's Amalgam Trial,” Environmental Research , Vol. 108, pp. 393-399, 2008. Lauterbach, M. et al. , “Neurological Outcomes in Children with and Without Amalgam-Related Mercury Exposure: Seven Years of Longitudinal Observations in a Randomized Trial,” Journal of the American Dental Association , Vol. 139, 138-145, February 2008. The developing neurological systems in fetuses and young children may be more sensitive to the neurotoxic effects of mercury vapor. Very limited to no clinical information is available regarding long-term health outcomes in pregnant women and their developing fetuses, and children under the age of six, including infants who are breastfed. The Agency for Toxic Substances and Disease Registry's (ATSDR) and the Environmental Protection Agency (EPA) have established levels of exposure for mercury vapor that are intended to be highly protective against adverse health effects, including for sensitive subpopulations such as pregnant women and their developing fetuses, breastfed infants, and children under age six. 20 Exceeding these levels does not necessarily mean that any adverse effects will occur. 20 Agency for Toxic Substances and Disease Registry (ATSDR) and Research Triangle Institute, Toxicological profile for mercury, U.S. Dept. of Health and Human Services, Public Health Service, Atlanta, Georgia, 1999. United States Environmental Protection Agency (EPA), “Integrated Risk Information System (IRIS) Screening-Level literature Review”—Mercury, elemental, 2002. FDA has found that scientific studies using the most reliable methods have shown that dental amalgam exposes adults to amounts of elemental mercury vapor below or approximately equivalent to the protective levels of exposure identified by ATSDR and EPA. Based on these findings and the clinical data, FDA has concluded that exposures to mercury vapor from dental amalgam do not put individuals age six and older at risk for mercury-associated adverse health effects. Taking into account factors such as the number and size of teeth and respiratory volumes and rates, FDA estimates that the estimated daily dose of mercury in children under age six with dental amalgams is lower than the estimated daily adult dose. The exposures to children would therefore be lower than the protective levels of exposure identified by ATSDR and EPA. In addition, the estimated concentration of mercury in breast milk attributable to dental amalgam is an order of magnitude below the EPA protective reference dose for oral exposure to inorganic mercury. FDA has concluded that the existing data support a finding that infants are not at risk for adverse health effects from the breast milk of women exposed to mercury vapors from dental amalgam.” The purpose of this labeling recommendation is address potential misunderstandings about the risk of exposure to mercury from the device and to help dental professionals plan appropriate treatment recommendations for their patients by providing them with FDA's assessment of the most current, best available evidence regarding potential risks to health from mercury vapor released from dental amalgams. iii. Performance Test Recommendation The special controls guidance recommends a performance test to determine the amount of mercury vapor released by a dental amalgam device during corrosion (ng/cm 2 in 4 hrs). Dental amalgam releases the highest levels of mercury vapor when it corrodes (Ref. 65). By measuring the amount of mercury vapor released during corrosion, the recommended performance test will quantify the highest levels of vapor release that can be expected from a dental amalgam device. The results of this test will enable FDA, through a premarket notification (510(k)) submission, to determine if these levels are acceptable and are comparable to legally marketed devices. 21 21 Dental amalgam devices currently on the market must also be in conformance with the special controls guidance. b. Risk of Allergic Response Including Adverse Tissue Reaction Dental amalgam is associated with a risk of adverse tissue reaction, particularly in individuals with a mercury allergy, who may experience additional allergic reactions. The special controls to address this risk are recommendations for: (i) Specific labeling and (ii) a performance test for biocompatibility. i. Specific Labeling Recommendation The special controls guidance recommends the following specific labeling: ■ 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: ▪ Compressive strength (MPa) @ 24 hrs. ▪ Dimensional change during hardening (%). ▪ Trituration time (s). ▪ 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: ▪ Complete chemical composition. ▪ Compressive strength (MPa) @ 1 hr. ▪ Compressive strength (MPa) @ 24 hrs. ▪ Maximum creep (%). ▪ Dimensional change during hardening (%). ▪ Particle size distribution (μ) and shape, i.e., spherical, irregular, etc. ▪ Trituration time (s). ▪ 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: ▪ 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: ▪ Contraindication: Do not use in persons with a known mercury allergy. ▪ Precaution: Single-use only. The recommended labeling contraindiation will alert dental professionals of situations in which the use of a dental amalgam device is not recommended, such as in patients with a known mercury allergy. The recommended labeling precaution will inform dental professionals