36582 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 5, 25, 170, 171, and 174

(Docket Nos. 77P-0122 and 92N-0181]

Food Additives; Threshold of

Regulation for Substances Used in

Food-Contact Articles

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending its

food additive regulations to establish a

process for determining when the

likelihood or extent of migration to food

of a substance used in a food-contact

article is so trivial as not to require

regulation of the substance as a food

additive. Although still a "food

additive," a substance exempted from

regulation under this process will not be

required to be the subject of a food

additive listing regulation. Under this

process, information about the proposed

use of the substance will undergo an

abbreviated review by FDA, as opposed

to the extensive review normally

required for food additives. This final

rule also lists the criteria that FDA will

use in its revieq in deciding whether it

is necessary to regulate the use of a

substance as a food additive and

identifieg the types of data that it will

need to make this determination.

EFFECTIVE DATE: August 16, 1995.

FOR FURTHER INFORMATION CONTACT:

Edward J. Machuga, Center for Food

Safety and Applied Nutrition (HFS216), Food and Drug Administration,

200 C St. SW., Washington, DC 20204,

202-418-3085.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of October 12,

1993 (58 FR 52719), the agency

proposed to establish a process for

determining when the likelihood or

extent of migration to food of a

substance used in a food-contact article

is so trivial as not to require regulation

of the substance as a food additive. The

proposal was in response to a number

of comments from representatives of the

food packaging and processing

industries suggesting that FDA establish a threshold of regulation policy whereby

those substances used in food-contact

articles that result in minimal migration into food would be exempt from

regulation as food additives.

The proposal also responded to a

citizen petition (Docket No. 77P-0122)

submitted by the Society of the Plastics

Industry, Inc., requesting that FDA

modify § 170.3(e) (21 CFR 170.3(e)), the

regulation that defines "food additive,"

to provide that the use of a substance

that does not result in detectable levels

of migration into food-simulating

solvents (using validated analytical

methods sensitive to at least 50 parts per

billion (ppb)) would be exempt from

regulation as a food additive unless

there-is scientific evidence that the

substance presents a significant risk of

harm to human health.

Traditionally, FDA had been reluctant

to adopt any of these suggestions in the

absence of data that clearly show that

substances present in the daily diet at

concentrations at or below the proposed

threshold level would not pose safety

concerns. However, data on the toxic

effects of a large number of

representative compounds have become

available over the last 5 to 10 years that

have made it possible for FDA to

evaluate the feasibility of establishing a

threshold of regulation for food-contact

articles. These data show that

noncarcinogenic and carcinogenic toxic

effects usually occur within predictable

ranges of dietary exposure. They make

it possible to identify a specific level of

dietary exposure that is well below the

range of dietary exposures that typically

induce toxic effects and, therefore, that

poses only negligible safety concerns. This level can function as the

"threshold of regulation" for

components of food-contact articles.

A Federal court has addressed the

issue of whether the use of a foodcontact material that results in

migration into food at insignificant

levels can be exempted from regulation

as a food additive. In Monsanto v.

Kennedy, 613 F.2d 947 (D.C. Cir. 1979).

the Monsanto Co. contended that no

detectable migration of acrylonitrile

copolymer resulted from the use of their

beverage bottles that contained the

substance, and that, therefore, the

copolymer did not have to be regulated

as a food additive. In its decision, the

court stated that the Commissioner of

Food and Drugs (the Commissioner)

may determine that the level of

migration into food of a particular

substance is so negligible as to present

no public health or safety concerns and,

in such cases, -may decline to define the

substance as a food additive even

though it comes within the strictly

literal terms of the statutory definition

of a food additive (613 F.2d at 956). The

court also stated that the Commissioner

has the discretion not to exercise this

exemption authority (id.).

Based on available toxicological data

showing that it is feasible to establish a

threshold level below which dietary

exposures to substances used in foodcontact articles are so negligible as to

pose no public health or safety

concerns, the discretionary authority of

the Commissioner to exempt those

substances that present no public health

concerns from regulation as food

additives, and the agency's

consideration of the comments that it

received on the October 12, 1993,

proposal, FDA is amending the food

additive regulations to establish a

process for determining when the

likelihood or extent of migration to food

of a substance used in a food-contact

article is so trivial as not to require that

the substance be regulated as a food

additive.

As part of this process, the agency is

establishing two types of thresholds for

the regulation of substances used in

food-contact articles. The first type of

threshold will exempt from regulation

those substances whose use in foodcontact articles results in a dietary

concentration of the substance of 0.5

ppb or less. The second type of

threshold will exempt regulated direct

food additives from regulation when

used in food-contact articles at levels

that result in a dietary exposure of 1

percent or less of the acceptable daily

intake (ADI) for the additive.

I. Comments on the Proposed Rule

The agency provided 60 days for

comment on the proposed rule. It

received two requests from industry for

an extension of the comment period.

The agency granted a 60-day extension

of the comment period to February 11,

1994, in a notice published in the

Federal Register of December 13, 1993

(58 FR 65139).

FDA received 20 comments from the

food packaging industry and trade

associations that represent the plastics

and paper industries. One of these

comments concerned the economic

impact of the proposed action. This

comment is discussed in section IV of

this document. The other issues raised

in the comments, and the agency's

response to them, are set forth below.

A. The Exemption

Appropriateness of the 0.5 PPB

Threshold Level for Components of

Food-Contact Articles

1. Eight comments expressed the

opinion that the 0.5 ppb threshold is

more conservative and restrictive than is

necessary to adequately protect the

public health. In general, these

comments expressed the view that

current scientific data support the
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

establishment of a dietary concentration

higher than 0.5 ppb as the threshold.

The agency does not agree that a 0.5

ppb threshold is unduly conservative,

especially in light of the fact that a

substance being considered for an

exemption may not have been the

subject of any toxicological testing. As

discussed in the proposed rule,

carcinogenic toxic effects in test animals

typically occur at lower dietary

concentrations than the levels at which

noncarcinogenic toxic effects occur.

Therefore, FDA's goal has been to

establish a threshold that is low enough

to ensure that even if an unstudied

compound that is exempted from

regulation is later shown to be a

carcinogen, its use would not have

represented any more than a negligible

risk to the p ublic, health.

Although eight comments were

received that expressed the opinion that

the 0.5 ppb threshold is more

conservative and restrictive than is

necessary to adequately protect the

public health, no data were provided in

any of these comments to show that a

threshold significantly higher than 0.5

ppb is adequate to ensure that

substances present in the diet at or

below the threshold would pose only

negligible safety concerns. Therefore, as

proposed, this final rule establishes 0.5

ppb as the threshold of regulatory

concern for substances used in foodcontact articles. We will reconsider this

threshold if we receive new data that

justify a higher level.

2. One comment objected to the

agency's apparent use of a 200-fold

safety factor when applying to humans

the results of studies showing the

noncarcinogenic toxic effects observed

in animals subjected to chronic

chemical exposure. The comment stated

that FDA guidelines employ only a 100-

fold safety factor. The comment argued

that the use of the 100-fold safety factor

would allow FDA to establish a

threshold of regulatory concern higher

than 0.5 ppb.

The agency emphasizes that it did not

base its propo'sed threshold on

noncarcinogenic toxic endpoints, and

that, therefore, it did not employ the

safety factor approach typically used

when applying to humans the results of

studies showing the noncarcinogenic

toxic effects observed in animals

subjected to chronic chemical exposure.

Because carcinogenic effects typically

occur in test animals at lower dietary

concentrations than those at which

noncarcinogenic toxic effects occur, as

stated above, FDA's goal was to

establish a threshold that is low enough

to ensure that substances that are

exempted from regulation under it will

pose only negligible safety concerns

even if they are ultimately shown to

have carcinogenic effects.

Based on its analysis of the

carcinogenic potencies of 477

chemicals, and using the assumptions

that the distribution of carcinogenic

potencies of the 477 chemicals studied

are representative of all known and

unknown carcinogens, and that it is

very unlikely that an unstudied

compound would both: (1) Be a

carcinogen and (2) have an intrinsic

carcinogenic potency far greater than

the typical potency observed for the

studied compounds, FDA has

determined that, if an exempted

substance present in the diet at 0.5 ppb

were later found to be a carcinogen, the

upper-bound lifetime risk resulting from

the use of the substance is likely to be

below one in a million. This level of risk

is generally regarded as very low (i.e.,

one that poses only negligible safety

concerns). Because carcinogenic effects

typically occur at lower dietary

concentrations than those at which

noncarcinogenic toxic effects occur, an

0.5 ppb threshold would ensure that

substances that pass under it pose

negligible safety concerns from

noncarcinogenic toxic effects as well.

However, the fact that a 0.5 ppb

threshold level happens to be 200,

rather than a 100, times lower than the

chronic exposure level at which potent

pesticides induce noncarcinogenic toxic

effects is merely coincidental and does

not reflect the agency's reasoning.

3. One comment expressed the

opinion that the threshold should have

been based on the mean TD5 0

2 value of

the 477 known carcinogens that were

the subject of FDA analysis as opposed

to the most probable TD50 value. This

comment stated that the use of a mean

TDs0 would allow FDA to establish a

threshold significantly higher than 0.5

ppb.

FDA does not agree that it is

appropriate to establish a threshold

level based on the mean TD50 value of

the 477 known carcinogens that were

the subject of FDA's analysis because

this approach would give inappropriate

weight to carcinogens with high TDso

IThe agency typically uses a 100-fold safety

factor when applying to humans the results of

animal data obtained from long term exposure to a chemical (i.e., 2-year chronic feeding studies). Short

term toxicological testing (i.e., 90-day subchronic

feeding studies) may not always be long enough to

show all of the toxic effects that may be induced

by long term exposure to a chemical, and, therefore,

in such cases, FDA often uses higher safety factors

(lO00-fold to 2000-fold). 2 The TDse, for the purposes of this regulation, is

the feeding dose that causes cancer in 50 percent

of the test animals when corrected for tumors found

in control animals.

values. Because the carcinogenic

potency of a substance is inversely

related to its TD50 value, this approach

would give too much emphasis to

carcinogens with low potencies. A more

meaningful approach to estimating the

likelihood that a substance will pose a

potential health hazard at a given

dietary concentration is to use the

potency that it is most likely to have if

it were later found to be a carcinogen.

Because such an approach would be

based on the frequency distribution of

the potencies of a large number of '

carcinogens (i.e., a distribution showing

the number of carcinogens whose

potencies occur within particular

dietary-concentration ranges) and would

not be based on the magnitude of the

potencies themselves, this approach

would not give undue weight to

carcinogens with low potencies (i.e.,

high TDso values).

In arriving at a threshold of

regulation, FDA's analysis of the

potencies of 477 animal carcinogens

consisted in part of grouping them by

dietary concentration ranges (Ref. 1).

The agency plotted the potencies as a

probability distribution on a

semilogarithmic scale and found that

they formed a bell-shaped distribution

curve. Using this probability

distribution for carcinogenic potencies,

FDA determined that most known

carcinogens pose less than one in a

million upper-bound lifetime risk if

present in the daily diet at 0.5 ppb or

less.

