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Rejection Rate Analysis
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
JUN 2 4 1992
OFFICE OF
PESTICIDES AND TOXIC
SUBSTANCES
Dear Interested Party,
I am pleased to send you the first chapter of EPA's
Rejection Rate Analysis, on the scientific discipline Residue
Chemistry. This document is the first in a series of guideline-
by-guideline analyses which will identify the factors that most
frequently cause studies required for pesticide reregistration to
be rejected.
EPA believes that the submission of unacceptable studies is
the most significant factor in delaying production of
Reregistration Eligibility Documents, or.REDs. Unless study
rejection rates are significantly reduced, EPA's Office of
Pesticide Programs (OPP) will not meet its REDs production
schedule.
*
Thus, OPP has launched an intensive effort, with the
cooperation and active involvement of the pesticide industry, to
analyze rejected studies, to determine why they were found to be
unacceptable, and to find ways to improve the quality and
increase the acceptability of studies submitted to EPA in the
future.
The Rejection Rate Analysis will enable OPP to provide
pesticide registrants with information on rejection factors to
minimize their reoccurrence in future studies; reassess the
adequacy of its guidance to registrants and internal review
processes and criteria; and determine the appropriate regulatory
response to future rejected studies. As a result, the quality
and acceptance rate of studies submitted for pesticide
reregistration are expected to improve.
The first chapter of the Rejection Rate Analysis focuses on
the discipline Residue Chemistry. This chapter was produced
through a workgroup effort involving OPP scientific and
regulatory staff, ten scientists representing the pesticide
industry, and the IR-4 Program. As you will notice in reading
the document enclosed, "Industry Comment" and "EPA Response" are
provided for each rejection factor considered.
Printed on Recycled Paper
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OPP will continue to involve the pesticide industry in its
development of future chapters of the Rejection Rate Analysis.
We plan to issue other completed chapters during the rest of
1992, and to complete the entire study early in fiscal year 1993.
We encourage all pesticide producers and all pesticide
testing laboratories to read and use the Residue Chemistry
chapter enclosed, when providing new pesticide studies to EPA and
when upgrading existing studies in support of pesticide
reregistration. About a dozen pesticide companies already have
made a commitment to conduct their own study rejection rate
analyses. OPP commends these companies, and we encourage others
to take similar action.
We will keep you informed of the progress of the Rejection
Rate Analysis, and of voluntary efforts on the part of the
industry to comply with its findings and recommendations, in the
"Pesticide Reregistration Progress Report." If you are not
already receiving this quarterly publication and would like to be
added to the mailing list, please contact the Special Review and
Reregistration Division (H-7508W), Office of Pesticide Programs,
US EPA, 401 M Street, SW, Washington, DC 20460, telephone 703-
308-8000. We are also interested in receiving your comments and
reactions regarding the enclosed Residue Chemistry chapter.
Thank you for your attention, and again, we encourage your
voluntary, active participation in this program to reduce
pesticide study rejection rates.
Sincerely yours,
\7^
A L^J
Off ice
D. Campt, Direct/or
Pesticide Programs
Enclosure
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REJECTION RATE ANALYSIS
RESIDUE CHEMISTRY
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TABLE OF CONTENTS
CHAPTER
I.
INTRODUCTION
II.
SCOPE OF ANALYSIS
III.
RESIDUE CHEMISTRY CHAPTER
IV.
V.
VI.
DESCRIPTION OF DISCIPLINE
CURRENT REJECTION RATE 8
REJECTION FACTORS 15
VII. SUMMARY TABLE OF
REJECTION FACTORS
VIII. IR-4 COMMENTS
IX. . INTERNAL EPA OBSTACLES
X. CONCLUSIONS
XI. RECOMMENDATIONS
XII. APPENDIX A - List of EPA
Guidance Documents
54
55
57
58
60
61
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LIST OF FIGURES:
Figure 1 -
List A - Rejection Rate for All Residue
Chemistry Guideline Requirements
Figure 2 -
List A - Current (Post 1988) Rejection Rate
by Residue Chemistry Guideline
Figure 3 -
List A - Residue Chemistry Rejection Rate by
Guideline Since Before 1986
Figure 4 -
List A - Residue Chemistry Guidelines with
Lower Rejection Rates Over Time (Guidelines
171-4B and 171-4K)
Figure 5 -
List A - Residue Chemistry Guidelines with
Constant Rejection Rates (Guidelines 171-4A
and 171-4L)
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REJECTION RATE ANALYSIS
I. INTRODUCTION
This rejection rate analysis has been undertaken by the
Special Review and Reregistration Division (SRRD), the Health
Effects Division (HED) and the Environmental Fate and Effects
Division (EFED) in the Office of Pesticide Programs (OPP) of the
Environmental Protection Agency (EPA). The purpose of this
guideline-by-guideline analysis is to identify those factors that
most frequently cause guideline studies required for
reregistration to be rejected. This information will enable OPP
to (a) provide registrants with information on rejection factors
to minimize their reoccurrence in future studies, (b) reassess
the adequacy of its guidance, (c) determine the appropriate
regulatory response to a future rejected study, and (d) make any
internal changes in process, procedures or criteria deemed
appropriate.
The decision to analyze these factors was made after a FIFRA
Reregistration recosting analysis, conducted in the Spring of
1991, indicated that rejected studies posed the most significant
potential for delays in the production of Reregistration
Eligibility Documents (REDs). Reregistration eligibility
decisions require that reasonable risk assessments be performed
for all relevant human health and ecological end points for each
chemical. Performing such risk assessments requires a
"substantially complete" data base. A "substantially complete"
data base requires that registrants submit studies of acceptable
quality. A significant reduction in rejection rates for most
disciplines is required for OPP to be able to meet its production
schedule for REDs.
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II. SCOPE OF ANALYSIS
The scope of this analysis is limited almost entirely to an
examination of rejected studies. While a scientist's review of a
study may result in a finding of acceptable, upgradable,
unacceptable or supplementary, rejected (i.e. unacceptable)
studies are the focus here because a .rejected study will more
than double the amount of time and resources required to satisfy
that guideline. Upgrading a study usually doesn't require as
much time to accomplish -as repeating the study. A rating of
supplementary by a scientist might require substantial new work
and add additional time delays to the process.
For residue chemistry, 6 percent (44/722) of the reviewed
studies were rated as supplementary. Sixty-one percent (27/44)
of these supplemental studies are concentrated in two
guidelines - animal metabolism (171-4B) and storage stability
(171-4E). For these two guidelines, an analysis of the
supplemental studies augments the analysis of the rejected
studies.
The scope of this analysis is also limited to List A
studies. The analysis was confined to List A because (1) List A
chemicals represent those chemicals with the longest
reregistration history - each chemical case had a Registration
Standard published between 1980-1988, (2) List A chemicals are
the high-volume food-use chemicals, which .could pose the greatest
potential risk to human health and the environment and therefore
have the highest priority in .reregistration, and (3) List A
chemicals generate the most extensive data requirements.
To what extent are List A rejection factors representative
of Lists B, C, and D? Unfortunately, it is not possible at this
time to make such a determination since a random sample of List
A, B, C, and D studies was not chosen as the basis for this
analysis. Such a sample was not feasible since List B chemicals
have only recently completed Phase 4 (FY91); List C chemicals
will complete Phase 4 this fiscal year (FY92), and List D
chemicals won't complete Phase 4 until next fiscal year (FY93).
Consequently, there was not an adequate pool of reviewed studies
across lists for each guideline to support a randomly drawn data
base. Furthermore, many List B and C study reviews, conducted in
Phase 4, were based on examination of the summaries only. For
consistency, the decision was made to limit this analysis to
consideration of full study reviews only.
The rejection factors identified in this assessment of List
A rejected studies could plausibly either overstate or understate
the number of rejection factors likely to be found in any future
assessment of List B, C, and D rejected studies. On the one
hand, many List A studies were initiated in response to the
Registration Standards prior to both the 1982 guidelines and
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development of acceptance criteria in Phase 3 (1989) and
consequently may have been rejected by criteria that were not in
place at the time the study was conducted. In this case the
corresponding rejection factors are not likely to be repeated in
List B, C, and D studies since the data-call-ins have all been
issued subsequent to OPP's publication of its guidelines and
acceptance criteria. On the other hand, many of the studies
judged to be acceptable now may be repeat studies. Consequently,
the rejection factors identified here may omit factors that were
responsible for previous submissions being rejected.
Process
First, the Agency reviewed the data evaluation records
(study reviews) on a guideline-by-guideline basis in order to:
(1) identify those factors that most frequently caused each
guideline study to be rejected;
(2) determine the rejection rates and trends (where the
sample size was adequate) for each guideline
requirement;
.(3) assess the adequacy of EPA's guidance documents with
respect to each rejection factor; and
(4) for each rejection factor determine if it is
"avoidable."
Secondly, a draft was provided to an industry workgroup of
residue chemists for review and comment in order to (1) obtain
from a user's perspective the adequacy of EPA's guidance
documents corresponding to each rejection factor, and (2) better
understand why the rejection factors occur. The industry
workgroup included: Chuck Baer (Dupont), Judy Ball (Uniroyal),
Jim Campbell (Nor-Am), Rick Holt (Dupont), Bob Larkin (Rohm and
Haas), John Magnussen (Dow Blanco), Paula Paul (Nor-Am), Fred
Pearson (ICI), Bill Stellar (American Cyanamid), and John
Thornton (Miles). Industry and EPA scientists met on April 23,
1992 to discuss the problem areas in order to develop a better
understanding of them.
The revised residue chemistry chapter explicitly includes
industry comments on each rejection factor and EPA's response to
them.
Finally, the revised chapter was sent to the IR-4 program
for comment. Their comments are included in this final residue
chemistry chapter.
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III. RESIDUE CHEMISTRY CHAPTER
This chapter examines the results of the residue chemistry
rejection rate analysis. The following information is discussed:
(1) a description of the discipline of residue chemistry, (2)
the current rate of rejection of residue chemistry studies, (3) a
list of the most common factors that have led to the rejection of
these studies, (4) industry comments on each rejection factor,
(5) EPA response to comments, (6) internal EPA obstacles, and (7)
conclusions and recommendations.
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IV. DESCRIPTION OF DISCIPLINE
Residue chemistry data are.used by the EPA to estimate the
exposure of,the general population to pesticide residues in food
and for setting and enforcing tolerances (maximum permissible
level) for pesticide residues in food or feed. The following is
a description of the residue chemistry studies thatare required
by EPA for reregistration:
Metabolism in Plants and Animals (guidelines 171-4A,B). The
purpose of conducting metabolism studies is to determine the
qualitative metabolic fate of the active ingredient, i.e. examine
what happens to it when it is applied to a plant or administered
to an animal. This is commonly referred to as the
"characterization" of residues of the compound. To obtain this
information, the pesticide is labeled with a radioactive atom, to
follow the compound to see if and where it breaks down within a
plant or animal. Sometimes the "parent" compound (original
active ingredient) breaks down into other compounds
(metabolites). Metabolism studies are required to document what
happens when the compound(s) breaks down within the plant or
animal. The determination of whether the residues have been
sufficiently characterized is dependent on many factors. Often
90% of the ."total radioactive residue" (TRR) is required to be
identified for complete characterization. Plant metabolism
studies are usually required for a minimum of three diverse crops
(unless the pesticide is to be used on only one or two .crops) .
