`[Federal Register Volume 62, Number 10 (Wednesday, January 15, 1997)]
[Rules and Regulations]
[Pages 2218-2250]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-947]



[[Page 2217]]

_______________________________________________________________________

Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Parts 101, 111, and 310



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

  Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / 
Rules and Regulations  

[[Page 2218]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 101, 111, 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: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is issuing regulations 
to require label warning statements on products taken in solid oral 
dosage form to supplement the dietary intake of iron or to provide iron 
for therapeutic purposes, and unit dose packaging for iron-containing 
products that contain 30 milligrams (mg) or more of iron per dosage 
unit. FDA is taking these actions because of the large number of acute 
iron poisonings, including deaths, in children less than 6 years of age 
attributable to accidental overdoses of iron-containing products. FDA 
is temporarily exempting one form of elemental iron, carbonyl iron, 
from the packaging requirements of this final rule. The temporary 
exemption will automatically expire 1 year from the effective date of 
this final rule. If, during the temporary exemption period, FDA 
receives animal data that establish that carbonyl iron is significantly 
less toxic than at least one commonly used iron salt, FDA will consider 
permanently exempting carbonyl iron from the packaging requirements of 
this final rule.

DATES: The regulation is effective July 15, 1997. For compliance dates 
see Secs. 111.50(b)(1) and (b)(2) and 310.518(b)(1) and (b)(2).

FOR FURTHER INFORMATION CONTACT: Linda S. Kahl, Center for Food Safety 
and Applied Nutrition (HFS-206), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-418-3101.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of October 6, 1994 (59 FR 51030), FDA 
published a proposed rule (the iron proposal) 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. 
The proposal did not cover liquid or powder forms of iron and did not 
bear in any way on conventional foods containing naturally occurring or 
added iron. FDA also proposed regulations to require unit-dose 
packaging\1\ for iron-containing products\2\ that contain 30 mg or more 
of iron per dosage unit.\3\
---------------------------------------------------------------------------

    \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 intended for administration 
directly from that container, irrespective of whether the 
recommended dose is one or more than one of these units.
    \2\ Throughout this document, the term ``iron-containing 
products'' refers to solid oral dosage forms of both dietary 
supplement and drug products.
    \3\ In this document, the term ``dosage unit'' is 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.
---------------------------------------------------------------------------

    FDA proposed 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 was 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. Since the publication of the iron proposal, 
FDA has obtained information from the American Association of Poison 
Control Centers (AAPCC) that indicates that accidental overdose of 
iron-containing products continues to be a problem in young children 
(Refs. 1 and 2). In 1994, at least 3,210 children under 5 years of age 
were treated in emergency rooms for exposure to iron-containing 
products, and two children are known to have died following such 
accidental overdose.
    The iron proposal responded to citizen petitions submitted by AAPCC 
(the AAPCC petition) (Docket No. 91P-0186/CP1) (Ref. 3); the Attorneys 
General of 34 States, Commonwealths, and Territories (the AG petition) 
(Docket No. 93P-0306/CP1) (Ref. 4); and the Nonprescription Drug 
Manufacturers Association (the NDMA petition) (Docket No. 93P-0306/CP2) 
(Ref. 5). These petitions 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.
    In the Federal Register of February 16, 1995 (60 FR 8989), in 
response to the Dietary Supplement Health and Education Act of 1994 
(DSHEA), FDA published a supplemental proposed rule reflecting a shift 
in the agency's authority to establish regulations for dietary 
supplements.
    The agency received over 100 responses to the iron proposal and the 
supplemental proposal with one or more comments each from dietary 
supplement, drug, and packaging trade associations; consumers; Federal 
and State Government agencies; State attorneys general; poison control 
centers; the international community; health care providers; and 
dietary supplement and drug manufacturers and packers. Comments on the 
proposed requirement for a warning statement on iron-containing 
products were generally supportive, although many comments disagreed 
with the specifics of the agency's proposed text and requirements for 
prominence and placement. Several comments stated that firms already 
are including a voluntary warning statement on the label of iron-
containing products. Comments on the proposed requirement for unit-dose 
packaging for iron-containing products that contain more than 30 mg of 
iron per dosage unit were divided on whether the proposed requirement 
was needed to ensure the safety of these products, and several comments 
challenged FDA's authority to establish such regulations.

II. Warning Statement for Iron-Containing Products

A. The Proposed Warning Statements

    FDA proposed to require label warning statements on iron-containing 
dietary supplements and drug products. FDA tentatively concluded that 
the warning statements should incorporate elements from both the AG 
petition and the NDMA petition, as well as other elements that are 
designed to ensure that the statements perform their function.
    FDA proposed two warning statements--one statement for use on iron-
containing products packaged in unit-dose packaging and a slightly 
different statement for use on iron-containing products packaged in 
other than unit-dose packaging, e.g., a container with a child-
resistant closure (CRC).
    The proposed warning statement for use on iron-containing products 
packaged in unit-dose packaging reads as follows:

    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.

    The proposed warning statement for use on iron-containing products 
packaged in other than unit-dose packaging reads as follows:


[[Page 2219]]


    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.

    Each of these proposed warning statements included a handling 
instruction (e.g., ``Close tightly and keep away from children''), an 
informational statement (``Contains iron, which can harm or cause death 
to a child''), a provisional statement (``If a child accidentally 
swallows this product''), and an instructional statement (``Call a 
doctor or poison control center immediately'').

B. Focus Group Findings

    In order to determine the effectiveness of the proposed warning 
statements in alerting consumers to the danger that an accidental 
overdose of iron poses to young children, FDA contracted with Macro 
International, Inc., to test several different potential warning 
messages for iron-containing products in a total of eight focus groups. 
A notice of the availability of the focus group report was published in 
the Federal Register of May 23, 1995 (60 FR 27321). The notice invited 
the public to comment on this report. This focus group research 
supported the agency's tentative conclusion, explained in the iron 
proposal, that many adults are not aware of the danger that an 
accidental overdose of iron poses to young children.
    In the focus groups, all participants were presented with an 
information piece detailing the danger that an accidental overdose of 
iron poses to young children. The information piece contained 
statistics that showed that accidental overdoses of iron-containing 
products are a leading cause of poisoning deaths in children under the 
age of 6, that illness can result from the ingestion of as little as 
250 mg of iron in a child weighing 10 kilograms (kg) or less (22 pounds 
(lb) or less) and that ingestion of 600 mg of iron has been reported to 
be fatal to children weighing 10 kg or less. Half of the eight groups 
(``pre-evaluation groups'') received the information piece before they 
evaluated the warning messages, and the other half (``postevaluation 
groups'') received the information piece after they evaluated the 
warning messages. Participants in the postevaluation groups initially 
heard only a brief statement about the need for a standardized warning 
statement on iron-containing products and heard nothing about the 
nature of the hazard posed by an accidental overdose of iron-containing 
products or about the number of children who had died. The 
postevaluation groups subsequently were given the opportunity to 
reevaluate the warning messages after hearing the longer, more detailed 
information piece.
    Participants in the postevaluation groups found warning messages 
such as ``iron can harm or cause death to a child'' to be unnecessarily 
severe, to the point that they considered the messages to be bizarre 
and unbelievable. The postevaluation groups tended to like a short 
generic message that did not identify a specific hazard. In contrast, 
participants in the pre-evaluation groups were more accepting of 
stronger statements of the hazard and tended to prefer statements that 
used the terms ``death'' or ``fatal''--the same statements that the 
postevaluation groups thought were unacceptably severe. When 
participants in the postevaluation groups were given information on the 
nature and magnitude of the hazard subsequent to their evaluation of 
the various statements, they evaluated the messages in the same way as 
did the pre-evaluation groups. Finally, when asked for their own 
suggestions, groups were virtually unanimous in recommending that the 
general public be better informed about the dangers of iron-containing 
products to young children.
    Most participants in the research expressed the opinion that a good 
warning statement includes at least three elements: (1) A handling 
instruction that the product should be kept out of the reach of or away 
from children; (2) an informational statement that the product contains 
iron, and that excess or large doses of iron can harm or cause death to 
a child; and (3) an instructional statement to call a doctor or poison 
control center immediately in case of overdose. Participants' choices 
reflected their desire for a concise and unambiguous message with some 
degree of quantification about the amount of iron that must be ingested 
to be dangerous. Participants differed over the exact contents and 
order of the wording for a warning message but agreed that, regardless 
of what is eventually contained in the message, it should be worded as 
succinctly and efficiently as possible.
    The focus group research also provided information on the language 
of the handling instruction in the warning statement. The focus group 
participants did not recognize a strong connection between the 
informational statement and the specific handling instruction that they 
were asked to evaluate and were not very positive toward statements 
such as ``Keep in original container'' and ``Close tightly.'' They were 
generally confused about how to interpret ``Keep in original package 
until each use'' with respect to blister-packaged products. 
Participants did not know whether the statement meant that they should 
keep the product in its original box or in its blister package. The 
``Close tightly'' language was seen as too obvious, intended for 
products without child-resistant caps or related to product freshness.
    The consumer research thus suggests that information about the 
nature and magnitude of the danger that accidental overdose of iron-
containing products poses to young children is essential to the 
consumer's understanding of the warning statement. It also suggests 
that the first sentence of a warning statement is likely to influence a 
consumer's decision as to whether to continue reading the rest of the 
statement, and that package-specific handling instructions are more 
likely to confuse consumers than provide a measure of safety. Finally, 
it evidences that consumers will handle these products appropriately 
(i.e., by keeping the products in the original package or by keeping a 
bottle tightly closed) if they are provided with information on the 
nature and magnitude of the hazard.

C. Comments on the Utility and Scope of the Proposed Warning Statements

    Several comments suggested that the warning statement should appear 
on all iron-containing dietary supplement and drug products rather than 
only on solid dosage forms. One comment from a State department of 
health services advised the agency that in September, 1993, a 5-year 
old child was hospitalized for a serious, though nonfatal, iron 
poisoning. The iron involved was in the form of a syrup prescribed for 
the victim. The comment stated that the department of health services 
did not know how many other children may have suffered injury as the 
result of ingesting liquid iron supplements.
    The agency appreciates receiving the information about the 
accidental ingestion of a liquid iron-containing product. In the iron 
proposal, the agency stated that it was not aware of incidents of 
poisoning being caused by iron-containing products in liquid or powder 
form, and thus, it did not propose to cover liquid or powder forms of 
iron-containing products. The agency stated, however, that it would 
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.

[[Page 2220]]

    The report of a single case in which a child was hospitalized for a 
serious, but not fatal, iron poisoning does not justify a change in the 
agency's tentative view concerning the need for a Federal regulation 
mandating labeling for liquid forms of iron-containing products. A 
Federal regulation is appropriate and necessary to protect the public 
health when safe use of a product cannot be ensured absent such a 
regulation. No regulation, however, will guarantee zero risk from 
products regulated by FDA. The existence of a single case report of a 
serious poisoning does not establish that illness or injury is likely 
to continue to occur. Rather, this single case report creates some 
ambiguity. It is not clear based on this report whether poisoning from 
liquid iron-containing products is an accident of low frequency or one 
that bears careful monitoring. Therefore, in this final rule, the 
agency is not including iron-containing products in liquid or powder 
form within the coverage of the labeling requirement. However, the 
agency would consider extending the coverage of the labeling and 
packaging requirements if it receives persuasive information that shows 
that accidental pediatric ingestion of liquid or powder iron-containing 
products is a problem, and that a warning statement or some special 
packaging requirement is necessary to ensure safe use of products that 
contain either of these forms of iron.
    One comment questioned the usefulness of a warning statement 
because children cannot read. One comment stated that dietary 
supplement bottles are small, and there is other information competing 
for attention. Another comment stated that consumers have become 
accustomed to warning statements, implying that warning statements have 
become so common that their usefulness is diluted. A comment from a 
dietary supplement manufacturer stated that a warning statement on all 
products is not necessary and noted that the firm puts warning 
statements on products most likely to be attractive to children.
    FDA does not agree that a warning statement is not useful because 
children cannot read. The warning statement is intended to be read by 
adults so that the adults will understand the nature and magnitude of 
the problem and the importance of keeping the product out of reach of 
children. FDA agrees that some dietary supplement and drug bottles are 
small, and that there is other information competing for attention. 
Nonetheless, the public health significance of accidental iron overdose 
compels that manufacturers overcome limitations in package size, if any 
there be. Therefore, FDA expects that industry will make appropriate 
revisions to labels on small product containers to provide appropriate 
space for the warning statement.
    FDA does not agree that a warning statement on iron-containing 
products would be diluted because consumers have become accustomed to 
such statements. The focus group research shows that consumers want a 
strong warning on these products, and that consumers will heed the 
warning if provided with information describing the nature and 
magnitude of the hazard. FDA disagrees that a warning statement on all 
products is unnecessary or only useful on products that are attractive 
to children because the seriousness of the consequences of accidental 
overdose compel that all products bear the warning. Thus, FDA finds no 
merit in these comments.

D. Comments on the Text of the Proposed Warning Statement

    FDA received a number of comments requesting modification of the 
wording of the proposed warning statements. The comments objected to 
the proposed warning statement in three main respects: (1) Failure to 
include the concept of ``overdose;'' (2) use of the term ``death;'' and 
(3) use of the phrase ``keep away from children.'' In response to these 
comments, FDA is revising the text of the wording statement. Table 1 of 
this document provides a side-by-side comparison of the text of the 
warning statement in the proposed and final rules.

Table 1--Comparison of the Text of the Warning Statement in the Proposed
                           and Final Rules \1\                          
------------------------------------------------------------------------
  Element of the Statement     Text of the Warning   Text of the Warning
-----------------------------   Statement in the      Statement in the  
                                    Proposal             Final Rule     
                             -------------------------------------------
                                     Warning               Warning      
------------------------------------------------------------------------
Informational statement.....  Contains iron, which  Accidental overdose 
                               can harm or cause     of iron-containing 
                               death to a child.     products is a      
                                                     leading cause of   
                                                     fatal poisoning in 
                                                     children under 6.  
Handling instruction........  Keep away from                            
                               children. Keep in                        
                               original package                         
                               until each use.\2\.                      
                              [or]                                      
                              Close tightly and     Keep this product   
                               keep away from        out of reach of    
                               children.\3\.         children.          
Provisional statement.......  If a child            In case of          
                               accidentally          accidental overdose
                               swallows this         * * *.             
                               product * * *.                           
Instructional statement.....  * * * call a doctor   * * * call a doctor 
                               or poison control     or poison control  
                               center immediately.   center immediately.
                                                                        
------------------------------------------------------------------------
\1\ The order of the statements in this table is the order of the       
  statements as they appear in the final regulation.                    
\2\ For use on unit-dose packages.                                      
\3\ For use on non-unit packages.                                       

1. Informational Statement
    Several comments requested that the wording of the warning 
statement be changed to refer to ``large doses'' of iron or ``excessive 
consumption'' of iron. These comments maintained that the proposed 
wording of the warning statements implies that iron is toxic at any 
level of intake, even though iron is only dangerous when consumed in 
excess. Other comments stated that the warning statements as proposed 
may frighten and discourage appropriate use of iron-containing 
products. Several comments stated that the essence of the message 
should be that ``an overdose of iron could be harmful'' because this 
would be more consistent with FDA's stated objective for the warning 
statement, which is to ensure that products containing iron or iron 
salts do not pose a health hazard to young children and infants. 
Another comment cited Sec. 330.1(g) (21 CFR 330.1(g)) as an example of 
a regulation that uses the term ``overdose.''
    One comment stated that the proposed warning statements appear to 
be too general and are misleading to the consumer as to the actual 
danger. This comment stated that it would be sufficient to mention that 
the products could have the negative effects only in cases of overdose.
    FDA has reevaluated the proposed wording of the warning statements 
in

[[Page 2221]]

response to these comments and concludes that the proposed wording 
implies that iron is inherently toxic and does not inform consumers 
about the actual nature of the hazard, i.e., an accidental overdose of 
an iron-containing product. Iron itself is an essential nutrient and is 
not harmful or fatal unless consumed in large quantities, as may occur 
in accidental overdoses. Therefore, a statement informing the consumer 
of the dangers of an accidental overdose is a more appropriate 
informational statement than those in the proposed warning statements.
    The findings of the focus group research support this conclusion. 
The focus group participants' preferences reflect a desire for some 
degree of quantification about the amount of iron that must be ingested 
to be dangerous. The term ``overdose'' conveys a degree of 
quantification that makes it unlikely that consumers will mistakenly 
infer that usual or prescribed dosages of iron-containing products are 
dangerous. For these reasons, the agency is revising the informational 
statement to clarify that the hazard is from an accidental overdose of 
an iron-containing product.
    Several comments requested that the agency not use the term 
``death'' in the warning statement because it is unduly alarming and 
too harsh and may cause avoidance of iron supplementation by patient 
populations already at risk for low iron intake. One comment stated 
that ``death'' may frighten or inflame. Another comment stated that use 
of the word ``death'' is a departure from most FDA warnings and from 
warnings recommended in the citizen petitions.
    Some comments suggested replacing the term ``death'' with the 
phrase ``harmful or fatal'' because this phrase conveys the danger of 
excessive iron while not unduly alarming the general population. A few 
comments noted that ``fatal'' is the term in the NDMA voluntary warning 
in use on many product labels. One comment cited the agency's 
regulations in 21 CFR 101.17(b)(1) (warnings for foods in self-
pressurized containers with hydrocarbon and halocarbon propellants), 21 
CFR 201.314 (warning statement on over-the-counter (OTC) drugs 
containing salicylates), and 21 CFR 201.319(b) (warning labels on OTC 
drugs containing water soluble gums) as precedent for use of the word 
``fatal.''
    FDA has reevaluated the use of the word ``death'' in this warning 
statement in light of these comments. FDA sees no reason to maintain 
the term ``death'' if, as the comments contend, it will unduly alarm 
consumers, because the term ``fatal'' means ``cause death'' (Webster's 
New Riverside University Dictionary, 2d ed., 1988). Therefore, FDA is 
revising the informational statement to remove the term ``death'' and 
add the term ``fatal.''
    As a result of the changes that the agency is making in response to 
this and the preceding comment, the revised informational statement 
reads: ``Accidental overdose of iron-containing products is a leading 
cause of fatal poisoning in children under 6.''
    The comments that requested that FDA clarify that the hazard was 
associated with an accidental overdose of iron-containing products, 
rather than consumption of iron-containing products under intended 
conditions of use, made clear that information about the nature and the 
magnitude of the danger that accidental overdose of iron-containing 
products poses to young children is essential to consumer understanding 
of the warning statement. This concept was reiterated by the consumers 
who participated in FDA's focus group research. Although participants 
in the consumer research were divided over the order of the elements 
(informational, handling, provisional, and instructional statements) of 
the warning statement, the consumer research supported a conclusion 
that the first sentence of a warning statement is likely to influence a 
consumer's decision as to whether to continue reading the rest of the 
statement. Therefore, in this final rule FDA is changing the sequence 
of the sentences in the warning statement so that the informational 
statement, which states the nature and magnitude of the danger that 
accidental overdose of iron-containing products poses to young 
children, precedes the handling instruction.
2. Handling Statement
    FDA proposed two different handling instructions based on whether 
the iron-containing product was in a unit-dose package or a non-unit-
dose package. FDA has reevaluated the need for, and utility of, 
different warning statements depending on the type of packaging. As 
already discussed, one of the findings of the focus group research was 
that package-specific handling instructions are more likely to confuse 
consumers than provide a measure of safety. Moreover, FDA believes that 
consumers will handle these products appropriately (i.e., by keeping 
the product in the original package or by keeping a bottle tightly 
closed) if they are provided with the information on the nature and 
magnitude of the hazard. Therefore, in this final rule the agency is 
removing the proposed package specific element of the handling 
instruction, which necessitated a different warning statement for 
products in unit-dose packaging than for products in other than unit-
dose packaging. FDA is revising proposed Sec. 101.17(e)(1) and proposed 
Sec. 310.518(b) (now Sec. 310.518(c)) (21 CFR 310.518(c))) to provide a 
single required warning statement for all iron-containing supplement 
and drug products in solid oral dosage form regardless of the type of 
packaging.
    A few comments objected to the phrase ``Keep away from children'' 
and suggested as an alternative the use of the phrase ``Keep out of 
reach of children.'' These comments argued that it would be confusing 
and inappropriate to say ``Keep away * * *'' on iron-containing 
products intended for children, and that the term ``Keep out of reach * 
* *'' is a targeted, well understood statement that clearly conveys the 
message that children should not be given free access to the product.
    FDA has reevaluated the proposed language of the handling statement 
``Keep away from children'' and agrees that this statement may imply 
that the product is inherently toxic to children. Thus, the statement 
would be confusing to consumers when used on a bottle of tablets used 
by children. The statement ``Keep out of the reach of children'' states 
the proper handling of the product without implying that the product is 
inherently toxic under intended conditions of use. Therefore, FDA is 
revising the proposed text of the handling instruction to read ``Keep 
this product out of reach of children'' rather than ``Keep away from 
children.''
    Some comments suggested that FDA should require two types of 
warning statements based on the level of iron in each dosage unit of 
the product. These comments suggested that products containing higher 
doses of iron (such as products that contain 30 mg or more of iron) be 
required to bear a warning statement, such as the industry voluntary 
warning statement, and that products containing lower doses of iron 
(such as multivitamin products) be required to bear a more general 
warning, such as: ``WARNING: Keep out of reach of children. In case of 
accidental overdose, contact a physician or Poison Control Center 
immediately.'' The comments asserted that products containing higher 
levels of iron are associated with a greater risk than multivitamin-
mineral products. In contrast, most participants in the agency's 
consumer research felt that a single warning message should be used on 
all iron-containing products regardless of the iron dose.

