[Federal Register Volume 59, Number 193 (Thursday, October 6, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-24476]


[[Page Unknown]]

[Federal Register: October 6, 1994]


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Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 101 et al.




Iron-Containing Supplements and Drugs; Label Warning Statements and 
Unit-Dose Packaging Requirements; Proposed Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 101, 170, and 310

[Docket Nos. 91P-0186 and 93P-0306]

 
Iron-Containing Supplements and Drugs; Label Warning Statements 
and Unit-Dose Packaging Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA) is proposing 
regulations to require label warning statements for products taken in 
solid oral dosage form to supplement the dietary intake of iron or to 
provide iron for therapeutic purposes. FDA is also proposing 
regulations to require unit-dose packaging\1\ for iron-containing 
products that contain 30 milligrams (mg) or more of iron per dosage 
unit.\2\ FDA is proposing these regulations because of the acute iron 
poisonings, including deaths in children less than 6 years of age, 
attributable to accidental overdoses of iron-containing products. The 
intent of these proposed regulations is to reduce the risk of 
accidental iron poisonings of young children by utilizing FDA's 
authority in conjunction with the existing requirements of the U.S. 
Consumer Product Safety Commission (CPSC) for child-resistant packaging 
for household substances. This proposal responds to three citizen 
petitions (Docket Nos. 91P-0186/CP1, 93P-0306/CP1, and 93-0306/CP2) 
that requested that FDA take action to ensure that products containing 
iron or iron salts do not pose a health hazard to young children and 
infants.

    \1\For the purposes of this document ``unit-dose packaging'' 
means a method of packaging a product into a nonreusable container 
designed to hold a single dosage unit intended for administration 
directly from that container, irrespective of whether the 
recommended dose is one or more than one of these units.
    \2\In this document, the term ``dosage unit'' will be used to 
denote the individual physical units of the iron-containing product 
such as tablets, capsules, caplets, or other physical forms, 
irrespective of whether one or more than one of these physical units 
comprises the recommended dose.
---------------------------------------------------------------------------

DATES: Written comments by December 20, 1994. The agency is proposing 
that any final rule that may be issued based upon this proposal become 
effective 180 days after its publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John N. Hathcock, Center for Food 
Safety and Applied Nutrition (HFS-465), Food and Drug Administration, 
8301 Muirkirk Rd., Laurel, MD 20708, 301-594-6006.

SUPPLEMENTARY INFORMATION:

I. Background

    Iron is an essential nutrient that, in certain circumstances, can 
be toxic. For some women of child-bearing age and for some young 
children, iron from dietary sources alone may be insufficient to meet 
their metabolic iron requirements. Access to products that provide iron 
is useful for these groups to ensure that their iron requirements are 
met. However, when consumed acutely in large quantities by young 
children, iron is toxic and can, in some cases, lead to death.
    Since the mid 1980's, an upsurge in reported accidental pediatric 
ingestion of iron-containing products has occurred (Ref.1). This fact, 
and the many resultant injuries and deaths of children, have created a 
dilemma with respect to how to ensure that iron sources are available 
while still minimizing the risks to children. In response, FDA is 
proposing regulations that require that a warning be placed on labeling 
about the adverse effects of acute, high dose iron ingestion by 
children and that unit-dose packaging be used for certain iron-
containing products. These requirements, if adopted, will apply to 
iron-containing products in addition to the existing requirements of 
CPSC, which provide that child-resistant packaging must be used for 
most iron-containing products available (see section II.B. of this 
document). The agency tentatively finds that the effect of these new 
requirements, in conjunction with those of CPSC, will be to 
significantly reduce the risk of accidental pediatric iron poisoning.
    The types of iron-containing products that have been associated 
with poisonings of young children are those offered in solid oral 
dosage form (e.g., capsules and tablets) as: (1) Children's and adult's 
multi-vitamin/mineral supplements that contain iron or iron salts 
(these products typically provide less than 30 mg of iron per dosage 
unit), (2) products intended for use as iron supplements (these 
products typically contain 30 mg or more of iron per dosage unit), and 
(3) drug products that contain iron or iron salts (these products 
typically contain 30 mg or more of iron per dosage unit). In this 
document, the term ``iron-containing products'' refers to all of these 
types of products.
    The agency is not aware of incidents of poisoning being caused by 
iron-containing products in liquid or powder form. Therefore, these 
products are not subject to this proposal. The agency will consider 
what regulatory action is appropriate to take with regard to iron-
containing products in liquid or powder form if it becomes aware of 
information indicating that these products have caused or can cause 
poisonings in children.
    This document also does not bear in any way on conventional foods 
containing naturally occurring or added iron. Pediatric iron poisoning 
from consumption of iron-containing foods in conventional food form is 
unlikely because of limitations inherent in the large quantity of food 
that would have to be ingested to cause an adverse effect in young 
children. For example, a serving of a highly fortified breakfast cereal 
that contains 100 percent of the recommended daily intake for iron of 
18 mg, would provide only 7 percent of the amount of iron that is 
considered necessary to produce symptoms of iron poisoning in a 10 
kilograms (kg) (22 pounds (lb)) child (i.e., 25 milligrams (mg) per (/) 
kg of iron, which equates to 250 mg total iron for a 10 kg (22 lb) 
child. (See section I.B. of this document.) Moreover, the agency is not 
aware of any pediatric iron poisonings that have resulted from 
ingestion of iron-containing foods in conventional food form.

A. The Iron Requirements of Children and Women of Childbearing Age

    Iron is an essential nutrient because it is a component of blood 
and muscle tissue and because of its role in metabolic reactions. Iron-
containing compounds in the body may be grouped into two categories: 
(1) Those that serve metabolic functions, and (2) those associated with 
iron storage. The compounds in the first category include hemoglobin (a 
component of red blood cells), myoglobin (a muscle protein), and iron-
containing enzymes. They account for approximately 80 percent of body 
iron. Compounds in the second category are involved in the maintenance 
of iron homeostasis and include the storage compounds ferritin and 
hemosiderin.
    When the supply of dietary iron becomes inadequate to meet the 
body's needs, iron is mobilized from iron stores to maintain the 
production of red blood cells and to perform other essential iron-
dependent functions. When body iron stores are low or depleted, as 
often occurs in women of child-bearing age and in very young children, 
a person is vulnerable to adverse effects associated with iron 
deficiency anemia and with a reduction in metabolic and body functions.
    Although the prevalence of iron deficiency in the U.S. population 
is low (Ref. 2), maintenance of adequate iron stores in women of 
childbearing age and in young children is an important public health 
issue. A woman's recommended daily allowance (RDA) for iron during 
pregnancy doubles from 15 to 30 mg/day (Ref. 3). The importance of 
prenatal iron supplementation in preventing depletion of iron stores in 
pregnant women has been shown in several clinical trials (Ref. 4). 
Thus, pregnant women are often counseled to increase their iron intake 
through dietary changes and the use of iron-containing supplements or 
drugs.
    A committee of the National Academy of Sciences (NAS) has 
recommended that all pregnant women should be screened for iron 
deficiency anemia at the first prenatal visit and at least once during 
each subsequent trimester (Ref. 5). The NAS committee recommended, 
however, that iron supplementation should only be given when iron 
status is low or marginal, as indicated by hemoglobin and serum 
ferritin, in comparison with standard values recommended by NAS for the 
specific trimester of pregnancy. When these clinical indicators reveal 
deficient iron status, the NAS committee recommended that the clinician 
prescribe 60 to 120 mg of supplemental iron per day. If iron status is 
marginal, the NAS committee recommended that the clinician prescribe 30 
mg of supplemental iron per day. If iron status is normal, the NAS 
committee recommended that these be no iron supplementation.
    Aside from the iron needs that arise during pregnancy, women of 
child-bearing age have a higher requirement for iron than other adults. 
(The RDA for women of child-bearing age is 15 mg/day because of the 
depletion of iron through menstrual blood loss. It is 10 mg/day for 
adult males and older adult women (Ref. 3).) The difficulty of 
obtaining dietary intakes high enough to replace those losses through 
consumption of a normal diet is responsible for iron deficiency in some 
women of child-bearing age. For these women also, the use of iron-
containing products may be prudent.
    Iron deficiency also affects young children (the RDA for iron for 
children is 10 mg/day), particularly during the rapid growth period 
from 6 months to 4 years of age. Some young children fail to develop 
adequate iron stores to supply the iron needed for their metabolic 
functions during this early growth period. Data from the National 
Health and Nutrition Examination Survey (NHANES II) for children show 
that the prevalence of impaired iron status ranges from an estimated 3 
to 12 percent (Ref. 2). Thus, iron supplementation may also be 
indicated in children whose iron needs are not met through dietary 
intake.

B. Iron Toxicity in Young Children

    Although the minimal toxic and lethal doses for iron have not been 
clearly established (Ref. 6), the severity of iron poisoning when an 
overdose has been ingested is related to the amount of iron absorbed 
into the circulatory system. Experts have stated that ingestion of 25 
mg/kg of iron (250 mg total iron for a 10 kg child) may produce 
symptoms of poisoning, and that ingestion of 60 mg/kg total iron for a 
10 kg child is the minimum intake for the development of significant 
iron poisoning (Refs. 6 and 7). One source recommends emergency room 
evaluation when ingestion of iron exceeds 50 mg/kg (Ref. 6). An acute 
ingestion of more than 250 mg/kg for a 10 kg child is typically 
considered a lethal dose for iron (Ref. 8). However, it has been 
reported that ingestion of 100 to 200 mg/kg for a 10 kg child can be 
fatal (Ref. 9), and that ingestion of as little as 650 mg of iron (65 
mg/kg for a 10 kg child) has resulted in death (Ref. 7). Based upon 
these reported values, acute ingestions of less than 1,000 mg of iron 
appear to be likely to cause nonfatal injuries of varying severity, 
depending on the amount of ingested iron.
    Iron overdose results in both local and systemic effects (Ref 10). 
Toxicity is caused by both a direct corrosive effect on the 
gastrointestinal mucosa and the presence of unbound iron in the 
circulatory system. Locally in the stomach and intestine, ingested iron 
is corrosive and produces death of cells in the mucosa lining the 
gastrointestinal tract, resulting in ulceration and hemorrhage. While 
intact mucosa limits the absorption of iron, eroded mucosa permits 
absorption of relatively huge amounts of iron into the portal 
circulation that goes immediately to the liver, causing damage to liver 
cells. Overload of the liver cells, which normally remove iron from the 
circulation, allows iron to enter the general circulation.
    When the circulating iron exceeds the capacity of certain proteins 
to bind it, free iron reaches other tissues, such as kidneys, lungs, 
heart and blood vessels, and the brain. The resultant death of cells in 
these tissues produces the following wide-spread symptoms and signs of 
iron poisoning: Kidney failure, edema in the lung, hemorrhage, 
hypotension from damage to the heart and blood vessels, coma from 
damage to the brain, and acidosis from release of organic acids.
    Severe iron poisoning is characterized by four clinical stages 
(Refs. 6 and 9):
    (1) Stage one, which may occur within 30 minutes (min) of 
ingestion, is characterized primarily by signs and symptoms of 
hemorrhagic gastroenteritis (i.e., nausea, vomiting, abdominal pain, 
hematemesis (vomiting blood), and bloody diarrhea) that may progress to 
shock, coma, seizures, and death.
    (2) During stage two, which occurs from 2 to 12 hours (hr) after 
ingestion, patients may be without symptoms and may appear to have 
recovered. Some children will recover, but some may progress to stage 
three. The appearance of recovery should not delay evaluation and 
treatment for iron poisoning because successful treatment is difficult 
once the iron is absorbed from the small intestine into the blood.
    (3) During stage three, from 12 to 48 hr after ingestion, there is 
a recurrence of gastrointestinal hemorrhage with severe lethargy or 
coma, and there may be liver and kidney failure and collapse of the 
heart and blood vessels.
    (4) Stage four, 3 to 4 weeks after survivors of poisonings ingested 
the iron, may include gastrointestinal obstruction and cirrhosis of the 
liver.
    In evaluating a child who is thought to have ingested an overdose 
of iron, an abdominal x-ray looking for iron-containing tablets, a 
qualitative color test for iron in the stomach contents, and an 
emergency determination of the concentration of iron in blood plasma 
may be performed.
    If an overdose of iron is indicated, an emetic agent may be 
administered to cause regurgitation of the iron if the patient is fully 
awake and alert. In addition to emesis, catharsis with saline or 
sorbitol may be used to induce gastric emptying. However, neither 
emesis nor catharsis is advised if hemorrhagic gastroenteritis is 
present. Gastric lavage, i.e., washing out of the stomach, with saline 
or sodium bicarbonate or whole bowel irrigation with a balanced 
polyethylene glycol-electrolyte solution by gastric tube have been used 
to remove undissolved tablets (Ref. 11).
    Treatment for an iron overdose frequently includes parenteral 
administration of deferoxamine (also referred to as desferrioxamine), a 
drug which chelates (i.e., binds) iron in the intracellular fluid and 
causes its excretion in urine (Ref. 6). Given that 1 g deferoxamine can 
bind 93 mg of iron, and that, to avoid hypotension, infusion is 
generally recommended at 15 mg/kg/hr, there is a limit to the amount of 
iron deferoxamine can bind. For example, safe administration of 
deferoxamine to a 10 kg child over a 24 hr period is capable of binding 
only 324 mg of iron (Refs. 11 and 12).
    Therefore, if very high levels of iron are absorbed, even prompt 
treatment with deferoxamine or another agent may not prevent a fatal 
outcome if chelation at the maximum safe rate cannot reduce the iron 
burden to levels below those that cause death.
    Speed of diagnosis and therapy are important. With earlier and more 
effective treatment, the mortality rate from iron poisoning has been 
reduced from as high as 45 percent to about 1 percent (Ref. 9).

C. Summary of Information on Pediatric Deaths and Injuries

1. Citizen Petitions
    Data have been submitted to or obtained by FDA on reports of deaths 
attributable to accidental pediatric iron poisoning that were made 
between 1983 and 1993 to the American Association of Poison Control 
Centers and between 1986 and 1993 to CPSC (Table 1). Although these two 
sets of data are not identical, they do have extensive overlap (cases 
included in both databases). They both point to an increase in reported 
fatalities from accidental iron poisonings of children in the early 
1990's.
    The number or rate of fatalities does not represent the totality of 
the health hazard, however. Data obtained by FDA from the American 
Association of Poison Control Centers (AAPCC) show that from 1986 
through 1992 there were nearly 63,000 reports to poison control centers 
involving ingestion of adult iron- containing products, with over 
47,000 of these reports involving children under 6 years of age (Refs. 
14 through 20). Many of these victims required hospitalization, and 
many others required some medical treatment. For example, Table 2 shows 
that over 1,500 of these cases were classified as having ``moderate 
outcomes,'' i.e., the patient had symptoms that, while not life 
threatening, usually required some form of treatment. One hundred 
fifty-nine cases were classified as ``major outcomes,'' i.e., they were 
life threatening or resulted in permanent injury. Except for 1992, 
AAPCC data do not indicate how many of the moderate and major outcomes 
involved children under 6 years of age. However, for 1992, 55 percent 
(17/31) of the major outcomes, and 51 percent (141/278) of the moderate 
outcomes, involved children under 6 years of age.

         Table 1.--Iron Poisoning Deaths for Children Under Six         
------------------------------------------------------------------------
                                                 Number of              
                                                  deaths      Number of 
                                                 reported      deaths   
                     Year                         to CPSC    reported to
                                                from 1986-   AAPCC from 
                                                   1993     1983-1993\1\
------------------------------------------------------------------------
1993..........................................        \2\1            3 
1992..........................................           9            7 
1991..........................................          11           11 
1990..........................................           7            5 
1989..........................................           3            2 
1988..........................................           5            3 
1987..........................................           3            1 
1986..........................................           4            1 
1985..........................................                        1 
1984..........................................                        1 
1983..........................................                       2  
------------------------------------------------------------------------
\1\Data through 1991 were taken from the AAPCC petition. Data for 1992  
  and 1993 were taken from AAPCC annual reports.                        
\2\Data through August 1993 (partial year) were taken from the Attorneys
  General petition.                                                     


   Table 2.--Outcomes of Ingestions of Adult Iron-Containing Products   
          Reported to Poison Control Centers From 1986-1992\1\          
------------------------------------------------------------------------
                                                          Outcomes for  
                                              Total          total      
                                           ingestions    ingestions\3\  
                  Year                       for all  ------------------
                                            ages\2\    Moderate         
                                                                  Major 
------------------------------------------------------------------------
1992.....................................     11,007        278       31
1991.....................................     10,671        276       26
1990.....................................      9,550        229       28
1989.....................................      9,734        194       22
1988.....................................      9,201        245       15
1987.....................................      7,132        153       20
1986.....................................      5,674        144      17 
                                          ------------------------------
      Total..............................     62,969      1,519     159 
------------------------------------------------------------------------
\1\Products included for the 1989-1992 data are iron-containing         
  supplements and drug products and adult multiple vitamin tablets with 
  iron. Products included for the 1986-1988 data are iron-containing    
  supplements and drug products and adult multivitamin type supplements 
  of unspecified dosage form. Some of the products also contained       
  fluoride.                                                             
\2\47,690 of this total involved children under 6 years of age.         
\3\Only the 1992 data report moderate and major outcomes for children   
  under 6 years of age. In 1992, 141 such moderate outcomes and 17 major
  outcomes were reported.                                               

    In addition, AAPCC data show that during the same 7-year period, 
there were over 76,000 reports to poison control centers involving 
ingestion of pediatric iron-containing products with over 69,000 of 
these reports involving children under 6 years of age (Refs. 14 through 
20). Table 3 shows that over 495 of these cases were classified as 
having ``moderate outcomes,'' and 29 cases were classified as ``major 
outcomes.'' Again, except for 1992, AAPCC data do not indicate how many 
of the moderate and major outcomes involved children under 6 years of 
age. However, for 1992, the single major outcome, and 91 percent (52/
57) of the moderate outcomes, involved children under 6 years of age.

  Table 3.--Outcomes of Ingestion of Pediatric Iron-Containing Products 
          Reported to Poison Control Centers From 1986-1992\1\          
------------------------------------------------------------------------
                                                           Outcomes for 
                                       Total      Less        total     
                                    ingestions   than 6   ingestions\2\ 
               Year                   for all    years  ----------------
                                       ages     of age   Moderate       
                                                                   Major
------------------------------------------------------------------------
1992..............................     11,803    10,769       57       1
1991..............................     10,900    10,022       42       2
1990..............................     10,910     9,883       55       4
1989..............................     10,313     9,275       72       1
1988..............................     10,475     9,483      104       1
1987..............................     10,013     9,024       94       5
1986..............................     11,676    10,622       71      15
                                   -------------                        
      Total.......................     76,090    69,078      495     29 
------------------------------------------------------------------------
\1\Products included for the 1989-1992 data are pediatric multiple      
  vitamin tablets with iron. Products included for the 1986-1988 data   
  are pediatric multivitamin type products of unspecified dosage form.  
\2\Only the 1992 data report moderate and major outcomes for children   
  under 6 years of age. In 1992, 52 such moderate outcomes and 1 major  
  outcome were reported.                                                

    Likewise, CPSC reports that, based upon data from its National 
Electronic Injury Surveillance System (NEISS) (NEISS is a probability 
sample of hospital emergency rooms in the United States that is used by 
the CPSC to measure the magnitude of the injury problem associated with 
consumer products and to provide a source for followup investigations 
of selected cases), there was a significant upward trend in the 
estimated number of hospital emergency room-treated iron ingestion 
cases involving children under 5 years of age in the 1980 to 1993 
period. Every annual estimate in the 1980 to 1985 period was smaller 
than every annual estimate in the 1986 to 1993 period. The estimated 
average number of cases annually was 1,240 for the 1980 to 1985 period 
and 3,170 for the 1986 to 1993 period (Ref. 1).
2. CPSC Case Reports
    CPSC considers iron-containing products to be potentially hazardous 
to children and, thus, has taken a number of significant steps designed 
to reduce the risk from these products. As part of its efforts, CPSC 
has collected detailed information on pediatric iron poisoning 
fatalities and has also conducted followup (from NEISS data) 
investigations of incidents of nonfatal pediatric iron ingestion where 
the victim was taken to a hospital emergency room. In order to evaluate 
the available data on specific occurrences of iron poisoning as fully 
as possible, FDA obtained from CPSC the case reports on 37 fatal 
pediatric poisonings (Ref. 21) and on 70 NEISS followup investigations 
of nonfatal pediatric iron ingestions for the years 1986 to 1993 (Ref. 
22). These data are described below and are summarized in Tables 4 and 
5.
    Table 4 summarizes the data obtained from CPSC on 37 iron poisoning 
fatalities of young children since 1986. Among these fatalities, the 
average age of the victim was 16.8 months. In 25 of these 37 deaths, 
the iron potency of the implicated product was reported. These 25 
products contained, on average, 63 mg iron per dosage unit. The lowest 
reported potency of an iron-containing product involved in these 
pediatric deaths was 40 mg iron per dosage unit. The potency of the 
iron-containing product involved in the 12 other deaths was not 
reported.
    Table 4 shows that, in 21 of the 37 fatalities, information on the 
number of tablets or capsules consumed by the victim was reported. 
Among these 21 reports, the average number of iron tablets or capsules 
consumed by the victim was 39.
    Table 4 also shows that in 56 percent of these 37 pediatric deaths 
(21/37), the iron-containing product visually appeared to be packaged 
in child-resistant packaging (CRP), and more specifically, in 
containers with apparently child-resistant closures (CRC). In 16 
percent of the deaths (6/37), the iron-containing supplement was not 
packaged in CRP. Among the remaining deaths (10/37), the type of 
packaging was not reported.