4. One comment expressed the view

that it was unlikely that a given

packaging material wouldbe present in

the daily diet over the course of a

lifetime. It asserted that, therefore, FDA

should not have based its threshold on

potential lifetime carcinogenic risks.

Because of the changing technology

associated with the food-packaging

industry, FDA agrees that is not always

possible to predict whether a given type

of packaging material is likely to be

present in the daily diet over the course

of a lifetime. However, because many of

the substances considered for an

exemption from regulation will not have

been the subject of any toxicological

testing, it is imperative, in establishing

a threshold level, to use an approach

that is not likely to underestimate the

risk associated with the use of such

additives. Therefore, the agency used an

approach that assumed that a given

packaging material would be present in

the daily diet for an entire lifetime.

Lifetime upper-bound risks have

traditionally been used by FDA to assess

the overall safety of packaging materials

containing small amounts of

carcinogenic impurities, and the agency

36583
36584 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

believes that it is appropriate to use a

similar approach in assessing the

likelihood of potential carcinogenic

effects associated with substances

exempted from regulation. Based on its

analysis of the potencies of 477 known

carcinogens and the lifetime upperbound risks that they would pose if

present in the daily diet over a lifetime,

FDA has determined that a substance

present in the daily diet for a lifetime at

0.5 ppb would pose only negligible risk

even if it were later shown to be a

carcinogen. Because of the

conservatisms used by the agency in its

approach to determining a threshold

level, FDA is confident that an

exempted substance present in the daily

diet for a lifetime at 0.5 ppb would pose

no regulatory concern.

5. Four of the comments

recommended that FDA establish a

higher threshold for substances that

have been shown to be nonmutagenic or

to have relatively high LD50

3 values. For

example, one comment recommended

that for substances that have been

shown to be nonmutagenic and to have

LDso values greater than 2,000

milligrams per kilogram (mg/kg), the

threshold should be raised to 5 ppb. FDA agrees with these comments that

it may be possible to establish separate

thresholds for compounds that have

been the subject of toxicological tests

that show that they are nonmutagenic,

or that they have high LDso values.

However, a direct correlation will need

to be firmly established showing that

such compounds, if carcinogenic, are

likely to be less potent than those that

have been shown to be mutagenic or to

have lower LDso values. Such a

correlation would provide confirmation

that a substance that has been shown to

be nonmutagenic or to have a high LDso

value poses a significantly lower risk

from potential carcinogenic effects

when present in the daily diet at the

same level than one that has been

shown to be mutagenic or to have a low

LD5o value.

The correlation between mutagenicity

or acute toxicity and carcinogenic

potency is the subject of ongoing FDA

analysis. If the results of FDA's analysis

confirm that the likelihood that a

substance poses a significant risk from

potential carcinogenic effects is

significantly lower when that substance

has been shown to be nonmutagenic or

to have a high LD5o value, it may be

possible to establish a threshold for

such substances that is higher than 0.5

ppb but that still ensures that their use

3 The LD5o is the dose in acute feeding studies

that causes lethality in 50 percent of the test

animals.

in food-contact articles will pose only

negligible health concerns.

6. Three comments suggested that

FDA establish a higher threshold for

compounds that do not possess

structural concerns (i.e., that do not

possess structural similarities to known

carcinogens).

In general, the principle behind the

use of quantitative structure activity

relationships is that the analysis of the

toxicity of a large number of compounds

of known structure enables one to

predict the relative toxicity of unstudied

compounds based on the degree of

similarity in chemical structure to

studied compounds. While FDA may

use structure activity relationships to

ascertain whether there is a basis to

suspect that a substance is a carcinogen,

knowledge about such relationships is

not reliable enough at this time to justify

reliance on an analysis of them to

establish a higher threshold of

regulation for some compounds. The

comments did not submit any evidence

to support a contrary conclusion.

7. Three comments recommended that

the threshold be raised for compounds

that have been shown to be

noncarcinogenic. For example, one

comment recommended that the

threshold be raised to 100 ppb for

substances that have been shown to be

negative in 2-year bioassays.

FDA agrees that it may be possible in

the future to establish a threshold higher

than 0.5 ppb for substances that have

been shown to be noncarcinogenic

based on results obtained from

appropriate 2-year bioassays. As

discussed above, carcinogenic effects in

test animals typically occur at lower

dietary concentrations than do

noncarcinogenic toxic effects. Therefore,

FDA proposed to establish 0.5 ppb as

the dietary concentration threshold

because this level is low enough to

preclude the likelihood of all but

negligible risk even if an unstudied

compound is later shown to be a

carcinogen. In the case of

noncarcinogens, however, the threshold

of regulation could be based solely on

the level at, and below which,

noncarcinogenic toxic effects are

unlikely to occur. As stated in the proposed rule (58 FR

52719 at 52722), FDA's analysis of the

data on 18,000 acute oral feeding

studies in rats and mice found that all

of the acute toxic effects occurred above

1,000 ppb. The results of 2-year chronic

oral feeding studies on 220 compounds

have shown that only 5 of the 220

chemicals exhibited toxic effects below

1,000 ppb, and that all 5 of these

chemicals were pesticides, compounds

that are expected to be more toxic than

most substances. Even for these five

pesticides, none exhibited toxic effects

at dietary concentrations below 100

ppb. These results suggest that it may be

feasible to establish a separate threshold

for substances that have been

appropriately tested and found not to be

carcinogens. Such a threshold would

likely be well below the level at which

noncarcinogenic toxic effects are likely

to occur but higher than the 0.5 ppb

threshold that FDA is establishing to

minimize the risk from potential

carcinogens. FDA is not establishing a

separate threshold for noncarcinogenic

substances at this time, however,

because the number of chemicals,

particularly pesticides, that have been'

analyzed is not sufficient to ensure that

the results of this analysis are

representative of substances used in the

manufacture of food-contact articles. An

analysis of the dietary concentrations at

which a large number and a wide

variety of potent toxicants, such as

pesticides, exhibit noncarcinogenic

toxic effects is needed before FDA can

determine whether establishment of a

threshold significantly higher than 0.5

ppb for noncarcinogenic substances is

justified.

Appropriateness of the 1-Percent ADI

Threshold for Regulated Direct

Additives

8. One comment recommended that

once the final rule has been established,

and the policy has been put into

practice for a time, FDA should reassess

the 1 percent of the ADI threshold for

regulated direct food additives used in

food-contact articles to see whether this

threshold can be raised.

As stated in the proposal, a 1-percent

ADI threshold for regulated direct food

additives used in food-contact articles is

appropriate because this level of dietary

exposure will contribute only a small

fraction of the ADI of a substance and,

therefore, will be well within the margin

of safety for those direct food additives

with small cumulative dietary

exposures. For substances with high

cumulative dietary exposures resulting

from regulated direct food additive uses,

a level of exposure that is 1 percent of

the ADI would be within the margin of

error for the estimated daily intake. It

would, therefore, not significantly affect

the cumulative dietary exposure, even

in the event that a particular substance

is granted exemptions for several

different types of uses in food-contact

articles.

The agency would like to emphasize

that no comments were received that

expressed any safety concern about the

1 percent of the ADI threshold. As for

raising this threshold above the 1-
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

percent ADI level, FDA's main concern

is with those cases in which a particular

substance may be granted exemptions

for a number of different types of new

uses, each of which results in a dietary

exposure at or near the threshold level.

In such cases, the dietary exposure

resulting from all of the exempted uses

could represent a significant increase in

the cumulative dietary exposure for the

substance and, in cases where the

estimated dietary intake from currently

regulated uses is close to the ADI, may

not be supported by existing safety data.

It is possible, however, that once the

threshold of regulation process is put

into practice, other factors will surface

that mitigate the agency's concerns on

this issue. If the latter situation proves

to be the case, the agen cy may find it

appropriate to reassess the 1 percent of

the ADI threshold for regulated direct

food additives used in food-contact

articles.

9. One comment recommended that

FDA publish or otherwise make

available the ADI's for currently

regulated direct food additives. In cases

where such ADI's are not readily

available, FDA should consider other

sources (e.g., the European Union's

Scientific Committee for Foods) or

provide guidelines for the calculation of

appropriate ADI's.

FDA agrees that the ADI's for

currently regulated direct food additives

should be made more readily available.

Therefore, FDA plans to incorporate this

information into its priority based

assessment of food additives (PAFA)

data base and make this data base

accessible to the public (Ref. 2). In the

meantime, requestors can obtain this

type of information on a specific

substance by submitting a written

request to FDA's Office of Premarket

Approval (HFS-200, 200 C St. SW.,

Washington, DC 20204). In some cases,

especially for those uses of direct

additives that result in low dietary

exposures such as flavoring agents, FDA

may not have an ADI in its files.

Therefore, in those relatively few cases

where FDA does not have an

appropriate ADI for a regulated direct

food additive, the agency would

consider the use of an ADI value from

another appropriate source, such as the

Joint World Health Organization/Food

and Agriculture Organization (WHO/

FAO), Expert Committee on Food

Additives, or the European Union's

Scientific Committee for Foods,

assuming that the data or other

information on which that ADI value is

based are also available. FDA is revising

proposed § 170.39(a)(2)(ii) to state that

FDA may use other appropriate sources

for ADI values.

FDA disagrees with the comment's

suggestion that the agency provide

guidelines for the calculation of

appropriate ADI's for review under the

process specified in this final rule.

Regulated direct food additives for

which an appropriate ADI does not exist

are not suitable candidates for an

abbreviated review under the threshold

of regulation process. This process is

not appropriate for reviewing

submissions containing detailed toxicity

studies on a substance for the purpose

of calculating an ADI value or for

verifying an ADI value calculated by the

requestor. Such extensive reviews are

better handled by the food additive

petition process. 10. One comment recommended that

FDA expand the proposed threshold of

regulation process for regulated direct

food additives to include exemptions for

direct uses in food, provided the dietary

exposures from such uses do not exceed

1 percent of the ADI. The proposed rule

limited such exemptions to only those

uses that may result in their indirectly

becoming components of food (i.e.,

resulting from their use in food-contact

articles).

FDA does not agree that the final rule

should be expanded in this manner.

There is a fundamental difference in

regulatory significance between

substances that are deliberately added

directly to food to accomplish a

technical effect in the food and

substances that are used in food-contact

articles in a manner such that they may

reasonably be expected to become

components of food indirectly and to

have no technical effect in that food.

The purpose of the food additive

provisions of the act is to ensure that

substances added to food are safe and

will have their intended technical effect

in the food that is to be consumed (S.

Rept. 2422, 85th Cong., August 18,

1958). Thus, given this purpose, there

simply would not be circumstances in

which a dirbct additive would be of

such little regulatory concern as to

justify application to it of the de

minimis 4 doctrine that underlies the

threshold of regulation concept (see

Monsanto v. Kennedy, supra). For

indirect food additives, in contrast, the

substance is being used for its technical

effect in a food-contact article, not in an

article that will itself be consumed.

