Natural Resources Defense Council, Inc. et al v. United States Food and Drug Administration et al

Filing 44

DECLARATION of Amy A. Barcelo in Support re: 40 MOTION for Summary Judgment.. Document filed by Center for Veterinary Medicine, Bernadette Dunham, Margaret Hamburg, Kathleen Sebelius, United States Department of Health and Human Services, United States Food and Drug Administration. (Attachments: # 1 Exhibit A, # 2 Exhibit B, # 3 Exhibit C, # 4 Exhibit D, # 5 Exhibit E, # 6 Exhibit F, # 7 Exhibit G, # 8 Exhibit H, # 9 Exhibit I, # 10 Exhibit J, # 11 Exhibit K, # 12 Exhibit L, # 13 Exhibit M, # 14 Exhibit N, # 15 Exhibit O, # 16 Exhibit P Part 1 of 5, # 17 Exhibit P Part 2 of 5, # 18 Exhibit P Part 3 of 5, # 19 Exhibit P Part 4 of 5, # 20 Exhibit P Part 5 of 5)(Barcelo, Amy)

54852
DEPRTEN

Federal Register /- Vol. 44, No. 185 / Friday, September 21, 1979 / Notices
OF. HELH

DEPARTMENT OF HIEALTH,
EDUCATION, AND WELFARE

-

regulation identified the mouse uterine/
paper chromatography method of
analysis as the approved method for
determining whether DES residues exist
Food and Drug Administration •
in edible tissues of cattle and sheep
[Docket No. 76N-0002]
treated with DES. As discussed below,
the adequacy of that or any other
Diethylstilbestrol; Withdrawal of
method for detecting DES residues was
Approval of New Animal Drug
an issue in the evidentiary hearing on
Applications; Commissioner's Decision th withdrawal of approval of the DES
NADA's. The order revoking 21 CFR
AGENCY: Food and Drug Administration.
556.190 states that nothing in the-iecord
ACTION: Notice.
of the evidentiary hearing demonstrates
that the agency's previously announced
SUMMARY: The agency is publishing the
decision to revoke that regulation is
Commissioner of Food and Drugs'
incorrect. My analysis of the evidence in
decision, which constitutes his findings
this record on that issue is contained in
of fact and conclusions of law on the
this Decision.
issues in a formal evidentiary public
The Initial Decision of the
hearing, withdrawing approval of new
Administrative Law Judg6 who presided
animal drug applications for
at the evidentiary hearing on the
diethylstilbestrol implants and liquid
withdrawal of the DES NADA's was
and dry feed premixes for use in cattle
issued on September 21, 1978. All parites
and sheep.
filed exceptions to that decision
EFFECTIVE DATE: June 29, 1979.
pursuant to 21 CFR 12.125(a). My
ADDRESS: The transcript of hearing,
decision accords with the Initial
evidence submitted and all other
Decision insofar as the Administrative
documents cited in the decision may be
Law Judge found that approval of the
seen in the office of the Hearing Clerk
NADA's must be withdrawn pursuant to
(HFA-305), Food and Drg
the-so-called "safety clause" of 21 U.S.C.
Administration, Rm. 4-65, 5600 Fishers
360(e)(1)(B) (discussed below). The
Lane, Rockville, MD 20857, from 9 a.m.
Administrative Law Judge also found
to 4 p.m. Monday through Friday.
that the Delaney Clause (also discussed
FOR FURTHER INFORMATION CONTACT.
below) did not apply to DES because no
Constantine Zervos, Scientific Liaison
DES residues have been found in edible
tissues by the approved analytical
and Intelligence Staff (HFY-31), Food
and Drug Administration, Departrfient of method. I do not reach that issue
Health, Education, and Welfare, 5600
because I find that the Delaney Clause
Fishers Lane, Rockville, MD 20857, 301applies to DES by virtue of the
443-4490.
revocation this day of 21 CFR 556.190.
The applicants who sought a hearing
SUPPLEMENTARY INFORMATION: Although
on the withdrawal of the DES NADA's
this document contains minor editorial
are American Home Products Corp.,
changes from the original decision, such
Dawes Laboratories, Inc., Hess &Clark,
changes are made only to comply withDivision of Rhodia Inc., and Vineland
document drafting guidelines issued by
Laboratories, Inc. They have filed joint
the office of the Federal Register;, there
-papers and are referred to as the
are no substantive differences between
"manufacturing parties." Nonparty
the document that follows and the
participants favoring continued
official copy of the Commissioner's
approval of DES are the American
Decision dated June 29, 1979.
Society of Animal Science, The-Pacific
The Commissioner's Decision
Legal Foundation, and the National
I As Commissioner of Food and Drugs, I' Cattleman's Association and are
referred to as the "intervenors." The
am, pursuant to 21 U.S.C. 360b(e](1) and
Bureau of Foods and the Bureau of
the authority delegated to me in 21 CFR
Veterinary Medicine of the Food and
5.1(a)(1), ordering withdrawal of
Drug Administration (FDA) appeared
approval of new animal drug
jointly in favor of withdrawal and are
applications (NADA's): 10421, 10964,
referred to as the "Bureaus."
11295, 11485, 12553, 15274, 31446, 34916,
Testimony was submitted in written
44344, 45981, and 45982. These NADA's
form, with an opportunity for oral corssare for diethylstilbestrol (DES) implants
and liquid and dry feed premixes for use examination. Written testimony was
given exhibit numbers. Citations to the
in cattle and sheep. This action is taken
record in this Decision are as follows:
on the basis of the record developed at'
manufacturing parties' exhibits (M-);
an administrative hearing held pursuant
Bureaus' exhibits (G-); intervenors'
to 21 U.S.C. 360b(e).
exhibits (PA-, PN-, PP-, PS-,); transcript
On this day I have also issued an
of cross-examination (Tr. at); entries in
order revoking 21 CFR 556.190. That

administrative (but not evidentlary)
record (Record No.); Initial Decision
(I.D. at). I also cite to the parties'
exceptions. Because the Bureaus'
arguments are most fully explained In
their brief to the Administrative Law
Judge, I sometinies refer to that
document.
The manufacturing parties have
requested oral argument (Manufacturing
Parties' Exceptions at 11), Because I do
not find oral argument necessary, I am
denying that request, cf. 21 CFR
12.125(e).
This Decision constitutes my findings
of fact and conclusions of law on the
issues in this hearing and supersedes the
initial decision. The statement of the
history of this proceeding set out below
is, however, taken with only slight
modification directly from the Initial
Decision.
Table of Contents
I. Introduction:
(A)Diethylstilbestrol
(B)History

(C] Issues
(D)General Introductory Comments
II.The Delaney Clause:
(A) Revocation of the Analytical Method
Regulation:
(1)Background

(2)Lack of Knowledge About Metabolism
of DES
(3) Inadequacy of Approved and the
Proposed Alternative Method:
(a)Inadequacy of Approved Analytical
Method
(b)The Gas Chromatography/Mass
Spectrometry Method
(4) Conclusion As to Analytical Methods
(B)Effect of Revoking Currently Approved
Method for Testing Drug Residues inEdible
.Animal Tissues Without Implementation of
Another Approved Method
(C)Conclusion As to Delaney Clause issue
II. The Safety Clause:
(A) Burden of Proof

.(B) Evidence That Dl9S Use Results In
Residues in Edible Tissues:
(1)The Withdrawal Period
(2)Radiotracer Studies:
(a)Oral Dosages in Cattle
(b)Implants in Cattle
(c)Oral Dosages in Sheep
(d)Implants in Sheep
(e)The Pseudo-DES Issue
(I)Conclusion As to Radiotracer Studies
(3) Findings by Department of Agriculture
Monitoring Program:
(a)Evidence of Residues
(b)The Question of Misuse
(c)Conclusion As to Findings By USDA
Monitoring Program
(4)GLC Residue Study
(C)The DES Conjugates Issue:
(1)Burden of Proof on Residue Issue'
(2)Failure of Manufacturing Parties to
Satisfy Burden of Proof
(3)Findings Assuming That Bureaus Have
Burden of Proof:
(a)Evidence That Residues Contain Pree
DES

Federal Register-/ Vol. 44, No. 185 1 Friday, September 21, 1979 / Notices
(b)Evidence eofack of Safety of DES
Residues
1c) Conclusion As to Conjugates Issues

Assuming Bureaus HaveBurden of Proof
(D) Evidence That DES Is Not Shown To Be
Safe
41) Relationship of DES to'Endogenous
Estrogens

(a) The Issues
(b) Differences Between DES and Natural
Estrogens
(c) Conclusion As to Relationship of DES to
Endogenous Estrogens
(2)Cancer Data
(a) Animal Carcinogenicity Data
(b) Human CancerData
(3) Adverse Effects of DES Other Than
Cancer
(a) Teratogenic Effects
(b) Mutagenic Effects
,(c) Other Effects
(d) No-Effect Level
(e) Conclusion As to Adverse Effects of
DES Other Than Cancer
fE) The Risk/Benefit Issue:
(1] Propriety of Risk/Benefit Analysis
(a) Legislative History
(b) The Agency's Position
[c) Policy Arguments
1d) Conclusion Asia Propriety oflRisk/
Benefit Analysis
(2) Risk/Benefit Analysis
(a) Quantitative Risk Assessment
(b) Introduction to Discussion of Bflnefits
(c) Health Benefits: Reduction in Fat
(d) Health Benefit: Feed Saving
(e) Economic Benefits

IF) Summary aT Safety Clause Issue:
IV. Liver Discard As an Alternative
Condition Of Use
V. Need for an Environmental Impact
Statement
VI. Exceptions to EvidentiaryRnlings
(A) Manufacturing Parties' Exceptions
(B)Bureaus' Exceptions
VIL Effective Date
VII1. Conclusion
I. Introduction
(A) DiethylstilhestrQo
DES is one of a class of chemicals
known as stilbenes. Stilbenes are not
produced.metabolically by animals: DES
does, however, produce effects similar
to those producedby endogenous
estrogens (G-189 at2).
DES is used as a growth promotant in
cattle and sheep. It is approved for use
as an additive to animal feed. 21 CFR
558.225. and as a subcutaneous ear
implant. 21 CFR 522.640. fIt is implanted
as a pellet of DES. which dissolves over
time and thereby provides DES
continuously to the animal's circulation.)
DES is a carcinogen in animals. See
section II below. This fact has been
noted by two different Courts of
Appeals, See Hess &Clark,Division of
Rhodia. Inc.. v. FDA. 495 F.2d. 975, 979
(D.C. Cir. 1974). Chemetzvn Corp.v,.
DHEW. 95 F2d. 995, 997 {D.C. Cir. 1974);
Bell v- Goddard,366 F.2d. 177, t1791h.
Cir. 1966). The "DES exception" to the .'

