oversight

Food and Drug Administration's Regulation of Food Additives

Published by the Government Accountability Office on 1977-01-13.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                                  DOCUMENT RESUME

 0052-   - [A0590977]

 Food and Drug Administrations           egulation of Food Additives.
January    13,   1977.   18 pp.

Testimcny before Sen. Gaylord Nelson, Chairaan, Senate Select
Committee on Small Business; by Gregory J. Ahart, Director,
Human Resources Div.
Issue Area: Consumer and Worker Protection: Standards, Laws, and
    Regulations Enforcement (903).
Contact: Hman Resources Div.
Budget Function: Health: Prevantion and Control c Health
    Problems (553).
Organization Concerned: Canadian Health Pro.ecticn Branch; Food
    and Drug Administration; G D. Searle and Co.; National
    Academy of Sciences; National Institutes of   ealth: National
    Cancer Inst.
Congressional Relevance: Senate Committee on the Judiciiry:
    Administrative Practice and Procedure Sutccomittee: Senate
    Committee on Labor and Public elfare: Health Subcommittee;
    Senate Select Committee on Small Business.
Authority: Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301;
    21 U.S.C. 348). 21 C.F.R. 121.1(k).

         Reviews of color and food additives--Red No. 2,
saccharin and aspartame--included (1) the history of FDA's
regulation, (2) the current status of testing, and (3) whether
the reLulatory actions taken complied with the appropriate act.
 Red No. 2, the ae of dye generically known as amaranth which
 « lets F)A composition and purity specifications, has teuen under
 suspicicn for 15 years s being possibly carcinogenic or toxic
 to the rrodtctive system Under existing law, action should
 have   ee taken 1 1/2 years after being placed on the
 provisionaIl list, but extensions were granted. Red No. 2 was
finally    arned in January 1976. FDA limited saccharin use,
because of initial studies indicating possible adverse effects.
No final proof has been obtained. Aspartame, an artificial
sweetener, never was put on the market ecause of outside
objections to it and discovery of a possible carcinogen in its
makeup, but it did cause its manufacturer's testing procedures
to be questioned and found faulty. The initial regulation for
marketing aspartame has been stayed, hut final resolution has
not been ade. Continued use of saccharin under the interi3 food
additive regulation should be justified, and, if justified,
should be used at the conventional level of 100 to 1, rather
than the present 30 to 1, with the level of toluenesulfonamide
decreased. All agencies responsible for protecting the public
from carcinogens should cooperate to develop a uiform policy
for identifying and regulating carcinogenic chemicals and for
allowing public exposure to carcinogens. FDA should be required
to have all approved and proposed food additives tested for
carcinogenity. (SS)
       UNITED STATES GENERAL ACCOUNTING OFFICE
               WASHINGTON, D.C. 20548




                               FOR RELEASE ON DELIVERY
                               Expected at 9:30 a.m. EST
                               January 13, 1977




                    STATEMENT OF
GREGORY J. AHART, DIRECTOR, HUMAN RESOURCES DIVISION
                     BEFORE THE
               SENATE SELECT COMMITTEE
                  ON SMALL BUSINESS
                         on
           FOOD AND DRUG ADMINISTRATION'S
            REGULATION OF FOOD ADDITIVES
        Mr. Chairman and Members of the Committee, we are

pleased to appear here today to discuss our reports on

the Food and Drug Administration's (FDA'-) regulation

of three color and fooc    additives--Red No. 2, saccharin
and aspartame.     In addition we have issued a report to
the Congress on chemical carcinogens including food additives

and we have recently initiated a broad scale review of

FDA's regulation of food additives.     We will discuss these
also.
        Our reviews concerning the three additives were

directed primarily toward developing information on (1) the

history of FDA's regulation of them,    (2) the current
status of testing the safety of the additives, and

(3) whether the regulatory actions taken by FDA on the

three additives complied with the Federal Food, Drug,

and Cosmetic Act (FD&C Act), as amended (21 U.S.C. 301).