[[Page 2222]]

    Iron-containing products cause injury, including serious injury and 
death, when children gain uncontrolled access to them. As discussed in 
the iron proposal (59 FR 51030 at 51036), children's vitamins were the 
type of product ingested in the majority (45 of 80 or 56 percent) of 
the cases of nonfatal pediatric iron ingestion reported to the CPSC 
from 1986 to 1993. Further, the amount of iron that may produce 
symptoms of iron poisoning (i.e., 25 mg/kg of iron) for a 10 kg child 
would be provided by as few as 25 tablets containing 10 mg of iron each 
or approximately 14 tablets containing 18 mg of iron each (59 FR 50130 
at 51041). Ten and eighteen mg of iron are the amounts typically 
contained in children's and adult multivitamin supplements with iron, 
respectively.
    Ingestion of as little as 650 mg of iron has resulted in death 
(Ref. 6). This amount of iron would be supplied by 65 tablets 
containing 10 mg of iron or 37 tablets containing 18 mg of iron.
    Based on these data, FDA concludes that the potential for poisoning 
exists with all iron-containing products in solid oral dosage form, 
regardless of the iron content, and that label warning statements are 
necessary on all these products. Therefore, the agency is making no 
changes in the warning statements in response to these comments.
3. Provisional Statement
    As already discussed, several comments maintained that the proposed 
wording of the warning statements implies that iron is toxic at any 
level of intake, even though iron is only dangerous when consumed in 
excess.
    The proposed provisional statement: ``If a child accidentally 
swallows this product, * * *'' implies that iron, rather than an 
overdose of iron, causes the harm. Therefore, FDA is revising the 
provisional statement to read: ``In case of accidental overdose, * * 
*'' to convey that it is an accidental overdose of iron that requires 
attention, rather than an accidental swallowing of any amount of iron.
4. Instructional Statement
    Several comments supported FDA's instructional statement to ``call 
a doctor or poison control center immediately.'' These comments 
concurred with FDA that medical personnel are best equipped to 
determine the significance of the dose a child has ingested, and that, 
thus, the label should include this instruction.
    One comment challenged FDA's proposed instructional statement to 
``call a doctor'' and suggested that the instructional statement 
provided in the voluntary industry warning to ``seek professional 
assistance'' was more appropriate because it was already understood and 
accepted when used on OTC products. The comment expressed the opinion 
that use of the term ``call a doctor'' would limit the assistance 
options for consumers by suggesting that only a doctor could help them. 
The comment pointed out that consumers in FDA's focus groups did not 
express a strong opinion either in favor of, or in opposition to, the 
substitution of the phrase ``call a doctor'' for the common phrase used 
on OTC products to ``seek professional assistance.''
    FDA realizes that a professional health care provider other than a 
doctor could provide assistance to a consumer in the event of 
accidental overdose. FDA disagrees, however, that the word 
``professional'' accurately conveys the meaning ``medical.'' The 
information that the instructional statement must convey is that 
consumers should seek medical assistance in the event of accidental 
overdose. FDA sees no reason to replace the phrase ``call a doctor'' 
with the phrase ``seek medical assistance'' because consumers will 
understand that ``call a doctor'' implies that they should seek medical 
assistance, regardless of whether their customary health care provider 
is a doctor or other medical professional, and because ``call a 
doctor'' is a more succinct phrase than ``seek medical assistance.'' 
Therefore, FDA is retaining unchanged the proposed instructional 
statement that describes the appropriate action to take when a child 
accidentally consumes multiple tablets (``call a doctor or poison 
control center immediately'').
5. Comments on the Consumer Research
    FDA received only a few comments on the agency's consumer research. 
These comments maintained that the consumer research showed that the 
agency's proposed warning statement was ineffective.
    FDA agrees that the consumer research showed that the proposed 
wording of the warning statement was ineffective because the proposed 
warning statement did not provide adequate information about the nature 
and magnitude of the hazard and did not provide such information before 
the handling, provisional, and instructional elements of the warning 
statement. However, the revised language of the warning statement (see 
Table 1 and discussion below) adequately responds to all the concerns 
raised by the comments and the consumer research.
6. Revised Text of the Warning Statement
    Based on the findings of the agency's focus group research, the 
comments on those findings, and the comments on the proposal, FDA is: 
(1) Revising the proposed warning statement by changing the sequence of 
the sentences so that the informational statement precedes the handling 
instruction; (2) modifying the informational statement so that it 
better describes the nature of the hazard; (3) eliminating the two 
different handling instructions based on whether the iron-containing 
product is in a unit-dose package or a non-unit-dose package; (4) 
modifying the handling instruction informing the consumer that children 
should not have free access to the product; and (5) including a 
reference to overdose in the provisional statement regarding the 
instruction on appropriate action in instances where a child 
accidentally consumes multiple tablets. FDA is taking this action to 
provide consumers with clear and appropriate information on the nature 
and magnitude of the hazard and to clarify that the hazard is not 
associated with use of iron-containing products under normal 
conditions. The revised warning statement reads:

    WARNING: Accidental overdose of iron-containing products is a 
leading cause of fatal poisoning in children under 6. Keep this 
product out of reach of children. In case of accidental overdose, 
call a doctor or poison control center immediately.
7. Other Comments on the Text of the Warning Statement
    Several comments suggested that FDA adopt the language of the 
industry voluntary warning and stated that it is not apparent that 
FDA's proposed warning statements provide an additional consumer 
benefit over the voluntary NDMA warning statement. One comment 
expressed the opinion that FDA's consumer research supported the 
positions taken by NDMA regarding labeling of products containing iron 
and did not support the warning statements proposed by FDA. The NDMA 
voluntary warning statement reads as follows:

    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.

    FDA has reviewed the language of the suggested NDMA voluntary 
warning statement in light of the focus group research. FDA agrees that 
none of the versions of warning statements tested in

[[Page 2223]]

the focus groups performed any better than the industry voluntary 
warning statement. However, none of the messages that were tested, 
including the industry voluntary warning, performed satisfactorily. The 
focus groups perceived the industry voluntary warning statement to be a 
standard kind of warning about product toxicity. Because such warnings 
are seen frequently on many different kinds of products and provide 
little new or useful information, they fail to command much consumer 
attention (Ref. 7). The consumer research did not show that the 
industry voluntary warning statement effectively conveys to consumers 
the nature of the hazard to young children presented by careless 
handling and storage of iron-containing products.
    The agency's modified warning statement remedies the deficiencies 
identified by the consumer research in the tested warning statements, 
including the NDMA voluntary warning statement, in two ways. First, the 
agency's modified informational statement stresses the nature and 
magnitude of the hazard as one of accidental overdose. Second, by 
placing the informational statement before the handling instruction, 
the modified informational statement will command consumer attention. 
In contrast, the key concept of overdose appears at the end of the 
informational statement of the NDMA voluntary warning statement: 
``Contains iron, which can be harmful or fatal to children in large 
doses,'' which diminishes its impact. In addition, the NDMA voluntary 
warning statement places the informational statement after the handling 
instruction: ``Close tightly and keep out of reach of children,'' where 
it will not command as much consumer attention. FDA therefore is not 
revising Secs. 101.17 and 310.518 to codify the language of the NDMA 
voluntary warning statement.
    Several comments provided variations of the agency's proposed 
warning statement or the voluntary NDMA warning statement or their own 
versions of a suitable warning statement. Examples of these proposed 
variations include:

    WARNING: Keep all containers of iron-containing products away 
from children at all times. Reclose the child resistant cap 
completely every time after use. Keep in original package until each 
use. Iron-containing products can harm or cause death to a child. 
Should you suspect a child has accidentally swallowed an iron-
containing product call a doctor or Poison Control Center 
immediately.
    WARNING: Keep out of reach of children. Contains iron which can 
harm or be fatal to a child in large doses. In case of accidental 
overdose, seek professional assistance or contact a poison control 
center immediately.

    FDA is not accepting any of these suggested statements. All of them 
share one or more fundamental problems with FDA's original proposed 
statement and the industry warning. Specifically, all of these warning 
statements begin with a handling instruction rather than an information 
statement. Some fail to incorporate the concept that it is an overdose 
of product that is harmful and would therefore lead to the 
misconception that iron is inherently harmful. Because all of the 
suggested warnings contain one or more fundamental problems, FDA has 
rejected these suggested variations.
    One comment requested that FDA strengthen the language of the 
warning so that it is clearly understood that iron may kill.
    FDA has considered this comment and determined that the new 
informational statement that it has developed (i.e., ``Accidental 
overdose of iron-containing products is a leading cause of fatal 
poisonings in children under 6.'') clearly articulates and strengthens 
the wording compared to the wording in the proposal. Therefore, FDA 
concludes that the concern expressed by this comment is fully 
addressed.
    A comment from 13 State Attorneys General stated that if the term 
``warning'' and the treatment-oriented information (i.e., the 
instructional statement) are included on the label in a prominent 
manner, then it is not necessary to include a reference to the harm 
that can come from ingestion of large doses or reference to the 
specific consequences. Other comments stressed the importance of the 
term ``WARNING'' and the importance of providing the instructional 
reference to contact a poison control center.
    FDA agrees that the term ``WARNING'' and the instructional 
statement advising that a doctor or poison control center be contacted 
are necessary to alert the consumer to the potential consequences of 
use of the product and the need to take immediate action. The agency 
disagrees, however, that the informational statement is not necessary 
when the term ``WARNING'' and the instructional statement are present. 
An informational statement provides consumers with the information they 
need to readily understand the serious consequences that may result if 
the warning is not heeded. Therefore, FDA is taking no action in 
response to these comments.
    One comment raised the concern that the proposed warning statement 
ignores other potential toxicities, such as that caused by an overdose 
of vitamin A, and suggested replacing the proposed iron-specific 
warning statement with a general cautionary statement in bold print. 
The suggested wording of this general cautionary statement was ``KEEP 
OUT OF REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, CONTACT A 
PHYSICIAN OR POISON CONTROL CENTER IMMEDIATELY.''
    The agency is not adopting the suggestion to replace the iron-
specific warning statement with a general warning statement. The agency 
has a longstanding policy of limiting the use of warning statements so 
that such statements do not become so common that they are ignored. The 
label warning statement required on solid oral dosage forms of iron-
containing products is a response to an immediate public health hazard 
of large proportions, the deaths and injuries of children who 
accidentally consumed large doses of these products. Therefore, the 
warning statement is specifically worded to alert consumers to the 
presence of iron and to the danger that accidental overdose of iron 
poses to young children.
    One comment requested that the label warning statement specifically 
state that all medicines should be stored in original containers.
    As already discussed, FDA has concluded, based on the results of 
consumer focus groups, that such specific handling instructions are 
more likely to confuse consumers than to provide an additional measure 
of safety. Participants in the focus groups were confused about how to 
interpret ``Keep in original package until use'' with respect to 
blister-packaged products. They did not know whether the statement 
meant that they should keep the product in its original box or in its 
blister package. Therefore, the agency is taking no action in response 
to this comment.
    One comment questioned the need for a specific warning message 
where general messages already state that supplements and drugs should 
be kept out of reach of children, or the packaging itself is child-
safe. This comment added that, given these facts, a specific warning 
message would appear to be more trade-restrictive than necessary.
    Dietary supplements marketed in the United States are not required 
to bear a general warning statement on the label. Drug product labels 
are required to bear warnings that are adequate to protect consumers. 
As stated in the response to a previous comment, general warning 
statements fail to describe the nature of the specific and immediate 
hazard of

[[Page 2224]]

accidental iron overdose in young children. Therefore, FDA has 
determined that the warning statement specified in this final rule 
responds to the known safety concerns associated with solid dosage form 
of iron-containing products. The warning statement will apply to both 
domestically produced and imported iron-containing products.
    In the Agreement on Technical Barriers to Trade from the Uruguay 
Round of the multilateral trade negotiations, ``technical regulation'' 
is defined as a:

    Document which lays down product characteristics or their 
related processes and production methods, including the applicable 
administrative provisions, with which compliance is mandatory. It 
may also include or deal exclusively with terminology, symbols, 
packaging, marking or labeling requirements as they apply to a 
product, process or production method.

    Article 2.2 under Technical Regulations and Standards states: ``* * 
* technical regulations shall not be more trade-restrictive than 
necessary to fulfil a legitimate objective, taking account of risks 
non-fulfillment would create. Such legitimate objectives are, inter 
alia * * * protection of human health or safety.''
    The warning statement for iron-containing products is necessary to 
protect the public health by helping to prevent accidental poisoning of 
young children. Therefore, the agency concludes that the warning 
statement is neither trade restrictive nor a trade barrier.
    One comment from a physician recommended placing a ``Mr. Yuk'' 
sticker or emblem on each bottle of iron-containing tablets because 
this label device is recognized by children as an indication of poison.
    FDA disagrees with this comment. The ``Mr. Yuk'' sticker alerts 
children that the product is not safe to eat. Iron-containing products, 
when consumed in appropriate quantities, are safe to eat. Placing a 
``Mr. Yuk'' emblem on a product such as a bottle of children's vitamins 
would mean that the label would present an inconsistent message that 
could confuse children about what is safe to eat and what is not. 
Therefore, FDA is not taking the action suggested in this comment.
    A few comments requested that the warning statement be accompanied 
by a pictograph to readily depict the hazard and to ensure that it will 
be readily understood by illiterate or non-English-speaking consumers.
    FDA recognizes that a pictograph can be useful to convey some 
information to consumers. However, no data were submitted to show that 
the message could not be communicated without a pictograph. Given this 
fact, FDA finds no basis to require the use of a pictograph. However, 
FDA would have no objection if manufacturers, in conjunction with the 
required message, used a pictograph (such as a slash line through a 
picture of a child with an open mouth reaching for something) in 
addition to the required warning statement.
    One comment requested that FDA reconsider its position and include 
the physical consequences and symptoms that may result from an iron 
overdose on the product package or container. This comment stated that 
adults will readily understand consequences and take effective action 
to eliminate the risk of an accidental child poisoning based on this 
information.
    In the iron proposal (59 FR 51030 at 51044), FDA stated that it 
feared that setting out this information could lead parents to conclude 
erroneously that the child is not in danger because he or she does not 
exhibit one of the listed symptoms. No information was submitted in 
this comment that would cause the agency to reach a different 
conclusion. Listing of symptoms is irrelevant because they may not be 
exhibited by a child, and the most important information is that an 
overdose may be fatal. Moreover, as discussed above, FDA has revised 
the warning statement to include an informational sentence describing 
the nature of the hazard and providing adults with information to 
motivate them to eliminate the risk. Therefore, FDA is taking no action 
in response to this comment.
    One comment requested that FDA require that the labeling of all 
iron-containing products display the exact name of the iron ingredient 
instead of the equivalent amount of iron present in the product. The 
comment added that this information is extremely important to the 
medical professionals and emergency personnel who treat iron 
poisonings.
    No action is necessary in response to this comment because this 
information is already required on the label of food products 
containing iron under 21 CFR 101.4(b), which requires that the ``name 
of an ingredient must be a specific name and not a collective (generic) 
name.'' For dietary supplements containing iron, the ingredient list 
must include the source of the iron (e.g., ferrous sulfate). In 
addition, the amount of iron must also be provided in the nutrition 
labeling.
    For drug products containing iron, section 502(e) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(e)) and 21 CFR 
201.10 require a label statement of a drug's established name and the 
established name and quantity of the product's active ingredients.

E. Appearance of the Warning Statement on the Label of Iron-Containing 
Products

    FDA proposed in Secs. 101.17(e)(2) and 310.518(b)(3) to require 
that the warning statement:

    * * * 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. In 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.
1. Comments on Requiring the Warning Statement to Appear Prominently 
and Conspicuously on the Immediate Container Labeling
    Several comments on the labeling aspects of the proposed rule 
opposed or questioned the agency's tentative conclusion that the 
warning statement should be placed on the principal display panel (the 
PDP) in order to be prominent and conspicuous. Many of these comments 
noted that warnings on consumer products are generally located together 
on the side or back panel, and that consumers are accustomed to finding 
warning information in these places. One comment argued that placing 
the warning statement on the PDP negates the purpose of the information 
panel (the IP) because the traditional location for warning statements 
is the IP, and consumers may overlook a warning statement that is not 
in the expected location.
    One of the comments elaborated upon warning placement by noting 
that warnings for self-pressurized containers and self-pressurized 
containers with halocarbons, hydrocarbon propellants, or 
chlorofluorocarbon propellants are not mandated to appear on the PDP 
(Sec. 101.17 (a), (b), and (c)). The regulations for foods containing 
aspartame also do not require that the warning statement for 
phenylketonurics appear on the PDP (21 CFR 172.804(e)(2)).
    Most of the participants in the focus groups believed that the 
warning statement should go on the back of the product rather than the 
front of the product. The participants reasoned that the front of the 
product was used for marketing purposes, and consumers

[[Page 2225]]

were used to looking at the back of the product for warnings. The focus 
groups also felt that the ``clutter'' on the front of the product label 
might dilute the warning message. Similarly, several comments pointed 
out that the placement of the warning statement on the PDP would 
overcrowd an already space-limited PDP and result in a diluted warning 
message, especially if a smaller type size was used.
    The agency recognizes that the PDP space is often very limited, and 
that warnings plus other required information could crowd the PDP. 
Therefore, in deciding how to provide for placement of the warning, the 
agency reflected on two basic questions: (1) What is the intent of this 
regulation? and (2) Can the intent be met by placing the warning 
statement on a panel other than the PDP?
    The agency's purpose in this rulemaking is to inform consumers of 
the dangers to small children from an accidental overdose of a product 
that contains iron. Because of the serious, life-threatening 
consequences of such an overdose, FDA tentatively concluded that 
warning statements are most likely to be read when they are placed on 
the PDP. This tentative conclusion followed the precedent established 
in the regulations requiring warning statements on the PDP of protein 
products (Sec. 101.17(d)), whose incorrect use can also result in dire 
health consequences.
    However, after evaluating the above comments and the results of the 
focus groups, the agency agrees that the warning statement does not 
need to be placed on the PDP to be effective in informing consumers of 
the hazard associated with overdose. The intent of the regulation can 
be met by placing the warning statement on the IP. The IP is the 
traditional location for warning statements. Information on the IP is 
readily accessible to consumers, particularly when it is presented in 
accordance with graphical requirements that enhance its prominence (see 
discussion below). Therefore, in this final rule the agency is revising 
proposed Secs. 101.17(e) and 310.518(b) (now Sec. 310.518(c)) to 
require that the warning statement be placed on the IP of the immediate 
container label.
    Several of the comments remarked that the proposal did not require 
that the warning statement be placed on the PDP of the immediate 
container if the immediate container was not the retail package.
    In the iron proposal (proposed Secs. 101.17(e)(2) and 
310.518(b)(3)), the agency proposed to require that: (1) The warning 
statement appear on the immediate container labeling; (2) it appear in 
such a way that the warning is intact until all of the dosage units to 
which it applies are used; and (3) if the immediate container is not 
the retail package, the warning statement must appear on the PDP of the 
retail package. FDA proposed these requirements as a single regulation 
that would apply to products in unit-dose packaging, in which the 
immediate container labeling does not have a PDP, as well as products 
in other than unit-dose packaging, in which the immediate container 
label does have a PDP. The comments that deduced that the proposed 
regulation did not require that the warning statement be placed on the 
PDP of the immediate container label if the immediate container was not 
the retail package indicate that the language of that single regulation 
did not clearly articulate the agency's intent, i.e., that the warning 
statement be on both the PDP of the retail package and the immediate 
container label, if there is one.
    Therefore, FDA is revising Secs. 101.17(e) and 310.518(b) (now 
Sec. 310.518(c)) to clarify where the warning statement must be placed. 
Specifically, FDA is splitting the applicable provisions into several 
subparagraphs, which are described below. In addition, the agency has 
revised the regulations, as already discussed, to require that the 
warning statement appear on the IP rather than on the PDP.
    In this final rule, Secs. 101.17(e)(2)(i) and 310.518(c)(2)(i) 
require that the warning statement for iron-containing dietary 
supplements and drugs appear ``on the information panel of the 
immediate container label.'' Sections 101.17(e)(2)(ii) and 
310.518(c)(2)(ii) provide that if iron-containing supplements and drugs 
are packaged in unit-dose packaging, and if the immediate container 
bears labeling,\4\ but not a label, the warning statement must appear 
``on the immediate container labeling.'' Sections 101.17(e)(3) and 
310.518(c)(3) require that, where the immediate container is not the 
retail package, the warning statement for all iron-containing dietary 
supplements and drugs (i.e., regardless of the manner in which the 
product is packaged) appear ``prominently and conspicuously on the 
information panel of the retail package label.''
---------------------------------------------------------------------------

    \4\ FDA recognizes that the package liner of a unit-dose package 
that bears no printed material is not labeling and would not need to 
bear the warning statement. Given the importance of the warning, FDA 
hopes that this fact will not cause manufacturers to cease putting 
printed material on the package liner.
---------------------------------------------------------------------------

    These requirements are necessary to ensure that the warning 
statement is seen by adults with responsibility for proper storage of 
the product. The placement of the warning statement on the retail 
package label will make it likely that the warning statement will be 
seen at the time the product is purchased to inform the purchaser of 
the product's potential to cause poisoning and of the need to store the 
product properly when it is brought into the house. However, under 
customary conditions of use, the retail container is frequently 
disposed of, and individuals other than the purchaser may use the 
product. Therefore, FDA is providing that the immediate container also 
bear the warning if it bears any labeling at all.
    In this final rule, Secs. 101.17(e)(4) and 310.518(c)(4) provide 
that the warning statement shall also appear on any labeling that 
contains warnings. These requirements are unchanged from the proposal, 
but they have been moved to a separate subparagraph as part of the 
overall reorganization of Secs. 101.17(e)(2) and 310.518(c)(2).
2. Comments on Prominence Through Graphical Requirements
    Several comments discussed the use of graphic requirements to set 
the warning statement apart from the rest of the label information. One 
comment pointed out that a warning statement can be made prominent and 
conspicuous by graphics such as surrounding the warning statement with 
a box, printing the warning statement in capital letters, printing the 
warning statement in bold typeface, and using contrasting graphics. 
Several comments recommended that the agency set requirements for 
graphics and discussed the need for type size specifications. Another 
comment suggested that FDA let the manufacturers determine the elements 
of prominence and conspicuousness needed to call attention to the 
warning statement. One comment cited the saccharin warning requirements 
as an example of a warning statement with specific contrasting graphic 
requirements.
    Most of the participants in the focus groups agreed that the 
warning statement should be in a boxed area to separate it from other 
information and to call attention to the warning. Many participants 
also felt that printing the warning statement in a color that contrasts 
with the predominant color of the packaging was eye-catching. Other 
graphical options considered by the focus groups included using 
contrasting

[[Page 2226]]

print and background, different sizes of print, and bolding of the 
message.
    In the iron proposal, FDA tentatively concluded that graphical 
requirements were not necessary to ensure that a warning statement 
placed on the PDP is prominent and conspicuous, because no data were 
supplied by the petitioners to support the use of graphics in the 
warning statement, and because the protein products regulation that the 
agency used as a precedent did not mandate specific graphical 
requirements. However, as discussed above, in this final rule the 
agency is moving the location of the warning statement from the PDP to 
the IP. The agency agrees that use of certain graphical requirements is 
an effective approach to ensuring that the warning statement is 
prominent and conspicuous. Moreover, a warning statement that appears 
on the IP, rather than on the PDP, needs graphical enhancements to 
ensure that it is prominent and conspicuous because the IP generally is 
more crowded than the PDP.
    Based on the comments and the results of the consumer research, the 
agency agrees that a box enclosing the warning statement will set the 
warning statement apart from the rest of the label. FDA has used this 
mechanism with the nutrition label in response to the directive in the 
Nutrition Labeling and Education Act of 1990 (the 1990 amendments) that 
the label be readily observable (Pub. L. 101-535, section 2(b)(1)(A) of 
the 1990 amendments). Therefore, the agency is requiring, in 
Secs. 101.17(e)(5) and 310.518(c)(5), that the warning statement for 
iron-containing products be separated from other information by a box. 
Manufacturers may use other graphics, in addition to the box, if they 
choose to do so.
    Three comments suggested that the cap or the PDP of the product 
bear a symbol or statement informing consumers that a new warning has 
been placed on the IP. For example, a prominent flag or a short 
statement saying ``See Iron Warning'' or ``See New Warning'' could be 
printed prominently on the PDP.
    FDA has decided not to require a flag or statement alerting 
consumers to the new warning label. The comments and the results of the 
consumer research have convinced the agency that consumers are already 
in the habit of looking at the IP for important information such as 
warnings, and the box around the warning statement will draw attention 
to it.
3. Comments on the Placement of the Warning Statement on Unit-Dose 
Packaging.
    To reinforce the message of the warning after the product is in the 
home, FDA proposed (proposed Secs. 101.17(e)(2) and 310.518(b)(3) (now 
Sec. 310.518(c)(3))) to require that the mandatory warning statement 
appear on the immediate container labeling in such a way that it is 
intact until all of the dosage units to which it applies are used. This 
provision would have effectively required that unit-dose packaged 
products bear the warning either directly on each individual cavity of 
the unit-dose packaging or on some section of the unit-dose packaging 
in such a way that separating an individual cavity would not destroy 
the warning label.
    FDA received several comments on this proposed requirement. 
Comments stated that the proposal was unclear as to whether the warning 
could appear along the full length of a strip of unit-dose packaging, 
or whether it must appear in its entirety on each unit dose (e.g., on 
each tablet in a blister pack). Several comments stated it would be 
physically impossible to place the entire lengthy warning proposed by 
FDA on each unit dose and still meet the minimum type size requirements 
of 21 CFR 101.2(c) or the requirements of 21 CFR 101.15(a)(6) that the 
labeling be prominent and conspicuous. One comment stated that the 
label space available for each cavity of a multipack blister type unit-
dose package is usually less than 1/2 inch by 1/2 inch and if, as 
proposed, a firm is required to print the entire warning statement, the 
print size would be so small that it would require magnification to 
read.
    Several comments suggested that the individual units of a unit-dose 
package be permitted to bear an abbreviated warning statement that 
alerts consumers to the hazard and preventive measures, such as: (1) 
``WARNING--Contains Iron. Keep Away From Children;'' and (2) ``WARNING: 
Keep in Original Package Until Each Use. Keep Away from Children.'' One 
comment also suggested that it would be helpful to manufacturers if FDA 
specified that the abbreviated warning could be printed on a strip or 
tab either above or below the individual cavities.
    FDA is requiring that the warning must appear on the immediate 
container of the product because, as discussed in the proposal in this 
proceeding, reports of 2,000 poisonings in children over approximately 
7 years provides strong evidence that many adults are not aware of the 
potential for serious harm posed by iron-containing products. The 
agency understands that printing the entire warning statement on each 
unit dose of an iron-containing product, while necessary to ensure that 
the warning statement remains intact until all of the individual dosage 
units to which it applied are used, would present problems in making 
the warning ``prominent and conspicuous.'' FDA disagrees, however, that 
placing an abbreviated warning statement on each cavity of a unit-dose 
package would be effective in alerting consumers to the risk that iron-
containing products poses to young children because, as discussed 
above, FDA has concluded that an informational statement that clearly 
communicates the nature and magnitude of the hazard is essential for 
the warning statement to be effective. Therefore, the agency has 
reconsidered how to achieve the intent of the proposed regulations 
without requiring that the warning statement remain intact until all of 
the dosage units to which it applies are used.
    FDA notes that, if for example, the full warning statement were 
placed on any side of a package (i.e., above, below, or on either side 
of individual cavities) of iron-containing products in unit-dose 
packaging that contains multiple, individual unit-dose packages that 
are connected without physical delineations (e.g. perforations) between 
the individual unit-dose packages, would allow the warning to remain 
intact until all of the dosage units to which it applies are used. 
Similarly, for iron-containing products in any unit-dose packaging 
(i.e., with or without physical delineations between the individual 
unit-dose packages), multiple copies of the warning statement across 
the immediate container label would increase the likelihood that at 
least one complete warning statement will remain intact until most of 
the individual units have been used. Although this second option could 
not ensure that the warning statement would remain intact until all of 
the dosage units to which it applies have been used, it is clear that 
options such as this can approach, if not fully achieve, the desired 
outcome of the proposed regulations.
    Therefore, in this final rule, FDA is revising 
Sec. 101.17(e)(2)(ii) to read:

    If a product is packaged in unit-dose packaging, and the 
immediate container bears labeling, the statements required by 
paragraph (e)(1) of this section shall appear prominently and 
conspicuously on the immediate container labeling in a way that 
maximizes the likelihood that the warning is intact until all of the 
dosage units to which it applies are used.


