United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(H7508W)
EPA 738-R-93-008
September 1993
Pesticide Registration
Rejection Rate Analysis
Occupational And
Residential Exposure

-------
      REJECTION RATE ANALYSIS
OCCUPATIONAL AND RESIDENTIAL EXPOSURE

-------
TABLE OF CONTENTS
CHAPTER                                      PAGE
I.        INTRODUCTION
II.       SCOPE OF ANALYSIS
III.      OCCUPATIONAL & RESIDENTIAL
          EXPOSURE CHAPTER
IV.       DESCRIPTION OF DISCIPLINE
V.        CURRENT REJECTION RATE             11
VI.       REJECTION FACTORS                  12

          i.   Four Major Study Rejection
               Factors                       12
          ii.  Protocol Submission and
               Review                        19
          iii. Examples of "Avoidable
               Rejection Factors"            20
VII.      SUMMARY TABLE OF
          REJECTION FACTORS                  26

VIII.     CONCLUSIONS                        27

IX.       RECOMMENDATIONS                    29

X.        APPENDIX A - List of EPA
          Guidance Documents                 31
          APPENDIX B - Actions Taken by
          OREB to Reduce the Rejection Rate  32

-------
REJECTION RATE ANALYSIS
I.  INTRODUCTION


     This  rejection rate  analysis  has  been  undertaken  by  the
Special  Review and  Reregistration  Division  (SRRD),   the  Health
Effects  Division  (RED)  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 acceptable quality  studies.  A  significant
reduction in rejection rates for most disciplines is required for
OPP to be able to meet its production schedule for REDs.

-------
II.  SCOPE OF ANALYSIS

     The scope of this analysis  is  limited first 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.    While  a  rating  of  supplementary by  a
scientist could  require  substantial  new work  and add additional
time delays to  the  process, this outcome  is not very frequent in
this discipline and has not been formally assessed.

     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  completed  Phase 4 last
fiscal  year  (FY92), and List D chemicals will  complete Phase 4 at
the end of this 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  1984 guidelines  and 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
occupational  and  residential exposure scientists  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:  Ed Day  (Dow
Elanco),  Monty Eberhart (Miles), and Paula Paul  (NOR-AM).  Industry
and EPA  scientists met on  March  4,  1993 to discuss  the  problem
areas in order to develop a better understanding of them.

     The  revised  occupational  and  residential  exposure  chapter
explicitly includes industry comments on each rejection factor and
EPA's response to them.

-------
III.  OCCUPATIONAL AND RESIDENTIAL EXPOSURE CHAPTER

     This chapter  examines the  results  of the  occupational and
residential  exposure  rejection  rate  analysis.    The  following
information is discussed:  (1) a description of the discipline of
occupational  and  residential exposure,  (2)  a  list  of  the most
common factors that have  led to the rejection of these studies, and
(3) conclusions.

-------
IV.  DESCRIPTION OF THE DISCIPLINE

     Occupational and residential exposure data are used by EPA to
estimate  non-dietary,  human  exposure  as  a  result  of  pesticide
applications.   With these data,  EPA  can determine  a  safe post-
application/reentry  interval  for individuals entering  pesticide
treated areas  and  determine appropriate  protective  measures for
individuals directly involved  in pesticide application activities.
Requirements for these data are delineated Subdivision K (Exposure:
Reentry  Protection)  and   Subdivision   U  (Applicator  Exposure
Monitoring) of the Pesticide Assessment Guidelines.