REGULATION OF RED NO. 2

        Red No. 2 is the name given to a certified lot of

the dye generically known as amaranth.     The composition
and purity of amaranth varies.     FDA has established composition
and purity specifications that amaranth must meet before

it can qualify for use in food, drugs, and cosmetics.

Only amaranth meeting such specifications is classified

as Red No. 2.
      Since July 12, 1960, the Color Additive Amendments

 to the FD&C Act have required FDA to establish regulations

listing color additives that are safe for use in food,

drugs, or cosmetics.   Such regulations may list color
additives for use generally in food, drugs, or cosmetics

or may prescribe the conditions under which the color

additives may be safely used.

     The act provides that a color additive is deemed

unsafe and should not be listed in a regulation permitting

its use in food, drugs, or cosmetics if it is found by

FDA to induce cancer   i man or a:!imal.
     The FD&C Act, as amended in 1960, placed all color

additives commercially established at that time, including

Red No. 2, on a provisional list to allow their use for

a reasonable period until their safety could be reviewed

and regulations for their use could be issued.   The 1960
amendments provided that the provisional listing was to

terminate no later than 2-1/2 years from the effective

date of enactment (July 12, 1960), or January 12, 1963.

The amendments also provided, however, that FDA could

postpone the termination date if such action was con-

sistent with the objective of carrying to completion,

in good faith, as soon as reasonably practicable, the

scientific investigations necessary for making a determina-

tion as to the additives' safety.

                             - 2-
    We found that FDA had permitted the use of Red No. 2

in food, drugs, and cosmetics for 15 years without making

a final determination of its safety.     FDA postponed
termination of the provisional listing for Red No. 2,

14 times on the basis of requests from manufacturers

or industry associations to allow completion of scientific

investigations concerning its safety.

        Since 1970 several scientific studies involving

animals, including some performed     r sponsored by FDA,
raised questions concerning the safety of Red No. 2 in

food.     In some of these studies Red No. 2 or amaranth

was shown in test animals to be toxic to reproductive

systems or to be carcinogenic.

        Because of its concern about the safety of Red No. 2,

FDA in July 1972 issued a proposal to limit human exposure

to the color additive.     However, at the time our report
was issued on October 20, 1975, FDA had not made a final

determination regarding its safety.

        Because we believed that continued use of Red No. 2

before resolving its safety exposed the public to

unnecessary risk, we recommended that the Secretary

of the Department of Health, Education, and Welfare

(HEW) direct the Commissioner of FDA to promptly establish

the safety of Red No. 2 or prevent its use in food, drugs,

and cosmetics.

                              - 3-
       On January 19, 1976. FDA announced
                                          a ban on the
 use of Red No. 2 in food, drugs,
                                   and cosmetics. FDA took
 the action because new evidence
                                  showed that Red No. 2
 caused a statistically significant
                                     increase in the number
 of malignant tumors in test animals
                                      and because of what
 it termed "the absence of other
                                  data to allow a definitive
 judgment of safety."

 REGULATION OF SACCHARIN

      In our report on saccharin we pointed
                                              out that
 saccharin was "generally recognized
                                      as safe" for use
 in food until about 1970 when studies
                                        raised questions
 about its potential to cause cancer
                                      in test animals.
      Saccharin is an acid and ue saccharin
                                                generally
is unsuitable for use in foods and
                                     beverages because
it is only slightly soluble.   It is most often combined
with eithe:  sodium, calcium, or ammonium salts
                                                  which
neutralize the acid and produce
                                 a more readily soluble
compound.

      The FD&C Act, as amended by the
                                        Food Additives
Amendment of 1958 (23 'U.S.C. 348),
                                     requires FDA to establish
regulations prescribing the conditions
                                          under which
a food additive may be safely used.
                                       The act defines "food
additive" as any substance which
                                  becomes or may be expected
to become a component of food,
                                either directly or indirectly,
or which may otherwise affect the
                                    characteristics of

                            - 4 -
 the food.   The proposed use of a food additive whose safety
 is not generally recognized by qualified scientists
                                                     must
 be approved by FDA.