that a dental amalgam device is not intended to be reused. B. Statutory Authority FDA regulates devices, including dental devices, under the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301 et seq. ), and the act's implementing regulations (parts 800 through 898 (21 CFR parts 800 through 898)). The Medical Device Amendments of 1976 (Pub. L. 94-295) amended the act to add premarket review authority and other authorities related to devices. Section 513 of the act (21 U.S.C. 360c) established three categories (classes) of devices, depending on the regulatory controls needed to provide reasonable assurance of their safety and effectiveness. The three categories of devices are class I devices, which are subject to general controls; class II devices, which are subject to general and “special” controls; and class III devices, for which premarket approval applications generally must be submitted. General controls include requirements for registration, listing, adverse event reporting, and good manufacturing practice (section 513(a)(1)(A) of the act). Special controls are controls that, in addition to general controls, are applicable to a class II device to help provide reasonable assurance of that device's safety and effectiveness (section 513(a)(1)(B) of the act). Under the 1976 amendments, class II devices were defined as devices for which there was insufficient information to show that general controls themselves would provide reasonable assurance of safety and effectiveness, but for which there was sufficient information to establish performance standards to provide such assurance. The Safe Medical Devices Act of 1990 (SMDA) (Pub. L. 101-629) broadened the definition of class II devices to mean those devices for which the general controls by themselves are insufficient to provide reasonable assurance of safety and effectiveness, but for which there is sufficient information to establish special controls to provide such assurance, including performance standards, postmarket surveillance, patient registries, development and dissemination of guidelines, recommendations, and any other appropriate actions the agency deems necessary (section 513(a)(1)(B) of the act). The premarket approval requirements specify data and information that must be provided to FDA to obtain approval of a class III device (section 515 of the act (21 U.S.C. 360e)). Devices that were in commercial distribution before the enactment of the Medical Device Amendments of 1976 (May 28, 1976) are commonly referred to as “preamendments devices.” Under section 513 of the act, FDA classifies preamendments devices according to the following steps: (1) FDA receives a recommendation from a device classification panel (an FDA advisory committee); (2) FDA publishes the panel's recommendation for comment, along with a proposed regulation classifying the device; and (3) FDA publishes a final regulation. FDA has classified most preamendments devices under these procedures. Section 513(e) of the act governs reclassification of preamendments devices. This section provides that FDA may reclassify a device by rulemaking based upon “new information.” FDA may initiate reclassification under section 513(e) or an interested person may petition FDA to reclassify a preamendments device. The term “new information,” as used in section 513(e) of the act, includes information developed as a result of a reevaluation of the data before the agency when the device was originally classified, as well as information not presented, not available, or not developed at that time. ( See, e.g., Holland Rantos v. United States Department of Health, Education, and Welfare, 587 F.2d 1173, 1174 n.1 (DC Cir. 1978); Upjohn v. Finch, 422 F.2d 944 (6th Cir. 1970); Bell v. Goddard, 366 F.2d 177 (7th Cir. 1966)). Reevaluation of the data previously before the agency is an appropriate basis for subsequent regulatory action where the reevaluation is made in light of newly available regulatory authority ( see Bell v. Goddard, supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762 F. Supp. 382, 389-91 (D.D.C. 1991)), or in light of changes in “medical science.” ( See Upjohn v. Finch, supra, 422 F.2d at 951). Whether data before the agency are past or new data, the “new information” to support reclassification under section 513(e) must be “valid scientific evidence,” as defined in section 513(a)(3) of the act (21 U.S.C. 360c(a)(3)) and 21 CFR 860.7(c)(2). ( See, e.g., General Medical Co. v. FDA, 770 F.2d 214 (DC Cir. 1985); Contact Lens Assoc. v. FDA, 766 F.2d 592 (DC Cir.), cert. denied, 474 U.S. 1062 (1985)). FDA relies upon “valid scientific evidence” in the classification process to determine the level of regulation for devices (§ 860.7). For the purpose of reclassification, the valid scientific evidence upon which the agency relies must be publicly available. Publicly available information excludes trade secret and/or confidential commercial information, e.g., the contents of a pending premarket approval application (PMA). ( See section 520(c) of the act (21 U.S.C. 360j(c)). C. Regulatory History of the Devices 1. Regulatory Status Dental amalgam 22 is a metallic restorative material that has been used for direct filling of carious lesions or structural defects in teeth since the 1890s. 23 It is a combination of two devices, mercury 24 (liquid) and amalgam alloy (powder), which is composed primarily of silver, tin, and copper. At the time FDA proposed to classify mercury and amalgam alloy, the devices were most commonly marketed individually in tablet/sachet or bulk form to be prepared by mixing the two devices in a dentist's office, although the devices were also available in an already combined predosed, encapsulated form. Since the mid-1980s, the device has been marketed most frequently in the predosed, encapsulated form. 22 “Dental amalgam,” as it is referred to in this final rule, is a device that is a combination of two component devices, mercury and amalgam alloy. 