Moreover, on occasion, it is

foreseeable that, while the exact amount

of an indirect additive that will get into

food is unclear, it will not exceed an

extremely small amount. It is in the

4This doctrine is expressed in Latin as de

minimis non curat lex (the law does not concern

itself with trifles).

latter circumstances that it is fair to say

that, given the purposes of the Federal

Food, Drug, and Cosmetic Act (the act),

the use of the substance is of no

significant regulatory concern, and thus

the use can be exempted from regulation

under the food additive provisions of

the act. In light of the purposes of the

food additive provisions, however, FDA

concludes that it is not appropriate to

extend the threshold of regulation

concept to substances intended for

direct use in food.

11. One comment expressed the

opinion that the proposed regulation is

unduly restrictive for the use of

regulated direct food additives in foodcontact articles when the direct additive

does not have any specific use level

restrictions. An example of the type of

situation raised by the comment would

be flavoring agents where the level of

their use in food would be self limiting

(i.e., use at high levels would make the

food unpalatable, and, therefore, FDA

did not find it necessary to impose,

specific maximum use levels as part of

the regulations authorizing the use of

such substances). The comment

emphasized that, because of the time

required to obtain FDA approval (as a

result of FDA's current backlog of work),

the consumer's access to new packaging

technologies is often delayed. Not

requiring premarket approval of such

substances would save FDA resources,

reduce the backlog of work, and enable

the consumer to have quicker access to

new packaging formulations.

The comment argued that, based on

the extremely small levels of dietary

exposure that would result from the use

of direct additives in food-contact

articles, particularly in comparison to

the levels of exposure that result from

the direct uses of these substances, and

based on the fact that direct food

additives have been the subject of

extensive safety testing, FDA should

modify §.174,5(d) (21 CFR 174.5(d)) to

allow those direct food additives that

are regulated without specific use level

limitations to be used as components of

food-contact articles. The comment

asserted, however, that four restrictions

on such use were appropriate: (1) The

use of the substance in a food-contact

article must not result in a dietary

exposure that exceeds 1 percent of the

ADI for that substance; (2) the use level

must not exceed good manufacturing

practice (GMP) or that necessary to

accomplish the intended technical

effect; (3) the substance must be of a

purity suitable for the intended use; and

(4) the technical effect for such

additives must be as a formulation aid

or some other technical effect for which

the substance has been listed as a direct

36585
36586 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

food.additive (e.g., a substance

approved for use as a stabilizer and

thickener in food would be allowed to

be used as a stabilizer and thickener in

the manufacture of food-contact

articles). The comment cited FDA's

approach to handling generally

recognized as safe (GRAS) substances as

a precedent for this approach. Under 21

CFR 186.1(a), ingredients affirmed as

GRAS for direct use in part 184 (21 CFR

part 184) are also affirmed as GRAS for

use as indirect human food ingredients

in accordance with § 184.1(a).

The agency notes that the issue raised

by this comment is outside the scope of

the proposed threshold of regulation

process. The comment is about whether

the uses in question should be approved

as food additive uses, not about whether

they should be exempted from

regulation under the food additive

provisions of the act.

Although outside the scope of this

rulemaking, FDA would like to

comment on the merits of the approach

recommended in this comment because

the agency is always interested in

evaluating ways that may help it to

more effectively implement the food

additive provisions of the act. FDA's

main concern with the recommended

approach is that those direct food

additives that are regulated without

specific use level limitations, and which

meet the other restrictions specified in

this comment, could be used as

components of food-contact articles

without any further safety review by

FDA. Although it is true that the dietary

exposure resulting from the use of a

substance added directly to food is

usually much higher than that resulting

from the use of that substance as a

component of a food-contact article, the

existing safety data in FDA files used to

support the direct additive use may not

always be adequate to support even a

modest increase in the dietary exposure

resulting from its use as an indirect food

additive.

Some direct food additives have been

regulated for uses in which only a

narrow margin exists between the

cumulative estimated dietary exposure

and the acceptable dietary exposure.

Many other direct additives have been

regulated for uses for which, initially,

the margin between the estimated daily

intake and the ADI was reasonably

broad, but as the substance has been

subsequently regulated for other uses,

the margin has become quite narrow.

Because existing safety data may not be

adequate to support the use of direct

additives as components of food-contact

articles in all cases, such uses must be

evaluated on a case by case basis, either

as the subject of a food additive petition

(if the dietary exposure is likely to be

greater than 1 percent of the ADI) or as

a request for an exemption from

regulation (if the dietary exposure is

likely to be below the 1-percent ADI

threshold of regulatory concern). . Another agency concern with the

recommended approach is that some of

the direct food additives may also have

been regulated at a time when FDA did

not conduct reviews on the possible

environmental effects resulting from

such uses. (FDA regulations for

considering the environmental effect of

its actions in accordance with the

National Environmental Policy Act

(NEPA) were established on March 15,

1973.) It may be possible that the

manufacture, use, and disposal of foodcontact articles containing regulated

direct food additives may have an

adverse impact on the environment.

Therefore, the potential environmental

effects resulting from the intended use

of a direct food additive in a foodcontact article need to be evaluated by

FDA either as part of a review of a

petition or as part of a review of an

exemption from regulation request.

Further discussion of this issue is found

later in this final rule in the agency's

response to comments 28 and 29.

For the reasons listed above, FDA has

concluded that the use of a regulated

direct food additive in a food-contact

article should either be the subject of a

specific food additive regulation

authorizing such use or be exempted

from regulation as a food additive by

FDA under the procedures specified in

this final rule. Application of the Food

Additive Definition

12. Two comments expressed the

opinion that the Monsanto decision

gives FDA the flexibility to consider

those substances migrating out of foodcontact articles in trivial amounts not to

be food additives. These comments

went on to say that the Delaney Clause

(section 409(c)(3)(A) of the act (21

U.S.C. 348(c)(3)(A)), which prohibits the

use of known carcinogens as food

additives, would therefore not apply. FDA disagrees with the comments. It

is true that Monsanto stated that the

Commissioner has discretion to

implement the statutory scheme

established by the Food Additives

Amendment, and that this discretion

includes the option of declining to

define a substance as a food additive

(613 F.2d at 956). However, the court

also said that the Commissioner's

discretion is limited (id.). The

Commissioner's exercise of discretion

must be consistent with the statutory

scheme. He cannot exercise his

discretion to vitiate that scheme. Under

the Food Additives Amendment, a

carcinogenic additive is deemed to be

unsafe, no matter how low the exposure

to the additive or how low the risk from

the additive (see Public Citizen v.

Young, 831 F.2d 1W8, 1122 (D.C. Cir.

1987), cert. denied, 485 U.S. 1006

(1988)). Given these facts, FDA has

formulated the threshold of regulation

regime to exempt substances from

regulation as food additives based on

the level of dietary exposure but has

conditioned that exemption on such

substances not having been shown to be

carcinogens. No other approach would

be consistent with the act.

13. Three comments recommended

that FDA clarify whether companies can

make their own threshold of regulation

determinations. The comments stated

that, in those cases where the use of the

substance meets the definition of a

"food additive" in section 201(s) of the

act (21 U.S.C. 321(s)), individual

manufacturers should be able to make

their own determination as to whether

the use of a substance in a food-contact

article meets the criteria for an

exemption from regulation. One of the

comments requested that the agency's

position on this issue be explicitly

stated in the final regulations. According to Monsanto, only the

Commissioner has the statutory

authority to exempt a substance from

regulation as a food additive. A

substance that meets the definition of a

food additive in section 201(s) of the act

must, therefore, either be the subject of

a regulation authorizing its use or be

exempted from regulation by FDA under

the process specified in new § 170.39,

unless the use of the substance

conforms to an exemption for

investigational use issued under section

409(i) of the act.

From a policy standpoint, the

procedure outlined in this final rule,

whereby FDA makes all exemption

decisions, offers a number of advantages

over an approach that allows individual

manufacturers to make their own

threshold of regulation decisions. One

advantage is that the agency's

determination as to whether a substance

used in a food-contact article meets the

criteria for an exemption from

regulation as a food additive will be

binding on the agency. Thus,

manufacturers of food-contact articles

will be able to rely on these

determinations and market their

products without fear of regulatory

action.

This approach also will result in more

consistent decisions. Qualified experts

may disagree on what specific

assumptions are appropriate for

estimating the dietary concentrations

resulting from the use of substances in
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

food-contact articles. Thus, allowing

individual manufacturers to make their

own determinations would increase the

likelihood of inconsistent decisions.

For example, in cases where there is

no detectable migration into food or

food simulants, or when no residual

level of a substance is detected in the

food-contact article by a suitable

analytical method, the validated

detection limit of the method used to

analyze for the substance would need to

be considered in order to estimate the

dietary concentration from the intended

use. Qualified experts may disagree not

only on the specific numeric value for

this detection limit but also on what

percentage of the detection limit should

be used in such situations to estimate

actual migration (e.g., 100 percent versus 50 percent). Qualified experts

may also disagree on the appropriate

consumption factor to use in estimating

dietary concentrations. Different

conclusions on the environmental

effects resulting from the use of a foodcontact article may also arise from such

independent determinations. The

agency believes that having all such

exemption decisions made by a review

team consisting of a small number of

agency personnel will help lessen the

likelihood of inconsistent decisions on

these matters.

Having such determinations made by

FDA will also mean that the agency will

have more complete information on

what materials industry is actually

using in food-contact articles. As a

result, FDA will be able to make more

informed decisions in the event that

data become available that raise

significant concerns about whether the

continued use of a component of a foodcontact article is safe.

Although only the Commissioner of

FDA has the statutory authority to

exempt a substance from regulation as a

food additive in those cases where the

use of the substance meets the "food

additive" definition in section 201(s) of

the act, FDA emphasizes that nothing in

this final rule limits the use of a

substance exempted by FDA from

regulation to only the manufacturer who

submitted the request for an exemption.

Other manufacturers may use exempted

substances in food-contact articles as

long as the conditions of use (e.g., use

levels, temperature, type of food

contacted, etc.) are those for which the

exemption was issued.

Consistent with this fact, FDA plans

to give general notice by means of the'

Federal Register, should it ever decide

to revoke an exemption. The notice will

state that continued use of such a

substance would constitute the use of an

unapproved food additive, unless a

petition is filed, and the substance is

listed for use in FDA's regulations. It

will also set out the reasons for FDA's

decision to revoke the exemption,

thereby providing manufacturers with

the opportunity to submit relevant data

to the agency and to request that the

exemption be reinstated.

FDA does not believe, however, that

it would be practical to routinely

provide notice in the Federal Register of

its intent to revoke an exemption. Such

a process would only unduly delay and

burden the revocation process. It would

be inconsistent with the intent of the

threshold of regulation process to

minimize the use of agency and

industry resources for those substances

whose use in food-contact articles poses

only negligible safety concerns.

Accordingly, FDA is revising § 170.39(g)

to make clear that the agency plans to

provide notice in the Federal Register

after it has decided to revoke an

exemption issued for a specific use of a

substance in a food contact article.