Delaney Clause, discussed below, was
written precisely because the Congress
understood thatDES is a carcinogen in
animals. See. e.g.. 108 Cong. Rec. 21077-

54&5

circumstances. As it appears in the
present new animal drug prorisil, the

added language is as follows 121 U.S-C.

W0bfd)(1l)H]}
[The Delaney Clause] shall not apply with
One of the issues in the hearing is
respect to [a drug that causes cancer] ifthe
stated as follows: "Is DES a carcinogen.
Secretary-finds That, under thetniiditions ol
and is there a known no-effect level for
use and feeding specified in pro psed
labeling and reasorably certain to be
its carcinogenic properties?" IID. at 2).
followed in practice (i) such drug will zot
The manufacturing parties do not argue
adversely affect the animals far which it is
that DES is not a carcinogen [though
Intended, and (it) no residue of such drug,will
they never concede that it is). Rather.
they argue that "there is a no-effect level be found (by methods of examination
prescribed or approved by theSecretary by
below which DES is not associated with
regulations. which regulations shall not be
carcinogenesis" (Manufacturing Parties'
subject to subsections 1c, (dJ. and (i) [of thIs
Narrative Statement at 1. Record No.
section), in any edible portion of such
76). In any case, manufacturing parties'
animals after slaughterir in any foods
yielded by or derived fronthe liviqg
witnesses have stated that DES is a
animals.* * *
carcinogen, though they argue it is only
as carcinogenic as endogenous
This amendment became known as
estrogens (see ManufacturingParties'
the "DES exception" because it was
Exceptions at 96-97).
enacted with the DES situationin mind.
The record shows that animal drug
See. e.g.: 108 Cong. Rec. 19916-1992
use of DES is banned in Canada (M-51
(Sept. 27,1962). (It has also been
at 29) and in many European countries
referred to as the "DES clause" or the
(M-64 at 24 G-84 at 59). DES was'once
"DES proiso.") In accordance with this
used as an implant in poultry, but
amendment. FDA in 1963 issued food
approval of thiat use has been
additive regulations providing for'the
withdrawn, see Bell v. Gcddacz , 5upra:
use of DES in animal feeds and
establishing official methods for
(B) History
detection, identificatioht and
The use of DES in feed premixes was
measurement of DES residues [28 FR
first approved in 1954 under section 505
15o7: Feb.1o. 19631.
of the Federal Food. Drug, and Cosmetic
The official assay method is
Act. The approval was based on data'
composed of the mouse uterine assay.
that demonstrated that. using the mouse
which measures total estrogeic activity
uterine test no residues could be
at 2 parts per billion (ppb). and the
detected in edible tissue of livestock 48
paper chromatography assay, which
hours after .withdrawal.
was thought to be capable of
Approval for DES implants in cattle
differentiating DES from other estrogens
also became effective in 1935 on the
at levels above 10 ppb. 21 CFR 555190.
basis of mouse uterine assay data
These assays have been approved since
demonstrating -no residue" under the
1963.
permitted conditions of use.
Since publication of the detection
Applications became effective for DES
method in 1963. a number of NADA's for
in sheep feed premixes and implants in
the use of DES have been approved by
1957 and 1959. respectively.
FDA (41 FR 1804: Jan. 12.1976.. In each
The current standards for approval of
instance, the agency concluded thatil
NADA's are set forth in 21 U.S.C. 360b.
when the drug was used in accordance
21 U.S.C. 3-0b(d)(l)(H) imposes
with the conditions of use prescribed in
additional Testrictions on the approval
the labeling. DES residues could notbe
of animal drugs that have been shown to detected in edible tissue bythe
cause cancer. Under that section, no
approved method, the requirements of
drug may be'found to be safe if:
the law were satisfied (id.). As
" . .such drug induces cancc: when
discussed in sections H(A) and 111(1B
ingested by man or animal or, after test:;
new information about DES and a
which are appropriate for the evaluation of
reevaluation of the data before the FDA
the safety of such drug. induces cancer In
at the time the method was approved
man or animal.' * "
have now placed this conclusion in
This language is the'codification in 21
question.
U.S.C. 360b of the anticancer clause that
Radioactive tracer studies conducted
was added to the Federal Food. Drug,
by the United States Department of
and Cosmetic Act by the Food Additives
Agriculture (USDA) in the early 1970"s
Amendmentof 1958. This language is
suggested that use of DES under the
referred to as the "Delaney Clause."
prescribed conditions of use ran result
In 1962, Congress amended the
in residues in edible tissues (id.). These
Delaney Clause to permitapproval of a
radioactive residues were found at
carcinogen as an animal drug in certain
levels that are below the sensitivity of
83 (1962).

54854

Federal Register / Vol. 44" No. 185 / Friday, September 21, 1979 / Notices

the'officially recognized assay methods.
(See section III(B)(2).)
On March 11, 1972, FDA published a
notice of opportunity for hearing on the
proposed withdrawal of approval of
NADA's for DES premixes (37 FR 5-264;
March 11, 1972). On June 21, 1972 (37 FR
122 1), a similar notice was issued for
both DES lremixes and implants under
the same provision of the a7t. The notice
'stated that the hearing procedures were
being invoked in order to develop on. the
public record the information necessary
for a formal decision on DES.
On August 4, 1972 (37 FR 15747),
hearings on DES liquid and dry feed
premixes were denied on the ground
that holders of NADA's failed to
demonstrate the presence of genuine
and substantial issues of fact. Approval .
of NADA's for DES premix was
therefore withdrawn (37 FR 15749)
pursuant to'21 U.S.C. 360b(d)(1)(H) and
360b(e](1](B). Final ruling on DES ,
implants was deferred pending receipt
of the results of a USDA study.
The USDA radioactive-tagged DES
implant study showed the presence of
DES residues 120 days after
implantation. On the basis of this
information, FDA withdrew approval of
NADA's for DES implants on April 27,
1973 (38 FR 10485) under 21 U.S.C.
360b(e)(1)(B). The same order denied the
requested hearings for lack of genuine
.issues of material fact.
The manufacturers petitioned for
review of the above orders under 21
U.S.C. 360b(h). The United States Court
of Appeals for the District of Columbia
Circuit reversed FDA's actions on the
procedural ground that it was necessary
to hold a public hearing before final
action could be taken. Hess & Clark v.
FDA, supra; Chemetron Corp. v. HEW,
supra.These decisions reinstated the
regulations and approvals for DES
NADA's.
On March 27, '1974 (39 FR 11299), the
FDA.proposed to revoke the approved
method of analysis for DES (mouse
uterine and paper chromatography) "on
the grounds-that this method failed to
meet the requirements of accuracy,
sensitivity and specificity. On January
12, 1976 (41 FR 1804), the agency
responded to the comments on this
proposal. On that date it also issued the
notice of opportunity for hearing that
initiated the present proceeding. The
FDA stated that it intended to revoke
the methods regulation at the time that ii
took final action on the notice of
opportunity for hearing.
The manufacturing parties requested a*
hearing and, on November 26, 1976 (41
FR 52105), FDA issued the notice of
hearing for this proceeding.

(C) Issues

The issues in this proceeding,
as set
forth at the February 14, 1977 Prehearing
Conference and modified by Order of
the Commissioner on March 23, 1977,
are as follows (I.D. at 2-3):
(1)Is DES a carcinogen, and is there a
known no-effect level for. its carcinogenic
properties?
(2) Does DES have any adverse biological
effects other than carcinogenesis that call its
safety into question under the previously
approved conditions of use and have safe
tolerapnce levels been established for those
effects?
(3)Has the existence of residues in edible
tissues resulting from the use of DES been
-sufficiently established to call its safety into
question under the previously approved
conditions of use?
(4) Have any residues resulting from the
use of DES implants and DES in feed been
detected in edible tissues of animals
presented for slaughter and are such residues
likely to 6ccur when the approved conditions
of use are followed?
(5).Are there adequate and reliable
methods, that are practicable for regulatory
purposes and capable of detecting and
identifying residues in edible tissue resulting
from the use of DES at all levels above the
level taken as the operational definition of no
residue, or at all levels above a level
established as a safe tolerance for any
noncarcinogenic adverse effects, whichever
is lower?
(6) Can adequate and necessary ion.ditions
for safe use be established?
(7) Is the mouse uterine/paper
chromotography mothod, which is th4 assay
currently approved for DES by regulation,
adequate and practicable for regulatory
purposes and capable of detecting and
identifying residues in edible tissues resulting
from the use of DES?
(8) If substances resulting from the use 6f
DES under the conditions of use on the basis
of which the NADA's were approved present
some potential hazard to the public health, do
the public health,'environmental and
economic benefits from the continued use of
DES as an animal growth promotant
outweigh that potential hazard?
(9) Will-the withdrawal from the market of
DES for use as an animal growth promotant
significantly affect the quality of the human
environment?
(D) GeneralIntroductoryComments
This Decision is a legal document in
which hre. resolved difficult scientific
issues. A few itroductory notes may be
helpful in understanding the discussion
that follows. First, the Decision discusses what'
might-at first appear to be very small-amounts of DES in edible tissues of
meat from treated animals. Yet, as a
respected cancer expert has testified,
we have no data upon which to base the
conclusion that any amount of a
carcinogen above the single-molecule
level would not produce a response (Tr.

at 266 (Dr. Shimkin)). (Two ppb DES in

100 grams (slightly less than a quarter of
a pound) of liver means that-there are
450 trillion molecules of DES In that
piece f liver (G-7 2 at 3),) The risk of
cancer would, of course, be expected Jo
be lower the smaller the number of
molecules of a carcinogen that are
ingested (cf. Tr. at 266).
Second, this Decision draws
conclusions from animal tests in which
relatively small numbers of animals are
fed relatively large amounts of DES. (As
discussed below in section llI(D)(2)(a) of
this opinion, however, some witnesses

testified that 6.25 ppb of DES caused
mammary tumors in mice'in the Gass
study.) Because animal tests can of
necessity use only a relatively small
number of animals (compared to the

total U.S. population that eats moat from
animals treated with DES), it would take
an extremely potent carcinogen to
demonstrate a response in an animal
test when a substance is adiministered at
the dose level at which humans actually
eat that substance, (See, generally, the
discussion of this problem at 42 FR
19998 (Apr. 15, 1977).)
A number of considerations are
involved in interpreting animal data,
and I do not wish to oversimplify that
task. But clearly, if one is concerned to
detect a substance that, at the dose level
at which it is.actually consumed, will
cause cancer in I in 10,000 individuals

(about 22,000 cancers in the U.S,
population), a test of that substance at
that dose level in 100 (or eien 1000)
animals is not likely to be successful,

Even-with 10,000 or 100,000 animals, the
number of "spontaneous" cancers Is

likely to obscure the effect of the
substance that causes cancer at the rate
of I in 10,000. For reasons of cost and

general practicality, most animal cancer
studies are limited to a couple of
hundred individual animals per dose
level. As explained at 42 FR 19998,
scientists generally assume that for
cancer and other toxic effects, the
amourit of an effect is a function of the
size of the dose administered although
there is controversy about effects of
very low doses. For these reasons, It Is
necessary and appropriate to utilize
results from higher dosages in small
numbers of animals to compute risks
from lower dosages in the human
population unless there is some reason
not to do so.
(As is discussed in section III(D)(1),
the manufacturing parties argue that
there are reasons for iot making this

extrapolation with DES. I explain in
'detail my reasons for rejecting those
arguments at the point in the opinion at
which the arguments are discussed.)