[[Page 2227]]


FDA also is revising Sec. 310.518(c)(2)(i) to include a parallel 
requirement. The revised wording of these regulations makes clear that 
the manufacturer bears the responsibility to show diligence in 
designing labeling that will meet the agency's goal of informing 
consumers of the dangers to small children from an accidental overdose 
of a product that contains iron but provides the manufacturer with 
flexibility in determining how it will do so.
4. Comments Specific to Prescription Drug Products
    One comment suggested that the warning statement on prescription 
drug products, if placed on a label, should contain a message to the 
pharmacist not to cover the warning with the prescription label so that 
the warning remains visible to the consumer.
    FDA believes that the comment raises an important point. However, 
the agency expects that pharmacists will be aware that warnings should 
not be covered by anything, not by a price tag, a pharmacy label, or 
anything else. Therefore, FDA is taking no action in response to this 
comment.

III. Packaging of Iron-Containing Products

    FDA also proposed to require unit-dose packaging of iron-containing 
drugs and dietary supplements with potencies of 30 mg or more of iron 
per dosage unit. FDA tentatively concluded that unit-dose packaging of 
such products would contribute in a significant way, over and above the 
protection provided by warning statements and CRP's, to reduce 
children's access to potentially fatal doses of iron.

A. FDA's Legal Authority to Establish Packaging Requirements for Iron-
Containing Products

    Several comments questioned FDA's legal authority to establish 
regulations requiring packaging of dietary supplements and drugs. The 
comments argued that Congress never authorized, and never intended, FDA 
to have such authority under the act. Moreover, these comments 
contended that even if FDA previously had such authority, Congress 
transferred this authority from the Secretary of Health, Education, and 
Welfare (HEW) (now Health and Human Services) to the CPSC under the 
Poison Prevention Packaging Act (PPPA) (15 U.S.C. 1471 et seq.) when 
that agency was created.
    These comments argued that the language of both the PPPA and the 
act are clear in expressing Congress' intent that FDA was not granted 
authority over the packaging of foods or drugs to prevent childhood 
poisonings. These comments contended that through passage of the 
Consumer Product Safety Act (Pub. L. 92-573) (CPSA), Congress intended 
that CPSC have exclusive jurisdiction over packaging to limit child 
access to poisonous substances. These comments noted that in enacting 
the CPSA, Congress transferred from the Secretary of HEW to CPSC 
certain functions under the Federal Hazardous Substance Act (HSA) (15 
U.S.C. 1261 et seq.) and the PPPA. In addition, in enacting the CPSA, 
Congress transferred the administrative and enforcement functions of 
the PPPA from the Secretary of HEW to CPSC (15 U.S.C. 2079).
    FDA disagrees with the comments' interpretation of the provisions 
of the laws in question. As discussed in the iron proposal and the 
supplementary proposal, FDA's authority to require unit-dose packaging 
of iron-containing dietary supplements and drugs derives directly from 
sections 402(a)(4) and (g) and 501(a)(2)(A) and (a)(2)(B) of the act 
(21 U.S.C. 342(a)(4) and (g) and 21 U.S.C. 351(a)(2)(A) and (a)(2)(B)). 
The existence of other laws to which foods and drugs are subject does 
not limit FDA's authority to fulfill its responsibility under the act 
to help ensure that foods, including dietary supplements, and drugs are 
not injurious to health.
    FDA disagrees with the comments that asserted that the agency has 
no authority over how food is packaged. This claim is belied by the act 
itself. Section 409 of the act (21 U.S.C. 348), although not applicable 
to this rulemaking, gives FDA authority to prescribe the conditions 
under which a food additive may be safely used, including packaging 
requirements deemed necessary to ensure the safety of such use (section 
409(c)(1)(A) of the act). Section 721(b)(3) of the act (21 U.S.C. 
379e(b)(3)) provides similar authority for color additives.
    More relevant to this rulemaking, sections 402(a)(4) and 
501(a)(2)(A) of the act provide that a food or a drug is adulterated if 
it has been packed under insanitary conditions whereby it may have been 
rendered injurious to health. Section 402(a)(4) has been read broadly 
(see United States v. Nova Scotia Food Products, Corp., 568 F.2d 240, 
247 (2d Cir. 1977)) as a grant of authority to ensure that foods are 
not packed in a manner, including process, package design, and 
packaging materials, that creates the possibility that the foods will 
cause harm under their reasonably foreseeable conditions of use. For 
example, parts 108, 113, and 114 (21 CFR parts 108, 113, and 114) 
address the steps necessary to ensure that the packaging of low acid 
and acidified foods does not permit the outgrowth of botulism, whose 
presence in the food would render the food injurious to health. Part 
110 (21 CFR part 110) defines current good manufacturing practice 
(CGMP) for food generally, and in Sec. 110.80(b)(13) requires that 
packaging be done in a manner that protects the food against 
contamination and that ensures that safe and suitable packaging 
materials are used (see also Sec. 110.5(a)(2)). These provisions 
provide authority for the agency to require the use of packaging that 
is designed to help ensure that dietary supplements that contain 30 mg 
or more of iron per dosage unit are not rendered injurious to health. 
FDA is aware of no reason why section 501(a)(2)(A) of the act, which 
contains virtually the same words as section 402(a)(4) of the act, 
should not be read equally as broadly.
    Section 501(a)(2)(B) of the act provides that a drug is 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 in conformity with, CGMP to ensure 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 have. The agency has determined that, 
under section 501(a)(2)(B) of the act, manufacturers are responsible 
for preventing certain foreseeable misuse of a drug product. A drug 
product may be safe and effective as manufactured, but used in an 
unsafe and ineffective manner. As discussed earlier, data demonstrate 
that the current manner of holding products that contain 30 mg or more 
of iron per dosage unit until their use by the intended consumer fails 
to ensure that the products will be safe (see 59 FR 51030 at 51033). 
Large numbers of children are ingesting such products and suffering 
serious injuries and death. Because unit-dose packaging technology is 
available and can reduce the danger of iron poisoning, CGMP dictates 
that such packaging be used for products containing more than 30 mg of 
iron per dosage unit.
    FDA concludes that unit-dose packaging will significantly reduce 
the likelihood of serious injuries to young children. FDA finds that 
this will be the case because unit-dose packaging will limit the number 
of unit doses that a child may consume once it gains access to the 
product, not because unit-dose packaging will make it any more

[[Page 2228]]

difficult to open the package.\5\ The fewer the number of tablets or 
capsules the child consumes, the smaller the dose of iron the child 
will ingest. The smaller the dose, the lower the risk that the child 
will suffer serious injury. Thus, FDA's unit-dose packaging requirement 
will significantly limit the likelihood that iron products containing 
30 mg or more of iron per dosage unit may be injurious to health 
because the requirement that the child open each package unit will 
limit the amount of iron that the child can consume (see 59 FR 51030 at 
51049). No comments provided any information to the contrary.
---------------------------------------------------------------------------

    \5\ Given CPSC's child resistance requirements, FDA's action 
will have no effect on how difficult it is to open the package.
---------------------------------------------------------------------------

    The CPSA, HSA, and PPPA do not prevent FDA from acting. Foods and 
drugs are neither consumer products (see 15 U.S.C. 2052(a)(1)(H) and 
(a)(1)(I)) nor hazardous substances (see 15 U.S.C. 1261(f)(2)). Thus, 
the CPSA and HSA are not relevant to this rulemaking. FDA's action is 
also not precluded by the PPPA because FDA is not establishing a 
special packaging performance standard for products that contain 30 mg 
or more of iron per dosage unit. As explained above, nothing in FDA's 
regulation is designed to define or modify what constitutes child-
resistance for iron-containing products. In this rulemaking, FDA is 
defining the requirements of CGMP for these products to help ensure 
that they are not packed under conditions whereby they may be rendered 
injurious to health (sections 402(a)(4), 402(g)(2), and 501(a)(2) of 
the act). Such action is fully within FDA's authority under the act. 
Therefore, FDA finds no merit to these comments.
    Several comments argued that section 402(f) of the act makes clear 
that FDA has the burden of demonstrating that any particular dietary 
supplement is adulterated or unsafe under the conditions of use 
recommended or suggested in the labeling, or in the absence of such 
labeling, under ordinary conditions of use. These comments contended 
that FDA cannot merely assert that a dietary supplement is no longer 
safe because of the form of packaging in which it is sold. Moreover, 
these comments contended that FDA must find, for each product, that 
under the recommended conditions of use, the product presents a 
significant or unreasonable risk of illness or injury.
    FDA disagrees with these comments. The DSHEA, which added section 
402(f) to the act, did not exempt dietary supplements that are foods 
(that is, e.g., that are not intended to prevent, cure, treat, or 
mitigate a disease) from the food provisions of the act (see section 
201(ff) of the act (21 U.S.C. 321(ff))). Under the act as amended by 
the DSHEA, a dietary supplement that is a food is adulterated if it is 
prepared, packed, or held under insanitary conditions whereby it may 
have become contaminated with filth, or whereby it may have been 
rendered injurious to health (section 402(a)(4) of the act). This 
situation is the one that FDA is addressing in this rulemaking. 
Moreover, section 402(g)(2) of the act specifically authorizes FDA to 
adopt good manufacturing practice regulations for dietary supplements. 
FDA is relying on this provision of the act, as well as sections 
402(a)(4) and 701(a) of the act (21 U.S.C. 371(a)), in adopting the 
unit-dose packaging requirement for dietary supplements that are foods 
that contain 30 mg or more of iron per dosage unit.
    The agency received a comment from the CPSC requesting that FDA 
amend its proposed regulations to clarify that iron-containing products 
conforming to FDA's regulation are subject to compliance with certain 
regulations issued by the CPSC.
    In light of the desire of both the CPSC and FDA to ensure that 
manufacturers of iron-containing products comply with both CPSC's 
regulations for child-resistant special packaging and FDA's CGMP 
regulations for iron-containing products, in this final rule FDA is 
revising proposed Secs. 111.50 (21 CFR 111.50) and 310.518(a) to make 
clear that products subject to these regulations are also subject to 16 
CFR parts 1700, 1701, and 1702.

B. Effectiveness of Unit-Dose Packaging

    The agency received a number of comments bearing on the 
effectiveness of unit-dose packaging to limit pediatric access to 
products. The majority of these comments expressed support for FDA's 
tentative conclusion that unit-dose packaging will effectively limit 
pediatric access to products. A few comments challenged this tentative 
conclusion. None of these comments provided data to support their 
views.
    One comment expressed the view that unit-dose packaging would not 
be effective because such packaging is subject to compromise. Another 
comment contended that the child-resistant effectiveness of child-
resistant unit-dose packaging is not absolute (i.e., because the CPSC 
specification is based on the number of units that a child is able to 
access in a period of time) in contrast to the effectiveness of CRC 
type packaging (i.e., in which the CPSC regulations specify that 
opening the closure within a period of time constitutes failure of the 
system).
    FDA recognizes that unit-dose packaging, like all packaging, can be 
compromised, and that packaging in and of itself cannot make a product 
safe. However, based on information available to the agency (Refs. 8 
and 9) and as discussed in the iron proposal (59 FR 51030 at 51049), 
unit-dose packaging, even conventional unit-dose packaging, limits 
pediatric access to multiple dosage units of product. Moreover, the 
effectiveness of unit-dose packaging to limit pediatric access to 
product is not dependent on proper reclosure of the packaging. In 
contrast, the effectiveness of closure type packaging to limit 
pediatric access is dependent on proper reclosure of the container. If 
the closure is compromised (i.e., opened, improperly reclosed, or 
damaged), all of the contents of the package are readily available for 
ingestion. FDA's concern is limiting the possibility that the product 
will be injurious to health. Unit-dose packaging, even conventional 
unit-dose packaging, will help to accomplish this end by limiting the 
amount of iron that a child can consume in a short period of time. 
Therefore, FDA finds that the comments provide no basis for modifying 
its approach to the problem of acute iron poisoning in young children.

C. Access to Products by Certain Persons

    The agency received several comments bearing on the potential 
difficulty that some elderly and handicapped persons may have in 
gaining access to products in unit-dose packaging. For example, one 
comment noted that unit-dose packaging may limit access to products by 
persons with rheumatoid arthritis. Two comments expressed their view 
that unit-dose packaging is inconvenient. Another comment expressed the 
view that for adults with limited dexterity, conventional unit-dose 
packaging is not difficult to open. None of these comments provided any 
data or information to support their views.
    A comment from CPSC noted the difficulty in assessing the extent to 
which elderly or handicapped persons may be hampered in accessing 
product packaged in conventional unit-dose packaging, because there are 
no ``accessibility'' standards for conventional unit-dose packaging. In 
their comment, CPSC provided a report of their study examining the 
accessibility of child-resistant and conventional unit-dose packaging 
with seniors, aged 60 to 75 years old. CPSC

[[Page 2229]]

reported that all four child-resistant unit-dose package types passed 
the senior accessibility test criteria. Moreover, all 100 seniors 
tested were able to open the conventional unit-dose packaging.
    In the iron proposal and the supplemental proposal, FDA anticipated 
the practical effect of the combination of new Secs. 111.50 and 
310.518(a) and CPSC's child-resistant packaging regulations for iron-
containing drugs and dietary supplements, 16 CFR 1700.14(a)(12) and 
(a)(13), respectively. Manufacturers and distributors of drugs and 
dietary supplements containing 30 mg or more of iron per dosage unit 
and containing 250 mg or more of total iron per package will have two 
options. One option will be to package their product in child-resistant 
unit-dose packaging (e.g., child-resistant blisters, child-resistant 
pouches, or other child-resistant packaging that accomplishes the 
objective of making a single dosage unit available at a time). A second 
option will be to package their product in conventional unit-dose 
packaging through exercising their right to an exemption to CPSC's 
special packaging regulations as required by the PPPA.
    FDA notes that since publication of the iron proposal, CPSC has 
amended its regulations in 16 CFR part 1700 (60 FR 37710, July 21, 
1995) for testing the child-resistant effectiveness of packaging to 
require a senior adult use effectiveness of not less than 90 percent 
for a senior adult test panel consisting of 100 adults aged 50 to 70 
years old. The intent of these amendments is to increase the use of 
child-resistant packaging by making it easier for adults to use them 
properly.
    It is not FDA's intent to circumvent the aim of the PPPA to allow 
access by elderly and handicapped persons who may be unable to use 
household substances packaged in child-resistant packaging. However, in 
the absence of information to the contrary, FDA has no basis to 
conclude that iron-containing products packaged in conventional unit-
dose packaging will unduly limit elderly or handicapped persons' access 
to such products. Therefore, FDA concludes that unit-dose packaging 
does not limit access to product by elderly or handicapped persons.

D. False Sense of Security

    Two comments expressed their view that unit-dose packaging should 
not be required for products containing 30 mg or more of iron per 
dosage unit because such a requirement will provide a false sense of 
security and will not limit pediatric access to product.
    FDA recognizes that no single approach is adequate to ensure the 
safe use of iron-containing products. However, a combination of 
educational programs, label warning statements, and packaging measures 
can reasonably be expected to be effective in reducing significantly 
the incidence of poisonings. As discussed in the iron proposal, FDA is 
sponsoring educational efforts to better inform health care providers 
and consumers of the risks presented by iron-containing products, and 
FDA is requiring label warning statements to provide information to 
consumers about the hazards to young children presented by iron-
containing products. These two approaches will effectively alert health 
care providers and consumers to the hazards presented by iron-
containing products. Moreover, contrary to the comments' contention 
that these measures, including unit-dose packaging, will provide a 
false sense of security, these measures more likely will support a 
heightened sense of concern. Persons informed of the pediatric hazard 
presented by iron-containing products will take extra measures to 
ensure that the products are handled appropriately, including ensuring 
that the unit-dose packaging is not compromised in any way. Therefore, 
FDA finds no merit in these comments.

E. CRC is Adequate

    One comment expressed the view that CRC packaging is adequate for 
limiting pediatric access to a toxic amount of iron.
    As discussed in the iron proposal, based on information available 
to the agency, misuse of CRC type packaging is one contributing factor 
to pediatric iron poisonings. For example, in 21 of the 26 pediatric 
iron poisoning deaths in which the type of packaging was reported, the 
product was packaged in CRC type packaging (Ref. 10). In the absence of 
information indicating that misuse of closure type packaging will no 
longer occur and in light of the potentially fatal consequences when a 
young child gains access to a lethal amount of iron, FDA is not 
persuaded that CRC type packaging is adequate to ensure that these 
products are packaged under conditions that are not injurious to 
health.
    Another comment expressed the view that: ``FDA's current effort to 
go beyond the CPSC requirement for child-resistant closures with 
respect to iron-containing supplements should be viewed as an anomaly 
and not as a failure of the CRC system.''
    The agency disagrees with the view that this rulemaking is an 
anomaly. Rather, FDA considers that this rulemaking is a special 
measure in response to a special circumstance, i.e., the large number 
of acute iron poisonings, including death in children less than 6 years 
of age, attributable to accidental overdoses of iron-containing 
products. FDA will continue to exercise its legal authority to fulfill 
its legislative mandate to ensure that foods, including dietary 
supplements, and drugs are not injurious to health.
    Nonetheless, FDA agrees that this rulemaking should not be viewed 
as a failure of the CRC system. The agency notes that it is 
establishing additional packaging requirements only for products that 
contain 30 mg or more of iron per dosage unit because of the 
irreversible and potentially fatal consequences presented by these 
higher dose iron-containing products rather than because of a view that 
the CRC system has failed in any way.

F. Difficulty in Making Child-Resistant Unit-Dose Packaging

    One comment stated that it is more difficult to make a child-
resistant unit-dose package that is accessible and acceptable to adults 
than to make a conventional unit-dose package. The comment further 
noted that this difficulty was the reason why so few highly toxic 
products in the market were packaged in a unit-dose package.
    FDA is not establishing packaging performance standards, child-
resistant or otherwise, for iron-containing products in this 
rulemaking. Such standards are the responsibility of the CPSC. Rather, 
FDA is establishing these packaging requirements as a matter of good 
manufacturing practice to ensure that dietary supplements and drugs 
that contain 30 mg or more of iron per dosage unit are not packed under 
conditions whereby they may be rendered injurious to health. Therefore, 
FDA finds that the comment is not relevant to this rulemaking.

