UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
June 11, 1980
OFFICE OF TOXIC SUBSTANCES
MEMORANDUM
SUBJECT: Special Review of Data Requirements for 2,4-D
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FROM: Dr. H. Wade Fowler, Jr.
Executive Secretary
FIFRA Scientific Advisory Panel
TO: Deputy Assistant Administrator
for Pesticide Programs
The FIFRA Scientific* Advisory Panel completed § special review of
possible data gaps with 2,4-D ,to determine test requirements needed to
support continued registration of the pesticide. The review was com-
pleted in an open meeting of the Panel held in Arlington, Virginia, on
May 28, 1980.
Attached is a report of findings by the Panel.
Attachment
cc: Mr. Oonlon
Dr. McGrath
Ms. Anita Schmidt
Panel Members
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FEDERAL INSECTICIDE, FWGICIDE, AND RODENTICIDE ACT (FIFRA)
SCIENTIFIC ADVISORY PANEL
Special Review of Data Requirements for
2,4-D
The FIFRA Scientific Advisory Panel completed a special review of possible
data gaps with 2,4-D to determine test requirements needed to support
continued registration of the pesticide. The review was completed in an
open meeting of the Panel held in Arlington, Virginia, on May 28, 1980.
f.
Maximum public participation is encouraged at all meetings of the Scientific
Advisory Panel. In respect to this session, the meeting was announced
in the Federal Register on May 12, 1980. In addition, the secretariat
of the Panel routinely sends telephonic notices and special mailings
to members of the general public who have indicated an interest in
activities of the Panel.
Written and oral statements were received from Dr. Dieter Riedel of the
Occupational Toxicology Division, Environment Health Directorate of
Canada; the National Forest Products Association; and from technical
staff of the Environmental Protection Agency.
The excellent briefings" by Mr. Johnson, Deputy Assistant Administrator
for Pesticide Programs (OPP), in company with Ms. Anne Barton, Ms. Anita
Schmidt and Dr. Henry Spencer of his staff, were of great value to
members of the Panel.
In consideration of all matters brought out during the meeting, the Panel
unanimously submits the following report in response to specific proposals
by the Agency for certification of test requirements involving studies
on oncogenicity; reproductive effects; mutagenicity; metabolism; neuro-
toxicity; acute toxicity; and dermal absorption:
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ONCOGENICITY
Test Requirements under Review by the Agency;
1. Standard oral exposure studies of acid in rats and mice.
2. A subcutaneous or dermal exposure study of isooctyl ester in
mice.
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PANEL COMMENTS;
The agency has suggested three oncogenicity studies in the list of
proposed data requirements for 2,4-D; (1) standard oral exposure
studies of acid in rats; (2) in mice; and (3) a subcutaneous or dermal
exposure study of the isooctyl ester in mice. The FIFRA Scientific
Advisory Panel concurs with the need for a cancer bioassay study in
mice since neither the Innes et al. nor the Archipov afid Kozlova studies
provide sufficient information to make a meaningful scientific judgment.
The Scientific Advisory Panel has noted previously the difficulty of
using data from the Innes et al. study as the basis for evaluating
oncogenicity in mice and would urge the Agency to avoid using data
from this study for either a positive or negative determination of
oncogenicity for any of the agents included in this study.
The FIFRA Scientific Advisory Panel does not concur with the Agency
suggestion for a subcutaneous or dermal exposure study of the isooctyl
ester of 2,4-D in mice for several reasons. First, oncogenicity bioassays
using the subcutaneous or dermal routes of exposure are generally less
reliable than the standard oral test in predicting oncogenicity in any
species. Second, the basis for this requirement appears to be a peripheral
study which was added to the Innes et al. study on 2,4-D and which has
serious defects (single sex, single dose, questionable controls, etc.)
in addition to those generally associated with the Innes et al. protocol
and evaluation. As indicated above, the FIFRA Scientific Advisory Panel
recommends against the use of data from this study for oncogenicity
evaluation of any of the agents included in the tests.