Federal Register / Vol. 44, No. 185 / Friday, September 21. 1979 / Notices
Third, the risk associated with DES
must be considered in light of the
widespread consumption of DES-treated
meat. In 1975, over 25 million head of
DES-treated cattle (and over 7 million
head of DES-treated sheep) were
reported slaughtered (G-68 at 3).
Fourth, although there is evidence,
discussed below, that DES used as
medication in pregnant women causes
cancer in some-of their female-offspring,
it is unlikely that -any individual will
ever be identified as having been
afflicted with cancer because he or she
consumed meat containing residues of
DES in the range of parts per billion. As
Dr. Saffiotti pointed out, because our
population is inevitably exposed to a
variety of carcinogens, it is generally
impossible (in the absence of evidence
of, for example, occupational exposure
to carcinogenic chemicals) to attribute
any specific cancer to any specific cause
(G-80 at 6]. Yet this record warrants a
finding that a significant (though
unquantifiable) number of the cancers
that do occur in this country today are
associated with the use of DES in foodproducing animals.
I. The Delaney Clause
There is no dispate that DES is a
carcinogen when ingested by animals
(see discussion above; G-22; G-34 at 1;
G-37 at 2; G-46 at 2; G-47; G-59 at 2; G-"
70 at 2; G-80 at 7-8; G-84; G-85 at 6). As
noted above in section I(B), I may not
approve (and must withdraw approval
of) the NADA for any animal drug that
induces cancer when ingested by
animals unless that drug comes within
the DES exception to the Delaney
Clause, 21 U.S.C. 360b(e)(1)(B); (d)(1)(H).
A drug comes within the DES exception
only if it is found that (1) the animals
treated with the drug will not be
adversely affected by it and (2) no
residue of the drug will be found, by
methods prescribed or approved by the
Commissioner by regulation, in the
edible products of the treated animals,
21 U.S.C. 360b(d)(1)(H.
The Administrative Law Judge found
that neither the approved analytical
method for DES nor any other analytical
method is adequate for use with DES
(I.D. at 51). He was not, however,
authorized to revoke the regulations
setting out the approved analytical
method for DES and did not purport to
do so. Because, at-the time of the Initial
Decision, there was an approved
method and no residues had been
reported by that method, the
Administrative Law Judge found that the
Delaney Clause had not been shown to
apply to DES {I.D. at 13),
For the reasons stated in the following
section, I am now revoking the

analytical method for DES. My decision
to do so is supported by the evidence in
the record, discussed in section II(A),
that no analytical method is acceptable
for DES. Because there is now no
approved method of analysis for DES, I
conclude that the Delaney Clause
applies to the drug. I therefore withdraw
approval of the DES NADA's on that
ground.
The Bureaus filed exceptions to the
Administrative Law Judge's ruling with
respect to the Delaney Clause. They
argue that, even if the methods
regulation were not repealed, the record
would nevertheless support withdrawal
of approval pursualnt to the Delaney
Clause under two theories:
First, they argde that the record shows
that DES causes adverse effects in cattle
(Bureaus' Exception at 7f). The question
whetherDES causes adverse effects in
animals was not stated as an issue in
this hearing. but some evidence that the
drug does cause such adverse effects
was elicited, primarily during crossexamination of an intervenors witness
(see Tr. at 2056-57; 2067; 2152).
Second, the Bureaus contend that the
showing by other analytical methods
that DES use causes residues above 2
ppb means that I cannot find that no
residues "will be found" by the
approved method (Bureaus' Exceptions
at 3). Under this theory, the lowest level
of detection of the approved method
would become, in effect, a tolerance
level, and a finding by another
(unapproved) method that an animal
drug caused residues above the
tolerance level would be a basis for
invoking the Delaney Clause.
Because I find that the revocation of
the analytical methods regulation for
DES requires invocation of the Delaney
Clause with respect to the DES NADA's.
I do not reach the issues raised by the
Bureaus' exceptions.
[A) Revocation of the Analytical
MAethod Regulation
(1) Background.The regulation
prescribing analytical methodology
necessary for invocation of the DES
exception (21 CFR 556.190) may be

revoked pursuant to the notice and
comment procedures prescribed in the
Administrative Procedure Act, 5 U.S.C.
553(c). Those regulations are specifically
exempted by 21 U.S.C. 360b(d)(1)(H)(ii)
from the additional requirements of
subsections (c), (d), and (h) of 21 U.S.C.
36ob.
The approved analytical method for
DES residues comprises two
independent measurements:
measurement of the uterotrophic effect
of DES in immature mice and
measurement of the migration

55

I
coefficient of DES by paper
chromatography, 21 CFR 556.19W. The
most recent proposal to revoke the FDA
regulation identifying this method as
approved was published on March 27,
1974 (39 FR 11299). The proposal stated
the agency's conclusion that the
approved method was inadequate to
satisfy the intent of 21 U.S.C.
360b(d(1)(H) (the Delaney Clause)
because its lowest limit of reliable
measurement was not shown to be.
acceptable. and because there were
unanswered questions about its
specificity and accuracy. That proposal
noted that the approved method was not
being used by the Department of
Agriculture in its monitoring program.
In the January 12. 1976 (41 FR 1804).

notice of opportunity for hearing in this
proceeding the FDA summarized, and
responded to, the comments received in
response to the March 27.1974 proposaL
That document stated that the method
would be revoked at the time of final
action on the notice of opportunity for
hearing (41 FR 1807).

In announcing the decision to revoke
the current regulations, the January 12,
1976 notice suggested that a replacement
method might be approved if
demonstrated to be adequate (id.). No
potential replacement, however, is
adequate. My analysis of the evidence
in the record on this issue with respect
to the approved method and the
manufacturing parties' proposed
replacement, the gas chromatography/
mass spectrometry method, follows. (A
second potential alternative method, the
radio-immunoassay, is not sufficiently
well developed for use (C-65 at 2 G--66
at 1-2) and is not relied upon by the
manufacturing parties.)
(2) Lack ofKnowledge About
Metabolism of DES. For an NADA to be
approvable pursuant to the DES
exception to the'Delaney Clause, that
NADA must contain an analytical
method that is capable of assuring that
no drug residue of toxicological concern
will appear in unsafe levels in edible
tissues of treated animals (see G-72 at 7;
G-5Z at 2). For DES we do not know
enough about the residues of
toxicological concerr to determine thatany analytical method would satisfy this
requirement.
Any substance that enters an animal
body is metabolized (changed) by being
broken down into smaller molecules, by
binding to other molecules already
present in the body, and/or by a
combination of breaking down and
binding. Therefore, it is expected (and in
this case shown by data) that part of the
DES administered to cattle and sheep is
metabolized into other substances (see.
e.g.. G-72 at 6-7). Residues of DES in the

. 54856

Federal Register / Vol. 44, No. 185 / Friday, September 21, 1979
----

I

edible tissues of cattle and sheep will,
therefore, be 'mlade up not only of DES
itself but also of the metabolites of DES.
The record reveals no testing.of the
metabolites of DES tiat would provide a
basis'fdr'determining which are the
metabolites about which one should be
concernid from-the perspective 'of public
health protection (cf. G-57 at 3). The
record provides no data that would
allow one to calculate at what-level any
metabolite that is a carcinogen might be
regarded as safe. Even if we knew what
the toxicologically important'
,
metabolites of DES were and what safe
levels of those metaboliteswere, I could
not find any analytical method
acceptable on this record. The record
provides no information about' the rates
of depletion of the different DES
residues in cattle and sheep. Without
that information,'I could not'determine
whether DES itself or any other residue
(i.e., a metabolite) of DES was tle
appropriate substance to be measured
by an analytical method. (Generally, a
method should detect one "marker"
residue, whose absence, as determined
by a method having a certain level of
sensitivity, assures that the total residue
wil not be-present above a safe level.
-computed for the total residue upon the
basis of testing of its components, see

I

the manufacturing parties' argument that
one need be concerned only about the
estrogenic effects of DES. Thus, I can
not presume that po nonestrogenic
metablite of DES i's 6 f' ublic health
signifi6anice. I caninot, therefore, find
that a method able to measure only
estrogenic DES metabolites is
acceptable.)
The lack of necessary information-,
about the DES residues to be measured
is itself a basis for revoking the
currently approved analytical method
and refusing to approve the gas
chromatography/mass spectrometry
method proffered by the manufacturing
parties as an alternative. Moreover,
there are serious faults with each of
these methods, which would make them
unusable even assuming 'that DES itself
were the only DES residue of concern.
(3) Inadequacy of the Approved and
the Proposed
Alternative Method. The
lack of a showing that either the "
approved analytical method or the gas
chromotography/mass spectrometry
method detects DES residues at a level
low enough so that those residues do not
pose a significant risk of cancer is the
most important failing of the methods.
Each of the.deficiencies discussed.
however, (exoept for the deficiency in
the approved method with respect to the
G-24 at 10423 (44 FR 17070, 17095; March attribute of specificity) is an
20, 1979).) ,
independent basis for disapproval of
these methods.
As the Administrative Law Judge
noted I.D. at 41), Congress recognized
(a) Inadequacy 6f Approved
that the safety of an animal drug to
AnalyticalMethod. The record in this
human consumers is dependent in part
case supports the FDA's previous
decision that the regulation setting out
upon their consumption of that-drug's'
metabolites ("any substance formed in. the mouse uteine/paper
or on food because of use of such drug"), chromatography method as approved
21 U.S.C. 360b(d)(2)(A). As noted, DES
must be revoked. The attributes upon
residues, may include both DES itself
the basis of whiidh a method of analysis
and itsmetabolites. Without knowledge
is judged include accuracy,
of (1) what the toxicologically important
dependability, lowest limit of reliable
measurement, practicality and
residues of DES are, (2) what levels of
these residues may be considered safe,., specificity (G-26 at 1-2; G-72 at 2, 9-10).
For a method to be approved or remain
and'(3) what the relationship of the
various residues of DES to each other is, approved by the FDA, each of the
method's attributes must be adequate
I cannot responsibly conclude that any
analytical method for DES will provide
for regulatory purposes.
assurance that edible tissues of'treated
(i) Accuracy and Dependability.The
aninials will not be hazardous. (See Cmouse uterine assay requires that the
72-at 6-7.)
uterine weight of mice fed the liver to be
(The manufacturing parties might
tested be compared to the uterine
weight of mice fed control. tissues. The
argue that I do not need information'
proposal to revoke the regulation
about the metabolites of DES because
approving the method noted the
the approved method would detect notpossibility that estrogenic substances in
only DES itself but also its metabolites
the control tissues might cause DES in
that produce an estrogenic effect (cf. M110 at 10). There are, however, a number the tested tissues to go unnoticed.
Therefore, a question was raised about
of metabolites of DES that are not
the accuracy of the method (39 FR
'known to produce an estrogenic effect
11300). At the hearing, Bureaus' witness
(see G-189 at 3-4). 1 discuss below, as
part of the section (section Im(D)(1) of
Dr. Rodricks stated his opinion that this
method had not been shown to be
this opinion) dealing with the so-called
"safety clause," my reasons for rejecting accurate, but he did not explain the