G. Alternative Approaches

    Two comments recommended that all iron-containing drugs and dietary 
supplements be packaged in child-resistant unit-dose packaging to 
ensure that they are inaccessible to young children.
    As discussed in the proposal, information available to FDA 
demonstrates that the iron-containing products presenting the greatest 
hazard to young children are those that contain 30 mg or more iron per 
dosage unit. As discussed above, FDA has concluded, based on the 
available evidence, that label warning statements and educational 
efforts are adequate to

[[Page 2230]]

address the problems with products containing less than 30 mg of iron 
per dosage unit, and that label warning statements, educational 
efforts, and unit-dose packaging are necessary to ensure that products 
containing 30 mg or more of iron per dosage unit are packaged under 
conditions that are not injurious to health. Therefore, the agency is 
rejecting this recommendation.
    One comment recommended that, rather than requiring unit-dose 
packaging of products containing 30 mg or more of iron per dosage unit, 
FDA should limit the total number of dosage units allowed per package 
based on the amount of iron that is toxic. No specific upper limit on 
the total iron to be allowed per container was provided in this 
comment.
    FDA notes that CPSC has taken an approach similar to that suggested 
by the comment by requiring child-resistant special packaging if the 
packaging contains more than 250 mg of total iron. In the iron 
proposal, FDA discussed the amount of ingested iron that is lethal to 
young children (i.e., to a 10 kg child) and noted that an acute 
ingestion of 25 mg/kg of iron may produce symptoms of poisoning, 60 mg/
kg of iron may develop into clinically significant iron poisoning, and 
250 mg/kg of iron may well be lethal for a young child. Because the 
comment did not specify an upper limit on the total iron to be allowed 
in the container, FDA will address the comment based on an upper limit 
of 250 mg of iron (i.e., the amount of iron that may produce symptoms 
of poisoning).
    If FDA were to limit the total number of dosage units in a 
container based on 250 mg of iron, then a manufacturer would be able to 
provide up to 8 dosage units of a product containing 30 mg of iron per 
dosage unit (240 mg of total iron), or 3 dosage units of a product 
containing 65 mg of iron per dosage unit (195 mg of total iron), per 
container to meet this requirement. Because CPSC's child-resistant 
special packaging requirement has a threshold of 250 mg of total iron, 
such products could be packaged in conventional packaging and still be 
in compliance with CPSC's child-resistant special packaging 
regulations.
    Packaging eight or fewer dosage units in closure-type packaging is 
impractical and actually is approaching a requirement of a ``unit-dose 
bottle.'' Moreover, iron-containing products frequently contain 90 to 
100 dosage units per bottle, and consumers who currently purchase iron-
containing products in such quantities would be likely to continue this 
practice, thereby purchasing 12 bottles of an iron-containing product 
that contains 30 mg of iron per dosage unit or 30 bottles of an iron-
containing product that contains 65 mg of iron per dosage unit. Because 
all of the vials perform the same function, consumers are likely to 
store them in one place. The existence of multiple vials, particularly 
if the products are packaged with conventional-type closures, means 
that a child who discovers and gains access to one vial is likely to 
gain access to multiple vials. Further, to minimize the space needed 
for storage, consumers who bring multiple vials into the home may 
choose to repackage the product into as few bottles as possible, 
thereby defeating the intent of the regulations. Therefore, FDA 
concludes that limiting the total number of dosage units per container 
based on the total amount of iron per container will not contribute in 
a significant way to achieving the agency's goal of limiting pediatric 
access to a toxic amount of iron by ensuring that iron-containing 
products are packaged in a manner that will not render the product 
injurious to health.
    The agency received two comments recommending that opaque packaging 
material be required for unit-dose packaging to provide additional 
safeguards to limit pediatric access to product. These comments noted 
that opaque packaging is required for child-resistant unit-dose 
packaging in New Zealand and throughout the European Community.
    FDA recognizes that opaque packaging is one approach that may 
reduce pediatric access to product. However, the comments did not 
provide the agency with sufficient information to enable FDA to 
conclude that opaque unit-dose packaging is necessary to ensure that 
iron-containing products are packaged under conditions that are not 
injurious to health. Given this fact, FDA finds no basis to require the 
use of opaque packaging at this time. However, FDA would have no 
objection if manufacturers used opaque unit-dose packaging.
    One comment recommended that the proposed regulation be modified to 
provide flexibility to permit manufacturers to try alternative 
packaging designs that achieve the same effect of limiting pediatric 
access to multiple doses of iron-containing products.
    In establishing unit-dose packaging requirements for iron-
containing products that contain 30 mg or more of iron per dosage unit, 
one of the agency's goals is to avoid restrictive requirements that 
unnecessarily limit technological advances that accomplish the 
objective of reducing pediatric access to potentially lethal amounts of 
iron. Under new Secs. 111.50 and 310.518, the term ``unit-dose 
packaging'' means any type of packaging that achieves the goal of 
allowing access to one dosage unit at a time. The agency wants to 
clarify that, for the purpose of this rulemaking, several types of 
packaging can satisfy the definition of ``unit-dose-packaging,'' 
including blister-type packaging, pouches, and dispensers that deliver 
one dosage unit at a time. Moreover, the agency anticipates that future 
advances in package design will result in other types of packaging that 
will also meet this definition. Therefore, because the regulations as 
proposed provide for flexibility in the type of packaging used to 
achieve unit-dose, FDA is taking no action in response to this comment.
    One comment asked whether the agency intends to eliminate the 
practice of packaging iron-containing drug products that are sold by 
prescription in dispensing size bottles for use by pharmacists. These 
bottles contain up to 1,000 tablets each. The comment stated that few 
pharmacists are capable of dispensing these products in unit-dose 
packaging and added that unit-dose packaging is not necessary for 
products obtained by prescription. The latter point was made by a 
second comment as well.
    FDA does intend that change be effected in the dispensing and 
packaging practices of some iron-containing products, including iron-
containing drug products sold by prescription. Some of the iron-
containing drug products that have caused injury to children have been 
sold by prescription, and the agency is concerned that their being sold 
by prescription has not caused adults to ensure that they are kept 
inaccessible to children. Consequently, the agency believes that unit-
dose packaging is necessary for iron-containing prescription drug 
products that contain 30 mg or more of iron per dosage unit. Therefore, 
the requirement of this final rule to package iron-containing products 
that contain 30 mg or more of iron per dosage unit in unit-dose 
packaging will result, as an unintended consequence, in an elimination 
of the practice of packaging such iron-containing prescription drug 
products in dispensing size bottles for use by pharmacists.
    One comment recommended that FDA revise the proposal to specify 
that all iron-containing tablets sold over-the-counter be sold with 
CRC's. The comment suggested that packaging for iron-containing drug 
products sold by prescription not be changed because

[[Page 2231]]

pharmacies will repackage the contents. The agency understands this 
latter suggestion to mean that packaging for products sold by 
prescription should not be subject to regulation since pharmacists will 
repackage tablets into pharmacy vials.
    FDA has not revised the regulations in response to this comment. 
The distinction between unit-dose packaging and CRC is essential to the 
rule. As explained above, decisions about child-resistant packaging are 
the province of CPSC. FDA is requiring unit-dose packaging for products 
that provide 30 mg or more of iron per dosage unit to ensure that these 
products are not rendered injurious to health. Serious injuries, 
including death, are attributable to accidental overdose of products 
containing this amount of iron per unit. FDA's conclusion, reached on 
the basis of this rulemaking, is that unit-dose packaging will limit 
the number of dosage units to which a child will gain access and 
thereby significantly limit the risk of injury. As noted above, to 
limit the risk of serious injury and death, the agency intends that 
such iron-containing drug products sold by prescription will also be 
packaged in unit-dose packaging.
    One comment suggested that FDA review its specifications for unit-
dose packaging in a public forum that would include packaging suppliers 
and associations to determine whether CRC might enhance safety more 
than unit-dose packaging.
    The agency declines to accept this suggestion. As stated 
previously, FDA is not setting specifications for unit-dose packaging 
or for CRC's. Such specifications are the responsibility of the CPSC. 
FDA has the responsibility to ensure that products are packed under 
conditions that will not render them injurious to health. Young 
children are gaining access to toxic and potentially fatal amounts of 
iron from iron-containing products packaged in CRC type packaging. It 
is for this reason that FDA has determined that unit-dose packaging of 
products containing 30 mg or more of iron per dosage unit is necessary 
to ensure that iron containing products are packaged under conditions 
that will not render them injurious to health.
    One comment requested that FDA review its implementation plan with 
industry and with individual suppliers of unit-dose packaging to 
discuss issues relevant to materials and machinery, including adequate 
supply of packaging, cost, validation, stability, and compliance.
    FDA declines this request because the agency's analysis of costs 
and benefits (see section VI. of this document) takes into account 
these aspects of compliance with the rule. Based on comments received 
from the packaging industry, the analysis has found that: (1) There is 
an adequate supply of packaging, and (2) not all firms will need to 
purchase packaging equipment because adequate capacity exists within 
the contract packaging industry. The analysis also takes into account 
other costs of complying with the requirements of this rule, such as 
administrative costs, storage and transportation costs, stability 
testing, and label redesign costs.
    One comment stated that the proposal failed to address certain 
regulatory concerns including the impact of the rule on product 
submissions currently under review by the Center for Drug Evaluation 
and Research (CDER) and whether new product submissions will be 
required by this rule.
    There currently are no submissions under review by CDER for iron-
containing drug products. If future submissions are made to CDER for 
such products, FDA expects that they will reflect any change in the 
stability of the products that may be caused by a change to unit-dose 
packaging. The rule does not, however, in and of itself, establish 
separate submission requirements for iron-containing drug products.

IV. 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 of the AG petition 
because 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. In the proposal, 
FDA requested comments on whether use of ``candy'' and ``colorful'' 
coatings on iron-containing products is hazardous to infants and young 
children because of the apparent attractiveness of the products. FDA 
stated that the agency would consider action in this regard if the 
information received presented an objective basis for additional steps 
that FDA could take to limit the appeal of iron-containing products to 
young children.
    FDA received several comments on the appearance of iron-containing 
products. Most of these comments expressed an opinion that the 
resemblance of certain iron-containing products, including products 
formulated specifically for use by children, to candy or to cartoon 
characters contributed to the problem of children ingesting large 
quantities of these products. One comment argued that experience 
demonstrated that children are attracted to bright, shiny, colorful 
objects, and that, although children will swallow most objects, they 
will continue to seek out objects that taste good. This comment stated 
that changing the sweet coating would be an additional safeguard to 
ensure that children do not ingest large quantities of these 
supplements. Another comment asserted that a candy-like appearance and 
taste both needlessly attract an unsuspecting child and encourage 
ingestion of large quantities of these products by a child who may be 
unlikely to chew through the sugar coat.
    Another comment, from a State department of health, reported that 
investigation of 5 of 17 deaths revealed evidence that children chewed 
or sucked on the iron tablets. A comment from a State consumer 
protection board expressed the opinion that hazardous products with a 
look-alike appearance to food products that are safe to consume present 
conflicting messages that can confuse children about what is safe to 
eat, and what is not. Some comments noted that current recommendations 
from industry trade organizations include a recommendation that 
products containing 30 mg or more of iron per dosage unit should not be 
manufactured to have a sweet, candy-like outer coating.
    In the proposal, FDA stated its tentative view that it may not be 
possible to objectively measure the candy-like appearance of iron-
containing products. None of the comments provided a basis for FDA to 
change this tentative view. Therefore, FDA is not adopting any 
requirements relating to the formulation or appearance of iron-
containing products.

V. Forms of Iron That May Be Less Toxic

A. Introduction

    Three basic types of elemental iron powders are marketed for use in 
foods: Reduced iron, electrolytic iron, and carbonyl iron. The terms 
``reduced,'' ``electrolytic,'' and ``carbonyl'' refer to the production 
process by which the iron is manufactured rather than the

[[Page 2232]]

composition of the product. In the iron proposal, FDA specifically 
requested comments on the appropriateness of elemental iron as a source 
of iron in drugs and dietary supplements. FDA stated that the agency 
would consider exempting iron-containing products that incorporate 
elemental iron from any regulations that result from the rulemaking 
instituted by the iron proposal if the information received was 
persuasive in establishing that the use of elemental iron would 
substantially decrease the risk of pediatric poisoning while allowing 
for effective dietary iron supplementation.

B. Public Workshop

    In the Federal Register of March 21, 1995 (60 FR 14918), FDA 
published a notice announcing a public workshop on the acute toxicity 
of elemental forms of iron relative to that of iron salts. The purpose 
of the workshop was to solicit scientific data and information about 
the acute toxicity of elemental forms of iron with regard to whether 
such forms are sufficiently safe in dietary supplement and drug 
products to warrant exemption from the special packaging and labeling 
requirements that FDA had proposed for products containing iron salts.
    Specifically, the notice stated that the purposes of the workshop 
were to: (1) Identify data that objectively describe the acute toxicity 
of elemental iron; (2) identify the market uses of elemental iron and 
any adverse reaction reporting systems or processes used by 
manufacturers and vendors; (3) identify any data on acute, accidental 
exposure of children or adults to products containing elemental iron; 
(4) discuss a possible conceptual framework for evaluation of the 
effects of elemental forms of iron upon acute exposure; and (5) discuss 
the validity and limitations of acute toxicity data in experimental 
animals in predicting the risk in young children.
    The notice also stated that specific topics that may be relevant 
and on which discussion was invited included: (1) Physiological factors 
that influence toxicity of elemental forms of iron, in comparison with 
those for iron salts; (2) the quality, results, and relevance of animal 
studies on acute toxicity of elemental iron and iron salts; (3) the 
quality and results of human studies for evaluating the effects of 
elemental iron; (4) factors influencing the validity of extrapolation 
of experimental animal data on acute toxicity of various forms of iron 
for predicting the risk in young children; and (5) current uses of 
elemental iron in dietary supplements and drugs and the data available 
for predicting the risk in young children.
    The workshop was held on April 20, 1995, in Rockville, MD. 
Statements were made by representatives of several manufacturers of 
iron-containing products, a trade association, a physician, and a law 
firm representing a manufacturer of iron-containing products. Most of 
the participants who made oral presentations at the public meeting also 
submitted written comments containing details of the information 
discussed at the meeting.
    The data and information submitted to FDA in response to the 
agency's request for data in the notice announcing the public workshop, 
as well as the data and information submitted to FDA in comments to the 
iron proposal and the supplementary proposal, are discussed below. Most 
of the data and information submitted to FDA addressed a single form of 
elemental iron, namely, carbonyl iron. However, one comment provided 
data and information on polysaccharide iron complex (PIC), a nonionic 
iron complex synthesized by the neutralization of a ferric chloride 
carbohydrate solution. Both forms of iron will be considered below.

C. Market Uses of Elemental Iron

    FDA received one comment from a manufacturer who claimed to be the 
sole producer of carbonyl iron in the United States and who stated that 
the firm had introduced a pharmaceutical/food grade of carbonyl iron 
into the marketplace in 1988. The comment provided information on the 
manufacturers of multivitamins and stand-alone iron supplements who 
have purchased carbonyl iron for use in those products, brand names of 
products containing carbonyl iron, the potency (expressed in mg of 
iron) of the various products, and the distributors who sold the 
products. The manufacturer stated that carbonyl iron had been used in 
more than 2 billion tablets marketed by 15 manufacturers in 35 brands 
of iron-containing dietary supplement and drug products.
    Another comment from an industry trade association stated that 
there are between 1,300 and 3,000 products containing iron, including 
carbonyl iron, on the market.
    The agency received one comment from a manufacturer of PIC, which 
is approximately 46 percent iron by weight and is sold in solid oral 
dosage forms in both dietary supplement and drug products in doses 
ranging from 18 mg of iron to 150 mg of iron. The comment provided 
information on the brand names of ten products containing PIC in solid 
oral dosage form and the potency (expressed in mg of iron) of the 
various products. The comment stated that approximately 255.8 million 
brand-name tablets or capsules containing PIC had been produced during 
the period 1993 to 1994.
    FDA appreciates receiving this information, which demonstrates that 
certain forms of elemental iron are used as ingredients in a range of 
iron-containing products that are marketed for use by children and 
adults. This information provides a context for evaluating the impact 
of an agency decision to exempt any form of elemental iron from any or 
all of the requirements of this final rule. At this time, it appears 
that between 1 percent and 3 percent of iron-containing products on the 
market contain carbonyl iron, and that between 0.3 percent and 0.8 
percent of iron-containing products on the market contain PIC.

D. Comments on the Acute Toxicity in Animals of Elemental Iron Compared 
to That of Iron Salts

    A comment from a professor of nutrition at a research university 
stated that there are apparently distinct advantages to the use of 
carbonyl iron as an alternative to the use of iron salts because of 
decreased toxicity at the doses that young children are likely to 
ingest. Another comment from a hematologist urged that carbonyl iron be 
exempted because of its low acute toxicity. Neither comment, however, 
supplied any data to support these statements.
    Several comments asserted that administering iron as carbonyl iron 
for the prevention and treatment of iron deficiency provides a greater 
margin of safety than administering iron as iron salts. One comment 
conceded that available data are limited but stated that while the 
estimated lethal dose (LD) of ferrous sulfate in rats was 200 to 300 mg 
of iron (Fe) (expressed in terms of iron content) per kg body 
weight,\6\ the LD of carbonyl iron in rats and guinea pigs was 50,000 
to 60,000 mg Fe/kg body weight or more\7\ (Ref. 11). This comment 
concluded that these studies in experimental animals suggested that 
carbonyl iron has a 100-to 200-fold

[[Page 2233]]

greater safety margin than ferrous sulfate.
---------------------------------------------------------------------------

    \6\ The comment did not provide a literature citation for these 
data. The comment also did not specify whether the data reflected 
LD50 values (i.e., the dose that is fatal to 50 percent of the 
animals) or LD100 values (i.e., the dose that is fatal to 100 
percent of the animals).
    \7\ The data cited are LD100 values. The comment also noted 
that the LD0 value (i.e., the dose at which all animals 
survive) for rats and guinea pigs was 10,000 to 15,000 mg Fe/kg body 
weight.
---------------------------------------------------------------------------

    Another comment from a manufacturer of carbonyl iron included a 
report, commissioned by that manufacturer, on the toxicity of carbonyl 
iron powder. This report acknowledged that little data were provided to 
directly compare the toxicity of carbonyl iron with ionic forms of 
iron.
    FDA has reviewed the animal toxicity data cited in the comments and 
other available animal toxicity data (Refs. 11 through 16). Most of the 
reported data were expressed as LD50 values (i.e., the dose that 
is fatal to 50 percent of the animals in the study), although some data 
were expressed as no-adverse-effect-level (NOAEL) values. For clarity 
and convenience, the LD50 data are summarized in Tables 2 through 
4. However, in most cases the data reported in these tables do not 
reflect studies in which the toxicity of one form of iron was directly 
(i.e., concurrently) compared to that of other forms of iron.

  Table 2.--Magnitude of Differences in Studies Reporting Median Lethal 
         Dose (LD50) Levels: Carbonyl Iron Versus Iron Salts \1\        
------------------------------------------------------------------------
                      LD50 (mg Fe/kg body weight)                       
    Species     --------------------------------------  Approximate fold
                   Carbonyl iron        Iron salt          difference   
------------------------------------------------------------------------
Rat                         30,000  298 to 1,000                30 to 90
                                     (ferrous                           
                                     sulfate)                           
                                    580 to >2,300               13 to 50
                                     (ferrous                           
                                     fumarate)                          
Guinea pig                  20,000  300 to 350                  57 to 67
                                     (ferrous                           
                                     sulfate)                           
                                    263 to 350                  57 to 76
                                     (ferrous                           
                                     gluconate)                         
                                    350 (ferric                       57
                                     ammonium                           
                                     citrate)                           
                                    2,000 (ferrous                    10
                                     carbonate)                         
Dog                        >25,000  160 (ferrous                    156 
                                     sulfate)                           
------------------------------------------------------------------------
\1\ Data summarized from published literature (Refs. 11 through 16).    


 Table 3.--Magnuitude of Differences in ST Reporting Median Lethal Dose (LD50) Levels: Differences Among Various
                                                 Iron Salts \1\                                                 
----------------------------------------------------------------------------------------------------------------
                                                                                                                
----------------------------------------------------------------------------------------------------------------
              Species                                                                                           
(1)Oral LD50 (mg Fe/kg body weight)  Approximate fold                                                           
                                      difference.                                                               
                                                                                                                
----------------------------------------------------------------------------------------------------------------
Mouse..............................  50-900 (ferrous sulfate)..  3,800 (ferrous carbonate).  4 to 25            
rat................................  298-1,000 (ferrous          580->2,300 (ferrous         2 to 8             
                                      sulfate).                   fumarate).                                    
Guinea pig.........................  263-350 (ferrous            2,000 (ferrous carbonate).  6 to 8             
                                      gluconate).                                                               
----------------------------------------------------------------------------------------------------------------
\1\ bid.                                                                                                        


         Table 4.--Median Lethal Dose (LD50) Levels Reported From Oral Exposure: Species Differences \1\        
----------------------------------------------------------------------------------------------------------------
                                                                                                    Approximate 
                 Iron source                            Animal species          Oral LD50 (mg Fe/      fold     
                                                                                 kg body weight)    difference  
----------------------------------------------------------------------------------------------------------------
Ferrous sulfate..............................  mouse..........................        150 to 900       1.1 to 10
                                               rat............................      298 to 1,000                
                                               guinea pig.....................        300 to 350                
                                               rabbit.........................        600 to 720                
                                               dog............................               160                
                                               cat............................               100                
Ferrous fumarate.............................  mouse..........................      516 to 1,100        2 to 4.5
                                               rat............................      580 to>2,300                
Ferrous gluconate............................  mouse..........................      320 to 1,100      1.3 to 4.2
                                               rat............................        518 to 865                
                                               guinea pig.....................        263 to 350                
                                               rabbit.........................        463 to 580                
Ferrous carbonate............................  mouse..........................             3,800             1.9
                                               guinea pig.....................             2,000                
                                               rabbit.........................             2,220                
Ferric ammonium citrate......................  mouse..........................             1,000             2.9
                                               guinea pig.....................               350                
                                               rabbit.........................               560                
Carbonyl iron................................  rat............................            30,000             1.5
                                               guinea pig.....................            20,000                
                                               dog............................           >25,000                
----------------------------------------------------------------------------------------------------------------
\1\ Ibid.                                                                                                       


[[Page 2234]]

    The data in Tables 2 through 4 show that the reported LD50 
values for carbonyl iron are at least an order of magnitude greater 
than those of iron salts. However, although these data do suggest that 
the acute oral toxicity of carbonyl iron is lower than that of iron 
salts, FDA does not agree that these data establish that carbonyl iron 
has a 100- to 200-fold greater safety margin than ferrous sulfate. As 
explained below, the variations in reported LD50 values within and 
between species, the variations in reported LD50 values between 
different ferrous salts within the same species, and the limited data 
directly comparing the toxicity of carbonyl iron to that of iron salts 
prevent the agency from reaching such a conclusion at this time.
    In evaluating the LD50 data, the agency compared the magnitude 
of the differences in the reported LD50 values for iron salts and 
for carbonyl iron (see Table 2) to the magnitude of differences in 
reported LD50 values for various iron salts (see Table 3) and to 
the magnitude of inter-species differences in reported LD50 values 
(see Table 4). For example, the maximum interspecies variation in 
reported LD50 values for ferrous sulfate is tenfold (see Table 4), 
and the maximum intraspecies variation in reported LD50 values for 
the mouse is twenty-fivefold (see Table 3). By comparison, the 
difference in the reported LD50 values for carbonyl iron and 
ferrous sulfate ranges from a minimum of thirtyfold in the rat to a 
maximum of 156-fold in the dog (see Table 2). Thus, while in laboratory 
animals carbonyl iron appears to be among the least toxic of iron 
preparations, wide variations in toxicity have been reported among 
different iron salts and within animal species. In some cases, the 
magnitude of the difference in reported LD50 values between 
carbonyl iron and iron salts is no greater than the magnitude of 
difference in reported LD50 values between various iron salts or 
between animal species. Given the facts that most of the LD50 data 
were reported several decades ago, that most of the studies were not 
conducted as concurrent comparisons of LD50 values for carbonyl 
iron and for iron salts, and that current practice is to characterize 
LD50 values within an order of magnitude range, e.g., 5 to 50 mg/
kg (Ref. 17), the agency finds that it is unable to conclude, despite 
the higher reported LD50 values for carbonyl iron, that carbonyl 
iron provides the quantitative margin of safety compared to iron salts 
claimed by the comment.
    In general, extrapolation from data on acute iron toxicity obtained 
with experimental animal species to predict acute iron toxicity in 
humans is not straightforward because there are large inter-species 
differences in response to large loads of iron. Hoppe, et al. (Ref. 16) 
reviewed case reports of human deaths from ingestion of ferrous sulfate 
and found that the average fatal dose of iron in children under 2 years 
of age was approximately 180 mg/kg body weight. Thus, the LD of ferrous 
sulfate in children is comparable to the reported LD50 values in 
the dog (160 mg/kg) and in the cat (100 mg/kg) but considerably lower 
than the reported LD50 values for the rat (300 to 1,000 mg/kg) and 
rabbit (600 to 720 mg/kg). Consequently, because of this variation, in 
attempting to predict iron toxicity in human children based on data 
obtained in experimental animals, it would be imprudent to rely on data 
derived from a single animal species.
    The available iron toxicity data primarily provide acute LD levels. 
Most of these LD50 values were reported several decades ago, and 
details of how the studies were conducted are not available in all 
cases. Moreover, there are a limited number of studies in which the LD 
for carbonyl iron was compared directly (i.e., in the same study) to 
that of iron salts. The known inherent variability and lack of 
precision in LD50 values reported from one study to another (Refs. 
17 and 18) make the available data unreliable for use in predicting a 
margin of safety that carbonyl iron would provide compared to iron 
salts in the event of accidental overdose. Finally, given the number of 
pediatric exposures, and the number of moderate and major outcomes 
associated with those exposures, other measures of acute toxicity, such 
as clinical chemistry measurements, pathology of the liver and 
gastrointestinal tract, and clinical signs and symptoms or injuries 
(e.g., vomiting) are appropriate and necessary to determine whether the 
acute toxicity of elemental iron is less than that of iron salts.
    In summary, the magnitude of the difference in reported LD50 
values between various iron salts, the magnitude of the inter-species 
difference in reported LD50, the limited data directly comparing 
the acute toxicity of carbonyl iron to that of other iron salts, and 
the lack of measures of acute toxicity other than death mean that the 
data submitted to support reduced toxicity of carbonyl iron are not 
suitable for quantitative comparisons of the acute toxicity of carbonyl 
iron to that of iron salts. Therefore, FDA concludes that the available 
animal toxicity data are consistent with, but do not establish, reduced 
toxicity for carbonyl iron relative to that of iron salts.