                                     Table 4.--Pediatric Deaths From Iron Exposure Reported to CPSC From 1986-1993                                      
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Case Report               Year                  Age\1\              Packaging         Number of tablets           Rx\2\                Potency      
--------------------------------------------------------------------------------------------------------------------------------------------------------
1...................  1986                   15..................  CRC\3\,\4\..........  15..................  Yes.................  65 mg\5\           
2...................  1986                   14..................  No Lid..............  NR..................  Yes.................  70 mg              
3...................  1986                   24..................  NR\6\...............  NR..................  NR..................  NR                 
4...................  1987                   11..................  CRC\7\..............  70..................  Yes.................  65 mg              
5...................  1987                   21..................  Non-CRC.............  5...................  NR..................  40 mg              
6...................  1988                   16..................  NR..................  NR..................  NR..................  60 mg              
7...................  1988                   17..................  Non-CRC.............  10-30...............  Yes.................  NR                 
8...................  1988                   18..................  CRC\8\,\9\..........  NR..................  Yes.................  65 mg              
9...................  1988                   19..................  CRC\9\..............  14.......  Yes.................  65 mg              
10..................  1988                   18..................  CRC\9\..............  NR..................  Yes.................  NR                 
11..................  1989                   18..................  CRC\4\..............  20..................  NO..................  65 mg              
12..................  1989                   9...................  CRC\10\.............  98..................  NR..................  65 mg              
13..................  1990                   10..................  Non-CRC.............  40..................  Yes.................  65 mg              
14..................  1990                   11..................  Non-CRC.............  18..................  Yes.................  65 mg              
15..................  1990                   12..................  CRC\10\.............  NR..................  Yes.................  NR                 
16..................  1990                   15..................  CRC\9\..............  30-35...............  Yes.................  65 mg              
17..................  1990                   16..................  NR..................  NR..................  Yes.................  NR                 
18..................  1990                   36..................  CRC\9\..............  30..................  Yes.................  NR                 
19..................  1991                   9...................  CRC\4\..............  15-35...............  NR..................  65 mg              
20..................  1991                   13..................  CRC\7\..............  30-40...............  Yes.................  NR                 
21..................  1991                   14..................  Non-CRC.............  60-80...............  Yes.................  65 mg              
22..................  1991                   15..................  CRC\10\.............  30..................  Yes.................  65 mg              
23..................  1991                   16..................  NR..................  NR..................  NR..................  NR                 
24..................  1991                   18..................  NR..................  NR..................  NR..................  65 mg              
25..................  1991                   21..................  CRC\4\..............  90..................  No..................  65 mg              
26..................  1991                   24..................  NR..................  NR..................  NR..................  NR                 
27..................  1991                   16..................  CRC\11\.............  NR..................  No..................  65 mg              
28..................  1991                   36..................  CRC\11\.............  20-40...............  Yes.................  65 mg              
29..................  1992                   11..................  NR..................  40..................  NR..................  65 mg              
30..................  1992                   12..................  CRC\4\..............  NR..................  NR..................  NR                 
31..................  1992                   15..................  NR..................  50..................  Yes.................  60 mg              
32..................  1992                   16..................  CRC\9\..............  40..................  Yes.................  60 mg              
33..................  1992                   20..................  CRC\7\..............  NR..................  Yes.................  65 mg              
34..................  1992                   16..................  NR..................  NR..................  Yes.................  60 mg              
35..................  1992                   18..................  CRC\11\.............  35-40...............  Yes.................  NR                 
36..................  1992                   17..................  CRC\10\.............  NR..................  Yes.................  65 mg              
37..................  1993                   14..................  Non-CRC.............  NR..................  Yes.................  NR                 
                                             Avg=................  Total:..............  Avg=................  Total:..............  Avg=63             
                                             16.8................  CRC=21..............  39..................  Yes=................  Range=             
                                             Range=..............  Other=..............  Range=..............  24..................  40-70              
                                             9-36................  16..................  5-98................  No=3................  NR=12              
                                                                                                               NR=.................                     
                                                                                                               10..................                     
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Age in months                                                                                                                                        
\2\Even though these products were obtained by prescription (Rx), some information suggests that they were not drug products, but rather, they were     
  dietary supplements dispensed by pharmacists for third party reimbursement purposes.                                                                  
\3\Child-resistant closure.                                                                                                                             
\4\No information in case report on who opened the CRC; or the CRC was not involved in the accidental poisoning. Total=5.                               
\5\All potency levels have been converted from weight of the iron salt to iron contents. Potency is expressed as mg iron per dosage unit.               
\6\No Reported (NR) or stated as unknown in the case report.                                                                                            
\7\Opened by sibling or another child (either actually or possibly). Total=3.                                                                           
\8\Container was dual use--conventional and child resistant.                                                                                            
\9\Opened by victim (actually or possibly). Total=6.                                                                                                    
\10\Left opened by the mother, or not closed properly. Total=4.                                                                                         
\11\CRC defective. Total=3.                                                                                                                             

    Among the 21 reported pediatric poisoning deaths that involved 
iron-containing products packaged in CRP, Table 4 shows that 29 percent 
(6/21) of these deaths resulted from iron- containing products whose 
child-resistant package was reportedly opened (actually or possibly) by 
the victim. In 14 percent (3/21) of these deaths, the CRP was reported 
to have been opened (actually or possibly) by another child. An adult 
was reported to have opened the CRP in 19 percent (4/21) of the 
pediatric iron poisoning deaths. Among the remaining reports of 
pediatric iron deaths in which the iron-containing product was packaged 
in child-resistant containers, the means of opening the container were 
not identified in 24 percent (5/21). The CRP was reported to be 
defective in 14 percent (3/21) of these deaths.
    Table 5 shows the total amount of iron ingested in the fatal 
poisoning incidents in which both the amount of tablets ingested and 
the iron potency of these tablets were reported. Among 17 fatalities, 
in all but 1 case, the iron potency of the tablets was 60 to 65 mg, and 
with 1 exception (the same reported case), the calculated amount of 
iron ingested was at least 900 mg.
    The 70 case reports of NEISS followup investigations of nonfatal 
pediatric iron ingestions involved 80 children. The 80 children were 
either treated in the emergency room and released or hospitalized for a 
period of time. Table 6 summarizes these case reports. The average age 
of the children was about 31 months. 

     Table 5.--Total Amount of Iron Ingested in Pediatric Deaths\1\     
------------------------------------------------------------------------
                                                  Potency,              
                                          Number  mg iron/      Total   
              Case report                   of     dosage    ingestion, 
                                         tablets    unit         mg     
------------------------------------------------------------------------
1......................................       15        65           975
4......................................       70        65         4,550
5......................................        5        40           200
9......................................  30 Fe...                     
Reformulation.......  X         X..................  X                  
                                                     No sweet           
                                                     Outer coating      
                                                     On products        
                                                     30 Fe   
Education...........  X         ...................  X                  
------------------------------------------------------------------------
\1\Included in petition to CPSC.                                        

    a. The AAPCC petition. The AAPCC petition was submitted on April 
30, 1991, and was supplemented by an additional submission by AAPCC on 
February 28, 1992. It was based upon pediatric poisoning data collected 
by the AAPCC National Data Collection System from 1983 through 1991. 
The petition stated that iron products are the leading cause of 
poisoning deaths in children under age six. A letter was submitted to 
the agency in support of the AAPCC petition by the American Academy of 
Pediatrics on February 17, 1993. The AAPCC petition requested that the 
agency take the following actions concerning the labeling and 
formulation of iron-containing products:
    (1) Labeling. The petition requested that FDA declare labels on 
drug products and food supplements containing 30 mg or more of iron per 
dosage unit as misleading if the label does not clearly state that 
accidental pediatric ingestion of these products can be lethal.
    (2) Formulation. The petition requested that the agency urge the 
industry to voluntarily reformulate iron-containing products containing 
30 mg or more of iron per dosage unit in less attractive dosage units, 
specifically avoiding resemblance to popular candies.
    The AAPCC petition also requested that the agency initiate an 
educational effort to alert the public and health professionals to the 
dangers of accidental pediatric ingestion of iron-containing products. 
The AAPCC stated that efforts need to be directed especially to 
parents, babysitters, daycare providers, and other consumers; to 
pediatricians, urging these health professionals to target parents at 
the 6-month visit; to obstetricians, urging these health professionals 
to educate mothers at the final postpartum visit; to other health 
professionals who prescribe iron-containing products; and to 
pharmacists who dispense them.
    b. The AG petition. The AG petition, submitted on August 16, 1993, 
cited data on injuries and deaths attributable to accidental iron 
poisoning in children reported to the AAPCC National Data Collection 
System and reported to CPSC through 1992. It requested that the agency 
take the following actions concerning the labeling, formulation, and 
packaging of iron- containing products:
    (1) Labeling. For iron-containing products containing 30 mg iron or 
more per tablet or capsule, the petition requested that the agency 
promulgate a regulation requiring that the label bear a conspicuous 
boxed warning that states:

    Warning--Keep away from children. Contains iron which can be 
harmful or fatal if swallowed by a child.

The petition recommended that this warning be in bold face type and in 
a color that contrasts with the background and with other printed 
material on the label and labeling.
    The petition also recommended that immediately following the above 
boxed warning, the following information appear:

    Acute overdosage of iron may cause nausea and vomiting and, in 
severe cases, cardiovascular collapse and death.

    For iron-containing products containing less than 30 mg iron per 
tablet or capsule, the petition recommended that the agency promulgate 
a regulation requiring that the label contain a conspicuous boxed 
warning that states:

    Warning--Keep away from children. Contains iron which can be 
harmful or fatal in large doses if swallowed by a child.

The petition recommended that this warning also be in boldface type and 
in a color that contrasts with the background and with other printed 
material on the label and labeling.
    (2) Packaging--The petition recommended that FDA require that iron-
containing products containing 30 mg or more of iron per tablet or 
capsule be packaged in child-resistant individual blister packs.
    (3) Formulation--The petition recommended that FDA prohibit the 
manufacture and sale of adult formulations of iron-containing products 
that look like candy or contain a sweet outer coating.

c. Nonprescription Drug Manufacturers Association petition.

    The Nonprescription Drug Manufacturers Association (NDMA), a trade 
association that represents U.S. manufacturers and distributors of 
nonprescription medicines and vitamin and mineral products, submitted a 
citizen petition to FDA on October 15, 1993, in response to the AG 
petition. The NDMA petition requested that FDA adopt into regulation 
the newly initiated voluntary NDMA program on the labeling, packaging, 
and formulation of iron-containing products. NDMA stated that it 
submitted a similar petition to CPSC requesting that CPSC adopt into 
regulation the elements of the voluntary industry program that are 
under the regulatory jurisdiction of CPSC. The petition also requested 
that FDA deny the other citizen petitions submitted on iron-containing 
products and pediatric poisoning insofar as they would contradict, add 
to, or subtract from the NDMA program.
    The NDMA petition requested that FDA adopt the following labeling, 
formulation, and packaging provisions:
    (1) Labeling. Iron-containing products must bear on the primary 
container (or box for blister packaging, glassine envelope, etc.), 
conspicuously, prominently, and clearly distinguished from other 
labeling by type, color, or contrast, the following warning statement:

    Warning: Close tightly and keep out of reach of children. 
Contains iron, which can be harmful or fatal to children in large 
doses. In case of accidental overdose, seek professional assistance 
or contact a Poison Control Center immediately.

The petition stated that in circumstances in which the packaging did 
not involve a reclosable CRP element (e.g., cap to a bottle), the term 
``close tightly'' would not need to appear in the warning statement.
    (2) Packaging. The NDMA specifically requested that FDA deny the 
request made by the AG petition to require that iron- containing 
products containing 30 mg or more of iron per tablet be packaged in 
child-resistant individual blister packs. In support of this request, 
NDMA pointed out that its voluntary program calls for the packaging of 
all iron-containing products with 30 mg or more iron per dose in 
complying CRP (i.e., there will be no CRP-exempt sizes for this type of 
product). (See discussion on CRP requirements of CPSC in section II.B. 
of this document.) NDMA noted that its voluntary program is being 
carried out in conjunction with a national consumer education campaign 
that it launched with CPSC on September 27, 1993, in conjunction with 
CPSC's Conference on Pediatric Iron Poisonings and Fatalities, which 
was held on September 28, 1993, in Washington, DC.
    (3) Formulation. The NDMA stated that iron-containing products with 
greater than or equal to 30 mg iron per solid dosage form will not be 
formulated with sweet outer coatings.
2. The Consumer Product Safety Commission Conference
    CPSC held this conference because of the increase in iron 
poisonings of children. The objective of the conference was to provide 
a forum for health care professionals and representatives of government 
and industry to identify solutions to this problem. The conference 
included invited speakers from CPSC, AAPCC, Georgetown University, FDA, 
NDMA, the National Nutritional Foods Association (NNFA), and the Office 
of the New York State Attorney General. This conference highlighted the 
seriousness of the pediatric iron poisoning problem and the steps that 
were being taken to address the problem.
    Factors that may have contributed to the increased incidence of 
pediatric iron poisonings were discussed, including the requirement by 
many women for iron supplementation during pregnancy; the use of iron-
containing products in homes where small children are present; the 
ability of older siblings of potential victims to open CRP; the 
misconception that vitamin and mineral products are inherently safe; 
improper use or failure to properly close child-resistant closures; and 
the formulation of some iron-containing products to appear like candy, 
potentially explaining why some children consumed large quantities of 
tablets (30 to 100 tablets).
    CPSC described the regulations that it issued in 1978 under the 
Poison Prevention Packaging Act, which require CRP on most drugs and 
food supplements with more than 250 mg of iron per container (see 
section II.B. of this document). CPSC noted that its Office of 
Compliance and Enforcement recently discovered that several 
manufacturers of iron-containing products were not using CRP, and that 
some of these manufacturers had voluntarily agreed to recall these 
products.
    At this conference, FDA explained that most iron-containing 
products are regulated as dietary supplements under the food provisions 
of the Federal Food, Drug, and Cosmetic Act (the act). FDA noted that, 
although there are currently no specific regulations for iron-
containing supplements, the general food safety and food labeling 
provisions of the act require that all foods, including iron-containing 
supplements, be safe under their intended conditions of use, and that 
their labeling be truthful and nonmisleading. FDA also noted that iron-
containing products that are regulated as drugs under the drug 
provisions of the act must be approved before marketing as safe and 
effective for their intended conditions of use and are subject to 
labeling and good manufacturing practice requirements.
    The industry's voluntary efforts in response to the iron poisoning 
problem were described by representatives of NDMA and NNFA. NDMA 
described its newly initiated voluntary program of packaging, labeling, 
and formulation changes which it had petitioned FDA to adopt into 
regulation. NDMA also described the newly launched joint consumer 
education campaign that it had developed in cooperation with CPSC to 
inform adults how to protect children from accidental iron poisoning. 
(See section IV.B. of this document.)
    NNFA stated that its members were adopting a voluntary program 
similar to NDMA's, with the added provision that iron will be limited 
to a maximum of 30 mg per dosage unit and 30 mg per recommended dose.
    In an open discussion of possible solutions, several ways to 
address the problem of pediatric iron poisoning were suggested. These 
suggestions included:
    (1) Labeling iron-containing products with statements warning that 
accidental ingestion by children can be lethal.
    (2) Packaging changes for iron-containing products with 30 mg or 
more iron per dosage unit, including packaging these products in child-
resistant unit-dose (e.g., blister) packages and not offering such 
products in packaging that is not child- resistant (no exempt sizes).
    (3) Reformulating iron-containing products that resemble candy and 
that have a sweet outer coating to discourage consumption of large 
amounts by small children.
    (4) Requiring prescription status for iron products, reducing the 
number of units per package, and closer monitoring of the iron status 
of pregnant women to determine whether iron supplementation is really 
needed.
    (5) Multi-ethnic educational efforts to increase public awareness 
of the dangers associated with iron and patient counseling by 
obstetricians, gynecologists, and pharmacists, because many poisonings 
involve iron-containing drug products.
    Several participants at the conference commended the trade 
associations for their voluntary programs. However, some participants 
urged that child-resistant unit-dose blister packaging, an element not 
included in the voluntary industry programs, be implemented as a 
significant measure to reduce the incidence of iron poisonings. The 
participants in the conference called upon industry, government, and 
the healthcare community to undertake efforts, including cooperative 
efforts, to address this problem.

E. The Scope and Purpose of this Document

    The purpose of this document is to: (1) Propose requirements 
designed to reduce the risk of pediatric poisonings from the accidental 
ingestion of iron-containing products, (2) solicit additional 
information concerning the issue, raised in the petitions, of 
reformulating iron-containing products to avoid the resemblance to 
candy and to avoid use of a sweet outer coating, and (3) describe the 
efforts that FDA intends to undertake to respond to the need for public 
education concerning iron poisonings, reinforcing the NDMA/CPSC 
education campaign.
    As stated above, the agency believes that the new requirements that 
it is proposing, in conjunction with CPSC's existing requirements for 
CRP for iron-containing products (see section II.B. of this document), 
will significantly reduce the risk of accidental pediatric iron 
poisoning. FDA and CPSC have worked together closely in coordinating 
their respective efforts toward this goal, and the two agencies intend 
to continue to work in close cooperation.

II. Regulation of Iron-Containing Products

A. Regulation by FDA

1. Types of Iron-Containing Products Addressed in this Proposal
    This proposal addresses iron-containing products available as 
dietary supplements and as prescription drug products.
    FDA defined ``dietary supplement'' as a food, not in conventional 
food form, that supplies a component to supplement the diet by 
increasing the total dietary intake of that component (59 FR 425, 
January 4, 1994).
    Section 201(f) of the act (21 U.S.C. 321(f)) defines ``food'' as: 
(1) Articles used for food or drink for man or other animals; (2) 
chewing gum, and (3) articles used for components of any such article. 
In Nutrilab Inc. v. Schweiker, 713 F.2d 335, 338 (7th Cir. 1983), the 
court noted that taste, aroma, or nutritive value were the primary 
reasons why people consume food. The Nutrilab court said that in 
section 201(f)(1) of the act, the statutory definition of ``food'' 
includes the common sense definition of food: ``When the statue defines 
`food' as `articles used for food, it means that the statutory 
definition of food' includes articles used by people in the ordinary 
way most people use food--primarily for taste, aroma, or nutritive 
value.'' Other courts have followed suit. (See United States v. 
Undetermined Quantities of Cal-Ban 3000, 776 F. Supp. 249, 254-255 
(E.D.N.C.1991); American Health Products Co. v. Hayes, 574 F. Supp. 
1498, 1508-1509 (S.D.N.Y. 1983), aff'd 744 F.2d 912 (2d Cir. 1984).)
    Types of iron-containing products that meet the definition of a 
dietary supplement and are regulated as foods include products intended 
for use primarily to supplement the dietary intake of iron (iron 
supplements) and multi-vitamin/mineral supplements that contain iron. 
Products intended for use as iron supplements generally contain 30 mg 
or more or iron per dosage unit, while multi-vitamin/mineral 
supplements generally contain 18 mg or less of iron per dosage unit.
    Under section 201(g)(1) of the act, drugs are defined as:

    (A) Articles recognized in the official United States 
Pharmacopeia, official Homeopathic Pharmacopeia of the United 
States, or official National Formulary, or any supplement to any of 
them; and (B) articles intended for use in the diagnosis, cure, 
mitigation, treatment, or prevention of disease in man or other 
animals; and (C) articles (other than food) intended to affect the 
structure or any function of the body of man or other animals; and 
(D) articles intended for use as a component of any articles 
specified in clause (A), (B), or (C).