FDA has decided, however, not to

include in § 170.39 a statement that only

the Commissioner can make threshold

of regulation determinations. It is not

the agency's usual practice to enumerate

in its regulations those regulatory

decisions that are reserved to the

agency. Therefore, the agency is not

doing so here.

Scope of the Exemption

14. Two comments recommended that

FDA expand its proposed threshold of

regulation to enable the agency to

exempt entire classes of compounds.

Under the scheme suggested by these

comments, FDA would review one or

more compounds within a given class,

and, if it determined that these

individual chemicals qualified for an

exemption, the agency would exempt all

of the chemicals within the class. One

of these comments expressed the yiew

that many manufacturers do not use

their proprietary chemicals for foodcontact applications because of FDA's

requirement that they be regulated

based on their chemical identity, and

that the use of such an approach would

remove impediments that stifle

innovation in the food industry.

FDA disagrees with this approach for

a number of reasons. Because the level

of migration, and resulting dietary

concentration, of the chemical depend

on both its molecular weight and

chemical properties, it would be

impossible to predict whether the use of

all compounds within a class would

result in dietary concentrations below

the threshold based on the migration

properties of just one or two sample

chemicals. For example, polymeric

materials manufactured from the same

monomer but having significantly

different molecular weights would

belong to the same class of chemicals

but would be expected to have different

migration properties. Similarly, the

intrinsic toxic potencies for chemicals

within a certain class may vary

significantly. For example, the

polychlorinated dibenzo-p-dioxins are a

class of 75 congeners that exhibits a

wide range of toxicity depending on the

degree of chlorination and the location

of the chlorine atoms within the

chemical structure. As a result, the

likelihood that a substance poses a

health hazard is not necessarily

determinable based on the information

about the toxicity of other chemicals

that are in the same class. In addition,

it would be difficult to predict the

environmental impact that would result

from the manufacture, use, and disposal

of all substances within a class based on

the impact of one or two chemicals.

Therefore, FDA does not believe that it

is possible, based on the review of one

or more compounds within a given

class, to justify an exemption for all

other chemicals belonging to the same

class.

For the foregoing reasons and because

the dietary concentration of a specific

chemical is dependent on the

conditions of its use (e.g., type of use,

temperature, food type, and contact

time), FDA concludes that to adequately

safeguard the public health, it is

necessary to limit exemptions under

§ 170.39 to those conditions of use of a

chemical that it has evaluated.

15. One comment recommended that

rather than require a submission for

each chemical and each proposed use,

FDA should publish guidelines based

on categories of uses that would provide

performance standards that could be

used by manufacturers to guide

customers on how to stay below the

threshold exposure. As discussed earlier, the dietary

concentration resulting from the use of

a substance in a food-contact article may

vary considerably depending on the

type of use and the conditions of use.

Therefore, it would not be feasible to

establish guidelines for use with respect

to all possible food-contact articles

under all possible conditions.

Interpretation of such complicated

guidelines by individual manufacturers

and customers would inevitably lead to

confusion and inconsistencies.

The process specified in this final

rule, as part of which a small team of

agency personnel will review each

request for an exemption, will result in

more consistent decisions. Having all

such determinations made by FDA

36587
36588 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

using the process specified in the final

rule should also result in the agency

having more complete information on

what substances are being used in foodcontact articles. This information will

permit the agency to take action in the

event that data become available that

raise significant questions as to whether

the continued use of a substance in a

food-contact article is safe.

16. One comment stated that the 0.5

ppb threshold was too low for the use

of pigments in food-contact articles

because such pigments are less toxic

than other chemicals. Because these

pigments are relatively insoluble, they

would also have lower bioavailability. FDA does not believe that it is feasible

to establish specific thresholds of

regulation for each of the many types of

chemicals used in food-contact articles.

Such an approach, with many different

thresholds, would be cumbersome.

Moreover, as discussed in a previous

comment, the toxicological properties of

chemicals within a class can vary

greatly. Therefore, it would be

extremely difficult to establish a single

threshold for all the chemicals within a

given class. Because of this difficulty,

FDA is not taking any action in response

to this comment.

The agency believes that it may be

feasible in the future to establish a

higher threshold based on a substance's

toxicological properties rather than

based on its type or on the class of

chemicals to which it belongs. For

example, as discussed in a previous

comment, it may be possible in the

future to establish separate thresholds

for substances that either have been

shown to be noncarcinogenic by

appropriate 2-year bioassays or, based

on the results of short-term toxicity

testing (e.g., mutagenicity and acute oral

feeding studies), are likely to have a low

carcinogenic potency if they are, in fact,

carcinogenic. 17. One comment requested that FDA

specifically address whether biocides . would be eligible for consideration

under the threshold of regulation

regime. Because such substances must

be registered with the Environmental

Protection Agency (EPA) in accordance

with the Federal Insecticide, Fungicide

and Rodenticide Act (FIFRA) (7 U.S.C.

136 et al), and must undergo an

extensive review for safety and efficacy,

the comment stated that biocides are

well suited for an abbreviated review

under FDA's threshold of regulation

process.

As long as the criteria specified in this

final rule are met, FDA will grant

exemptions from regulation as food

additives for biocides that become

components of food-contact articles.

18. Two comments requested that

FDA clarify how the presence of a

"barrier" (one that would limit the

migration of a packaging substance into

food) would be factored into threshold

of regulation decisions. In particular,

the comment asked whether, in cases

where there is a functional barrier, and

no migration can be detected, FDA

would still consider the validated

detection limit of the method used to

analyze for the substance in its dietary

exposure estimate.

The key factor in FDA's decision to

grant an exemption from regulation for

a substance used in a food-contact

article is whether the dietary

concentration of the substance resulting

from its use is below the threshold.

Thus, if the presence of a functional

barrier limits the migration of the

substance into food such that the

resulting dietary concentration is below

the threshold, FDA will grant an

exemption for the intended use of that

substance, provided that the other

criteria specified in this final rule are

met.

In most cases, the effectiveness of a

material to act as a barrier to migration

will depend not only on the physical

and chemical properties of the barrier

material and the potential migrant but

also on the thickness of the barrier layer

and the conditions of use (e.g.,

temperature, food type, contact time).

Therefore, it is usually not possible to

draw any conclusions regarding the

effectiveness of a barrier material in the

absence of migration data. In such cases,

requests for exemptions from the food

additive regulations would need to

contain data showing that the barrier

material precludes all but minimal

migration of the substance into food

(i.e., the resulting dietary concentration

is at or below the threshold). FDA will

consider the validated detection limit of

the method used to analyze for the

substance in arriving at its dietary

exposure estimate.

There are a number of specific

situations, however, where FDA would

not require data to show that a barrier

material precludes all but minimal

migration of the substance into food. For

example, some packaging materials such

as aluminum foil, when used as the

inner layer of laminates, have been

generally recognized as being able to

provide an effective barrier to migration

of the outer layer components into food

under a variety of conditions. In such

cases, it would not be necessary for the

requestor to carry out and submit

extraction studies designed to show the

effectiveness of the barrier layer.

Another example involves those cases

in which FDA has reviewed the barrier

material and has established specific

conditions under which the material

would indeed function as a barrier. In

these cases, the agency will be able to

make decisions on similar constructions

in the absence of any additional

extraction studies, as long as the

conditions of use do not differ

significantly from those the agency

reviewed.

19. One comment inquired as to

whether the final rule establishing a

threshold of regulation for substances

used in food-contact articles will be

applicable to regulated direct animal

feed additives that are intended to be

used as components of articles that may

contact animal feed (i.e., indirect animal

feed additives). This final rule will allow those

substances exempted under § 170.39 to

be used in articles contacting animal

feed as long as the intended conditions

of use of the substance are those for

which the exemption was issued. This

result follows from §§ 174.6 and

§ 570.14 (21 CFR 570.14) of FDA's

regulations. Under § 174.6 Threshold of

regulation for substances used in foodcontact articles, FDA will exempt

substances from regulation as food

additives whose use ii food-contact

articles meet the criteria in § 170.39.

Authority to, use substances exempted

under § 174.6 in articles contacting

animal feed is set out in § 570.14

In direct food additives resulting from

packaging materials for animal feed and

pet food, which states that the

regulations providing for the use of

food-packaging materials in parts 174

through 179 (21 CFR parts 174 through

179) are applicable to packaging

materials used in animal feed and pet

food.

Moreover, in cases where the

exemption request concerns the use of

a substance in an article that is used

only in contact with animal feed, the

criteria used by FDA to determine

whether an exemption from regulation

is warranted will be those specified in

new § 170.39. Because § 570.14 contains

a cross-reference that includes § 174.6,

in accordance with that provision, FDA

can review a request for exemption of a

substance used only in contact with

animal feed under § 170.39.

Sections 170.39, 174.6, and 570.14,

however, will not provide for the use in

articles contacting animal feed, at a

level that is 1 percent or less of their

ADI, of substances that are currently

regulated for direct use in animal feed

in part 573 (21 CFR part 573). To

provide for such a review, FDA will

have to adopt a regulation similar to

§ 170.39 that applies to direct animal

feed additives that have not been
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

regulated for direct addition to human

food. However, such a regulation is

outside the scope of this rulemaking and

would require a separate proceeding.

Application of the Exemption

20. One comment inquired whether

exempted substances may be used in

contact with all types of food.

Because the dietary concentration

resulting from the use of a substance in

a food-contact article is dependent on

the type of food with which it comes in

contact, the use of a substance in an

article contacting one type of food may

result in a dietary concentration below

the threshold, while the use of the same

material in contact with another type of

food may not. Therefore, FDA will limit

exemptions to those conditions of use

warranted by the available data.

B. The Regulation

21. One comment recommended that

FDA revise the language in

§ 170.39(a)(1) to make clear whether the

phrase "there is no reason, based on the

chemical structure of the substance, to

suspect that the substance is a

carcinogen" refers to impurities within

the substance or the substance itself.

FDA agrees with this comment and is

revising proposed § 170.39(a)(1) to make

it clear that the phrase "there is no

reason, based on the chemical structure

of the substance, to suspect that the

substance is a carcinogen" refers only to

the substance itself.

22. One comment recommended that

FDA revise the language in proposed

§ 170.39(c)(1) to make clear that the

description of the chemical composition

of the substance for which the request

is made should include, whenever

possible, the name of the chemical in

accordance with current chemical

abstracts service (CAS) nomenclature

guidelines and a CAS registry number if

available.

FDA agrees with this comment and

has revised proposed § 170.39(c)(1)

accordingly. 23. One comment recommended that

the word "substance" in proposed

§ 170.39(c)(4)(ii) and (c)(4)(iii) should

refer to the singular case for

consistency.. FDA agrees and has made the changes

that respond to this comment in this

final rule.

24. One comment recommended that

the regulation define in detail the types

of information required by FDA in

submissions requesting exemptions

from the food additive regulations.