The FIFRA Scientific Advisory Panel has reviewed the chronic toxicity
study on 2,4-D carried out in rats and dogs by Hansen et al. which was
published in Toxicology and Applied Pharmacology (TAP). In addition
to peer review of this study by the editor and editorial board of TAP,
the study has also been reviewed by the National Cancer Institute (NCI)
and by Dr. M. Rueber. The NCI review agreed with the conclusion of the
authors of this paper that a carcinogenic effect was not demonstrated
for 2,4-D whereas Dr. Rueber's conclusion was that 2,4-D is carcinogenic
in male and female rats and probably also in mice. In Dr. Rueber's
report, he agreed (page 5) that this FDA study (Hansen et el.) must be
considered as an acceptable study, and thus the major difference in the
conclusions of Dr. Rueber and the authors of this study derives primarily
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from differences in the interpretation and evaluation of the rat histo-
pathologic data. Dr. Rueber agrees with the authors of the FDA study
that 2,4-D was not shown to be carcinogenic in dogs but argues that two
years is an insufficient study period to detect carcinogensis in this
species. It should be pointed out that carcinogenic effects have been
produced in dogs in studies of less than 2 years duration and the 2-year
period is the recommended exposure period in the current FIFRA guidelines
for chronic toxicity studies 'in dogs. The FIFRA Scientific Advisory
Panel recommends that the Agency attempt to resolve the apparent controversy
between Dr. Rueber's pathologic interpretation of the rat nistologic
findings and those of the authors of the FDA .study before requesting any
additional oncogenicity testing in rats with 2,4-D.
In connection with the issue of additional oncogenicity testing
with 2,4-D in rats, the FIFRA Scientific Advisory Panel wishes to remind
the Agency that it is virtually impossible to carry ou£ a chronic toxicity
study that is totally without flaws. The decision of whether these flaws
are inconsequential or whether they render the study useless for toxicologic
evaluation depends both on the judgment and experience of the evaluator
and on the rest of the information contained in the toxicity data base.
Thus, the existence of "data gaps" and "inadequate studies" in a toxicity
data base for a compound does not £ priori preclude a toxicologic evaluation
of the compound, although it should increase the "uncertainty factor"
or safety factor associated with any such predictive effort. The FIFRA
Scientific Advisory Panel supports the efforts of the Agency to improve
the quality of the toxicity data base through mechanisms such as the
identification of "data gaps", the development of guidelines for toxicity
testing protocols, and the RPAR process, but it is equally aware of the
fact that the requirement of additional animal studies which are not
clearly justified will waste resources which are already in short supply
and damage Agency credibility.
It is recommended, therefore, that in establishing requirements for
additional toxicity studies the Agency distinguish between those require-
ments which it considers to be essential (need to know) and those which
it considers to be desirable (nice to know). This priority ranking should
also provide an indication of the urgency associated with the requirement
for additional testing. This approach would provide the Agency with
greater flexibility in dealing with the older pesticides (like 2,4-D)
which have a relatively good "track record" in terms of producing adverse
effects on human health and the environment.
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SUMMARY OF PANEL COMMENTS;
The Panel is of the opinion that the Agency should resolve the contro-
versy between the study conducted by Hansen et al, 1971 and the pathologic
interpretation of that study by Reuber 1979 prior to certification that
additional oncogenicity studies are required. In the event the results
of the oncogenicity studies of Hansen et al. 1971 are validated as a
result of examination of the appropriate slides related to lymphosarcoma
in female rats, then the Panel would recommend that the testing require-
ment be limited to a standard oral exposure study in mice. In the event
the results of the report by Hansen et al, 1971 are not validated on
reexamination of tissue specimens, then an oral exposure study in both
rats and mice is recommended.
REPRODUCTION
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Test Requirements under Review by the Agency;
1. A multigeneration study to establish NOELS for the acid form
of 2,4-D in one species.
2. Teratology/fetotoxicity studies to establish NOELS in rats
for:
a. Acid
b. Butoxy Propyl Ester
c. Alkanol Amine
d. Isopropyl Ester
e. Dichlorophenol metabolite
PANEL COMMENTS;
The Panel is of the opinion that an additional multigeneration study
to establish NOELS for the acid form of 2,4-D in one species is not
warranted. Although the Hansen et al study had some discrepancies,
it still represents an adequate study of the potential reproductive
hazard of 2,4-D. The study shows a statistically significant effect
at 1500 ppm. However, except for the Fia generation, 500 ppm and
100 ppm of 2,4-D do not cause any reproductive anomalies. In our
opinion 500 ppm should be considered as a no observed effect level
(NOEL) for reproductive toxicity in rats exposed to 2,4-D, and should
be used in estimating the potential reproductive toxicity of 2,4-D to
humans exposed to this compound.