    Iron-containing products that are regulated as prescription drugs 
include iron preparations that also contain folic acid and that are 
prescribed to meet requirements during pregnancy. These products are 
regulated as drugs because of the amount of folic acid that they 
contain. These products generally contain 30 mg or more of iron per 
dosage unit.
    Thus, how an iron-containing product is regulated turns on its 
intended use.
2. Legal Authority for FDA Regulation of Iron-Containing Products
    a. Safety of iron and iron salts added to dietary supplements. The 
act is intended to ensure that all food, including dietary supplements, 
is safe. The act does so, in part, by stipulating that no substances 
may be added to food unless they are safe. FDA has defined ``safe'' as 
meaning there is a reasonable certainty that no harm will result from 
the use of an ingredient in food (Sec. 170.3(i)(21 CFR 170.3(i)). The 
determination as to whether there is a ``reasonable certainty of no 
harm'' can be made in a number of ways. The two most common are the 
existence of general recognition among qualified experts that the 
substance will be safe for its intended use (GRAS) (see Sec. 170.3) or 
a determination by FDA that the use of the substance is safe (see 
sections 201(s), 402(a)(2)(C), and 409 of the act (21 U.S.C. 
342(a)(2)(C) and 348)).
    Under section 201(s) of the act, for a substance to be GRAS, 
general recognition of its safety must exist among experts qualified by 
scientific training and experience to evaluate the safety of substances 
directly or indirectly added to food. The experts' conclusion as to the 
safety of the substance for its intended use may be based on either: 
(1) Scientific procedures, that is, published scientific evidence that 
provides the quantity and quality of scientific evidence that would 
justify listing the use of the substance as a food additive; or (2) in 
the case of a substance used in food prior to January 1, 1958, evidence 
derived from common use of the substance in food.
    Under section 409(c)(1)(A) of the act, the agency is authorized to 
prescribe the conditions of safe use of the substance, including, but 
not limited to: ``* * * specifications as to the particular food or 
classes of food in or on which such additive may be used, the maximum 
quantity which may be used or permitted to remain in or on such food, 
the manner in which such additive may be added to or used in or on such 
food, and any directions or other labeling or packaging requirements 
for such additive deemed necessary by [the Secretary of Health and 
Human Services] to assure the safety of such use.''
    Section 402(a)(1) of the act also provides authority to take action 
to ensure that food is not harmful. It states:

    A food shall be deemed to be adulterated--(a)(1) If it bears or 
contains any poisonous or deleterious substance which may render it 
injurious to health; but in case the substance is not an added 
substance such food shall not be considered adulterated under this 
clause if the quantity of such substance in such food does not 
ordinarily render it injurious to health.

    Using its authority under these sections of the act, FDA has 
reviewed the safety of various iron salts that are used in food. FDA 
listed reduced iron, ferrous gluconate, ferrous lactate, ferrous 
sulfate, ferric phosphate, ferric pyrophosphate, and ferric sodium 
pyrophosphate as GRAS nutrients in a regulation published in the 
Federal Register of November 20, 1959 (24 FR 9368). Subsequently, FDA 
listed iron and these compounds as GRAS ``nutrients and/or dietary 
supplements'' in a regulation published in the Federal Register of 
January 31, 1961 (26 FR 938). In addition, the ferrous salt of fumaric 
acid (Sec. 172.350 (21 CFR 172.350)) (originally promulgated as 21 CFR 
121.1130 (29 FR 559, January 23, 1964) and iron-choline citrate complex 
(Sec. 172.350 (21 CFR 172.370)) (originally promulgated as 21 CFR 
121.247 (28 FR 4509, May 4, 1963)) have been listed by the agency as 
food additives for use in foods for special dietary use.
    In a final rule published in the Federal Register of September 5, 
1980 (45 FR 58837), the agency divided the ``nutrients and/or dietary 
supplements'' category into separate listings for ingredients whose 
intended use was as a dietary supplement (part 182 (21 CFR part 182), 
subpart F) and for ingredients whose intended use was as a nutrient 
supplement in foods in conventional food form (part 182, subpart I). 
For example, reduced iron is listed as GRAS in Sec. 182.5375 for use as 
a dietary supplement ingredient and in Sec. 182.8375 for use in food in 
conventional form as a nutrient. Similarly, ferric phosphate 
(Sec. 182.5301), ferric pyrophosphate (Sec. 182.5304), ferric sodium 
pyrophosphate (Sec. 182.5306), ferrous gluconate (Sec. 182.5308), 
ferrous lactate (Sec. 182.5311), and ferrous sulfate (Sec. 182.5315) 
are listed as GRAS for use as dietary supplement ingredients and are 
listed in Sec. 182.8301, 182.8304, 182.8308, 182.8311, and 182.8315, 
respectively, as GRAS for use as nutrients in food in conventional food 
form.
    In a regulation published on May 12, 1988 (53 FR 16862), the agency 
affirmed that elemental iron (21 CFR 184.1375), ferrous ascorbate (21 
CFR 184.1307a), ferrous carbonate (21 CFR 184.1307b), ferrous citrate 
(21 CFR 184.1307c), ferrous fumarate (21 CFR 184.1307d), ferrous 
gluconate (21 CFR 184.1308), ferrous lactate (21 CFR 184.1311), ferrous 
sulfate (21 CFR 184.1315), ferric ammonium citrate (21 CFR 184.1296), 
ferric citrate (21 CFR 184.1298), ferric phosphate (21 CFR 184.1301), 
and ferric pyrophosphate (21 CFR 184.1304) are GRAS for use as nutrient 
supplements, as that use is defined in 21 CFR 170.3(o)(20), and removed 
their listing from part 182, subpart I. However, in the final rule, FDA 
did not affirm that these iron salts are GRAS for use in dietary 
supplements (i.e., in forms such as capsules, tablets, or liquids) 
because there were insufficient data on their consumption as dietary 
supplement ingredients. However, these ingredients continue to be 
listed as GRAS for use in dietary supplements under part 182, subpart 
F.
    Even though FDA has affirmed as GRAS the use of numerous iron salts 
in foods, there are differences in the toxicity of these various salts.
    b. Safety and efficacy of iron-containing drugs. The act also 
authorizes FDA to regulate the marketing of any products to help ensure 
that the products are safe and effective for their intended uses. ``New 
drugs'' may not be introduced into interstate commerce unless they are 
the subject of approved new drug applications (NDA's)(25 U.S.C. 
355(a)). The act defines a ``new drug'' as: (1) Any drug (except a new 
animal drug or an animal feed bearing or containing a new animal drug) 
the composition of which is such that such drug is not generally 
recognized among experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, as safe 
and effective for use under the conditions prescribed, recommended, or 
suggested in the labeling thereof; or (2) any drug the composition of 
which is such that such drug, as a result of investigations to 
determine its safety and effectiveness for use under such conditions, 
has become so recognized, but which has not, otherwise than in such 
investigations, been used to a material extent or for a material time 
under such conditions (21 U.S.C. 321(b)). In order to be approved, an 
NDA must contain adequate data to demonstrate that the drug product is 
safe and effective for use under the conditions prescribed, 
recommended, or suggested in the labeling (21 U.S.C. 355(d)). In 
addition, for NDA approval, the product must be manufactured using 
current good manufacturing practice and the product labeling must not 
be false or misleading (21 U.S.C. 355(d)).
    Section 411 of the act (21 U.S.C. 350) provides that the Secretary 
of Health and Human Services may not classify any natural or synthetic 
vitamin or mineral (or combination thereof) as a drug solely because it 
exceeds the level of potency which the Secretary determines is 
nutritionally rational or useful except in the case of a vitamin, 
mineral, other ingredient of food, or food, which is represented for 
use by individuals in the treatment or management of specific diseases 
or disorders, by children (individuals under the age of 12 years), or 
by pregnant or lactating women.
    Most of the iron-containing products that FDA regulates are 
considered dietary supplements. The iron-containing products that FDA 
currently regulates as drug products are generally prescription 
products and are so designated, in most cases, because they contain an 
amount of folic acid that exceeds the amount in which folic acid may be 
used as a food additive (see 21 CFR 172.345).
    FDA currently has no packaging or labeling requirements 
specifically for iron-containing drug products. As prescription drug 
products, these iron-containing products must comply with the labeling 
requirements of section 503(b)(2) of the act (21 U.S.C. 353(b)(2)) and 
21 CFR part 201, as well as other applicable provisions.

B. CPSC Regulations

    CPSC, under authority of the Poison Prevention Packaging Act of 
1970 (PPPA) (15 U.S.C 1471-1475), regulates the packaging of household 
substances, including food, drugs, and cosmetics, as these terms are 
defined under the PPPA. Under this authority, CPSC has promulgated 
regulations establishing special packaging\1\ standards for several 
household substances, including noninjectable animal and human iron-
containing drugs (16 CFR 1700.14(a)(12)) and dietary supplements (16 
CFR 1700.14(a)(13)) containing a total amount of iron in a single 
package\2\ equivalent to 250 mg or more per container.
---------------------------------------------------------------------------

    \1\``Special packaging means packaging that is designed or 
constructed to be significantly difficult for children under five 
years of age to open or obtain a toxic or harmful amount of the 
substance contained therein within a reasonable time and not 
difficult for normal adults to use properly, but does not mean 
packaging which all such children cannot open or obtain a toxic or 
harmful amount within a reasonable time.'' 16 CFR 1700.1(b)(4).
    \2\``Package means the immediate container or wrapping in which 
any household substance is contained for consumption, use or storage 
by individuals in or about the household and, for purposes of 
section 4(a)(2) of the act, also means any outer container or 
wrapping used in the retail display of any such substance to 
consumers * * *.'' 16 CFR 1700.1(b)(3).
---------------------------------------------------------------------------

    For nonprescription covered products, the PPPA permits one type of 
package for each product to be sold without special packaging if all 
other package types of the product comply with the requirements. 
However, exempt packages must bear a conspicuous label stating: ``This 
package for households without young children.'' CPSC may, by 
regulation, prescribe a substitute statement to the same effect for 
packaging too small to accommodate this statement.
    In the case of prescription drugs, the PPPA allows for an exemption 
to such packaging requirements only when directed in the prescription 
or when requested by the purchaser.
    CPSC provides for testing for special packaging in 16 CFR 1700.20. 
This regulation establishes test protocols to evaluate child-resistant 
effectiveness and adult accessibility to such packaging. Recently, CPSC 
proposed to amend 16 CFR 1700.20 to establish new test protocols under 
which CRP is evaluated (55 FR 40856, October 5, 1990, and 59 FR 13264, 
March 21, 1994).
    In establishing these regulations, CPSC considered the degree and 
nature of the hazard to children from accidental acute overdose of 
dietary supplements and drugs containing iron. It found that special 
packaging is required to protect children from serious injury from 
ingesting iron-containing drugs and dietary supplements. This finding 
was based on: (1) Data from FDA's National Clearing House for Poison 
Control Centers (no longer in operation) and NEISS, which showed that 
products containing iron are frequently ingested by children under the 
age of 5 years; (2) published human experience data, symptomatology 
associated with many of the National Clearinghouse for Poison Control 
Centers ingestion reports, and data from death certificates, which 
showed that the accidental ingestion of 250 mg or more of iron has 
caused death or serious illness; and (3) the fact that iron-containing 
drugs and dietary supplements are normally stored in their original 
containers, and that many accidental ingestions of these products 
result from children gaining access to the contents of the original 
container (43 FR 17335, April 21, 1978).

III. Proposed Regulation

A. Labeling

1. Review of Labeling Issues in Citizen Petitions
    As noted in section I.D.1. of this document, the AG and NDMA 
petitions agreed that iron-containing products should bear label 
warning statements. However, these petitions did not agree on what the 
warning should state, or on how it should appear on the label.
    In requesting the labeling provisions described in section I.D.1. 
of this document, the AG petition stated that the hazard presented by 
iron-containing products is the result, in part, of the perception that 
they are nontoxic household products. Thus, according to this petition, 
they are likely to be left within easy reach of children and not kept 
properly secured. The petition also noted that these products are 
extremely attractive to children because of their typical candy-like 
appearance and sweet outer coating and pointed to case reports that 
illustrate how children ingest iron tablets in large quantities (see 
Table 4).
    The AG petition stated that the recent increase in iron poisoning 
deaths among children might reflect an increase in the extension of 
primary health care, especially prenatal care. It noted: ``While more 
doctors are prescribing prenatal iron supplementation to more women, 
there has been no concomitant increase in warnings regarding their 
potentially lethal effects.''
    The AG petition also noted that, while more women were using iron-
containing products, the labeling of these products does not reflect 
the dangers inherent in their misuse:

    While labeling for a few multi-vitamins containing iron bears 
the statement that iron can be harmful in large doses, most iron 
supplements bear only the non-specific phrase, ``Keep out of reach 
of children.'' Few, if any, packages of iron supplements contain the 
word ``WARNING'' or ``CAUTION,'' words universally accepted as 
denoting danger, to alert the user to the dangers of iron overdose. 
Further, the meager statements that do exist are, for the most part, 
printed in the same color and type size as other material on the 
label and therefore fail to catch anyone's attention. The statements 
are often obscured within other small print on the labeling and are 
neither prominent nor specific enough to reach parents with a 
warning about these pills' potential fatal effect on children. 
Consumers who have no knowledge of iron's hazards before purchasing 
iron supplements will not gain that knowledge by purchasing the 
product and examining the label.

    The AG petition presented data showing that many iron-containing 
products commonly available do not carry any label information 
conveying the need to keep the product out of the reach of children or 
conveying any message specific to iron poisoning. A summary, which was 
included as part of the AG petition, of the label information found on 
25 commonly available iron-containing products revealed that 10 of the 
25 did not include information on the label that the product should be 
kept away from children, and that 17 did not contain information 
stating that iron could be harmful. Six of the products had no 
cautionary information at all, and none of the products that did have 
cautionary information used the terms ``WARNING'' or ``CAUTION,'' to 
accompany the statements on the label.
    NDMA, in its petition, stated that its proposed warning label was 
more appropriate than that proposed in the AG petition because its 
warning goes beyond awareness in its focus and extends its message to 
include information that is preventive in nature, i.e., ``Close 
tightly,'' and treatment oriented, i.e., ``In case of accidental 
overdose seek professional assistance immediately.''
    NDMA also argued for allowing for flexibility in the manner in 
which the warning statement is to be applied to the label. The petition 
stated:

    It has been the experience of NDMA members in implementing the 
Association's Label Readability Guidelines that such factors as 
contrast, color, type size, substrate, paragraphing, etc. are inter-
related in a complex way on labeling, such that goal- oriented 
flexibility is perhaps the most important principle in assuring 
prominence to special label language. That is to say, specifying a 
box, when boxed labeling may already be stipulated under NLEA 
regulations, is not necessarily as good a way to ensure prominence 
to label language as is a more flexible approach whose goal is to 
ensure that the language is conspicuous, prominent and clearly 
distinguishable from other labeling.

2. Agency Response
    FDA considered the following questions in evaluating and responding 
to the labeling issues raised in the citizen petitions: (1) Should 
label warning statements that alert users to the potential dangers that 
iron-containing products pose to young children be required on these 
products? (2) If so, what legal authority does the agency have to 
require such statements on food and drug products? (3) What should the 
warning be required to state? and (4) How should the warning appear on 
the label?
    a. Should label warning statements be required for iron-containing 
products? Based on the data in the AAPCC and AG petitions and in the 
CPSC case reports, iron-containing products can cause injury, including 
serious injury, and death when children gain access to these products. 
FDA finds from these data that the potential for harm exists for all 
three types of iron-containing products available, i.e., multi-vitamin/
mineral supplements that contain iron, iron supplements, and iron-
containing drugs.
    Supporting this finding are the data cited in Tables 1, 2, and 3 
that show that, since 1983, at least 40 deaths have been attributed to 
the accidental ingestion of iron supplements and iron-containing drugs, 
and that, since 1986, nearly 190 poisonings that were life threatening 
or that resulted in permanent injury, and over 2,000 poisonings 
requiring some form of treatment, have resulted from accidental 
ingestion of adult iron-containing products.
    Further support is provided by the data in the CPSC case reports, 
which show 80 ingestions of iron leading to hospital emergency room 
visits with varying types of injury, including vomiting, lethargy, 
diarrhea, and elevated serum iron (see Table 6).
    The data in Tables 4 and 6 show that in several documented 
poisoning incidents, children have ingested 30, 40, 50, or more tablets 
of iron-containing products when these amounts of tablets were 
accessible. Aside from the potential for such ingestion of iron-
containing supplements and drugs to be fatal, the consequences of 
ingesting even multi-vitamin/mineral type products in these amounts is 
evident from Table 8. This table shows that an amount of iron that may 
produce symptoms of iron poisoning (i.e., 25 mg/kg) can be ingested by 
a 10 kg child if the child consumes 25 tablets containing 10 mg of iron 
each or approximately 14 tablets containing 18 mg each. (Ten mg and 18 
mg of iron are the amounts typically contained in multi-vitamin/mineral 
supplements with iron including children's vitamins.) Based upon the 
data in Tables 4 and 6, ingestion of this many tablets is not atypical. 
Thus, FDA finds that injury can result anytime a small child is able to 
gain access to even the lowest potency iron-containing products 
available.
    Further, the fact that over 2,000 reported poisoning incidents of 
varying severity have been recorded in recent years (Tables 2 and 3), 
and the fact that AAPCC reports that accidental iron poisoning is 
presently the leading cause of pediatric poisoning deaths, lead FDA to 
find that pediatric iron poisonings have occurred, and continue to 
occur, with significant frequency. Further, FDA finds that the fact 
that these poisonings continue to occur, even though there have been 
over 40 deaths from accidental iron ingestion (See Table 1), strongly 
suggests that many adults are not aware of the potential for serious 
harm or death in young children from accidental ingestion of iron-
containing products. Support for this finding is provided by statements 
made by the parents of the victims in several of the poisoning 
incidents, described in the case reports obtained from CPSC as follows:
    (1) ``The mother stated that she thought the pills (prenatal iron 
pills) were just vitamins and would not harm the victim'' (Ref. 21, 
case report No. 10).