FDA agrees that a detailed description

of the information that needs to be

included in a request for an exemption

should be readily available to interested

parties. However, FDA does not believe

that it is necessary or appropriate to

include this information in the Code of

Federal Regulations (CFR). The agency

considers it appropriate to make this

information available in a manner

similar to that which FDA uses with

respect to the contents of food additive

petitions. For food additive petitions,

FDA generally describes the information

that must be submitted in part 171 (21

CFR part 171) of its regulations and

maintains more detailed guidelines that

are available from the agency upon

request. While FDA publishes

modifications in the CFR only annually,

it can modify guidelines whenever

necessary, thereby providing requestors

with up-to-date guidance. This

flexibility in modifying detailed

guidelines is needed to take into

account ongoing advances in the

development of food-contact articles

and in the methodologies used to

quantify migration of components of

such aticles into food.

Therefore, FDA is adding § 170.39(h),

which states that guidelines to assist

requestors in the preparation of

submissions seeking exemptions from

the food additive regulations are

available from FDA's Office of

Premarket Approval (HFS-200), 200 C

St. SW., Washington, DC 20204.

Because it is not practical to provide

guidelines that would cover all of the

possible topics associated with these

types of submissions, this final rule

encourages interested parties to obtain

specific guidance from FDA on the

protocols to use in obtaining extraction

data, on the validation of the analytical

methods used to quantify migration

levels, on the procedures to use to relate

migration data to dietary exposures, and

on any other issue not specifically

covered in FDA's guidelines.

FDA formerly proposed to announce

the availability of guidelines in

§ 170.39(c)(4)(v) because the guidelines

were meant to focus on questions

associated with the dietary

concentration resulting from the

intended use of a substance in a foodcontact article. However, the agency

believes it is more appropriate to

include such language as part of

§ 170.39(h) to emphasize that interested

parties may seek guidance on any issue

involving exemption requests.

Therefore, FDA is revising § 170.39 to

include this provision and has deleted

proposed § 170.39(c)(4)(v).

C. Procedural Issues

Obtaining an Exemption

25. One comment commended FDA

for its statement in the preamble that

manufacturers may make their own

determination as to whether the use of

a substance in a food-contact article

meets the "food additive" definition in

section 201(s) of the act and

recommended that FDA explicitly state

this fact in the final regulation.

In response to this comment, FDA

would like to reaffirm its position that

nothing in the regulatory scheme

presented in this rule would prevent a

company from making its own

determination that a particular use of a

substance does not meet the definition

of a "food additive" in section 201(s) of

the act. However, as noted in the

proposal, companies make such

determinations at their own risk. If the

agency learns of the use of a substance

from, for example, a competitor and

reaches a different conclusion than the

company, the agency may take

regulatory action against the substance

as an unsafe food additive or against the

company that makes the substance for

introducing an adulterated food injo

interstate commerce. Therefore, in cases

where it is not clear whether the use of

a food-contact article meets the "food

additive" definition, FDA recommends

that manufacturers seek a determination

under the procedures specified in this

rule to avoid the possibility of

regulatory action.

FDA does not believe, however, that

it is appropriate to address this issue in

the regulation. The issue raised by the

comment applies generally to FDA's

application of the "food additive"

definition in section 201(s) of the act.

This rulemaking concerns only the

threshold of regulation process.

Therefore, the question of whether, and

how, to incorporate into FDA's

regulations the statement that the

comment seeks is outside the scope of

this rulemaking. 26. Seven comments recommended

that the agency establish a time limit for

reviewing and responding to requests

for exemptions from regulation as food

additives to ensure timely responses.

Two of the comments suggested specific

time limits of 60 and 90 days. The agency agrees that such reviews

should be carried out in a timely

manner. Timely review will mean that

manufacturers and suppliers of

substances that are exempted from

regulation as food additives will be able

to market their products much more

quickly than has been the case. Timely

review will also mean that

manufacturers and suppliers of

substances that are not exempted will

receive prompt notice of the need to file

a food additive petition. A pilot study carried out by FDA

showed that such reviews can usually

36589
36590 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

be completed within 3 to 4 months as

compared to the 1 to 2 years typically

required for indirect food additive

petitions. The agency is concerned,

however, that establishing a formal time

limit for completion of such reviews

will unduly restrict its ability to allocate

its limited resources to projects that may

be more critical. Therefore, the agency

has decided not to establish a time limit

for reviewing and responding to

requests for exemptions from regulation

as food additives at this time. As the

agency gains experience with its

threshold of regulation policy, it will

consider establishing an appropriate

time limit. In the interim, however, the

agency is committed to reviewing

exemption requests as expeditiously as

resources allow.

27. One comment recommended that

there be a phase-in process that would

allow companies to carefully evaluate

products that are on the market and to

obtain exemption determinations where,

and if, required.

As discussed previously" if the use of

a substance results in, or is reasonably

expected to result in, migration into

food, even at low levels, and is not

specifically excluded from the

definition of a "food additive" in

section 201(s) of the act, then thesubstance is a food additive that must

either be the subject of a regulation

authorizing its use or be exempted from

regulation by FDA under the process

specified in this rule. However, if the

use of a substance in a food-contact

article currently on the market involves

low levels of migration into food (i.e.,

results in a dietary concentration at or

below the threshold of regulatory

concern), and is the subject of a request

for an exemption under the process

specified by this final rule, it is unlikely

that FDA would take regulatory action

during the time needed by the agency to

complete its review. Therefore, the

agency does not believe it is necessary

to establish a phase-in program to allow

companies to evaluate food-contact

articles currently on the market.

28. One comment recommended that

§ 170.39 be revised to include an

abbreviated review (i.e., one that does

not require a review of environmental

impact data and toxicological feeding

study data) for those exemption requests

that deal only with new uses of

regulated indirect food additives that

involve the same manufacturing process

but a different technical effect (e.g., a

substance currently regulated as a

defoamer in the manufacture of paper

and paperboard under § 176.170 that is

the subject of an exemption request for

its use as a deposit control agent in the

manufacture of paper and paperboard).

The agency is currently reevaluating

its environmental regulations under

NEPA, and is committed to expanding

the list of categorical exclusions found

in § 25.24 (21 CFR 25.24). However, as

indicated earlier, a key factor in FDA's

decision to grant an exemption from

regulation is whether the substance has

a significant impact on the environment.

A new use of a regulated indirect food

additive that involves the same

manufacturing process but a different

technical effect may have, as a result of

its use or subsequent disposal, a

significantly different environmental

exposure than any previously regulated use of the substance. Therefore, an

abbreviated review (i.e., one that does

not include a review of environmental

impact data) is not justified for all such

substances. Although these types of uses

do not currently qualify for a categorical

exclusion, some may qualify in the

future (the categorical exclusion list is

currently under consideration for

expansion).

In regard to reducing the requirements

for the submission of toxicological

feeding studies, FDA emphasizes that

§ 170.39 requires only that submissions

contain the results of an analysis of

existing toxicological information on the

substance and its impurities. This

information is needed to show whether

an animal carcinogen bioassay has been

carried out, or whether there is some other basis for suspecting that the

substance is a carcinogen or potent

toxin. FDA also requires this type of

information to enable it to determine

whether any of the impurities present in

the substance-have been shown to be

carcinogenic, and, if carcinogenic,

whether their TD50 value is greater than

6.25 mg/kg bodyweight per day (see

§ 170.39(a)(1)). To clarify this issue,

FDA is revising the language in

§ 170.39(c)(5) to state that the only

toxicological information that must be

included in a submission for an

exemption from the food additive

regulations is an analysis of existing

toxicological information on the

substance and its impurities.

29. Two comments stated that

exempted substances should not be

subjected to the environmental impact

reviews typically required for food

additives. The comments asserted that,

instead, exempted substances should

come under a newly created

"categorical exclusion" that would

exclude such actions from the

requirement that an environmental

assessment be prepared.

An FDA decision to exempt a substance from regulation as a food

additive is an agency action under the

National Environmental Policy Act

(NEPA) (42 U.S.C. 4321). Under NEPA,

an agency action must include a

consideration of the environmental

effects resulting from the intended use,

unless it is the subject of one of the

categorical exclusions listed in 21 CFR

25.24. Actions are made subject to an

exclusion either because, as a class, they

will not result in the production or

distribution of any substance and,

therefore, will not result in the

introduction of any substance into the

environment, or because they meet

specific criteria that are intended to

ensure they will not cause significant

environmental effects. As stated above,

the agency is actively examining its

categorical exclusion regulations.

However, neither of the subject

comments provided information to

show that as a class, substances used in

food-contact articles would not be

introduced into the environment or to

support the establishment of a new categorical exclusion. The agency

welcomes the submission of data and

information that would support the

establishment of a categorical exclusion

for these substances. At this time,

however, all requests for threshold of

regulation exemptions must include an abbreviated environmental assessment.

Availability of the Information

Submitted

30. Six comments were submitted on the general subject of what types of

information contained in submissions

under § 170.39 should be made publicly

available (i.e., on display at the Dockets

Management Branch or released in

response to requests submitted under

the Freedom of Information Act (FOIA)

(5 U.S.C. 552)). Three of these

comments were quite general,

recommending that FDA handle the

confidential information contained in

such submissions in the same manner that it has traditionally treated other

documents submitted. A more specific

comment recommended that the

information released under FOIA

should be consistent with that released

from food additive petitions. One

comment expressed the opposite

viewpoint, stating that exempted

substances should not be considered

food additives, and that, therefore, the

rules governing the release of

information submitted on food additives

should not apply. This comment also

requested that the final regulation

include a statement recognizing the

possible trade secret status of

information submitted in support of an

exemption request. Another comment

stated that the names of companies

receiving exemption letters are trade

secret.
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

As a general matter, the FOIA requires

that agencies make the fullest possible

disclosure of records to the public. The

procedures that FDA uses to handle the

release of public information in

accordance with FOIA are described in

part 20 (21 CFR part 20). Under these

procedures, information submitted to

FDA, including that submitted on the

use of food additives, is made publicly

available to the greatest extent possible.

As for substances that become

components of food below the threshold

that FDA is establishing, they will be

exempt from the requirement that their

use be the subject of a food additive

listing regulation. This exemption, like

a listing regulation, allows these

substances to be used in food contact

articles. Given the similarity in effect

between a food additive listing and the

grant of an exemption, FDA concludes

that it is appropriate for it to make

publicly available under § 170.39(e) the

same type of information that is

releasable on regulated food additives.

This information includes the name of

the company that sought and received

authorization to use the substance.

In response to the request that the

final regulation include a statement

recognizing the possible trade secret

status of information submitted in

support of an exemption request, FDA is

revising § 170.39(e) to state that the

agency will respond to all FOIA

requests for information subnmtted

under § 170.39 in accordance with part

20. Thus, data and information that are

trade secret or confidential commercial

or financial information are not

available for public disclosure in

accordance with § 20.61(c).

31. One comment stated that

information contained in submissions

under § 170.39 should not be released in

response to FOIA requests.

FDA does not agree with this

comment. As discussed in the previous

comment, FOIA requires that agencies

make the fullest possible disclosure of

records to the public. The agency,

however, recognizes that it has an

obligation to protect trade secret and

confidential commercial or financial

information as defined in § 20.61(a) and

(b). Therefore, FDA will not disclose

this type of information.