1

Notices
II II

n

reasons for this statement (G-72 at 910).
FDA did not rely upon the lack of
accuracy of the approved method In the
1i976 decision to revoke theegulations. I
do not, on the basis of this record, now
rely on the alleged inadequacy of he
method with respect to that attribute,
The Bureaus offered no evidence
(other than the unexplained opinion of
Dr. Rodricks (id.]) that the mouse
uterine/paper chromatography method
is not dependable. The Bureaus did"
argue that certain problems-namely,
technical and environmental controls
and performance time-may affect
dependability and accuracy. These
problems, however, are matters of
practicality and are treated below under
the discussion of that attribute. Thus, I
do not find the approved method
inadequate with respect to the attributes
of dependability and accuracy. The
mouse uterine/paper chromatography
method, however, has been shown to be
unacceptable for regulatory purposes
with respect to the remaining three
attributes.
(H)Lowest Limit of Mebwuremenl. The
prime attribute of i method, the lowest
limit of reliable measurement, is the
level (or amount) of the chemical under
analysis below which the assay will
_yield no interpretable results (-72 st 2).
The mouse uterine assay can
consistently measure estrogenic activity
at the levels of 2ppb DES equivalents
(G-67 at 2; G-72 at 2-3; M-2 at 1; see
also M-153 at 1; M-170 at 2). it does not,
however, distinguish DES from other
estrogens G-67 at 3; M-02 at 1).
Paper chromatography is used with
the mouse uterine assay in an attempt to
provide the requisite specificity. Paper
chromatography is alleged to be able to
distinguish DES from other estrogens at
levels equal to, or greater than, 10 ppb
(G-72 at 10; cf. M-170 at 2). Assuming
that this claim for the paper
chromatography method is correct, the
*lowest level of reliable measurement of
the approved method is effectivelylo
ppb DES in liver tissues.
The manufacturing parties argue that
2 ppb should be accepted as the lowest
limit of reliable measurement of the
approved method. They argue, in effect,
that if no residue is detected by the
mouse uterine assay, one can be assured
that no residue of 2 ppb DES or above
exists. If a residue is detected by the
mouse uterine assay, on the other hand,
they argue that "additional samples of
tissue can be analyzed by a variety of
more specific techniques, such as gas
liquid chromatography with mass
spectrographic analysis" (M-110,at 31:
Manufacturing Parties' Exceptions at
193). This argument, rather than

Federal Register / Vol. 44, No. 185 / Friday, September 21, 1979 / Notices
supporting the current method, in fact
suggests that a new combination of
assays should be substituted for those
currently approved.
In any case, whether the lowest limit
of the approved method is 2 ppb or 10
ppb, that limit is not acceptable because
there is no basis for concluding that
residues below either of those levels
will not cause cancer in human
consumers. (As the Administrative Law
Judge noted, each of these limits is very
close to the 6.25 ppb dosage that was
reported to have resulted in a
carcinogenic effect in the Gass mouse

study (G-22) see section III(D)(2)(a)).)
My conclusion that no no-effect level
has been shown for the carcinogenic
effects of DES is discussed in detail
below in section III(D)(2). Bureaus'
witnesses Dr. Gross and Dr. Rodricks
did calculate, using the Gass study (G22) data, that no more than I part per
trillion (ppt) of DES in the diet would be
consistent with a risk of I cancer in one
million consumers (a cancer rate
assumed to be "acceptable" or
"insignificant" or tantamount to-no
cancer) (G-34 at 2; G-72 at 4). (Another
witness, Dr. Condon, had calculated the
same figure from the Gass data, but did
not purport to apply it to human beings
(G-21 at 3).] Neither the approved
analytical method nor any other method
known to me is capable of iheasuring
DES at the I ppt level.
Dr. Gross' testimony suggests, but,
read carefully, does not state, that his
calculation accorded with the
regulations published by FDA to
describe the agency's requirements for
analytical methods under the DES
exception (see G-24). That regulation

has been invalidated on procedural
grounds, Animal Health Institute v.
FDA, Civil No. 77-806 (D.D.C. Feb. 8,
1978) and reproposed in a somewhat

modified form (44 FR 17070; March 20,
1979). I do not, in this Decision, rely on
either the invalidated regulation or the
proposal. It must be noted, however,
that the I ppt calculation of Dr. Gioss
and Dr. Rodricks neither accords with
the procedure set out in the regulation
nor represents an appropriately
conservative calculation of a "safe"
level for DES (cf. Tr. at 1082).
As discussed in section II(A)(2), DES
residues in meat can be expected to be
made up not only of DES but also of
various metabolites of that substance.
The computation of a "safe" level of
DES must therefore be based upon the
results of animal testing not only of DES
but also of the metabolites of DES that
appear suspect (cf. G-72 at 10). If steers
transform DES into a metabolite that is
not produced when DES is fed to mice
and that metabolite is more carcinogenic

-

.54857

claimed as the lowest level of
than DES itself, calculations from the
Gass mouse data will provide a "safe"
measurement for the approved method.
dose that is too high.
My rejection of 2 ppb as an adequate
The criticisms of the Bureaus'
lowest limit of measurement does not
witnesses' calculations of a I ppt "no
reflect any "never-ending search for
residue" level for DES set out above
more and more delicate methods of
show only that that calculation is not
analysis" (see Manufacturing Parties'
sufficiently conservative. Testing of DES Exceptions at 28). Rather, it reflects a
metabolites might produce a lower "no
"rule of reason" (id.), which embodies
residue" level for the totality of DES and the basic principle that a method of
its metabolites but would not produce a
analysis should have a lowest limit of
higher one.
meaurement that is low enough to
The manufacturing parties, however,
protect the public from cancer caused by
argue that the procedure utilized in
an animal drug. My dissatisfaction with
calculating the I ppt figure is totally
the limit of 2 ppb is based on the
invalid from a completely different
evidence of record that DES is an
perspective. They rely on the testimony
animal carcinogen and the lack of
of their witness, Dr. Weaver, and upon
information sufficient to show that DES
various internal FDA memoranda to
and its metabolites, when present at the
support their criticisms of the method of level just below 2 ppb, are safe or
calculation used. They argue that that
present an acceptable risk.
method is based upon unduly
The
(iii)Practicality. manufacturing
conservative assumptions and has not
parties argue that practicality is not an
been shown to provide consistent
attribute necessary for approval of an
results when the same data are utilized
analytical method for purposes of the
as a basis for calculation
DES exception to the Delaney Clause
(Manufacturing Parties' Exceptions at
(Manufacturing Parties' Exceptions at
195-204). They also argue that the
210). They base their argument on
Bureaus' witnesses used the wrong data
statements made by former FDA chief
as a basis for their conclusion. They
counsel Peter Hutt before a
contend that a proper calculation would
Congressional committee (id.). Contrary
(1) be based upon all data in the Gass
to the manufacturing parties' position.
study, (2) ignore the 6.25 ppb result, and
however, Mr. Hutt did not say that an
(3) incorporate results from the
uncompleted NCTR study (discussed in. approved method need not be
sufficiently practical for regulatory
section Ilr{D)(2)[a) of this Decision) (id.
purposes. Rather, he said that a method
at 204-06).
need not be approved to be used for
The FDA, as noted above, had issued
regulatory purposes. Hearing before the
a regulation that relied upon the method
Health Subcommittee of the Senate
of calculation purported to have been
Labor and Public Welfare Comm. on S.
used by Drs. Condon and Rodricks (but
2818, 92d Cong., 2d Sess. 41 (1972). More
not by Dr. Gross (Tr. at 423) (G-24)). I
importantly, as a matter of common
decline to decide, on this record,
sense, I can not find that no residues of
whether the method utilized (the
a drug will be found in edible tissues of
modified "Mantel-Bryan technique") is
treated animals by an analytical method
-appropriate for use-or was applied
correctly here-because, for the reasons if that method is not practical enough to
be used to analyze such tissues in the
stated above, I find I ppt calculation
normal course of business.
unusable in any event and I do not rely
The mouse uterine/paper
on it.
The decision not to rely upon the 1 ppt chromatography method is not practical
for regulatory purposes. As the record
figure avails the manufacturing parties
shows, it takes over 2 weeks to perform
not at all, however.My criticism of the
the assay (G-26 at 2-3; G-67 at 3; M-170
Bureaus' 1 ppt calculation applies with
equal force to the manufacturing parties' at 2]. The meat of animals whose livers
were examined would normally have
alternative calculation; they, too, ignore
moved to market in a 2-week period (Gthe issue of DES metabolites. I am left,
26 at 3]. One manufacturing parties'
therefore, with the conclusion that no
no-effect level or acceptable level of risk witness did testify on cross-examination
that he performed the assay in 9 days
has been shown for DES. The record
(Tr. at 1846). The fact that one
does not allow me to determine what
laboratory can perform the assay in 9
level of DES might be low enough to
days does not mean that regulatory
cause less than one cancer in one
million persons (assuming that that level laboratories carrying on a variety of
work can consistently perform it in that
may be equated to "no residue"). The
period. Moreover, even if the assay
record provides no basis for concluding
that that level is not well below the 2
could be completed consistently within
ppb that the manufacturing parties have 9 days. that length of time would
-

