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Pesticide Reregistration
Rejection Rate Analysis
   Summary Report
    February 1995

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                    Table of Contents
Executive Summary 	 i
Introduction	1
Problem statement .	2
Impact on REDs Schedule
Process
        ,15
Findings
(i    *  *  * 15
Results to date	57
Recommendations  	 61
Footnotes
         62

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                        Executive
     Rejected studies impose large costs on EPA and the pesticide
industry and can cause significant delays in meeting
reregistration goals.  This joint EPA/ industry effort is
successfully addressing the high rejection rate problem.

     o    Rejected studies could potential delay as many as 230
          more REDs beyond the FY97 statutory deadline than is
          projected by the Agency's best case scenario which
          assumes no further study rejections.

     o    Rejected studies could cost reregistration up to 97,800
          additional review hours for scientists to review
          repeated studies.

     o    Company-specific rejection rates for reregistration
          ranged from 20% to 57% in 1991.

     o    The additional cost to industry to repeat rejected
          studies in reregistration is estimated at $0.6-$1.2
          billion.

     o    Rejected studies also cause large costs to industry
          when a new pesticide registration is delayed one or
          more growing seasons while a rejected study is
          repeated.

     o    In 1991, rejection rates for each scientific discipline
          were:  residue chemistry - 12%; toxicology - 7%;
          environmental fate - 28%; ecological effects - 21%, and
          occupational and residential exposure - less than 25%.

     o    As a result of this project residue chemistry's three
          highest rejection rates have dropped significantly.
          The processed food study's rejection rate fell from 29%
          to 16%; the plant metabolism study's rejection rate
          fell from 27% to 8%; and the crop field trials
          rejection rate fell from 16% to 12%.  Residue chemistry
          is the only discipline that could be evaluated at this
          time.

     o    As a result of this project two companies have reported
          significant drops in their rejection rates. DowElanco's
          rejection rate in 1991 was 52%.  In 1994 it has fallen
          to 20%.  Rhone Poulenc's rejection rate in 1990 was
          45%.  In 1994 it has fallen to 13%.

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REJECTION RATE ANALYSIS

INTRODUCTION

     This report summarizes the process, findings;, and
recommendations of an evaluation of factors that contributed
to rejection of studies submitted to support rerejgistration.

     The purpose of this guideline-by-guideline emalysis was
to identify those factors that most frequently caiused guideline
studies required for reregistration to be rejected.  This
information enabled OPP to (a) provide registrants with
information on rejection factors to minimize their recurrence
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 meide 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 Decision documents (REDs).  Reregistration
eligibility decisions require that reasonable risk assessments be
performed for relevant human health and ecological end points for
each "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.

      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) in conjunction with
industry scientists and the Inter Regional 4 (IR-4) program,
which conducts residue chemistry studies to support minor uses.

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PROBLEM STATEMENT

     Historically, approximately 30% of the studies submitted to
OPP to support the reregistration of pesticide products have been
judged unacceptable by Agency scientists.11  Each rejected study
has the potential to delay a RED until the study has been
repeated since the appropriate risk assessments may not be able
to be conducted until the data base is "substantially complete".
In a worse case scenario where rejection rates are formally
incorporated into a probabilistic REDs schedule, the Agency
estimates that as many as 230 more REDs could be delayed beyond
the FY97 statutory deadline than is projected by the Agency's
best case scenario which assumed no further studies are rejected.
(See Impact on REDs Schedule section).  In addition, rejected
studies represent a significant increase to the Agency's
administrative and science review costs at a time when budgets
are being cut.  An expected additional 97,800 review hours could
be required to review repeated studies.21

     The cost to the regulated community of rejected studies is
also very large.  For reregistration, the additional cost to
industry to repeat rejected studies is estimated at $0.6- $1.2
billion.31  These costs are not borne evenly by registrants.
Company-specific rejection rates vary from 20% to 57%.4]  These
additional expenditures for repeating rejected studies for
existing chemicals, that companies are supporting through
reregistration, come out of company research and development
budgets that could otherwise be directed towards the development
of newer and safer pesticides.                           :

     Rejected studies impose potentially large costs to industry
and EPA in the registration of new pesticides as well.  A
rejected study can delay the date when a new registration is
granted (while the rejected study is being repeated and then
reviewed).  Depending on the amount of expected market
penetration and the number of missed growing seasons, the loss in
sales can be in the tens of millions of dollars per year.
Meanwhile, the patent clock, the data compensation clock, and in
the case of new uses, the exclusive use clock are all continuing
to tick making it more difficult for the company to recover its
up front losses over time.

     The Agency's concern in registration is three-fold.  First,
rej ected studies create rework to review repeated studies at a
time when science review resources are scarce and backlogs of
pending actions are high.  Secondly, rejected studies cause
delays in granting registrations for new and potentially safer
pesticides, which could replace riskier ones.  Third, delays in
granting new registrations can adversely impact growers who need
more alternatives to control pests.  Reliance on only one
pesticide over time to control a pest can accelerate the degree

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to which that pest  develops resistance to the pesticide.  As pest
resistance grows, more pesticide use usually results unless
another alternative is developed.  High rejection rates, then,
can frustrate the Agency's goal of use/risk reduction as well.

     High rejection rates can also adversely impact the public.
First, by delaying  reregistration eligibility decisions, the
public's lack of confidence in the safety of thesir food supply
and food production system is prolonged.  Secondly, by delaying
the registration of newer, safer and often lower use-rate
pesticides, the public's desire for less pesticide usage and
lower pesticide risks is also frustrated.

IMPACT ON REDS SCHEDULE

     As previously  stated, the reregistration recosting analysis
conducted in the Spring of 1991 indicated that rejected studies
posed the most significant potential for delays in the production
of REDs.  In their  report, Pesticide RereqistratioB May Not Be
Completed Until 2006  (May 1993), GAO recommended that a REDs
schedule that formally incorporated the results of the rejection
rate analysis be developed.  The critical questions that need to
be addressed are how many REDs could be delayed by rejected
studies and for how long?

     By incorporating study-specific rejection rates for each
unsatisfied guideline requirement for a chemical, a probabilistic
RED schedule can be generated for that chemical.  The probability
that a chemical will be completed on time or be delayed one, two,
three or four years will depend on the number of one, two, three
and four-year studies still unsatisfied for that chemical and
their corresponding rejection rates.5]  Once probability
distributions have  been generated for each chemical, the
probabilities for a given year can be aggregated across all
chemicals to provide the expected number of REDs for that year.