     The Pesticide Assessment Guidelines Subdivision K, Exposure:
Reentry Protection,  present  EPA requirements for the  following
studies (Post-application/reentry data  are required  under 40 CFR
158.390):

Post-application/Reentrv Data

     132-1A    Foliar Dislodgeable Residue Dissipation
     132-1B    Soil Residue Dissipation
     133-3     Dermal Passive Dosimetry Monitoring
     133-4     Inhalation Exposure Monitoring

     The Pesticide Assessment  Guidelines Subdivision  U, Applicator
Exposure  Monitoring present  EPA requirements for the  following
studies (Subdivision U has yet to be published in the CFR although
the guidelines were made available in 1987):

Mixer/Loader/Rpplicator Exposure Monitoring

     231  Estimation of Dermal Exposure at Outdoor Sites
     232  Estimation of Inhalation Exposure at Outdoor Sites
     233  Estimation of Dermal Exposure at Indoor Sites
     234  Estimation of Inhalation Exposure at Indoor Sites
     235  Requirements  for Exposure  Monitoring  at  Outdoor and
          Indoor Sites by Biological Monitoring

     The driving factors for determining data requirements are 1)
the pesticide's  toxicity,  and 2) the  human activities associated
with the pesticide's use pattern  that can lead to exposure.  Before
EPA requires a study, both the toxicity  and exposure  criteria must
be  met.    ORES relies  on  HED's  Toxicology Branches   for  the
toxicology  information.   Often,  the  occupational  and residential
data requirements for a given pesticide are held in  reserve until
a complete toxicology database is established.

     The  initial toxicity  criteria for  determining these  data
requirements are acute toxicity  studies using the Technical Grade
Active  Ingredient  (TGAI).   These studies must  indicate  that the
pesticide is in either Toxicity  Category  I or II for acute dermal
and/or  inhalation toxicity to trigger the acute toxicity criteria

-------
for post-application/reentry data requirements.   In 40 CFR under
158.390, reentry data were  originally required for pesticides in
Toxicity Category  I only.      EPA now  requires these  data for
pesticides in Toxicity Category I and II.   Under Subdivision K, the
acute  toxicity criteria  are met  if  the  TGAI,  or  one of the
pesticide  metabolites  meets one  or  more  of  the  following   (the
corresponding   toxicity  guideline   numbers  are   enclosed  in
parentheses):

Dermal     LD50: up to and including 2000 mg/kg  (81-2);
Inhalation LC50: up to and including 0.5 mg/1 (81-3);
(4-hr exposure)

     Other toxicity criteria that trigger post-application/reentry
data requirements include:

     neurotoxic,  developmental  (teratogenic),  or  carcinogenic
     effects identified in toxicity studies (81-7,  82-7,  83-2, and
     83-3);

     other adverse effects  identified  in subchronic, chronic, and
     reproduction studies (82-1, 82-2, 82-3, 82-4, and 83-4);

     pesticide poisoning incident data or  scientifically  validated
     toxicological  or  epidemiological evidence  showing that  a
     pesticide, its residues, or its metabolites can  cause adverse
     effects.

     Mixer/loader/applicator data  are required for pesticides in
Toxicity Category I for dermal and/or  inhalation toxicity.   Under
Subdivision  U, the toxicity criteria  are met if the TEP, TGAI, or
one  of the  pesticide's  metabolites   meets  one  or  more of the
following   (the  corresponding  toxicity   guideline  numbers  are
enclosed in  parentheses):

Dermal     LD50: up to and including 200 mg/kg  (81-2) ;
Inhalation LC50: up to and including 0.05 mg/1  (81-3);
(4-hr exposure)

     Other toxicity criteria may include:

     neurotoxic,  developmental  (teratogenic),   or  carcinogenic
     effects identified in toxicity studies (81-7,  82-7,  83-2, and
     83-3);

     other adverse effects  identified in  subchronic, chronic, and
     reproduction studies  (82-1, 82-2, 82-3, 82-4,  and 83-4);

     pesticide poisoning incident data or scientifically  validated
     toxicological  or  epidemiological evidence  showing  that a
     pesticide, its residues, or its metabolites can cause adverse

-------
     effects.