 Table 8.--Number of Iron-Containing Tablets Ingested Resulting in Toxic
                           and Lethal Dosages                           
------------------------------------------------------------------------
                                                       Number of Tablets
                                    Number of Tablets      Containing   
 Potency of Iron Product, mg Iron    Containing Toxic     Potentially   
         per Dosage Unit              Dose (25mg/kg)   Lethal Dose (100-
                                    for a 10 kg Child   250mg/kg) for a 
                                                         10 kg Child\1\ 
------------------------------------------------------------------------
10................................                 25            100-250
18................................                 14           55.5-139
30................................                  8              33-83
60................................                  4          16.5-41.5
100...............................                2.5              10-25
130...............................                  2          7.5-19.5 
------------------------------------------------------------------------
\1\Values for a lethal dose cited by authorities generally range from   
  100 to 250 mg of iron per kg of body weight. The Attorneys General    
  petition states that fatality has occurred at doses as low as 60 mg/  
  kg.                                                                   

    (2) ``She (the mother) said that she did not think he (the victim) 
had taken very many pills at the time, and that she was unaware of the 
danger of iron overdose'' (Ref. 21, case report No. 20).
    (3) ``The mother stated that she called her sister and asked if 
iron tablets could hurt the victim. The mother stated, that her sister 
told her that the tablets were just vitamins and would not hurt the 
victim'' (Ref. 21, case report No. 37).
    (4) ``The mother thought at the most if her son had taken more than 
a couple of the vitamins he would simply throw up and that would be the 
end of it. She had no idea what a dangerous situation her child was 
in'' (Ref. 22, case report No. 62).
    (5) ``Later in the day (after child had ingested 30-40 iron 
tablets) the mother went to the pharmacy to get a prescription for the 
daughter's ear infection and she asked the pharmacist about the 
possible ingestion of iron tablets'' (Ref. 22, case report No. 73).
    In addition, as stated above, the data presented by the AG petition 
show that few, if any, of the commonly available iron-containing 
products have carried label statements using terms such as ``WARNING'' 
or ``CAUTION.'' Because these terms are universally accepted as 
connoting danger, they could be expected to promote awareness among 
adults of the danger that these products pose to young children and of 
the importance of preventing children from gaining access to these 
products.
    Therefore, because the data demonstrate that: (1) Iron-containing 
products of all types can cause injury or death when small children 
gain access to them, (2) more than 2,000 poisonings have occurred over 
approximately 7 years and continue to occur, (3) a small child is at 
risk of injury any time he or she gains unlimited access to any iron-
containing product, and (4) many adults are not aware of the potential 
for serious harm posed by iron-containing products, FDA tentatively 
concludes that it should require label warning statements for iron-
containing products to ensure that adults are fully informed as to the 
potential of these products to cause devastating outcomes and, thus, to 
promote the safe handling and storage of these products.
    b. FDA's legal authority to require label warning statements on 
foods. FDA's authority to require label warning statements on food 
products derives from sections 201(n), 403(a)(1), and 701(a) of the act 
(21 U.S.C. 321(n), 343(a)(1), and 371(a)). Under section 403(a)(1) of 
the act, a food is misbranded if its labeling is false or misleading in 
any particular. Section 201(n) of the act states, ``If an article 
(e.g., a food product) is alleged to be misbranded because the labeling 
or advertising is misleading, then in determining whether the labeling 
or advertising is misleading there shall be taken into account (among 
other things) not only representations made or suggested by statement, 
word, design, device, or any combination thereof, but also the extent 
to which the labeling or advertising fails to reveal facts material in 
the light of such representations or material with respect to 
consequences which may result from the use of the article to which the 
labeling or advertising relates under the conditions of use prescribed 
in the labeling or advertising thereof or under such conditions of use 
as are customary or usual.'' These statutory provisions, combined with 
section 701(a) of the act, which grants the agency authority to 
promulgate regulations for the efficient enforcement of the act, 
clearly authorize FDA to promulgate a regulation designed to ensure 
that persons using iron-containing multi-vitamin/mineral products and 
iron supplements will receive information that is material with respect 
to consequences that may result from the use of the product under its 
labeled conditions or under conditions that are customary or usual.
    FDA requires label warning statements on certain types of protein 
products represented for use in reducing weight. The agency adopted 
this requirement in response to a series of sudden deaths of 
individuals, mostly young women, who consumed high protein, very low 
calorie diets (Sec. 101.70(d)(21 CFR 101.17(d)). Use of such diets was 
intended to achieve rapid weight loss. As a result of these deaths, 
which occurred in the late 1970's, FDA promulgated the warning 
requirement for such products to ensure that users of these products 
are aware of the potential adverse consequences of very low calorie 
protein diets, to indicate the necessity for appropriate medical 
supervision for persons on such diets, and to identify individuals, 
i.e., infants, children, or pregnant or nursing women, who should not 
use these products (49 FR 13679, April 6, 1984).
    FDA's legal authority under sections 201(n), 403(a)(1), and 701(a) 
of the act to require a warning statement on dry, whole protein 
products was upheld in Council for Responsible Nutrition v. Goyan, Food 
Drug Cosm. L. Rep. (CCH)  38,057 (D.D.C. 1980). In that case, the 
plaintiff asserted that the fatal consequences arising from the use of 
dry, whole protein products while dieting were not the result of the 
customary or usual use of these products, but rather, the result of 
unusual misuse of such products. Based on FDA's showing that the 
consumption of dry protein products could occur in the course of a 
diet, and that, under certain circumstances in dieting, serious adverse 
effects could arise from such use of these products, the court found 
that FDA properly invoked sections 201(n), 403(a)(1), and 701(a) of the 
act to impose a requirement that manufacturers warn consumers of the 
consequences that could result from the use of such products.
    The facts presented by the evidence on iron poisonings parallel 
those that led the agency to require a warning on protein products. The 
use of iron-containing products in households where children are 
present is in no way an unusual practice. Multi-vitamin/mineral 
supplements with iron are routinely taken by children, and products of 
this type specifically intended for use by children are widely 
available and commonly sold. Iron supplements and adult vitamin/mineral 
supplements with iron are frequently taken by pregnant women (often 
with a prescription) and other women of child-bearing age because they 
require more iron than other adults (see discussion in section I.A. of 
this document). Yet, the evidence on poisonings and deaths shows that 
the use of any type of iron-containing product in such households can 
readily lead to accidental injury or death if children gain access to 
the products, even though the products are not intended to be used by 
children or to be taken in the numbers in which iron-containing tablets 
or capsules are consumed when poisonings occur. Thus, Council for 
Responsible Nutrition v. Goyan provides strong support for the agency's 
authority to require label warning statements concerning the risk of 
accidental poisoning from iron-containing food products.
    Based upon FDA's authority under sections 201(n), 403(a)(1), and 
701(a) of the act, the agency proposes to require that manufacturers of 
iron-containing dietary supplements (i.e., children's and adult's 
multi-vitamin/mineral supplements that contain iron and products 
intended for use as iron supplements) disclose information about their 
products in the form of a label warning statement that would appear on 
such products in the manner described below.
    c. FDA's legal authority to require label warning statements for 
drugs. The act authorizes FDA to regulate the marketing of drug 
products to ensure that such products are properly labeled. To carry 
out the public health protection purposes of the act, FDA, among other 
things, monitors drug labeling to ensure that it provides accurate 
information about drug products.
    Under section 502(a) of the act (21 U.S.C. 352), a drug product is 
misbranded if its labeling is false or misleading in any particular. 
The provisions of section 201(n) of the act concerning failure of the 
labeling to reveal material facts are applicable to drugs as well as to 
foods in determining whether labeling is misleading. In addition, under 
sections 505(d) and (e) of the act (21 U.S.C. 355(d) and (e)), FDA must 
refuse to approve a new drug application, and may withdraw approval for 
a product, if the product's labeling is false or misleading in any 
particular.
    These statutory provisions, together with section 701(a) of the 
act, clearly authorize FDA to promulgate a regulation designed to 
ensure that patients using drugs will receive information that is 
material with respect to consequences that may result from the use of a 
product. (See Pharmaceutical Manufacturers Association v. Food and Drug 
Administration, 484 F. Supp. 1179 (D. Del. 1980), aff'd per curiam, 634 
F.2d 106 (3d Cir. 1980).)
    The act also authorizes FDA to regulate the marketing of drug 
products to ensure that such products are safe and effective for their 
intended uses. Iron-containing drug products are not safe for their 
intended use as currently labeled, in part because the labeling fails 
to warn of iron-containing products' toxic effects in children. Adults 
are, therefore, not aware of the need to prevent children from 
ingesting these products. Because the labeling fails to warn adequately 
that these products may produce toxic effects in children, iron-
containing products are not being used as intended; that is, even 
though they are not intended for children, they are handled in a way 
that permits their ingestion by children.
    The act anticipates that new information about the safety or 
effectiveness of marketed drugs may require changes in labeling to 
reflect necessary limitations on use or to warn of previously 
unanticipated hazards (see e.g., 21 U.S.C. 355(e)). FDA has required by 
regulation that manufacturers provide warning statements for specific 
drug products (e.g., drugs for internal use which contain mineral oil, 
21 CFR 201.302; isoproterenol inhalation preparations, 21 CFR 201.305; 
acetophenetidin (phenacetin)-containing preparations, 21 CFR 201.309). 
The impetus for requiring warnings for each of these products or 
product classes was evidence of risk in a specific patient population 
or from a specific use of the product. FDA responded to these risks by 
requiring warnings to help patients use prescription drug products more 
safely and effectively. For example, given the particular risk of 
severe paradoxical bronchoconstriction associated with repeated, 
excessive use of isoproterenol inhalation preparations, FDA requires 
that warning information to patients be included as part of the label 
and as part of the instructions included in the package dispensed to 
patients (See 21 CFR 201.305). The specified warning statement may be 
placed on the immediate container with a statement to the pharmacist 
not to remove it or may be included in a package with instructions to 
pharmacists to place the warning on the container prior to dispensing 
(see 21 CFR 201.305(c)(2)).
    Based upon FDA's authority under sections 201(n), 502(a), 505 and 
701(a) of the act, the agency is proposing to require that 
manufacturers of prescription iron-containing products disclose 
information about the risks presented by their products in the form of 
a warning statement that would appear on such products in the manner 
described below.
    d. What should the label warning be required to state? FDA has 
considered what information should be required in the warning statement 
to ensure that, as required by sections 201(n), 403(a)(1), 502(a), and 
505 of the act, users of iron-containing products are made aware of the 
potential consequences of their use, i.e., that the labeling of iron-
containing products states the facts that are material with respect to 
the consequences that may result from the use of these products. The 
proposed warning statements in the AG and NDMA petitions contained the 
various information elements as shown in Table 9. FDA tentatively 
concludes that to fulfill the requirements of the act, the warning 
statement should incorporate some elements from both of these 
petitions, as well as other elements that are designed to ensure that 
the statement performs its function. In reaching this tentative 
conclusion, FDA considered several factors.
    FDA agrees with the AG petition that the term ``Warning'' is 
necessary to alert the user to the potential consequences of the use of 
the product, that is, to the dangers of iron overdose. This term is 
universally accepted as denoting danger. FDA tentatively concludes that 
the potential for iron-containing products to cause death or serious 
injury any time a small child gains access to the product warrants the 
use of this term.
    FDA tentatively concludes that the statement must bear the 
instruction to ``Keep away from children.'' Because a child is at risk 
of serious injury or death any time he or she gains access to iron-
containing products, this statement is a material fact about the 
consequences of use of the product and is also necessary to ensure the 
safe use of the product.

            Table 9.--Elements of Petitioners' Warning Labels           
------------------------------------------------------------------------
   Information Elements                         Petitioner              
------------------------------------------------------------------------
Fe\1\1 Overdose Warning     AAPCC.............           AG         NDMA
 Label Elements.                                                        
``WARNING'' (stated first)  ..................            X            X
``Close tightly'' (for      ..................  ...........            X
 bottles).                                                              
Accessible to children....  ..................         X\2\         X\3\
Consequences of Fe          X (For products...            X            X
 overdose (injury and        30 mg                           
 death).                    Fe; no suggested                            
                             language).                                 
Warning language dose       ..................         X\4\  ...........
 dependent.                                                             
Reference to ``large        ..................         X\5\         X\6\
 doses'' as presenting a                                                
 greater hazard.                                                        
Listing of symptoms.......  ..................         X\7\  ...........
Treatment action..........  ..................  ...........        X\8\ 
------------------------------------------------------------------------
\1\Fe denotes iron.                                                     
\2\``Keep away from children.''                                         
\3\``Keep out of reach of children.''                                   
\4\Products  30 mg Fe: ``Contains iron which can be harmful  
  or fatal if swallowed by a child.''                                   
\5\Product < 30 mg Fe: ``Contains iron which can be harmful or fatal in 
  large doses if swallowed by a child.''                                
\6\All iron-containing products: ``Contains iron, which can be harmful  
  or fatal to children in large doses.''                                
\7\Products  30 mg Fe: ``Acute overdosage of iron may cause  
  nausea and vomiting and, in severe cases, cardiovascular collapse and 
  death.''                                                              
\8\``In case of accidental overdose, seek professional assistance or    
  contact a Poison Control Center immediately.''                        

    FDA also recognizes that the warning needs to be crafted to reflect 
the type of packaging used. Iron-containing products may be packaged in 
unit-dose packages, e.g., blister packs, or in containers with 
closures, e.g., a bottle with a cap. FDA tentatively concludes that for 
iron-containing products packaged in unit-dose packages, the warning 
statement should include the instruction ``Keep in original package 
until each use.'' This statement instructs the user not to misuse the 
product by removing more dosage units from their individual packs than 
will be ingested at one time. This instruction is important because 
such misuse can result in poisoning if children gain access to the 
dosage units that have been removed from their original packaging. This 
instruction was not specifically requested by any of the petitions. 
Because some incidents of pediatric iron poisoning have occurred after 
adults removed multiple dosage units from their original containers and 
stored them in nonchild-resistant vessels (see section I.C. of this 
document), however, the agency tentatively concludes that this 
statement is necessary to ensure that the product is properly used.
    The agency concurs with the NDMA petition that the statement 
``Close Tightly'' should be included in the warning statement for 
containers with closures. Such a statement provides information on how 
to maintain the child-resistance of the container. FDA finds that this 
message is a material fact. FDA bases this finding, in part, on the 
fact that some incidents of iron poisoning have occurred even though 
the product was in child-resistant packaging. Children were able to 
gain access to iron products because the child-resistant closure was 
not properly secured (See section I.C. of this document). Thus, to 
ensure that iron-containing products are used safely, the child-
resistance of the packaging must be maintained, and FDA tentatively 
concludes that inclusion of the statement ``Close Tightly'' is 
necessary to ensure that condition of use is maintained.
    FDA also tentatively concludes that the label must include the 
information ``Contains iron, which can harm or cause death to a 
child.'' This statement informs the user or the serious and potentially 
life-threatening nature of the consequences that can occur when a child 
ingests an uncontrolled amount of these products.
    FDA also tentatively concludes that the label must state: ``If a 
child accidentally swallows this product, call a doctor or a poison 
control center immediately.'' FDA agrees with the NDMA petition that 
treatment-oriented information should be included on the label because 
it informs attending persons in a poisoning incident of the need to 
take immediate action that could save the child's life and about what 
that action should be. Thus, it relates directly to the consequences of 
use of the product.
    FDA does not believe that the warning statement should be based 
upon or contain information relating to the potency of the iron product 
(i.e., different statements for products above and below 30 mg per 
dosage unit as requested by the AG petition, or reference to ``large 
doses'' of iron as a factor in determining whether poisoning may 
occur). The agency tentatively finds that such statements could cause 
members of the public to attempt to determine whether a large dose has 
been taken in a possible poisoning incident. Because most people are 
not capable of determining what dosage of iron may be nontoxic, toxic, 
or capable of causing serious harm or death, qualified medical or 
poison control personnel should determine the significance of the dose 
a child has ingested.
    Nor does there appear to be any reason to require that the 
statement include reference to the specific types of consequences that 
may arise from acute overdosage, i.e., nausea, vomiting, cardiovascular 
collapse, as requested by the AG petition. FDA does not believe that 
this information would materially add to the label statement that 
overdose can cause harm or death, and fears that it may lead to the 
erroneous conclusion that, because a child does not exhibit one of the 
listed symptoms, the child is not in danger.
    e. How should the warning appear on the label? FDA agrees with the 
AGs' contention that the warning statement should appear prominently on 
the label of iron-containing products to effectively convey its 
message. Further, the act specifically requires, in sections 403(f) and 
502(c), that information required to appear on the label of a food or a 
drug be prominently placed and appear with such conspicuousness, as 
compared with other printed matter, as to render it likely to be read 
by the ordinary individual under customary conditions of use.
    However, the AG petition provided no evidence to support the 
specific presentation elements that it requested for the warning 
statement, i.e., that it be boxed, in boldface type, and in a color 
that contrasts with the background and with other printed material on 
the label or labeling. The agency is not aware of any basis on which it 
can conclude that any of these specific elements are necessary to 
ensure that the statement appears on the label in a prominent and 
conspicuous manner.
    Further, in the agency's rulemaking that mandated warning 
statements on certain protein products, the agency decided not to 
mandate specific requirements for letter size and other format 
elements. However, the agency did require that the warning statement 
appear ``prominently and conspicuously on the principal display panel 
of the package label'' (21 CFR 101.17). FDA made a determination to 
give manufacturers flexibility to design their own label warning 
formats, while ensuring that the statement is prominent and 
conspicuous, so that consumers are given adequate notice of the 
information contained in the warning (47 FR 25379 at 25382, June 11, 
1982). In addressing the placement of the label warning, the agency 
noted that the seriousness and nature of the risk associated with the 
use of protein products in very low calorie diets was sufficient to 
require placement of the warning statement on the principal display 
panel (49 FR 13679 at 13689).
    Section 201(k) of the act defines the term ``label'' as ``a display 
of written, printed, or graphic matter upon the immediate container of 
any article'' and further states that a requirement ``that any word, 
statement, or other information appear on the label shall not be 
considered to be complied with unless such word, statement, or other 
information also appears on the outside container or wrapper if any 
there be, of the retail package of such article * * *.'' Thus, if FDA 
requires a label warning statement to appear on the immediate container 
of iron-containing products, it would also have to appear on the retail 
package of such a product if that package is not the immediate 
container.
    As stated above, the fact that iron-containing products have 
resulted in reports of 2,000 poisonings in children over approximately 
7 years provides evidence that many adults are not aware of the 
potential for serious harm posed by iron-containing products. Based on 
this fact, FDA tentatively finds that there are sufficient grounds to 
require that the label warning statement be printed directly on the 
immediate container of the product, i.e., the container that holds the 
tablet or capsule, and on the principal display panel of the retail 
package, i.e., an outer box, if such package is not the immediate 
container (many iron-containing products are packaged in this manner). 
If a product is sold in unit-dose packaging, this requirement will mean 
that the product will have to bear the warning directly on each unit-
dose package or on a strip of unit-dose packages in such a way that 
separating the unit dose packages would not destroy the warning 
labeling.
    The placement of the warning statement on the principal display 
panel of the retail package will make it likely that the warning 
statement will be seen at the time the product is purchased. The 
statement will inform the purchaser of the product's potential to cause 
poisoning and of the need to keep the product away from children when 
it is brought into the house. FDA tentatively concludes that placement 
of the warning statement on the principal display panel is necessary to 
fulfill the requirement of sections 403(f) and 502(c) of the act, that 
information required to appear on the label of a food or a drug be 
placed with conspicuousness (as compared with other printed matter) as 
to render it likely to be read by the ordinary individual under 
customary conditions of use. Moreover, placement of the warning 
statement on the principal display panel is consistent with the 
requirement that FDA established for protein product warning statements 
discussed previously. In both cases, the products in question could 
cause serious, even life-threatening, problems if misused. Thus, FDA 
tentatively concludes that the standard of conspicuousness established 
in the protein products case should also be adopted for iron-containing 
products.
    The agency tentatively concludes that placement of the warning 
statement on the immediate container is also necessary to fulfill the 
requirement of sections 403(f) and 502(c) of the act because, under 
customary conditions of use, the retail container is frequently 
disposed of, and individuals other than the purchaser may use the 
product. Therefore, the warning statement must be printed on the 
immediate container if this statement is to perform its function 
throughout the life of the product.
    Regulating the placement of the warning is consistent with other 
labeling requirements that the agency has imposed. In 21 CFR 
201.314(h)(1) and (h)(2), FDA has required that the labeling of orally 
or rectally administered aspirin and aspirin-containing drug products 
intended for sale without prescription bear a warning that reads: 
``WARNING: Children and teenagers should not use this medicine for 
chicken pox or flu symptoms before a doctor is consulted about Reye 
syndrome, a rare but serious illness reported to be associated with 
aspirin.'' The warning must appear on the immediate container labeling. 
In cases where the immediate container is not the retail package, the 
retail package must also bear the warning statement. (see 51 FR 8180, 
March 7, 1986).
    FDA tentatively concludes that the objectives of the proposed 
regulation regarding the packaging and labeling of iron-containing 
products will be best met if the agency requires that the proposed 
warnings appear on the immediate container. In case the strip packaging 
or individual unit-dose packages are removed from the box in which they 
are sold to the consumer, or in case a strip of unit-dose packages is 
transferred by a pharmacist to a vial, each unit-dose package, or strip 
of unit dose packages, would bear the warning that FDA considers 
essential to the safe use of these products. The warning would remind 
adults not to remove the iron-containing products from the unit-dose 
package. In addition, it would ensure that each time an adult takes one 
of these products, he or she is reminded of the danger that the product 
poses to children.

    In addition, if the warning accompanies each tablet or group of 
tablets, an adult who finds a child eating the product will know to 
call for help immediately and will know, when asked by a health care 
professional, that the ingested tablets contain iron.