     This rejection-rate corrected REDs schedule represents a
worst case schedule scenario.   First, all rejection rates impact
the probability distribution (i.e. amount of delay)  for a RED.
In reality some rejected studies cause no delay in the RED
because the weight  of the available evidence allows for a
reasonable risk assessment to be performed,  and the repeat of the
rejected study is considered "confirmatory".   Secondly,  the full
rejection rate is applied to all unsatisfied guidelines including
those studies deemed .upgradable as well as those studies
currently being conducted which are themselves repeat studies.
This assumption will result in an overstatement of the
probability of delays.  Third,  it is assumed that rejection rates
haven't improved.

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     The graphs on pages 5-15 depict two RED  schedule
scenarios - - the best case and worst case RED schedules.
The most optimistic REDs schedule is titled, the "Earliest
Possible REDs Schedule".  This schedule is generated by taking
the last-study-due-date and adding one year to that date to
complete the RED.  It assumes that no studies are rejected.

     The worst case scenario is the rejection-rate corrected REDs
schedule.  The worst case scenario projects 230 more REDs could
be delayed beyond the FY97 statutory deadline than is projected
by the best case scenario.  The worst case scenario projects 68
more List A REDs, 87 more List B, and 76 more List C&D REDs could
be delayed beyond the FY97 statutory deadline than is projected
by the best case scenario.
     Actual RED outputs will fall between these two best and
worse case scenarios.  The more that rejection rates are reduced,
the closer actual RED output will come to the best case scenario.

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PROCESS

     An initial customer/supplier assessment indicated that OPP
is both a customer of industry studies and a supplier to industry
of OPP guidance on how to conduct these studies.  Conversely,
industry is both a supplier to OPP of final studies and a
customer of OPP guidance.  This interdependent customer/supplier
alignment required an assessment of both the rejection factors
that most frequently caused studies to be rejected as well as the
adequacy of the existing guidance that corresponds to each
rejection factor.

     First, OPP reviewed the data evaluation records (study
reviews by Agency scientists) of rejected studies for each
guideline study requirement to identify those factors that most
frequently caused each different kind of study to be rejected.
Secondly, a workgroup of industry scientists (.a) assessed, from a
customer's perspective, the adequacy of guidance associated with
each rejection factor, (b) explained why rejection factors
occurred, and  (c) proposed solutions to minimize the reoccurrence
of these rejection factors in the future.  Third, the industry
workgroup submission was reviewed by Agency scientists, and a
meeting was held between industry and Agency scientists to
discuss each rejection factor, develop the best understanding
possible of its underlying causes, and discuss potential
solutions.  The final step was for Agency scientists to make a
final determination of changes required and implement them.

     This process was repeated for study requirements in each of
the five science disciplines 	 residue chemistry, toxicology,
occupational   and residential exposure, environmental fate and
ecological effects.  A separate chapter, that included a
description of the discipline, an analysis of rejection rates,
identification of rejection factors, discussion of rejection
factors by industry scientists and the Agency's final
determination  of the changes that were required, was published
for each science discipline.  The residue chemistry chapter was
published in July 1992, toxicology in July 1993, environmental
fate in September 1993, occupational and residential exposure in
September 1993, and ecological effects in December 1994.

FINDINGS

     The following graphs and lists indicate:   (a) the overall
rejection rate for each science discipline and how it has changed
over time,  (b) the rejection rates for each required study in
each discipline and how they have changed over time, and  (c) the
rejection factors that most  frequently caused the studies to be
rejected.  Due to the  limited number of studies examined, the
rejection rates reported here have not been tested for
statistical significance, and therefore caution should be
exercised in their interpretation.  The purpose is not to develop

                                15

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 an  empirically defensible rejection rate value.   Rather,  the
 intent  is  to  use rejection rates  as the  best  indicator  available
 of  where additional  Agency/registrant  attention  and  efforts are
 warranted  to  improve the  quality  of the  studies.

 (1) Residue Chemistry

     Rejection rates for  residue  chemistry are Characterized  on
 the following five graphs.  Key implications  that might be drawn
 from these graphs include:

           (1)  overall rejection rates  in residue  chemistry appear
               to have gone down significantly;

           (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.

Discussion between Agency and registrant scientists  revealed that
the tight time frames and limited resources imposed  by FIFRA 88
forced industry to start  studies before results from other
pertinent studies had been  reviewed and approved by  the Agency.
Consequently, rejection factors in the earlier studies cascaded
down into the  subsequent  sequence of studies  causing them to be
rejected as well.
                               16

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 SUMMARY  TABLE  OF  REJECTION  FACTORS  -  RESIDUE CHSK.ISTRY
 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 the 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
                                                  22

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(2)  Toxicology

     Rejection rates for toxicology are characterised on the
following seven graphs.  Key implications that might be drawn
from these graphs include:

          (1) Overall rejection rates in toxicology are low and
              have remained relatively constant.

          (2) A substantial number of toxicology studies have
              been rated supplementary (i.e., upgradable), and
              the supplementary rate appears to be rising.

          (3) The CORT studies have shown substantial declines in
              their rejection rates.

          (4) The Mutagenicity studies and the General Metabolism
              study have also shown decreasing rejection rates.

          (5) Dermal Penetration, Subchronic 90-day Feeding -rat,
              Acute Dermal Sensitization studies have all shown
              substantial increases in their rejection rates over
              time.

     The Agency also reviewed the amount of time that had elapsed
in attempting to upgrade supplementary studies and found, in some
cases, that  it took five, six, or even seven years, which is
significantly more time than is required to repeat the study.
The  long elapsed times of four years or more occurred for studies
submitted between 1985 and 1988 before the initiation of FIFRA
88.  While the long lapse times may accurately reflect past
Agency/registrant performance, there is good reason to believe
that the results do not accurately reflect current performance.
First, FIFRA 88 desk top  computers have been provided to all
chemical review managers  (CRMs) and product managers  (PMs) and
data tracking systems  have been developed and implemented.  Prior
to FIFRA 88, only a limited access main-frame tracking system was
available.   Thus, the  Agency's capability to track the timeliness
of responses and reviews  has been greatly enhanced.   Second,
prior practice did not require imposing time limits on registrant
response for supplementary data.  In reregistration,  all
supplementary data requests have a time limit imposed.  Third,  in
reregistration all supplementary-data-request correspondence is
sent as certified mail to ensure that  the registrant  receives  it.
                                23

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SUMMARY TABLE OF REJECTION  FACTORS - TOXICOLOGY

GUIDELINE                   REJECTION FACTOR
ACUTE ORAL TOXICITY
81-1
-Lack of characterization of. the test substance
-Inadequate  dose  levels to calculate LD50
ACUTE DERMAL TOXICITY
81-2
ACUTE AND 90-DAY
INHALATION
81-3 and  82-4
PRIMARY  EYE IRRITATION
81-4
-Lack of characterization of. the test substance
-Inadequate percentage of body surface area
exposed
-No quality assurance statement
-Improper number of animals tested per dose
group
-Only one sex tested
-Omitted source, age, weight, or strain of test
animal
-Less than 25%  of particles were < 1 /im
-Three exposure concentrations were not used;
LC50 could not  be calculated; highest
concentration did not produce toxicity
-Inadequate reporting of exposure methodology.
-Protocol errors
-Lack of characterization oi: the test substance
-Test substance preparation
-Chamber concentration not measured