     The  following  is  a  description  of the  occupational  and
residential exposure studies that are  required  by EPA to support
the  reregistration  of  pesticides  that  meet  the  exposure  and
toxicity criteria discussed above:

Post-application/Reentry

     Foliar  Dislodgeable  Residue  Dissipation   (Subdivision  K,
guideline 132-1A).  The purpose of conducting a foliar dislodgeable
residue dissipation study is to measure pesticide residues that are
deposited on and remain on plant surfaces following application.
These are the residues likely to be touched and dislodged by people
as they conduct post-application activities such as hand harvesting
and pest scouting.

     Soil Residue  Dissipation  (Subdivision K,  guideline 132-1B) .
The purpose of this  study is to measure  pesticide  residues that
have been  deposited  on, incorporated  into,  or diffuse  into the
surface soil following application.   This study is  required when
post-application activities involve  substantial contact with the
treated soil,  such as hand harvesting of potatoes.

     It should be noted that there is a difference between a soil
residue dissipation study and a terrestrial field dissipation study
(Subdivision N, guideline 164-1).  Soil residue dissipation studies
are designed to measure the dislodgeable residues on soil particles
(less  than  147 microns  without grinding) situated on  the soil
surface to a depth  of one centimeter (cm).   These are the particles
likely to be inhaled by or collected on  the  skin or clothing of
individuals reentering fields treated  with pesticides.   Residues
are to be expressed  as ug  or mg/cm2.   The residues to be measured
are limited to  the  pesticide and or toxic metabolites  of concern as
determined by HED's Toxicology Branches.   Soil residue dissipation
studies  must  be  conducted  concurrently  with  dermal  passive
dosimetry and  inhalation exposure  monitoring  to determine worker
exposure.

     Terrestrial   field  dissipation   studies   are   designed  to
determine the overall fate  of the pesticide and all its metabolites
under  field conditions.    The  metabolites   to  be  studied  are
determined  from   previous  hydrolysis,   photolysis,   and  soil
metabolism studies required by the Agency  that have been conducted
in the laboratory.   Soil samples for  this  study  are collected from
the soil surface to a depth of 15 cm.   Soil samples from this study
would grossly underestimate residue levels likely to be encountered
by a field worker.    In addition, the units of measurement for the
terrestrial field  dissipation  study  are  expressed  as  parts per
million (ppm)  or parts per billion (ppb).

-------
     Dermal Passive Dosimetry Monitoring  (Subdivision K, guideline
133-3).  Passive dosimetry monitoring is required when there is a
potential  for  post-application pesticide  residues  to  come into
contact with the  skin and clothing of workers  and/or residents.
Passive dosimetry is used to  estimate the amount of pesticide that
may impinge on the skin or clothing of workers.   The residues are
captured by placing dosimeters on study participants during reentry
activities (i.e.  a whole body dosimeter or cloth patches on various
body parts  such  as arms,  legs, chest etc.).  The pesticides are
then extracted from the dosimeters for analysis.   EPA is currently
requiring   that   passive  dosimetry   monitoring   be   conducted
concurrently with foliar dislodgeable residue dissipation and soil
residue dissipation where applicable.   This guideline requirement
is  also  applicable for  dermal exposure concerns in residential
situations for such pesticide applications as carpet treatments.

     Inhalation Exposure Monitoring (Subdivision K, guideline 133-
4) .   The  purpose  of this  study is  to measure the  amount  of
pesticide  that may be inhaled by  individuals  engaged  in  post-
application activities having the highest potential for exposure.
Various  personal  and  stationary  air monitors  which  draw  known
volumes of  air over a given time period are used to measure the
amount of a pesticide  in the breathing zone.  The exposure criteria
for requirement of inhalation exposure monitoring includes both the
use pattern and the volatility of the pesticide.  Currently, data
are  required  if  the  vapor pressure of  the pesticide  (TGAI)  at
standard temperature  and pressure (mm Hg  at  25C) is  > 1CT3  for
outdoor applications  and  > 10"4 for indoor applications.  When the
new  158.390  regulations are published,  inhalation  exposure data
will be required for outdoor  applications if the vapor pressure is
>  104,  and  data  will be required  for  any indoor application
regardless of vapor pressure.  Inhalation of airborne particles or
dusts containing  pesticide residues may also be of concern.  This
guideline  requirement is  also  applicable for inhalation exposure
concerns  in indoor locations  following  total release  fogger or
aerosol applications.