      Food additives ':generally recognized as safe"
                                                     are
 referred to as GRAS substances. Such substances
                                                   added
 to food are not considered food additives and
                                               are exempt
from the requirement for FDA approval.
Spccharin's safetynot established

     FDA's food additive regulations (21 C.F.R. 121.1(k))

define GRAS substances as those which experts
                                              determine,
based on scientific data or reasoned judgment
                                              founded
in experience with common food use, pose "no significant

risk of harm if used as insended."    If an important question
of safety has been raised regarding a GRAS substance,

it may be removed from GRAS status.   An interim food
additive regulation may be issued to permit its
                                                use
while the safety question is being resolved, provided

there is reasonable certainty that the substance
                                                 is not
harmful and that no harm to the public health
                                              will result
from its continued use.

     On February 1, 1972, FDA removed saccharin
                                                and its
various salt forms from the GRAS status and issued
                                                   an
interim food additive regulation limiting the
                                              use of
saccharin in foods.
      The interim regulation   tited that preliminary results
 from studies on long-term feeding of saccharin to
                                                   animals
 conducted by FDA and others indicated "possible
                                                 adverse
effects."    According to the regulation, if the experimental
 findings indicate that continued use of saccharin
                                                   poses
a "significant risk" to the public health, action
                                                  would
be taken as warranted to minimize the risk.    The regula-
tion authorized saccharin's use as a sweetening
                                                agent
only in special dietary food and for certain technological

purposes such as reducing bulk and enhancing flavors

in chewable vitamin tablets.   This authority for saccharin's
use was to e.xpire June 30, 1973.

     However, on May 25, 1973, FDA issued a Federal

Register notice extending saccharin's interim regulation

indefinitely.   The Federal Register identified several
completed or nearly completed long-term feeding
                                                studies
made of three different animal species.   These study
results showed a statistically significant incidence
                                                     of
bladder tumors in the male offspring of test animals
                                                     fed
saccharin.

     The Federal Register indicated that these studies

were referred to the National Academy of Sciences
                                                  for
review and that a final determination of saccharin's

safety would be made after FDA received recommendations

from the Academy.   In December 1974 the Academy submitted

                            - 6 -
  to FDA its report on the safety of
                                     saccharin which pointed
 out problems with the studies and concluded
                                               that existing
 stuaies had "not established conclusively
                                            whether saccharin
 is or is not carcinogenic when administered
                                              orally to
 test animals." The Academy recommended
                                          that certain
 additional studies be made to resolve
                                        the question of
 whether saccharin is carcinogenic or
                                       otherwise unsafe
 in the human diet.

      In hearings on FDA's fiscal year 1976
                                            appropriations
before a subcommittee of the House Committee
                                              on Appropria-
tions, the Acting Director of FDA's
                                     Bureau o Foods
stated that most tsts recommended in
                                       the Academy's
1974 report were being made by the Health
                                            Protection
Branch of the Canadian Government.
                                     He estimated that
the tests would be completed in 3 years
                                         and that in the
meantime "saccharin will continue to
                                      be interim listed
for use as a food aditive until such
                                       time as conclusive
evidence is obtained that saccharin
                                     is or is not carcinogenic."
Safety factor us3 for
saccharin uestionable

      The level of saccharin allowed in food
                                             under FDA's
interim food additive regulation is
                                     based on a safety
factor of 30 to i rather than the conventional
                                                100 to
1 safety factor. Use of a safety factor
                                          less than 100
to   for saccharin, which was removed as
                                          a GRAS substance

                            - 7 -
because questions were raised about its potential to

cause cancer, seems questionable.

     In determining whether the proposed use of a food

additive is safe, the FD.C Act (21 U.S.C. 348(c)(5)(C))

requires FDA to consider safety factors generally recognized

by qualified experts as appropriate for the use of animal

experimentation data.   FDA's regulations provide that
except where evidence is submitted which   ustifies use
of a different safety factor, a food additive     L
                                                  -      e
by man will not be granted a tolerance that will exceed

1/100th of the maximum amount demonstrated to be wthout

harm to experimental animals.