If the metabolism in each of these crops is similar, then the
metabolism in other crops is assumed to be similar. If the
pesticide is applied to crops used for animal feed, or if the
pesticide is intended for treatment of livestock, then animal
metabolism studies are required in addition to plant metabolism
data. Animal metabolism studies are generally carried out on
ruminants (cows or goats) and poultry (chickens).
Significant Metabolites and Tolerance Expression. Using the
results of plant and animal metabolism studies, EPA determines
which metabolites are of concern and need to be included in the
tolerance expression. In each case, this decision is based on
(1) the toxicity of the metabolite, and (2) the magnitude of its
residue. Metabolites that are toxicologically significant and
occur at significant levels require a suitable analytical method.
The pesticide active ingredient and any significant metabolites
are together called the "total toxic residue" (TTR).
Analytical Methods (guidelines 171-4C,D). Based on plant
and animal metabolism study results, EPA requires tolerance
petitioners to develop analytical methods to determine all
components of the TTR. In some cases, it is not possible to
develop a single method that can determine all components of the
residue, and several methods are required. Pesticide analytical
methods are used to obtain residue data on which dietary exposure
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assessment and tolerances are based, and to enforce the tolerance
after it is established. Enforcement methods are validated by an
independent laboratory before submission to EPA as required by PR
Notice 88-5. EPA then validates each new analytical method using
a method trial, to ensure that the procedures can actually be
used for tolerance enforcement.
Residue Field Trial Data (guideline 171-4K). Once the
metabolism data indicate what to look for, and methods are
developed to measure the TTR, field experiments are conducted to
determine the magnitude of the pesticide residue in or on raw
agricultural commodities (RACs). Field trials are required to
reflect pesticide use patterns that could lead to the highest
possible residues. The pesticide must also be applied at known
application rates and in a manner similar to the use directions
intended for the pesticide label. Data are normally required for
each crop or crop group for which a tolerance and registration is
requested and for each raw agricultural commodity derived from
the crop.
Storage Stability (171-4E). These studies are required to
validate the rate of decomposition of the TTR in or on the RAG
between the time of harvest and the final analysis of residues.
Determining the Tolerance Level. A petitioner to obtain a
tolerance proposes a tolerance level, based on residue field
trial data, which reflects the maximum residue that may occur
under "worst-case" conditions as a result of the proposed use of
the pesticide. The tolerance must include significant
metabolites and must be high enough to cover all components of
the TTR. If one component of the residue is significantly more
toxic than other components, two levels may be included in the
tolerance expression.
Processing data (171-4L). Processing studies are required
to determine whether residues in raw commodities may be expected
to degrade or concentrate during food processing. If residues do
concentrate in processing, one or more food or feed additive
tolerances must be established. However, if residues do not
concentrate in processed commodities, the tolerance for the RAG
itself applies to all processed food or feed derived from it.
Feeding Studies (171-4J). Whenever pesticide residues are
detected in feed items, data on the transfer of residues to meat,
milk, poultry, and eggs are required. These studies are also
required if a pesticide is to be applied directly to animals.
Data from these studies determine which components of the TTR are
present and at what concentration secondary residues could result
in meat, milk, poultry and eggs in order to set appropriate
tolerances.
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From the rejection rate perspective, the most critical
residue chemistry guideline requirements are the metabolism
studies for plants and animals. All other residue chemistry
guidelines are contingent upon the adequacy of their results.
Since pesticides often undergo significant metabolic changes
within crops and livestock, the composition of the toxic residues
must first be characterized before the amount of residue present
can be determined. Additionally, analytical methods capable of
adequately detecting the TTR must be developed prior to
conducting field residue trials. Once ,the TTR is known and
adequate methods are developed, field trials can proceed.
Storage stability studies, processing studies, and livestock
feeding studies may then be conducted.
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V, CURRENT REJECTION RATE
The following graphs demonstrate the current and historical
rejection rates for each of the residue chemistry guidelines.
The historical rate does not include studies that were submitted
prior to the publication of the Registration Standards. Due to
the limited number of cases, none of the results reported in this
section have been tested for statistical significance, and
therefore caution should be exercised in their interpretation.
Figure 1 illustrates the overall rejection rate for residue
chemistry, which is now estimated at approximately 12 percent.
This is down from the overall rate of around 47 percent prior to
1986. As indicated in Figure 1, the overall rejection rate for
residue chemistry guidelines has decreased by about 25 percent
every year since 1986. However, within the residue chemistry
discipline, there are large discrepancies in the rejection rates
between guidelines. Therefore, the following graphs show trends
by guideline. Some residue chemistry guidelines with an
insufficient number of studies were omitted. These guidelines
include 171-2, 171-4F, 171-4G, 171-4H, 171-4J, and 171-5.
Figure 2 illustrates what the Agency believes is the current
rejection rate within each guideline. The current rate refers to>
all post-1988 studies that were reviewed by the EPA. The
rejection rate (percentage of rejected studies) is given at the
top of each guideline bar and the number of rejected studies over
the number of studies reviewed are listed inside each bar.
Figure 2 depicts the discrepancy in the rejection rate between
guidelines.
In order to explore the reasons for such varying rates of
rejection, Figure 3 illustrates the rejection rates over time.
For each guideline, the rejection rates from three time frames
are listed for comparison. The time frames include (a) pre-1986
(not including information received for Registration Standards),
(b) from 1986 to 1988, and (c) post 1988. In this figure, the
trends across guidelines have been quite different, with no
consistent pattern. This comparison illustrates the drop in the
rejection rate over time for some guidelines including 171-4B,
171-4D, and 171-4K, and a slight increase over time in the
rejection rate for guideline 171-4A. Guideline 171-4C
experienced a 14 percent increase in the rejection rate from 1986
to 1988, which dropped to zero again since 1988.
Figure 4 portrays the trend in the crop fiel'd trial (171-4K)
and livestock metabolism (171-4B) guidelines, which have
experienced a dramatic drop in the rate of rejection since pre-
1986. The livestock metabolism rejection rate dropped from 80
percent before 1986 to 9 percent since 1988. The crop field
trial rejection rate dropped from 45 percent before 1986 to 16
percent since 1988. While the livestock metabolism rejection
8
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rate decreased, the plant metabolism increased slightly during
the same time period. The trends for plant metabolism (171-4A)
and processed food (171-4L), which have remained relatively
constant over time, are portrayed in Figure 5.
Key implications that might be drawn from these graphs
include:
(1) overall rejection rates in residue chemistry appear to
have gone down dramatically;
(2) the livestock metabolism (171-4B) and crop field trials
(171-4K) guidelines have shown substantial declines in
their rejection rates;
(3) for the plant metabolism (171-4A) and processed food
(171-4L) guidelines, the rejection rate trends do not
reflect substantial improvement;
(4) processed food (171-4L), plant metabolism (171-4A) and
crop field trials (171-4K) still have high rejection
rates;
(5) none of the implications discussed above are based on
statistically significant results, and therefore
caution should be exercised in interpreting them.
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VI.
REJECTION FACTORS
The following residue chemistry guidelines were analyzed to
determine the most common reasons that studies submitted to meet
these guidelines were rejected. EPA scientists listed these
rej ection factors below in ranking order according to the
frequency of their occurrence. After each rejection factor,
specific references to EPA guidance addressing that factor are
given. The EPA guidance is analyzed and is referred to in this
report, to determine if the guidance documents available to
registrants adequately cover the areas where problems have
occurred. (A list of all guidance documents available for
residue chemistry studies is provided in Appendix A, at the end
of this document.)
After each rejection factor and the corresponding references
to EPA guidance, an Industry Comment section has been provided
with the industry scientists' (a) assessment of the adequacy of
the EPA guidance, (b) explanation of technical difficulties, if
any, associated with the rejection factor, and (c)
recommendations. Following each Industry Comment section, is
EPA's response to that comment.
After each guideline, the rejection factors are assessed in
terms of the registrants' ability to avoid the factor in the
future. This is presented in a list, which represents what EPA
would consider to be rejection factors that could/should be
avoidable on the part of the registrants. It is the intention of
the Agency in the future to take the appropriate regulatory
action should such "avoidable" factors cause a future study
submission to be rejected. This standard will not be applied
retrospectively to the studies analyzed in this assessment.
15
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GUIDELINE 171-4A PLANT METABOLISM STUDIES
1. Rejection Factor; Essentially no characterization of
residues in crop parts used, for food or
feed.
EPA Guidance on this Factor
Guidance on this topic appears in Subdivision 0-Residue
Chemistry Guidelines (pages 10-12) and in a 7/25/89 memorandum
from Richard Schmitt to Dietary Exposure Branch Staff, which is
included in the Overview of Subdivision 0 portion of the Phase 3
Guidance package-(pages E-25 through E-27). It is also included
in the acceptance criteria (#8) as follows: "Major components or
portion of the terminal residue identified (preferably by at
least two techniques-e.g., Thin Layer Chromatography, High
Performance Chromatography, Mass Spectrometry)" [see page C-363
of the Phase 3 Guidance].
The metabolism study is the key study in residue chemistry
because it defines the residue to be quantified in later studies
such as crop field trials. On page 10 ,of the Guidelines it
states that "The composition of the terminal residue must
therefore be determined before complete residue detection
methodology and residue quantification data can be developed."
On page 11 one of the purposes of an adequate plant metabolism
study is noted to be to "identify the major components of the
terminal residue".
In the past registrants could argue that residues were
simply too low to even attempt their characterization. However,
clear guidance has been issued on this topic in the 7/25/89 R.
Schmitt memo. The latter discusses "trigger values" that serve
as guides to the degree of characterization needed in metabolism
studies. For example, if total radioactivity is <0.01 ppm in a
crop part or animal tissue treated at a sufficiently high rate,
no characterization is necessary. However, for radioactivity
feO.Ol ppm attempts to extract the activity and then to
characterize the extractable activity are required.
Industry Comment
1. Under Plant Metabolism Rejection Factors (p. 16), the Agency
has listed the memorandum from Richard Schmitt to the Dietary
Exposure Branch Staff as a guidance document for plant metabolism
studies. This document does not really emphasize plant
metabolism!
2. If this document is to be used for plant metabolism study
guidance, the EPA should change the document title to include
"plant metabolism" and the guidance portion on plant metabolism
16
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should be expanded.
3. In general, Dr. Schmitt's memo has been extremely helpful
for animal metabolism studies.
EPA Response
The Agency agrees that additional guidance in the area of
metabolism studies, especially for plants, is needed. The Agency
agreed to develop a "Metabolism Guidance Paper" to address topics
such as the need for identification by two techniques, techniques
that should be used in attempts to release bound residues, and
the clarification of trigger values for bound residues. This
guidance paper will also include a roadmap.of acceptable
techniques to be tried before giving up on releasing bound
residues.