54858

Federal Register / Vol. 44, No. 185 / Friday, September 21, 1979 / Notices

constitute an unacceptable delay in the
(i) Lowest Limit of Reliable
The first type of measurement of the
regulatory process.
approved method, i.e., measurement of
Measurement. Expert testimony at trial
The evidence also revealed that the
firmly established that for regulatory
uterotrophic effect in immature mice,
mouse uterine/paper chromatography
purposes the lowest limit of reliable
can provide either one of two answers
method is technically difficult to perform to this question:
measurement is 2 ppb (M-38 at 17-18:
(-67 at 3). A large number of mice are
M-93 at 2; M-12a at 8; M-164 at 1; 'Tr.at
'"herais no DES at levels at or above 2
required (Tr. at 514], and their
1361). For the reasons discussed In
ppb"; or alternately, "There are X DES
environment-including cages and
detail in section II(A)(3)(a)il) above,
equivalents (di or above 2 ppb some of
feed-must be carefully controlled (G-that limit is not acceptable for approval
which might be DES."
67 at 3). Neither the quantity of animals
of an analytical method for DES.
are expressed as
nor the technical expertise necessary for (Measured residuesbecause the re ' idue
(i) Specificity. Like the mouse
"DES equivalents"
use of this method are generally
uterine/paper chromatography method,
content of analyzed tissues is compared
available in government regulatory
the gas chromatography/mass
to known amounts of DES added to
monitoring laboratories (G-26 at 3). The
spectrometry method is not adequately
tissues fed to control mice.)
United States Department of Agriculture
specific for regulatory purposes. The gas
The record contains no inforimiation to chromatography/mass spectrometry
has determined that the method is not
practical forregulatory use (Tr. at 487]. I show-that an analyst finding X DES
method upon which the expert
equivalents can say with some specific
reach the same conclusion.
testimony was based (known as the
(iv) Specificity. Specificity is one of
level of confidence, say 50 or 60 or 90,
modified Donoho procedure) is
the cardinal attributes of a regulatory
that no more (or less) than a fraction of
described in M-39. This method
method. The method should respond,,'
those equivalents is-indeed DES. Thus,
provides for the selection of a single
the measurement of uterotrophic effects
monotonically to (i.e., show a
mass or ion for identification (M-39 at
continuously increasing response to)
in immature mice is entirely nonspecific. 521-22], Yet, as'the manufacturing
increasing concentrations of the,
parties' Dr. Abramson testified, the
This is so evenoif it is assumed that
substance measured (DES) and that,identification of a Single mass or idn
.increasing DES equivalents in the tissue
substance only. My analysis of t6he°,
does not allow definitive identification
will cause increasing responses, i.e., if
evidence on the issue reveals a problem. monotonicity of response is assunmed. It
without a confirmatory step in which
more than one ion must be monitored
The Bureaus did not provide xpertT
has not been demohstrated, however,testimony that the approved method is.
(M-38 at 13-14). Therefore, It appears
that this method-even prbduces a
not sufficiently specific. Indeed, one
that the method as described In M-39 is
monotdnic response. (It is conceivable
Bureau witness stated that'the paper ,
and indeed, judging fro& tie developers' not sufficiently sensitive to detei~nine
I ....
chromatography assay provides the
identity ieliably. -,,
, description of this assay'(G-68 at 811
requisite spd6ifidity-to the approved
There is a direct relationship betwd0n
and 812, Fijue 3],.likely that, at some
the number of ions monitored and the
method (G-7Z at 10). Yet, there is no
leVel, an increase in DES-could fail to
objective evidence in'
lowest limit of reliable measurement In i
therecord--i
increase'uterine growth.]
Paper chromatography of tissue
elsewhere, as far as I know-thilat the
this method. Increasing the number'of
approved method is sufficiently specific.
monitored ions yields a higher lowest
Iconclude that the approved methods _.xtracts was incorporafed into the;
limit of reliable measurement (see, e.g.,
approved analytical method s6 thatithe
are notadequately specific forise;I
M-38 at 19), Thus, achieving specicity
•analyst.' could ascertain
it fraction, if
recognize that, becafuse the Bureaus
with the gas chromatography/mass
any, of whaat might be! DES is indeed
failed to advance this argun'enf, it
spectrometry method will yield a higher
DES. lrgdneral, chioinatography of anny
would be unfair to ely upo ftit a' a
lowest limit of reliable measurement
kind is 'anon-specificxethod of
basis forrevoking the approved-:
than the 2 ppb suggested by the experts,
analysis.'Thid lack of specificity of
methods. There axe,_ however, th~ee
(4] Conclusio Aa to Analytical , chromatog .aphic methods ias alluded
Methods. For the foregoing reasons, I
other independent bases fdr my &
dcision
to by Dr, Abiamson in his testimony (M- find that neither the approved:method
to revoke the approi.aI of this me thod:•38) discusSing gas liquid '
.
nor any other method is acceptable as
(1)'the fact that there has bebn 'no,
chromatography, one of the most
an analytical method for DES fdr
showing that this assay provides
'specific chromatographic methods of
information about the levels in ediblepurposes of the DES exception to the
today. Single run paper chromatography, Delaney Clause, As noted, by order
tissues of all of the metabolites of DES
one of the most primitive
issued today, I have revoked 21 CFR
that potentially have a carcinogenic
chromatographic methods, is Iss
556.190, the regulation approving the
effect. (2) the failure of the method to
specific than.gas chromiatography. I can
measure DES residues at a level at .
current analytical method for detection
not agree that this assay is specific
of residues of DES.;
which those residues are shown-not to
enough for the purposes at hand.
present a significant risk from cancer
(B)
Effect of RevokAig Currently
(b)-The Gas Chromatography/Mass
and (3) the method's impracticability.
Approved Methddfor Testing'Drug
Spectrometry.Method.The-evidence
For that reason, I reject the idea that I
Residues in Edible Animal Tissues
that the gas chromatography and mass
must either accept the consensus of
spectrometry assays when used together WithoutImplementatiogofAnother
testifying experts that the method is
Approv~dMethod
sufficiently specific or remand the issue, constitute a method that is accurate,
An applicant for approval of art
dependable, and practical (M-38 at 15for further consideration. I wish to make
18, M-12 at a) is convincing and not
NADA for a carcinogenic drug must
clear, however, that I do not rely. on the
submit, as part of that NADA, an
seriously controverted by the Bureaus.
following expression of my views on
acceptable method of analysis to detect
Like the mouse uterine/paper this subject as basis for my rejection
chromatography method, however, the
residues of the drug in edible products
of the approved method.
gas chromatography/nisS spectrometry
of the treated animal. 21 CFR
The question that must be answered
514.1(b(7)lii). The statutory provision
by-an analyticai method for DES is: "in method is inadequate with respect to its
lowest limit of reliable measurement
this tissue;is there DES and, if so, how
describing the contents of an NADA is
and with respect to its specificity.,
clear- it requires the submission of a
much?"

Federal Register I Vol. 44, No. 185 1 Friday, September 21, 1979
NADA beyond those listed in 21U.S.C.
360b(e)(1) (ManufactringParties"
Exceptions at 27-32).
The -manufacturingparties' reliance on
the Hess , Clark and Chemetron
opinions is misplaced. Neither opinion
addresses the issue of the operation of
21 U.S.C. 360b[d)(1)(H) in the ubsence of
regulations Zescribing an approved
method for determining whether drug
residues exist inedible tissues. The court
in Chemetron does state: "The 'DES'
exception to the Delaney Clause,
discussed above, continues effective
unless the agency detects residues in a
September 14,'1971 (36 FR 18375). was
slaughtered animal while using an
the first interpretation by regulation of
approved test method. "495 F.2d at 999.
the 1968 New Animal Drug
The context in-which this statement is
Amendments.)
made, however, makes it clear that the
When an applicant for approval of an
court was not considering a situation in
NADA for a carcinogen fails to submit
an adequate analytical method to detect which no method was approved. Rather,
the court was assumning the continued
residues, it of rcourse follows thatno
existence of an approved method.
regulation setting out an approved
The legislative history of the DES
analytical method will be promulgated
for the applicant's drug.7The agency then exception does not support the
manufacturing parties' argument. The
cannot find that no residue of the drug
Delaney Clause was added to the Food
will be found by an approved method;
Additives Amendment pased in 1958
the DES exception to the Delaney
(Pub. L No. 85--929. 72 Stat. 1785). The
Clause can not be applied; the Delaney
Delaney Clause was then incoiporated
Clause does apply and the NADA may
not'be approved, 21 US.C. 360b[d}[1)(H). in the 1960 Color Additive Amendments
(Pub. 1. No. 86-618,74 StaL. 399). The
If the Commissioner determines,
based on new information together with DES exception was first proposed during
consideration of the Color Additive
previously available information. that
Amendments in 1960. See. eg.. -LR.
the approved analtyical method for
RepL No. 171, 86th Cong., 2d Sess. 89
detecting residues of an animal drug is
(1960). It Finally was added Jo theFood
inadequate, it is his responsibility to
additive and color additive provisions
revoke the regulation that sets out that
as part of the Drug Amendments of 1962
method. 21 U.S.C. 360b[e)(1) then
(Pub. L. No. 87-781. 76 Stat. 785). The
compels him to withdraw all NADA
1968 New Animal Drugs Amendment
approvals that were based on
compliance with that regulation because (Pub. L. No. D0-399, 2 Stat. 343).
consolidated the Food additive and new
21 U.S.C. 360bld)(1}[ (the-Delaney
drug provisions that dealt with animal
Clause) becbmes applicable to the drug.
drugs and incorporated the DelanEy
The manufacturing parties argue that
Clause and DES exception from the food
the DES exception remains in effect
additive provision.
unless and until the FDA finds illegal
The legislative history-does not
residues, using an approved analytical
contain any direct statements of haw
method, in the edible tissues of animals.
the Delaney Clause and DES exception
They contend-that if there is no
should apply to a drug for which no
approved analytical method to measure
analytical method is approved. That
residues, the Delaney Clause does not
history does clearly support. howerer,
authorize withdrawal of NADA
two propositions, each of which is a
approvals, no matter how high the
basis for the agency's in!'rpretaticn of
residue levels may be. The
the statute and its rejection of the
manufacturers claim support for their
manufacturing parties' contrary
theory in the opinions in Hess &Cark
interpretation.
supra,and Chemetron,supra. the
Firstit is clear that the burden was
legislative history of 21 U.S.C.
placed upon the NADA appEcant to
360bd)[1)(H), and statements made by
develop an appropriate method of
FDA officials in 1972. In addition, they
argue that withdrawal of approval of the detection. In a letter submitted to the
committee holding hearings on the DES
DES NADA's due to revocation of the
exception as proposed in 1950, the
currently approved analytical method
Secretary of Health, Education and
would constitute an administrative
Welfare, stated:
repeal of the DES exception and permit
the Commissioner to expand the
illt should be clearly understood that the