    FDA is not proposing specific requirements for the graphics (e.g., 
type size, bold type) of the warning statement but is proposing to 
require that the label warning appear prominently and conspicuously on 
the immediate container of the product and on the principal display 
panel of the retail package, so that consumers are given adequate 
notice of the information contained in the warning. These proposed 
requirements for the warning statement are consistent with the 
requirement FDA established for protein products. FDA tentatively 
concludes that they will effectively achieve, through placement rather 
than graphical requirements, the objective sought by the AG petition of 
reaching consumers who have no knowledge of iron's hazards.

    If FDA adopts the regulations that it is proposing, manufacturers 
will have the flexibility, as requested in the NDMA petition, to design 
their own label and warning notice formats. The agency is requesting 
comments on the most efficient way to ensure that warnings on the 
immediate container will accompany every tablet until the time it is 
used. Suggestions about the placement and design of unit-dose packaging 
that can best accommodate the required warnings are invited.

    FDA also specifically solicits comments on whether the general 
requirement that the label warning appear prominently and conspicuously 
on the label is adequate. Should the agency more explicitly define in 
its regulation the level of prominence and conspicuousness that it 
expects? If so, what should the agency require? The agency notes, for 
example, that in a final rule that required a new warning on Reye 
syndrome for aspirin, it specifically stated that the requirement of 
``prominence'' in its regulations meant that manufacturers of aspirin 
and aspirin-containing drug products had to use an attention-getting 
statement, such as ``see new warning'' on the label for at least 1 year 
(53 FR 21633, 21635, June 9, 1988). Similarly, in the final rule on 
nutrition labeling that FDA adopted in response to the Nutrition 
Labeling and Education Act of 1990, FDA specified a number of format 
elements to ensure that the nutrition facts label would be readily 
observable and comprehensible (see 58 FR 2079, January 6, 1993). FDA 
requests comments on whether, to ensure that the warning statement will 
have its intended effect, the agency should specify more completely how 
the warning should be presented on iron-containing products.
3. Proposed Labeling Requirements
    Having tentatively concluded that label warning statements should 
be required on iron-containing products, and having evaluated the 
information that the warning statement should include, FDA is proposing 
to amend its regulations by adding new Sec. 101.17(e) for foods, and 
new Sec. 310.55 for drugs, to require label warning statements for 
iron-containing products offered in solid oral dosage form. As noted 
above, under these proposed regulations, the warning statement that 
must be used will depend upon how the product is packaged. For products 
that are packaged in unit-dose packaging (e.g., blister packs) the 
agency is proposing to require the following warning:

    WARNING--Keep away from children. Keep in original package until 
each use. Contains iron, which can harm or cause death to a child. 
If a child accidentally swallows this product, call a doctor or 
poison control center immediately.

    Under this proposal, this warning statement will be required for 
all iron-containing products packaged in unit-dose packaging. 
Therefore, it would be required to appear: (1) On the labeling of 
products containing 30 mg or more iron per dosage unit, which are 
subject to the proposed requirement for unit-dose packaging described 
below (see section III.B. of this document); and (2) on the labeling of 
products that contain less than 30 mg iron per dosage unit but that are 
packaged voluntarily in unit-dose packaging.
    For products that contain less than 30 mg iron per dosage unit and 
that are packaged in any form of packaging other than unit-dose 
packaging, e.g., containers with child-resistant closures, the agency 
is proposing to require the following warning:

    WARNING--Close tightly and keep away from children. Contains 
iron, which can harm or cause death to a child. If a child 
accidentally swallows this product, call a doctor or poison control 
center immediately.

    The agency may conduct focus group research to evaluate consumer 
understanding of the proposed warning messages and to ensure that the 
messages are not misleading. Focus group research involves gathering 
small, representative groups of consumers (no more than nine consumers 
per group) and leading then in a directed discussion of the research 
topic. For the present research, consumers will provide feedback as to 
their level of understanding of the warnings and the degree to which 
the specific wording of the messages is believable, relevant, 
confusing, or irritating. The agency intends to consider the results of 
the focus group research in arriving at any warning statement that is 
included in the final regulations. FDA will make a report on the 
results of its research available for public comment before it issues 
the final regulations.

B. Packaging

1. Review of Packaging Issues in Citizen Petitions
    Two of the citizen petitions suggested that FDA take action with 
respect to the packaging of iron-containing drugs and dietary 
supplements. Both petitions recommended packaging requirements as a 
means of reducing pediatric poisonings from ingestion of multiple doses 
of drugs and dietary supplements containing 30 mg or more iron per 
dosage unit.
    The AG citizen petition requested that FDA use its authority under 
the act to require that all iron-containing drugs and dietary 
supplements containing 30 mg or more iron per dosage unit be packaged 
in child-resistant blister packs.
    The NDMA petition recommended that FDA incorporate into its 
regulations the NDMA-initiated voluntary program to address pediatric 
poisonings by such iron-containing products. This voluntary program 
includes, in part, a proviso that all iron-containing products 
currently subject to CPSC's special packaging regulations that contain 
30 mg or more of iron per dosage unit be packaged in CRP's, and that 
there be no exemption to CPSC's child-resistant special packaging 
requirements for these types of products. As discussed previously, 
NDMA's voluntary program also specifies labeling statements and 
includes an educational program. Implicit in NDMA's recommendation is 
the view that CRC's, labeling warning statements, and consumer 
education programs are sufficient to ensure the safe use of iron-
containing products.
2. Agency Response
    FDA considered the following questions in evaluating and responding 
to the packaging issues raised in the citizen petitions: (1) Can 
educational efforts and label warning statements alone sufficiently 
reduce pediatric iron poisonings? (2) Are noncomplying child-resistant 
packages a principal cause of iron poisoning deaths? (3) Are additional 
packaging requirements necessary to ensure the safe use of certain 
iron-containing products? (4) What is FDA's legal authority to regulate 
packaging for foods and drugs? (5) Should child-resistant blister 
packaging be required for iron-containing products?
    a. Can educational efforts and label warning statements 
significantly reduce pediatric iron poisonings? FDA agrees with NDMA 
that educating consumers on the proper use of CRC's and on the hazards 
posed by iron-containing drugs and supplements is very important. 
However, based on the available evidence, even if all CRC's were 
properly used, these closures could not have prevented the majority of 
the 37 reported fatalities. Improper use of CRC's was reported in only 
4 of the 21 (19 percent) pediatric iron fatalities known to involve 
child-resistant packaging (Table 2). Educational programs and label 
warning statements should help to increase proper use of reclosable 
CRC's, and thereby help to prevent some pediatric iron-poisonings. 
However, FDA knows of no information showing that a consumer education 
program, either that recommended by NDMA or any other such program, 
will be adequate to ensure that children will not be able to defeat 
even properly closed CRC's, or that improper use of such closures will 
cease. In the absence of such information, FDA believes that measures 
beyond consumer education programs are necessary to ensure that the use 
of certain iron-containing products is safe.
    FDA also tentatively finds that label warning statements will not 
be sufficient to ensure the safe use of these products. This tentative 
conclusion is based on the fact that label warning statements do not in 
any way bar access to the product. Label statements are an important 
educational tool for making adults aware of the significant 
consequences for young children if they gain access to the product. 
Young children, however, cannot read and have little judgment. Thus, a 
warning statement is likely to have little or no effect on their 
efforts to gain access.
    The available data show that poisonings are occurring in large 
measure because of the efforts of children. Table 4 shows that in 9 of 
the 21 reported pediatric poisoning deaths that involved iron-
containing products packaged in containers with CRC's, the victims 
gained access to multiple doses of iron-containing product by their own 
efforts or through the efforts of another child. Most of these children 
were under 51 months of age. Thus, a label warning statement is 
unlikely to have any meaning or significance to them.
    FDA requests comments on its tentative conclusion that label 
warning statements are not sufficient to ensure that the use of certain 
iron-containing products will be safe. Comments that bear on the 
effectiveness of labeling warning statements to deter young children 
from directly gaining access to these products will be most compelling 
if they contain supporting data and information.
    As stated above, FDA believes that label warning statements will 
help to reduce the incidence of pediatric poisoning because they will 
ensure that adults are aware of the pediatric toxicity of iron and will 
encourage responsible adults to properly reclose and store iron-
containing products. However, FDA is concerned that warning statements 
alone will not prevent the misuse of CRP's that has contributed to the 
epidemic of iron poisonings of children. FDA notes that CRP's 
themselves are a de facto warning that the contents of the package 
present hazards for children. Yet, in 21 of the 26 pediatric poisoning 
deaths in which the type of packaging was reported, the product was 
packaged in containers with CRC's (Table 4).
    Furthermore, the effectiveness of label warning statements is 
generally considered to be dependent on several factors including, but 
not necessarily limited to: The personal relevance of the warning 
information; familiarity with the warning information; perceived hazard 
from the product; and desensitization or habituation to warnings after 
repeated exposures (Ref. 24). Moreover, a report on the effectiveness 
of a labeling and educational program to prevent pediatric poisonings 
from accidental ingestion of prescription drugs shows that labeling and 
educational programs are not always sufficient to prevent pediatric 
poisonings, and that, in some instances, additional packaging 
safeguards are necessary to ensure the safe use of certain substances 
(Ref. 25). Therefore, FDA tentatively concludes that label warning 
statements will not be sufficient to ensure the safe use of certain 
iron-containing products.
    FDA finds that iron-containing drugs and dietary supplements pose a 
unique hazard to young children. The pediatric hazard presented by 
these products is directly related to their iron content. As discussed 
above in section I.B. of this document, ingestion of 25 mg or more iron 
per kg of body weight is considered a toxic dose, and ingestion of 100 
to 200 mg iron per kg of body weight can be lethal. Once a potentially 
lethal dose of iron has been ingested and absorbed, medical 
intervention to halt the toxic progression of iron poisoning is 
difficult and often unsuccessful. Successful treatment for iron 
poisoning is determined primarily by the amount of iron ingested and 
how rapidly medical intervention occurs. In light of the risk of 
pediatric iron poisonings with irreversible and potentially fatal 
consequences that is presented by higher potency iron-containing 
products, and of the inherent limitations on the effectiveness of 
labeling and educational programs, FDA tentatively concludes that it 
would be inappropriate to rely solely on these measures to ensure the 
safe use of these products.
    b. Are noncomplying CRP's a principal cause of iron poisoning 
deaths? The NDMA contends that new packaging requirements beyond those 
outlined in its petition are not necessary to reduce the incidence of 
pediatric iron poisonings. The NDMA petition asserts that the available 
data on pediatric iron-poisonings are deficient to the extent that it 
cannot be determined whether products associated with the poisonings 
were packaged in compliance with CPSC's packaging requirements, and it 
suggests that iron-containing products packaged in noncompliant CRP's 
are the principle cause of pediatric iron-poisonings. However, NDMA 
provided no information to support its view.
    FDA has carefully examined the available information on pediatric 
iron poisonings and could find no evidence to support the NDMA's 
contention that the iron-containing products associated with these 
poisonings were packaged in CRP's that did not comply with regulations 
established by CPSC. In the absence of such evidence, FDA can find no 
basis on which to conclude that noncompliant, child-resistant special 
packaging is the primary cause of pediatric iron-poisonings.
    c. Are additional packaging requirements appropriate? FDA 
tentatively concludes that full compliance with CPSC's CRP 
requirements, even if there are warning statements in labeling of iron-
containing products and appropriate educational programs, will not be 
adequate to ensure the safe use of certain iron-containing drugs and 
dietary supplements if bottle and closure packaging were to continue as 
the predominant means of packaging such products. FDA recognizes that 
each of these measures either has been successful in limiting the 
number of poisonings or can be reasonably expected to be effective in 
reducing the number of poisonings. However, given the potentially fatal 
outcome that can result from pediatric iron-poisoning, FDA is not 
persuaded that these measures are adequate to ensure the safety of the 
use of certain iron-containing drugs and dietary supplements. FDA 
tentatively concludes that to reduce the incidence of pediatric iron 
poisonings to a level that would permit the agency to conclude that 
there is a reasonable certainty of no harm from the use of these 
products, it is necessary to require a specific type of physical 
barrier to access these products. Therefore, FDA tentatively concludes 
that additional packaging requirements are necessary.
    FDA requests comments on this tentative conclusion. The agency is 
particularly interested in receiving comments that bear on the 
effectiveness of different types of packaging to limit pediatric access 
to toxic amounts of iron. Comments will be most persuasive if they are 
supported by studies and other data and information.
    d. Consideration of legal authority of FDA and other agencies to 
require specific packaging measures for foods and drugs. In its 
consideration of what action to take concerning the packaging of iron-
containing drugs and dietary supplements to ensure their safe use, FDA 
recognized that it must act within the limits of its statutory 
authority and consider the statutory authority of other government 
agencies. As noted above, under the PPPA, CPSC has authority to 
regulate the packaging of household substances. Under the PPPA, CPSC 
can establish special packaging performance standards. Thus, by 
regulation, CPSC has established special packaging standards and 
performance criteria for special packaging, 16 CFR 1700.15 and 1700.20, 
respectively. However, the PPPA specifically limits CPSC from 
establishing regulations that require specific packaging designs, 
product content, and package quantity for household substances, 
including food and drugs.
    i. Packaging for iron-containing dietary supplements. The act 
provides FDA with broad authority to ensure that food is safe and 
wholesome. In particular, the act prohibits the adulteration of food in 
sections 301 and 402 (21 U.S.C. 331 and 342) and requires, in sections 
409(a) (21 U.S.C. 348(a)) and 402(a)(2)(C), that all food additives be 
listed for use by FDA before they are added to food.
    In section 409(a), the act deems a food additive to be unsafe 
unless its use conforms to the conditions specified in the listing 
regulation. These conditions include, but are not limited to, 
specifications as to the particular food or classes of food to which 
the additive may be added, as to the manner in which the additive may 
be added to such food, and any directions or other labeling or 
packaging requirements for such additive deemed necessary to ensure the 
safety of such use (section 409(c)(1)(A) of the act. Thus, under the 
act, the agency is authorized to specify packaging requirements for a 
food additive when it finds that use of such packaging is necessary to 
ensure the safe use of the additive.
    In section 201(s), the act provides an exemption to the food 
additive definition for substances that are generally recognized as 
safe (GRAS) under the conditions of their intended use. FDA has issued 
regulations delineating conditions under which use of certain 
substances is GRAS. If the conditions of a particular use of a 
substance are not those that are generally recognized as safe, the use 
is not GRAS, but subject to regulation under the food additives 
provisions of the act.
    Should FDA determine that a particular type of packaging is 
necessary to ensure the safe use of iron substances in dietary 
supplements, either as GRAS substances or as listed food additives, 
then any use of iron substances in dietary supplements that does not 
involve use of that type of packaging would constitute a use of an 
unapproved food additive and render the dietary supplements adulterated 
under the act.
    ii. Packaging for iron-containing drug products. Section 
501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B)) states that a drug 
shall be deemed to be adulterated if the methods used in, or the 
facilities or controls used for, its manufacture, processing, packing, 
or holding do not conform to, or are not operated or administered in 
conformity with, current good manufacturing practice to assure that 
such drug meets the requirements of the act as to safety and has the 
identity and strength, and meets the quality and purity 
characteristics, which it purports or is represented to possess.
    A drug product may be safe and effective as manufactured but used 
in an unsafe and ineffective manner. Current good manufacturing 
practice is, to some extent, an evolving standard. To remain 
``current,'' a manufacturer must take into account advances in 
technology as well as new information about the use of the product 
including, but not limited to, information about any dangers associated 
with use of the drug product. Manufacturers must use this knowledge to 
alter, adapt, or change their manufacturing procedures to ensure that 
all possible measures have been implemented to eliminate known dangers. 
Therefore, advances in technology and new information about dangers 
associated with a drug product can mean that further steps by the 
manufacturer are necessary to guard against such foreseeable dangers, 
in order to hold the drug product in a manner that ensures its safety 
and, thus, comports with current good manufacturing practice.
    FDA has promulgated regulations to ensure that, among other things, 
drug products are held, pending use by the intended consumer, in a 
manner that ensures their safety (Parts 210 and 211 (21 CFR parts 210 
and 211)). The term ``held'' includes not only manufacturing and 
shipping time, but also the time from point of purchase to consumer 
use. Thus, manufacturers are responsible for the manner in which their 
products are held pending actual consumer use, and they are responsible 
if the packaging that they use is not adequate to prevent unintended 
ingestion of iron by children.
    The regulations are replete with examples of FDA's authority to 
regulate the manufacturer beyond the point of shipping the product from 
the manufacturing site. For example, Sec. 211.94(b) requires that 
container closure systems ``provide adequate protection against 
foreseeable external factors in storage and use that can cause 
deterioration or contamination of the drug product (emphasis added).'' 
This regulation requires that manufacturers protect against 
deterioration or contamination occurring during storage of drug 
products throughout the chain of distribution, up to the point of use 
by the consumer.
    Under section 501(a)(2)(B) of the act, manufacturers also are 
responsible for preventing intentional misuse of a drug product. In 
1982, in response to a series of capsule tamperings, FDA promulgated a 
regulation (Sec. 211.132) that requires tamper-resistant packaging for 
all over-the-counter (OTC) human drug products except dermatologics, 
dentifrices, and insulin (47 FR 50442). The agency's action assured 
greater package integrity and product security beyond the point of 
manufacture. FDA's authority to require tamper-resistant packaging is 
found primarily in section 501(a)(2)(B) of the act.
    Significantly, the health risk that prompted the tamper-resistant 
packaging regulation was not attributable directly to manufacturing or 
packing practices that contravened the current good manufacturing 
practice regulations in effect at that time. Rather, despite compliance 
with existing regulations, drug product quality was compromised because 
of previously unforeseeable and unintended intervention by persons 
other than the consumer.
    Because tamper resistant packaging was a means to obviate a newly 
apparent danger, and because tamper-resistant packaging technology was 
available, current good manufacturing practice mandated that it be 
used.
    Similarly, in 1989, recognizing the persistent vulnerability of the 
hard-capsule dosage form, FDA amended the tamper-resistant regulation 
to require that OTC products marketed in two-piece, hard-gelatin 
capsules be packaged using at least two tamper-resistant features (54 
FR 5227, February 2, 1989). Likewise, in 1994, the agency proposed to 
amend the tamper-resistant regulation to require that the packages for 
all OTC human drug products marketed in two-piece, hard-gelatin 
capsules be sealed (59 FR 2542, January 18, 1994). The proposed 
amendment is part of ``the agency's continuing review of the potential 
public health threat posed by product tampering,'' and was proposed to 
``address specific vulnerabilities in the OTC market and to improve 
consumer protection.'' (59 FR 2543). In the preamble to the proposed 
rule, FDA recognized that, although the packaging used at the time of 
the latest poisoning incidents met FDA requirements in effect at that 
time, the packaging was not designed to reveal visible evidence of 
tampering. The proposed rule would change ``tamper-resistant'' to 
``tamper-evident'' to underscore the fact that current packaging 
technology is not invulnerable to tampering and would require packaging 
that not only erects barriers to tampering, but also alerts the 
consumer to signs of tampering.
    In addition, in September 1993, FDA published a regulation that 
requires the imprinting of solid oral dosage form drug products for 
human use (See 58 FR 47948, September 13, 1993). The regulation 
requires that every such product be imprinted with a code that allows 
identification of the drug product and its manufacturer or distributor. 
The regulation will ensure, among other things, that consumers and 
health care professionals will have this information available in the 
event of an emergency. The imprinting rule, like the proposed rule for 
iron-containing products, responds to concerns that are related to 
consumer use of drug products rather than concerns focused on the 
integrity and composition of such products.
    The proposed rule, therefore, like those pertaining to tamper-
evident packaging and drug imprinting, is intended to enhance the 
safety of drug products, specifically iron-containing drug products. 
The recent statistical data available to FDA demonstrate that the 
current manner of holding iron-containing drug products until their use 
by the intended consumer fails to ensure that the drug products will be 
safe because large numbers of children are ingesting such products and 
suffering serious injuries or death. Existing technology permits 
additional safeguards, such as child-resistant blister packs, to be 
used for holding iron-containing drug products. Given the known dangers 
and the ability to minimize or eliminate such dangers through the use 
of existing technology, FDA tentatively concludes that current good 
manufacturing practice dictates that unit-dose packaging be used.
    e. Should child-resistant blister packaging be required? Requiring 
child-resistant blister packaging of iron-containing drugs and 
supplements, as recommended by the AG petition, is one packaging 
approach to reduce the incidence of pediatric iron-poisoning 
fatalities. This approach can be viewed as embodying three distinct 
packaging components: (1) Require unit-dose packaging; (2) require a 
specific type of unit-dose packaging (i.e., blister packs); and (3) 
require CRP's.
    FDA recognizes that unit-dose packaging provides certain packaging 
features that reclosable containers do not provide. Products packaged 
in unit-dose packaging require that the packaging be opened for each 
individual dosage unit. The additional time and effort needed to open 
each unit restricts the number of doses available for ingestion during 
the time that a child has access to the package. In contrast, a multi-
dose reclosable package (i.e., a bottle and closure) allows a child 
access to all of its contents once the closure is opened. In addition, 
the effectiveness of child-resistant unit-dose packaging does not 
depend upon adults' properly resecuring a cap as is the case with 
reclosable CRP's. Therefore, FDA tentatively concludes that unit-dose 
packaging of products will contribute in a significant, over and above 
the protections provided by warning statements and CRP's, to reduce 
children's access to potentially fatal doses of product.
    This tentative conclusion is supported by studies of the pediatric 
accessibility of products in different types of conventional (i.e., 
nonchild resistant) packaging. The results from these studies show that 
unit-dose packaging, in comparison to snap type and screw cap closure 
packaging, will limit access to multiple doses of product by young 
children. Studies of pediatric accessibility of product packaged in 
conventional unit-dose ``pouches,'' conventional unit-dose ``blister 
cards,'' and containers with conventional ``snap type'' and ``screw 
cap'' closures have been reported. Children, 42 to 51 months old, 
participated in each of these studies. Results from the study of 
conventional pouch packaging show that 55.5 percent of the children (n 
= 200) were unable to access more than eight tablets in 10 min (Ref. 
26). In a similar study of conventional blister card packaging 64 
percent of the children (n = 200) were unable to access more than eight 
tablets in 10 min (Ref. 27). In contrast, studies of pediatric 
accessibility of conventional ``snap type'' and ``continuous threaded 
type'' packaging show that most young children are able to gain access 
to products packaged in these types of conventional packaging in a 
relatively short period of time. Results from studies of ``snap type'' 
packaging show that with upward opening forces of less than 3 lb 
(average 1.9 lb), 96 percent of the children (n = 650) were able to 
open such packaging within 12 to 75 seconds (Ref. 28). Results from 
studies of pediatric accessibility of conventional, 33 mm diameter, 
``screw type'' packaging and having caps with 2, 4, 6, and 8, torque-
inch-pounds (TIP) rotational closing forces, show that approximately 
100 percent of the children (n = 400) were able to open the packaging 
within an average of 11 seconds. Fifty-four percent of the children 
were able to open ``screw type'' packaging with rotational closing 
forces of 10 to 25 TIP within 71 seconds (Ref. 29).
    As noted above, blister packaging is one type of unit-dose 
packaging. However, FDA does not agree with the AG petition's 
contention that blister packaging is necessary to ensure the safe use 
of iron-containing drugs and supplements. FDA tentatively finds that 
requiring a specific type of unit-dose packaging may be more 
restrictive than necessary if other types of unit-dose packaging 
accomplish the same objective. As discussed above, other types of 
conventional unit-dose packaging provide a comparable length of time 
for children to open as that required by conventional blister 
packaging.
    With regard to the child-resistant component of the AG petition's 
recommendation, FDA notes that CPSC has established regulations that 
require CRP's for iron-containing drugs and dietary supplements in 
packages that contain 250 mg or more total iron (16 CFR 1700.14(a)(12) 
and (13)). In addition, CPSC has promulgated regulations for 
performance standards to establish the effectiveness of CRP's (16 CFR 
1700.20). FDA finds that establishing CRP's standards for iron-
containing drugs and dietary supplements therefore would be redundant 
and could place an unnecessary regulatory burden on manufacturers of 
such iron-containing products. Furthermore, requiring CRP's for all 
iron-containing products with 30 mg or more iron per dosage unit would 
circumvent the intention of the PPPA to allow access by elderly and 
handicapped persons who are unable to use such household substances 
when packaged in compliance with CRP's requirements. Therefore, FDA is 
not proposing to separately require CRP's of iron-containing drugs and 
dietary supplements.
3. Proposed Packaging Requirements
    FDA is proposing to amend its regulations to establish safe 
conditions of use for iron-containing products by requiring that all 
such products that contain 30 mg or more iron per dosage unit be 
packaged in nonreusable, unit-dose packaging. FDA tentatively concludes 
that the use of iron and iron salts in products at potencies at or 
above 30 mg iron per dosage unit is not safe (and, therefore, is not 
GRAS) unless the food to which it is added, or the drug which contains 
it, is packaged in a manner that is adequate to prevent unintended 
ingestion by children. Thus, while iron and several of its salts will 
continue to be listed as GRAS under 21 CFR part 182 for use as dietary 
supplements and under part 184 (21 CFR part 184) for use as nutrient 
supplements, FDA is proposing to add Sec. 170.55, which will require 
unit-dose packaging when iron or iron salts are used at a level of 30 
mg or more per dosage unit in dietary supplements. Section 170.55 will 
also apply to approved food additive uses of iron salts in foods for 
special dietary and nutritional uses. Unit-dose packaging of drug 
products that contain 30 mg or more of iron per dosage unit is required 
under proposed Sec. 310.518(a).
    a. Rationale for requiring unit-dose packaging for iron-containing 
products with 30 mg or more iron per dosage unit. FDA is proposing to 
require unit-dose packaging for iron-containing drugs and supplements 
with 30 mg or more iron per dosage unit to ensure that the use of these 
products is safe. FDA's tentative conclusion to use 30 mg per unit-dose 
as the threshold for requiring unit-dose packaging is based on its 
consideration of a number factors including: (1) The amount of ingested 
iron that can cause pediatric fatality; (2) the amount of ingested iron 
that can cause significant iron poisoning; (3) the average number of 
dosage units associated with pediatric fatalities; (4) the types and 
potency of iron-containing products associated with pediatric iron 
poisoning fatalities; (5) information on how iron products are sold; 
and (6) the citizen petitions that were submitted to FDA. These factors 
pointed to the use of 30 mg per unit-dose as a threshold.
    As discussed above, the toxicity of any iron ingestion is related 
to the total amount of iron ingested and absorbed (section I.B. of this 
document). Ingestion of 250 mg iron per kg of body weight (2.5 g total 
iron for a 10 kg child) is typically considered to be a lethal dose of 
iron. However, there have been reports of fatalities from ingestion of 
lesser amounts (less than 2.5 g) of iron, and the available data bear 
this out. For example, Table 5 shows that several pediatric fatalities 
have been associated with ingestion of approximately 1 g of iron. 
Moreover, the amount of iron that can cause serious adverse effects is 
given as 60 mg/kg (section I.B. of this document). For a 10 kg child 
this translates to 600 mg of iron.
    FDA recognizes that there is variability among individuals with 
respect to the lethal dose of iron. Because of this variability, and 
because of the variable size and age of children at risk, FDA 
tentatively concludes that, to protect the wide range of susceptible 
children, it is necessary through packaging measures (unit-dose 
packaging) to limit pediatric access to iron-containing drugs and 
dietary supplements at potencies that can be reasonably expected to 
provide 1 g of iron. Restricting pediatric access to this amount of 
iron by packaging measures will substantially reduce the potential for 
a fatal or significant iron poisoning outcome should an accidental 
pediatric ingestion of iron-containing products occur. As discussed 
above, because of the time and effort needed to access products 
contained in unit-door packaging, the likelihood that young children 
will be able to ingest a lethal amount of iron will be significantly 
reduced, thereby reducing the likelihood that they will be seriously 
injured or die.
    In the 37 case reports of iron poisoning fatalities available, the 
average number of dosage units ingested by the pediatric victim was 39 
tablets or capsules, with a range of 5 to 98 (Table 2). FDA notes that 
ingestion of 39 tablets or capsules at potencies of 25 to 30 mg iron 
per dosage unit is sufficient to provide a potentially lethal dose of 
iron (i.e., approximately 1,000 mg) to a young child.
    As for the types of products that have been involved in pediatric 
iron poisonings, none of the 37 pediatric fatalities was reported to be 
associated with a multivitamin/mineral supplement product. All of the 
products reported to be involved in these fatalities were either single 
or double nutrient products that were provided for use as prenatal 
supplements. Single or double nutrient iron-containing products 
generally contain 30 mg or more iron per dosage unit.
    As for the potency of the products involved, all of the pediatric 
fatalities were reported to be associated with iron-containing products 
at potencies of 40 mg iron or more per dosage unit. FDA is not aware of 
any pediatric iron poisoning fatalities associated with iron-containing 
products whose potency was less than 40 mg iron per dosage unit. 
Moreover, only 1 of the 37 pediatric fatalities was reported to be 
associated with an iron-containing product that contained less than 60 
mg iron per dosage unit. Thus, FDA observed that requiring unit-dose 
packaging of products that contain 30 mg or more iron per dosage unit 
will provide about a two-fold margin of safety from the potency of 
products that have usually been associated with pediatric fatalities.
    The information available to the agency shows that products that 
contain 30 mg or more iron per dosage unit are primarily sold to women 
of childbearing age for prenatal use. Prenatal iron-containing products 
may be obtained as dietary supplements or prescription drug products. 
FDA notes that all of the iron-containing products associated with the 
37 pediatric poisoning fatalities were apparently obtained as prenatal 
drugs or supplements. FDA finds that prenatal iron-containing drugs and 
supplements present the greatest potential for pediatric iron 
poisonings and fatalities because of their iron content, and because 
they are likely to be available in households with young children. 
Prenatal iron-containing products are likely to be in households with 
young children either because they remain in the household after 
childbirth, or because young children are present in the household 
during pregnancy.
    Fourth, FDA notes that both the AG and NDMA citizen petitions 
recommended 30 mg iron per dosage unit as an appropriate level to 
establish additional safeguards to reduce the incidence of pediatric 
iron poisonings.
    Therefore, FDA is proposing unit-dose packaging for all dietary 
supplements and drugs containing 30 mg or more iron per dosage unit. 
FDA tentatively concludes that unit-dose packaging will reduce the 
incidence of pediatric poisonings by providing the additional 
safeguards necessary to limit pediatric access to a potentially fatal 
amount of iron.
    b. Practical effect. As discussed above, CPSC's child-resistant 
packaging regulations require that any iron-containing drug or dietary 
supplement packaged in a container with 250 mg or more iron must be 
packaged in accordance with their child-resistant packaging regulations 
(16 CFR 1700.14(a)(12) and (a)(13)). Therefore, FDA anticipates that 
manufacturers and distributors of drugs and dietary supplements 
containing 30 mg or more iron per dosage unit, and containing 250 mg or 
more total iron per package, under this proposed action and CPSC's 
current regulations (16 CFR 1700.14(a)(12) and (a)(13)), a manufacturer 
or packer will have the option of packaging the product in child-
resistant unit-dose packaging (e.g., child-resistant blisters, child-
resistant pouches), or of exercising its right to an exemption to 
CPSC's special packaging requirements to allow access by elderly or 
handicapped persons. However, under this proposed rule, in the latter 
case, the products will have to be packaged in conventional unit-dose 
packaging and will be subject to CPSC's requirements for exempt 
packaged products (16 CFR 1700.5).
    FDA tentatively concludes that, regardless of which packaging 
option a manufacturer or packer uses, unit-dose packaging of all iron-
containing drugs and supplements that contain 30 mg or more per dosage 
unit will ensure the safe use of such products by limiting unintended 
access to such products by young children.
    In proposing this action, it is not FDA's intention to circumvent 
the aim of the PPPA to allow access by elderly and handicapped persons 
who may be unable to use such household substances when packaged in 
CRP's. The agency requests comments on the effect that this proposed 
packaging requirement will have on the accessibility of iron-containing 
drugs and dietary supplements to elderly and handicapped persons.
    c. Iron-containing drug products that are removed from and 
dispensed in other than unit-dose packaging are adulterated and 
misbranded. In order to be exempt from the requirement in section 
502(f)(1) of the act that a drug bear adequate directions for use, a 
prescription drug product for human use must bear, among other things, 
a statement, directed to the pharmacist, specifying the type of 
container to be used in dispensing the drug product to maintain the 
product's identity, strength, quality, and purity (21 CFR 
201.100(b)(7)). However, directions for repackaging are ``not required 
for prescription drug products packaged in unit-dose, unit-of-use, or 
other packaging format in which the manufacturer's original package is 
designed and intended to be dispensed to patients without 
repackaging.'' (Id.) If FDA ultimately determines that unit-dose 
packaging is necessary to ensure the identity, strength, quality, and 
purity of iron- containing drug products, the agency would consider 
such products that are dispensed to consumers in other than unit-dose 
packaging to be adulterated and misbranded. Products marketed by the 
manufacturer in unit-dose packaging would remain exempt from the 
requirement for repackaging instructions because FDA expects that 
pharmacists will not compromise such packaging systems.
    FDA has, in certain cases in the past, prohibited pharmacists from 
repackaging products because the original manufacturer's packaging was 
necessary to ensure the product's identity, strength, quality, and 
purity. In 1972, FDA concluded that improper packaging of nitroglycerin 
preparations was causing substantial loss of potency of the drug. 
Commonly used plastic containers and strip packaging failed to prevent 
appreciable evaporation of nitroglycerin from nitroglycerin tablets. 
FDA determined that it was necessary to require that these products be 
packaged and dispensed in glass containers to ensure the potency of the 
product ((37 FR 15859, August 5, 1972); 21 CFR 250.300 (1973)). In 
addition, manufacturers were required to include a statement directed 
to pharmacists that the product should be dispensed only in the 
original, unopened container (21 CFR 250.300(b)(1973)).
    FDA revoked the nitroglycerin packaging and labeling requirements 
in 1985 because action taken by FDA and the United States Pharmacopeial 
Convention, Inc., after publication of the requirements, had made them 
unnecessary and duplicative (50 FR 7584, February 25, 1985). When it 
proposed to revoke the regulation, FDA observed that the U.S.P. 
monograph for sublingual nitroglycerin tablets duplicated most of the 
packaging and labeling requirements that initially had been set forth 
in the rule (49 FR 24031, June 11, 1984). In addition, FDA found that 
the suitability of any packaging not in conformance with the rule or 
the monograph under CGMP regulations would have to be shown to FDA by 
adequate data (id.).
    Like the nitroglycerin regulation, this proposed regulation 
regarding iron-containing products is intended to address a public 
health problem that, FDA has tentatively concluded, can be alleviated 
by requiring specific packaging. As was the case with nitroglycerin 
before FDA required specific packaging, iron- containing products are 
not safe as currently packaged. FDA has tentatively determined that it 
is necessary to prohibit repackaging by pharmacists in order to protect 
product integrity and to provide the greatest assurance that iron-
containing products will be used safely and as intended.
    FDA recognizes that pregnant women can receive their iron 
supplements by way of third-party reimbursement, which generally 
requires that a health care professional prescribe the supplements. 
These women present their prescriptions to pharmacists who, often, 
repackage iron dietary supplements in pharmacy vials.
    FDA recognizes the vital importance of iron supplements to prenatal 
health care and emphasizes that the proposed rule should not diminish 
the availability of iron tablets to pregnant women or to any other 
patient population. FDA expects that pharmacists will dispense the 
tablets in their original unit-dose packaging. Under the proposed rule, 
pharmacists would be free to dispense iron-containing products in the 
manufacturer's box, or in any other outer container, as long as the 
original unit-dose packaging remained intact.
    FDA does not believe that the proposed mandatory packaging and 
labeling regulation will encroach upon the practice of pharmacy. Under 
the proposed requirement, products will reach the pharmacy in unit-dose 
packaging with a warning statement printed directly on the immediate 
wrapping or container. FDA tentatively concludes that such a 
requirement, rather than representing an encroachment on the practice 
of pharmacy, is necessary to ensure that consumers receive adequate 
warning about the serious dangers associated with the use of iron-
containing drugs.