2. Rejection Factor;
Partial characterization of residues
In these studies portions of the residue have been
characterized, but not a sufficient percentage to completely
delineate the metabolism of the pesticide. This is a "gray, area"
and it is not possible to define an exact percent of the residue
that has to be identified in all cases. Although the EPA
normally states that registrants should strive for 90%
identification, it is often not possible to reach this level.
The final decision as to whether the residue has been adequately
characterized depends upon factors such as the actual level (ppm)
of unidentified activity, the importance of the matrix containing
the residue as a food or feed, the chemical structure and
toxicity of the active ingredient, and the toxicity of similar
chemicals (pages 10-11 of Residue Chemistry Guidelines). Another
factor which involves judgement is how the dosage or application
rate in the metabolism study compares to the actual use of the
pesticide (see 7/25/89 R. Schmitt memo). ,
EPA Guidance on this Factor
Due to this complexity involved in making the final
decision, the EPA does not have formal guidance on the percent of
the total residue that must be identified. Determination of the
adequacy of metabolism studies must be done on a case-by-case
basis.
Industry Comment
1. The terms "identification" and "characterization" seem to be
used interchangeably by the Agency and this is very confusing.
This confusion alone could be the number one reason for rejection
of plant metabolism studies. "Identification" is a much more
precise and difficult goal to attain than is "characterization".
17
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We believe that "identification" means pretty much the same to
everyone, whereas "characterization" may mean different things to
different people (especially study directors vs. reviewers).
We would propose that the Agency always use the term
"identification/characterization" together when they are speaking
in general terms, and that they clearly delineate what they
require when they use the terms individually (i.e. identification
ซ structure elucidation, match with standards, etc., and
characterization = aqueous vs. organic solvent soluble, polar vs.
non-polar, acidic, basic, bound, etc.)
2. Due to the low residue levels generally found in samples
from the plant metabolism studies, registrants are often faced
with the task of trying to identify/characterize fractions
representing very low levels of extractable or nonextractable
radioactivity even though these fractions represent a significant
proportion (>10%) of the total radioactive residue (TRR). As
stated in the rejection document, work with these types of
fractions often falls into a "gray area" which is not well
defined in the guidelines. As a result, this has led to the
perception that decisions dealing with these matters are often
based on the reviewer's own personal views. Issuance of the
Schmitt memo has helped to somewhat temper this perception by
defining what needs to be done with extractable residues;
however, additional guidance is still needed on the "trigger
values" for bound or nonextractable (NE residues).
As stated in the Schmitt memo, further characterization of
NE residues should be attempted when the NE activity is greater
than ซ0.1 ppm or 10% of the TRR. For samples containing a TRR of
less than 1.0 ppm, this could result in the need to characterize
NE residues which are considerably less than 0.1 ppm. Thus
guidance is sought on how to deal with NE residues which
represent more than 10% of the TRR but represent <=0.01 ppm or
less in the original sample; ซ0.01-0.05 ppm in the original
sample; and greater than 0.05-0.1 ppm in the original sample. In
addition, input is also sought on whether NE residues from crops
treated at rates higher than the maximum label rate can be
factored down (e.g., if the NE or bound residues are from samples
treated at a 2x rate, can the residue levels they represent be
divided in half for purposes of deciding what additional
characterization needs to be done?) ..'
3. When residues in the RAG are too low for meaningful
characterization, we would solicit the Agency's view on the
possibility or need for characterizing other plant parts which
may contain significant residue but are of no regulatory concern,
in order to gain insight into the type of metabolic alterations
which might be taking place. We would equate this situation to
identifying activity found in urine and feces in animal
metabolism studies.
4. A difficult task for the registrant is deciding how far to
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go in identifying structures of water-soluble, highly polar
metabolites that have undergone multiple molecular
transformations. These metabolites are the most challenging and
time-consuming to extract, purify, and identify/characterize. In
addition, because of the number of "detoxifying" steps they have
undergone, they represent the least value for the effort since
they are highly unlikely to be toxicologically significant.
EPA Response
With regard to the first comment, the Agency agrees that the
terms "characterization" and "identification" should not be used
interchangeably. An effort will be made to use the terms as
industry has described them. As discussed above for the previous
rejection factor, additional guidance will be developed to
address identification of bound residues (Comment 2). With
regard to Comment 3, identification of residues on inedible plant
parts can be useful. However, EPA prefers that some evidence be
provided to show similar residue profiles for edible and inedible
plant parts to accept such data. In response to the fourth
comment on water soluble residues, EPA will address
identification of such residues in the "Metabolism Guidance
Document".
3. Rejection Factor;
Characterization conducted on only
immature crop parts or cell cultures as
opposed to mature plants.
The third most frequent factor for rejecting a study is that
the characterization of residues is conducted on immature crop
parts or cell cultures, where the use of mature plants is
required.
EPA Guidance on this Factor
This subject is addressed on the bottom of page 11 of the
Residue Chemistry Guidelines: "The metabolism studies should be
carried to plant maturity whenever possible, so that the
composition of the residues is indicative of that in the terminal
residues at harvest." Although the acceptance criteria do not
mention mature plants by name, they do note that the major
components of the "terminal residue" should be identified
(criterion #8-page C-363 of Phase 3 Guidance). In addition,
criterion #5 refers to plant parts used for human food or animal
feed. Thus, both criteria imply that plant parts associated .with
harvest of the mature crop should be analyzed. However,
registrants should be reminded to examine mature crops in
metabolism studies. EPA suggests in many cases that the residues
on the immature crop be characterized in addition to those at
harvest. This is especially true for at-planting or early season
uses where the immature crop usually has much higher residues
than the crop at harvest.
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Industry Comment
1. The Agency "suggests in many cases that the residues in the
immature crop be characterized in addition to those at harvest",
even though they have just stated in the first sentence of the
paragraph, that the "composition of the residues" should be
"indicative of that in the terminal residues at harvest". They
give as their reason that for at-planting or early season uses
the immature crop usually has much higher residues than the crop
at harvest". This may be true, but the residue in the immature
crop may have no bearing on the most prevalent (qualitatively and
quantitatively) metabolites in the terminal residues.
Unless the immature crop is used as a feed item (green wheat
forage), the Agency should not suggest that this type of
metabolism work be done. The emphasis should always be on the
"terminal residue".
If the Registrant wishes to do this type of work to
supplement the terminal residue work, that should be alright, but
if the Agency suggests it should be done, some reviewers and
Study Directors may believe that this is a requirement, and
unnecessary time and effort may be expended for no good reason.
2. Even though the guidelines wisely state that metabolism
studies should be carried to plant maturity whenever possible,
some reviewers ignore the words in bold. Especially troublesome
are those situations where the level of agro-chemical needed to be
applied to incorporate sufficient activity into the mature plant
is lethal to the plant, thus maturity is unattainable.
EPA Response
This topic will be addressed in the Metabolism Guidance
Document. The Agency agrees that emphasis should be on the
terminal residue. However, in cases where it can't be
identified, additional work on the immature crop (or mature crop
parts other than the rac) may be required. Prior to studies
being conducted EPA will not state that use of immature crop is
required (unless it is an animal feed), but will continue to
suggest its use as an aid to identify residues.
4. Re-lection Factor;
Treatment of plants with wrong material
such as an isomer of the pesticide or
pesticide radiolabeled in a potentially
labile site which could preclude our
ability to track that portion of the
molecule of potential toxicological
significance.
EPA Guidance on this Factor
The first acceptance criterion for 171-4a states "Pesticide
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radiolabeled in non-labile portion of molecule (tritium label
strongly discouraged)" [Page C-363 of Phase 3 Guidance]. The
second paragraph on page 10 of Subdivision 0-Residue Chemistry
Guidelines also addresses this issue. It is noted that ring
labeling is preferred for most aromatic or cyclic compounds. If
a potentially labile side chain or tritium labeling is chosen,
the study is acceptable only if all significant activity is
identified and found to be associated with the basic structure of
the pesticide, not with loss of the label or side chain.
Industry Comment
Industry agrees that this is an appropriate cause for
rejection.
5. Rejection Factor;
Application of pesticide at less than
maximum registered rates such that very
low radioactivity resulted in crop
parts.
EPA Guidance on this Factor
This factor is addressed in the Residue Chemistry Guidelines
and the Acceptance criteria. On the bottom of page 11 of the
Residue Chemistry Guidelines it notes that the minimum
application rate should approximate proposed label rates. It
further states that "exaggerated rate studies may be necessary in
order to obtain sufficient activity for identification."
Acceptance criterion #4 (page C-363 of Phase 3 Guidance)
specifies that the pesticide be applied to the plant in a manner
simulating the expected use. This point has been emphasized to
registrants over the years in reviews and at meetings.
Industry Comment
Guidelines are clear concerning the need to use at least the
maximum label rate in metabolism studies. The problem is in the
need for exaggerated use rates to obtain sufficient activity for
identification when these rates prevent normal growth of the
plant. Does a sick plant metabolize a xenobiotic the same way a
healthy plant does?
Are there any criteria based on plant morphology or other
phytotoxic effects which could help in'determining what the
maximum tolerated application rate should be?
EPA Response
This will also be addressed in the Metabolism Guidance
Document. The latter will have a maximum exaggerated rate (e.g.,
lOx) to be used in plant metabolism studies. If this maximum
exaggerated rate kills the plant, the plants should be treated
just to the point of phytotoxicity (analogous to maximum
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tolerated dose concept in animals).
6. Rejection Factor;
EPA Guidance on this Factor
Need for confirmation of residue
identities by second technique.
Although Subdivision 0 does not specify confirmation of
identities, this is addressed in the Phase 3 Guidance package on
pages E-6 and C-363. On page E-6 it states that residues should
be identified by matching Rf values in at least two different
solvent systems if TLC is the only procedure used. "If possible,
we really prefer that two separate techniques (e.g., TLC and MS)
be used to identify residues". The last acceptance criterion on
page C-363 also mentions identification "preferably by at least
two techniques-e.g., TLC, HPLC, MS". Confirmation of identities
has also been discussed in our Standard Evaluation Procedures on
"Metabolism in Food Animals: Qualitative Nature of the Residue"
(page 8, paragraph 5) and on "Qualitative Nature of the Residue:
Plant Metabolism" (page 9, paragraphs 1 and 2).
Industry Comment
1. In some cases, the low levels of radioactivity available may
preclude the exploitation of a totally'separate technique. A
realistic requirement might be the use of two sufficiently
different aspects of the same procedure such as HPLC with
different solvent (or column) systems, if that would qualify as a
"separate technique".
2. The guidelines state that "Major components or portions of
the terminal residue be identified preferably by at least two
techniques". Reviewers ignore the term in bold and demand two
techniques even when levels are low.
EPA Response
As noted above under rejection factor 1, this will be
addressed in the Metabolism Guidance Document. EPA notes that it
normally would be acceptable to identify minor metabolites (low
percent of total residue, not likely to be toxic) using only one
technique. With regard to what constitutes a second technique,
the Agency feels that use of a different.column or adsorbent is
acceptable. However, use of a second solvent system with the
same column or adsorbent is questionable.