E. Comments on the Acute Toxicity in Humans of Elemental Iron Compared 
to the Acute Toxicity of Iron Salts

    Several comments cited data from a study (Ref. 19) of human 
volunteers who, following ingestion of a single dose of 6,000 mg of 
carbonyl iron (approximately 84 mg Fe/kg body weight), experienced only 
mild diarrhea without cramp. The comments compared these data to 
medical guidelines (Refs. 20 and 21) that recommend hospitalization and 
close observation in response to the acute ingestion of iron salts in 
doses of 60 mg Fe/kg body weight. One comment from a medical researcher 
stated that in a study conducted in his own laboratory four adult human 
volunteers took oral doses of 10,000 mg of carbonyl iron (approximately 
140 mg Fe/kg body weight) ``without distress'' (Ref. 22). The same 
comment cited a published report in which a single adult human 
volunteer swallowed 10,000 mg of carbonyl iron ``without deleterious 
effects'' (Ref. 23).
    The studies described by these comments are small and include so 
few subjects that they do not, in and of themselves, provide reliable 
data concerning the toxicity of carbonyl iron. As discussed below, 
other comments pointed that the incidence of side effects in volunteers 
who ingested carbonyl iron during a randomized, double-blind study 
designed to evaluate the bioavailability of carbonyl iron (Ref. 24) was 
similar to that of volunteers who ingested ferrous sulfate. However, 
these reports are consistent with other data that suggest that carbonyl 
iron may be less toxic than iron salts and could be corroborated by 
larger studies that are specifically designed to evaluate the safety 
and side effects of using carbonyl iron.
    One comment from a physician noted that the reported side effects 
(such as diarrhea, heartburn, headache, epigastric discomfort, nausea, 
and abdominal cramps) from comparable doses of carbonyl iron and 
ferrous sulfate in a randomized, double-blind study designed to 
evaluate the bioavailability of carbonyl iron (Ref. 24) were similar. 
This comment stated that it did not make sense that similar side 
effects with similar dose amounts would translate to total impunity of 
carbonyl iron from toxic effects.
    FDA agrees that reports that side effects in persons who consumed 
carbonyl iron as a dietary supplement or for therapeutic purposes are 
similar to side effects in persons who consumed

[[Page 2235]]

iron salts for the same purposes signify a need for caution in 
evaluating the limited evidence concerning the toxicity of carbonyl 
iron and do not translate to ``total impunity'' from toxic effects. 
However, these reports of similar side effects in a therapeutic setting 
do not necessarily mean that the physiological factors leading to 
injuries with accidental overdose will be the same for carbonyl iron 
and iron salts. Moreover, the body's response to an accidental overdose 
may be different from the body's response to a therapeutic dose.
    The requirements of this final rule are intended to help prevent 
the acute iron poisonings, including deaths, in children less than 6 
years of age attributable to accidental overdose of iron-containing 
products. Although the reports of side effects in adults who consume 
carbonyl iron as a dietary supplement or for therapeutic purposes raise 
potential questions of safety, available data are inadequate to 
document that these observations are necessarily predictive of acute 
poisoning in young children from accidental overdose of carbonyl iron. 
These reports, by themselves, do not provide a sufficient basis to 
determine that carbonyl iron is as toxic as iron salts.

F. Comments Supplying Data on Acute, Accidental Exposure of Children to 
Products Containing Elemental Iron

    One comment from a manufacturer of carbonyl iron stated that the 
firm had reviewed its files and found no complaints regarding toxicity 
associated with its carbonyl iron products since the introduction of 
its pharmaceutical/food grade carbonyl iron product in 1988. The 
comment also stated that its carbonyl iron had been used in over 2 
billion tablets marketed in 35 brands of iron-containing dietary 
supplement and drug products by 15 manufacturers, and that the firm was 
unaware of any adverse toxic effects associated with use of those 
products.
    The same comment included data obtained from the Toxic Exposure 
Surveillance System (TESS) of the AAPCC. The comment summarized 
exposures, outcomes, symptoms, age group, and iron potency for carbonyl 
iron exposures and all iron exposures during the period 1989 to 1994. 
Table 5 compares the exposures and outcomes as summarized in the 
comment.

    Table 5.--Reported Exposures \1\ for Iron-Containing Vitamins and   
                                Minerals                                
------------------------------------------------------------------------
                                                  Carbonyl              
                                                    iron       All iron 
                                                  (Number)     (Number) 
------------------------------------------------------------------------
Reported exposures:                                                     
    Accidental................................        2,635      120,086
    Intentional...............................           58        9,854
    Adverse Reaction..........................           18          863
    Unknown/other.............................            3           15
                                               -------------------------
      Total...................................        2,714      130,818
Outcomes of Exposures: \2\                                              
    No effect \3\.............................        1,081       54,837
    Minor effect \4\..........................          173       17,218
    Moderate effect \5\.......................            4        2,012
    Major effect \6\..........................            0          177
    Death.....................................            0          35 
------------------------------------------------------------------------
\1\ The data in the table reflect the data supplied in comment 150 to   
  the iron proposal under Docket No 93P-0306.                           
\2\ See ref. 25 of this document.                                       
\3\ The patient developed no signs or symptoms as a result of the       
  exposure.                                                             
\4\ The patient developed some signs or symptoms as a result of the     
  exposure but they were minimally bothersome, and generally resolved   
  rapidly with no residual disability or disfigurement.                 
\5\ The patient developed signs or symptoms as a result of the exposure 
  which were more pronounced, more prolonged, or more of a systemic     
  nature than minor symptoms. Usually, some form of treatment is        
  indicated.                                                            
\6\ The patient exhibited signs or symptoms as a result of the exposure 
  which were life-threatening or resulted in significant residual       
  disability or disfigurement.                                          

    One comment from a manufacturer of iron-containing supplements 
stated that the firm had not received a single report of adverse side 
effects or toxicity in 3 years of marketing products containing 
carbonyl iron.\8\ Another manufacturer of iron-containing supplements 
submitted data on the composition of two of its multivitamin products 
containing 10 mg or 18 mg of carbonyl iron and summaries of 133 adverse 
event reports for the product containing 18 mg of carbonyl iron. This 
comment also provided data from a poison control center on 10 reports 
of exposures to a product containing carbonyl iron. Reported exposures 
ranged from approximately 160 mg of iron (approximately 11 mg Fe/kg) to 
approximately 1,975 mg of iron (unknown mg Fe/kg). The most common 
outcome was vomiting. The 2\1/2\-year old child who ingested 1,975 mg 
of carbonyl iron was treated with Ipecac and experienced headache, 
dizziness, hot flashes, and vomited twice. No further followup was 
reported for these exposures.
---------------------------------------------------------------------------

    \8\ The comment did not provide information about the nature of 
its reporting system, e.g., whether the system was systematic.
---------------------------------------------------------------------------

    A trade association commented that it had conducted a confidential 
adverse experience survey of its members and stated that the results 
supported a conclusion that products containing carbonyl iron are safe 
and do not require special packaging and labeling. The survey results 
included data from members who marketed a total of seven products 
containing carbonyl iron. The survey found a total of 15 instances in 
which children aged 17 months to 4 years old ingested doses of various 
products in the range of 180 to 2,000 mg of iron. Only 3 of these 15 
exposures resulted in minor outcomes, and none of these exposures was 
associated with moderate outcomes, major outcomes, or death.
    One comment from a physician noted that much of the argument for 
exempting carbonyl iron from the requirements of the proposal was the 
data on accidental exposure. This comment pointed out that the absence 
of clinically significant effects associated with accidental exposure 
to carbonyl iron may reflect the fact that most of the preparations 
with carbonyl iron are multivitamin preparations containing lower 
dosages of iron compared to the preparations that have been associated 
with clinically significant effects. The comment expressed the opinion 
that there was a reasonable possibility that if carbonyl iron was 
exempted from the requirements of the proposal and categorized as a 
``nontoxic substance,'' then experience with sublethal toxic exposure 
would accumulate rapidly. The author of the comment stated that he was 
``not in favor of such uncontrolled experimentation.'' The comment 
further expressed the opinion that it would be prudent to wait until 
accidental exposure numerically equalled accidental exposure to other 
forms of iron, or at least to ferrous sulfate, when expressed in dose 
equivalent amounts.
    FDA has evaluated the submitted information on acute, accidental 
exposure to products containing elemental iron. The summary information 
from poison control centers showed that: (1) Accidental overdose of 
carbonyl iron-containing products has resulted in 173 minor outcomes; 
(2) accidental overdose of carbonyl iron-containing products has 
resulted in four moderate outcomes; and (3) there were no reported 
exposures to carbonyl iron-

[[Page 2236]]

 containing products that resulted in major outcomes or death. However, 
the total number of accidental exposures to carbonyl iron is likely to 
be underestimated because information on the form of iron ingested was 
not always reported. For example, information on the form of iron 
ingested is not available in the original report or followup 
investigation for 8 of the 37 fatalities described in the iron 
proposal. This likely underestimation of total accidental exposures 
raises the question of whether the total number of minor, moderate, 
major, and fatal outcomes resulting from accidental overdose of 
carbonyl iron is also underestimated. Moreover, the lack of reported 
major outcomes or death associated with accidental overdose of products 
known to contain carbonyl iron may be a reflection of both the small 
number of total exposures to date and the insensitivity of passive 
reporting systems.
    Furthermore, information supplied in the comments concerning the 
identity and potency of currently available products that contain 
carbonyl iron indicate that only 7 of 32 brand-name products contained 
high doses of carbonyl iron (i.e., greater than or equal to 30 mg of 
iron).\9\ This paucity of products containing high-potency carbonyl 
iron amplifies the agency's concern that the lack of reported major 
outcomes or death associated with accidental overdose of products known 
to contain carbonyl iron may be a function of the small number of total 
exposures to high doses of carbonyl iron (i.e., 30 mg or more of iron) 
rather than the low toxicity of the substance. Therefore, these data, 
while encouraging, must be interpreted with caution and do not by 
themselves provide a sufficient basis for a conclusion of reduced 
toxicity for carbonyl iron compared to iron salts.
---------------------------------------------------------------------------

    \9\ Of these seven brand-name products, three contained 50 mg 
iron, two contained 65 mg iron, and two contained 150 mg iron.
---------------------------------------------------------------------------

    Although FDA agrees that it would be prudent to defer a decision on 
whether carbonyl iron is sufficiently less toxic than iron salts to 
merit an exemption from the requirements of this final rule until the 
amount of data available concerning accidental human exposures to 
carbonyl iron approaches that for iron salts, the agency realizes that, 
given the current market share of carbonyl iron-containing products of 
1 to 3 percent (see section V.C. of this document), such a delay is not 
practicable. Moreover, such a delay would not be in the interest of the 
public health if carbonyl iron is in fact significantly less toxic than 
iron salts. On the other hand, FDA recognizes that there may be some 
basis for the concern expressed by the comment. Therefore, although FDA 
is not adopting the suggestion that the agency wait until exposure to 
carbonyl iron numerically equals exposure to other forms of iron or to 
ferrous sulfate before reaching a decision on whether to exempt 
carbonyl iron from the requirements of this final rule, FDA will remain 
cautious in evaluating the existing information concerning the toxicity 
of carbonyl iron.

G. Comparison of Animal Toxicity Data to Human Toxicity Data

    One comment from a physician stated that it may be premature to 
make a regulatory decision about an exemption for carbonyl iron because 
the toxicity data were based almost entirely on animal studies. Another 
comment, in a report commissioned by a manufacturer of carbonyl iron, 
attempted to relate data on the toxicity in humans of carbonyl iron and 
iron salts to animal toxicity data. First, the report stated that adult 
humans who were acutely exposed to a single dose of 6,000 mg (i.e., 
approximately 100 mg/kg) of carbonyl iron experienced no toxicity other 
than diarrhea,\10\ and that adult humans who were acutely exposed to 
carbonyl iron at doses ranging from 100 to 10,000 mg (i.e., 1.4 to 142 
mg/kg) \11\ experienced diverse side effects (such as gastrointestinal 
tract disturbances and headache) but no fatality. Moreover, the report 
noted that the effects of exposures to carbonyl iron in rats and guinea 
pigs in this dose range (i.e., 1.4 to 140 mg/kg) also were not life-
threatening.\12\
---------------------------------------------------------------------------

    \10\ The report did not provide a direct literature citation for 
this statement, but likely was referring to the study by Sacks and 
Crosby (Ref. 19) cited by another comment.
    \11\ The report did not provide a direct literature citation for 
this statement, but included the studies by Gordeuk et al. (Refs. 22 
and 26) in a bibliography.
    \12\ The report did not provide a direct literature citation for 
this statement, but included the study by Shelanski (Ref. 11) in a 
bibliography.
---------------------------------------------------------------------------

    Second, the report noted that as the ingested dose in cases of 
accidental overdose of iron salts in children approached and exceeded 
200 mg/kg, the likelihood of death seemed to markedly increase. By 
comparison, the report noted that LD50 values in rats for iron 
salts are similar (300 to 1,000 mg/kg, expressed in terms of iron 
content) \13\ to the dose that is frequently fatal in children. The 
report presented the similarity in lack of toxicity for carbonyl iron 
in adult humans and experimental animals, and the similarity in 
toxicity for iron salts in children and experimental animals, as 
evidence that the data on experimental animals can be extrapolated to 
humans.
---------------------------------------------------------------------------

    \13\ The report did not provide a direct literature citation for 
this statement, but LD50 values for iron salts are reported in 
this range in Ref. 12.
---------------------------------------------------------------------------

    FDA has considered the reasoning in the comments that the available 
toxicity data in experimental animals can be extrapolated to predict 
whether carbonyl iron has reduced acute toxicity in children compared 
to that of iron salts. The available animal toxicity data qualitatively 
imply reduced toxicity for carbonyl iron compared to iron salts, but 
the data are not suited for quantitative comparisons, even among animal 
species. As discussed above, the quantitative toxicity information 
available consists for the most part of LD50 values calculated 
from nonconcurrent acute toxicity studies with few animals and few 
doses, and such values are neither precise nor easily compared from one 
study to another. The fact that most of the available LD50 values 
are derived from studies conducted more than 30 years ago, for which 
there are only brief details of the experimental methods and test 
material identity (including comparability to currently marketed forms 
of iron), further makes comparison of the LD50 values difficult. 
Moreover, the available information does not contain data regarding 
levels at which there are no toxic effects, and such data are most 
directly relevant to this rulemaking considering that the issue at hand 
is one of acute toxicity. Finally, adults are less sensitive to toxic 
effects than young children, and most of the available data relates to 
adult humans and animals. Therefore, FDA is unable to say that the 
available toxicity data can be extrapolated to reliably predict reduced 
acute toxicity in children of carbonyl iron compared to that of iron 
salts.

H. Comments on the Bioavailability of Elemental Iron for Dietary Iron 
Supplementation

    FDA requested information with respect to the bioavailability of 
carbonyl iron to determine whether carbonyl iron provides desirable 
iron nutrition to those who need iron supplementation. FDA requested 
this information because it anticipated that an exemption for carbonyl 
iron from any packaging or labeling requirements in the final 
regulations would likely result in a shift in product formulations to 
replace iron salts with carbonyl iron.
    Several comments asserted that administering iron as carbonyl iron 
is as effective for the prevention and treatment of iron deficiency as

[[Page 2237]]

administering iron as iron salts. In support of this assertion, one 
comment from a medical researcher described several published studies 
in female blood donors comparing the bioavailability of carbonyl iron 
with that of ferrous sulfate. These published studies were also cited 
in several other comments.
    In one study (Ref. 27) comparing treatment with carbonyl iron or 
ferrous sulfate with use of a placebo, the treatment was intended to 
replace, within 56 days, the amount (approximately 200 mg) of iron 
removed by phlebotomy from 75 menstruating women who were regular blood 
donors. Blood donor volunteers were assigned randomly to one of three 
treatment groups: (1) High dose (600 mg) carbonyl iron; (2) standard 
dose (300 mg) ferrous sulfate (equivalent to 60 mg of iron); or (3) 
placebo. Each treatment was administered three times daily for 1 week 
immediately after blood donation.
    The reported incidence of side effects was similar in both groups 
receiving sources of iron, even though the dose of iron was 10 times 
higher in the group receiving carbonyl iron than in the group receiving 
ferrous sulfate. The authors of the study estimated total iron 
absorption of 95 percent, 76 percent, and 64 percent of the iron lost 
through blood donation by the carbonyl iron group, the ferrous sulfate 
group, and the placebo group, respectively, and concluded that short-
term ingestion of carbonyl iron was an efficacious means of replacing 
iron lost through blood donation.
    A followup study (Ref. 28) of the effects of short-term iron 
supplementation in female blood donors was designed to develop a 
regimen that would minimize side effects of iron supplementation 
compared with a placebo while replacing iron losses in all, or nearly 
all, donors. In this study, a treatment regimen of 100 mg of carbonyl 
iron given once daily at bedtime was compared with that of a 
placebo.\14\ The conclusions of the study were that, overall, enough 
iron was absorbed to replace that lost at donation in 85 percent of the 
carbonyl iron group but in only 29 percent of the placebo group.
---------------------------------------------------------------------------

    \14\ The treatment was administered at bedtime to allow the 
carbonyl iron to remain in the gastrointestinal tract for as long as 
possible without food that would buffer the stomach acid required 
for solubilization of the elemental iron to the ferrous form.
---------------------------------------------------------------------------

    In another study (Ref. 24) comparing the bioavailability of 
carbonyl iron with that of ferrous sulfate, 49 female blood donors with 
iron deficiency were treated with equal doses (100 mg) of iron once 
daily at bedtime over a 12-week period. The doses were administered 
either as carbonyl iron (100 mg) or as ferrous sulfate (500 mg 
(equivalent to 100 mg of iron)) in a randomized, double-blind fashion. 
The incidence of side effects was similar in the two groups, and 
measures of iron status did not differ significantly throughout the 
study. The conclusions of the study were that estimates of net changes 
in total body iron suggested that the overall bioavailability of 
carbonyl iron is approximately 70 percent that of ferrous sulfate.
    The comment also included a description of a long-term 2\1/2\-year 
unpublished study, in which repeated courses of 56 days of low dose 
(100 mg) carbonyl iron were given to one group of volunteers once daily 
at bedtime after each blood donation. Two other groups of volunteers 
were permitted unsupervised self-supplementation, with volunteers in 
one group donating blood in an unscheduled manner, and volunteers in 
the second group donating blood on a schedule identical to that of the 
carbonyl iron group. The conclusion of the study was that the 
prevalence of iron deficiency in the group receiving carbonyl iron 
declined substantially compared with its prevalence in the two groups 
who were permitted unsupervised self-supplementation. In addition, the 
researchers concluded that increases in measures of iron status in the 
subjects in the carbonyl iron group over the 30-month course of the 
study suggested that their iron balance was improved during the course 
of the study.
    At the public workshop, the researcher who conducted this study 
pointed out that the population of subjects in this study was chosen 
because it is a population in which individuals are iron deficient but 
not for any pathological reason. The researcher categorized this 
population as having ``probably the highest demands on iron absorption 
that are seen in normal populations.''
    However, the comment described as ``unexplained'' a published study 
(Ref. 29) conducted in Sweden in which a preparation of carbonyl iron 
radiolabeled with a particular isotope (55Fe) was used to fortify 
wheat flour in which the naturally occurring iron of the wheat was 
extrinsically labeled with another radioisotope of iron (59Fe). 
Doubly labeled wheat rolls prepared from this flour were served with 
different meals to human adult volunteers. The authors of the study 
claimed that the ratio of absorbed 55Fe to absorbed 59Fe is a 
direct measure of the carbonyl iron that joins the nonheme pool and is 
made potentially available for absorption. The authors stated that the 
relative bioavailability of carbonyl iron was unexpectedly low and 
varied from 5 percent to 20 percent when the iron fortified wheat rolls 
were served with different meals. The authors also stated that factors 
such as the baking process or the addition of ascorbic acid did not 
change the relative bioavailability. The authors of the study concluded 
that this low and variable bioavailability of carbonyl iron in humans 
makes it necessary to reconsider the rationale of using elemental iron 
powders for the fortification of foods for human consumption.
    FDA recognizes the apparent discrepancy between the conclusions of 
the multiple studies conducted in female blood donors and the 
conclusions of the study conducted in human volunteers who consumed 
wheat rolls fortified with radiolabeled carbonyl iron. Iron 
bioavailability is a complex issue affected by a number of factors, 
including the state of physiological iron stores and state of health, 
in addition to the iron source and the food matrix and meal composition 
in which the iron is ingested. In fact, the agency has stated its 
intent to publish a notice of proposed rulemaking concerning the 
bioavailability of iron used to fortify food (final rules for the iron 
fortification of flour and bread, (43 FR 38575 at 38576, August 29, 
1978) and (46 FR 43413, August 28, 1981)). At this time, FDA believes 
that following through with such a proposal makes more sense than 
trying to resolve such a complex issue as part of this rulemaking. 
Accordingly, FDA is not requiring demonstrated bioavailability as a 
precondition in its determination on whether to exempt carbonyl iron 
from the labeling requirements, packaging requirements, or both 
requirements of this final rule.

I. Comments on Physiological Factors That Influence Toxicity of 
Elemental Forms of Iron

    Several comments cited animal studies (Ref. 30) that were 
undertaken to characterize the mechanism by which elemental iron such 
as carbonyl iron is absorbed (i.e., by conversion of non-ionized to 
ionized iron in the presence of hydrochloric acid in the stomach) and 
postulated that the toxicity associated with ionized iron is minimized 
by both the rate of gastric acid production and the equilibrium between 
formation of ionized iron and the discharge of the ionized iron from 
the stomach to the intestine. In light of

[[Page 2238]]

this postulated mechanism, some of these comments also discussed the 
importance of the particle size of carbonyl iron in the conversion 
process, i.e., the smaller the particle size, the faster the conversion 
process.\15\ A representative of a U.S. manufacturer of carbonyl iron 
stated that the firm manufactures approximately 40 different grades of 
carbonyl iron, but only 1 grade is designated for pharmaceutical or 
nutritional use. The average particle size of this grade is 
approximately 5 to 6 microns.
---------------------------------------------------------------------------

    \15\ Many of the comments that addressed the influence of 
particle size on the physiological properties of elemental iron 
discussed the role of particle size from the perspective of the 
bioavailability of the elemental iron. However, as discussed above, 
FDA has decided not to require demonstrated bioavailability of an 
iron source as a criterion in exempting that iron source from any of 
the requirements of this final rule. Therefore, the discussion of 
the importance of particle size emphasizes its potential role in 
toxicity rather than bioavailability.
---------------------------------------------------------------------------

    FDA agrees that the particle size of carbonyl iron is a key factor 
in the conversion of the carbonyl iron to the ionized form, and that 
carbonyl iron with a small particle size will be ionized (and thus 
absorbed) more rapidly than carbonyl iron with a large particle size. 
FDA also recognizes that this conversion may be necessary for the 
carbonyl iron to exhibit the full toxicity associated with iron salts. 
Therefore, the protocol of any animal studies comparing the toxicity of 
carbonyl iron to the toxicity of iron salts should specify the particle 
size of the carbonyl iron used in the studies. If FDA exempts carbonyl 
iron from any of the requirements of this final rule, FDA will consider 
including particle size, based on the particle size of the carbonyl 
iron used in the comparative studies, as a specification for carbonyl 
iron.

