2218 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

1For 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.

2Throughout this document, the term ‘‘ironcontaining 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 ironcontaining 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.

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

§§ 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

packaging1 for iron-containing

products2 that contain 30 mg or more of

iron per dosage unit.3

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 ironcontaining 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 ironcontaining 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 IronContaining 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 ironcontaining 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:
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 ironcontaining products and heard nothing

about the nature of the hazard posed by

an accidental overdose of ironcontaining 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 blisterpackaged 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.
2220 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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 Statement in the Proposal Text of the Warning Statement in the Final Rule

Warning Warning

Informational statement ........ Contains iron, which can harm or cause death to a

child.

Accidental overdose of iron-containing 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 away from children.3 .................. Keep this product out of reach of children.

Provisional statement ........... If a child accidentally swallows this product * * * .......... In case of accidental overdose * * *.

Instructional statement ......... * * * call a doctor or poison control center immediately * * * call a doctor or poison control center immediately.

1The order of the statements in this table is the order of the statements as they appear in the final regulation.

2For use on unit-dose packages.

3For 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 § 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 ironcontaining 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 ironcontaining 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 selfpressurized 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 ironcontaining 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 ironcontaining products poses to young

children, precedes the handling

instruction.

2. Handling Statement

FDA proposed two different handling

instructions based on whether the ironcontaining 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 § 101.17(e)(1) and

proposed § 310.518(b) (now

§ 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.
2222 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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-unitdose 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 ironcontaining products under normal

conditions. The revised warning

statement reads:

WARNING: Accidental overdose of ironcontaining 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 §§ 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 ironcontaining products away from children at

all times. Reclose the child resistant cap

completely every time after use. Keep in

original package until each use. Ironcontaining 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 ironspecific 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
2224 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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 ironcontaining 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 ironcontaining 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 ironcontaining 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. Ironcontaining 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-Englishspeaking 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 ironcontaining 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 IronContaining Products

FDA proposed in §§ 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

(§ 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2225

4FDA recognizes that the package liner of a unitdose 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.

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 (§ 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 §§ 101.17(e) and 310.518(b)

(now § 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

§§ 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

§§ 101.17(e) and 310.518(b) (now

§ 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, §§ 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.’’

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, §§ 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 §§ 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
2226 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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

§§ 101.17(e)(5) and 310.518(c)(5), that

the warning statement for ironcontaining 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

§§ 101.17(e)(2) and 310.518(b)(3) (now

§ 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 unitdose 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 unitdose 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 § 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.
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2227

FDA also is revising § 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 unitdose 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 IronContaining 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 § 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

§ 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
2228 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

5 Given CPSC’s child resistance requirements,

FDA’s action will have no effect on how difficult

it is to open the package.

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.

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 unitdose 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 ironcontaining 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 childresistant special packaging and FDA’s

CGMP regulations for iron-containing

products, in this final rule FDA is

revising proposed §§ 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 childresistant 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 §§ 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, childresistant pouches, or other childresistant 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 unitdose 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 ironcontaining 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 unitdose 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 childresistant 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
2230 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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 childresistant 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 ironcontaining 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 childresistant 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 §§ 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 ironcontaining products, including ironcontaining drug products sold by

prescription. Some of the ironcontaining 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-thecounter be sold with CRC’s. The

comment suggested that packaging for

iron-containing drug products sold by

prescription not be changed because
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 childresistant 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 unitdose 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 unitdose 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 ironcontaining 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 ironcontaining 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 ironcontaining 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 candylike 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 ironcontaining 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
2232 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

6The 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).

7The 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.

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 ironcontaining 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 brandname 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 ironcontaining 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 more7 (Ref. 11). This comment

concluded that these studies in

experimental animals suggested that

carbonyl iron has a 100-to 200-fold
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2233

greater safety margin than ferrous

sulfate.

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-adverseeffect-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

Species

LD50 (mg Fe/kg body weight) Approximate fold

difference Carbonyl iron Iron salt

Rat 30,000 298 to 1,000 (ferrous sulfate) 30 to 90

580 to >2,300 (ferrous fumarate) 13 to 50

Guinea pig 20,000 300 to 350 (ferrous sulfate) 57 to 67

263 to 350 (ferrous gluconate) 57 to 76

350 (ferric ammonium citrate) 57

2,000 (ferrous carbonate) 10

Dog >25,000 160 (ferrous sulfate) 156

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 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 sulfate) ..................................... 580–>2,300 (ferrous fumarate) ............................... 2 to 8

Guinea pig ...................... 263–350 (ferrous gluconate) ................................... 2,000 (ferrous carbonate) ....................................... 6 to 8

1 bid.

TABLE 4.—MEDIAN LETHAL DOSE (LD50) LEVELS REPORTED FROM ORAL EXPOSURE: SPECIES DIFFERENCES 1

Iron source Animal species

Oral LD50 (mg

Fe/kg body

weight)

Approximate

fold 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.
2234 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2235

8The comment did not provide information about

the nature of its reporting system, e.g., whether the

system was systematic.

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

(Number)

All iron

(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

1The data in the table reflect the data supplied in comment 150 to the iron proposal

under Docket No 93P–0306. 2See ref. 25 of this document.