IV. Other Issues

A. Formulation and Appearance of Iron-Containing Products

    The AG petition recommended that FDA prohibit the manufacture and 
sale of adult formulations of iron-containing products that look like 
candy or contain a sweet outer coating. The AAPCC petition asked FDA to 
urge the industry to voluntarily reformulate iron-containing products 
containing 30 mg or more of iron per dosage unit to be in less 
attractive dosage units, specifically avoiding resemblance to popular 
candies.
    NDMA asked FDA to reject the recommendation from the AG petition 
for several reasons. First, NDMA stated that ``candy can be--and is--
made to look like just about any other consumable product. Once a 
supplement manufacturer decides on a shape, size, color--of which there 
are limited selections--for a supplement product, a candy manufacturer 
could choose independently to introduce a candy that looks like that 
dietary supplement.'' Second, NDMA stated that it is not known what a 
pill looks like to a very young child. ``A very young child puts 
everything into his or her mouth, and in fact there are no hard data to 
say that candy-like appearance is why a very young child chooses to 
investigate a consumable consumer product. It is quite likely that it 
may be even more important that the very young child sees his or her 
mother take that pill every day.'' Third, NDMA asserted that candy-like 
appearance is in the eye of the beholder and is simply too subjective a 
standard. It would be impossible to have an objective measure of candy-
like appearance. Thus, NDMA stated that any provision for ``no candy- 
like appearance'' would not be practical and would be difficult to 
administer because of the subjective nature of assessing candy-like 
appearance.
    The agency does not have data or other information specific to the 
question of how a candy-like appearance may contribute to the potential 
for an iron-containing supplement product to constitute a hazard to a 
young child. FDA's tentative view, however, is that it may not be 
possible to objectively measure the candy-like appearance of iron-
containing products. Therefore, FDA requests comments on the use of 
``candy'' and ``colorful'' coatings on iron-containing drugs and 
dietary supplements and information on whether these types of coatings 
make iron-containing products hazardous to infants and young children 
because of their apparent attractiveness. If the information received 
presents an objective basis for additional steps that FDA could take to 
limit the appeal of iron-containing products to young children, FDA 
will consider action in this regard.

B. Forms of Iron That May Be Less Toxic

    NAS has reported that, during the period from 1970 to 1987, food 
manufacturers increased their use of elemental iron (i.e., finely 
divided metallic iron) by 120-fold and decreased their use of ferrous 
sulfate by 30 percent (Ref. 30). The increase in the use of elemental 
iron in conventional food may be attributed to its low cost and minimal 
reactivity in food. FDA is not aware of any reports of accidental 
ingestions or adverse reactions associated with the few commercially 
available iron-containing dietary supplements and drug products that 
incorporate elemental iron instead of an iron salt.
    Three basic types of elemental iron powders are marketed for use in 
foods. The three types are reduced iron, electrolytic iron, and 
carbonyl iron. The term ``carbonyl'' refers to the production process, 
not the composition of the product. The bioavailability of these 
various elemental iron sources is dependent primarily on their physical 
characteristics, which in turn depend on the manufacturing method. For 
example, higher relative bioavailabilities of elemental iron are 
obtained with smaller particle sizes.
    Some evidence suggests that carbonyl iron may be a useful 
substitute for the more commonly used chemical compounds of iron in 
reducing risk of accidental iron poisonings. Data from studies in 
animals suggest that carbonyl iron may be only 1/100th as toxic as 
ferrous sulfate in single doses, i.e., the LD50 (lethal dose for 
50 percent of the test group) of ferrous sulfate is approximately 0.30 
g Fe/kg (Ref. 32) and the LD50 for carbonyl iron is approximately 
30.0 g Fe/kg body weight (Ref. 31). Thus, carbonyl iron, in comparison 
with ferrous sulfate, appears to have a much larger margin of safety 
between the level that would provide adequate iron nutrition and the 
level that causes acute toxicity. Consequently, carbonyl iron may be 
inherently safer to use. At the same time, data from human subjects 
indicates that the overall bioavailability of carbonyl iron in 
supporting the nutritional functions of iron is about 70 percent that 
of ferrous sulfate (Ref. 31). Thus carbonyl iron is reasonably as 
effective in providing iron in the amounts needed to achieve the 
nutritive effects of iron. Its use may help to reduce the risk of iron 
poisoning in children.
    FDA specifically requests comments on the appropriateness of 
elemental iron as a source of iron in drugs and dietary supplements, 
focusing on whether its use in iron-containing products would decrease 
the risk of pediatric poisonings while providing desirable iron 
nutrition to those who need iron supplementation. The agency is 
interested in receiving data on the potential of elemental iron for 
acute toxicity in humans and particularly in children.
    FDA will carefully consider any information it receives on this 
subject. If the information is persuasive in establishing that the use 
of elemental iron would substantially decrease the risk of pediatric 
poisoning while allowing for effective dietary iron supplementation, 
FDA will consider exempting iron-containing products that incorporate 
elemental iron from any regulations that result from this rulemaking.