-Lack of characterization of the test substance
PRIMARY DERMAL
IRRITATION
81-5
DERMAL SENSITIZATION
81-6
-Lack of characterization of the test substance
-No quality assurance statement and/or no Good
Laboratory Practice  (GLP) statement
-Improper test substance application/preparation
-Omitted source,  age, weight, or strain of test
animal
-Missing individual/summary animal data

-Control problems
-Dosing level problems
-Lack of characterization of the test substance
-Unacceptable protocol or other protocol
problems
-Individual animal scores or data missing
-Scoring method or other scoring problem
-Reporting deficiencies or no quality assurance
statement
                                      31

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90-DAY  FEEDING
RODENT
82-l(a)
90-DAY  FEEDING
NON-RODENT
82-1(b)
21-DAY DERMAL  TOXICITY
82-2
90-DAY DERMAL  TOXICITY
82-3
CHRONIC  FEEDING/
ONCOGENICITY  -
RATS
83-1(a)  and 83-2(a)
ONCOGENICITY  -
MICE
83-2(b)
-A NOEL was not established
-Lack of characterization of the test substance
or incorrectly reported
-Lack of clinical  chemistry and/or lack of
histopathology
-Reporting deficiencies
-Lack of characterization of the test substance
-A NOEL was not established
-An investigatibnal parameter missing
-Information on the pilot study and other
problems associated with dose level selection

-Lack of characterization of the test substance
-Raw data analyses incomplete or missing
-A systemic NOEL was not established
-Inadequate percentage of body surface area
exposed in each dose group
-Insufficient number of dose levels tested

-Lack of characterization of the test substance
-A systemic NOEL was not established
-Incomplete/missing raw animal data analyses
-Insufficient number of dose levels tested
-Poorly controlled test environment
-Missing histopathology information
-Missing information in study reports
-MTD was not achieved
-Missing historical control data
-Lack of characterization of the test substance
-Deficiencies in reporting the study data
-Histopathology information missing
-MTD was not achieved
-Lack of historical control data
-Information missing in study reports
-Lack of characterization of the test substance
-Deficiencies in reporting of study data

-------
DEVELOPMENTAL  TOXICITY
RODENTS
83-3(a)
-Missing historical controls
-Lack of characterization of  the  test substance
-Information missing or requiring clarification
of the laboratories methods
-Information missing or requiring clarification
of the laboratories results
-A NOEL was not established
-Statistical problems
-Did not use conventional assessments for
skeletal or visceral examinations
DEVELOPMENTAL  TOXICITY
NON-RODENTS
83-3(b)
REPRODUCTION
83-4
MUTAGENICITY  TESTING
84-2
      A)   Gene mutations
-Clarification of laboratory procedures or
interpretation of the data
-Individual maternal or fetal data missing
-Missing historical controls
-Lack of characterization of the  test  substance
-Excessive maternal toxicity
-A NOEL was not established
-Statistical problems

-Information missing from laboratory results
-Lack of characterization of the  test  substance
-Information missing or requiring clarification
of laboratory methods or results
-Missing historical controls
-A NOEL was not established due to effects at
the lowest dose tested
-Low fertility and/or inadequate  number of
animals were used per dose level
-A NOEL was not established in the absence of
reproductive effects
                              -Purity,  batch numbers,  stability, or analytical
                              concentration information missing
                              -MTD issue,  no range-finding  study; inadequate
                              high dose;  no evidence  of toxicity at any dose;
                              insufficient (or no)  cytotoxicity and limit-dose
                              level (5000 /ig/plate) not reached and/or test
                              substance not tested up to  solubility limits
                              -Insufficient (or inappropriate) tester strains
                              used in Ames assays
                              -Tester strains not verified  in Ames assays
                              -For mammalian cells in culture, harvest time
                              was not determined by cell-cycle analysis
                              -Missing protocol; missing  raw data
                              -The results were "equivocal"
                              -Only 1 dose was administered
                                       33

-------
B)   Structural chromosome aberrations

      1)    Tests  include:   Mouse micronucleus  assay and in
            vivo mammalian  cytogenics assay with rodent bone
            marrow
                       -Dose  levels  were too low or no explanation of
                       why this is the maximum attainable
                       concentration; no or low cytotoxicity indicating
                       that an insufficient level of  test substance was
                       transported to the target tissue (MTD issue)
                       -Purity or test substance missing; analysis of
                       concentration in solution; or  analysis of
                       stability missing
                       -Less  than 3  dose levels were  performed
                       -Missing:  individual clinical  signs, body weight
                       data,  or raw  data (e.g., route of
                       administration, slide code information, strain
                       or source of  animals)
                       -Inappropriate sampling times,  or cells were not
                       exposed during the entire hematopoietic cycle

      2)    Dominant lethal - rats  or mice

                       -MTD issue
                       -No evidence  that the test material reached the
                       target cells
                       -Low pregnancy rates
                       -Missing positive control

C)    Other genotoxic effects

      1)    Tests  include:  in vitro unscheduled DNA synthesis
            (UDS)  in rat hepatocytes,  the human Hela cell
            line,  human fibroblasts,  or  rat kidney cells

                       -No analytical or stability data to define the
                       test substance concentration,  purity, or>
                       solubility in solution question
                       -Missing:  raw data,  results for metabolic
                       activation, background frequencies for UDS,
                       protocol;  or  that insufficient data was
                       presented to  support conclusions
                       -MTD issue, no evidence of cytotoxicity, missing
                       dose selection data
                       -High  cytoplasmic grain count  in solvent
                       control;  repeat study with different rat
                       hepatocyte preparation, or lower cytoplasmic
                       background, or high cytoplasmic and nuclear
                       grain  counts, or counts were not provided
                       -Duplicate cultures were not performed

      2)    Tests  include:  In vitro transformation assay: a)
            BALB/3T3 (mouse);  (BO C3H10T 1/2  (mouse)

                       -Only  one  test dose used,  or MTD issue
                       -Purity and stability of test  substance
                              34

-------
            3)    Tests  include: In vivo  sister chromatid  exchange
                  (SCE) :  (a)  Chinese hamster;  (b)  rait  bone marrow