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GUIDELINE 171-4B LIVESTOCK METABOLISM STUDIES
Several of the rejection factors discussed under 171-4A are
also relevant.to livestock metabolism studies. These include
partial characterization of residues, treatment with wrong
material (isomer; labile site for radiolabel), and need for
confirmation of identities. The guidance described for these
factors under 171-4A is also applicable to livestock metabolism.
Acceptance criteria 1 and 10 for 171-4B also deal with these
rejection factors (page C-367 of Phase 3 Guidance package). Two
additional causes for rejection of livestock metabolism deserve
more discussion: no characterization of residues and dosing with
a mixture of compounds.
1. Re-lection Factor;
No characterization of residues
EPA Guidance on this Factor
Many livestock metabolism studies were rejected in the past
due to no (or perhaps minimal) characterization of .residues in
tissues, milk, and eggs. In many instances this was due to
dosing at a too low level. This problem has been addressed by
the 7/25/89 R. Schmitt memo (pages E-25 to E-27 of Phase 3
Guidance). This memo specifies that the minimum dose should be
10 ppm in livestock metabolism studies. It also provides
guidance ("trigger values") as to the degree of characterization
required in metabolism studies based on the total radioactivity
observed in a tissue, crop part, etc.
Industry Comment
See Industry Comment at the end of this section.
2.Renaction Factor;
Dosing with a mixture of compounds
Some livestock metabolism studies have been rejected in the
past due to dosing with a mixture of radiolabeled chemicals
(e.g., parent plus metabolites) rather than a pure compound.
When dosing with such a mixture, it is impossible to determine
whether plant metabolites are also animal metabolites.
Therefore, animal metabolism studies should reflect feeding of
only one compound, usually the parent. If a plant metabolite
comprises a major portion of the residue on feed or is not found
to be an animal metabolite, additional animal metabolism studies
involving dosing with that plant metabolite may be required.
EPA Guidance on this Factor
Guidance on this factor was issued on page E-7 of the Phase
3 Guidance package. (The latter points out that this does
represent a change from the Residue Chemistry Guidelines in that
they state "The material fed should simulate the terminal
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residues in feed items as closely as possible ....") The feeding
of a single compound is also specified on page 3 of the Standard
Evaluation Procedure on Metabolism in Food Animals: Qualitative
Nature of the Residue.
Industry Comments on This Section
Industry acknowledges that many of the comments on
identification/characterization for plant metabolism also hold
true for animal metabolism.
When referring to the 7/25/89 memo by R. Schmitt, the Agency
should emphasize that the minimum dose of 10 ppm referred to is
10 ppm in the feed and not 10 ppm by body weight. This is very
important.
In some livestock metabolism studies, the bulk of the
radiolabel is excreted and exaggerated doses are required to
produce radioactivity in the tissues. It is possible that
extreme doses of compound or vehicle can produce anomalous
results.
EPA Response
, i
The Agency,will emphasize the 10 ppm in the feed (i.e., 10
mg pesticide per kg feed) in the Metabolism Guidance Document.
General Industry Comments on Metabolism Studies
The following industry comments regarding metabolism studies
were not directed at any specific rejection factor.
Reviewers tend to interpret technical guidance too
conservatively by ignoring the statements about identification of
activity "above the ppm trigger value are not absolute
requirements, but rough guides as to how much characterization is
adequate."
There should be an intermediate step in the registration
process in which the Agency will quickly review the registrant's
metabolism data, and the Agency and the registrant can agree on
what should constitute the total toxic residue, so that work on
an appropriate method can proceed.
If this type of procedure cannot be accomplished in an
expedient fashion, then clear "trigger values" for toxicity of
metabolites should be developed, so that the registrant and the
Agency use the same criteria in deciding if a metabolite should
be included in the analytical method or not.
EPA Response
With regard to reviewers' interpretations of guidance, all
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reviews are examined by a section head and branch senior
scientist for consistency with branch policy and are often
changed to ensure such consistency. The Agency tends to ask for
additional data in those situations that are close calls.
Registrants can challenge such requests for additional data.
For chemicals undergoing reregistration the Agency is not
willing to delay field trials while metabolism studies are being
reviewed. However, metabolism studies have been placed in high
priority review status in reregistration to allow decisions on
the total toxic residue to be made as soon as possible.
Registrants are also encouraged to consult with EPA as soon as
possible when questions arise regarding the need to regulate a
recently discovered metabolite.
In the case of new chemicals registrants are encouraged to
request pre-registration conferences to discuss metabolism
results. EPA suggests that summaries of available toxicology
data (including rat metabolism and acute studies) be submitted
prior to such conferences. Literature searches on the toxicity
of any known metabolites would also be useful.
Animal Metabolism - Supplementary Assessment
Twelve animal metabolism studies on five chemicals were
classified as supplementary. Upon analysis of the reviews, the
following was determined: six studies should have been
classified as rejected; three studies are supplementary because
they were done using the wrong animals (rats and non-lactating
goats); two studies are interim reports; and one study was not
accepted, but could be upgraded, due to insufficient
characterization.
Examples of "Avoidable Rejection Factors" for Metabolism Studies
In assessing the factors above and other reasons that
studies submitted to the EPA might get rejected, the following is
a list of what EPA believes would be avoidable rejection factors
on the part of the registrants. Should these factors cause a
future study submission to be rejected, the Agency would likely
consider taking the appropriate regulatory actions. This
assessment would only be applied to future studies submitted to
the Agency. This judgement would not be applied retroactively.
1. No attempt to extract or characterize radioactivity at
levels aO.05 ppm unless such activity resulted from
application rates or dosages well above the actual use
of the pesticide.
2. Studies which fail to identify significant portions of
the residue and in which the radiolabel was placed in a
potentially labile site.
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3. Plant metabolism studies which fail to identify
significant portions of the residue and in which the
pesticide was applied at well below label rates.
4. Livestock metabolism studies which fail to identify
significant portions of the residue and in which the
pesticide was fed to animals at well below expected
dietary burdens or well below 10 ppm in those cases
where low residues are present in feeds.
5. Livestock metabolism studies in which animals were
dosed with a mixture of compounds unless an adequate
rationale for doing so is presented.
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171-4(C and D) - ANALYTICAL METHODS
1, Rejection Factor;
Method inadequately validated (recovery
data, radiovalidation, independent lab
validation, interference data)
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 13-17
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures-; Analytical
Methods/Residue Chemistry (1990)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-369 through C-371. and E-8 through E-9.
PR Notice 88-5: Tolerance Enforcement Methods -
Independent Laboratory Confirmation by Petitioner
In many cases, methods rejected due to validation
deficiencies may be upgraded by the submission of additional
data/information.
Industry Comment
No comments were recorded on this factor.
Example of an "Avoidable Rejection. Factor" for Analytical Methods
Studies
In assessing the factor above and other reasons that studies
submitted to the EPA might get rejected, EPA believes that
circumstances such as where no validation data are submitted
would constitute an "avoidable" rejection factor on the part of
the registrant. Should this kind of factor cause a future study
submission to be rejected, the Agency would likely,consider
taking the appropriate regulatory actions. This assessment would
only be applied to future studies submitted to the Agency. This
judgement would not be applied retroactively.
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171-4E - STORAGE STABILITY
1, Re-lection Factor;
Samples not fortified with all
components of the total toxic residue
EPA Guidance on this Factor
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp C-372-3.
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
Industry Comment
1. The phrase "all components of the total toxic residue" needs
to be clearly defined as applying only to residues of
toxicological concern. Magnitude of the residue studies, crop
processing studies, and their companion storage stability studies
need to be sequentially scheduled after plant and animal
metabolites are completed. Adjusting the Reregistration time
frames to allow identification of the components of the total
toxic residue before subsequent studies are conducted would
reduce the number of requests,for waivers and time extensions.
2. Obtaining EPA's evaluation of the total toxic residue before
proceeding with the remaining residue studies is ideal.
Magnitude of the residue, processing and storage stability
studies are often initiated in conjunction with the growing
season, and are conducted before EPA's "sign-off" on the total
toxic residue.
EPA Response
Registrants should consult with the Agency as soon as ,
possible if questions arise as to what residues to include in the
TTR. EPA also advises that some control samples be spiked when
field trial samples are collected even if a method is not
available to do the zero day analyses.
2. Re-lection Factor;
Fortification with a mixture for which
the analytical method is not able to
quantitate residues individually
Other causes for rejecting storage stability studies
involved the fortification with a mixture where the analytical
method did not determine residues individually or the method gave
low and variable recoveries.
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EPA Guidance on this Factor
.FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp C-372-3. '
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
Storage stability.studies that do not provide data regarding
the stability of each individual component of the total toxic
residue are unlikely to be upgradable.
Industry Comment
Fortification with a mixture is suitable for all products
which meet the following conditions:
The total toxic residue shows no appreciable
degradation.
None of the mixed compounds has a specific
toxicological concern.
Conversely, it is not appropriate to use the analytical
method, either total or specific to each compound in the mixture,
to .determine when to fortify with a mixed spike.
EPA Response
Spiking with a mixture is acceptable in those instances
where the method is capable of measuring each, component of the
residue separately. In those cases where the method converts all
residues to a common moiety the Agency is concerned about the
possibility of the disappearance of one component being masked by
the presence of the other components of the mixture. Therefore,
spiking with mixtures or using weathered residues is not
encouraged with such analytical methods. The type of chemical
and toxicity involved would determine the acceptability in these
cases. For example, with chemicals like alachlor or triazines
where similar chronic toxicity concerns exist over numerous
components of the residue, spiking with a mixture followed by use
of a common moiety method is probably acceptable. On the other
hand, it would not be acceptable to use a common moiety method
for cholinesterase inhibitors where significant differences in
toxicity may occur as the parent compound oxidizes to assorted
metabolites. In other words, in the latter case the method would
need to detect each of the metabolites separately.
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3. Rejection Factor;
Use of an Analytical method which gives
low and variable recoveries
EPA Guidance on this Factor
For a summary of guidance in the analytical method area,
refer to 171-4 (C and D). Storage stability studies conducted
using invalid analytical methods are unlikely to be upgradable.
Industry Comment
"Low" and "variable" need to be defined. It is standard
practice to allow limits of a residue method to vary between 70%
and 120% (Subdivision 0, p. 14). To reduce variability in a
fortified storage stability study, the registrant may take
certain measures such as spiking with an adequate level,
averaging results of duplicate samples for each stability time
point, and preparing 'additional samples for use if method
recoveries do not fall within the allowed limits. To correct for
variability in the method, stability recovery data may also be
corrected for the method recovery data obtained with each set of
stored samples.
EPA Response
"Low" recoveries normally means <70%. "Variable" depends
upon the level of residues present. A much higher variability is
acceptable for residues of 1 ppb than for those at 1 ppm. The
Agency recommends that spiking levels in storage stability
studies be at least lOx the limit of detection with the minimum
being 0.1 ppm. Preferably, spiking levels should be close to
typical residue levels observed in the field.
4. Rejection Factor;
Insufficient information regarding
dates, storage conditions, and
descriptions of analytical methods
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982) p.