"description of practicable methods for
determining thequantty, ff;any, of [thel
drug in or on food, and any substance
formed in or xn food, because of its use
* * *,.21 J.S.C. 36oblb)t7). In addition,
as the legislative history of the DES
exception (discussed below) shows, that
provision contemplates that the
applicant will have the responsibility for
developing an analytical method for a
carcinogenic drug. This has been-the
FDA's consistent interpretation of the
new animal drag provision. (21 CFR
514.1(b)(7](ii), promulgated on

grounds for withdrawal ofan approved

industry still would have the responsibility of

1 Notices

52. 59

developing adequate analytical methods for
detectingxesidues andfurnishing them to the
government with a petition for the approval

or an additive.
(Cited in Hearings of FDA "Study of
the Delaney Clause and Other
Anticancer Clauses"Before a
Subcommittee of the Committee on
Appropriations, 93rd Cong., 2d Sess.
203-0411974).) The manufacturing
parties have cited nothing in the
legislative historyof the DES exception
that conflicts with the Secretary's
expressed understanding of that
exception.
Congressional inquiries into the DES
exception since its passage have also
supported the agency's view that an
applicant must produce an acceptable
analytical method. See, e.g.. HR. Rept.
No. 93-70K. 93rd Cong., 1st Sess. [1973),
at17, 26-27.
This allocation of burden is consistent
with the general scheme oT aUl the
premarketing clearance provisions of
the Food, Drug, and Cosmetic Actthose coveming food additives (21U.S.C
348, adopted in 1958). color additives (21
U.S.C 376, adopted in 1960). human
drugs (21 U.S.C 355, adopted in 1938 and
amended in 1962) and animal drugs (21
1968). Under all
U.S.C 360b. adopted in
of these provisions Congress has
consistently required that the
manufacturer or other sponsor seeking
approval of a substance or aproduct
satisfy the burden or proving every
Pelment necessary for approval. See 21
U.S.C 348[b; 355b(b); Z0(b), S76(b). The
present case merely illustrates this
fundamental and broadly applicable
principle of public health protection
.deeply embedded in the Federal Food,
Drug, and Cosmetic Act. There is no
reason to treatthe requirement for an
adequate analytical method for residues
caused by a carcinogenic animal drug
any differently than the requirement that
a food additive or color additive or
human drug be shown to be safe.Thus,
it is the manufacturing parties'
responsibility to develop an acceptable
method, and it follows logically that, if
there is no acceptable method, Congress
did not intend the manufacturing parties
to benefit from that fact.
Second, the legislative history
illustrates Congress' understanding that
the Delaney Clause would apply unless
the Commissioner could make a finding
that no residues will be found in the
products of the treated animal In
responding to the argument that-the DES
exception would diminish the Delaney
Clause's protection of the public health,
Congressman Harris stated (06 Cong.
Rec. 21081 (19621:

54860

-I

I Federal Register / VoL 44, No. 185 / Friday, September 21, 1979 / Notices

This amendment places the. resonsibility ora
the Secretary of Health, Education and
Welfare to make a positive finding that unde
the conditions of use and feeding'specified in
the proposed labeling and reasonably certain
to be followed in practice, the feed'additive
will not.,first, affect the animal; and, second,
that no residue of the additive will be found
in any edible portion of the animal after
-slaughter (emphasis added).-

forwarded by FDA to Senator Proxmre
-The congressional:understanding that
in 1972 (M-167 at 4191-92), This
the Secretary (or, by delegation, the
statement, that the Delaney Clause
Commissioner) could find that "no
requires findings by the approved
residues" would be found in edible
method, assumed, as did Mr. Hutt's
tissues may have been based on an
statements, that an approved analytical
operational definition of the term "no
method existed for the drug in question
residue" as equivalent to no residues
above a level that can be considered
(there DES), That statement did not
the question of the applicability
virtually safe. FDA has interpreteed the.
DES Exception in this way (see, e.g., 44
of that clause when there Is no approved
As the manufacturing parties point out,
FR 17070 (March 20,1979); G-24).
method.
Congressman Harris had earlier.been
Another conceivable explanation, which
The manufacturing parties' argument
assured that the DES exception
I consider improbable, is that the
that withdrawal of an NADA on the
'provided "the authority for the Sectetar Y Congress was less scientifically
basis of revocation of the methods
to see that no residue of the additive.I sophisticated and believed that it was
regitlation is an administrative repeal of
shall be found" (id. at 21080)..
possible for the Commissioner to find
the DES exception is without merit. As
Senatoi Kefauver, a sponsor of the
that absolitely no residues would exist
Commissioner, I may not, of course,
Drug Amendments in the Senate,
in the edible tisisues of treated animals.
simply ignore the DES exception to the
In any case.'there was, without
explained the DES exception as follows
Delaney Clause, Aor may I act
(108 Cong. Rec. 20869 (Oct. 3, 1952)):
question, a c6ngressional concern that
arbitrarily and capriciously when a
the Com'ixssioiier find that there are
method is submitted for approval. I must
The provision stipulates that the anti--approve an analytical method Ifan
cancer proviso of existing law shall not app y "no re'sidifes" in edible tissues and there
was a belijf onthe part of the legislators 'appropriate one is presented. On the
with respect to the use of a substance-for
example, a, veterinary drug- as an ingredier it that the DES exception did nothing to
other hand, it is implicit in the statutory
of feed for animals which are raised for foodI
diminish the irotection to the public
requirement that the Commissioner
* * *'thatI
production if the Secretaryfihds
,health affided by' the Delaney Clause.
"prescribe or approve" the methods of
no residue of the additive will befound dftei
It is hardly cionsistent with that,
analysis that he must evaluate the
slaughter or rn any food product of the living
congressional intent to urge that
method submitted and refuse approval
animal-such as milk oreggs (emphasis
Congress meant the Delaney Clause to
of that method if he finds It inadequate.
added).
be inapp46able whenever no analytical
In sum the withdrawal of approval of an
method had-been approved for a drug.
SenatorHumphrey, also a itrong
NADA upon revocation of the analytical
'-The iniufacturing parties rely upon a method upon which approval is based
supporter of the Drug Amendments (10f
statementby foimer FDA chief counsel
Cong. Rec. 2Z,053 (1962)), described the
implem'ents, rather than subverts, the
Peter Hutt at a 1972 Congressional
DES exception and then stated that it
statute, including the DES exception.
hearing. In the 'atnent referred to,,he
(c) ConclusionsAs to Delanoy Clause
preserv[esl in its full vigor the Consumer
defended the-proposition that the
protection now afforded by [the Delaney
Issue. Foi the reasons discussed in this
Delaney Clause did not sanction
Clause].
section I, I find that (1) approved
I reiterate-consumer protection is assure d. withdrawalofapproval of NADA's
analyticaIl method for detecting DES
based on the-fifidiiig of residues by
residues is inadequate and that (2) no
These quotations (particularly the finat unapprove'd'.ithods, hearings on
alternative method is adequate for, use
two) reinforce the conclusion that is
Regulatioi-of Dieiylstilbestrol Before
as an analytical method to detect DES
already clear from the language of the
the Interg6v niitaI Subconimittee of
residues.I reject the manufacturing
statute: the operations of the DES the House' Go~erient Operations
parties' argument that the DES
exception depends on the Commissione
Committee, 92d Cong:, 2d Sess. 385
exception to the Delaney Clause is
making a finding of no residue (byuse f (1972). Mr. Htit. advocated-his position
applicable if there is no approved
a method approved by regulation). The
e forcefully arid 9xtemporaneously (at one analytical method for DES residues, I
DES exception does not begin to operat e point iiformimig th& Committee that
conclude, therefore, that the revocation
without that prerequisite finding. Clear]Y Congress did not appreciate what it was
of 21 CFR 556.190 requires the
excluded by the language and.the ,
doing in pasihg 1he DES exception (id.
withdrhwal of approval of the DES
legislative history is the manufacturing
at ;86)). His statements cannot fairly be
NADA's hursuant to 21 U.S.C.
parties' interpretation that the exceptio n taken out of context to bear upon a
360b(e)(1)(B) and 360b(dJ(1j[H).
"questio--4Avhether the Delaney Clause
can apply without the prerequisite ,
finding and that the discovery of some
applies if tre is' fio approved method
III. The Safety Clause
residue is'necessary to prevent or stop
fora'drug--entirely different from the
[a) Burden of Proof
its operation. That interpretation is
-issue he vas addressing.,'
totally inconsistent with the
.To the'extent that Mr. Hutt's
for purposes of convenience, I refer to
comments'may be read to suggest that
explanations offered by Rep. Harris an(
that part of 21 U.S.C, 360b(e)(1)(B) that,
the Clause does not apply when no
Senator Kefauver and it certainly wouk
does not deal with the Delaney Clause
not preserve consumer protection "in itis method exists, I explicitly disavow them
as the "safety clause," The' burden of
full vigor" as stated by Senator
on-behalf of the FDA. Such a reading
proof in this proceeding on the safety
would be inconsistent with the
clause issue is derived from the clause
Humphrey. Indeed, under the
languagejlegislative history, and
manufacturing parties' interpretation,.
itself, which is as follows (21 U.S.C.
purpose of the statute and with the FDA
any deficiencies in analytical
360b):
policy that supports the proposed ....
methodology-that prevented
(e)(1) The [Conmmissionerl shall, after due
regulations setting-requirements for identification of residues in the range
notice arid opportunity foi hearing to the,
analytical methods (44 FR 17070 (March
material to protection of public health
applicant, issue an order withdrawing
.
.
would be at the expense of public healfl 20, 1979), cf. G-2).
approval of an application filed pursuant to
I The maunfacturing parties also.refer
, subsection [b) of thid section with rospe bt to
,protection. That certainly-is not-what
any new-animal drug Ifthe [Commlslonerl
to-a statement included in.material I .
Congress intended.-address

Federal Register J Vol. 44, No. 185 1 Friday, September 21, 1979
finds* * ' (b) that newevidence-not
contained in such -application or not available
to the lCommissionerl until aftersuch
application was approved, or tests by new
methods. -or tests by methodsnot deemed
reasonably applicable when such application
was approved, evaluatedtogetherwith the
evidence availableto thelCommissioner
when the application was approved,shows
that such drug is not shom to be safe for use
under the conditions oT use upon the basis of
-which the application -wasapproved
(Emphasis added).