                              -MID issue; dose selection not  supported by
                              range-finding study; no cytotoxicity was
                              indicated at highest dose
                              -No analytical data to support  test  substance
                              stability, concentration,  or missing test
                              substance purity
                              -Missing procedural descriptions
                              -Inadequate statistical analyses
METABOLISM
85-1
DERMAL PENETRATION
85-2
      -Inadequate or missing data on identification of
      metabolites
      -Improper methodology or dosing regimen
      -Inadequate number of animals were used in the
      dose groups
      -No individual animal data
      -Improper reporting
      -Inadequate or missing tissue residue analysis
      data
      -Testing at only one dose level
      -Only one sex of animal used
      -Lack of an intravenous dose group
      -No collection of 14CO2

-Incomplete/missing data evaluation
      -Improper test substance preparation/application
      -Raw data missing and incomplete summary tables
      -No signed quality assurance statement
      -Missing purity or concentration of  test
      substance
                                      35

-------
 (3) Environmental Fate                                    :

     Rejection rates for environmental fate .are characterized on
the following five graphs.  Key implications that might be
drawn from these graphs include:

          (1)  overall rejection rates in environmental fate
               appear to have gone down significantly;

          (2)  the photodegradation - water (161-2), photo-
               degradation - soil (161-30, leaching  (163-1),
               terrestrial field dissipation (164-1) and aquatic
               field dissipation (164-2) guidelines have shown
               a continuous and substantial decline in their
               rejection rates;

          (3)  for the aerobic soil metabolism (162-1), anaerobic
               soil metabolism (162-2), confined crop rotation
               (165-1) and bioaccumulation in fish  (165-4)
               guidelines, the rejection rate trends do not
               indicate substantial improvement;

          (4)  all of the guidelines examined still have high
               rejection rates when compared to the goal of
               reducing all rejection rates to 10% or less;

     Discussions between Agency and registrant scientists
revealed that the tight time frames and limited resources imposed
by FIFRA 88 forced industry to start studies before results from
other pertinent studies had been reviewed and approved by
the Agency.   Consequently, rejection factors in the earlier
lab studies cascaded down into the subsequent field study
causing it to be rejected as well.
                               36

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 SUMMARY  TABLE  OF   REJECTION  FACTORS   -   ENVIRONMENTAL  FATE


 MM      HYDROLYSIS STUDY

 1)         A material balance was not provided
 2)         The study was not conducted in the dark.
 3)         The study duration and number of sampling intervals were insufficient to establish the decline and half-life.
 4)         It was not specified that the buffer solutions were sterile; before, it could not be determined if degradation was due to hydrolysis or biotic processes.
 5)         Tho teat substance was not characterized.
 6)         Tho incubation temperature was not maintained.
 7)         Insufficient data were presented to supportthe reported conclusion.
 8)         Degradation curves and regression analysis were not provided.


 161-2      PHOTODEGRADATION STUDIES IN WATER

 1)         Tho light source was not adequately characterized and was not compared to sunlight.
 2)         Degndates were not identified.
 3)         The material balances were incomplete.
 4)         The test solutions were not buffered and the pH of the water was not reported.
 5)         The analytical methodology was incomplete and no raw data was provided to supportthe conclusions.
 6)         The sampling protocol was inadequate:
 7)         The temperatures of the test solutions were not reported.
 8)         Volatilization was neither measured nor controlled.
 9)         A photosensitizerwas used as the co-solvent.
 10)        It was not specified that the test solutions were sterile.
 11)        Thestudywas terminated before the half-life of the test substance was established or before 30 days.
 12)        The coefficients of determination for the data used to determine the half-lives were very poor.
 13)        Tho stability of the pesticide under refrigeration was not addressed.


 161-3      PHOTODEGRADATION ON SOIL

 1)         The material balance was incomplete.
 2)         Volatilization was neither measured nor controlled.
 3)         Artificial light source was  not similar to natural sunlight.
4)         The test substance was not technical grade or pure.
 5)         Raw data were not provided.
 6)         The incubation temperature was not provided.
 7)         Degradatcs were not identified.
 8)         The test was not performed on soil.
 9)         The treatment rate was not reported.


 161-4      PHOTODEGRADATION IN AIR

 1)         The pesticide degradation in the vapor phase could not be distinguished from degradation that occurred in material adsorbed to the sides of the glass
           container.
2)         Air samples were never analyzed separately from nonvaporizedpesticide.
3)         The material balance was low.
4)         High percentages of unidentified material were reported.
5)         Tho registrant did not measure the vapor pressure at the temperature the study was conducted.
 6)         The analytical method was inadequate.
7)         Tho spectrum of the artificial light source was not similar to that of natural sunlight.
 8)         A photosensitizerwas present in the primary stock solution.
9)         No raw data was submitted.


 162-1      AEROBIC SOIL METABOLISM

 1)         Residue identification was  incomplete.
2)         The material balance was inadequate.
3)         The study was conducted for an inadequate length of time to establish the patterns of formation and decline.
4)         Purity of the test substance was not specified.
5)         Tho experimental design was inadequate to assess the metabolism m soil.
6)         Tho incubation temperature was not reported.
7)         The soil textures could not be confirmed because the soils were not classified using the USDA Soil Textum! Classification System.
 8)         The analytical methodology was incomplete and no raw data were provided to support conclusions.
9)         The raw data examined did not supportthe half-life reported by the registrant.
 10)        Degradato characterization data were presented as percent of recovered rather than percent of applied.
                                                                    42

-------
162-2
           ANAEROBIC SOIL METABOLISM
1)         Residue identification was incomplete.
2)         The material balance was inadequate.
3)         The purity of the test substance was not specified.
4)         The storage stability data were not provided, although the raw data indicate that both soU samples and extnwts were stored prior to analysis.
S)         Degradates present in small concentrations were not identified.
6)         The experimental design was inadequate to accurately assess the degradation under anaerobic conditions.
7)         The length of frozen storage was not specified.  Frozen storage stability data are required to confirm that tte residues were stable.
8)         Method detection limits were not provided.
9)         Large discrepancies existed in the data for duplicate samples collected after anaerobic conditions were established. The data, therefore, cannot be
           used reliably to calculate the rate of degradation in soil under anaerobic conditions.
10)        The study was conducted for an inadequate length of time to establish the patterns of formation and decline of the pesticide under anaerobic
           conditions. The study should have been conducted for 60 days.
11)        No raw data were provided to  support the conclusions.
12)        A complete description of the test water, including the pH and dissolved oxygen content, was not provided.
13)        The soil was not classified according to the USDA Soil Textural Classification System.


162-3     ANAEROBIC AQUATIC METABOLISM

1)         The sampling protocol was inappropriate because it contained too few sampling intervals and was inadequate to establish the half-life for the
           pesticide.
2)         The pesticide residues were quantified using a chemically nonspecific analytical method.  No attempt was made to characterize the pesticide residue:
           in soil and water matrices.
3)         Material balances were incomplete.
4)         Degradates were not identified.
5)         The test substance was  not technical grade or purer.
6)         The test water was not characterized. Foreign soils were not completely characterized and may not have bn typical of those in the United States.
           The soil must be representative of that found at an intended use site.