J. Other Comments

    At the public workshop, a representative of a manufacturer of 
carbonyl iron expressed the opinion that, in a rulemaking proceeding, 
it is FDA's responsibility to establish a need for a regulation for a 
particular product and suggested that the agency had not presented 
evidence that products containing carbonyl iron need the same kind of 
protective measures as those that the agency has proposed for products 
containing iron salts. In addition, a representative of a manufacturer 
of iron-containing products expressed the opinion that products 
containing carbonyl iron and bearing a warning statement such as 
``Contains iron, which can harm or cause death to a child'' would be 
falsely labeled and therefore misbranded under the act if the carbonyl 
iron is in fact a safe source of iron.
    At the public workshop, in response to this statement, agency 
representatives pointed out that the source of the iron in some deaths 
attributable to iron poisoning has not been identified, and that FDA 
therefore cannot say with certainty that carbonyl iron was not involved 
in any of the poisoning deaths that were discussed in the iron 
proposal. Moreover, as discussed above, the lack of reported major 
outcomes or death associated with accidental overdose of products known 
to contain carbonyl iron may be attributable to the small number of 
total exposures to date, particularly exposures to high dosages of 
carbonyl iron. These comments did not dispute that accidental overdose 
of iron-containing products can kill a small child, and that such 
overdoses are a leading cause of fatal poisoning in children under the 
age of 6.
    Faced with this information, the agency is compelled to err on the 
side of caution. Unless presented with convincing data demonstrating 
that some forms of iron are sufficiently less toxic that they are 
unlikely to cause injury and illness, including death, FDA must assume, 
to ensure that the public health is adequately protected, that all 
forms of iron have the potential to cause injury and illness, including 
serious illness and death.

K. Exemption for Carbonyl Iron From the Labeling Requirements of This 
Final Rule

    FDA has considered the kinds of data and information that would be 
necessary to enable the agency to reach a decision on an exemption for 
any form of elemental iron, such as carbonyl iron, from the regulations 
on labeling of iron-containing products. In the iron proposal, FDA 
stated that the agency would focus on data and information in two topic 
areas: Toxicity and bioavailability. Specifically, FDA stated that it 
would focus on whether use of a source of elemental iron would decrease 
the risk of pediatric poisoning while providing desirable iron 
nutrition to those who need iron supplementation (59 FR 51030 at 
51052).
    As already discussed, FDA has decided not to require demonstrated 
bioavailability of an iron source as a criterion in exempting carbonyl 
iron from any of the requirements in this final rule. Therefore, the 
agency's decision on whether to exempt carbonyl iron from the labeling 
requirements of this final rule turns on whether the available data 
demonstrate that carbonyl iron is significantly less toxic than iron 
salts.
    In the iron proposal, FDA tentatively concluded that it should 
require a label warning statement for iron-containing products because 
a small child is at risk of injury any time he or she gains unlimited 
access to any iron-containing product. Therefore, the basis for 
exempting products containing carbonyl iron from the labeling 
requirements of this final rule would be data that persuade the agency 
that carbonyl iron is so much less toxic than ionic forms of iron that 
accidental overdose of products containing carbonyl iron is unlikely to 
place a small child at risk of injury (including minor, moderate, and 
major outcomes as well as death). The most compelling information 
bearing on this question is the available data on the outcomes of 
acute, accidental exposure of children to iron-containing products 
because these data, in contrast to animal studies that must be 
interpreted and extrapolated to predict toxicity in human children, are 
directly relevant to the question at hand.
    As discussed above, the information available from poison control 
centers shows that accidental overdose of carbonyl iron-containing 
products has resulted in 173 minor outcomes and 4 moderate outcomes. 
Even though there were no reported exposures to carbonyl iron-
containing products that resulted in major outcomes or death, the 
reported occurrences of minor and moderate outcomes show that a young 
child who accidentally consumes an overdose of a carbonyl iron-
containing product is at risk of illness or injury. Therefore, the 
available data on the acute, accidental exposure of children to iron-
containing products do not support an exemption for carbonyl iron from 
the labeling requirements of this final rule. Accordingly, FDA is not 
exempting products containing carbonyl iron from the labeling 
requirements of this final rule.

L. Exemption for Carbonyl Iron From the Packaging Requirements of This 
Final Rule

    FDA has considered the kinds of data and information that would be 
necessary to enable the agency to reach a decision on an exemption for 
any form of elemental iron, such as carbonyl iron, from the regulations 
on packaging of iron-containing products. As discussed with respect to 
an exemption from the labeling requirements of this final rule, the 
basis for the agency's decision on whether to exempt carbonyl iron 
would be data on whether the use of carbonyl iron would decrease the 
risk of pediatric poisoning.
    In the iron proposal, FDA stated that the agency was not persuaded 
that full

[[Page 2239]]

compliance with CPSC's CRC requirements, even in the presence of 
warning statements, would be adequate to ensure the safety of the use 
of iron-containing products. FDA proposed that iron-containing products 
that contain 30 mg or more of iron per dosage unit be packaged in 
nonreusable unit-dose packaging in light of the potentially fatal 
outcome that can result from pediatric iron poisoning. Moreover, many 
accidental overdoses of iron-containing products that do not result in 
fatal consequences do have life-threatening consequences. In light of 
the potentially fatal or life-threatening outcomes that can result from 
pediatric iron poisoning, the basis for exempting products containing 
30 mg or more of carbonyl iron per dosage unit from the packaging 
requirements would be data that persuade the agency that carbonyl iron 
is so much less toxic than ionic forms of iron that accidental overdose 
of products containing a high dose of carbonyl iron is unlikely to 
result in major outcomes or death. The information bearing on this 
question is: (1) Data on the outcomes of acute, accidental exposure of 
children to iron-containing products; (2) data on acute toxicity in 
animals of carbonyl iron compared to that of iron salts; and (3) the 
ability to extrapolate from the acute toxicity data in animals to 
predict a reduced toxicity for carbonyl iron in children.
    As discussed above, the information available from poison control 
centers shows no reported exposures to carbonyl iron-containing 
products that resulted in major outcomes or death. However, the data 
from the poison control centers did not always include the source of 
iron, and therefore the total number of accidental exposures to 
products containing carbonyl iron is likely to be underestimated. 
Consequently, the total number of major and fatal outcomes may also be 
underestimated.\16\ The lack of reported exposures to carbonyl iron 
that resulted in major outcomes is encouraging in light of the fact 
that at least three major outcomes would be predicted if carbonyl iron 
was as toxic as iron salts. However, even if carbonyl iron was as toxic 
as iron salts, less than one death would be predicted from exposure to 
carbonyl iron. The lack of reported exposures to carbonyl iron that 
resulted in major outcomes or death therefore may be attributable to 
both the insensitivity of passive reporting systems and the small 
number of total exposures to carbonyl iron, particularly exposures to 
high doses of carbonyl iron, rather than to any reduced toxicity of 
carbonyl iron relative to that of iron salts. Therefore, although FDA 
acknowledges that the data are consistent with an interpretation that 
accidental overdose of carbonyl iron is unlikely to result in major 
outcomes or death, FDA finds that the data are too preliminary to allow 
it to comfortably conclude that accidental overdose of carbonyl iron-
containing products is unlikely to result in major outcomes or death.
---------------------------------------------------------------------------

    \16\ At the public workshop, FDA stated that the ingested 
substance had been identified as ferrous sulfate in ``16 or 17 out 
of 37 or 40 deaths.'' Review of the supporting medical records for 
the 37 deaths reported in the iron proposal now shows that the 
source of the iron involved in the accidental overdose exposures 
resulting in death is known in 29 of those 37 cases and that in each 
of these 29 cases the source was not carbonyl iron. In addition, FDA 
is aware that 2 additional children died of accidental overdose of 
an iron-containing product in 1994, and that the source of iron in 
both of these cases was ferrous sulfate (Refs. 1 and 2). Therefore, 
the number of reported pediatric deaths attributable to accidental 
overdose of an iron-containing product in which the source of iron 
is not known to FDA is 8 of 39 reported pediatric deaths.
---------------------------------------------------------------------------

    Moreover, as already discussed, the available animal toxicity data 
are unsuited for the agency's purpose in evaluating whether the acute 
toxicity in children of carbonyl iron is less than that of iron salts, 
and it would be premature for FDA to exempt carbonyl iron absent data 
that permit such an evaluation. In order to reach a decision on whether 
to exempt carbonyl iron from the packaging requirements of this final 
rule, FDA needs animal data comparing the acute toxicity of carbonyl 
iron to that of at least one iron salt that is commonly used in the 
manufacture of iron-containing supplements and drug products.
    In summary, given the possibility that accidental overdose of 
products containing carbonyl iron could result in death of a small 
child, the available data on accidental exposure to carbonyl iron-
containing products are too preliminary to provide a basis for an 
exemption for carbonyl iron from the packaging requirements of this 
final rule. Moreover, it would be premature for FDA to exempt carbonyl 
iron from the packaging requirements of this final rule given the lack 
of animal data that clearly establish the lower toxicity of carbonyl 
iron compared to at least one commonly used iron salt.
    Nonetheless, FDA is encouraged by the fact that accidental overdose 
of products containing 30 mg or more of carbonyl iron per dosage unit 
thus far is not known to have caused major outcomes or death. FDA also 
is encouraged by the fact that the existing animal data, limited though 
they are, are consistent with an interpretation that carbonyl iron may 
be so much less toxic than iron salts that an accidental overdose of a 
carbonyl iron-containing product is unlikely to result in a major 
outcome or death. Therefore, FDA finds that it is appropriate to 
provide a temporary exemption from the packaging requirements of this 
final rule to enable interested parties to conduct appropriate animal 
studies that could establish a reduced toxicity for carbonyl iron 
relative to that of iron salts.
    Accordingly, Secs. 111.50(b) and 310.518(b) temporarily exempt 
carbonyl iron from the packaging requirements of this final rule. The 
temporary exemption will automatically expire 1 year after date of 
publication of this final rule in the Federal Register. If, during the 
temporary exemption period, FDA receives animal data that clearly 
establish that carbonyl iron is significantly less toxic than at least 
one commonly used iron salt, FDA will consider permanently exempting 
carbonyl iron from the packaging requirements of this final rule. If, 
following the temporary exemption period, FDA does not extend the 
exemption, the packaging requirements of this final rule will become 
effective for products containing carbonyl iron according to the same 
principle as for products containing other forms of iron, i.e., on the 
date that is 180 days after the date of expiration of the temporary 
exemption, or on July 15, 1998. (See discussion of the effective date 
in sections VI.B.7. and VIII. of this document.)
    To predict the margin of safety that carbonyl iron would afford 
relative to iron salts in the event of accidental overdose, the agency 
needs data, in weanling/juvenile laboratory animals of 2 to 3 
species,\17\,\18\ in which the acute/short-term toxicity of orally 
administered elemental iron of known particle size \19\ is compared to 
the acute/short term toxicity of at least one iron salt that is 
commonly used in the manufacture of iron supplements. The range of 
particle sizes of the carbonyl iron used in the comparative studies 
should correspond to that of the product proposed to be exempted.
---------------------------------------------------------------------------

    \17\ As discussed above, extrapolation from data on iron 
toxicity obtained with experimental animal species to predict iron 
toxicity in humans is not straightforward. Consequently, it would be 
imprudent to rely on data derived from a single animal species.
    \18\ The studies should be performed on at least one weanling/
juvenile rodent and one weanling/juvenile nonrodent species whose 
gastrointestinal physiology is similar to that of infants and 
children (e.g., swine).
    \19\ As discussed above, particle size is an important factor in 
the rate of ionization, and thus the potential toxicity, of 
elemental iron.

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

[[Page 2240]]

    The studies should be carried out over a range of doses, so that 
they can provide information relevant to the acute/short term 
toxicological profile, including dose responses and NOAEL's for toxic 
effects. The endpoints of these studies should include deposition of 
iron in tissues, clinical measures of iron status (e.g., hematocrit, 
hemoglobin, serum iron, serum ferritin, total iron binding capacity), 
assessment of systemic tissue damage using biomarkers (e.g., liver 
enzymes in serum for liver damage; blood urea nitrogen for kidney 
damage), gross necroscopy examination, histopathology (with emphasis on 
known primary target organs of acute oral toxicity of iron such as the 
gastrointestinal tract and liver, and on any gross lesions observed on 
necropsy), effects on lipid peroxidation in tissues (liver, intestines, 
red blood cells), and systematic evaluation and recording of clinical 
signs and symptoms. Such data will provide a direct comparison of the 
thresholds for toxic effects of carbonyl iron relative to those of 
ferrous salts. If the inter-species variability is large, the agency 
will need data in at least one species that closely resembles the human 
child, such as a primate species, in order to be able to extrapolate 
from the animal data to predict whether the toxicity of carbonyl iron 
in children is reduced relative to that of iron salts.
    FDA intends to evaluate the animal data described above, as well as 
any relevant data from studies in humans that may become available, to 
determine whether they support a reduced toxicity for carbonyl iron 
such that an extension, temporary or permanent, of the exemption for 
carbonyl iron from the packaging requirements of this final rule is 
justified. However, animal data can only be used to support an 
interpretation that accidental exposure to a carbonyl iron-containing 
product is unlikely to result in a major outcome or death and cannot 
supersede data obtained from human exposure to carbonyl iron-containing 
products. Thus, animal data would not be a sufficient basis for a 
continued exemption in the event that FDA receives information that 
accidental exposure to a product containing 30 mg or more of carbonyl 
iron per dosage unit resulted in a major outcome or death. Accordingly, 
if, during the period of temporary exemption or during any period of 
extended or permanent exemption, FDA receives information that 
accidental exposure to a product containing 30 mg or more of carbonyl 
iron per dosage unit resulted in a major outcome or death, FDA will 
likely move quickly to revoke the exemption.
    The temporary exemption identifies the form of iron that is 
exempted as carbonyl iron that conforms to Sec. 184.1375 (21 CFR 
184.1375). Section 184.1375 should accurately describe the carbonyl 
iron used in iron-containing dietary supplement and drug products, and, 
given the need for promulgation of this final rule, FDA finds that it 
is appropriate to incorporate it into the final regulation. However, 
FDA invites the submission of information on whether this description 
of carbonyl iron is adequate, and whether alternative or additional 
information is appropriate and necessary in the event that FDA decides 
to extend, or make permanent, the exemption. For example, FDA solicits 
information on whether it is appropriate and important to include a 
specification for the particle size of carbonyl iron that is used to 
manufacture dietary supplement and drug products. FDA also solicits 
information on factors other than particle size, such as the physical 
and chemical properties of the iron as well as binders and excipients, 
that may influence the rate of ionization of carbonyl iron and 
recommendations on whether it is appropriate and important to include 
specifications for such factors used in the manufacture of products 
containing carbonyl iron.

M. Other Non-Ionic Forms of Iron

    The agency received one comment from a manufacturer of PIC. The 
comment included data obtained from the TESS database of the AAPCC on a 
total of 228 potentially toxic exposures to products containing PIC. 
None of the exposures resulted in death. One exposure, which involved a 
suspected suicide attempt by an adult and was accompanied by the 
concomitant consumption of other drug products, resulted in a major 
outcome. The 228 total exposures also resulted in 3 moderate outcomes 
and 24 minor outcomes. The comment concluded that the overall risk of 
accidental iron poisoning or death associated with PIC is low.
    In order to determine whether PIC merits an exemption from the 
labeling requirements of this final rule, FDA has considered whether 
the information supplied in the comment supports a conclusion that 
accidental overdose of a PIC-containing product is unlikely to place a 
small child at risk of illness or injury any time he or she gains 
unlimited access to such products. The total number of reported acute, 
accidental exposures in humans to PIC is very small, but already has 
resulted in 3 moderate outcomes and 24 minor outcomes. Therefore, the 
available data on acute, accidental exposure of humans to PIC does not 
support an exemption for PIC-containing products from the labeling 
requirements of this final rule. Accordingly, FDA is not exempting 
products containing PIC from the labeling requirements of this final 
rule.
    The comment also included data from an acute 14-day oral toxicity 
study in rats. The study was initiated with a range-finding test 
consisting of one male and one female rat at five doses ranging from 
500 to 5,000 mg Fe/kg body weight. Following the range-finding test, a 
limit test was performed in which one group of five male and five 
female rats received a single oral administration of PIC at a dose of 
5,000 mg Fe/kg body weight. Following dosing, the limit test rats were 
observed daily and weighed weekly. A gross necroscopy examination was 
performed on all limit test rats, and no gross internal findings were 
observed at necropsy after the 14-day exposure. No mortality occurred 
during the limit test, and the acute oral LD50 for PIC in rats 
therefore was estimated to be greater than 5,000 mg Fe/kg body weight.
    As discussed above for carbonyl iron, the basis for exempting 
products containing 30 mg or more PIC per dosage unit from the 
packaging requirements would be data that persuade the agency that 
accidental overdose of products containing 30 mg or more of PIC per 
dosage unit is unlikely to result in major outcomes or death. The 
information bearing on this question is: (1) Data on the outcomes of 
acute, accidental exposure of children to iron-containing products; (2) 
data on the acute toxicity in animals of carbonyl iron compared to that 
of iron salts; and (3) the ability to extrapolate from the acute 
toxicity data in animals to predict a reduced toxicity for carbonyl 
iron in children.
    As already discussed, the available data on accidental human 
overdoses are unclear as to whether there have thus far been any major 
outcomes resulting from exposure to PIC-containing products because the 
one report of major outcome was not clearly attributable to the 
consumption of a PIC-containing product. However, the lack of reported 
major outcomes or death associated with accidental overdose of products 
known to contain PIC may be attributable to both the insensitivity of 
passive reporting systems and the small number of total exposures to 
date. Therefore, FDA finds that the data on accidental exposures to 
PIC-containing iron products are too preliminary to

[[Page 2241]]

provide a basis for an exemption for PIC from the packaging 
requirements of this final rule.
    Moreover, there are no animal toxicology studies directly comparing 
the acute toxicity of PIC in animals to that of iron salts. The 
available animal data therefore have limitations similar to those 
already discussed for the data submitted in comments discussing the 
toxicity of carbonyl iron and are unsuited for the agency's purpose in 
evaluating whether the acute toxicity in children of PIC is less than 
that of iron salts. It would be premature for FDA to exempt PIC absent 
such data. In order to reach a decision on whether to exempt PIC from 
the packaging requirements of this final rule, FDA needs animal data, 
discussed in detail above for studies with carbonyl iron, comparing the 
acute toxicity of PIC to that of at least one iron salt that is 
commonly used in the manufacture of iron-containing supplements and 
drug products.
    At this time, the use of PIC in iron-containing products is not 
included in any FDA regulations. The comment did not submit sufficient 
information bearing on the manufacturing process, composition, and 
physical properties of PIC to allow the agency to adequately describe 
PIC in any exemption from the packaging requirements of this final 
rule. For example, the comment did not discuss the role, if any, of 
particle size and solubility of PIC, or the role of excipients and 
binders, as factors that may influence the toxicity of PIC. Before FDA 
can consider an exemption for PIC from the packaging requirements of 
this final rule, FDA needs information that adequately describes the 
manufacturing process, composition, and physical properties of PIC. If 
the agency reached a decision to exempt PIC from the packaging 
requirements of this final rule, FDA would use this information to 
define, in the agency's regulations, the substance that is exempt. FDA 
also solicits information on factors other than the properties of PIC 
itself, such as the physical and chemical properties of binders and 
excipients, that may influence the absorption and toxicity of PIC and 
recommendations on whether it is appropriate and important to include 
specifications for such factors used in the manufacture of products 
containing PIC.
    In summary, the available data on accidental exposure to PIC-
containing products are too preliminary to provide a basis for 
exempting PIC from the packaging requirements of this final rule. 
Further, FDA is concerned whether the available data on accidental 
exposure to PIC-containing products actually signify that PIC is no 
less toxic than ionic forms of iron. Moreover, it would be premature 
for FDA to exempt PIC from the packaging requirements of this final 
rule given the lack of animal data that clearly establish the lower 
toxicity of PIC compared to at least one commonly used iron salt. In 
addition, FDA lacks information that would allow the agency to describe 
the substance that is exempt. Therefore, at this time FDA is not 
exempting products containing PIC from the packaging requirements of 
this final rule.
    Regardless of whether FDA receives animal data that support a 
conclusion of reduced toxicity for PIC, the agency cautions that animal 
data alone may not provide a sufficient basis for an exemption in light 
of the extremely small number of exposures in humans to date. Further, 
as already discussed for carbonyl iron, animal data can only be used to 
support an interpretation that accidental exposure to a PIC-containing 
product is unlikely to result in a major outcome or death and cannot 
supersede data that may be obtained in the future from accidental human 
exposure to PIC-containing products.

VI. Other Matters

    One comment requested an exemption from both the labeling and unit-
dose packaging requirements for the inert, iron-containing tablets that 
are included in packages of oral contraceptives. The inert tablets are 
taken on the days on which the active drug product is not taken to 
facilitate proper and regular use of the contraceptives by enabling 
women to take a pill each day rather than having to remember which day 
to resume after the days for which an active pill is not provided. The 
comment argued that meeting the requirement for an additional warning 
statement on the immediate container labeling of oral contraceptive 
products would be impossible because of the lack of space, the small 
size of the immediate container, and preexisting label requirements. 
The comment stated that oral contraceptives are a special class of 
prescription products that should be exempted from the labeling 
requirements of this rule.
    The agency observes that the inert tablets in oral contraceptive 
products contain up to 75 mg of ferrous fumarate (equivalent to 25 mg 
of iron), and therefore a 1-month supply of oral contraceptives 
containing 7 inert tablets will contain up to 175 mg of iron. The total 
amount of iron in a 1-month supply of oral contraceptives is only 70 
percent of the amount (250 mg) that experts have stated is sufficient 
to produce symptoms of poisoning in a 10 kg child (see discussion 
above). Moreover, FDA is not aware of any reported cases of poisoning 
caused by the inert, iron-containing tablets in packages of oral 
contraceptives. Moreover, these products are separately regulated. 
Therefore, FDA is granting the requested exemption from the specific 
labeling requirement of this final rule (see Sec. 310.518(d)). If FDA 
becomes aware of poisoning caused by the ingestion of the inert, iron-
containing tablets in oral contraceptive packages, it may reconsider 
the exemption.
    The amount of iron per tablet is below the threshold level for 
unit-dose packaging of 30 mg of iron per dosage unit. Therefore, an 
exemption from the unit-dose packaging requirement is not necessary.

VII. Economic Impact

    FDA has examined the economic implications of the final rule as 
required by Executive Order 12866 and the Regulatory Flexibility Act (5 
U.S.C. 601-612). Executive Order 12866 directs agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select the regulatory approach which 
maximizes net benefits (including potential economic, environmental, 
public health and safety effects; distributive impacts; and equity). 
Executive Order 12866 classifies a rule as significant if it meets any 
one of a number of specified conditions including having an annual 
effect on the economy of $100 million or adversely affecting in a 
material way a sector of the economy, competition, or jobs, or if it 
raises novel legal or policy issues. If a rule has a significant impact 
on a substantial number of small entities, the Regulatory Flexibility 
Act requires agencies to analyze options that would minimize the 
economic impact of that rule on small businesses. Though not 
economically significant, FDA finds that this final rule is a 
``significant regulatory action'' as defined in Section 3(f)(4) of the 
Executive Order because it raises novel policy issues. The agency also 
finds under the Regulatory Flexibility Act that the final rule is 
likely to have a significant impact on a substantial number of small 
entities. Finally, the agency, in conjunction with the Administrator of 
OIRA, OMB, finds that this rule is not a major rule for the purposes of 
congressional review (Pub. L. 104-121).
    The rule will result in costs in the first year of approximately 
$56 million and $4.3 per year starting in year two for total discounted 
costs of $118 million

[[Page 2242]]

(discounted to infinity at 7 percent). The rule will also result in per 
year benefits of between $31.5 million and $61 million for total 
discounted benefits of between $426 million and $847 million 
(discounted to infinity at 7 percent). Below is a detailed description 
of FDA's economic analysis.
    In response to the iron proposal, the agency received many comments 
regarding the economic impact of the proposed actions. The comments 
were from a variety of sources including consumer advocacy 
organizations, manufacturers, distributors, and trade associations.