32. Two comments stated that the

chemical identities of exempted

substances should not be publicly

disclosed. One of these comments stated

that such information is trade secret and

considered by economists as "circumstantially relevant business

information." The comment stated that,

if the company requesting an exemption

regards this information as trade secret,

keeping such information confidential is

consistent with controlling case law

interpretation of the confidentiality

standard that is applied to FDA under

Critical Mass Energy Project v. NRC, 975

F. 2d 871 (D.C. Cir. 1992). This

comment also stated that, because these

substances are exempt from regulation

as food additives, FDA is not under any

obligation to disclose their chemical

identities. The comment stated that

release of proprietary information could

force companies to make their own

determinations as to whether a food

additive regulation is needed. This

comment suggested that FDA adopt a

system whereby the chemical would be

identified only by the general class of

chemicals to which -it belongs. This

comment also pointed out that EPA has

used this type of system in PreManufacture Notifications submitted

under the Toxic Substances Control Act

(40 CFR 720.85). One of these comments

raised the possibility that exempted

substances could be referred to only by

their trade names. FDA disagrees with the suggestion

that exempted substances be referred to

only by trade names or by reference to

the general class of chemicals to which

they belong. Two factors underlie FDA's

disagreement. First, the provisions of

the act added by the 1958 Food

Additives Amendment permit any

manufacturer to use any regulated food

additive as long as the substance meets

all applicable specifications, including

those associated with the identity of the

additive. Second, as previously

discussed, FOIA requires that agencies

make the fullest possible disclosure of

records to the public. Under the

procedures used by FDA to determine

the releasability of information under

FOIA, the agency has traditionally

considered the chemical identity of food

additives to be disclosable information,

and thus, the regulations implementing

the 1958 Food Additives Amendment

refer to food additives by their chemical

names. Because FDA's approach to

exempted substances derives from the

food additive provisions of the act, and,

as stated above, FDA is acquiescing in

the use of the substance, FDA concludes

that the.chemical identities of exempted

substances are disclosable under FOIA.

Critical Mass is not to the contrary.

While a company has an alternative to

making a submission to FDA under

§ 170.39 (i.e., filing a food additive

petition), and thus, the submission is in

a sense voluntary, the key question

under Critical Mass is whether the

information is of a kind that would

customarily not be released to. the

public by the person from whom it was

obtained (975 F.2d at 879). As stated

above, information about the chemical

identity of food additives for which

listing is sought is routinely disclosed to

the public in the Federal Register,

pursuant to section 409 of the act.

Submitters are well aware of this fact.

Thus, FDA finds no merit to the

suggestion by the comment that the

identity of substances subject to

§ 170.39 must be kept confidential. To

provide differently for substances

subject to § 170.39 would be to create a

special exemption. Clearly, Critical

Mass does not require such a result.

From a practical standpoint, chemical

nomenclature has typically been used to

characterize food additives because

chemical names are universally

recognized and are not subject to change

as trade names often are. Moreover,

trade names are often used to refer to

formulations in which the chemical

composition is held confidential. In

such cases, referring to regulated food

additives by trade names would make it

impossible for other manufacturers to

determine whether their chemical

substances meet applicable regulations.

A similar situation would occur if the

list of exempted substances made

publicly available did not include the,

chemical identities of such substances.

Making available the chemical

identities of substances exempted from

regulation will permit other

manufacturers to use these substances

as long as the conditions of use are no

more likely to result in migration to

food than those for which the

exemption was originally issued. It will

also allow interested persons to

determine what substances have been

exempted by FDA under the process

established by this final rule. FDA

believes that, in the interest of open

government, it is essential that decisions

made under this policy be available to

the public. Therefore, for the reasons

specified above, FDA will make

publicly available the chemical

identities of exempted substances.

33. One comment stated that the

technical effect or function of the

substance should not be made publicly

available.

Under the procedures used by FDA to

implement FOIA, the agency has not

considered information on the technical

effect or functionality of a food additive

to be trade secret as defined in § 20.61(a)

or confidential commercial or financial

information as defined in § 20.61(b).

Because the dietary exposure resulting

from the use of a substance in a foodcontact article may vary considerably

depending on the technical effect of that

additive, it is often necessary to include

such information in the regulation

authorizing a specific type of use of the

food additive in order to restrict the

36591
36592 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

dietary exposure to levels that can be

supported by existing safety data. For

example, substances regulated in 21

CFR 178.3400 are restricted to use as

emulsifiers and/or surface active agents

in the manufacture of articles or as.

components of articles contacting food.

Moreover, the provisions of the act

added by the 1958 Food Additives

Amendment permit any manufacturer to

use any regulated food additive as long

as the use of the substance meets all

applicable specifications and

limitations. Such limitations include

those that restrict the use of the additive

to a specific technical effect. Therefore,

it is often necessary to include this

information as part of the conditions of

use set forth in the regulation

authorizing the use of the additive so

that other manufacturers may use the

same substance under only those

conditions that are safe. In addition to

being made available as part of a

regulation, the agency has routinely

made technical effect information .

contained in food additive petitions

available to the public in response to

FOIA requests in accordance with

§ 171.1(h)(1)(i). Consistent with the

explanation above, FDA sees no reason

to change this policy with regard to food

additives exempted from regulation.

Treatment of the List of Exempted Uses

of Substances

34. One comment recommended that

in addition to making available a list of

exemptions at the Dockets Management

Branch, FDA should publish this list in

the Federal Register.

The public should have ready access

to an up-to-date list of those uses of

substances that have been exempted

from regulation as food additives by

FDA. However, maintaining such a list,

updated on a regular basis, on display

at the Dockets Management Branch, is

the most efficient way of achieving this

result. FDA anticipates being able to

respond to exemption requests within 3

to 4 months. Thus, the list of exempted

substances would be continually

changing. Monthly updates in the

Federal Register would be expensive

and yearly updates of little value.

Therefore, FDA has no plans to publish

this list in the Federal Register.

However, to ensure that interested

persons are aware that FDA is

maintaining such a list at its Dockets

Management Branch, the agency plans

to publish annually a brief notice in the

Federal Register on the availability of

this list. An updated list of exempted

substances can also be obtained by

contacting FDA's Office of Premarket

Approval (address above). FDA is

revising § 170.39(e) to reflect this fact.

Revocation

35. One comment recommended that

FDA establish timeframes for the

revocation process. The comment

suggested that the requestor would have

60 days to respond to FDA's tentative

decision to revoke an exemption. Once

the response is submitted, FDA would

have 60 days to reach its final decision.

FDA agrees that in cases in which

new information becomes available

showing that continued exemption of a

substance in a food-contact article from

regulation under the food additive

provisions cannot be supported in light

of existing safety data, the requestor's

response to FDA's tentative decision to

revoke an exemption, and FDA's

subsequent decision, should occur in a

timely manner. However, because the

complexity of such reviews may vary

greatly and require varying amounts of

time to complete, FDA does not

consider it to be appropriate to establish

specific timeframes for such reviews.

III. Other Actions

FDA is revising § 170.39(c) to state

that three copies of a request for an

exemption from regulation are to be

submitted. The agency is requiring three

copies to help expedite its review of

such requests. To further expedite such

reviews, the agency is revising

§ 170.39(c) to state that if part of the

submitted material is in a foreign

language, it must be accompanied by an

English translation verified to be

complete and accurate in accordance

with § 10.20(c)(2) (21 CFR 10.20(c)(2)).

IV. Analysis of Impacts

FDA has examined the impacts of this

final rule under Executive Order 12866

and the Regulatory Flexibility Act (Pub.

L. 96-354). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits.

(including potential economic,

environmental, public health and safety

effects; distributive impacts; and

equity). Under Executive Order.12866, a regulatory action is economically

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. A

regulation is otherwise considered

significant under Executive Order 12866

if it raises novel legal or policy issues.

The Regulatory Flexibility Act requires

analyzing options for regulatory relief

for small businesses. FDA finds that this

final rule is not a significant regulatory

action as defined by Executive Order

12866. In compliance with the

Regulatory Flexibility Act, the agency

certifies that this final rule will not have

a significant impact on a substantial

number of small businesses.

38. One comment suggested that the

proposed threshold of regulation

process would have an adverse impact

on small businesses. FDA disagrees. The

regulation that FDA is adopting does not

prohibit or restrict any present activity

and, therefore, does not generate

compliance costs for either large or

small firms. In addition, FDA has

received no information that the

benefits of the proposed action will

accrue differentially to large firms. In

fact, this approach should minimize the

burden on all businesses by providing a

procedure that is less burdensome than

the food additive petition process.

Without this threshold of regulation

process, those components of foodcontact materials whose use results in

low levels of migration into food would

require premarket approval through the

food additive petition process.

Based on information provided to

FDA by representatives of the food

packaging and processing industries, the

collection of information and

preparation of an exemption request for

review under the process established by

this final rule is estimated to cost

anywheit from $1,400 to $25,000

depending on the complexity of the

project. If analytical studies are required

to be carried out to show that the dietary

exposure resulting from the proposed

use is below the threshold of regulation,

FDA estimates that the additional cost

would vary from $10,000 to $50,000

depending on the complexity of the

project (e.g., the number of substances

or food simulating solvents involved,

and the method of analysis). Thus, the

agency estimates that the total cost to

submit exemption from regulation

requests may vary from $1,400 to

$75,000.

The time required to prepare such

requests would also vary with the type

of data needed to estimate the dietary

exposure associated with the intended

use. A simple request (i.e., one that does

not contain any analytical work) would

typically contain: (1) Identity and use

information; (2) a literature search of the

existing toxicological data on the

substance and its impurities; and (3)

information on the environmental

impact resulting from the proposed use

of the substance. Based on information

provided to FDA by representatives of

the food packaging and processing

industries, the average time to prepare

such requests is estimated to be 68
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

* hours. The average time to prepare

requests that include analytical work

(e.g., extraction studies carried out using

food-simulating solvents, analytical

studies to determine the residual level

of the substance in the food-contact

article) is estimated to be 108 hours.

Although the preparation of requests

for exemptions from regulation may cost

anywhere from $1,400 to $75,000 and

require on average 68 hours to complete

(108 hours for submissions requiring'

analytical data), these estimates

demonstrate that there will be a

significant decrease in the overall

burden to businesses for those

components of food-contact articles that

are exempted from regulation by this

expedited process but that previously

would have required premarket

approval via the food additive petition

process. (Petitions on these types of

issues can require on average 2,600

hours to prepare and cost anywhere

from $85,000 to $100,000.) Whenever

possible, FDA will provide assistance to

requestors to minimize the likelihood

that unnecessary work will be

performed. Based on the preceding

considerations, FDA finds that the

proposed action will not have an

adverse impact on small businesses.

In summary, the comments do not

provide a basis on which to change the

conclusions of the economic analysis

prepared for the proposed rule or to

establish that another option would

provide higher net benefits.