C. Educational Efforts

1. Review of Consumer Education Issues in Citizen Petitions
    Two of the three petitions submitted discussed the benefits of 
educational efforts for the public and health professionals, focusing 
on the prevention of accidental pediatric iron poisoning. The AAPCC 
petition and the NDMA petition advocated educational efforts and 
outlined specific actions as described herein.
    a. The AAPCC petition. The AAPCC petition called for the initiation 
of an FDA educational campaign for four different segments of the 
population. The four target segments are: (1) Parents, babysitters, 
daycare providers, and other consumers; (2) pediatricians; (3) 
obstetricians; and (4) other health professionals such as physicians, 
others who can prescribe iron, and pharmacists. The petition suggested 
that pediatricians discuss the dangers of an iron overdose with parents 
at the 6-month checkup, and that obstetricians inform mothers at the 
final postpartum checkup.
    b. The NDMA petition. In the fall of 1993, NDMA in cooperation with 
CPSC, developed and launched a national consumer education campaign to 
be carried out in conjunction with the voluntary labeling and packaging 
measures (described above in section I.D. of this document) that were 
undertaken by the members of NDMA and NNFA. The purpose of the 
campaign, as stated in the petition, is to inform adults about how to 
protect children from accidental iron poisoning. The three major themes 
of the educational campaign mirror some of the messages in NDMA's and 
NNFA's voluntary warning statements for iron-containing products and 
are as follows:
    (1) Adult awareness of the dangers to children if iron is 
accidentally swallowed in excess,
    (2) Reclose the child-resistant package after every use, and,
    (3) Keep iron-containing products out of the reach of children.
    NDMA and CPSC began the educational campaign by distributing video 
and print news releases, radio news releases in English and Spanish, 
and public service announcements emphasizing the three-pronged message. 
The public service announcements are also being sent to consumer, 
health, and women's magazines.
2. Agency Response
    FDA agrees with the petitioners that the public needs to be 
informed of the dangers of pediatric iron poisoning through public 
education efforts. Such efforts can be one important element in 
combating a cause of injury and deaths that has affected thousands of 
children over the last approximately 10 years. Thus, FDA commends NDMA 
and CPSC for their joint efforts in developing and distributing a 
national educational campaign targeting accidental iron poisoning, to 
coincide with the voluntary packaging and labeling measures for iron-
containing products that have been undertaken by the members of NDMA 
and NNFA. FDA believes that the themes of this campaign are appropriate 
and are responsive to a fundamental need that exists for more awareness 
among adults of the dangers of pediatric iron poisoning and of the 
means to prevent these poisonings. Because of the seriousness of the 
problem, i.e., accidental iron ingestion is the leading cause of 
poisoning deaths among children, FDA intends to contribute to educating 
the public.
    Accordingly, FDA is developing materials for a public information 
campaign that would address AAPCC's request and complement NDMA and 
CPSC's educational efforts by emphasizing the same awareness and 
prevention elements as the NDMA/CPSC campaign, as follows:
    (1) Iron-containing products can seriously injure or even kill 
young children who accidentally swallow them.
    (2) Reclose the child-resistant package completely and every time 
iron-containing products are opened.
    (3) Keep all containers of iron-containing products out of reach of 
children all the time.
    FDA's campaign will also address steps that should be taken by 
adults if an accidental ingestion of iron occurs:
    (4) When children accidentally ingest iron-containing products, the 
attending person should quickly call a poison control center and follow 
their instructions, or take the child to an emergency room.
    (5) Although the first symptoms, vomiting and diarrhea, may occur 
within 30 minutes, and these symptoms may be followed by an appearance 
of recovery, the child may still be in danger. Therefore, immediate 
professional consultation is critical.
    The FDA materials will include print pieces available for 
distribution to different audiences, such as a backgrounder, a flyer, 
an FDA Consumer magazine article, and camera-ready newspaper columns. 
The FDA Medical Bulletin, which has 1,000,000 physician subscribers, is 
another vehicle that can be used to publicize this message.
    The diversity of the audiences to be targeted by FDA's information 
campaign will include the AAPCC's suggested target populations. The FDA 
backgrounder will be a detailed handout for health professionals and 
consumer organizations. The flyer will be a short piece conveying the 
elements of FDA's message in a simple and concise manner for use in the 
home by parents, grandparents, and babysitters. The FDA Consumer 
article will reach the 23,000 subscribers to the magazine, a group that 
includes physicians and other health professionals, educators, 
reporters, and consumers. The camera-ready newspaper columns will be 
distributed to 10,000 smaller-circulation newspapers nationwide. In 
addition, FDA intends to provide information to consumer newsletter 
editors and consumers through ``Dear Editor'' letters and ``Dear 
Consumer'' letters about the efforts to prevent accidental pediatric 
iron poisoning.
    Different offices in FDA, such as the Office of Public Affairs and 
the Office of Consumer Affairs, and offices of the Department of Health 
and Human Services will assist with the distribution of these 
materials. FDA intends to utilize its staff of public affairs 
specialists to distribute these materials to the widely varied 
constituencies with whom these specialists frequently interact, such as 
other government agencies at the Federal, State, and local levels, 
advocacy organizations, trade associations, consumer groups, health 
professional organizations, and other interested groups.

V. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this action. FDA has concluded that the action will not have 
a significant impact on the human environment, and that an 
environmental impact statement is not required. The agency's finding of 
no significant impact and the evidence supporting that finding, 
contained in an environmental assessment, may be seen in the Dockets 
Management Branch (address above) between 9 a.m. and 4 p.m., Monday 
through Friday.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.

A. Description of the Industry

    There are approximately 300 iron-containing products that may be 
affected by these proposed actions, of which approximately one-half 
contain 30 mg or more iron per dosage unit. The types of iron-
containing products that have been associated with poisonings of young 
children are products offered in solid oral dosage form as multi-
vitamin/mineral supplements, products intended for use as iron 
supplements, and drug products. Typically, multi-vitamin/mineral 
supplements provide less than 30 mg of iron per dosage unit. Iron 
supplements and drug products typically contain 30 mg or more iron per 
dosage unit. The proposed action to require warning statements would 
affect all iron-containing products. On the other hand, FDA is 
proposing to require unit-dose packaging for products containing 30 mg 
or more iron per dosage unit. Therefore, most multi-vitamin/mineral 
supplements would be subject to the warning statement requirements but 
not to the packaging requirements. Most iron supplements and iron-
containing drug products would be subject to both proposed 
requirements.
    Iron-containing products may be purchased by consumers on their own 
initiative as dietary supplements, or they may be prescribed by 
physicians. The information available to the industry suggests that the 
overwhelming majority of iron- containing products are currently 
packaged in bottles (Ref. 33). Additional information suggests that 
iron-containing products administered in hospitals are commonly 
packaged in unit-dose packaging (Ref. 34). Unit-dose packaging is 
preferred by hospitals because with this type of packaging, each dosage 
unit has an identification and an expiration date, and the hospital can 
continue to use unit-dose packaged drugs rather than having to discard 
a bottle opened for a specific patient after that patient is 
discharged. Based on this information, FDA assumes that iron-containing 
products dispensed in hospitals are currently packaged in unit-dose 
packaging.
    According to the National Center for Health Statistics, of the 
approximately 169 million persons of age 18 or older, 19.7 percent 
consume iron-containing products (Ref. 35). If it is assumed that each 
individual consumes one dosage unit per day,there are approximately 12 
billion dosage units of iron- containing products consumed annually in 
the United States. The agency does not have complete information on the 
number of dosage units of iron-containing products that contain 30 mg 
or more iron. However, because only pregnant women require 30 mg/day, 
FDA assumes that the portion of higher-dosage iron-containing products 
can be estimated by the number of pregnant women in the United States. 
In 1991, the most recent year for which data are available, there were 
4.1 million live births (Ref. 36). FDA is assuming a one-to-one 
correspondence between the number of live births and the number of 
pregnancies in concluding that there are about 4.1 million pregnant 
women on any one day in the United States. The number of live births 
may overestimate the number of pregnant women because multiple births 
by one woman are ignored. Also, the number of live births ignores 
pregnancies not resulting in a live birth, which may result in an 
underestimate of the number of pregnant women. If it is assumed that 
the number of live births is an estimate of the number of dosage units 
of products containing 30 mg or more iron, then the number of dosage 
units per year can be estimated at 4.1 million times 365 days per year 
or about 1.5 billion.

B. Regulatory Options

    There are many possible regulatory alternatives available that may 
reduce the number of cases of pediatric poisonings from the accidental 
ingestion of iron-containing products. The options include packaging, 
warning statements, product reformulation, and educational efforts.
1. Packaging
    One regulatory option available to FDA is to require that products 
containing iron be packaged in unit-dose containers. Because of the 
CPSC regulations, most iron-containing products currently must be 
packaged in CRC's. Therefore, the effect of this option would be to 
require child resistant unit-dose packaging for most of these products. 
FDA could require unit- dose packaging for all products or for only 
higher dosage products. For comparison, FDA will consider potencies of 
30 mg, 40 mg, and 60 mg as the minimum potencies per dosage unit of 
iron that would trigger unit-dosage packaging.
    a. Costs. There are four types of costs associated with a mandated 
packaging change: Equipment, materials, transportation, and 
administrative costs. If this option is selected, many packagers of 
iron-containing products will be required to purchase new packaging 
equipment. The cost of equipment used in packaging blisters, one common 
form of unit-dose packaging, is between $50,000 and $250,000, or on 
average $132,500. New equipment will not be purchased for each product 
sold because some manufacturers already possess unit-dose packaging 
equipment.
    The cost of child-resistant bottles, currently the most common form 
of packaging, is approximately $7 per 1,000 dosage units. Child-
resistant blisters cost approximately $9 per 1,000 dosage units, a 
difference of $2 per 1,000 dosage units.
    FDA does not have information to estimate additional transportation 
costs caused by unit-dose packaging requirements and requests comments 
on increased transportation costs.
    Additionally, firms are expected to incur administrative costs of 
approximately $500 per product in the first year. Administrative costs 
are the dollar value of the incremental administrative effort expended 
in order to comply with a regulation. Administrative activities 
include, but are not limited to, identifying the underlying policy of 
the regulation, interpreting that policy relative to the firm's 
products, establishing a corporate position, formulating a method for 
compliance, and managing the compliance effort.
    If FDA were to require unit-dose packaging for all iron- containing 
products irrespective of their potency per dosage unit, the cost of 
equipment would be $39 million (300 products  x  $132,500). The annual 
materials cost would be $24 million ((12 billion dosage units/1,000) 
x  $2.00), or $260 million over the next 20 years (discounted at 7 
percent). Administrative costs would be $150,000. Total costs 
associated with requiring unit- dose packaging for all iron-containing 
products would be $299 million over 20 years (discounted at seven 
percent).
    If FDA were to require unit-dose packaging for products with 30 mg 
iron/dosage unit or higher, the cost of equipment would be $20 million 
(150 products  x  $132,500). The cost of materials would be $3 million 
per year or $32 million over 20 years (discounted at 7 percent). 
Administrative costs would be $75,000 (150  x  $500). Total costs 
associated with requiring unit-dose packaging for products containing 
30 mg or more per dosage unit would be $52 million over 20 years 
(discounted at 7 percent).
    If FDA were to require unit-dose packaging for products with 40 mg 
iron/dosage unit or higher, the cost of equipment would be $13 million 
(100 products  x  $132,500). The cost of materials would be $2 million 
per year or $22 million over 20 years (discounted at 7 percent). 
Administrative costs would be $50,000 (100  x  $500). Total costs 
associated with requiring unit-dose packaging for products containing 
40 mg or more iron per dosage unit would be $35 million over 20 years 
(discounted at 7 percent).
    If FDA were to require unit-dose packaging for products with 60 mg 
iron/dosage unit or higher, the cost of equipment would be $5 million 
(37 products  x  $132,500). The cost of materials would be $0.8 million 
per year or $8 million over 20 years (discounted at 7 percent). 
Administrative costs would be $19,000 (37  x  $500). Total costs 
associated with requiring unit-dose packaging for products containing 
60 mg or more iron per dosage unit would be $6 million over 20 years 
(discounted at 7 percent).
    b. Benefits. In the past 7 years, there have been at least 37 cases 
of pediatric fatality from the accidental ingestion of iron-containing 
products, or a mean of 5.3 deaths per year. Data on the potency of the 
product consumed is available for 25 cases.
    In all cases for which information is available, the product 
consumed contained at least 40 mg of iron. In the same 7-year period, 
there were nearly 190 poisonings reported that were life threatening or 
that resulted in permanent injury, and over 2,000 reported poisonings 
requiring some form of treatment. FDA believes that most, if not all, 
such deaths and some poisonings can be prevented by requiring that 
higher-potency iron-containing products be packaged in unit-dose 
packaging. Studies indicate that the child is less likely to consume 
the number of dosage units that may be fatal.
    Although no studies have attempted to directly estimate the value 
of reducing the risk of death and illness to children in particular, 
many studies have attempted to estimate the value of reducing these 
risks to adults. Most of these estimates are based on wage differences 
between high and low risk jobs and, thus, are derived from the labor 
market decisions of middle-aged adults. Although these estimates 
cluster around a fairly small range, $2 million to $10 million, it is 
not clear that these estimates are valid when applied to children.
    FDA has used estimates of the value of reducing risks to adults to 
a level that would avoid one statistical fatality between $1.5 million 
and $5 million in past rulemaking proceedings, including recent food 
labeling regulations and a current proposal to require domestic and 
foreign processors and importers of fish and fishery products to 
establish Hazard Analysis Critical Control Points (HAACP) controls to 
prevent the occurrence of hazards that could affect the safety of these 
seafood products (59 FR 4142, January 28, 1994). One method of 
estimating the value of reducing risks to children is to adjust the 
value of reducing risks to adults by accounting for the difference in 
the number of life-years saved. Under this approach, an often used 
estimate of the value of the risks to adults to a level that would 
avoid one statistical fatality is $5 million for a middle-aged adult. 
If this value does not vary with life years remaining (that is, if we 
assume that an infant is willing to pay the same amount to avoid risk 
of death as a 40-year old would be willing to pay and assuming the same 
distribution of wealth exists in both age groups), then $5 million is a 
reasonable estimate. If, however, this value does vary with life years 
remaining, then the corresponding value for reducing the risks to small 
children would be $11 million. FDA will use these figures ($5 to 11 
million) to provide a range of estimates. Although FDA is using these 
values in this analysis, FDA stresses the tentative nature of these 
estimates and requests comments on an appropriate method of estimating 
the value of reducing risks to children.
    The number of fatalities prevented by requiring unit-dose packaging 
for iron-containing products at any potency level less than 60 mg iron/
dosage unit will not be significantly different. Because all fatalities 
for which FDA has information resulted from ingestion of dosage units 
of at least 40 mg iron potency, all three of these options (all 
products, 30 mg and above, and 40 mg and above) would result in 
benefits of reducing an average of 5.3 deaths per year, valued at 
between $280 million and $618 million over 20 years (discounted at 7 
percent).
    If, however, FDA were to select the option of requiring unit-dose 
packaging for all iron-containing products of potencies of 60 mg iron 
per dosage unit and above, an average of 5 deaths would be prevented 
per year leading to total discounted benefits of preventing fatalities 
over 20 years of between $265 million and $583 million.
    Requiring unit-dosage packaging for iron-containing products will 
also reduce the number of nonfatal cases of pediatric iron poisoning. 
FDA has obtained from CPSC case reports for 78 iron ingestions 
necessitating emergency room treatment reported over 7 years, or an 
average of 11 illnesses per year. The potency of the product consumed 
was reported for 12 cases. In five of those cases, the potency reported 
was under 30 mg iron/dosage unit. In seven cases, the potency reported 
was over 60 mg iron/dosage unit. AAPCC data shows that from 1986 
through 1992 there were nearly 190 reported poisonings that were life 
threatening or that resulted in permanent injury, and over 2,000 
reported poisonings requiring some form of treatment as a result of 
accidental ingestion of adult and pediatric iron-containing products, 
or an average of 286 per year. FDA is unable to predict the percentage 
of these nonfatal poisonings which would be prevented by substituting 
unit-dose packaging for bottles. It is possible that not all nonfatal 
poisonings will be prevented because a child can still gain access to 
the product. However, he or she will gain access to fewer dosage units 
than if the product is in a bottle. FDA requests comments on this 
issue.
    Using a methodology developed previously for FDA to value morbidity 
risks, FDA is able to estimate the value of reduced risk of nonfatal 
poisoning. By comparing similar symptoms and medical interventions, the 
agency has derived an estimate of the value of preventing a nonfatal 
pediatric iron poisoning of $20,000 per case. (Ref. 37) As stated 
previously, 7 out of 12 cases of nonfatal poisonings were a result of 
ingestion of products of potencies over 60 mg iron per dosage unit. If 
this proportion can be extrapolated to the remaining cases for which 
information is unknown, and if unit-dose packaging will prevent all 
nonfatal cases (at least 2,000 cases in 7 years), then requiring unit-
dose packaging for products of 60 mg or more iron per dosage unit will 
add approximately $35 million to the benefits over the next 20 years 
(discounted at seven percent). Because no nonfatal cases for which 
information is known were a result of ingesting products with potencies 
between 30 mg and 60 mg iron per dosage unit, the options of requiring 
unit-dose packaging for products with potencies of 40 mg and 30 mg iron 
per dosage unit will not add more to the benefits than the previous 
option. Still assuming that all nonfatal cases can be prevented by 
unit-dose packaging, requiring packaging changes for all products would 
result in reduced morbidity valued at $61 million over the next 20 
years.
    The total value of the benefits of unit-dose packaging options is 
the sum of the value of reducing both mortality and morbidity risks. 
The selected option, requiring unit-dose packaging for all products 
containing 30 mg or more iron per dosage unit, would result in benefits 
of reducing mortality risks of between $280 million and $618 million 
and reduced morbidity valued at $61 million. Therefore, total 
discounted benefits of this option are between $315 million and $618 
million. Table 7 summarizes the costs and benefits of the packaging 
options. 