19
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures: Storage Stability
Study/Residue Chemistry
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp C-372-3. and C-387 through 390.
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
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In many cases, studies rejected due to storage stability
data problems may be upgraded by the submission of additional
data/information.
Industry Comment
Concerning storage conditions for a stability study, the
above information should be provided.
Once the stability is proven for representative crops
(fruit, oilseed, non-oily grain, representative by-products)
stored under a set of related storage conditions (frozen), these
core studies should be considered as a unit to define the storage
stability pattern.
Producing storage stability data mimicking exact conditions
under which the magnitude of the residue or processed commodity
samples have been stored is quite difficult. If stability has
been demonstrated in representative crops, then no further
storage stability studies should be required. Representative
stability data should be adequate to support, pre-GLP or pre-Phase
3 guidance residue studies, where only the approximate storage
conditions are known.
EPA Response
As noted above under EPA Guidance, storage stability studies
rejected for lack of details on dates, storage conditions, etc.
may be upgraded by submission of that information.
A cohesive document on storage stability will be prepared to
address topics such as representative commodities and
temperatures to be examined in these studies. In general, the
studies should be conducted at the same temperature at which
field trial samples were stored. To coyer older field trials the
Agency suggests conducting storage stability studies at two
temperatures (e.g., -5C and -20C) to address the uncertainty
regarding exact temperature at which older samples were stored.
5. Rejection Factor:
Failure to include a sufficient range of
commodities
Another frequent cause for incomplete storage stability data
was the failure to include a sufficient range of commodities. In
general, one crop from each crop grouping having tolerances
should have been examined. In addition, some representative
processed commodities such as fruit juice, pomace, milled
products (e.g. flour bran), and oil should be included.
EPA Guidance on this Factor
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp E-9-10.
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Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
Industry Comment
1. A revision of Subdivision 0 of the Pesticide Assessment
Guidelines incorporating the Agency's most current views (Phase 3
Guidance, for example) would enable registrants to plan storage
stability studies that are acceptable to the Agency and
logistically feasible to conduct.
2. The Phase 3 Guidance allows combining crop groups, and
conducting stability studies on representative crops, i.e., an
oilseed, a fruit, and a non-oily grain, and representative
processed products. The 1990 "Storage Stability Study" SEP (p.
10) reminds the reviewer to consider storage stability data for
the test compound on other commodities, thus acknowledging the
usefulness of related storage stability data.
3. Once a compound has been shown to be stable in
representative crops stored under similar conditions, the
registrant need not continually demonstrate that stability. If
instability is shown in any of the representative crops then
additional data may be required on other crops. Generating
excessive stability data, as suggested in the 1987 Position
Document, "Effects of Storage (Storage Stability)", is
prohibitively expensive. It can cost more than the RAG residue
studies or processing studies themselves, without contributing to
the validity of those studies.
4. We also recommend that storage stability not be required for
samples analyzed within 30 days from harvest, provided samples
are frozen after harvest. In most field-trials one month is
needed to ship samples and schedule them for analysis.
EPA Response
As stated previously, EPA plans to prepare a cohesive
document on storage stability that would address the concept of
representative commodities. This paper will follow and expand
upon the guidance issued in the Phase 3 Guidance Package.
Unless a compound is otherwise known to be volatile or
labile, the Agency agrees that storage stability data are not
needed for samples stored frozen for <30 days.
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Additional Industry Concerns
EPA lists five rejection factors for storage stability
studies. Industry has concerns regarding piecemeal issuance of
storage stability requirements, and requests for increasing
numbers of crops and commodities. The expanding and conflicting
requirements doom storage stability studies to be considered
inadequate, especially for studies which are in progress or in
queue for EPA review.
Studies performed before the issuance of any new requirement
should be reviewed according to the regulation in effect when the
study was conducted.
Increasing and conflicting requirements, both written and
verbal from reviewers, for storage stability studies are the
principle reasons why residue chemistry studies are considered
deficient at the time they are reviewed. The varying
regulations need to be combined, after industry comments are
considered, into one cohesive document so that once established,
it will provide a framework for acceptable studies.
The concurrent storage stability requirement specified in
the 1987 position Document requires preparation of a set of
stability samples for virtually every set of treated samples.
This entails preparing stability spikes and performing a 0-day
analysis on the day samples are placed in storage. Thus,
analytical methods must be validated on all matrices, including
processed products, at the time the samples arrive at the
analytical lab. Also, samples of processed products may not be
available in advance of shipment to the analytical laboratory,
and, therefore, method development and validation may not be
completed at the time samples are shipped.
EPA Response
A cohesive document will be prepared addressing issues such
as representative commodities, temperatures, and the need for
concurrent storage stability data. With regard to the latter,
such data are not required in most cases. However, in instances
where residues are known or suspected to be unstable, concurrent
studies may be needed. The Agency advises that control samples
of all crops be spiked at the time field trial samples are placed
into storage in case stability questions arise at a later time.
Storage Stability - Supplementary Assessment
Fifteen storage stability submissions on four chemicals were
classified as supplementary. Upon analysis of the reviews, each
submission was an interim report for the full study.
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Examples of "Avoi<
Studies
for Storac
In assessing the factors above and other reasons that
studies submitted to the EPA might get rejected, the following
list are what EPA believes would be "avoidable" rejection factors
on the part of the registrant. Should these factors cause a
future study submission to be rejected, the Agency would likely
consider taking the appropriate regulatory actions. This
assessment would only be applied to future studies submitted to
the Agency. This judgement would not be applied retroactively.
The following are examples:
1. Lack of storage stability data provided for key
components of the total toxic residue.
2. There are no method validation data provided or
referenced.
3. No information regarding sample storage conditions or ,
intervals are provided.
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171-4J - MEAT/MILK/POULTRY/EGG STUDIES
These studies are very rarely rejected. Registrants should
keep in mind the following key factors when conducting livestock
feeding studies:
(1) Feed the appropriate material (parent pesticide and/or
metabolites) at sufficient levels (normally 1, 3 and 10
times the anticipated dietary burden for the species of
interest).
(2) Continue dosing until residues plateau in milk or eggs
(minimum of 28 days even if residues plateau earlier).
(3) Sacrifice animals within 24 hours of the final dose.
(4) Use a validated analytical method to measure the total
toxic residue in edible tissues, milk, and eggs.
(5) Provide storage stability data to show behavior of
residues during storage of samples prior to their
analysis.
EPA Guidance on this Factor
Sources of guidance for this study include pages 22-23 of
Subdivision O, pages C-382 to 384 and E-13 and 14 of the Phase 3
Guidance package, and the Standard Evaluation Procedure entitled
Residues in Meat, Milk, Poultry and Eggs: Feeding Studies/Feed-
troughs .
Industry Comment
The Agency indicates that dosing should continue "until
residues plateau in milk or eggs (minimum of 28 days even if
residues plateau earlier)." Industry believes the Agency should
simply set a certain duration for the feeding studies (28 days,
30 days, 35 days, 40 days, 50 days, or something), and not leave
this so open-ended.
These studies are very costly, and they require more than
the average amount of man-power for a residue chemistry study.
In these studies it is sometimes very difficult to keep up with
the residue analyses to verify that a plateau has been reached so
that the dosing can be stopped. In addition, the number of doses
to be prepared is never known exactly in the current situation.
EPA Response
Although it is rare that residues do not plateau in 28 days,
this has been observed with some pesticides. In order to cover
those cases where residues may not plateau for a long time
35
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period, the Agency prefers to maintain the present requirement of
"until residues plateau ... (minimum of 28 days) ..."
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171-4K - CROP RESIDUE STUDIES
1. Rejection Factor:
Method inadequately validated or
described
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 13-15
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures: Analytical
Methods/Residue Chemistry (1990)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-369 through C-371. C-387 through C-390.
and E- 8 through E-9.
In many cases, crop residue studies rejected due to method
problems may be upgraded by the submission of additional
data/information.
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
2. Re-iection Factor;
Insufficient geographical representation
The second most frequent reason for rejection was
geographical distribution, where field trials were not conducted
in states that represent a sufficient portion of U.S. crop
production. These deficiencies are difficult to resolve without
further field trials.
EPA Guidance on this Factor
Subdivision O: Residue Chemistry Guidelines. (1982) pp.
19-20
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). PP. C-387 through 390 and E-28 through E-30.
In most cases, additional field trials were needed when
there was inadequate geographical representation.
Industry Comment
1. Vague guidance on this subj ect has led to a variety of
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interpretations by reviewers regarding the adequacy of data.
Questions are raised about insufficient number of sites per state
and per crop. Reviewers have commented that residue trials must
cover both ends of a state,, with test sites at each end.
Registrants have also been told that two sites in a
geographically similar area count as only one site.
The Agency should provide more specific guidance on
requirements for number of sites per state, number of sites per
crop, and geographical distribution of test sites within a state.
We believe that unless there is a distinct climatic difference
within a state, geographical distribution of sites within a state
is not relevant, and all sites within a state should be
considered valid.
We recognize that providing this guidance is,not easy.
Therefore, we propose that representatives of EPA, USDA, IR-4,
and industry jointly address this topic, to resolve the
ambiguities for both registrants and reviewers.
2) Guidance varies regarding the specific states where residue
tests should be conducted. For example, the 1985 NACA
"Guidelines for Conducting Agricultural Chemical Residue Field
Trials in the USA" lists TX, NM, and WA as the major crop
producing states for bulb onions, based on USDA's 1985
Agricultural Statistics. EPA's Phase 3 Technical Guidance (p.
E-28) lists NY, MI, OR/WA, and ID or CO for that crop, based on a
1983 list prepared for IR-4. Only one state is common to the two
lists. One List A Registration Standard required residue tests
for bulb onions in CA, NY, and ID/OR. Which guidance should the
registrant follow? The only safe choice is to cover all the
states listed by the three lists, but that defeats the purpose of
guidance documents.
We propose that the group of representatives mentioned above
also address proper geographic representation for the various
crops. A single reference source for crop production statistics
should be identified or prepared as guidance for all crops.
3) The phrase, "a sufficient portion of U.S. crop production"
is too vague. The Phase 3 Technical Guidance lists CA, FL,
TX/AR, NY/NJ, CO and WA as required states for lettuce. Based on
the 1985 Agricultural Statistics. these states comprise 95% to
97% of U.S. lettuce production. However, for peaches the Phase 3
document lists the states of CA, GA/SC, MI, NJ/PA, and WA,
representing 80% to 88% of U.S. production. This guidance does
not consider the number of states to be required for major vs.
minor crops, or for non-detectable vs. detectable residues.
The group defined above should also define the percent of
crop production that must be accounted for. We propose that
trials in states representing 75% of crop production be
considered adequate.
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EPA Response
EPA suggests that industry working in conjunction with IR-4
prepare a package for Agency review that addresses the definition
of a site, the number of sites needed for various crops, the
states in which trials should be conducted, and the percent of
national production to be accounted for. The Agency believes
that the number of sites in each state/region for a given crop
should be weighted to follow the distribution of the production
of that crop. The Agency is also concerned about setting 75% of
crop production as adequate for any commodity. EPA considers
geographic variability as well as climate and growing seasons.
