Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles

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 review in deciding whether it is

necessary to regulate the use of a substance as a food additive and

identifies 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 (HFS-216), 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 Sec. 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

food-contact 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 food-contact 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 food-contact 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.

II. 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

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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

public 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 food-contact 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 proposed 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.1

\1\ The 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

(1000-fold to 2000-fold).

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3. One comment expressed the opinion that the threshold should have

been based on the mean TD502 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 TD50 would allow FDA to establish a threshold significantly

higher than 0.5 ppb.

\2\ The TD50, 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.

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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 TD50 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 TD50

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 would be 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

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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 upper-bound 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 LD503 values. For example, one comment

recommended that for substances that have been shown to be nonmutagenic

and to have LD50 values greater than 2,000 milligrams per kilogram

(mg/kg), the threshold should be raised to 5 ppb.

\3\ The LD50 is the dose in acute feeding studies that

causes lethality in 50 percent of the test animals.

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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 LD50 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 LD50 values. Such a correlation would

provide confirmation that a substance that has been shown to be

nonmutagenic or to have a high LD50 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 LD50 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 LD50 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 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-

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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 agency 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 Sec. 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

direct 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.

\4\ This doctrine is expressed in Latin as de minimis non curat

lex (the law does not concern itself with trifles).

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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 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

food-contact 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 Sec. 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

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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 Sec. 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 food-contact

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

food-contact 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

food-contact 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 1108, 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 Sec. 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

[[Page 36587]]

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 food-contact 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 food-contact 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 Sec. 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 Sec. 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 view that many manufacturers do not use

their proprietary chemicals for food-contact 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 Sec. 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

[[Page 36588]]

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 food-contact 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

Sec. 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 Secs. 174.6 and

Sec. 570.14 (21 CFR 570.14) of FDA's regulations. Under Sec. 174.6

Threshold of regulation for substances used in food-contact articles,

FDA will exempt substances from regulation as food additives whose use

in food-contact articles meet the criteria in Sec. 170.39. Authority to

use substances exempted under Sec. 174.6 in articles contacting animal

feed is set out in Sec. 570.14 Indirect 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 Sec. 170.39.

Because Sec. 570.14 contains a cross-reference that includes

Sec. 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 Sec. 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 Sec. 170.39 that applies to direct animal feed additives

that have not been

[[Page 36589]]

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

Sec. 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

Sec. 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 Sec. 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

Sec. 170.39(c)(1) accordingly.

23. One comment recommended that the word ``substance'' in proposed

Sec. 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 articles

into food.

Therefore, FDA is adding Sec. 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

Sec. 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 food-contact article. However, the

agency believes it is more appropriate to include such language as part

of Sec. 170.39(h) to emphasize that interested parties may seek

guidance on any issue involving exemption requests. Therefore, FDA is

revising Sec. 170.39 to include this provision and has deleted proposed

Sec. 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 into 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

[[Page 36590]]

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 the substance 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 Sec. 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

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

FDA is revising the language in Sec. 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 Sec. 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.

[[Page 36591]]

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 Sec. 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

Sec. 170.39(e) to state that the agency will respond to all FOIA

requests for information submitted under Sec. 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 Sec. 20.61(c).

31. One comment stated that information contained in submissions

under Sec. 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 Sec. 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 Pre-

Manufacture 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 Sec. 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 Sec. 170.39 must

be kept confidential. To provide differently for substances subject to

Sec. 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 Sec. 20.61(a) or

confidential commercial or financial information as defined in

Sec. 20.61(b). Because the dietary exposure resulting from the use of a

substance in a food-contact 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

[[Page 36592]]

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

Sec. 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 Sec. 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 Sec. 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

Sec. 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

Sec. 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 food-contact

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 anywhere 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

[[Page 36593]]

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 Management 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 Sec. 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 Sec. 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 Sec. 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, Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 170.39(a)(1) (see comment 28 of this document).

(7) FDA is revising Sec. 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 Sec. 170.39(e) to state that FDA will

handle requests for copies of releasable information contained in

submissions requesting exemptions from the food additive

[[Page 36594]]

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

document: Other Actions). In addition to these changes, FDA is

clarifying its definition of TD50 in Sec. 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 III, ``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, 242l, 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:

Sec. 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 Sec. 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, 263b-264); 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:

Sec. 25.22 Actions requiring preparation of an 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:

Sec. 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 following 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

[[Page 36595]]

by adding new paragraph (e)(2) to read as follows:

Sec. 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

food-processing 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 Sec. 170.39.

* * * * *

8. New Sec. 170.39 is added to subpart B to read as follows:

Sec. 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 food-processing 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 TD50 value based

on chronic feeding studies reported in the scientific literature or

otherwise available to the Food and Drug Administration of less than

6.25 milligrams per kilogram bodyweight per day (The TD50, for the

purposes of this 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

Sec. 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 food-contact 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 worst-case 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 food-contact 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 Sec. 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 requestor 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

[[Page 36596]]

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 Sec. 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 Sec. 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 Sec. 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 food-contact 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 Sec. 171.8 is added to subpart A to read as follows:

Sec. 171.8 Threshold of regulation for substances used in food-contact

articles.

Substances used in food-contact articles (e.g., food-packaging or

food-processing equipment) that migrate or that may be expected to

migrate into food at negligible levels may be reviewed under

Sec. 170.39 of this chapter. The Food and Drug Administration will

exempt substances whose uses it determines meet the criteria in

Sec. 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 Sec. 174.6 is added to read as follows:

Sec. 174.6 Threshold of regulation for substances used in food-contact

articles.

Substances used in food-contact articles (e.g., food-packaging or

food-processing equipment) that migrate, or that may be expected to

migrate, into food at negligible levels may be reviewed under

Sec. 170.39 of this chapter. The Food and Drug Administration will

exempt substances whose uses it determines meet the criteria in

Sec. 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]

BILLING CODE 4160-01-P