23 Earlier prototypes were available from the 1830s. 24 FDA is no longer using the term “dental mercury,” but instead is using “mercury,” to more accurately reflect the fact that the mercury used in dental amalgam is elemental mercury. FDA classified mercury and amalgam alloy separately in accordance with the classification procedures for preamendments devices. In 1980, FDA published a proposed rule to classify amalgam alloy into class II, based on the recommendation of a device classification panel (Dec. 30, 1980, 45 FR 85979), and finalized the classification of amalgam alloy into class II in the Federal Register of August 12, 1987 (52 FR 30099). Although FDA proposed classifying mercury into class II, in the Federal Register of August 12, 1987 (52 FR 30089) FDA issued a final rule classifying mercury into class I. FDA explained that it believed that the general controls of the act, particularly the requirement that the device bear adequate directions for use, were sufficient to provide reasonable assurance of the safety and effectiveness of the device and to address the risk of rare allergic reactions among patients as well as the risk of toxicity among dental health professionals. FDA did not classify dental amalgam at the time it classified its two components, mercury and amalgam alloy. However, in accordance with its customary practice regarding regulation of devices composed of two or more devices, FDA has regulated the predosed, encapsulated form of dental amalgam in accordance with the requirements applicable to its component with the highest classification, i.e., amalgam alloy. Accordingly, dental amalgam devices entering the market have been regulated as class II devices under 21 CFR 872.3050, amalgam alloy. 2. Proposed Rule In the Federal Register of February 20, 2002 (67 FR 7620), FDA published a proposed rule entitled “Dental Devices: Classification of Dental Amalgam and Reclassification of Dental Mercury; Issuance of Special Controls for Amalgam Alloy.” The proposed rule was based on the recommendation of the device advisory panel, information submitted in citizen petitions requesting the agency to take various actions with respect to the devices, a substantial amount of scientific data, and the results of several government safety assessments related to the devices (Refs. 3, 4, 12). The Dental Products Panel 25 (the Panel) unanimously recommended that FDA classify dental amalgam in its encapsulated form into class II (Ref. 1). The Panel concluded that there are no major risks associated with encapsulated dental amalgam, when used as directed, but recognized there is a small population of patients who may experience allergic hypersensitive reactions to the materials in the device. The Panel also noted that improper use of the device exposes professionals to risks associated with mercury toxicity. To address these risks, the Panel recommended that the device be subject to voluntary performance standards, voluntary testing guidelines, and requirements that the device be used only on the written or oral authorization of a licensed practitioner, and only by persons with training or expertise in its use. 25 A panel of FDA's Center for Devices and Radiological Health Medical Devices Advisory Committee. The proposed rule included the following actions: (1) Classify encapsulated dental amalgam into class II (special controls); (2) amend the class II classification for amalgam alloy by designating special controls; and (3) reclassify mercury from class I (general controls) to class II (special controls). In the 2002 proposed rule, FDA identified risks to health associated with the use of dental amalgam, mercury, and amalgam alloy that it believed required the imposition of special controls that, in conjunction with the general controls of the act, would provide reasonable assurance of the safety and effectiveness of the device. The risks identified were mercury toxicity associated with the improper use of dental amalgam and allergic reactions in a small subpopulation of individuals. To mitigate these risks, FDA proposed a labeling guidance and compliance with recognized consensus standards as special controls for these devices. FDA proposed that all three devices be subject to the same special control guidance document, “Special Control Guidance Document on Encapsulated Amalgam, Amalgam Alloy, and Dental Mercury Labeling,” dated February 20, 2002, as well as the following consensus standards, as relevant: (1) International Standards Organization (ISO) 1559:1995 Dental Materials-Alloys for Dental Amalgam, and (2) American National Standards Institute/American Dental Association (ANSI/ADA) Specification No. 6-1987 for Dental Mercury. The comment period on the proposed rule was reopened on July 17, 2002 (67 FR 46941), and again on April 28, 2008 (73 FR 22877), to permit additional opportunities for public comment (Docket No. FDA-2008-N-0163). 