     We believe that while resolution of safety questions

are pending, saccharin's authorized levels o    use in
food should be based on the conventional margin of safety

provided by FDA's regulations.

Impurities in saccharin
should be limited to
lowest achievable levels

     We noted also that the levels of o-toluenesulfonamide

(OTS), an impurity in saccharin with possible cancer-

causing potential, was not being limited to the lowest

level achievable under present manufacturing tech,-ology.

FDA limits the level of OTS to 100 parts per million.

We were told that this limit was established in 1974

because

                            - 8 -
      -- substantial levels of the impurity
                                            were identified
        in saccharin sample= used in two studies,

      -- the impurity has possible carcinogenic
                                                potential,
        and

      -- industry was capable of reducing
                                          its levels to 100
         parts per million.
 According to a 1974 National Academy
                                      of Sciences report
 to FDA, impuri:ies in saccharin, especially
                                             OTS, may
 have been the possible cause of the
                                     bladder tumors observed
 in certain studies.

      Technology advancements have since
                                         made it rossible
to reduce the levels of OTS in saccharin
                                          to less than
50 parts per million and as low as 1
                                      to 3 parts per million.
The scientific community questioned
                                     the prudence of
allowing saccharin on the market with
                                       levels of impurities
that exceeded levels which industry
                                     could reasonably
achieve.
Conclusions and recommendations

     We believe that allowing an interim
                                           food additive
regulation to remain in effect for
                                    several years while
safety questions concerning the additive
                                          are being resolved
seems contrary to F's intent of permitting
                                               use of such
additive for a limited period. Potential
                                            hazards from
the use of saccharin could be further
                                       minimized by applying
the conventional 100 to 1 safety factor
                                         and by reducing
                            - 9   -
 the levels of OTS in saccharin to the lowest level
                                                    practically
 achievable under present manufacturing technology.

      Because saccharin has been used under an interim
                                                       food
 additive regulation for about the past 4 years and
                                                    because
 safety guestions about it are not expected to be
                                                   resolved soon,
 we recommended that the Secretary of HEW direct
                                                  the FDA
 Commissioner to promptly reassess

      ·--
        the justification for continued use of free saccharin

        and its three salt forms under the interim food
                                                        additive
       regulation and

     -- the need for issue       a permanent regulation or possibly
       discontinuing their use in food.

     We also recommended that if continued use under
                                                     the interim
regulation is justified, consideration be given
                                                 o the need
for increasing the safety factor to the onventional
                                                     level
set forth in FDA's regulations and to reducing the
                                                   permissible
levels of OTS in saccharin to the lowest achievable
                                                    levels.
     On December 10, 1976, HEW advised us that the FDA

Commissioner had reassessed the justification for
                                                  the interim
listing of saccharin for use as a food additive.
                                                  He conclLded
that continuation of the interim listing t.as appropriate.
                                                                  On
January 7, 1977, FDA published       wo notices concerning saccharin.
One extended the interim regu'ation to permit saccharin's

continued use until Canadian studies on its safety
                                                   are completed
and evaluated.   The other notice proposed to amend the interim
food additive regulation to establish a tolerance
                                                  of 25 parts
per million for toluenesulfonamide.      FDA does not believe a
change in the safety factor is necessary.

                             -   I   _
 REGULATION OF APARTAME

      Our third report concerned aspartame, an artificial

 sweeener that was developed by G. D. Searle
                                             and Company.
      On February 9, 1973, Searle submitted to FDA
                                                    a
 petition proposing the issuance of a food additive

 regulation to provide for the use of aspartame
                                                in foods.
 The petition included general information on
                                              the characteristics
and specifi-.ations of aspartame, its proposed
                                               uses, and
summaries of scientific animal and human studies
                                                  regarding
its safety.