 162-4      AEROBIC AQUATIC METABOLISM

 1)          The sampling schedule was inadequate.
 2)          Material balances were incomplete.
 3)          Residues were incompletely characterized.
 4)          The test water was  not characterized.                                                                              '


 163-1      LEACBDQVG/ADSORPTION/DESORPTION              .

 1)         Degradates were not identified.
 2)         The test soils were autoclaved prior to conductingthe study.
 3)         The material balance was incomplete.
 4)         Soils and sediments were incompletely characterized.
 5)         Desorptioh of a major degradate was not addressed.
 6)         Foreign soils were  used which may not be typical of soils in the United States.
 7)         Kd values (values of soil/water relationships) were not reported.
 g)         The desorption phase was done serially, with incomplete removal of the supernatant at each step.
 9)         The soil texture could not be  confirmed because the soil was not classified using the USDA Soil Textural Classification System.
  10)        It was not established that the equilibrium time used was sufficient for the soilisohition slurries to reach equilibrium.
  11)        The bioassay methods used in the study were not acceptable analytical techniques.
  12)        Soil used in the study was not prepared properly.
  13)        Test solution was not characterized.
  14)        The data were presented on a percentage basis with no actual concentrations.


  163-2     LABORATORY VOLATILITY

  1)         Analytical methodology was insufficient.
  2)         The study was not carried out over a long enough period of time to clearly define a volatility decline curve.
  3)         The soil was not analyzed immediately after treatment. Therefore, the application rate was not confirmed.
  4)         No material balance was reported or me data reported was insufficient.
  5)         Not all major formulation categories were tested.
  6)         The soil was autoclaved before the test.
  7)         The rate of volatilization was incorrectly calculated and could not be determined with the information provided.
  g)         The experiments were not replicated.
                                                                           43

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 163-3
            FIELD VOLATILITY
 I)         The soil data were inadequate to confirm the application rate.
 2)         Data on soil samples was not provided.
 3)         Tho description of experimental conditions were insufficient.


 164-1 TERRESTRIAL FIELD DISSIPATION

 1)         The original concentration of the pesticide was not reported or the reported application rate was not confinnud hi soil samples taken immediately
            post-treatment,
 2)         The pattern of formation and decline of the degradates was not addressed.'
 3)         Tho sampling was not done to depths sufficient to define the extent of leaching.
 4)         Characterization of residues was not provided for all sites or the soil was not analyzed for the correct residues or for all residues.
 5)         Complete soil characteristics and field test data were not provided.
 6)         The analytical methodology was insufficient to identify the residues (in one cose, the analytical method could not distinguish between the parent and
            its degradates).
 7)         The data were too variable to accurately assess the dissipation of the test substance.
 8)         The freezer storage stability data were inadequate.
 9)         Tho maximum label rates were not used, and the soil incorporation procedure recommended on the label was not followed.
 10)        The formulation and method of application were notspecified.
 11)        Tho plants were harvested after application and the time of harvest was not given.
 12)        Prclreatmcnt samples were contaminated.
 13)        More than ono pesticide was applied to the crop.
 14)        The experiment was conducted at only one site instead of the two recommended in the Guidelines.
 IS)        The method of detection limit and recovery efficiencies were not reported.


 l-2      AQUATIC FIELD DISSIPATION

 1)         Complete field test data were not provided.
 2)         The analytical methodology was insufficient to determine the residue.
 3)         The material balance was insufficient.
 4)         Data were too variable to assess dissipation.


 1S4-3      FORESTRY FIELD DISSIPATION

 1)         Tho data provided were either insufficient or too variable to accurately establish a pattern of dissipation of a chemical and its primary degradate in a
            forest environment.
 2)        Tho sampling protocol was inadequate.
 3)        Tho application rate was not reported.
 4)        No storage stability data were provided to confirm that samples did not degrade prior to analysis.
 5)         Field test data were incomplete.


 I6S-I      CONFINED ACCUMULATION IN ROTATIONAL CROPS

 1)        Tho residues  in soil were not characterized.
 2)         The length of freezer storage of the crops was not reported and no freezer storage stability data were provided.
 3)         The study application rate docs not reflect normal or maximum use rates and the application rate was not confirmed.
 4)         Tho test substance was less than analytical grade.
 5)         The supportingraw data were not provided.

 16S-2      FIELD ACCUMULATION IN ROTATIONAL CROPS

 1)         The source of pesticide residues in control samples of both crops  and soils were not verified.
 2)         Thcrewaa a largedegreeofvariability inthedatawithnoexplonationprovided.
 3)         Residues in soil were not analyzed.
 4)         Planting to harvest intervals were not provided.
5)         Tho field test data were incomplete.
 6)         The test substance was not characterized.

 1S5-4      ACCUMULATION IN FISH

 1)         Tho analytical methodology was insufficient to detect the residue.
2)         Some degradates present in small concentrations hi edible and non-edible fish tissues were not identified anrii or quantified.
3)         The study on  the effects of storage on the analytical results of samples was not completed.
4)         Data on the concentration of the parent and its degradates in the exposure water were not submitted.
S)         Mortality and growth/weightpattems of fish throughoutthe study were not provided.
                                                                      44

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(4) Ecological Effects

     Rejection rates for ecological effects are characterized
on the following six graphs.  Key implications that might be
drawn from these graphs include:

          (1)  overall rejection rates in ecological effects
               appear to have gone down significantly, but
               current rates remain high;

          (2)  for both avian and aquatic reproduction studies,
               the high rejection rates indicate significant
               problems;

          (3)  five of the six fish acute toxicity studies have
               current (post-1988) rejection rates greater than
               10%;

          (4)  four acute toxicity guidelines-71-1, acute avian
               oral; 72-1C, acute toxicity trout; 72-2, acute
               toxicity Daphnia; and 72-3B, acute toxicity
               mollusk-have shown encouraging and consistent
               reductions in their rejection rates over time.