3The patient developed no signs or symptoms as a result of the exposure. 4The 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. 5The 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. 6The patient exhibited signs or symptoms

as a result of the exposure which were lifethreatening 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 21⁄2-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.

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 ironcontaining products has resulted in four

moderate outcomes; and (3) there were

no reported exposures to carbonyl iron-
2236 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

9Of these seven brand-name products, three

contained 50 mg iron, two contained 65 mg iron,

and two contained 150 mg iron.

10The 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.

11The 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.

12The report did not provide a direct literature

citation for this statement, but included the study

by Shelanski (Ref. 11) in a bibliography.

13The 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.

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.

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 ironcontaining 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 lifethreatening.12

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.

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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2237

14The 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.

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.

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 21⁄2-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 nonionized 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
2238 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

15Many 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.

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.

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 ironcontaining 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 2239

16At 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.

17As 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.

18The 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).

19As discussed above, particle size is an

important factor in the rate of ionization, and thus

the potential toxicity, of elemental iron.

compliance with CPSC’s CRC

requirements, even in the presence of

warning statements, would be adequate

to ensure the safety of the use of ironcontaining 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 ironcontaining 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.

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 ironcontaining 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, §§ 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.
2240 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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

§ 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 PICcontaining 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 ironcontaining 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 PICcontaining 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 § 310.518(d)). If FDA

becomes aware of poisoning caused by

the ingestion of the inert, ironcontaining 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
2242 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

(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 ironcontaining 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 ironcontaining products are packaged in

bottles. Additional information

suggested that iron-containing products

administered in hospitals are commonly

packaged in unit-dose packaging. Unitdose 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 ironcontaining 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

× $4,000).

Several comments expressed concern

over the cost of equipment. One
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 ironcontaining 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 × $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 ×

$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 higherdosage 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 lifeyears 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
2244 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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 unitdose 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 ×

$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 ironcontaining 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
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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
2246 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

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 ironcontaining 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 ironcontaining 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 ironcontaining 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 ironcontaining product manufacturers, e.g.,

members of a particular trade

organization. Other sources collect

information at such an aggregated level

that the information specific to ironcontaining products cannot be separated

out. Therefore, it is either impossible or

impracticable to estimate the number of

small entities that produce ironcontaining 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 overthe-counter iron-containing

supplements through grocery stores and

cannot be considered as representative

of the entire industry. Many other ironcontaining 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 ironcontaining 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 ironcontaining 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 ironcontaining products (median = 5). A

total of 67 products were produced by

the large firms in the sample. On

average, large firms would experience
Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations 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 ironcontaining 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
2248 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

20Under 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.’’

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 ironcontaining 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 ironcontaining 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 ironcontaining 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.

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

§ 101.17 Food labeling warning and notice

statements.

* * * * *

(e) Dietary supplements containing

iron or iron salts. (1) The labeling of any

dietary supplement in solid oral dosage

form (e.g., tablets or capsules) that

contains iron or iron salts for use as an

iron source shall bear the following

statement:

WARNING: Accidental overdose of ironcontaining products is a leading cause of fatal

poisoning in children under 6. Keep this

product out of reach of children. In case of

accidental overdose, call a doctor or poison

control center immediately.

(2)(i) The warning statement required

by paragraph (e)(1) of this section shall

appear prominently and conspicuously

on the information panel of the

immediate container label.

(ii) If a product is packaged in unitdose 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 § 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).

§ 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
2250 Federal Register / Vol. 62, No. 10 / Wednesday, January 15, 1997 / Rules and Regulations

packaged in unit-dose packaging. ‘‘Unitdose 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). Ironcontaining 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 § 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 § 310.518 is added to subpart

E to read as follows:

§ 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 § 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 § 111.50(a) of this

chapter on or before July 15, 1998.

(c) Labeling. (1) The label of any drug

in solid oral dosage form (e.g., tablets or

capsules) that contains iron or iron salts

for use as an iron source shall bear the

following statement:

WARNING: Accidental overdose of ironcontaining products is a leading cause of fatal

poisoning in children under 6. Keep this

product out of reach of children. In case of

accidental overdose, call a doctor or poison

control center immediately.

(2)(i) The warning statement required

by paragraph (c)(1) of this section shall

appear prominently and conspicuously

on the information panel of the

immediate container label.

(ii) If a drug product is packaged in

unit-dose packaging, and if the

immediate container bears labeling but

not a label, the warning statement

required by paragraph (c)(1) of this

section shall appear prominently and

conspicuously on the immediate

container labeling in a way that

maximizes the likelihood that the

warning is intact until all of the dosage

units to which it applies are used.

(3) Where the immediate container is

not the retail package, the warning

statement required by paragraph (c)(1)

of this section shall also appear

prominently and conspicuously on the

information panel of the retail package

label.

(4) The warning statement shall

appear on any labeling that contains

warnings.

(5) The warning statement required by

paragraph (b)(1) of this section shall be

set off in a box by use of hairlines.

(d) The iron-containing inert tablets

supplied in monthly packages of oral

contraceptives are categorically exempt

from the requirements of paragraphs (a)

and (c) of this section.

Dated: October 24, 1996.

David A. Kessler,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 97–947 Filed 1–14–97; 8:45 am]

BILLING CODE 4160–01–P