-

As is apparent from-the italicized language, approval-may be withdrawn
pursuant to the "safety clause" if new
evidence, evaluated together with
1-previously existing evidence, shows the
-drug is not-shown to be safe. As
Congress was careful to make clear,
.. new evidencd" includes any evidence
not available at the time the application
was approved, tests by new methods,
and tests by methods not originally
considered applicable.
There does not appear to be an issue
about the "newness" of the evidence
upon which the-Bureaus rely. DES was
firstapproved in1954.-The Gass study
was published in 1964, and did not-come
-to the attention of FDA until 1971 [see
M-1). The evidence-concerningJES
residues was not-available until the
1970's..
'Because the Bureaus are the
proponents -ofwithdrawal, it is
appropriate that they have the burden-of
-proving that the first "showing" (i.e., a
showing that the -drug is no longer
shown to be safe] hasbeen made, see
Hess-a Clark Division of Rhodia, Inc.,
v. FDA, supra,495 F. 2d at 992. The
Bureaus did not dispute this point.
The controversy arises over what is
sufficient to constitute the required
showing. The manufacturing parties
argue that theBureaus' burden is,in
-effect, to show that -useof the drug is
unsafe. There is, however, a clear
congressionally recognized difference
between "unsafe" and "not-shown to be
safe:' Indeed, the statute uses both
terms and clearly distinguishes between
them. 'Compare 21 U.S:C. 360be)(1)(A)
with 21 U;S.C. 360b(e)(1)(B). The former
paragraph requires a finding that a drug
is "unsafe"; the latter,;a finding that the
drug is "not shown to be safe:' If the
two terms were the same, there would
not be two subparagraphs.
The Court of Appeals in Hess &Clark,
Division of Rhodia,Inc., v. FDA, supra,
495 F..2d at-993, focusing on the residue
issue (discussed below in sections III (B)
and {C) of this Decision), stated its-view
of the burden question:
We think it implicit in the statute that when
4he FDA proposes-to withdraw an approval.
because-new evid.ence shows the drug leaves

residues, it has an initial burden of coming
forward with some evidence of tMe
relationshipbetween the residiteand safEty
to warrant shifting to the manufacturer the
burden of showing safety. This Is at least the
case where, as here. the residuqs are of
unknown composition. (Emphasis added.]
It is, of course, not possible to write a
formula, semantic or otherwise, that will
tell the decisionmaker-exactly how
much evidence is required to show that
a drug is no longer shown to be safe.
The Administrative Law Judge's
formulationis as good asany: "In-other
-words, 4he Bureaus must provide a
,reasonable basis from which serious
questions about the ultimate safety of
DESand thexesidues that may result
from its usemay be inferred" (I.D. at 8).
I adopt thisstatementf theburden.of
proof in this proceeding.Evenif the
Bureaus had the burden to show that the
presently approved uses of DES were
unsafe, however. I would have to find,
on this record, that they have carried
that burden.
(B) Evidence That DES Use Results in
Residues in Edible Tissues
I have carefully considered whether
the evidencein the record shows that
use of DES as an animal drug results in
DES residues in edible tissues. lExcept
where the context indicates otherwise, a
reference to "'DES
residues" inihis
Decision refers to residues identifiable
as DES and/or its conjugates.) I have
foundconvincing-evidence on this issue
from two separate sets of data: the
radiotracer studies discussed in
subsection 12) below and the results of
the Department of Agriculture
manufacturing program discussed in
subsection (3). Though each supportsihe
other, Ifindthat each of these sets of
data-provides -an independent basis for
the conclusionthat animal drug use
under each of the approved DES
-NADA's does resuitin residues of DES
and/or its conjugates in the edible
tissues of-treated cattle. I rely solely
upon the radiotracer studies for my
conclusion that approved uses of DES
result in DES residues in the edible
-tissues of sheep.(As is discussed in
detail in-section III(D) below, I also find
that-these resulting resilues are
harmful.)
The residues in the tissues of treated
animals observed by both the
radiotracer studies and'the Department
of Agriculture monitoring program are
-not surprising. Anything administered:to
an animal's system remains in that
system in-small amounts indefinitely
(see, e.g., M-167 at 4191; G-2 at 1192).
The amounts-oTthose -residues, however,
generally-decrease as the time-following
adminristralion increases. (One-can

1 Notices

54861

visualize this phenomenon as an
asymptotic or "decay" curve (see G-Z4

at 10428].]
When the withdrmvalperiod for oral
DES was originally set at 7 days, that
action was not based Upon the belief
that after 7 days no DES residues would
exist in meat (see G-72 at2].Rather
that withdrawal period wasset because
at that point on thecurve almost all
residues would be below 2 ppb, -which
was once thought to be the safe dosefor
DES. It would be expected that the 7day withdrawal period would result in
residues in the 0.5 to 2ppb range. Evena
14-day withdrawalperiodwould
reasonably be expected to result in
residues at some level. What is said
about the -withdrawal periods forDES in
feed is equally-applicable to the
required period between implantation of
DES implants and slaughterof cattle
with implants.
'(1) The 14ithdrawalPeriod.
A
withdrawalperiod is the period before
slaughter during "whichthe -animal
feeder maynot administer an animal
drug. The withdrawal period-allows the
animal'sbody todispose of-some of the
drug in its -system. The approved
withdrawal period for DES for both
cattle and sheep feedis 7 days, 21 CFR
558.225. In 1974, FDA-urged
manufficturersto label their products for
a 14-day-withdrawalperiod [39 FR
11323; March 27,1974). The agency has,
'however, taken-the position that it will
not approve supplemental NADA's to
change the-withdrawal date until-the
safety problems with respect to DES
have been esolved; hence 1he
continuation of the official 7-day
withdrawal period in FDATegulatons.
Some manufacturers have apparently
relabeled their drug for4-day
withdrawal (without objection from
FDA). and others have not
(Manufacturers' Exceptions at 46m.].
Meamvhile, the Department ot
Agriculture has issued regulations
requiring certification that DES was
withdrawn from feed at least 14 days,
before slaughter (9 CFR309.16).
The manufacturing parties argue that,
because 14-day periods are actually
used. their NADA's should be evaluated
on the basis ofthoseperiods.the statute
is clear, however, that in deciding
'whether approval of an NADA should
be withdrawn, the Commissioner is to
consider whether new-evidence shows
that the drug Is not shown to'he safefor
use "under the conditions of use upon
the basis oTwMch the application was
approved," 21 U.S.C. 360b(e)(1](B].
Should -the manufacturing partieswish
to seek approval pT DES in feed-under
different-conditions-of use,,they are free
to do so. They must carry, however, the

54862

Federal Register / Vol. 44, No. 185 / Friday, September 21, 1979

burden of provingthat the proposed new
conditions of use are safe.
In'order to provide as complete-an:
analysis of the record as possible,
however, I have made findings with
respect to not only the 7-day withdrawal
period but also the 14-day period. The
latter findings assume, for purposes of
argument, that the 14-day period is the
approired withdrawal period.
(2) RadiotracerStudies.,Several
radiotracer studies were performed by
scientists of the Department of
Agriculture to determine the fate of DES
in.cattle and sheep, The results showed
,thatvery small amounts-of DES remain
in a number of different tissues of the
animals treated with the drug.
In radiotracer studies, the scientist

The replort of this study stat's the
concentrations of radioactive material
(above background) in the various
tissues in- ppb equivalents of DES, on
the
the assumption that all'radioactive
material is radioactive DES (G-2 at 1190,
Table 4). The 7-day steers had, in their
livers, 0.13 and'O.37 ppb. Standard"
deviations were listed as 0.04 and 0.07
for the first and second steers,
respectively. After 10 days, 0.08 ppb
(with a 0.04-standard deviation) was
calculated for the livers of each of the
two steers sacrificed. Therefore, the
radioactive residues attributable to DES
were found in livers of steers after more
than the approved withdrawal period.
The evidence from-this study supports a
findifig that normal feeding of DES, even
substitutes radioactive carbon (14C)
with a 7-day -withdrawal period, results
atoms for some of the non-radioactive
in DES residues in the animals' livers.
carbon 12 atoms in the DES molecule.
This finding also applies by
The molecule thus formed is biologically extrapolation to a 14-day withdrawal
identical to the normal DES molecule
period. As discussed in the second
except that it is now radioactive. The
paragraph of section III(B), tha amount
radioactivity allows the scientist to
of DES present after 7 days wuld ' •
establish the absorption, distribution
decline but not disappear during the
and excretory patterns of the compound
following-7 days.
of interest or its metabolites in
. It'is
true-that the amounts of
biological systems, in this case, foodradioactivity found were small.. The
producing animals (G-76 at 3).
amounts of'radioactive DES
(a) OralDosages-in Cattle.--{i)
adriinistdred to the test animals also
Studies. The currently approved
were'small however, compared to the'
conditions of use for DES in cattle feed. -amounts tht are administered under the
permit up to 20mg perhead per day,
approved conditioris of use.
with a withdrawal period of 7 days, 21
The report'notes that radioactivity
-CFR558.225. As discussed above, some
was detected in the muscle of the steers
manufacturers have labeled their
sac rificed 24 iours, 5 days and 10 days'
products for a 14-day withdrawal
after dbsage, but not in the muscle
period.
Two studies were done with cattle fed -tissues of other. treated steers (id.). .The
manufacturing parties' Dr. Tennent"
DES. The first, by Aschbacher and
stated his opinion that because of
Thacker (G-2), involved the feeding to
possible cross-contamination it isnot
,steers-of a single oral dost of.10 mg 14CDES after the steers had been fed 20 mg '.possible t'base any conclusions on the
radioactivity found in muscle tissues'
per head of DES daily for 14 days.
(M-13Z at 19). The Bureaus' Dr.
Because residues are observed in this
.Aschbacher also stated his opinion that
type of study by detecting radiation in
nxoconclusions could be based upon the
the tissues of treated animals (G-76 at
radioactivity found in muscle tissues,of
3), any radiation found would be
animals sacrificed5 and 10days after
attributable to the 10 mg of "C-DES.
Cattle may be fed for-up to 135 days (Tr. dosing.[Tr.at 604). The published report
14
at 2023). Thus, total consumption of DES of the study stated that Ccontamination ridnot appear to be an
by a steer may amount to.2700 mg (20
mg X 135 days), or 270 times the amounit important factor in the liver, kidney, and
bile-gall bladder samples when levels
of 14C-DES administered in this study.
were above 0,1 ppb DES-equivalents (GIn this study, two animals each were
2at 1191).
sacrificed at 1, 2, 3, 5, 7, and 10 days
* In a 1975 report of his study to the
after the ;4C-DES feeding. Dr.
Department ofAgriculture, Dr.
,
Aschbacher testified that radioactivity
Aschbacher had also stated that,
was observed in all sections of the
gastrointestinal tract and in liver, kidney -because of the low levels of
xadioactiyity observed in muscle and the
and bile-gall baldder in the animals
sacrificed after 1, 2, 3, 5, and 7 days (G-1 apparent randomness with which that
radioactivity was seen there, he thought
at 3). The report of this test shows that
some radioactivity was also observed in it was not possible to discount crdsstissues of the steers sacrificed 10 days * contamination as the source of the
radioactivity observed in muscle and-'.
after the one-time "C-DES feeding(G-.
cdrcass in the animals slaughtered-after
2)_..