A. Description of the Industry

    In the analysis of the proposed rule, FDA stated that there are 
approximately 300 iron-containing products that may be affected by this 
action, of which approximately one-half contain 30 mg or more of iron 
per dosage unit. FDA received one comment from an industry trade 
association stating that there are between 1,300 and 3,000 iron-
containing products. The comment did not specify the number or 
percentage of products containing 30 mg or more of iron per dosage 
unit.
    The agency acknowledges that it originally underestimated the 
number of iron-containing products that may be affected by these 
actions. Therefore, the analysis of the final rule will be based on an 
estimate of 2,150 products ((1,300 + 3,000)/2). The agency will 
continue to assume that approximately one-half, or 1,075 products, 
contain 30 mg or more of 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 multivitamin/mineral supplements, products intended for 
use as iron supplements, and drug products for therapeutic purposes. 
Although this final rule requiring warning statements affects all iron-
containing products, the requirement for unit-dose packaging affects 
only products containing 30 mg or more of iron per dosage unit. 
Typically, multivitamin/mineral supplements provide less than 30 mg of 
iron per dosage unit and therefore are subject to warning statement 
requirements but not to packaging requirements. Iron supplements and 
drug products typically contain 30 mg or more of iron per dosage unit 
and therefore are subject to both requirements.
    Iron-containing products may be purchased by consumers on their own 
initiative as food supplements, or they may be prescribed by 
physicians. Information available to the agency at the time of the 
proposal suggested that the overwhelming majority of iron-containing 
products are packaged in bottles. Additional information suggested that 
iron-containing products administered in hospitals are commonly 
packaged in unit-dose packaging. Unit-dose packaging is preferred by 
hospitals because use of this type of packaging provides each dosage 
unit with an identification and an expiration date and allows the 
hospital to continue to dispense product from a partially used package 
of drugs rather than discard a bottle opened for a specific patient 
after that patient is discharged. There were no comments challenging 
FDA's assumption that iron-containing products dispensed in hospitals 
are packaged in unit-dose packaging, and, therefore, this assumption is 
being retained in this analysis.
    In the proposed analysis, FDA reported that, 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. 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 of iron nor did any 
comments provide such information. According to the recommended dietary 
allowance published in 1989 by the Food and Nutrition Board of the 
National Academy of Sciences, only pregnant women require 30 mg Fe/day. 
Therefore, FDA assumes that the number of higher-dosage iron-containing 
products consumed per year can be estimated by multiplying the number 
of pregnant women in the United States by the number of days in 1 year.
    In the most recent year (1991) for which data is available, there 
were 4.1 million live births. Assuming further that each live birth 
resulted from a distinct pregnant woman (as opposed to more than one 
birth per pregnant woman), this data implies that there are about 4.1 
million pregnant women on any 1 day in the United States, and that the 
number of dosage units per year can be estimated at 4.1 million times 
365 days per year or about 1.5 billion (assumes women who give birth 
take iron-containing products for 3 months of nursing after delivery). 
The number of pregnant women may be overestimated because multiple 
births by one woman are ignored. The number of pregnant women may also 
be underestimated because using the number of live births ignores 
pregnancies not resulting in a live birth. In addition, all pregnant 
women may not necessarily take iron-containing products or begin on the 
first day of pregnancy, another source of potential overestimation.

B. Comments on Regulatory Options

    The proposed analysis raised 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
    In the proposal, FDA proposed to require that products containing 
30 mg or more of iron per dosage unit be packaged in unit-dose 
containers. Because of Consumer Product Safety Commission regulations, 
most iron containing products currently must be packaged in CRC's. 
Therefore, this option would likely result in child resistant unit-dose 
packaging for most of these products.
    a. Costs. In the analysis of the proposed actions, FDA stated that 
there are four types of costs associated with a mandated packaging 
change: Equipment, materials, transportation, and administrative costs. 
FDA received one comment stating that the changes in packaging will 
require additional storage costs of $10,800 for four products. In 
addition, several other comments stated that the packaging requirements 
would cause manufacturers to incur additional stability testing at a 
cost of $4,000 per product.
    FDA agrees that the packaging requirements will increase storage 
costs and has changed its analysis to reflect that change. Using the 
data provided in the comment, the agency estimates storage costs to be 
approximately $1.4 million per year.
    As discussed above, stability testing with new packaging is 
required under drug CGMP regulations. Therefore, FDA agrees that the 
packaging requirements of this final rule will increase costs for drug 
products containing 30 mg or more of iron per dosage unit and will 
change its analysis to reflect that change. There are approximately 150 
drug products containing 30 mg or more iron per dosage unit. Total 
stability testing costs will be $0.6 million (150 drug products  x  
$4,000).
    Several comments expressed concern over the cost of equipment. One

[[Page 2243]]

comment from a manufacturer stated that machine tooling costs would be 
approximately $20,000 per product. However, one comment from a trade 
association stated that contract packaging firms can provide unit-dose 
packaging services at a cost that would be significantly less than 
purchasing machinery, although there was no data supporting this 
statement.
    In the analysis of the proposed rules, FDA stated that many 
packagers of iron-containing products will be required to purchase new 
packaging equipment. Incorporating the costs provided in the comments 
with information used to develop the estimates used in the proposed 
analysis, FDA now estimates the cost of equipment used in packaging 
blisters, one common form of unit-dose packaging, is between $20,000 
and $250,000, or on average $135,000. New equipment will not be 
purchased for each product sold because some manufacturers already 
possess unit-dose packaging equipment, and some manufacturers will use 
the services of contract packaging firms. FDA will not change its 
equipment cost per product, but it will reduce the number of products 
requiring new equipment based on the assumption that many firms will 
use contract packagers. If approximately one-third of the 1,075 
products containing 30 mg or more of iron per dosage unit require the 
purchase of new equipment, the total equipment cost will be $48 
million.
    The cost of child-resistant bottles, currently the most common form 
of packaging, is approximately $7 per 1,000 dosage units. Child 
resistant blister packaging materials cost approximately $9 per 1,000 
dosage units, a difference of $2 per 1,000 dosage units. FDA received 
no comments challenging these cost estimates.
    In the proposed analysis, FDA stated that it did not have 
information to estimate transportation costs and requested comments. 
FDA received one comment providing an estimate of additional 
transportation costs caused by unit-dose packaging requirements to be 
approximately $340,000 per year.
    Because no other information was provided to the agency, FDA will 
use this estimate in its analysis.
    FDA received one comment regarding administrative costs. One 
manufacturer stated that its administrative cost of reviewing and 
implementing the regulation would be $13,000.
    FDA notes that this estimate, when examined on a cost-per-product 
basis, is not out of line with its estimate 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, reading and interpreting the regulation, establishing a policy to 
comply with the regulation (which may include, for example, challenging 
the regulation, compliance with direct requirements, remarketing 
product, or withdrawal from the market), and identifying the 
appropriate staff to comply with the regulation, monitoring to ensure 
staff efforts are consistent with corporate policy, and interacting 
with Federal inspectors.
    The cost for equipment for unit-dose packaging for all products 
with 30 mg or more of iron per dosage unit is estimated to be $48 
million (358 products  x  $135,000). The cost of materials is estimated 
to be $3 million per year or $43 million (discounted to infinity at 7 
percent). Transportation costs are estimated to be $.34 million per 
year or $4.86 million (discounted to infinity at 7 percent). Storage 
costs will be approximately $1.4 million per year or $20 million 
(discounted to infinity at 7 percent). Administrative costs are 
estimated to be $0.54 million (1,075  x  $500). Total costs associated 
with requiring unit-dose packaging for products containing 30 mg or 
more of iron per unit dose are estimated to be $116 million (discounted 
to infinity at seven percent) with annual costs not exceeding $54 
million in any 1 year.
    b. Benefits. FDA received two comments concurring with its analysis 
of the benefits of unit-dose packaging, and no comments challenging 
that analysis. In the past 8 years, there have been at least 39 cases 
of pediatric fatalities from the accidental ingestion of iron-
containing products, or a mean of 4.9 deaths per year. Data on the 
dosage of the product consumed is available for 25 of these cases. In 
all cases for which information is available, the product consumed 
contained at least 40 mg of iron. In a 7-year period, there were nearly 
190 poisonings that were life threatening or resulted in permanent 
injury, and over 2,000 poisonings that required some form of treatment. 
FDA believes that most, if not all, such deaths and some poisonings can 
be prevented by requiring that higher-dosage iron-containing products 
be packaged in unit-dose containers, because studies indicate that the 
child is less likely to consume the number of dosage units that may be 
fatal if the child must first remove each tablet from a unit-dose 
package.
    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 $3 million 
and $5 million in past regulations, including food labeling and Hazard 
Analysis Critical Control Points (HACCP). 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 reducing 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 used these figures ($5 to 11 
million) in the proposed analysis to provide a range of estimates. FDA 
received no comments objecting to these estimates and is, therefore, 
continuing to use these values in this analysis.
    Requiring unit-dose packaging for iron-containing products at 30 mg 
or more of iron per dosage unit would result in benefits of reducing an 
average of 4.9 deaths per year, valued at between $24.5 million and $54 
million per year, or between $350 million and $771 million (discounted 
to infinity at 7 percent).
    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 dosage consumed was reported for 
12 of these cases. In five of those cases, the dosage reported was 
under 30 mg of iron per dosage unit. AAPCC data show that from 1986 
through 1992 there were nearly 190 poisonings that were life

[[Page 2244]]

threatening or resulted in permanent injury, and over 2,000 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 percent of these nonfatal poisonings 
that would be prevented by substituting unit-dose packaging for 
bottles. In the proposed analysis, FDA assumed that all nonfatal 
poisonings would be prevented by the proposed packaging requirements. 
The agency received no comments on this issue and is, therefore, 
continuing the assumption in this final analysis.
    Using a methodology developed previously for FDA to value morbidity 
risks, FDA is able to estimate the value of reduced risk of nonfatal 
poisoning. As described in the proposed analysis, 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. Seven out of twelve cases of nonfatal poisonings were 
a result of ingestion of products of dosages over 60 mg of iron. 
Assuming this proportion is extrapolated to the remaining cases for 
which information is unknown, and assuming unit-dose packaging will 
prevent all nonfatal cases (2,000 cases in 7 years), then requiring 
unit-dose packaging for products containing 30 mg or more of iron per 
unit dose will result in reduced morbidity valued $5 million per year, 
or $71 million (discounted to infinity at 7 percent).
    The total value of the benefits of unit-dose packaging options is 
the sum of the value of reducing both mortality and morbidity risks. 
Requiring unit-dose packaging for all products containing 30 mg or more 
of iron per dosage unit, would result in benefits of reducing mortality 
risks of between $24.5 million and $54 million per year or between $350 
million and $771 million (discounted to infinity at 7 percent) and 
reduced morbidity valued at $5 million per year or $71 million 
(discounted to infinity at 7 percent). Therefore, total discounted 
benefits are between $29.5 million and $59 million per year or between 
$421 million and $842 million (discounted to infinity at 7 percent).
2. Warning Labels
    a. Costs. FDA received two comments providing estimates of the cost 
of relabeling. One manufacturer estimated graphic and design costs at 
$2,850 per product. Another estimated artwork costs of $240,500 for 100 
products, or $2,405 per product.
    In the analysis of the proposed actions, FDA estimated that the 
cost of relabeling was $1,500 per label. Manufacturers of 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 of iron per dosage unit will also be required to 
change their packaging, they will not incur any incremental cost of 
adding a warning statement to the product container. Therefore, the 
redesign cost per product was estimated in the proposal was estimated 
to be $2,250 ($1,500 x 1.5). FDA notes that this estimate is similar to 
redesign costs submitted in the comments. Therefore, the analysis will 
not be changed based on this comment. The total cost of the warning 
label requirements is one-time cost of $5 million (2,150 products  x  
$2,250).
    In the proposed analysis, FDA stated that 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. It is possible that incidence of iron-deficiency anemia 
may actually increase as a result of this final action. According to 
NHANES II, approximately 7.2 percent of women age 15 to 19 and 6.3 
percent of women age 20 to 44 suffer from iron-deficiency anemia. In 
addition, men had a prevalence of less than 1 percent. FDA received no 
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. Whether or not the 
warning messages prescribed in this final rule will cause a change in 
behavior will depend on a number of factors, including the degree to 
which the statement is noticed, read, understood, and acted upon.
    There is some evidence that warning statements can change behavior. 
For example, research indicates that the rate of increase of sales of 
diet soft drinks declined after saccharin warnings were put on the 
labels of these products (Ref. 31). However, 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.
    FDA did not receive any comments challenging its estimate of the 
benefits of warning statements. Therefore, the analysis will not be 
changed by the comments. If all products containing 30 mg or more of 
iron per dosage unit are subject to the packaging requirements, and 
packaging 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 will have an impact. If each nonfatal case of iron 
poisoning is valued at $20,000, and the one-time cost of warning 
statements is $5 million, then benefits of requiring warning statements 
will exceed costs if warning statements prevent at least 15 nonfatal 
cases every year out of an average of 285.
3. Product Reformulation--Appearance
    In the proposed rule, FDA requested comment on the option of 
reformulating iron-containing products to be less visually attractive, 
i.e., not look like candy. FDA received several comments on this issue. 
As discussed above, none of these comments presented data to support 
their contention that FDA should take steps to limit the appeal of 
iron-containing products to young children, and therefore, FDA is not 
including in this final rule any requirements relating to the 
formulation and appearance of iron-containing products.
4. Product Reformulation--Taste
    In the proposed rule, FDA also requested comment on the option of 
adding a bitter substance to products containing iron which would 
discourage multiple ingestions. FDA did not receive any comments 
specifically addressing this issue. However, as discussed above, FDA 
did receive a comment expressing an opinion that a candy-like taste 
needlessly encourages an unsuspecting child, who may be unlikely to 
chew through the sugar coat, to ingest large quantities of these 
products. Another comment from a State department of health reported 
that investigation of 5 of 17 deaths revealed that children chewed or 
sucked on the iron tablets. However, none of these comments presented 
data to support a requirement by FDA for adding a bitter substance to 
products containing iron to discourage multiple ingestions.
5. Forms of Iron That May Be Less Toxic
    Several comments requested that iron-containing products containing 
carbonyl iron, an elemental iron powder, be exempted from the labeling 
and packaging requirements. Comments stated their belief that carbonyl 
iron is effective in the prevention or treatment of iron deficiency and 
yet is less toxic

[[Page 2245]]

than other forms of iron commonly used in iron-containing products. 
Comments also stated that a permanent exemption from both packaging and 
labeling would dramatically reduce the costs of the regulation.
    FDA agrees that such an exemption would reduce the costs of this 
final regulation. According to one producer of carbonyl iron, there are 
approximately 35 iron-containing products marketed by 15 manufacturers 
currently using carbonyl iron. It is likely that, if given an exemption 
for carbonyl iron, most, if not all, of the rest of the industry would 
convert their products to this form of iron. Therefore, an exemption 
from both labeling and packaging requirements would reduce costs by the 
difference between the cost of switching to carbonyl iron and the cost 
of making labeling and packaging changes. The cost of carbonyl iron is 
approximately $5.28 per lb as compared with ferrous sulfate which costs 
approximately $1.70 per lb. However, carbonyl iron has an iron content 
which is three times as high as ferrous sulfate. Therefore, on an 
equivalency basis, the price of the two types of iron are approximately 
equal ($5.28 for carbonyl iron and $5.10 for ferrous sulfate).
    The cost savings from providing an exemption from packaging 
requirements is $54 million in the first year, or $116 million 
discounted to infinity at 7 percent. There are minimal cost savings 
from providing an exemption from labeling requirements because most 
labels will still be changed to reflect a change in ingredients.
    However, as stated previously, although there may be some 
probability that carbonyl iron is less toxic, FDA is not entirely 
convinced that carbonyl iron is sufficiently less toxic than other 
commonly used forms of iron to substantially decrease the risk of 
pediatric poisoning. Thus, it is possible that providing an exemption 
from either labeling or packaging requirements, while substantially 
reducing costs, could also substantially reduce benefits. If carbonyl 
iron is not sufficiently less toxic than other forms of iron, then 
encouraging the industry to convert to carbonyl iron will result in 
lost benefits of between $426 million and $847 million (discounted to 
infinity at 7 percent). A permanent exemption for carbonyl iron from 
labeling requirements could result in a net loss to society of 
approximately $5 million. An exemption for carbonyl iron from packaging 
requirements could result in a net loss to society of between $421 
million and $842 million. On the other hand, if carbonyl iron is 
sufficiently less toxic than other forms of iron such that accidental 
overdose of products containing a high dose of carbonyl iron is 
unlikely to result in major outcomes or death, then an exemption from 
the packaging requirements would result in a cost savings of $54 
million annually with no corresponding loss in benefits.
    Because of the uncertainty regarding the relative toxicity of 
carbonyl iron, FDA is temporarily exempting products containing 
carbonyl iron from the packaging requirements. At the end of 1 year, 
those products will be subject to the unit-dose packaging requirements. 
However, if FDA receives sufficient data to convince the agency that an 
exemption from carbonyl iron will not result in any loss in benefits, 
the exemption will be made permanent. The temporary exemption for 
carbonyl iron will allow manufacturers of iron containing products to 
delay making changes to their packaging while conducting further 
studies on the toxicity of carbonyl iron. This delay will result in 
cost savings equal to the interest on the cost of the packaging changes 
(7 percent of $54 million, or $4 million). The cost of the studies will 
depend on the species selected. FDA estimates that conducting the 
necessary studies will cost approximately $30,000.
6. Consumer Education Campaign
    Two of the three petitions submitted 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 requiring some kind of 
treatment occurred, may indicate 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 FDA.
7. Effective Dates
    The agency proposed to make any final rule based on the proposed 
rule effective 6 months after date of publication of the final rule in 
the Federal Register. FDA received many comments objecting to this 
effective date.
    Several comments stated that the proposed effective date is not 
feasible for relabeling, urging FDA to consolidate the effective date 
with the date for the new nutrition labeling rules for dietary 
supplements that would be issued as a result of the DSHEA and were 
statutorily mandated to be effective after December 31, 1996. This 
would amount to a compliance period of approximately 1 year after 
publication of the final rules, a delay of approximately 6 months 
compared to the proposed effective date. One comment requested that 
firms be allowed to use up existing stocks of labeling bearing the 
voluntary warning statement. One comment stated that revising labeling 
requires at least 1 year.
    FDA agrees that costs of compliance with labeling requirements are 
reduced with extended effective dates. In general, costs of compliance 
for labeling are less for longer compliance periods because firms can 
incorporate mandatory changes to product labeling with regularly 
scheduled changes. In general, labeling costs are reduced by 50 percent 
when a compliance period is extended from 6 months to 1 year. However, 
benefits are also delayed.
    FDA has considered the requests to extend the effective date for 
implementing the labeling requirements of this final rule from a period 
of 6 months to a period of 1 year. FDA would select the regulatory 
option of extending the compliance period for the warning statement 
requirements if the marginal benefit of the option exceeds the marginal 
cost. The marginal benefit of extending the compliance period to 1 year 
is the reduction in benefits caused by not preventing nonfatal cases 
for 6 months. Marginal costs will exceed marginal benefits if 125 cases 
are not prevented. FDA believes that it is likely that the number of 
additional nonfatal cases not prevented during the 6-month period will 
exceed this number. Thus, the savings to manufacturers from a 1-year 
compliance period will not be as great as the savings from injuries 
avoided by having the warning statement on all products. Consequently, 
FDA is denying the requests to extend the compliance period to 1 year.
    FDA also has considered the requests to consolidate the effective 
date for the labeling requirements of this rule with the dietary 
supplement labeling requirements that would be issued as a result of 
the DSHEA. At this time, the effective date of this final rule is after 
December 31, 1996, which is the statutorily mandated date of compliance 
for the labeling requirements imposed by the DSHEA. However, it is 
questionable whether FDA's regulations implementing the DSHEA labeling 
requirements will be finalized before that date. FDA has previously 
stated its intent to provide a reasonable compliance period for the 
provisions of DSHEA (61 FR 16423, April 15, 1996). In light of the 
comments that discussed the extent of the current compliance with the 
industry's voluntary labeling program, FDA considers that a

[[Page 2246]]

reasonable response to the requests for a single compliance date, which 
still places public health at the forefront, is to retain the effective 
date of 180 days as proposed but to use enforcement discretion, 
consistent with its announced intent to provide a reasonable compliance 
period for the provisions of the DSHEA, for those products that bear a 
voluntary warning statement (such as the statement suggested by the 
NDMA). Products that do not bear any warning statement, however, must 
be in compliance with this final rule within 6 months of its date of 
publication. In the interest of fairness, the agency is likely to 
follow a similar approach with respect to iron-containing drug products 
even though iron-containing drug products are not subject to the 
agency's labeling regulations implementing DSHEA.
    Several comments requested an extension of the effective date for 
the packaging requirements. One comment stated revising packaging 
requires at least 1 year. The comment stated that the time required to 
order, obtain, and implement new tooling and equipment easily exceeds 
180 days. Another comment suggested that many firms would have to use 
outside contractors for unit-dose packaging with resultant costs and 
time delays but did not provide any estimates. One comment expressed 
uncertainty about whether the capacity of the packaging industry was 
sufficient to handle the extra work. One comment from the packaging 
industry stated that enough capacity exists to unit-dose pack all iron-
containing products currently sold in the United States.
    FDA agrees that costs of compliance with packaging requirements are 
reduced with extended effective dates. In general, extending the 
compliance date for packaging to 1 year would reduce costs of 
materials, transportation, storage, and administration. The total 
reduction in cost of packaging due to a 6-month extension would be 
approximately $5 million. However, the 6-month extension would also 
decrease benefits. The cost of extending the compliance date for 
packaging requirements for products containing 30 mg or more of iron 
per dosage unit is a reduction in benefits caused by not preventing 
fatal cases for 6 months, valued at an amount between $16 and $32 
million.
    FDA has considered the requests to extend the effective date for 
implementing the packaging requirements of this final rule. The 
agency's calculations show that the reduction in costs that would be 
expected by extending the compliance period to 1 year is small compared 
to the overall costs of the rule. Moreover, the reduction in benefits 
that would be expected by extending the compliance period to 1 year 
exceed the reduction in costs by a factor of 3 to 6. Therefore, FDA is 
denying the requests to increase the time for compliance with this 
final rule.