3. Scientific Information, Safety Assessments, and Adverse Event Reports Regarding Dental Amalgam a. Information and Assessments Discussed in the Proposed Rule Before issuing the proposed rule, FDA carefully examined extensive information related to the safety and effectiveness of dental amalgam. This information included a comprehensive safety assessment of dental amalgam performed by the U.S. Public Health Service (PHS), U.S. government research related to dental amalgam, studies and other information submitted in citizen petitions to the agency, several national and international comprehensive reviews of scientific information about the risks and benefits of the device, comprehensive safety assessments of dental products that contain mercury by international health organizations and foreign countries, and the scientific literature reviewed by the Panel. See 67 FR 7621-7625 (Feb. 20, 2002). b. Information and Assessments That Have Become Available Since Publication of the Proposed Rule i. Life Sciences Research Office (LSRO) Report In 2004, the Trans-agency Working Group on the Health Effects of Dental Amalgam completed a comprehensive review of approximately 300 peer-reviewed studies of dental amalgam and mercury vapor published from 1996 through 2003 (LSRO report) (Ref. 13). The project was completed under contract by Life Sciences Research Office, Inc. (LSRO), and was funded by the National Institutes of Health (NIH), in cooperation with FDA, the Centers for Disease Control and Prevention (CDC), and the Office of the Chief Dental Officer of the Public Health Service. In conducting the review, LSRO engaged an independent panel of experts from academia in the fields of immunotoxicology, immunology, and allergy; neurobehavioral toxicology and neurodevelopment; pediatrics; developmental and reproductive toxicology; toxicokinetics and modeling; occupational health and epidemiology; pathology; and general toxicology. The LSRO report concluded that there is little evidence to support claims of a causal relationship between mercury fillings and human health problems, such as kidney or cognitive dysfunction; neurodegenerative disease, specifically Alzheimer's disease or Parkinson's disease; or autoimmune disease (Refs. 13, 67). The report also identified important data gaps, including whether low-level mercury vapor results in neurotoxicity, whether low-level in utero exposure to mercury vapor affects the developing brain, and whether occupational exposure to mercury vapor affects reproductive and/or pregnancy outcomes. ii. White Paper and Addendum Scientific Reviews In an effort to assess whether peer-reviewed literature published since FDA's 1997 safety assessment of dental amalgam (Ref. 12) presented new information on the potential health risks of dental amalgam, FDA's National Center for Toxicological Research (NCTR) prepared a White Paper review (Ref. 10). Rather than duplicate previous extensive reviews of the scientific literature by U.S. government agencies and international organizations, NCTR chose to build on the previous reviews and conducted an in-depth evaluation of 34 primary research articles that were chosen for their scientific merit, relevance, and potential to provide the most significant current information regarding the potential health risks associated with exposure to mercury in dental amalgam. The conclusion in the draft White Paper was that the peer-reviewed scientific information published since 1997 was consistent with FDA's previous assessment that, except for persons with rare allergic or hypersensitivity reactions, individuals with dental amalgam restorations do not experience adverse effects from the device. On September 6 and 7, 2006, FDA presented the findings of the White Paper in draft to a joint meeting of the Dental Products Panel and the Peripheral and Central Nervous System Drugs Advisory Committee (the 2006 Panel). At that time, FDA also opened a docket related to the meeting to facilitate public submission of information regarding the potential health risks of mercury in dental amalgam (Docket No. FDA-2006-N-0543 (formerly 2006N-0352)). The 2006 Panel heard from numerous public speakers, and then deliberated and made recommendations on a series of questions FDA had posed on its draft White Paper (Ref. 66). The committee concluded that FDA's draft White Paper had significant limitations, such as the fact that the literature search used a single database (PubMed), the Paper did not satisfactorily explain how the scientific references were chosen, 26 and it failed to identify significant gaps in the scientific knowledge, particularly with respect to exposure limits and possible health risks for sensitive subpopulations. The majority of the 2006 Panel voted that it could not find the conclusions of the draft White Paper to be “reasonable” in light of these limitations. In their closing comments, the panelists provided individual recommendations, including the individual (not consensus) recommendations that FDA consider labeling requirements related to the use of dental amalgam in pregnant women and small children, that manufacturers be required to provide information to patients to ensure that they understand that the devices contain mercury, and that the Federal government (public health agencies) research the effects of dental amalgam mercury on reproductive health and developing fetuses. 