Defining geographic areas rather than individual states might be
considered.
3. Rejection Factor;
Mo data for aerial/sprinkler application
on label
Chemistry Branch/HED policy regarding the need for field
trials reflecting aerial application has recently changed such
that aerial field trial data will be required less frequently.
EPA Guidance on this Factor
Letter dated December 6, 1991 from Robert S. Quick,
Acting Chief, Chemistry Branch I/HED to Dr. Richard F.
Holt, Chairman, NACA Registration Committee.
Prior to this change in policy, the following guidance on
aerial data requirements was available:
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 19-20
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986) . ' .
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-387 through 390
The present policy is if the registrant is willing to amend
their label (s) such that the product is applied in .> 2 gal
water/acre (>. 10 gal water/acre for orchard crops) , no field
trial data specifically for aerial use will be required (i.e.,
this rejection factor may be satisfied by a label change if the
registrant is willing to pursue that route).
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
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4 R@1eetionFactor; Relevant formulation not tested
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 19-20
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986) , ,
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-387 through 390
If the registrant wishes to maintain use of the formulation
in question, residue field trials in which a representative
formulation is used must be conducted.
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
5, Rejection Factor;
:ered use/minimum PHI not reflected
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 19-20
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-387 through 390
Crop residue studies rejected because the registered
use/minimum PHI was not reflected may be upgradable only if
registrants amend their label(s) such that the existing residue
studies reflect the uses specified on the label.
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
6. Rejection Factor;
Inadequate storage stability data
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
12.
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Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures: Storage Stability
Study/Residue Chemistry
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp C-372-3. C-387 through 390 and E-9-10.
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
In many cases, crop residue studies rejected due to storage
stability data problems may be upgraded by the submission of
additional data/information.
Industry Comment
Industry addresses this issue in the storage stability
section. .
7. Rejection Factor; Application number/rate too low
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982)
pp. 19-20
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
' - FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-387 through 390
Crop residue studies rejected because the application
number/rate was not reflected may be upgradable only if the
registrants amend their label(s) such that the existing residue
studies reflect the uses specified on the label.
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
8. Rejection Factor;
TTn.trea.ted. RAG contam.ina.ted.
No specific guidance is needed for this factor. It is
obvious that a study must be repeated if the reason for rejection
was contamination of the control samples.
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Industry Comment
Industry agrees that this is an appropriate rejection
factor.
9, Re-iection Factor;
Summary data presented, not supported by
raw data
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982) p.
37.
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-387 through 390
Crop residue studies rejected due to the absence of
representative raw data may be upgraded by submission of the
missing data/information.
Industry Comment
The term "raw data" is too open-ended. Registrants have
continually been faced with varying expectations for raw data,
depending on the particular reviewer. Some want weather data,
others don't. Some want hand-written field observation data,
others don't. Registrants must try to satisfy all reviewers,
which adds extra paperwork, preparation, and review time to every
report. To limit this confusion, it is in the Agency's best
interest to be consistent in defining what raw data are to be
submitted.
Therefore, we propose that the Agency clearly define the
term "raw data," and clearly specify which raw data must
accompany a report.
EPA Response
The Agency will prepare a document outlining which raw data
should be submitted with residue chemistry studies.
10. Rejection Factor; No data on relevant metabolites
EPA Guidance on this Factor
Subdivision O: Residue Chemistry Guidelines. (1982) p.
15
Data Reporting Guidelines: Residue Chemistry - Addendum
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2. (1986)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989) . pp. C-387 through 390
Crop residue studies rejected due to the absence of data on
relevant metabolites may, in some cases, be upgradable by
additional analysis of stored samples from the residue studies.
Industry Comment
At present, List A compounds are given timelines that
require the magnitude of residue in crop study to start
concurrently with the nature of the residue in plant study.
However, the total toxic residue is not clearly defined until the
completion, submission, and review of the nature of the residue
study. Such schedules do not allow time for assessment of the
components of the total toxic residue in planning residue
analyses. If new metabolites of toxicological concern are
identified, then new analytical methods must be developed and
residue samples must be reanalyzed. Obviously, no freezer
stability data are available on the new metabolite. Thus, the
registrant is faced with generating freezer stability data to
cover a lengthy storage period on the new metabolite or running
all new crop trials.
The solution requires two components. First, for products
subject to reregistration, allow time for plant metabolism
studies to be conducted, submitted, and reviewed before the field
residue trials are scheduled to start. Second, the Agency needs
a mechanism to quickly determine the residues of toxicological
concern after metabolism studies are submitted. Often it is over
one year before such a determination is made. This is of special
concern for new active ingredients.
EPA Response
This issue is discussed above under "General Industry
Comments on Metabolism Studies". The Agency reiterates that
metabolism studies have been placed in a high priority review
status in the reregistration process. Registrants should also
consult with the Agency as soon as possible when questions arise
regarding the need to regulate a recently discovered metabolite.
In some cases the Chemistry Branch may refer the question to the
recently formed HED Metabolism Committee for a final decision.
11. Rejection Factor; No data on relevant commodity
EPA Guidance on this Factor
Subdivision O: Residue Chemistry Guidelines. (1982) p.
18-19 and Table II
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Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. E-20 through E-24
In cases where the relevant commodity was not collected for
analysis or the sample was treated inappropriately following
harvest (e.g., washed), the study will most likely need to be
repeated, i.e., the study will not be upgradable.
Industry Comment
Industry agrees that this is an appropriate rejection
factor.
Industry Comment Overview
EPA lists 11 rejection factors for crop field trial studies.
Industry is concerned about the lack of specific guidance on the
number of sites required, the definition of raw data, the
identification of metabolites of toxicological concern, and
various new requirements being proposed as extensions of the
guidelines. After all industry comments are considered, the
guidelines and supporting documents need to be upgraded to
clearly state the requirements for studies in this area.
At present, registrants are faced with new interpretations'
of old guidance, new interpretations of vague guidance, and
evolving specific requirements based on chemical classes'of
compounds. We seek more Agency guidance on the vague areas of
the guidelines and ask that the Agency not impose new study
requirements retroactively. Rather, the Agency should
acknowledge that it will take 24 months before new regulations
can be met in ongoing crop field studies. Industry agrees that
factors 1,3,4,5,7,8 and 11 are appropriate for rejection.
Rejection factor 6 is addressed within our storage stability
comments.
Other Crop Field Trial Issues from Industry
1. Reviewers have frequently stated that two years of field
residue data are required on major crops, while the available
guidance documents do not indicate such a requirement. If two
years are required, the Subdivision 0 guidance document needs to
be revised to reflect this requirement.
We believe that two years of data should not be needed.
Adequate geographic representation of data from one year should
also account for the climatic variation needed to evaluate the
potential for residues in the various crops.
2. The present guidance on rinsing, cleaning, trimming, or
brushing of raw agricultural commodities prior to residue
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analysis needs to be clarified.
Subdivision 0 (p. 18) states: "The samples taken should be of
the whole raw agricultural commodity (RAC) as it moves in
interstate commerce . . .The sample should not be brushed,
stripped, trimmed or washed except to the extent that these are
commercial practices before shipment, or to the extent allowable
in 40 CFR 180.1(j), the PAM, or the codex Document Alinorm 81/24,
Appendix III. It should be noted in the enforcement program,
produce is examined for residues on an "as is" basis, regardless
of whether it meets any Federal or State quality grading
standards with respect to washing, brushing or number of wrapper
leaves retained. Because certain crops (cabbage, celery and
lettuce) may be shipped without having been stripped or trimmed,
samples of these crops should reflect both trimmed and untrimmed
samples; only obviously decomposed outer leaves should be
removed. The preparation of each sample prior to analysis should
be indicated."
Virtually all produce is washed, brushed, stripped or
trimmed for direct sale to the consumer before it is moved in
interstate commerce. Is there now a conflict between the
condition of crops as they move in interstate commerce and as
they are examined for residues by FDA on an "as is" basis? How
does this impact the samples that should be analyzed for field
residue trials?
We propose that extraneous foliage and soil should be
removed before the RAC is analyzed for field crop trials.
Neither is part of a consumable product.
3. The number of samples required per site needs to be defined.
Some reviewers require more samples per site for acutely toxic
substances. The Subdivision O Guidelines refer to the 1981 FAO
CCPR document which states, ". . .it is usually not necessary to
replicate treatment at individual sites. However, it is useful
to have three or four replicates at one site to study
experimental uniformity and determine within site variations."
Some reviewers want replicates from every site.
We propose that the group described above develop firm
guidance on this issue.
4. Presently, field residue studies are designed to ensure
greatest potential crop exposure to pesticide residues that would
be allowed by proposed or registered use patterns (highest use
irate, shortest application interval, shortest PHI).
Occasionally, a residue data value from one test site is an
obvious outlier, where the field data indicate no application
irregularity, yet the value is far outside the normal cluster of
residue values.
We propose that the Agency should disregard obvious outlier
data when establishing tolerances for pesticide residues.
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5. In objecting to residue analysis of composited samples, the
Agency has argued that all of the residue in the composited
sample could come from a single commodity or single fruit.
According to such an argument, a ten-apple composite sample
having residues of 1 ppm, could consist of one apple with 10 ppm
and 9 apples with no residues.
Is the Agency moving toward this position? If so, does this
mean individual sampling? If so, how will the Agency regulate?
The approach may have merit in specific limited circumstances,
but bears further detailed discussion to establish reasonable,
realistic guidance.
EPA Response
1. Provided that field trials in one year have adequate
geographic representation, studies representing a second year are
not mandatory, although such data will be utilized if available.
When additional studies are requested, it is usually just due to
there being too few studies, not because a second crop year was
not represented. However, in certain cases of unusual weather
conditions, field trials from a second year may be required
regardless of the number of studies done in the first year.
2. As long as removal of extraneous foliage or soil is part of
normal harvesting procedures, such treatment of crop samples
prior to residue analysis is acceptable. It is currently
acceptable to brush root crops such as potatoes to remove
adhering soil. An interagency (EPA/FDA/USDA) workshop is
developing a regulation on portion of commodities to be analyzed.
This regulation will probably specify that root and tuber and
bulb vegetables be lightly rinsed in running water to remove
adhering soil.
3. Although EPA statisticians think more samples should be
required, only one sample per site is presently required. We
prefer that more sites' (with one sample per site) be included for
a given crop versus fewer sites with multiple samples per site.
Industry can address this issue in their proposal on geographic
representation (states, # sites, etc.).
4. The Agency does discard residue values that it believes are
outliers. However, there are numerous ways of determining what
constitutes an outlier. EPA recommends that registrants identify
outliers and give reasons as to why they should not be used.
5. In the case of acutely toxic pesticides the Agency is
developing guidelines that should be issued in fall 1992 (Acute
Tolerance Project). The options being considered include
continuing to set tolerances on composite samples (but at a level
low enough to ensure residues on individual commodities do not
present an unreasonable risk), setting separate tolerances on
composite and individual samples, and setting tolerances on
individual samples. The guidelines will list the specific
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commodities for which analyses of individual samples may be
required. Public comment on this policy will be requested.