-------











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Summary Table of Rejection Factors - Ecological Effects
            GUIDELINE
                REJECTION FACTORS
  Avian Oral LDSO
   71-1
-Failure to establish a valid LDX value with corresponding 95 %
confidence limits or an LD^ greater than 2000 mg/kg.
-Use of a "split-dosing" procedure.
-Fasting period prior to dosing not specified.	
  Avian Dietary LC50
   71-2
-Mortalities attributed to interactions between animals (rather than to
test chemical), when such interactions were not observed in the
controls.
-High variability in the measured test concentrations in the test diet.
-Test material was not technical grade.
-LCX not established when testing at dose levels  < 5000 ppm a.i.
-Variation in test concentration and/or failure to adequately justify the
variations.
  Freshwater Fish LC50
  (Bluegffl)
   72-1
-Concentration level < 100 mg/1, not high enough to produce an
LCs,.
-Aeration of test chambers.
-Biological loading of test vessels twice the recommended amount.
-Test substance purity not identified.
-Inappropriate test species and/or test species not clearly identified.
-Fish fed during the exposure period.
-Minimum limit of detectability, or the minimum quantifiable limit,
not defined quantitatively.
-Test concentrations variability limit > 1:5.
-Levels of lead, iron and aluminum present in dilution water higher
than recommended.
-No solvent control.
-Results for some test concentrations obtained from tests conducted
after the definite study.
-Not all test solutions measured at 96 and 0 hours.
-No control group for the inert/carrier ingredient component of the
formulation.
-Acclimation  period half that recommended.
                                                   52

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           GUIDELINE
                 REJECTION FACTORS
 Freshwater Fish LCSO
 (Rainbow)
  72-1
 Acute LCSO Freshwater
 Invertebrates
  72-2
Wild Mammal Toxicity
 71-3
Avian Reproduction  Quail
 71-4
Avian Reproduction
Duck
 71-4
Acute LCSO Estuarine and
Marine Organisms   Fish
 72-3D
 -All of the rejection factors listed above for guideline 72-1, Bluegill.
 -Fish acclimation period overlapping with the definite study period.
 -Contamination of the controls with test chemical.
 -Low recovery of test chemical from the stock solutions.
 -Fish weights exceeding the recommended range.
 -Test temperature exceeding the recommended for the test species.
 -Biological loading of the system greater than recommended.
 -Fish mortality during the acclimation period higher than
 recommended.
 -Supersaturation of oxygen.
 -Organisms not randomly distributed to test vessels.
 -Water temperature not monitored.
 -Chemical analyses (concentration levels) not performed on test
 solutions.
 -No control group for the inert/carrier ingredient component of the
 formulation.
 -Minimum limit of detectability, or the minimum quantifiable limit,
 not defined quantitatively.
 -Test concentrations variability limit  > 1.5.
 -Not all test concentrations measured at 0 iand 48 hours.
 -Levels of lead, iron and  aluminum present in dilution water higher
 than recommended.
 -Percent of a.i. of the test formulation not identified.
 -Photoperiod not as recommended.
 -Raw temperature data not provided.
 -Use of dechlorinated water as a portion of the dilution water.
-Diet preparation method not adequate.
-Improper animal caging, as indicated by extensive cannibalism.
-Percent of cracked eggs in the control higher than in treatment
groups.
-Data discrepancies:
 =inappropriate photoperiod;
 =reasons for administration of medication not provided;
 =total number of data points not included in statistical evaluation.
-Data discrepancies:
 =inappropriate photoperiod;
 =inappropriate egg collection procedures;
 =low overall fertility of control birds.
-Unexplained variations in concentrations.
-Concentration level < 100 mg/1, not high enough to produce an
Ley
-Dissolved oxygen levels lower than recommended.
-Analytical determination of the concentration in the test vessels not
provided.
                                                53

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          GUIDELINE
               REJECTION FACTORS
Acute LCSO Estuarine and
Marine Organisms Mollusc
 72-3B and E
-Insufficient new shell growth in control oysters.
-Insufficient dosage levels to produce a reliable LCy,.
-Raw data on shell deposition not provided.
-Aeration of test chambers without chemical analyses of test
solutions.
-Dissolved oxygen levels lower than recommended.	
Acute LC50 Estuarine and
Marine Organisms Shrimp
 72-3C
-Test substance purity not identified.
-Chemical analysis of test solutions concentration not performed.
-Type and quantity of solvent used not provided.
-Solubility needed to achieve LC^ not obtained.	
Fish Early Life Stage
 72-4
-Mortality too high at all concentrations.
-Raw data not submitted.
-Survival rate in the control group lower than recommended.
-Erratic results in measured test concentrations.
Aquatic Invertebrate Life
Cycle
 72-4
-Raw data not submitted.
-NOEL values for reproduction and growth cannot be established
from study results.
-Survival rate in the control group lower than recommended.
-Adults' growth (length and weight) not measured quantitatively.
 Invertebrate Life Cycle
 Estuarine Species
  72-4
 -Reproduction rates too low to be statistically analyzed.
 -Adult body lengths not measured at the end of the study.
 -Feeding rate below the recommended daily ration.
 -Raw data not provided.                  	
                                                54

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 (5) Occupational and Residential Exposure

     There were no rejected mixer/loader applicator studies in
the reregistration data base that could be used in the rejection
rate analysis.  For post-application/reentry studies the data
base indicated 18 out of 71 reviewed studies were coded as
rejected (a 25% rejection rate).  This number overestimates the
number of studies that have to be repeated because an examination
of some of these rejected studies indicated reasons for rejection
that could be rectified without repeating the study.  Rejection
factors are provided below.

Summary Table of Rejection Factors

Guideline                     Rejection Factor
132-1A, 132-1B,

133-3, 133-4
-Inadequate or complete lack of quality
 assurance/quality control data
-Did not provide meterological data.
-Used inappropriate toxicological end points
 and transfer coefficients when calculating
 reentry levels.

-Insufficient sampling intervals.
                               55

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     In summary the following generic factors can account for
most of the study rejections:

     (1) inadequate QA/QC by data doers;

     (2) inadequate or conflicting guidance to address
         rejection factors provided by the Agency;

     (3) changing criteria for conducting acceptable quality
         studies by the Agency; and

     (4) inadequate time frames provided in legislation to
         conduct studies leading to cascading rejection
         factors.
                                 56

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  RESULTS TO DATE


       To what extent this project succeeds  in reducing rejection
  *   caV\^antitatively assessed.  However, wh^studiS to
  assess and when to assess them isn't so straightforward.
                     studies reviewed from the date of this project
                   an  accurate assessment of the impact of this
        0V3dUCing  Cation rates because many of^ne studies
             ay have been sittin* ^ OPP's backlog of unreviJwed
                   and Were comPleted before this project was even
 ailv           f2?Ct clearlv has had no impact on the accJpl-
         of those studies already submitted and in the unreviewed
            ?g a^ the  tiffle this Project was initiated? ^d    W
           them in an  assessment would only bias the results.

      Counting only those studies received and reviewed since 1-he
  robf in VhVeleva*t rejection rate cSap 2 Is alia   ^
 problematic.  First,  some of the "solutions" that have been
 implemented to reduce the occurrence of the rejection faclSrs can
 only be implemented at the initiation of a study?  Therelorl
 studies already ongoing at the time of publication of a reaction
 rate chapter may not have benefitted from the consents of the

 pSblicatfon^^^11^116 2?Udy WaS submitted after tSe copter's
 tS^ iaoi?" dateZ  Secondly/  for a given scientific discipline,
 the rejection rate chapter is not the only source of "solution^"
 For some  rather difficult problems uncovered in th 'as Segment   '
          <      fllow^P. guidance have been warranted?  Fo?'