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The Panel concurs that teratology/fetotoxicity studies to establish
NOELS in rats should be conducted in all the proposed data requirement
areas.
MUTAGENICITY
Test Requirements under Review by the Agency;
None.
PANEL COMMENTS;
The Panel concurs with the appraisal by the Agency.
METABOLISM
Test Requirements under Review;
1. Standard metabolism studies in dogs and rats for acid, isooctyl
ester and PGBE.
2. A standard metabolism study in pregnant rats for acid, isooctyl
ester, and PGBE.
PANEL COMMENTS;
The Panel agrees with the appraisal by the Agency for standard
metabolism studies in dogs and rats for acid, isooctyl ester, and
PGBE. However, the Panel is of the opinion that standard metabolism
studies in pregnant rats should not be done.
NEUROTOXICITY
Test Requirements under Review by the Agency;
1. Subchronic neurotoxicity studies in dogs, rats, and chickens
by oral route (including a recovery period) for acid and
dimethylamine.
2. A subacute dermal neurotoxicity study in dogs.
PANEL COMMENTS;
The Panel agrees that subchronic neurotoxicity studies in dogs,
cats, rats, and chickens by the oral route (including a recovery period)
for acid and dimethylamine should be conducted. However, the Panel is
of the opinion that the subacute dermal neurotoxicity study in dogs
should be delayed or not conducted.
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ACUTE TOXICITY
Test Requirements under Review by the Agency;
1. Oral LE>5o in rats for each formulation.
2. Dermal LD$Q in rats for each formulation.
PANEL COMMENTS;
The Panel concurs with the appraisal by the Agency for acute
toxicity data.
DERMAL ABSORPTION
Test Requirements under Review by the Agency;
.*•
A radiolabeled dermal absorption study in an appropriate species for
each formulation meeting the following criteria:
1. It contains an active ingredient which has shown fetotoxic
effects at relatively low doses (this includes all 2,4-D
forms included in the teratology study request plus the isooctyl
ester and PGBE).
2. Its use is likely to result in dermal exposure to human females.
PANEL COMMENTS;
The Panel concurs with the appraisal by the Agency for dermal
absorption data.
FISH AND WILDLIFE
SPECIAL PANEL COMMENTS;'
The Panel is concerned about the potential adverse effects of 2,4-D
to fish and wildlife. The Panel notes a potentially serious data gap
in this vital area and respectfully requests that the Agency review
the matter and present a report on possible studies to be conducted
at a future meeting of the Panel.
Selected References;
1. ARCHIPOV, G. N. and I. N. Kozlova. 1974. Study of the carcinogenic
properties of the herbicide amine salt of 2,4-D. Voprosy Pitaniya
5:83-84.
2. HANSEN, W. H., M.L. Quaife, R.T. Habermann and O.G. Pitzhugh. 1971.
Chronic toxicity of 2,4-dichlorophenoxyacetic acid in rats.
Toxicol. Appl. Pharmacol. 20:122-129.
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3. INNES, J.R.M., B.M. Ulland, M.G. Valeric, L. Petrucelli, L. Fishbein,
E.R. Hart, A.J. Pallotta, R.R. Bates, H.L. Falk, J..J. Gart,
M. Klein, I. Mitchell and J. Peters. 1969. Bioassay of pesticides
and industrial chemicals for tumorigenicity in mice: A preliminary
note. J. Nat. Cancer Inst. 42:1101-1114.
4. REUBER, M.D. Carcinogeniclty of 2,4-dichlorophenoxyacetic acid.
June 12, 1979. Unpublished manuscript.
FCR THE CHAIRMAN:
H. Wade Fowler, Jr., Ph.D.
Executive Secretary
FIFRA Scientific Advisory Panel
DATE: June 13, 1980
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