V. Environmental Impact

Considerations

The agency has previously reviewed

the environmental effects of this rule as

announced in the proposal (see 58 FR

52719, October 12, 1993). The agency

determined under 21 CFR 25.24(a)(8)

that neither an environmental

assessment nor an environment impact

statement is required. No new

information or comments have been

received that would affect the agency's

previous determination.

The agency is required to consider the

environmental impact of each action to

exempt a component of a food-contact

article from regulation as a food

additive. The final rule sets out the type

of information that FDA needs to

determine the impact on the

environment resulting from the.

intended use. The agency's finding of no

significant impact, and the evidence

supporting that finding, contained in an

environmental assessment, will be made

available for public inspection at the

Dockets Management Branch (address

above) for those substances whose use

in food-contact articles has been

exempted from regulation by the

process established by this rule.

VI. Paperwork Reduction Act

Section 170.39 of this final rule

contains information collection

requirements that were submitted for

review and approval to the Office of

Mafhagement and Budget (OMB), as

required by section 3504(h) of the

Paperwork Reduction Act of 1980. The

requirements were approved and

assigned OMB control number 0910-

0298.

VII. Conclusions

Although a number of comments

expressed the opinion that the 0.5 ppb

threshold is more conservative and

restrictive than is necessary to

adequately protect the public health, no

data were submitted that would justify

FDA establishing a threshold of,

regulatory concern at a dietary

concentration level higher than 0.5 ppb.

Based on its analysis of the available

evidence, FDA concludes that this

evidence does not support a threshold

significantly higher than 0.5 ppb,

especially where the substance being

considered for an exemption has not

been the subject of any toxicological

testing. Therefore, this final rule

establishes 0.5 ppb as the threshold of

regulatory concern for substances

intended for use in food-contact articles.

This final rule also establishes the

threshold of regulatory concern for

regulated direct food additives used in

food-contact articles as that dietary

exposure that is at or below 1 percent

of the ADI for that substance.

Listed below are the revisions that are

being incorporated into this final rule

based on comments received in

response to the proposal:

(1) FDA is revising § 170.39(a)(1) to

make it clear that the'phrase "there is

no reason, based on the chemical

structure of the substance, to suspect

that the substance is a carcinogen"

refers only to the substance itself (see

comment 21 of this document).

(2) FDA is revising § 170.39(a)(2)(ii) to

state that, for requests seeking an

exemption on the basis that the

substance is a regulated direct food

additive whose use in a food-contact

article will result in a dietary exposure

at or below 1 percent of the ADI for that

substance, FDA's review will not

necessarily be restricted to ADI values

based on data in FDA files. In particular,

in cases where FDA has not calculated

an ADI value for a regulated direct food

additive, the agency will consider ADI

values from other appropriate sources

(see comment 9 of this document).

(3) FDA is adding paragraph (h) to

§ 170.39 to state that guidelines to assist

requestors in the-preparation of

submissions seeking exemptions from

the food additive regulations are

available from FDA's Office of

Premarket Approval (HFS-200, 200 C

St. SW., Washington, DC 20204).

Because it is not practical to provide

guidelines that would cover all of the

possible topics associated with these

types of submissions, § 170.39(h)

encourages interested parties to obtain

specific guidance from FDA on the

appropriate protocols to be used for

obtaining extraction data, on the

validation of the analytical methods

used to quantify migration levels, on the

procedures used to relate migration data

to dietary exposures, and on any other

issue not specifically covered in FDA's

guidelines (see comment 24 of this

document).

(4) FDA is revising § 170.39(c)(1) to

state that the description of the

chemical composition of the substance

for which the request is made should

include, whenever possible, the name of

the chemical in accordance with current

CAS nomenclature guidelines and a

CAS registry number, if available (see

comment 22 of this document).

(5) For consistency, FDA is revising

§ 170.39(c)(4)(ii) and (c)(4)(iii) so that

the word "substance" refers to the

singular case (see comment 23 of this

document).

(6) FDA is revising the language in

§ 170.39(c)(5) to state that the only

toxicological information that must be

included in a submission for an

exemption from the food additive

regulations is an analysis of existing

toxicological data on the substance and,

its impurities. This information is

needed to show whether an animal

carcinogen bioassay has been carried

out, or whether there is some other basis

for suspecting that the substance is a

carcinogen or potent toxin. This type of

information on the impurities is needed

to show whether any of them are

carcinogenic and, if carcinogenic,

whether their TD50 value is greater than

6.25 mg/kg bodyweight per day in

accordance with § 170.39(a)(1) (see

comment 28 of this document).

(7) FDA is revising § 170.39(e) to state

that interested persons may obtain a list

of exempted substances by contacting

FDA's Office of Premarket Approval

(HFS-200), 200 C St. SW., Washington,

DC 20204 (see comment 34 of this

document).

(8) FDA is also revising § 170.39(e) to

state that FDA will handle requests for.

copies of releasable information

contained in submissions requesfing

exemptions from the food additive

36593
36594 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

* regulations in accordance with FDA's

FOIA procedures as described in part

20. In particular, data and information

that fall within the definitions of a trade

secret or confidential commercial or

financial information are not available

for public disclosure in accordance with

21 CFR 20.61(c) (see comment 30 of this

document).

(9) FDA is revising the language in

§ 170.39(g) to state that the agency plans

to notify manufacturers by means of a

notice published in the Federal Register

of its decision to revoke 'an exemption

issued for a specific use of a substance

in a food-contact article (see comment

13 of this document).

(10) FDA is revising § 170.39(c) to

state that three copies of a request for an

exemption from regulation are to be

submitted. If part of the submitted

material is in a foreign language, it must

be accompanied by an English

translation verified to be complete and

accurate in accordance with

§ 10.20(c)(2) (see Section III. of this

document: Other Actions). In addition

to these changes, FDA is clarifying its

definition of TDso in § 170.39(a)(1). This

minor change from the October 12,

1993, proposal ensures the scientific

soundness of this definition.

VIII. 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. Rulis, A., "Threshold of Regulation:

Options for Handling Minimal Risk

Situations," in Food Safety Assessment,

edited by Finley, J. W., S. F. Robinson, and

D. J. Armstrong, American Chemical Society Symposium Series 484, pp. 132-139, 1992.

2. Rulis, A. M., D. G. Hattan, and V. M.

Morgenroth II, "FDA's Priority Based

Assessment of Food Additives," Regulatory

Toxicology and Pharmacology, vol. 4, pp.

37-56, 1984.

List of Subjects

21 CFR Part 5

Authority delegations (Government

agencies), Imports, Organization and

functions (Government agencies).

21 CFR Part 25

Environmental impact statements,

Foreign relations, Reporting and

recordkeeping requirements.

21 CFR Part 170

Administrative practice and

procedure, Food additives, Reporting

and recordkeeping requirements.

21 CFR Part 171

Administrative practice and

procedure, Food additives.

21 CFR Part 174

Food additives, Food packaging.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under .

authority delegated to the Commissioner

of Food and Drugs, 21 CFR parts 5, 25,

170, 171, and 174 are amended as

follows:

PART 5-DELEGATIONS OF

AUTHORITY AND ORGANIZATION

1. The authority citation for 21 CFR

part 5 continues to read as follows:

Authority: 5 U.S.C. 504, 552, App. 2; 7

U.S.C. 138a, 2271; 15 U.S.C. 638, 1261-1282,

3701-3711a; secs. 2-12 of the Fair Packaging

and Labeling Act (15 U.S.C. 1451-1461); 21

U.S.C. 41-50, 61-63, 141-149,467f, 679(b),-

801-886, 1031-1309; secs. 201-903 of the

.Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321-394); 35 U.S.C. 156; secs. 301,

302,303,307, 310, 311,351,352, 354,361,

362, 1701-1706, 2101, 2125, 2127, 2128 of

the Public Health Service Act (42 U.S.C. 241,

242, 242a, 2421, 242n, 243, 262, 263, 263b,

264, 265, 300u-300u-5, 300aa-1, 300aa-25,

300aa-27, 300aa-28); 42 U.S.C. 1395y,

3246b, 4332, 4831(a), 10007-10008; E.O.

11490, 11921, and 12591; secs. 312, 313, 314

of the National Childhood Vaccine Injury Act

of 1986, Pub. L. 99-660 (42 U.S.C. 300aa-1

note).

2. Section 5.61 is amended by adding

new paragraph (h) to read as follows:

§ 5.61 Food standards, food additives,

generally recognized as safe (GRAS)

substances, color additives, nutrient

content claims, and health claims.

(h) The following officials are

authorized to issue letters concerning

substances determined to be below the

"threshold of regulation" under § 170.39

of this chapter:

(1) The Director and Deputy Directors,

Center for Food Safety and Applied

Nutrition (CFSAN).

(2) The Director, Office of Policy,

Planning and Strategic Initiatives,

CFSAN.

(3) The Director, Office of Premarket

Approval, CFSAN.

(4) The Directors of the Divisions of

Petition Control and Product Policy,

Office of Premarket Approval, CFSAN.

PART 25--ENVIRONMENTAL IMPACT

CONSIDERATIONS

3. The authority citation for 21 CFR

part 25 continues to read as follows:

Authority: Secs. 201-903 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C.

321-393); secs. 351, 354-361 of the Public

Health Service Act (42 U.S.C. 262, 263b264); 42 U.S.C. 4321, 4332; 40 CFR parts

1500-1508; E.O. 11514 as amended by E.O.

11991; E.O. 12114.

4. Section 25.22 is amended by

revising paragraph (a)(10) to read as

follows:

§25.22 Actions requiring preparation otan

environmental assessment.

(a) * * *

(10) Approval of food and color

additive petitions, approval of requests

for exemptions for investigational use of

food additives, and granting of requests

for exemption from regulation as a food

additive.

* * * * *

5. Section 25.31a is amended by

revising the introductory text of

paragraphs (a), (b)(1), and (b)(2) to read

as follows:

§25.31a Environmental assessment for

proposed approvals of FDA-regulated

products-Format 1

(a) For proposed actions to approve

food or color additives, drugs, biological

products, animal drugs, and class III

medical devices, for proposed actions to

affirm food substances as generally

recognized as safe (GRAS), and for

proposed actions to grant requests for

exemption from regulation as a food'

additive, the applicant or petitioner

shall prepare an environmental

assessment in the following format: * * * * *

(b)(1) For actions (either to approve

food additive petitions or to grant

requests for exemption from regulation

as a food additive) concerning

components of food-contact articles

present in the finished food-packaging

-material at a level not greater than 5-

percent-by-weight, the following

information is required for the format

items specified: * , *¢ * * *

(b)(2) For actions (either to approve

food additive petitions or to grant

requests for exemption from regulation

as a food additive) concerning

components of food-contact articles to

be used in surfaces of permanent or

semipermanent equipment or of other

food-contact articles intended for

repeated use, the f6llowing information

is required for the items specified: • * * * *

PART 170-FOOD ADDITIVES

6. The authority citation for 21 CFR

part 170 continues to read as follows:

Authority: Secs. 201, 401, 402,408,409,

701 of the Federal Food, Drug, and Cosmetic

Act (21 U.S.C. 321, 341, 342, 346a, 348, 371).