      Table 10.--Costs and Benefits of Unit-Dose Packaging Options      
                        [In millions of dollars]                        
------------------------------------------------------------------------
                                  Total   Total benefits                
         Trigger level            costs                    Net benefits 
------------------------------------------------------------------------
All products...................     $299     $341 to 679      $42 to 380
>30 mg.........................       52      315 to 653      263 to 601
>40 mg.........................       35      315 to 653      280 to 618
>60 mg.........................        6      300 to 618      294 to 612
------------------------------------------------------------------------

2. Warning Labels
    a. Costs. Every petition submitted to FDA requested that the agency 
require that iron-containing product labels contain warning statements 
about the potentially fatal effects of pediatric poisonings from 
accidental ingestion of iron-containing products. The cost associated 
with warning statements are the cost of redesigning the label, 
disposing of old labels, and administrative costs. In January, 1994, 
FDA published final rules regarding nutrition labeling of dietary 
supplements in accordance with the Nutrition Labeling and Education Act 
of 1990 (NLEA) and the Dietary Supplement Act of 1992. In its analysis 
of those rules (59 FR 352), FDA determined that the incremental cost of 
label changes for dietary supplement manufacturers is approximately 
$1,500 per label. FDA is proposing that the label warning statement be 
printed directly on the immediate container of the product, i.e., the 
container that holds the tablet or capsule, and on the principal 
display panel of the retail package, if such package is not the 
immediate container. If a product is sold in unit-dose packaging, the 
product would be required to bear the warning directly on each unit-
dose package or on a strip of unit-dose packages in such a way that 
separating the unit-dose packages would not destroy the warning 
labeling. Manufacturers of all 300 iron-containing products will be 
required to change their labels on both the product container and the 
retail package to incorporate warning statements. However, because 
manufacturers of iron-containing products with 30 mg or more per dosage 
unit will also be required to change their packaging, they will not 
incur any incremental cost in adding a warning statement to the product 
container. Therefore, the labeling costs will be incurred by all 300 
products for the retail package and for 150 products for the product 
container. The total cost would be a one-time cost of $675,000 (300  x  
1.5  x  $1,500).
    An additional cost of this regulation may be an increase in iron 
deficiency anemia if susceptible adults react inappropriately to a 
warning label targeted for children. According to NHANES II, 
approximately 7.2 percent of females age 15 to 19 and 6.3 percent of 
females age 20 to 44 are iron-deficient but less than one-fourth of 
these women had anemia associated with the deficiency. In addition, 
males had a prevalence of less than 1 percent. FDA requests comments on 
this issue.
     b. Benefits. Warning statements will only prevent pediatric iron 
poisonings to the extent that they lead to changes in the behavior of 
the adult controlling the use of the product (presumably the parent). 
Whether the warning messages prescribed in this proposed rule will 
cause a change in behavior will depend on a number of factors, 
including the degree to which the statement is noticed, read, and 
understood.
     There is some evidence that warning statements can change 
behavior. For example, research indicates that rate of increase of 
sales of diet soft drinks declined after saccharin warnings were put on 
the labels of these products (Ref. 38). FDA is unable to predict 
exactly how many cases of pediatric iron poisoning will be prevented as 
a result of warning statements. To the extent that warning statements 
will cause adults to take proper care in handling iron-containing 
products, and to the extent that such care is not taken in the absence 
of warning statements, some cases of pediatric iron poisoning will be 
prevented.
     If the agency requires unit-dose packaging, and this measure is 
100 percent effective in preventing both fatal and nonfatal cases, then 
there are no benefits from warning labels on these products. However, 
for those products still packaged in bottles, warning labels may have 
an impact. If each nonfatal case of iron poisoning is valued at $20,000 
and the one-time cost of warning statements is $675,000, then benefits 
of requiring warning statements will exceed costs if warning statements 
prevent at least three nonfatal cases every year for the next 20 years 
(discounted at 7 percent).
3. Product Reformulation--Appearance
    Two petitions recommended product reformulation as a preventive 
measure. The petitions suggested that some adult formulations of iron-
containing products look and taste like candy and thus are more 
appealing to children. The petitions stated that if the product were 
less appealing to children, the incidence of accidental ingestion would 
be reduced. The petition from NDMA urged FDA to reject reformulation 
for several reasons, including a lack of knowledge about what a pill 
looks like to a very young child, and about why the child is motivated 
to consume the product. The agency does not have information to 
determine either the costs or the benefits of reformulating the 
appearance of iron-containing products. Because reformulation costs are 
highly dependent on the individual decisions of firms, they are very 
difficult to estimate. Also, because there are currently no objective 
measures of the candy-like appearance of iron-containing products, the 
benefits are also difficult to determine.
4. Product Reformulation--Taste
    Another possibility is to add a bitter substance to products 
containing iron which would discourage multiple ingestions. Such 
substances have been used in the past on products which discourage 
thumbsucking and nailbiting. It is highly likely that such a substance 
will not add significantly to the cost of producing iron-containing 
products. FDA requests information on a policy option that would 
require altering the taste of iron-containing products. Such 
information would include the potential substances that would make the 
pills bitter and data on their safety and whether this approach would 
be effective in preventing acute overdose of iron-containing products 
by children. FDA notes, however, that such an option may have the 
unintended side effect of causing persons who need iron supplementation 
to avoid the product. FDA requests information on both the costs and 
benefits of this option.
5. Forms of Iron that May be Less Toxic
    As previously discussed in this document, some evidence suggests 
that carbonyl iron, an elemental iron powder, seems to be effective in 
the prevention or treatment of iron deficiency, and that it might be 
significantly less toxic than other forms of iron commonly used in 
iron-containing products. The agency requested data on the acute 
toxicity in humans, and particularly in children, of elemental iron. 
FDA stated that, if information is received that is persuasive that the 
use of elemental iron will substantially decrease the risk of pediatric 
poisoning while allowing for effective dietary iron supplementation, it 
will consider exempting iron-containing products that incorporate 
reduced iron from any regulations that result from this rulemaking. FDA 
does not have any information regarding the availability of such forms 
of iron for use in iron-containing products. Nor does FDA possess any 
information that would allow it to determine how many products would be 
reformulated with less toxic forms of iron in order to take advantage 
of such an exemption. FDA requests comment on the economic impact of 
exempting products containing less toxic forms of iron.
6. Consumer Education Campaign
    Two of the three petitions that FDA received advocated educational 
efforts for the public and health professionals. FDA agrees that the 
public needs to be informed of the dangers of pediatric iron poisoning. 
The fact that in 7 years over 2,000 poisonings have occurred that have 
required some kind of treatment indicates that the public is not aware 
of the potential for serious harm or death in young children from 
accidental ingestion of iron-containing products. FDA is developing 
materials for a public information campaign utilizing the channels 
available to the agency.
7. Effective Dates
    The agency is proposing to make any final rule that may issue based 
upon this proposal become effective 180 days after its publication in 
the Federal Register. FDA is requesting comments on this effective 
date. In general, costs of compliance for labeling and other 
requirements are less if longer compliance periods are provided because 
firms can incorporate mandatory changes to product, labeling, and 
packaging with regularly scheduled changes. FDA requests information on 
the ability of manufacturers of products that contain 30 mg or more 
iron per dosage unit to convert their packaging within the suggested 
compliance period.

C. Regulatory Flexibility

    The Regulatory Flexibility Act requires analyzing options for 
regulatory relief for small businesses when possible. FDA is not aware 
that any small businesses will be affected by this proposed rule. 
Therefore, FDA tentatively concludes that this proposed rule will not 
result in a significant burden on small businesses. FDA requests 
comments on any potential adverse effect on small businesses.

D. Summary

    FDA has examined the impact of the proposed rule in accordance with 
Executive Order 12866 and has determined that it is not an economically 
significant rule. The rule will result in total costs of approximately 
$53 million and discounted benefits of between $315 million and $653 
million over the next 20 years (discounted at 7 percent).
    FDA has also examined the impact of this proposed rule on small 
businesses in accordance with the Regulatory Flexibility Act. FDA is 
unaware of any iron-containing products manufactured by small 
businesses. Therefore, FDA has determined that this rule will not 
result in a significant burden on small businesses.

VII. Effective Date

    The agency is proposing to make any final rule that may issue based 
upon this proposal became effective 180 days after its publication in 
the Federal Register. The agency is requesting comments on the proposed 
effective date. All comments concerning the effective date should be 
accompanied by data to support or justify any change in the proposed 
effective date.

VIII. Comments

    The agency's intention in proposing this action is to reduce the 
incidence of pediatric iron poisonings from ingestion of iron-
containing supplements and drug products. FDA has examined all relevant 
information available to the agency. The agency requests comments on 
this proposed action and is particularly interested in receiving 
comments that bear on the effectiveness of the proposed action to 
reduce the incidence of pediatric iron poisoning.
    Interested persons may, on or before December 20, 1994, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. U.S. Consumer Product Safety Commission, ``Pediatric Iron 
Poisonings and Fatalities,'' p. 3, May 1994.
    2. ``Assessment of the Iron Nutritional Status of the U.S. 
Population Based on Data Collected in the Second National Health and 
Nutrition Examination Survey, 1976-1980,'' Federation of American 
Societies for Experimental Biology, Life Sciences Research Office, 
Bethesda, MD (under contract to FDA, Contract No. 223-83-2384, 
August 1984).
    3. Subcommittee on the 10th Edition of the RDA's, Food and 
Nutrition Board, Commission on Life Sciences, National Research 
Council, ``Recommended Dietary Allowances, 10th Ed.'' Washington, 
DC, National Academy Press, pp. 195-205, 1989.
    4. Dawson, E. B., W. J. McGanity, ``Protection of Maternal Iron 
Stores in Pregnancy,'' The Journal of Reproductive Medicine, 32:478-
487, 1987.
    5. Committee on the Prevention, Detection, and Management of 
Iron Deficiency Anemia Among U.S. Children and Women of Childbearing 
Age, Food and Nutrition Board, Institute of Medicine, ``Iron 
Deficiency Anemia: Recommended Guidelines for the Prevention, 
Detection, and Management Among U.S. Children and Women of 
Childbearing Age,'' by Earl R. and C. E. Woteki, (editors) National 
Academy Press, Washington, DC, pp. 17-18, 1993.
    6. ``Iron,'' in Rudolph's Pediatrics, A. Rudolph, J.I.E. 
Hoffman, C. D. Rudolph, editors; Appleton & Lange, Norwalk, CT, 19th 
ed., p. 806, 1991.
    7. ``Iron,'' in Nelson Textbook of Pediatrics, by R. E. Behrman, 
R. M. Kliegman, W. E. Nelson, and V. C. Vaughan (editors), W.B. 
Saunders Co., Philadelphia, PA, 14th ed., pp. 1780-1781, 1992.
    8. ``Iron,'' in Manual of Toxicology Emergencies, Noji, K. 
(editor), by Year Book Medical Publishers, Inc., pp. 496-506, 1989.
    9. ``Hematopoietic Agents: Growth Factors, Minerals, and 
Vitamins,'' in The Pharmacological Basis of Therapeutics, edited by 
A. G. Gilman, T. W. Rall, A. S. Nies, P. Taylor (editors), Pergamon 
Press, Elmsford, New York, 8th ed., pp. 1291, 1990.
    10. Troendle, G., FDA memorandum, July 12, 1994.
    11. Temeck, J., FDA memorandum, August 10, 1994.
    12. American Association of Poison Control Center, Inc., 
petition to FDA, 91P-0186/CP1, 1991.
    13. Attorneys General Petition to FDA, 93P-0306/CP1, 1993.
    14. Litovitz, T.L., T.G. Martin, B. Schmitz, ``1986 Annual 
Report of the American Association of Poison Control Centers 
National Data Collection System,'' American Journal of Emergency 
Medicine, 5:405-445, 1987.
    15. Litovitz, T. L., B. Schmitz, N. Matyunas, T. G. Martin, 
``1987 Annual Report of the American Association of Poison Control 
Centers National Data Collection System,'' American Journal of 
Emergency Medicine, 6:479-515, 1988.
    16. Litovitz, T. L., B. Schmitz, K. C. Holm, ``1988 Annual 
Report of the American Association of Poison Control Centers 
National Data Collection System,'' American Journal of Emergency 
Medicine, 7:495-545, 1989.
    17. Litovitz, T. L., B. Schmitz, K. M. Bailey, ``1989 Annual 
Report of the American Association of Poison Control Centers 
National Data Collection System,'' American Journal of Emergency 
Medicine, 8:394-442, 1990.
    18. Litovitz, T. L., K. M. Bailey, B. Schmitz, K. C. Holm, W. 
Klein-Schwartz, ``1990 Annual Report of the American Association of 
Poison Control Centers National Data Collection System,'' American 
Journal of Emergency Medicine, 9:461-509, 1991.
    19. Litovitz, T. L., K. C. Holm, K. M. Bailey, B. F. Schmitz, 
``1991 Annual Report of the American Association of Poison Control 
Centers National Data Collection System,'' American Journal of 
Emergency Medicine, 10:452-505, 1992.
    20. Litovitz, T. L., K. C. Holm, C. Clancy, B. F. Schmitz, L. R. 
Clark, G. M. Oderda, ``1992 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' American Journal of Emergency Medicine, 11:494-555, 1993.
    21. U.S. Consumer Product Safety Commission iron fatality case 
reports.
    22. U.S. Consumer Product Safety Commission iron poisoning 
emergency room followup case reports.
    23. Nonprescription Drug Manufacturers Association Petition to 
FDA, 93P-0306/CP2.
    24. Stewart, D. W. and I. M. Martin, ``Intended and Unintended 
Consequences of Warning Messages: A Review and Synthesis of 
Empirical Research,'' Journal of Public Policy and Marketing, 
13(1):1-19, 1994.
    25. Breault, H. J. ``Five Years with 5 Million Child-Resistant 
Containers,'' Clinical Toxicology, 7(1):91-95, 1974.
    26. Wilbur, C. J., ``Child Resistant Effectiveness Conventional 
Pouch Packaging (Non-Child Resistant),'' U.S. Consumer Product 
Safety Commission, C-805-9864, 1978.
    27. Wilbur, C. J., ``Child Resistant Effectiveness Conventional 
Blister Card Packaging (Non-Child Resistant,'' U.S. Consumer Product 
Safety Commission, E-850-3006, 1978.
    28. Wilbur, C. J., ``Closure Testing Equipment (CTE) Studies 
Non-Child Resistant (NCR) Snap Type Packaging, U.S. Consumer Product 
Safety Commission, 1990.
    29. Wilbur, C. J., ``Closure Testing Equipment (CTE) Studies 
Non-Child Resistant (NCR) Continuous Threaded Type Packaging,'' U.S. 
Consumer Product Safety Commission, 1990.
    30. Whittaker, P., V. C. Dunkel, ``Iron, Magnesium and Zinc 
Fortification of Food,'' in Handbook on Metal-Ligand Interactions of 
Biological Fluids: Metal-Ligand Interactions in Human Biology and 
Medicine, vol. 2, by G. Berthon (editor), Marcel Dekker, Inc., New 
York, New York, pp. 1-12, 1994.
    31. Devasthali, S. D., V. R. Gordeuk, G. M. Brittenham, J. R. 
Bravo, M. A. Hughes, and L. J. Keating, ``Bioavailability of 
Carbonyl Iron: A Randomized, Double-Blind Study,'' European Journal 
of Haematolgy, 46:272-278, 1991.
    32. The Merck Index, ``An Encyclopedia of Chemicals, Drugs, and 
Biologicals,'' S. Budavari, M. J. O'Neil, A. Smith, and P. E. 
Heckelman (editors), Merck and Co., Inc., Rahway, New Jersey, 11th 
ed., pp. 635, 1989.
    33. Memoranda of telephone conversations between Peter Mayberry, 
Health Care Compliance Packaging Council, and Elizabeth Ann Cox, 
FDA, dated May 31 and June 8, 1994.
    34. Memoranda of telephone conversations between Tom McGinnis, 
Office of Health Affairs, FDA and Elizabeth Ann Cox, FDA, dated 
August 3 and 15, 1994.
    35. National Center for Health Statistics, ``Use of Vitamin and 
Mineral Supplements in the United States: Current Usere, Types of 
Products, and Nutrients.'' U.S. Department of Health and Human 
Services, 174:1-19, 1989.
    36. U.S. Bureau of the Census, 1993, Statistical Abstract of the 
United States: 1993 (113th Ed.), page 73; Government Printing 
Office, Washington, DC 20402.
    37. RTI, ``Estimating the Value of Consumers' Loss from Foods 
Violating the FD&C Act,'' FDA Contract No. 233-86-2097, Project 
Officer--Richard A. Williams, Jr., Research Triangle Park, NC, 
September 1988.
    38. Orwin, R. G., R. E. Schucker, and R. C. Stokes, ``Evaluating 
the Life Cycle of a Product Warning: Saccharin and Diet Soft Drinks, 
Evaluation Review, 8 (6), 801-822, 1984.

List of Subjects

21 CFR Part 101

    Food labeling, Nutrition, Reporting and recordkeeping requirements.

21 CFR Part 170

    Administrative practice and procedure, Food additives, Reporting 
and recordkeeping requirements.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 101, 170, and 310 be amended as follows:

PART 101--FOOD LABELING

    1. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act 
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342, 
343, 348, 371).

    2. Section 101.17 is amended by adding a new paragraph (e) to read 
as follows:


Sec. 101.17  Food labeling warning and notice statements.

* * * * *
    (e) Dietary supplements containing iron or iron salts. (1) The 
labeling of any dietary supplement in solid oral dosage form (e.g., 
tablets or capsules) that contains iron or iron salts for use as an 
iron source shall bear the following statement:
    (i) If the product is packaged in unit-dose packaging as defined in 
Sec. 170.55 of this chapter:

    WARNING--Keep away from children. Keep in original package until 
each use. Contains iron, which can harm or cause death to a child. 
If a child accidentally swallows this product, call a doctor or 
poison control center immediately.

    (ii) If the product contains less than 30 milligrams of iron per 
dosage unit and is packaged by the manufacturer in other than unit-dose 
packaging as defined in Sec. 170.55 of this chapter, e.g., a container 
with a child-resistant closure, its label shall bear the following 
statement:

    WARNING--Close tightly and keep away from children. Contains 
iron, which can harm or cause death to a child. If a child 
accidentally swallows this product, call a doctor or poison control 
center immediately.

    (2) The statement required by paragraph (e)(1)(i) of this section 
shall appear prominently and conspicuously on the immediate container 
labeling in such a way that the warning is intact until all of the 
dosage units to which it applies are used. The statement required by 
paragraph (e)(1)(ii) of this section shall appear prominently and 
conspicuously on the immediate container labeling. In all cases where 
the immediate container is not the retail package, the warning 
statement shall also appear prominently and conspicuously on the 
principal display panel of the retail package. In addition, the warning 
statement shall appear on any labeling that contains warnings.

PART 170--FOOD ADDITIVES

    3. The authority citation for 21 CFR part 170 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 408, 409, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 346a, 348, 
371).

    4. New Sec. 170.55 is added to subpart C to read as follows:


Sec. 170.55  Iron and iron salts in dietary supplements not in 
conventional food form.

    The use of iron and iron salts as iron sources in dietary 
supplements is safe, or generally recognized as safe, only when the 
package in which the supplements are sold is labeled in accordance with 
Sec. 101.17(e) of this chapter and, if the dietary supplements are 
offered in solid oral dosage form (e.g., tablets or capsules) and 
contain 30 milligrams or more of iron per dosage unit, when such 
supplements are packaged in unit-dose packaging. ``Unit-dose 
packaging'' means a method of packaging a product into a nonreusable 
container designed to hold a single dosage unit intended for 
administration directly from that container, irrespective of whether 
the recommended dose is one or more than one of these units. The term 
``dosage unit'' means the individual physical unit of the product, 
e.g., tablets or capsules.

PART 310--NEW DRUGS

    5. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e; secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).

    6. New Sec. 310.518 is added to subpart E to read as follows:


Sec. 310.518  Drug products containing iron or iron salts.

    Drug products containing elemental iron or iron salts as an active 
ingredient in solid oral dosage form, e.g., tablets or capsule shall 
meet the following requirements:
    (a) Packaging. If the product contains 30 milligrams or more of 
iron per dosage unit, it shall be packaged in unit-dose packaging. 
``Unit-dose packaging'' means a method of packaging a product into a 
nonreusable container designed to hold a single dosage unit intended 
for administration directly from that container, irrespective of 
whether the recommended dose is one or more than one of these units. 
The term ``dosage unit'' means the individual physical unit of the 
product (e.g., tablets or capsules).
    (b) Labeling. (1) If the product is packaged by the manufacturer in 
unit-dose packaging, its label shall bear the following statement:

    WARNING--Keep away from children. Keep in original package until 
each use. Contains iron, which can harm or cause death to a child. 
If a child accidentally swallows this product, call a doctor or 
poison control center immediately.

    (2) If the product contains less than 30 milligrams of iron and is 
packaged by the manufacturer in other than unit-dose packaging, e.g., a 
container with a child-resistant closure, its label shall bear the 
following statement:

    WARNING--Close tightly and keep away from children. Contains 
iron, which can harm or cause death to a child. If a child 
accidentally swallows this product, call a doctor or poison control 
center immediately.

    (3) The statement required by paragraph (b)(1) of this section 
shall appear prominently and conspicuously on the immediate container 
labeling in such a way that the warning is intact until all of the 
dosage units to which it applies are used. The statement required by 
paragraph (b)(2) of this section shall appear prominently and 
conspicuously on the immediate container labeling. In all cases where 
the immediate container is not the retail package, the warning 
statement shall also appear prominently and conspicuously on the 
principal display panel of the retail package. In addition, the warning 
statement shall appear on any labeling that contains warnings.

    Dated: September 28, 1994.
David A. Kessler,
Commissioner of Food and Drugs.
[FR Doc. 94-24476 Filed 10-4-94; 4:30pm]
BILLING CODE 4160-01-P