26 Appendix A of the draft White Paper did list the inclusion and exclusion criteria for identification of relevant studies. In response to the deliberations and recommendations of the 2006 Panel, FDA conducted a more comprehensive review of the scientific literature in an Addendum to the White Paper (Ref. 11). In total, more than 200 scientific articles, including 33 case studies, were considered in the White Paper and its Addendum. 27 27 FDA decided to conduct this comprehensive review of the literature and prepare the Addendum rather than revise the White Paper. FDA finalized the White Paper with the addition of the Addendum. The conclusions of the Addendum generally confirmed the conclusions of the White Paper and previous assessments by other organizations and agencies regarding the potential health risks presented by the presence of mercury in dental amalgam. More specifically, the articles and case studies reviewed in the Addendum to the White Paper were consistent with the conclusion in earlier government safety assessments (Refs. 3, 4, 12) that exposures to mercury vapor from dental amalgam are not associated with adverse health effects in the population age six and older ( see also section I.A.). As discussed in the Addendum, FDA also concluded that prospective clinical studies of dental amalgam published to date (Refs. 31, 32, 34, 40, 46, 47, 68) found no neurological deficits in children who first received dental amalgam restorations at ages six to ten and were followed for five or seven years. FDA concluded, however, that the clinical data are limited regarding certain subpopulations (pregnant women and their developing fetuses, and children under the age of six, including breastfed infants). c. Adverse Event Reports As part of FDA's effort to determine the appropriate regulatory controls to provide reasonable assurance of the safety and effectiveness of dental amalgam, FDA reviewed all adverse event reports submitted to MedWatch for dental amalgam devices through 2008. The review identified 141 reports, dating back to 1988, including 102 reports of injuries, 12 reports of malfunctions, 26 miscellaneous complaints, and 1 misreported death. 28 The large majority of the injury reports were submitted voluntarily by individual patients. The malfunction reports were submitted primarily by health professionals and two reports were submitted by manufacturers. 28 The death report appears to have been misclassified because it was self reported (an actual death had not occurred). This report attributes symptoms of joint pain, neurological spasms, a compromised immune system, and a variety of other physical symptoms to dental amalgam. The malfunction reports described problems with encapsulated amalgam such as product shrinkage, inaccurate powder to liquid ratios, and capsule leaking. There were also some reports of mercury spills as a result of mixing (triturating) amalgam capsules. The injury reports described a wide array of conditions and symptoms that individual patients believed to be caused by their dental amalgam fillings. The conditions and symptoms reported included fatigue, headaches, joint pain, brain “fog,” depression, neuropathy, rheumatoid arthritis, hypothyroidism, visual impairments, hearing loss, allergies, kidney damage, attention deficit disorder, irritable bowel syndrome, seizures, abnormal menstrual cycle, weight loss, and developmental problems, such as autism, attention deficit hyperactivity disorder, and unidentified congenital defects. Several reporters stated that they experienced relief from their symptoms when their amalgam fillings were removed, while others stated that their symptoms did not appear until after their fillings were removed. The great majority of the adverse event reports submitted to FDA regarding dental amalgam are anecdotal and lack specific details, such as when symptoms first appeared, how they progressed, and what may have caused onset or relief of certain symptoms. In addition, the reports frequently were not made until years after the events occurred. Because of these factors, FDA is unable to assess the relationship of the reported adverse effects with the device. FDA notes, however, that the number of adverse event reports it has received regarding dental amalgam is quite low in light of the device's long history of use in tens of millions of dental restorations in the United States each year. 29 29 FDA estimates that dental amalgam has been used in approximately one billion restorations between 1988 and 2008. II. Development of the Final Rule In developing this final rule, FDA considered the comments and information submitted in response to the proposed rule, the scientific reviews, studies, and safety assessments described above, and its analysis of the adverse event reports submitted. The final rule and the special controls guidance document are consistent with the proposed regulation, although they reflect several changes made in response to the comments and information received. As proposed, the final rule classifies dental amalgam into class II, reclassifies mercury from class I to class II, and designates a special control for dental amalgam, mercury, and amalgam alloy. However, the final