Examples of "Avoidable Rejection Factors" for Crop Field Studies
In assessing the factors above and other reasons that
studies submitted to the EPA might get rejected, the following
list are what EPA believes would be "avoidable" rejection factors
on the part of the registrant. Should these factors cause a
future study submission to be rejected, the Agency would likely
consider taking the appropriate regulatory action. This
assessment would only be applied to future studies submitted to
the Agency. This judgement would_nQt be applied retroactively.
The following are examples:
1. The method submitted lacks validation data.
2
3
The key production states are not represented in crop
residue trials.
The registered use is poorly represented in crop
residue trials and there is no indication of intention
to amend the label.
There are no storage stability data submitted or
referenced with the crop field trial.
The relevant metabolites or relevant commodity are
omitted from crop field trial data with no explanation
or rationale for the omission.
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171-4L - FOOD PROCESSING STUDIES
1. Rejection Factor;
EPA Guidance on this Factor
Subdivision O: Residue Chemistry Guidelines. (1982)
21 and Table II
Data Reporting Guidelines: Residue Chemistry - Addendum
4. (1988)
Standard Evaluation Procedures: Magnitude of the
Residue - Processed Food/Feed Studies (1988).
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. E-10 through E-12 and E-20 through E-24.
Industry Comment
If "relevant commodity" means a major commodity, such as
soybean oil, this is an appropriate reason for rejection. If it
refers to a minor commodity, such as soapstock, where the residue
in the RAG has been accounted for in other processed products,
such as the oil. and meal, then this is not a valid reason for
study rejection.
EPA Response
In cases where analysis of a given fraction is not possible
(e.g., loss of sample), this argument is acceptable as a reason
for not rejecting the study. However, if samples of processed
fractions listed in Table II of the Guidelines are available,
they should be analyzed.
2. Reaction Factor;
Method - Inadequate
description/validation data
EPA Guidance on this Factor
Subdivision O: Residue Chemistry Guidelines. (1982)
pp. 13-15
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures:
Analytical Methods/Residue Chemistry
(1990)
Magnitude of the Residue: Processed
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Food/Feed Studies (1986)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. C-369 through C-371. C-391 through C-392.
and E-8 through E-9.
In many cases, food processing studies rejected due to
method problems may be upgraded by the submission of additional
data/information.
Industry Comment
B
This is an appropriate reason for rejection. However, as
the draft report points out, such a study should be upgradable,
by submission of the appropriate description and validation data.
EPA Response
EPA agrees that such studies may often be upgraded.
3. Rejection Factor;
Industry Comment
No processing study available
If the 408 tolerance for the RAG reflects finite, detectable
residues over 0.1 ppm for pesticides applied to fruits or
vegetables close to harvest, a processing study would be
required. Hence, this would be an appropriate reason for
rejection.
However, many pesticides (primarily herbicides) are applied
at low rates early in the growing season to crops,such as
soybeans, corn, and peanuts, long before any hairves table
commodity is present or forming. In many of these situations the
established tolerance (usually 0.1 ppm) reflects the sensitivity
of the analytical method;'residue samples show nondetectable
residues. Actual residues can be estimated only by extrapolation
from samples treated at exaggerated rates.
In these situations there is usually no possibility of
residues in the processed commodity that would exceed the 408
tolerance level for the RAG. Unfortunately, essentially all of
the Agency guidance on this issue confusedly states, "If
detectable residues are found on a crop for which Table II of the
Guidelines lists a processed commodity, then a processing study
is required, and if the data show a concentration of residues,
then a Food Additive Tolerance (FAT) is required." This
statement is not equivalent to 40 CFR ง190.l(f) (2) which states:
(f) Where raw agricultural commodities bearing residues that
have been exempted from the requirement of a tolerance, or
which are within a tolerance permitted under section 408 are
used, the processed foods will not be considered unsafe
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within the meaning of section 406 if: (2) the concentration
of the pesticide in the preserved or processed food when
ready to eat is not greater than the tolerance permitted on
the raw agricultural commodity.
In order for a Food Additive Tolerance to be required, residues
in the processed food product must exceed the tolerance on the
RAG, not merely the residue in the RAG. Therefore, in the
situation described above, a processing study should not be
required. However, a table should be prepared which lists the
percentage range of the RAG represented by each processed
commodity, so that registrants and reviewers can clearly
determine when a processing study should and should not be
required. Because of the cost of these studies and the limited
facilities available to perform them (e.g. Texas A&M for corn,
soybeans, peanuts, etc. and Lake Alfred for citrus), the Agency
should not require processing studies when there is no reasonable
expectation for residues in the processed commodity to exceed the
tolerance on the RAG.
EPA Response
In those instances where the tolerance on the RAG is set at
the limit of quantitation and residues in the RAG could not
theoretically concentrate above the RAG tolerance, a processing
study is not required. An example might be a tolerance of 0.1
ppm (limit of quantitation) for oilseed where residues in the
seed are s;0.02 ppm (limit of detection) and the theoretical
concentration factor for oil is 4x.
When processing studies are conducted in situations where
residues in the RAG are below the limit of quantitation (LOQ) but
above the limit of detection, the observed concentration factor
will be applied to the highest residue observed in the RAG in
field trials, not to the RAG tolerance. The Agency emphasizes
that this concept will be applied only to tolerances set at the
LOQ. For those RAC's where real residues are observed above the
LOQ, the concentration factor will be applied to the RAG
tolerance to determine the food additive tolerance.
4, Rejection Factor; Exaggerated application rate needed
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982) p.
21
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp. E-10 through E-12
A processing study rejected due to this factor will most
likely need to be repeated, i.e., the existing study will not be
upgradable.
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Industry Comment
We assume that this means that an exaggerated field
application rate was needed to obtain residues in the RAG at or
near the tolerance for processing purposes. In certain marginal
situations where a RAC was processed with no detectable residue,
eliminating any possibility of detecting residues in any of the
processed commodities, this would be an appropriate reason for
rejection. However, the only detailed guidance on the use of
RACs from exaggerated rate application [Phase 3 Guidance (1989) p
E-12] is difficult to interpret. It pertains more to the later
section just discussed with relevance to when a processing study
should not be required.
EPA Response
The response to the previous rejection factor is related to
this comment. In addition, the Agency notes that the Phase 3
Guidance Package recommends maximum practical exaggeration levels
for certain types of applications. For example, 5x is considered
to be an upper limit for foliar applications.
5. Re-lection Factor!
No data on storaiae conditions/stability
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982) p.
19
Data Reporting Guidelines: Residue Chemistry - Addendum
2. (1986)
Standard Evaluation Procedures: Storage Stability
Study/Residue Chemistry
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989). pp C-372-3.C-391 through 392 and E-9-10.
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data.
(1987)
In many cases, food processing studies rejected due to
storage stability data problems may be upgraded by the submission
of additional data/information.
Industry Comment
This is an appropriate reason for rejection. However, as
the draft report indicates, in most cases such a study should be
upgradable with the subsequent submission of the appropriate
data.
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6. Re-lection Factor;
Application rate less than maximum
Food processing studies would not typically be rejected
because the rate was less than maximum, provided detectable
residues of concern were present in the raw agricultural
commodity prior to processing.
Industry Comment
Industry agrees with the stated conclusion.
7. Eelecfcion Factor!
Relevant metabolite not analyzed
EPA Guidance on this Factor
Subdivision 0: Residue Chemistry Guidelines. (1982) p.
Data Reporting Guidelines: Residue Chemistry - Addendum
4. (1988)
Standard Evaluation Procedures: Processed Food/Feed
Studies (1988)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989) . pp. C-391 through 392
Food Processing studies rejected due to the absence of data
on relevant metabolites may, in some cases, be upgradable by
additional analysis . of stored samples from the processing
studies .
Industry Comment
If this statement means that metabolites in the tolerance
expression and in the RAG sample utilized for processing were not
assayed in the processed commodities, then this is an appropriate
reason for rejection.
Industry Comment Overview
Subdivision O: Table II (Raw Agricultural Commodities and
Feeds derived from Field Crops) needs to be updated and revised,
incorporating all the changes listed in the Phase 3 Technical
Guidance pp. E-20 to E-24. Clarification of the Feed Items is
critical since some of the currently listed feed items are not
normally part of animals diets and could not substantially
contribute to meat, milk, or egg residues. Such atypical or only
occasionally used items include such products as rice straw,
soapstock, cannery waste, grain dust, wet and dry pomace, citrus
molasses, etc. which should probably be removed from this table.
Clarification of the uses of commodities such as crude vegetable
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oil that may be nothing more than intermediates to some final
product, should also be incorporated into this revised table.
A new table is required listing the processed commodities
for each RAC and the corresponding proportion of each processed
commodity in the RAC. A realistic livestock diet from an
authoritative source is needed. .
EPA Response
EPA is planning to update Table II with regard to which
processed commodities need to be analyzed, which commodities are
used as animal feeds, and the percentages of these items in
livestock diets. An EPA contract on "What a Cow Eats" is
scheduled for completion this fall. Theoretical concentration
factors may also be included in the updated table. In the
meantime the Dietary Risk Evaluation System has default
concentration factors with respect to drying and FDA's Pesticide
Analytical Manual-Volume I has information on oil or fat content
of various commodities.
Examples of "Avoidable Rejection Factors" for Processing Studies
In assessing the factors above and other reasons that
studies submitted to the EPA might get rejected, the following
list are what EPA believes would be "avoidable" rejection .factors
on the part of the registrant. Should these factors cause a
future study submission to be rejected, the Agency would likely
consider taking the appropriate regulatory actions. This
assessment would only be applied to future studies submitted to
the Agency, due to the fact that adequate guidance documents may
not have been available to registrants in the past. This
judgement would not be applied retroactively. The following are
examples:
1. The major processed products (outlined in Table II of
Subdivision O and in the Phase 3 Guidance package) are
not analyzed.
2. The method was submitted without validation data,
3. No storage stability data was submitted or referenced
with the processing studies.
4. .The relevant metabolites were omitted from the
processing data with no explanation or rationale for
omission.