     After reviewing the petition, FDA considered
                                                  certain
aspects of the animal study data submitted
                                           in support
of aspartame's safety to be incomplete and suggested

to Searle that the petition be withdrawn unless
                                                the issues
could be promptly resolved. Searle submitted
                                              additional
suprnrt   ita and on Juiv 26, 1974, FDA published a regulation
approving the use of aspartame in certain? foods.

Objections filed against aspartame

     The FD&C Act provides that individuals adversely

affected by a food additive regulation may
                                           object and
request a formal public hearing.  FDA received three
statements of objection relating to the aspartame

regulation.   One statement raised objections to a labeling
requirement for cold cereals containing aspartame
                                                  but
did not contain a request for a hearing.  The other
                           -   11 -
statements raised questions about the possibility of

aspartame causing brain damage in infants and young children

and requested a hearing to resolve those questions.

     After reviewing the objections FDA considered te

uses of aspartame authorized by the regulations safe

but recognized there was a difference of opinion and

agreed to convene a hearing to address the safety issues

raised by the objectors.

     Plans to convene a hearing were suspended, however,

as subsequent testing data submitted by Searle indicated

that diketopiperazine (DKP), a manufacturing byproduct

in aspartame, could be carcinogenic.   FDA did not take
regulatory action to prevent the marketing of aspartame

because Searle and General Foods Corporation, a co-marketer,

voluntarily agreed to withhold it from the market until

DKP's carcinogenic potential was resolved.

FDA uestions data
submitted by Searle

     Besides aspartame, Searle also manufactures a number

of drugr   hich FDA has approved for marketing.   In July
1975 FDA raised questions about Searle's performance

of animal experiments and its reporting of safety data

to FDA concerning two drugs--flagyl, used to treat

infections and aldactone, an antihypertension drug.

Because of the importance and sensitivity of these


                           - 12 -
questions, the FDA Commissioner, on July 23, 1975,

established a task force to

     -- review the practices followed by Searle in conducting

          animal experiments, analyzing the experiments'

          data, and submitting the data to FDA;

     -- determine if there is eidence that any practices

          of Searle in carrying out the above functions

          violated the FD&C Act or any other laws of the

          United States; and

     -- recommend an appropriate course of action based

          on the investigation's findings.

     FDA officials said that the :nvestigation was directed

primarily toward evaluating drug data submitted to FDA

since 1968.     They stated that the review of aspartame
data was included as part of the investigation, however,

because (1) of the additive's recent approval, (2) of

its potential for wide use in foods, and (3) its inclusion

would provide a broader product base to evaluate Searle's

practices.

AsEartame regulation stayed

     Preliminary results of the task force investigation

indicated possible discrepancies in the data and the

research summaries submitted to FDA supporting aspartame's

safety.    On December 5, 1975, FDA stayed the regulation

approving the use of aspartame.

                           - 13 -
     In joint hearings held on January 20, 1976, before

the Senate Subcommittees on Health and on Administrative

Practice and Procedure, Committees on Labor and Public

Welfare, and the Judiciary, the FDA Commissioner disclosed

preliminary task force findings.     He stated that 11 studies
submitted supporting the food additive petition for

aspartame had been reviewed and numerous problems had

been noted.   These problems included poor methods of

distribution and identification of control and treated

animals, poor records of weighings, poor animal husbandry

practices, discrepencies between Searle's pathology sheets

and pathology summaries submitted to FDA, and problems

in the design of some of the studies.    The Commissioner
stated that a final decision on whether to revoke the

regulation approving the use of aspartame would be made

after the task force had officially completed its investi-

gation and added that aspartame would not be permitted

to be marketed until all questions about its safety had

been aired and resolved.

     An FDA Bureau of Foods official told us that as

of January 1, 1977, no decision had been made on whether

to revoke the regulation.