rule classifies the three devices together in a single regulation and uses the term “mercury” instead of “dental mercury.” The special controls guidance document specifically revises the draft special controls guidance document as follows: • Includes recommendations related to the updated relevant consensus standards, rather than designating these standards as separate special controls. • Includes recommendations regarding device composition, performance data, warnings, and labeling precautions. • Recommends a contraindication against use in persons with a known mercury allergy. • Recommends that the labeling include an information for use (IFU) statement. • Updates recommendations regarding performance testing to be included in 510(k) submissions to include strength, creep, dimensional change, particle shape and distribution, corrosion products, and amount of mercury vapor released. • Replaces the recommendation that each ingredient of the device be listed in the labeling with the recommendation that the primary ingredients be listed, and that the labeling state that the device contains mercury. • Replaces the recommendation that the labeling warn that the device contains zinc with the recommendation that the labeling warn that the device contains mercury. FDA believes that the effects of zinc on the expansion of dental amalgam are well understood and that a warning that the device contains zinc is not necessary to provide a reasonable assurance of the safety and effectiveness of the device. In contrast, as discussed in section I.A., FDA recommends that the device bear a warning that the device contains mercury because FDA believes such a warning is necessary to provide a reasonable assurance of safety and effectiveness because of the potential risks to health of exposure to mercury and toxicity and adverse tissue reaction. • Deletes recommendations regarding packaging and handling because FDA has concluded that these recommendations are not necessary to provide a reasonable assurance of the safety and effectiveness of the device. In this final rule, FDA is designating a special controls guidance document (described in section I.A.) that, along with the general controls under the act, will provide reasonable assurance of the safety and effectiveness of the device. Elsewhere in this issue of the Federal Register , FDA is announcing the availability of the special controls guidance. Following the effective date of this final rule, any firm submitting a 510(k) premarket notification for dental amalgam, as well as any firm currently marketing the device, must address the risks to health identified in the special controls guidance document. Firms marketing or intending to market mercury or amalgam alloy must address the risks to health identified in the special controls guidance document that apply to those devices. When a guidance document is established as a special control by rulemaking, manufacturers are required to address the issues identified in the guidance, either by following the recommendations in the guidance or by some other means that provides equivalent assurances of safety and effectiveness. If a manufacturer proposes to use a means other than the recommendations set forth in the special controls guidance, it is required to demonstrate that the alternative means provides equivalent assurances of safety and effectiveness. III. Comments and FDA's Responses As stated previously, in addition to the comment period provided when the proposed rule was issued in 2002, FDA reopened the comment period on the rule in July 2002 and again in April 2008. Altogether, FDA received more than 1,400 comments on the proposed rule and the draft special controls guidance document. The commenters included consumers, health professionals, industry, academia, State and Federal agencies, professional societies, and organizations. Because of the intertwined nature of the documents and the significant duplication of comments, FDA is summarizing and responding to the comments it received on both the proposed rule and the draft special controls guidance document in this preamble. 30 30 FDA also received more than 1,800 comments to the docket for the 2006 Panel meeting on dental amalgam (Docket No. 2006N-0352), which had been established to permit persons to comment and provide information on the issues and questions raised at the meeting. FDA reviewed and considered those comments in finalizing this regulation. In the 2008 Federal Register notice reopening the comment period on the proposed rule, FDA requested comments supported by empirical data and scientific evidence on specific topics relating to the classification of the devices and the special controls that should apply to them if they were classified into class II. FDA requested comments on whether the proposed special controls (materials and labeling) would provide reasonable assurance of the safety and effectiveness of the devices if they were placed in class II, and on whether the proposed special controls guidance document should be revised in light of the recommendations and discussions of the 2006 Panel. FDA also sought information related to the agency's analysis of the benefits and costs of the various regulatory options for classifying the devices, including the number of annual procedures in which the devices are used, trends in the use of various restorative