                               ^^^
 chemistry rejection  rate chapter in July 1992?
          d
                                              that can be

should be considered preliminary because many of the follow-p
guidance were not published for a considerable amount of time
had the highest rejection rate in residue chemistry - 29*
publication of the rejection rate chapter, ^2 |ection rat
                               57

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uojioafsy
58

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 down into subsequent studies causing them to be rejected as well.
 The crop field trial study [171-4(k)] rejection rate has only
 been reduced slightly from 16% to 12%.  Since this is the single
 most frequently levied data requirement, a greater reduction in
 the rejection rate is needed.  The current results, however, are
 not surprising since the follow-up guidance addressing the most
 critical rejection factor for this study (inadequate geographical
 representation) was only published in June 1994 ^   Sufficient time
 has not elapsed to assess the impact of this additional guidance.
 The analytical methods study [171-4(c)] rejection rate increased
 from 0 to 8%.  since no rejected studies appeared in the sample
 used for the residue chemistry rejection rate analysis, no
 attention was given to this guideline requirement.   Should this
 rejection rate continue to increase, an assessment of the
 rejection factors would be warranted in the future.

      In addition to working with Agency scientists to resolve
 underlying factors causing study rejection,  registrants also
 initiated internal, company-specific efforts to identify factors
 or processes within their own companies that warranted
 improvement.  Seventeen companies and the IR-4 agreed to
 undertake this effort.   They are:  Rhone Poulenc,  Agrevo,  Id,
 Ciba,  Miles, Monsanto,  Rohm & Haas,  Dupont,  Cyanamid,  DowElanco,
 Valent,  Uniroyal,  FMC,  ISK Biotech,  Hazleton,  ABC  Laboratories
 and ETI.

      Only two companies have submitted reports at  this time.
 DowElanco had a company rejection rate of approximately 52%  as  of
 November 1991.   According to Craig  Barrow, DowElanco's regulatory
 manager,  the company initiated changes to increase  (1)  the
 individual accountability of  the registration  managers and lab
 study directors for the outcomes of  their studies and  (2)
 increase the communication between  company and agency  scientists.
 DowElanco implemented an "on  time,  right  the first  time"
 performance  standard for their  personnel.  A quarterly report is
 distributed  widely throughout the company to track  progress.  It
 includes  each study,  the name of the study director and
 registration manager responsible for it, when  it was submitted to
 the Agency,  whether it was  submitted on time,  and the  review
 outcome -  accepted or rejected  (rejected  includes both studies
 that have  to be repeated as well  as studies that are
 upgradeable).

     At the  same time DowElanco  sought to improve the
 communication between company scientists performing the studies
 and Agency scientists responsible for reviewing them.  Company
 scientists were brought to Washington for meetings with the
Agency, and ARI was used to fund a visit by Agency scientists to
a DowElanco  lab to view and discuss how new neurotoxicity studies
should be carried out.
                                59

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I
              In 1993 66% of DowElanco's studies (137 out of 207)  for
         reregistration were submitted on time and 70% of the studies
         reviewed (189 out of 270) were acceptable.  For 1994, 94% (136
         out of 145) were submitted on time, and 80% of the studies
         reviewed (139 out of 174) were acceptable.  In three years
         DowElanco's rejection rate performance has improved from one of
         the worst in the industry to one of the best.

              Rhone Poulenc had a company specific rejection rate of 45%
         in 1990.  According to Peg Cherny, Rhone Poulenc's regulatory
         manager, the company:

              (1)  developed a study review outcome data base and tracking
                   system that includes each study, when it was submitted
                   to the Agency and whether it was accepted or rejected
                    (rejected includes studies that must be repeated as
                   well as studies that are upgradeable);

              (2)  identified problematic studies which had the highest
                   rejection rates for Rhone Poulenc;

              (3)  initiated process improvement teams in areas of concern
                   to reengineer core processes where necessary;

              (4)  reorganized scientists into different functional teams
                   to better utilize resource and  experience base and
                   shifted more personnel into critical groups where
                   shortages existed;

              (5)  brought in company scientists to meet with Agency
                    scientists to  improve communication and understanding;

              (6)  developed a centralized  library of EPA guidance
                   documents easily accessible to  company scientists;  and

               (7)   consolidated the number  of independent labs that Rhone
                    Poulenc contracted studies out  to  as part  of the
                    company's  lab  management strategy  to improve their
                    quality and timeliness.

              In 1991,  69% of Rhone Poulenc's studies that were reviewed
         were acceptable.  In 1992, 73% of  the  studies  submitted  and
         reviewed were  acceptable.  In  1993, 88% were acceptable,  and  in
         1994,  87%  were acceptable.   In four years Rhone  Poulenc^s
         rejection  rate performance improved to one  of  the  best  in the
         industry.
                                          60

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RECOMENDATIONS!

The following recommendations are warranted:
1.
3.
The Agency shall continue to monitor periodically the
rejection rates for individual guideline studies.  Any
rejection rate that persists above 10% should warrant future
management/industry attention.

Individual companies should closely monitor their own
rejection rates to avoid the huge costs associated with
repeating rejected studies and potentially missing a growing
reason for new chemicals.  Companies should be able to reduce
rejection rates to 10% or less.

It is imperative that the Agency review its backlog of
unreviewed studies because (1) many of these studies were
submitted prior to this rejection rate project, (2)  are more
likely to be rejected than new studies that have benefitted
from the lessons learned from this project, and (3)  could
cause significant delays in completing the rsjregistration
program.
                               61

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                              Footnotes

1. Based on a November 1991 Rejection Rate Report for Lists A &
   B.

2. By multiplying the number of hours to review a study by the
   probability that the study will be rejected, the expected
   additional review hours due to future rejected studies can be
   predicted.  This algorithm was applied to all unsatisfied
   data requirements for each chemical case as of 1993.  300 out
   of the remaining 324 chemical cases were covered.  By list,
   the estimated number of additional review hours is:
                   List

                  List A
                  List B
                  List C
                  List D
                    Additional Review Hours