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VII. SUMMARY TABLE OF REJECTION FACTORS
GUIDELINE
REJECTION FACTOR
PLANT METABOLISM STUDIES:-No characterization of residues
171-4A -Partial characterization of residues
-Characterization conducted on immature crop parts/cell cultures
-Plants treated with wrong material such as an isomer of die pesticide or pesticide
radiolabeled in a potentially labile site
-Application of pesticide at less than maximum registered rates
-Need for confirmation of residue identities by second technique
LIVESTOCK
METABOLISM STUDIES:
171-4B
ANALYTICAL METHODS:
171-4C.D
STORAGE STABILITY:
171-4E
-No characterization of residues
-Dosing with a mixture of compounds
-Partial characterization of residues
-Animals dosed with wrong material such as an isomer of the pesticide or pesticide
radiolabeled in a potentially labile site
-Need for confirmation of residue identities by second technique
-Method inadequately validated
-Samples not fortified with all components of the total toxic residue
-Fortification with a mixture
-Use of an Analytical method which gives low and variable recoveries
-Insufficient information regarding dates, storage conditions, and descriptions of
analytical methods
-Failure to include a sufficient range of commodities
CROP RESIDUE STUDIES:
171-4K
FOOD PROCESSING STUDIES:
171-4L
-Method inadequately validated or described
-Insufficient geographical representation
-No data for aerial/sprinkler application on label
-Relevant formulation not tested
-Registered use/minimum PHI not reflected
-Inadequate storage stability data
-Application number/rate too low
-Untreated RAC contaminated
-Summary data presented, not supported by raw data
-No data on relevant metabolites
-No data on relevant commodity
-No data on relevant commodity
-Method - Inadequate description/validation data
-Exaggerated application rate needed
-No data on storage conditions/stability
-Application rate less than maximum
-Relevant metabolite not analyzed
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VIII. IR-4 COMMENTS
As part of the review process for this analysis, IR-4 was
asked to comment on this chapter. This section summarizes those
comments. . -
IR-4 noted that it has similar problems as industry in
developing data for the reregistration of specific uses. Even
with the EPA's Minor Use Policy, the residue chemistry
requirements are the same for IR-4 as they are for industry. To
the extent possible, IR-4 relies upon the industry's generic core
data packages that are submitted to EPA. The reregistration
data gaps normally make up the bulk of the major turndowns for
IR-4 petitions. However, IR-4 believes that once the
reregistration process is completed, the generic core data base
will be state-of-the-art. This fact alone will permit IR-4 to
improve its success rate. Also, IR-4 believes that with positive
results from EPA's Rejection Rate Analysis, IR-4, growers, and
the public will all benefit.
To help minimize residue chemistry rejections for new and
reregistration uses, some of the high priority points for IR-4
(minor crops/uses) are:
1. Improved listing of required crop sites for residue
data development to include;
- individual crops,
-individual crop groups, and
- individual crop subgroups,
2. List of concentration factors for crops that are
processed.
3. Improved listing of crop fractions to be analyzed.
4. Consistent definitions (e.g. raw data and much) and
record requirements that meet the regulatory end points
of what EPA reviewers will require under residue
chemistry and GLP's.
5. As appropriate, have EPA work with industry to develop
generic core data bases for;
-storage stability (adequate duration), and
-metabolism (plant/animal)
that will help IR-4 and the growers clear needed uses
in a timely fashion.
EPA Response
With respect to IR-4's priority 1 spelled out above, EPA
suggests that industry and IR-4 prepare a package for Agency
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review that addresses the number of sites needed for various
crops and the states in which the trials should be Conducted.
For more details see the EPA response (page 39) to Rejection
Factor 2 under 171-4K.
The needs for concentration factors and an updated Table II
of the Residue Chemistry Guidelines are discussed under the 171-
4L portion of this chapter. As noted on pages 53 and 60
(Recommendations), the Agency plans to update Table II (crop
parts, processed commodities, livestock feeds) by mid-1993 and
issue a list of theoretical concentration factors by December
1992.
The need for guidance on "raw data" is discussed under
Rejection Factor 9 for 171-4K (see page 42). By December 1992
the Agency plans to prepare a document outlining which raw data
should be submitted with residue chemistry studies.
With respect to priority 5 of IR-4, a major goal of
reregistration in the residue chemistry area is to ensure
development of plant and animal metabolism data that clearly
define the residues of concern for each active ingredient.
Industry will also need to develop an adequate storage stability
data base for each pesticide.
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IX. INTERNAL EPA OBSTACLES
One outcome of this rejection rate study was an examination
of the data review process in OPP, which handles reregistration.
Two internal problems that were identified involve the timeliness
of the review and intra-agency communication.
Sometimes the rejection rate is tied to what priority the
review has. If the studies are reviewed early, the chance for
upgrading them are better because the samples are fresh. The
longer the wait, the more likely it is that new samples will have
to be generated, i.e. redo the study.
Another internal EPA problem identified is inadequate
communication between divisional personnel. In some cases, the
science divisions that conduct the technical review of studies
have concluded a particular study is "upgradable" or
"acceptable," however, the review manager in the reregistration
program has interpreted the review as "rejected." However, in
compiling the statistics for this report, this problem was
corrected. This problem is being addressed by the following
modification being made to the science reviews. One problem is
that multiple studies on different crops are required to satisfy
plant metabolism requirements. The science reviews will begin to
provide study (MRID) specific conclusions as well as guideline
specific conclusions in their reviews. Secondly, where relevant,
the science review will, articulate whether the study deficiencies
require:
(1) more additional information but no additional lab
work,
(2) additional lab work on existing samples, or
(3) the generation of new samples.
Requirement (1) above, should be interpreted as an "upgradable"
study. Requirement (2), should be also interpreted as an
"upgradable" study as long as the probability is high that the
deficiencies can be addressed by further analysis of existing
samples. Requirement (3) should be interpreted as a "rejected"
study.
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X. CONCLUSIONS
Overall, the rejection rates for residue chemistry have
shown dramatic improvement. The pre-1986 aggregate rejection
rate for residue chemistry was 47 percent, and the post-1988
rejection rate is 12 percent. Two key guidelines, livestock
metabolism (171-4B) and crop field trials (171-4K), have shown
similar dramatic improvement. The rejection rate for livestock
metabolism has dropped from 80 percent (pre-1986) to 9 percent
(post-1988), and the rejection rate for crop field trials has
dropped from 45 percent (pre-1986) to 16 percent (post-1988).
Two guidelines have not shown improvement, and their
rejection rates remain at high levels. Plant metabolism (171-4A)
has a post-1988 rejection rate of 27 percent, and processed food
(171-4L) has a post-1988 rejection rate of 29 percent. Of the
two, the plant metabolism rejection rate is the most problematic
in terms of its potential for delaying REDs, because the other-
studies are contingent upon the adequacy of the characterization
of the metabolites of the compound in the plant. Crop field
trials (171-4K) also has a high rejection rate, at about 16
percent, inspite of improvements since pre-1986.
The Health Effects Division has provided a substantial
amount of guidance to date for residue chemistry, starting with
the Residue Chemistry Guidelines in 1982, two Data Reporting
guidelines in 1986 and 1988, six Standard Evaluation Procedures
between 1988 and 1990 and several miscellaneous items - a PR
Notice, and position document and a policy letter - as recently
as December 1991 .(see Appendix A for a list of all guidance
documents). Nevertheless, as a result of this assessment
process, additional guidance needs have been identified, and the
Agency is committed to addressing these needs (see
Recommendations) in order to help reduce rejection rates.
The Agency's commitment to reducing rejection rates will not
be limited merely to upgrading its guidance. For future studies
rejected for factors where the Agency believes its guidance is
adequate and the rejection factor is deemed "avoidable,"
regulatory action may be appropriate.
Two internal problems were identified. For a significant
number of instances the chemical review manager misinterpreted
the science reviews and concluded that the study was rejected
when, in fact, the scientist's finding was that the study was
upgradable and in some cases even acceptable. Secondly, it was
learned that the timeliness of science reviews can aiffect the
rejection rate. The longer the delay in reviewing the study, the
less likely it is that stored samples can be used to upgrade a
study and consequently the more likely it becomes that the study
would have to be repeated.
Industry input provided substantial insight into (1) where
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further Agency guidance would be most useful and (2) why certain
rejection factors occur. Some of the rejection factors reflect
very difficult technical problems. For example, inadequate
characterization of the residue in plant metabolism studies is a
frequently occurring rejection factor. It was pointed out that
in situations where the application rate is very low,
identification/characterization of portions of the residue in the
plant becomes exceedingly difficult. Increasing the dose to
facilitate identification is often not possible since it may kill
the plant (especially for herbicides).
The tight time frames imposed by FIFRA 88 force industry to
start studies before results from other pertinent studies have
been reviewed and approved by the Agency. Consequently,
rejection factors in the earlier studies can cascade down into
the subsequent sequence of studies causing them to be rejected as
well.
Industry also pointed out areas where the lack of clear
guidance may have contributed to the occurrence of the rejection
factor as well as having resulted in the application of different
criteria by different reviewers. However, industry also
acknowledged areas where there did appear to be adequate
guidance.
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XI. RECCK
As a result of this rejection rate analysis and the ensuing
discussions with industry, EPA realizes the need for additional
guidance on various residue chemistry requirements. The Agency
plans to issue the following documents:
Metabolism Guidance Document
Acute Toxicity Guidelines
Storage Stability Guidance
Theoretical Concentration Factors
Raw Data Guidance
Table II Revision
July 1992
Fall 1992
Dec. 1992
Dec. 1992
Dec. 1992
Mid. 1993
The Agency also recommends that industry develop a proposal
with respect to the number of sites and geographic distribution
of crop field trials for EPA review.
The development of the above documents should further reduce
the rejection rate for residue chemistry studies.
With regard to the cascading effect of rejection of studies,
EPA recommends that registrants consult with the Agency as soon
as possible when questions arise regarding the need to regulate a
recently discovered metabolite. EPA will continue to place
metabolism studies in a high priority review status for
reregistration.
The Agency also plans to modify its science reviews to make
it clearer when a study is upgradable and what information or
data are needed to accomplish that.
Finally, SRRD intends to continue tracking rejection rates
for residue chemistry guideline studies in general and plant
metabolism (171-4A) , crop field trials (171-4K) and process foods
(171-4L) in particular. If a significant reduction in the
rejection rates for these studies is not observed, another
analysis of causes for rejection may be conducted in the future.
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XII. APPENDIX A - EPA GUIDANCE DOCUMENTS
EPA distributed the following documents to guide registrants
on the correct procedures for conducting residue chemistry
studies. Specific references to these materials are made under
each of the rejection factors listed.
Subdivision O: Residue Chemistry Guidelines (1982)
FIFRA Accelerated Reregistration - Phase 3 Guidance
(1989)
Data Reporting Guidelines:
Residue Chemistry - Addendum 2 (1986)
Residue Chemistry - Addendum 4 (1988)
Standard Evaluation Procedures:
Analytical Methods/Residue Chemistry (1990)
Qualitative Nature of the Residue:
Metabolism in Food Animals (1990)
Qualitative Nature of the Residue:
Plant Metabolism (1989)
Residues in Meat, Milk, Poultry and Eggs:
Feeding Studies/Feed Troughs (1990)
Storage Stability Study/Residue Chemistry (1990)
i
Magnitude of the Residue:
Processed Food/Feed Studies (1988)
PR Notice 88-5: Tolerance Enforcement Methods -
Independent Laboratory Confirmation by Petitioner
Position Document: Effects of Storage (Storage
Stability) on Validity of Pesticide Residue Data (1987)
Letter dated December 6, 1991 from Robert S. Quick,
Acting Chief, Chemistry Branch 1/HED to Dr. Richard F.
Holt, Chairman, NACA Registration Committee Regarding
Aerial Application Field Studies.
Memorandum dated July 25, 1989: Guidance on When and
How to Conduct Livestock Metabolism Studies, Richard
Schmitt, PhD, Chief, Dietary Exposure Branch, Health
Effects Division.
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6 U.S. GOVERNMENT PRINTING OFFICE:1992-617-003/67033
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