devices, information regarding alternatives to dental amalgam, how labeling describing the risks in certain populations might affect demand, how such risks should be communicated, information regarding the current level of mercury to which patients and professionals are exposed, and whether that exposure might be reduced by using alternatives to dental amalgam. A. Classification (Comment) FDA received many comments regarding the appropriate classification of these devices. The comments generally did not distinguish among dental amalgam, mercury, and amalgam alloy, treating them as one device, dental amalgam. Many comments urged the agency to classify the device into class III (premarket approval), frequently stating safety concerns. For example, some commentators urged the agency to classify dental amalgam into class III because, as a class III device, “[it would be] presumed as unsafe and needing to be proven safe before general use can be allowed” and that “it should be placed in class III where manufacturers are forced to prove that it is safe, not the class II where it can continue to be grandfathered.” Others believed the device should be classified into class II because there is sufficient information to establish special controls for the device that would provide reasonable assurance of its safety and effectiveness. One comment stated that special controls were unnecessary because it believed that the general controls of the act are sufficient to provide reasonable assurance of the safety and effectiveness of the device. (Response) FDA has determined that class II with a designated special controls guidance document will provide a reasonable assurance of safety and effectiveness for dental amalgam. In reaching this determination, FDA made the findings required by § 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.” § 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. § 860.7(c)(2). The standard for determining whether there is reasonable assurance that a device is safe is described in § 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 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 § 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 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 μg/day for adults (Refs. 3, 22). FDA also recognizes that good dental hygiene practices, such as the use of vacuum pumps and chair-side traps, have greatly reduced the level of mercury to which dental professionals are exposed. Nevertheless, because dental amalgam releases mercury vapor and is associated with a risk of human exposure to this vapor, and because some individuals have a known allergy to mercury, FDA is recommending that the labeling warn that the device contains mercury, contain a precaution that it should be used with proper ventilation, and include a contraindication against use in persons with a known allergy to mercury. (Comment) A few comments stated that dental amalgam fillings contribute to the majority of the mercury body burden in the general population and that urinary mercury concentrations are not measures of mercury body burden, but rather represent a combination of the amount of mercury to which an individual has been exposed and his or her ability to excrete mercury. The comments added that 90 percent of mercury is excreted from the body through the fecal route, and that low urinary mercury concentrations are not an accurate predictor of mercury exposure. Some comments stated that data obtained from autopsies demonstrate that high mercury levels are present in the brain and kidneys, despite dental amalgam mercury exposure levels being below safety limits. A few comments noted that mercury passes through both the umbilical cord and the blood/brain barrier. (Response) FDA recognizes that dental amalgam contributes to the majority of the body burden of mercury for many people not occupationally exposed to mercury (Ref. 22). FDA recognizes that urine and feces are major routes of mercury excretion, but also recognizes that which excretion route predominates is dependent on the mercury species. The “90% mercury excreted by the fecal route” relates to excretion of organic methylmercury, and this high percent is not the case for inorganic forms of mercury, where the urinary route predominates, especially in the case of chronic mercury vapor exposure (Refs. 14, 69, 70). The amount of mercury excreted into feces is not a well-accepted index of exposure to elemental mercury vapor. Further, the correlation of fecal mercury levels, mercury vapor exposure, and adverse health effects has not been reliably established, as has been shown for urinary mercury concentrations. Fecal mercury concentrations might increase during removal of dental amalgams due to swallowing amalgam particles. Fecal levels might also be elevated from dietary exposure to methylmercury, which undergoes extensive enterohepatic recycling between the GI tract and liver biliary excretion system. FDA disagrees with the comment that urinary mercury concentrations are not accurate measures of inorganic mercury, including mercury vapor, exposure. In fact, FDA and other public health agencies, such as ATSDR (Ref. 14), and WHO (Refs. 21, 22), consider urinary mercury concentrations to be the most accurate and widely use [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3AE9-18447. Public record. Not legal advice.