                            17,026
                            46,454
                            29,881
                             4.429
                            97,790
3. The upper bound estimate of $1.2 billion was derived in the
   following manner:  (1) From a June 1991 Workload Management
   Report, a sample of 87 List A cases was used to determine the
   average number of unsatisfied guidelines per case, which was
   57 studies.  From a sample of 86 List B cases the average
   number of unsatisfied guidelines per case was 101.  From a
   sample of 30 cases from Lists C & D (15 cases  from each list)
   the average number of unsatisfied guidelines per case was 77
   studies for List C and 43 studies for List D.  (2) An industry
   survey Cost of Conducting Studies for Pesticide Registration
   (June 1993) provided individual costs of conducting 105
   different studies (not including product chemistry studies)
   which totaled $15,445,977.  The average cost per study was
   $147,104.  By multiplying the average cost per study by the
   average number of unsatisfied studies per case and then
   multiplying that product by the number of cases per list, the
   total cost of conducting the studies in reregistration is
   estimated.
                Avg #                      # of
             of studies  *   Avg Cost  *   cases   =    Cost
List          per case       per study   per list     per list
 A
 B
 C
 D
 57
101
 77
 43
$147,104
$147,104
$147,104
$147,104
151     $1,266,124,128
104     $1,545,180,416
 81     $  917,487,648
 69     $  436.457.568
        $4,165,249,760
By multiplying the $4,165,249,760 sum by the historical rejection
rate of 30%, the upper bound estimate of $1.2 billion for
repeating rejected studies is derived.
                                62

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     A lower bound estimate is warranted because rejection rates
have been falling during reregistration.  By multiplying the cost
to conduct the study by the current rejection reite for that
study, the expected additional costs to repeat rejected studies
can be estimated for each chemical.  By list th expected
additional cost estimates are:
                                Expected Additional Costs
                                   to Repeat Studies
              A                      $ 66,973,119
              B                      $284,627,203
              C                      $186,629,365
              D                      5 22.4S0.265
                                     $560,719,652

The lower bound estimate is approximately $0.6 billion to repeat
rejected studies.

4.  Based on November 1991 rejection rate reports for individual
    companies.

5.  An actual List A chemical is used here as an example of how
    the probabilistic RED schedule is generated.for this
    chemical.  On the chemical profile sheet (on next page) the
    unsatisfied study requirements (as of March 1993)  are listed
    in columns IS 2.   The unsatisfied guidelines are aggregated
    into three groups - all one-year studies, all two-year
    studies and all four-year studies.  Column 3  contains the due
    date for each study.  Columns 4 & 5 contain the study-
    specific rejection rates and the corresponding acceptance
    rate (1.0 - rejection rate).  The probability that all of the
    one-year studies will be acceptable is the joint product of
    their individual acceptance rates.  This joint product is
    0.16 (in column 5 below the one-year studies)  and is referred
    to as Ql.  The probability that all of the two-year studies
    will be acceptable is the joint product of the individual
    acceptance rates for the two-year studies..  This joint
    product,  referred to as Q2, is 0.76.   Similarly,  the
    probability that all of the four-year studies will be
    acceptable is the joint product of the individual  acceptance
    rates for the four-year studies.   This joint  product,
    referred to as Q3,  is 0.71.  The probability  that  this List
    A RED will be issued on time is the joint probability that
    all studies will be acceptable which can be expressed as:
    (1)  Probability of RED
        issued on time
(Q1*Q2*Q3)  - (.16*.76*.71)  - .08
    The probability that one or more one-year studies will be
    rejected is 1 - Ql.   Therefore,  the probability of a one-
    year delay in the RED is the joint probability of one or
    more one-year studies being rejected and all  two and four-
    year studies being acceptable.   This can be expressed as:
                               63

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CHEMICAL PROFILE - LIST A CHEMICAL
1
IHEMlCALNAMe:
is oft

GUIDELINE
NUMBER

;-y*w studies
7-4{o)
S-KW
181-1
161-2
[61-3
163-1

PmMerj^tf^-x
FbtorOQ


2-year studies
(2-2
(2-5{b)
I71-4f
11-S-SS

RcducJrfAwiptaflC*
tote (03


4-yev studies
J3-1(b)
83-4
166-3

ftcdwtf or Axptux
RiXfOOJ


Probability on Umo
(QI'OZ'QS)
Probability o(1yr
dlav(1-Q1)Q2'Q3
Probability o( 2 yr
delay (1-02X33
PtobaltmyoW
delay (1-Q3)

TOTAL

ASSUMPTIONS:
2
JstARED
3/24/93

GUIDELINE
NAME


Eartv life stage ffeh
nvortobrals life cycle
-fydrotvsls
3hotodoflradatton -water
3hotodoaradatkxi - soil
.cach/adsofb/dosofpilon





21-day dermal rabbit/rat
90-day neurotox - mammal
Storage stability
toute neurotox - rat





Chronic-dog
2-osnerat!on repro - rat
Sroundwater monitoring




Nov-95
May-97
May-98
May-00




1. R*M(vod studio* are not included
3



DUE
DATE


Nov-93
Nov-93
JR
Mar-93
Mar-93
JR





JR
Nov-94
May-93
Nov-93





Nov-93
Nov-93
UR




Nov-95
May-97
May-98
May-00





2. Studies conducted by the Spray Drift Task Force are not included
3. Craven DCtsaro not Included since the data has not yet been called hi
4. The RED dtay date Is based on an additional 1. 1/2 years


KEY:



WP" Waiver Pending
LfR  Unrsvtowed study






  Due da!* for 1 68-1 study is not considered as the last study duo date
4



REJECTION
RATE


0.44
0.33
023
0.19
0.18
0.19





0.04
0.07
0.08
0.07





O.OC
0.02
0.2E




FY96
FY97
FY98
FYOO














5



ACCEPTANCE
RATE


0.56
0.67
0.77
0.81
0.82
0.81

0.16



0.96
0.93
0.92
0.93

0.78



1.00
0.9
0.72

0.71

Probabilistic
0.08
0.46
0.17
029

1XX












6



AGENCY
MRS TO REVIEW


8
6
8
8
8
15





1725
22
78.4
90





11025
19
36C



LSDO+1year


















7



REGISTRANT
COST


65.311.50
~67.500.00
66.443.50
81.138.00
90,108.00
66.445.00





62,600.00
160.913.00
29,190.00
104,825.00





455,749.00
402,524.50
2,776.666.50






















~-Cw)tractof
-------
(2) Probability of  = [(1-Q1)*Q2*Q3]=[(1-.16)*.76*.71]= .46
    a one year delay
    in the RED

The probability that one or more two-year studies will be
rejected .is 1-Q2..  The probability of a two year delay in
the RED is the joint probability of one or more two-year
studies being rejected and all four year studies being
acceptable.  This can be expressed as:
(3) Probability of
    a two year delay
    in the RED
[(1-Q2)*Q3]  - [1-.76)*.71 = .17
The probability that one or more four-year studies will be
rejected is 1-Q3.  Therefore, the probability of a four year
delay in the RED can be expressed as:
(4) Probability of
    a four year delay
    in the RED
  1 - Q3  =  1 - .71    .29
This list A chemical, then, has a 8% probability of being
completed on time in FY 96, a 46% probability of being one
year late and being completed in FY97 , a 17% probability
of a two year delay and being completed in FY98, and a 29%
probability of a four-year delay and being completed in
FY2000 as depicted in the following graph.
                           65

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