/

Notices

more than 24 hours (M-134 at 00097).
With respect to the finding 24 hours
after dosage, Dr. Aschbacher stated that
the radioactivity observed in the muscle
tissue was the result of the "C-DES
dosage administered (id.). (He also
noted that the fact that this residue was
not analyzed meant that he could not
conclude that DES was present, As
discussed elsewhere, however, his
analysis of other residues attributable to
l4C-DES showed that they bontained
DES and/or its conjugates, and I
conclude therefore that this residue also
contained DES or its conjugates.)
I do not rely upon the findings in
-muscle tisshe in the animals sacrificed 5
and 10 days after dosage. I do, however.
find that, as the researchers concluded,
(see M-134 at 00097), the radioactivity
observed in the steers sacrificed 24
hours after dosage was a valid
observation.
An isotope' dilution procedure was
used to characterize the radioactive
material in liver tissues from two steers
slaughtered after 2 days and one steer
slaughtered after 7 days, Twenty-two
percent of the radioactivity was
confirmed as AlC-DES in the 7-day steer.
and 36 and 46 percent were. so
confirmed, respectively, lh the Z-day
steers (G-2 at 1190-91). Thus, I find that
at least a part of the residues found In
liver in this study is either free DES or a
conjugate that hydrolyzes to free DES.
As a scientific matter, this finding Is also
applicable to the radioactivity detected
'in muscle 24 hours a$ver dosage.
Therefore, I find the feeding of DES to
cattle in this study resulted in residues
of DES or its conjugates in muscle as
well as in liver. See discussion of the
conjugates issue below (section III(C) of
this Decision).
A second radiotracer study with cattle
was performed by Dr. Rumsey, et al. (G79). In this study, 7 heifers and 8 steers
were administered 3 daily radioactive
doses of 1.68 mg 10-DES after havilg
been pretreated with 10 mg daily doses
of unlabeled'DES for at least 60 days,
One heifer and one steer each were then
slaughtered after respective .withdrawal
times of 0.75, 1.5, 3, 5, 7, 9, and 14 days.
Ohe steer was slaughtered 30 days after
withdrawal.Radioactivity above the
background rate (which indicates
residues traceable to the 14C-DES
dosages) was found in all parts of the
liverof the 7-day steer and in two of five
parts examined from the 7-day heifer.
Thus, this study provides evidence that
doses of DES that, combined, represent
a level one quarter tht size (i.e, 5 mg v.
20 mg) of the daily dose approved for
use, result in "C-DES residites in liver'
when the approved withdrawal period Is -

Federal Register / Vol. 44, No. 185 1 Friday, September 21, 1979 / Notices
observed. Radioactivity qalculated to be

small, but such residues were detected.
It is fair to jnfer from these results, in
the absence of evidence to the contrary,
that had the "C-DES been fed at 20 mg
daily for 135 days, the residues observed
would have been larger. On the other
band. it is also fair to assume that a 14day withdrawal period would have led
to smaller residues. I find that, on
balance, the studies' results show that
DES feeding of cattle under approved
conditions of use leaves residues in
edible tissues (including liver and
muscle), whether a 7 day or 14 day
withdrawal period is observed.
(b) Implants in Cattle.-(i) Studies.
The approved conditions of use for DES
implants in cattle allow implantation of
two 15 mg-pellets per animal or,
alternatively, three 12 mg-pellets per
animal "at the start of the feeding period
99 at 3). Dr. Williams, by further testing,
or approximately 120 days before
marketing," 21 CFR 522.640(d) (2) and
confirmed that the DES he had
discovered was not pseudo-DES (see
(3). Two studies were done with steers
discussion in section III(B)(2)(e) (G-99 at
implanted with DES pellets.
The first, performed by Dr.
5).
According to Dr. Rumsey, Dr.
Aschbacher, et al., involved the
Williams' test showed the presence of
implantation of four steers with 28 mg of
radio-labeled DES. The steers were
0.03 ppb of DES equivalents in the livers
of the animals sacrificed 7 days after
killed at intervals of 30, 60, 90, and 120
last feeding (G-76 at 4). Dr. Rumsey
days after implantation (G-5 at 530). A
stated the results of the isotope dilution
control group was made up of four
studies cautiously, saying that those
steers implanted with DES pellets not
results "suggested the possibility of but
containing radioactivity. These steers
did not prove to me" the presence of
were slaughtered on the 28th. 58th, 88th,
DES in the livers (id. at 3)- Dr. Williams,
and 118th days after implantation (id. at
on the other hand, was unequivocal in
531). The tissues from the control
his statement that DES and/or its
animals were used to establish a
conjugates had been found in the livers
background rate for radioactivity.
he tested (G-99 at 3). I accept Dr.
Radioactivity above the background
rate (and thus traceable to the "C-DES
Williams' evaluation of his own results
in these tests.
implant) was observed in all tissues
(ii) ConclusionAs to OralDosage in
from treated animals examined,
0
Cattle.The fact that radioactivity was
including muscle, liver, kidney, adrenals,
found in some tissues of treated animals
heart, etc., with the exception of the
visceral fat of one of the 90-day animals
and not in others could be because (1)
the study was not sufficiently sensitive
(G-1 at 4; G-5 at 535, Table 2). The
to detect all DES residues in each tissue
radioactivity in the livers was further
characterized by isotopic dilution
analyzed or (2) DES residues did not
exist in the tissues in which
procedures and determined to be, in
radioactivity above background was not
part, either free DES or a hydrolysable
detected. Because DES was found in all
conjugate of DES (G-1 at 5; G-5 at 535).
tissues (including muscle) in the animals The report states that the amount
with the shortest withdrawal dates, and
characterized as 14C-DES in the livers
no viable theory has been proffered to
was equivalent to 0.07 to 0.13 ppb of
DES (G-5 at 535). (These figures were
explain why all DES would disappear
apparently derived from a calculation
totally from some but not other tissues, I
accept the former explanation. I
based on the 14C activity observed in the
-therefore find that these radiotracer
tissues and the specific activity of 14CDES.)
studies establish that when DES is fed
Part of one of the two ',_-DES pellets
to cattle, it leaves residues of DES and/
in the animal slaughtered after 120 days
or its conjugates in the edible tissue
had not dissolved and was retrievable
(including liver and muscle) of treated
at the time of slaughter (G-5 at 534; G-1
cattle.
at 4). Thus, presumably, the implant was
One "4C-DES feeding test used a
-radioactive dose of 10 mg. The other
still delivering DES to the system at the
-used, in three doses, approximately 5 mng time of slaughter.
A second study on cattle with
of radioactive DES. Resulting
implants was performed by Dr. Rumsey,
radioactive residues detected were
at or above the level of 0.2 ppb DES
equivalents in wet tissues was found in
the muscle tissues of steers sacrificed
0.75 and 1.5 days after dosing (see
discussion of the significance of findings
in muscle tissues in the conclusion of
this section bel6w).
Some of the liver tissues from the test
animals were taken by the Bureaus to
Dr. Kenneth Williams of the Worcester
Foundation for Experimental Biology for
further analysis. He subjected the
samples to reverse isotope dilution
procedures to determine the identity of
the radioactive material in the livers. Dr.
Williams reported that all of the
samples tested, some of which were of
livers of animals that had been
slaughtered 7 days after dosage,
contained DES and/or its conjugates (G-

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54863

et al. (G-77). This study involved the'
implantation of '4.-DES pellets into
eight steers. Two implanted steers and
one control animal were slaughtered
respectively at 30, 60, 90, and 120 days
after implantation. All but one of the
treated steers sacrificed received two
implants totaling 32.2 mg C-DES. One
of the two steers slaughtered after 120
days, which was of a lighter weight,
received only one implant of 15 mg (G77 at 551, 554, Table 1).
The steers slaughtered after 120 days
showed radioactivity significantly (p
less than 0.05) above background in
tongue. spleen, adrenals, lung. kidney,
bile, and liver (G-76 at 5). One of the
steers showed radioactivity significantly
above background in cheek muscle (id.].
Radioactivity above background was
not found in shoulder or rib muscle or in
the brisket (id.).
As in the feeding studies discussed
above, the lack of a finding of
radioactivity in some tissues in this
study may be the result of either (1) the
relative insensitivity of the tests or (2)
the fact that no residues actually exist in
these tissues. Acceptance of the former
explanation is the conservative
approach and is also supported by the
findings in the Aschbacher implantation
study. Therefore, I adopt it. Thus,
although Dr. Rumsey'sresults may be
taken as evidence that DES residues in
the shoulder or rib muscle and brisket
tissues are not found at as high levels as
those found in other edible tissues (e.g.,
tongue. kidneys, livers), they do not
show that no residues would, in fact,
occur in shoulder or rib muscle and
brisket.
In this study, like the Aschbacher
implant study, part of the implant still
remained in the steers 120 days after
implantation (G-76 at 6; G-77 at 559).
Livers from this study were provided
to Dr. Williams for characterization of
the radioactivity observed. All of the
livers were found to contain DES or its
conjugates, including livers from
animals slaughtered 120 days after
implantation (0,-99 at 3; cf. G-76 at 6].
For the reasons stated in my discussion
of Dr. Williams' analysis of livers from
the feeding studies, his findings here
with respect to livers apply also to other
tissues.
(ii] Con'clusionsAs to Implant Studies
in Cattle.For the reasons discussed with
respect to the feeding studies. I attribute
the variations in the findings of
radioactivity in the implant studies to
inherent limitations in the levels of
detection of the methods utilized.
As noted, approved conditions of use
allow 30 to 36 mg implants inserted 120
days before slaughter. Since residues
were observed (in the Aschbacher study