Federal Register, Volume 62 Issue 10 (Wednesday, January 15, 1997)

[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:

(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:

(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}}}}}