7. Section 170.3 is.amended by

redesignating paragraph (e) as (e)(1) and
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

by adding new paragraph (e)(2) to read

as follows:

§ 170.3 Definitions.

(e)(2) Uses of food additives not

requiring a listing regulation.

Substances used in food-contact articles

(e.g., food-packaging and foodprocessing equipment) that migrate, or

may be expected to migrate, into food at

such negligible levels that they have

been exempted from regulation as food

additives under § 170.39.

8. New § 170.39 is added to subpart B

to read as follows:

§ 170.39 Threshold of regulation for

substances used In food-contact articles.

(a) A substance used in a food-contact

article (e.g., food-packaging or foodprocessing equipment) that migrates, or

that may be expected to migrate, into

food will be exempted from regulation

as a food additive because it becomes a

component of food at levels that are

below the threshold of regulation if:

(1) The substance has not been shown

to be a carcinogen in humans or

animals, and there is no reason, based

on the chemical structure of the

substance, to suspect that the substance

is a carcinogen. The substance must also

not contain a carcinogenic impurity or,

if it does, must not contain a

carcinogenic impurity with a TDs0 value

based on chronic feeding studies

reported iii the scientific literature or

otherwise available to the Food and

Drug Administration of less than 6.25

milligrams per kilogram bodyweight per

day (The TD5o, for the purposes of th*s

section, is the feeding dose that causes

cancer in 50 percent of the test animals

when corrected for tumors found in

control animals. If more than one TD50

value has been reported in the scientific

literature for a substance, the Food and

Drug Administration will use the lowest

appropriate TD50 value in its review.);

(2) The substance presents no other

health or safety concerns because:

(i) The use in question has been

shown to result in or may be expected

to result in dietary concentrations at or

below 0.5 parts per billion,

corresponding to dietary exposure levels

at or below 1.5 micrograms/person/day

(based on a diet of 1,500 grams of solid

food and 1,500 grams of liquid food per

person per day); or

(ii) The substance is currently

regulated for direct addition into food,

and the dietary exposure to the

substance resulting from the proposed

use is at or below 1 percent of the

acceptable daily intake as determined

by safety data in the Food and Drug

Administration's files or from other

appropriate sources;

3) The substance has no technical

effect in or on the food to which it

migrates; and

(4) The substance use has no

significant adverse impact on the

environment.

(b) Notwithstanding paragraph (a) of

this section, the Food and Drug

Administration reserves the right to

decline to grant an exemption in those

cases in which available information

establishes that the proposed use may

pose a public health risk. The reasons

for the agency's decision to decline to

grant an exemption will be explained in

the Food and Drug Administration's

response to the requestor.

(c) A request for the Food and Drug

Administration to exempt a use of a

substance from regulation as a food

additive shall include three copies of

the following information (If part of the

submitted material is in a foreign

language, it must be accompanied by an

English translation verified to be

complete and accurate in accordance

with § 10.20(c)(2) of this chapter):

(1) The chemical composition of the

substance for which the request is made,

including, whenever possible, the name

of the chemical in accordance with

current Chemical Abstract Service

(CAS) nomenclature guidelines and a

CAS registry number, if available;

(2) Detailed information on the

conditions of use of the substance (e.g.,

temperature, type of food with which

the substance will come into contact,

the duration of the contact, and whether

the food-contact article will be for

repeated or single use applications);

(3) A clear statement as to whether the

request for exemption from regulation as

a food additive is based on the fact that

the use of the substance in the foodcontact article results in a dietary

concentration at or below 0.5 parts per

billion, or on the fact that it involves the

use of a regulated direct food additive

for which the dietary exposure is at or

below 1 percent of the acceptable

dietary intake (ADI);

(4) Data that will enable the Food and

Drug Administration to estimate the

daily dietary Concentration resulting

from the proposed use of the substance.

These data should be in the form of:

(i) Validated migration data obtained

under worst-case (time/temperature)

intended use conditions utilizing

appropriate food simulating solvents;

(ii) Information on the amount of the

substance used in the manufacture of

the food-contact article; or

(iii) Information on the residual level

of the substance in the food-contact

article. For repeat-use articles, an

estimate of the amount of food that

contacts a specific unit of surface area

over the lifetime of the article should

also be provided. (In cases where data

are provided only in the form of

manufacturing use levels or residual

levels of the substance present in the

food-contact article, the Food and Drug

Administration will calculate a worstcase dietary concentration level

assuming 100 percent migration.) A

detailed description of the analytical

method used to quantify the substance

should also be submitted along with

data used to validate the detection limit.

(iv) In cases where there is no

detectable migration into food or food

simulants, or when no residual level of

a substance is detected in the foodcontact article by a suitable analytical

method, the Food and Drug

Administration will, for the purposes of

estimating the dietary concentration,

consider the validated detection limit of

the method used to analyze for the

substance.

(5) The results of an analysis of

existing toxicological information on the

substance and its impurities. This

information on the substance is needed

to show whether an animal carcinogen

bioassay has been carried out, or

whether there is some other basis for

suspecting that the substance is a

carcinogen or potent toxin. This type of

information on the impurities is needed

to show whether any of them are

carcinogenic, and, if carcinogenic,

whether their TD50 values are greater

than 6.25 milligrams per kilogram

bodyweight per day in accordance with

paragraph (a)(1) of this section.

(6) Information on the environmental

impact that would result from the

proposed use of the substance.

Depending on the type of use, this

information should be in the form of an

abbreviated environmental assessment

as specified in § 25.31a(b)(1) or (b)(2) of

this chapter.

(d) Data to be reviewed under this

section shall be submitted to the Food

and Drug Administration's Office of

Premarket Approval (HFS-200), 200 C

St. SW., Washington, DC 20204.

(e) The Food and Drug Administration

will inform the requester by letter

whether the specific food-contact

application is exempt from regulation as

a food additive or not. Although a

substance that migrates to food at a level

that results in a dietary concentration at

or below the threshold of regulation will

not be the subject of a regulation

published in the Federal Register and

will not appear in the Code of Federal

Regulations, the Food and Drug

Administration will maintain a list of

substances exempted from regulation as

36595
Federal Register / Vol. 60, No. 136 /,Monday, July 17, 1995 / Rules and Regulations

food additives under this section on

display at the Dockets Management

Branch. This list will include the name

of the company that made the request,

the chemical name of the substance, the

specific use for which it has received an

exemption from regulation as a food

additive, and any appropriate

limitations on its use. The list will not

include any trade names. This list will

enable interested persons to see the

types of uses of food-contact materials

being exempted under the regulation.

Interested persons may also obtain a

copy of the list of exempted substances

by contacting the Food and Drug

Administration's Office of Premarket

Approval (HFS-200), 200 C St. SW.,

Washington, DC 20204. The agency's

finding of no significant impact and the

evidence supporting that finding,

contained in an environmental

assessment, also will be available for

public inspection at the Dockets

Management Branch in accordance with

§ 25.41(b)(2) of this chapter. Requests

for copies of releasable information

contained in submissions requesting

exemptions from the food additive

regulations will be handled in

accordance with the Food and Drug

Administration's, Freedom of

Information Act procedures, as

described in part 20 of this chapter. In

particular, data and information that fall

within the definitions of a trade secret

or confidential commercial or financial

information are not available for public

disclosure in accordance with § 20.61(c)

of this chapter.

(f) If the request for an exemption from regulation as a food additive is not

granted, the requestor may submit a

petition to the Food and Drug

Administration for reconsideration of

the decision in accordance with the

provisions of § 10.33 of this chapter.

(g) If the Food and Drug Administration receives significant new

information that raises questions about

the dietary concentration or the safety of

a substance that the agency has

exempted from regulation, the Food and

Drug Administration may reevaluate the

substance. If the Food and Drug

Administration tentatively concludes

that the information that is available

about the substance no longer supports

an exemption for the use of the foodcontact material from the food additive

regulations, the agency will notify any

persons that' requested an exemption for

the substance of its tentative decision.

The requestors will be given an

opportunity to show why the use of the

substance should not be regulated under

the food additive provisions of the act.

If the requestors fail to adequately

respond to the new evidence, the agency

will notify them that further use of the

substance in question for the particular

use will require a food additive

regulation. This notification will be

placed on public display at the Dockets

Management Branch as part of the file

of uses of substances exempted from

'regulation as food additives. The Food

and Drug Administration recognizes

that manufacturers other than those that

actually made a request for exemption

may also be using exempted substances

in food-contact articles under

conditions of use (e.g., use levels,

temperature, type of food contacted,

etc.) that are similar to those for which

the exemption was issued. Because only

requestors will be notified as part of the

revocation process described in this

section, the Food and Drug

Administration plans to notify other

manufacturers by means of a notice

published in the Federal Register of its

decision to revoke an exemption issued

for a specific use of a substance in a

food contact article.

(h) Guidelines to assist requestors in

the preparation of submissions seeking

exemptions from the food additive

regulations are available from the Food

and Drug Administration's Office of

Premarket Approval (HFS-200), 200 C

St. SW., Washington, DC 20204.

Interested persons are encouraged to

obtain specific guidance from the Food

and Drug Administration on the

appropriate protocols to be used for

obtaining migration data, on the

* validation of the analytical methods

used.to quantify migration levels, on the

procedures used to relate migration data

to dietary exposures, and on any other

issue not specifically covered in the

Food and Drug Administration's

guidelines.

PART 171-FOOD ADDITIVE

PETITIONS

9. The authority citation for 21 CFR

part 171 continues to read as follows:

Authority: Secs. 201,402,409, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 342, 348, 371).

10. New § 171.8 is added to subpart A

to read as follows:

§ 171.8 Threshold of regulation for

substhnces used In food-contact articles.

Substances used in food-contact

articles (e.g., food-packaging or foodprocessing equipment) that migrate or

that may be expected to migrate into

food at negligible levels may be

reviewed under § 170.39 of this chapter.

The Food and Drug Administration will

exempt substances whose uses it

determines meet the criteria in § 170.39

of this chapter from regulation as food

additives and, therefore, a food additive

petition will not be required for the

exempted use.

PART 174-INDIRECT FOOD

ADDITIVES: GENERAL

11. The authority citation for 21 CFR

part 174 continues to read as follows:

Authority: Secs. 201, 402, 409, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 342, 348, 371).

12. New § 174.6 is added to read as

follows:

§ 174.6 Threshold of regulation for

substances used In food-contact articles.

Substances used in food-contact

articles (e.g., food-packaging or foodprocessing equipment) that migrate, or

that may be expected to migrate, into

food at negligible levels may be

reviewed under § 170.39 of this chapter.

The Food and Drug Administration will

exempt substances whose uses it

determines meet the criteria in § 170.39

of this chapter from regulation as food

additives and, therefore, a food additive

petition will not be required for the

exempted use.

Dated: July 11, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95-17435 Filed 7-14-95; 8:45 am]

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