C. Regulatory Flexibility

    FDA stated in the original analysis that it was not aware that any 
small businesses would be affected by the proposed rule and therefore 
determined that the rule will not result in a significant burden on 
small businesses. In response to those statements, FDA received 
comments indicating that some small businesses will be adversely 
affected by the rule if finalized as proposed.
    One comment requested that FDA conduct an Initial Regulatory 
Flexibility Analysis and republish the proposed rule with that 
analysis, allowing for an appropriate period for public comment. FDA is 
denying this request. The risk of harm from accidental iron pediatric 
poisonings is too great for FDA to postpone rulemaking on this matter. 
Republishing the proposed rule would postpone action on this issue for 
at least 6 additional months. During that time, FDA estimates that 2 
fatal cases and as many as 1,000 nonfatal cases that could be prevented 
by publishing the final rule rather than republishing the proposal. 
Further, FDA received many comments to the proposed rule providing 
information that FDA used to modify the provision of the rule to be 
less burdensome for small entities. FDA does not believe that 
republishing the proposed rule would result in a final rule that is 
significantly different from this one.
    According to the Small Business Administration's (SBA) size 
standards, a maker of iron-containing products is small if it employees 
fewer than 500 persons. According to the National Nutritional Foods 
Association (NNFA), of approximately 100 of their members that produce 
iron-containing products, over 90 percent have fewer than 500 
employees. However, because not all iron-containing products are 
produced by members of NNFA, there are probably more than 90 firms 
producing iron-containing supplements. According to the Bureau of the 
Census, approximately 84 percent, or 504 firms, of the pharmaceutical 
industry, which is not limited to manufacturers of iron-containing 
products, are small. Therefore, a significant portion of the affected 
industry is small by SBA's definitions. However, sources of information 
on the number of firms that produce iron-containing products are 
limited. Several sources collect information only on a subgroup of 
iron-containing product manufacturers, e.g., members of a particular 
trade organization. Other sources collect information at such an 
aggregated level that the information specific to iron-containing 
products cannot be separated out. Therefore, it is either impossible or 
impracticable to estimate the number of small entities that produce 
iron-containing products.
    FDA was able to gather specific data on 10 small and 12 large 
producers of iron-containing supplements. The firms for which data were 
available sold over-the-counter iron-containing supplements through 
grocery stores and cannot be considered as representative of the entire 
industry. Many other iron-containing products are distributed through 
pharmacies or clinics or are marketed through other types of retail 
outlets and mail order catalogs. Nevertheless, because these were the 
only firms for which FDA could find data on the number of employees, 
annual revenues, and number of iron-containing products produced, the 
analysis was restricted to these 22 firms.
    The 10 small firms employed between 4 and 440 persons (median = 
111), had annual sales ranging from $450,000 to $116 million (median = 
$17 million), and produced between 1 and 8 iron-containing products 
(median = 3). A total of 35 iron-containing products were produced by 
small firms in the sample. The impact was heaviest on the two firms 
with the smallest annual revenues. For these two small firms, the 
regulatory cost as a percentage of annual revenues were 3 and 6 
percent. The regulatory cost could be expected to raise total company 
expenses by 4 and 8 percent for these two small firms. In addition, the 
regulatory cost as a percentage of total company profits was 16 and 30 
percent for these two small firms. On average, the ten small firms in 
the sample would experience an increase in total company expenses of 
1.6 percent (median = .68 percent). The costs of the regulation as a 
percentage of total company profits was 6.27 percent on average for the 
10 firms in the sample (median = 2.64 percent).
    By comparison, the 12 large firms in the sample employed between 
600 and 82,000 persons (median = 21,950), had annual sales between $60 
million and $19 billion (median = $6.1 billion), and produced between 1 
and 15 iron-containing products (median = 5). A total of 67 products 
were produced by the large firms in the sample. On average, large firms 
would experience

[[Page 2247]]

an increase in total company expenses of 0.05 percent (median = .0021 
percent). Regulatory costs as a percent of annual revenues would be 
0.04 percent for the average large firm (median = .0017 percent). 
Regulatory costs as a percent of total company profits would be 0.21 
percent on average for large firms (median = .0083 percent).

D. Alternatives to Provide Regulatory Relief for Small Business

    There are five alternatives that the agency considered to provide 
regulatory relief for small entities. First, FDA considered the option 
of exempting small entities from the requirements of this rule. Second, 
FDA considered lengthening the compliance period for small entities. 
Third, the agency considered exempting products containing elemental 
iron, such as carbonyl iron, from packaging requirements because of its 
low potential for toxicity. Fourth, FDA considered less restrictive 
warning label requirements for small entities. Finally, FDA considered 
the option of establishing performance rather than design standards.
1. Exempt Small Entities
    One alternative for alleviating the burden for small entities would 
be to exempt them from the provisions of this rule. However, the 
majority of the firms engaged in the manufacture of iron-containing 
products are small. Even accounting for the fact that large firms 
produce more products on average than small firms, exempting small 
firms would exempt a large proportion of iron-containing products. 
Although this option would clearly eliminate the burden on small firms, 
it would also result in a significant decrease in the number of 
pediatric iron poisonings prevented. Therefore, FDA concludes that 
selecting this alternative would defeat the purpose of the regulation.
2. Lengthen the Compliance Period
    As discussed above, the agency proposed to make any final rule 
effective 6 months after publication of the final rule. The DSHEA 
imposes certain labeling requirements on dietary supplements to be 
effective in December 1996. FDA could consolidate the effective date 
for the warning label requirements with the effective date for the new 
nutrition labeling format for dietary supplements, thus reducing costs. 
FDA received many comments stating that extending the compliance period 
for labeling requirements would reduce the burden for small entities 
without significantly reducing the benefits of the actions.
    FDA agrees that extending the compliance period for the labeling 
requirements to coincide with the effective date for the requirements 
of DSHEA would significantly reduce the burden of the labeling 
requirements on small entities. However, a delay in the effective date 
for small entities would reduce the number of accidental poisonings 
that would be prevented by between 7 and 100 nonfatal cases. Therefore, 
the agency does not agree that the reduction in costs exceeds the 
reduction in benefits that would be expected. However, because 
compliance with the industry's voluntary labeling program appears to be 
significant, as stated previously in this document, FDA is retaining 
the effective date of 180 days as proposed but intends to exercise its 
enforcement discretion, consistent with its announced intent to provide 
a reasonable compliance period for the provisions of the DSHEA, for 
those products bearing a voluntary warning statement, such as the 
statement suggested by NDMA, until after the agency begins to enforce 
the labeling regulations implementing DSHEA. FDA believes that this 
response will relieve some of the burden associated with the warning 
statement requirements.
3. Exemption for Carbonyl Iron
    Several comments to the proposed rule suggested that an exemption 
for carbonyl iron would reduce the impact on small entities. Because it 
is less expensive to switch to carbonyl iron than to comply with the 
packaging requirements, most or all small producers would likely take 
advantage of the exemption. Thus, FDA acknowledges that exempting 
products made with carbonyl iron would significantly reduce the burden 
on small entities. Because of the uncertainty regarding the relative 
toxicity of carbonyl iron, FDA is temporarily exempting products 
containing carbonyl iron from the packaging requirements for 1 year. If 
FDA receives sufficient data to convince the agency that an exemption 
from carbonyl iron will not result in a significant loss in benefits, 
the exemption will be made permanent. Because this exemption would 
apply to large firms as well as small, FDA does not believe that small 
entities will bear the cost of developing the necessary data.
4. Less Stringent Labeling Requirements
    Elsewhere in this preamble, FDA has responded to comments from both 
large and small firms regarding more flexible requirements with respect 
to warning statements. Upon consideration of the comments, FDA has 
amended its proposed warning label requirements to allow as much 
flexibility as is possible. For example, FDA is no longer requiring 
that the warning statement appear on the principal display panel. FDA 
is also allowing firms that currently use warning statements additional 
time to modify their labels. Because the requirements of the final 
warning statements requirements are as flexible as possible, there is 
no room for additional flexibility for small firms.
5. Performance Standards Rather Than Design Standards
    FDA considered the possibility of establishing performance rather 
than design standards for this final rule. Although specifically 
prescribing packaging and labeling changes, FDA has written performance 
based criteria for certain provisions of this rule. In the case of 
warning label statements for unit-dose containers, FDA has revised the 
wording of the regulation in such a way that makes clear that the 
manufacturer bears the responsibility in designing labeling that will 
meet the agency's goal of informing consumers of the dangers to small 
children from an accidental overdose of a product that contains iron 
but provides the manufacturer with flexibility in determining how it 
will do so. Also, FDA has decided specifically not to require any 
particular type of packaging, for example blister packs or pouches. 
Instead, FDA is allowing the manufacturer to determine the most 
appropriate packaging for its product provided that the packaging meets 
the goal of allowing access to only one dose at a time.
    FDA considered the potential for establishing an acceptable 
toxicity for iron-containing products rather than prescribing packaging 
and labeling requirements to reduce risk of harm. It is not clear that 
this option would be less costly for small entities. For most sources 
of iron, the available toxicity data either does not exist or is 
unsuited for the purpose of evaluating the toxicity of the form of iron 
in humans.

E. Summary

    FDA has examined the impact of the final rule in accordance with 
Executive Order 12866 and has determined that it is not an economically 
significant rule. The rule will result in costs in the first year of 
approximately $56 million and $4.3 per year starting in year two for 
total discounted costs of $118 million (discounted to infinity at 7 
percent). The rule will also result in per year benefits of between 
$31.5 million and $61 million for total discounted benefits of

[[Page 2248]]

between $426 million and $847 million (discounted to infinity at 7 
percent).
    FDA has also examined the impact of this final rule on small 
businesses in accordance with the Regulatory Flexibility Act. This 
analysis with the rest of the preamble constitutes the Final Regulatory 
Flexibility Analysis. FDA has determined that this rule is likely to 
have a significant impact on a substantial number of small entities. 
However, if the temporary exemption for products made with carbonyl 
iron is made permanent, the impact on small entities will be 
significantly reduced. FDA is also reducing the impact on small 
entities by exempting from the labeling requirements those products 
bearing a voluntary warning statement until after the agency's labeling 
regulations implementing DSHEA take effect. FDA, in conjunction with 
the Administrator of OIRA, OMB, has determined that this rule is not a 
major rule for purposes of congressional review.

F. Public Outreach

    FDA has conducted extensive outreach to a wide audience on the 
problem of accidental overdose of iron-containing products in small 
children. This outreach included independent FDA activities as well as 
cooperative efforts between FDA and professional trade organizations.
    One focus of FDA's outreach effort was to educate consumers about 
the danger that iron-containing products posed to small children to 
foster changes in behavior with respect to safe handling of these 
products. This effort included direct outreach to consumers through TV 
and radio public service announcements in English and in Spanish; a 
camera-ready newspaper column in English and Spanish; multicolored 
posters, in English and in Spanish, distributed to retail pharmacists 
and clinics operated by the Women, Infants, and Children Program of the 
U.S. Department of Agriculture; an FDA backgrounder, which described 
the agency's efforts to protect children from accidental iron 
poisoning, that was both disseminated in printed form and made 
available through electronic means as a special feature in the FDA News 
section of the agency's home page on the World Wide Web (August 1995); 
an article in FDA Consumer, the agency's official consumer publication; 
a ``Dear Consumer'' letter distributed to more than 500 organizations 
with more than 10,000 affiliates; and a ``Dear Consumer Newsletter 
Editor'' letter to more than 150 consumer publications. FDA believed 
that many of these efforts would be noticed by small producers of iron 
supplements.
    A second focus of FDA's outreach effort was to inform the 
professional health care community of the danger that iron-containing 
products posed to small children so that health care providers could 
help disseminate educational materials to consumers and promote the 
safe handling of iron-containing products. FDA notified several dozen 
pharmacy, medicine, and nursing organizations of the proposed 
regulation by telefax, including a copy of the press release, 
backgrounder, and summary of the regulation; mailed a ``Dear Doctor'' 
letter to obstetricians/gynecologists; issued a Medical Bulletin; and 
published columns in leading medical journals.
    A third focus of FDA's outreach effort was to inform manufacturers 
of iron-containing products of the agency's proposed regulations on 
packaging and labeling such products and encourage them to work 
together with the agency to develop a final rule based on the proposal. 
The initial outreach consisted of a telefax notification, including a 
copy of a press release from the Department of Health and Human 
Services and the above-mentioned FDA backgrounder, to several trade 
associations to alert them to the publication of the agency's proposed 
rule, followed by a direct mailing of a copy of the proposed rule to 
those organizations. In addition, FDA met with representatives of two 
manufacturers' trade organizations shortly after the publication of the 
proposed rule to discuss specific aspects of the proposed regulation. 
FDA also placed a summary of key provisions of the proposed rule in the 
FDA News section of the agency's home page on the World Wide Web.

VIII. Environmental Impact

    The agency has previously considered the environmental effects of 
this rule as announced in the proposed rule of October 6, 1994 (59 FR 
51030). No new information or comments have been received that would 
affect the agency's previous determination that there is no significant 
impact on the human environment and that an environmental impact 
statement is not required.

IX. Paperwork Reduction Act

    The labeling requirement of this final rule is not within the scope 
of the Paperwork Reduction Act of 1995, because under 5 CFR 
1320.3(c)(2),\20\ it is excluded from the definition of collection of 
information.
---------------------------------------------------------------------------

    \20\ Under 5 CFR 1320.3(c)(2), the public disclosure of 
information originally supplied by the Federal Government to the 
recipient for the purpose of disclosure to the public is not 
included within the definition of ``collection of information.''
---------------------------------------------------------------------------

X. Effective Date

    As discussed above (see section VII.B.7. of this document), the 
effective date of the labeling requirements of this final rule is 180 
days after the date of its publication in the Federal Register except 
that the effective date for iron-containing dietary supplement and drug 
products bearing a voluntary warning statement (such as the statement 
suggested by the NDMA) is after December 31, 1996 (i.e., after the 
agency's labeling regulations implementing DSHEA take effect).
    As also discussed above (see section VII.B.7. of this document), 
the effective date of the packaging requirements of this final rule is 
180 days after date of its publication in the Federal Register, except 
that FDA is temporarily exempting products that contain carbonyl iron 
as the sole source of iron from these packaging requirements. The 
temporary exemption will automatically expire 1 year after date of 
publication of this final rule in the Federal Register. If, following 
the temporary exemption period, FDA does not temporarily or permanently 
extend the exemption, the packaging requirements of this final rule 
will become effective for products that contain carbonyl iron as their 
sole source of iron source according to the same principle as for 
products containing other forms of iron, i.e., on the date that is 180 
days after date of expiration of the temporary exemption, or on July 
15, 1998.

XI. 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. Memorandum of telephone conversation between Paul Whittaker, 
FDA, and Rose Ann Soloway, American Association of Poison Control 
Centers, dated October 13, 1995.
    2. Memorandum of telephone conversation between Paul Whittaker, 
FDA, and Suzanne Barone, U.S. Consumer Product Safety Commission, 
dated November 30, 1995.
    3. American Association of Poison Control Center, Inc., petition 
to FDA, 91P-0186/CP1, 1991.
    4. Attorneys General, petition to FDA, 93P-0306/CP1, 1993.
    5. Nonprescription Drug Manufacturers Association, petition to 
FDA, 93P-0306/CP2.
    6. ``Iron,'' in Nelson Textbook of Pediatrics, edited by R. E. 
Behrman, R. M. Kliegman, W. E. Nelson, and V. C. Vaughan, W. B.

[[Page 2249]]

Saunders Co., Philadelphia, PA, 14th ed., pp.1780-1781, 1992.
    7. 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.
    8. Wilbur, C. J., ``Child Resistant Effectiveness Conventional 
Pouch Packaging (Non-Child Resistant),'' U.S. Consumer Product 
Safety Commission, C-805-9864, 1978.
    9. Wilbur, C. J., ``Child Resistant Effectiveness Conventional 
Blister Card Packaging (Non-Child Resistant),'' U.S. Consumer 
Product Safety Commission, E-850-3006, 1978.
    10. U.S. Consumer Product Safety Commission iron fatality case 
reports.
    11. Shelanski, H. A., ``Acute and Chronic Toxicity Tests on 
Carbonyl Iron Powder,'' Bulletin of the National Formulary 
Committee, 18:87-94. 1950.
    12. Life Sciences Research Office, Federation of American 
Societies for Experimental Biology, ``Evaluation of the Health 
Aspects of Iron and Iron Salts as Food Ingredients,'' (SCOGS-35). 
Contract No. FDA 223-75-2004, 1980.
    13. National Academy of Sciences. Committee on Animal Nutrition, 
Subcommittee on Mineral Toxicity in Animals, ``Mineral Tolerance of 
Domestic Animals,'' 1980.
    14. Twenty-seventh Report of the Joint Federal/World Health 
Expert Committee on Food Additives, ``Toxicological Evaluation of 
Certain Food Additives and Contaminants,'' Word Health Organization 
(WHO) Technical Report Series No. 696, 1983.
    15. Weaver, L. C., R. W. Gardier, V. B. Robinson, and C. A. 
Bunde ``Comparative Toxicology of Iron Compounds,'' American Journal 
of the Medical Sciences, 241:296-302, 1961.
    16. Hoppe, J. O., G. M. A. Marcelli, and M. L. Tainter, ``A 
review of the toxicity of iron compounds,'' Progress of Medical 
Science, 230:558-571, 1955.
    17. Casarett and Doull's Toxicology, The Basic Science of 
Poisons, 4th ed., edited by M. O. Amdur, J. Doull, and C. C. 
Klaassen, Pergamon Press, New York, p. 22, 1991.
    18. U.S. Food and Drug Administration, Bureau of Foods, 
``Toxicological Principles for the Safety Assessment of Direct Food 
Additives and Color Additives Used in Food,'' National Technical 
Information Service, Springfield, VA, p. 21, 1982.
    19. Sacks, P. V., and W. M. Crosby, ``Bioavailability and 
Toxicity of Carbonyl Iron,'' Journal of Clinical Research, 22:562, 
1974.
    20. Klein-Schwartz, W., G. M. Oderda, R. L. Gorman, F. Favin, 
and S. R. Rose, ``Assessment of Management Guidelines. Acute Iron 
Ingestion,'' Clinical Pediatrics, 29:316-321, 1990.
    21. Mann, K. V., M. A. Picciotti, T. A. Spevack, and D. R. 
Durbin, ``Management of Acute Iron Overdose,'' Clinical Pharmacy, 
8:428-440, 1989.
    22. Gordeuk, V. R., G. M. Brittenham, C. E. McLaren, M. A. 
Hughes, and L. J. Keating, ``Carbonyl Iron Therapy for Iron 
Deficiency Anemia,'' Blood, 67:745-752, 1986.
    23. Crosby, W. H., ``Prescribing Iron? Think Safety,'' Archives 
of Internal Medicine, 138:766-767, 1978.
    24. 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 Haematology, 46:272-278, 1991.
    25. American Association of Poison Control Centers, Toxic 
Exposure Surveillance System (TESS), ``Field Definitions,'' 1992-
1994.
    26. Gordeuk, V. R., G. M. Brittenham, M. Hughes, L. J. Keating, 
and J. J. Opplt, ``High-dose Carbonyl Iron for Iron Deficiency 
Anemia: A Randomized, Double-blind Trial,'' American Journal of 
Clinical Nutrition, 46:1029-1034, 1987.
    27. Gordeuk, V. R., G. M. Brittenham, M. A. Hughes, and L. J. 
Keating, ``Carbonyl Iron for Short-term Supplementation in Female 
Blood Donors,'' Transfusion, 27:80-85, 1987.
    28. Gordeuk, V. R., G. M. Brittenham, J. Bravo, M. A. Hughes, 
and L. J. Keating, ``Prevention of Iron Deficiency With Carbonyl 
Iron in Female Blood Donors,'' Transfusion, 30:239-245, 1990.
    29. Hallberg, L., M. Brume, and L. Rossander, ``Low 
Bioavailability of Carbonyl Iron in Man: Studies on Iron 
Fortification of Wheat Flour,'' American Journal of Clinical 
Nutrition, 43:59-67, 1986.
    30. Huebers, H. A., G. M. Brittenham, E. Csiba, and C. A. Finch, 
``Absorption of Carbonyl Iron,'' Journal of Laboratory Clinical 
Medicine, 108:473-478, 1986.
    31. 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 111

    Drugs, Packaging and containers, and labeling.

21 CFR Part 310

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

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, title 21 CFR 
chapter I is 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 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:

    WARNING: Accidental overdose of iron-containing products is a 
leading cause of fatal poisoning in children under 6. Keep this 
product out of reach of children. In case of accidental overdose, 
call a doctor or poison control center immediately.

    (2)(i) The warning statement required by paragraph (e)(1) of this 
section shall appear prominently and conspicuously on the information 
panel of the immediate container label.
    (ii) If a product is packaged in unit-dose packaging, and if the 
immediate container bears labeling but not a label, the warning 
statement required by paragraph (e)(1) of this section shall appear 
prominently and conspicuously on the immediate container labeling in a 
way that maximizes the likelihood that the warning is intact until all 
of the dosage units to which it applies are used.
    (3) Where the immediate container is not the retail package, the 
warning statement required by paragraph (e)(1) of this section shall 
also appear prominently and conspicuously on the information panel of 
the retail package label.
    (4) The warning statement shall appear on any labeling that 
contains warnings.
    (5) The warning statement required by paragraph (e)(1) of this 
section shall be set off in a box by use of hairlines.
    3. Part 111 consisting of Sec. 111.50, is added to read as follows:

PART 111--CURRENT GOOD MANUFACTURING PRACTICE FOR DIETARY 
SUPPLEMENTS

    Authority:  Secs. 201, 402, 701 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 342, 371).


Sec. 111.50  Packaging of iron-containing dietary supplements.

    (a) The use of iron and iron salts as iron sources in dietary 
supplements offered in solid oral dosage form (e.g., tablets or 
capsules), and containing 30 milligrams or more of iron per dosage 
unit, is safe and in accordance with current good manufacturing 
practice only when such supplements are

[[Page 2250]]

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). Iron-
containing dietary supplements that are subject to this regulation are 
also subject to child-resistant special packaging requirements in 16 
CFR parts 1700, 1701, and 1702.
    (b)(1) Dietary supplements offered in solid oral dosage form (e.g., 
tablets or capsules), and containing 30 milligrams or more of iron per 
dosage unit, are exempt from the provisions of paragraph (a) of this 
section until January 15, 1998, if the sole source of iron in the 
dietary supplement is carbonyl iron that meets the specifications of 
Sec. 184.1375 of this chapter.
    (2) If the temporary exemption is not extended or made permanent, 
such dietary supplements shall be in compliance with the provisions of 
paragraph (a) of this section on or before July 15, 1998.

PART 310--NEW DRUGS

    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).

    4. 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 capsules 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., tablet or capsule. Iron-containing drugs that are 
subject to this regulation are also subject to child-resistant special 
packaging requirements in 16 CFR parts 1700, 1701, and 1702.
    (b) Temporary exemption. (1) Drug products offered in solid oral 
dosage form (e.g., tablets or capsules), and containing 30 milligrams 
or more of iron per dosage unit, are exempt from the provisions of 
paragraph (a) of this section until January 15, 1998, if the sole 
source of iron in the drug product is carbonyl iron that meets the 
specifications of Sec. 184.1375 of this chapter.
    (2) If this temporary exemption is not extended or made permanent, 
such drug products shall be in compliance with the provisions of 
Sec. 111.50(a) of this chapter on or before July 15, 1998.
    (c) Labeling. (1) The label of any drug 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:

    WARNING: Accidental overdose of iron-containing products is a 
leading cause of fatal poisoning in children under 6. Keep this 
product out of reach of children. In case of accidental overdose, 
call a doctor or poison control center immediately.

    (2)(i) The warning statement required by paragraph (c)(1) of this 
section shall appear prominently and conspicuously on the information 
panel of the immediate container label.
    (ii) If a drug product is packaged in unit-dose packaging, and if 
the immediate container bears labeling but not a label, the warning 
statement required by paragraph (c)(1) of this section shall appear 
prominently and conspicuously on the immediate container labeling in a 
way that maximizes the likelihood that the warning is intact until all 
of the dosage units to which it applies are used.
    (3) Where the immediate container is not the retail package, the 
warning statement required by paragraph (c)(1) of this section shall 
also appear prominently and conspicuously on the information panel of 
the retail package label.
    (4) The warning statement shall appear on any labeling that 
contains warnings.
    (5) The warning statement required by paragraph (b)(1) of this 
section shall be set off in a box by use of hairlines.
    (d) The iron-containing inert tablets supplied in monthly packages 
of oral contraceptives are categorically exempt from the requirements 
of paragraphs (a) and (c) of this section.

    Dated: October 24, 1996.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 97-947 Filed 1-14-97; 8:45 am]
BILLING CODE 4160-01-P`