                            - 14 -
 TESTING FOOD ADDITIVES
 FOR CARCINOGENICITY

       In addition to these reports, we
                                          issued a report
  to the Congress on June 16, 1976,
                                     on Federal efforts
 to protect the public from cancer-causing
                                              chemicals.
       In this report we discussed the
                                        need for a Federal
 policy concerning carcinogens.
                                  Federal agencies have
 problems accepting and applying
                                  the results of animal
tests to people because (1) the National
                                          Cancer Institute
has only recently developed minimum
                                     testing guidelines
for determining a chemical's carcinogenicity
                                              and other
agencies have not officiallv adopted
                                      the guidelines
as a basis for carcinogenicity testing
                                        and (2) there
are no scientific principles to help
                                     Federal agencies
apply animal test results to humans.
                                       As a result, some
carcinogens are not regulated at all
                                     while others are
regulated differently by the various
                                     regulatory agencies.
All agencies responsible for protecting
                                        the public from
Carcinogens should, we believe, cooperate
                                          to develop
a uniform policy for identifying
                                 and regulating carcinogenic
chemicals and the products in which
                                     they appear. The
policy should also deal with such
                                  issues as the conditions
under which regulatory agencies will
                                      allow public
exposure to carcinogens.




                           - 15 -
       We pointed out in the report that under the FD&C Act

 the safety of certain products and substances, including

 food additives, is to be assured before they are approved

 for commercial use.   We found that in some cases, however,
 they did not receive the kind of long-term tests that

experts agree are needed to detect cancer-causing potential.

       According to officials in FDA's Division of Food

and Color Additives, all intentional'food additives
                                                    must
receive long-term tests to detect carcinogenicity before

FDA will approve them.    Intentional additives are t
(1) improve nutritional value, (2) maintain freshness,

(3) improve esthetic appeal, or (4) aid in processing.

       Unintentional additives are used mainly in packaging

fcods and, according to the FDA officials, receive
                                                   long-
term te ting only when the consumer would be exposed
                                                     to
more than 1 or 2 parts per million of the additive
                                                   in
the food unless FDA had valid reasons to suspect that

the additive might be carcinogenic.    FDA officials
explained that the long-term tests were expensive,

and because virtually none of the unintentional additives

migrate from the packaging material to the food, the

amount of the additive which may be ingested is virtually

nil.   FDA's principle in this regard is the higher the

anticipated human exposure, the greater the amount
                                                   of
toxicological data required to assure human safety.

                           - 16 -
 According to an April 1970 report to the Surgeon General
 by the Ad Hoc Committee on the Evaluation of Low Levels
 of Environmental Chemical Carcinogens
      -- no level of exposure of a chemical carcinogen
           should be considered toxicologically Insignificant
           for humans and
     -- no chemical substance should be assumed safe
           for human consumption without proper negative
           lifetime biological assays of adequate size.
     HEW said that, although extending carcinogenicity
testing to unintentional food additives that have only
remote possibilities of risk might be reassuring, it
did no- foresee any benefit to the public great enough
to justify the substantial costs of such a policy.
     W-e do not agree tha    FDA can assure safety for
unintentional additives when the additive migrates to
the food and leaves a residue of less than 1 or 2 parts
per million.     Based on the Ad Hoc Committee's criteria,
we do not believe that FDA can assure that all food additives
are safe unless the additives receive carcinogenicity
testing.
     Accordingly, we recommended that the Secretary,
HEW, require FDA to have all approved and proposed food
additives tested for carcinogenicity.



                              - 17 -
 CURRENT GAO WORK

     Because our work to date on
                                  food additives has pointed
out certain problems concerning
                                 the regulation of food
and color additives, we have
                              recently initiated a broad
survey of FDA's programs to
                             regulate these additives.
During this survey we will attempt
                                   to determine whether
current legislation and FDA
                            regulatory practices adequately
protect consumers with respect
                               to F.:.stances which are
added to food.

     Mr. Chairman, that concludes
                                  my prepared statement.
We will be pleased to answer
                             any questions that you or
other members of the Committee
                               may have.




                         -   18 -