Some Key Terms

     Allowable  Exposure  Level  (AEL)  -  The  amount  of pesticide
residues at a  given site  that  pose no reentry hazards.  AEL's are
derived  using  a no observed effect  level  (NOEL)  from  subchronic
dermal  or  inhalation studies   which  are  evaluated  by  HED's
Toxicology  Branches.   AELs are expressed  either  as mg/kg/day or
mg/m3.  Safety  factors are applied to NOEL's for calculation  of the
AELs.   ORES  relies  on  the  Toxicology  Branches  to  provide the
appropriate NOELs and safety factors.

     Transfer  Coefficient -   transfer coefficients  are used to
predict the amount of pesticide residues  that are  transferred from
the  plant/soil  surfaces to  field workers.    Although  EPA now

-------
requires   that  passive   dosimetry   monitoring   be   conducted
concurrently with foliar  dislodgeable  residue  dissipation and/or
soil  residue  dissipation studies  (and  that   a  correlation  be
developed between the two),  transfer  coefficients  selected from
published  literature were  previously  used to estimate  dermal
exposure  to  foliar  residues.    One  such  reference  is  "The
Relationship Between Dermal Pesticide Exposure by Fruit Harvesters
and Dislodgeable Foliar Residues," by G. Zweig, J. Leffingwell, and
W. Popendorf.

     Reentry Level  - the  "safe" level of a  pesticide  allowed on
surfaces at the time of reentry.  For field reentry, this level is
expressed as jug/cm2.   The  reentry level is calculated by dividing
the AEL by the transfer coefficient,


Mixer/Loader/Applicator

     Estimation of Dermal  Exposure at Outdoor Sites  (Subdivision U,
guideline 231).   The purpose of this  study  is  to  measure dermal
exposure  to  appropriate  body  parts  during mixing/loading  and
application activities conducted under field conditions.  Passive
dosimeters like those mentioned under guideline 133-3 are used in
these   studies.      Separate   measurements   are   made   during
mixing/loading, application,  and clean-up activities.  M/L/A dermal
exposure  studies  are required to be conducted  concurrently with
inhalation exposure  studies,  discussed below.

     Estimation   of  Inhalation   Exposure  at  Outdoor   Sites
(Subdivision U, guideline 232).  The purpose of this study is to
measure inhalation exposure during mixing/loading and application
activities conducted under field conditions.  Various air monitors
like  those mentioned  under  guideline  133-4 are  used  in  these
studies.   Separate  measurements are made during mixing/loading,
application, and  clean-up activities.   M/L/A inhalation exposure
studies  are required to  be  conducted concurrently with dermal
exposure  studies.

     Estimation of Dermal  Exposure at Indoor  Sites  (Subdivision U,
guideline 233).  This study is  similar  to  the estimation of dermal
exposure at outdoor  sites.  Besides the  obvious difference inherent
in  the  titles of the two studies,  studies  conducted  under this
guideline  also  include   additional exposure   monitoring  during
applicator reentry to the treated area.

     Estimation of Inhalation Exposure at Indoor  Sites (Subdivision
U,  guideline  234)    This  study is  similar  to   the  estimation of
inhalation  exposure  at   outdoor sites.     Besides  the  obvious
difference  inherent in the  titles  of  the   two  studies,  studies
conducted under this guideline also include additional exposure
monitoring during applicator reentry to the treated area.

-------
     Requirements for  Monitoring Exposure at Outdoor  and Indoor
Sites by  Biological Monitoring  (Subdivision U,  guideline  235) .
This study is used  to  determine  the  internal dose of a pesticide
that an individual  may receive by: 1)  measuring a body burden in
selected tissues and/or fluids (blood), or 2) measuring the amount
of the pesticide/metabolites in a person's excreted fluids (sweat,
urine, saliva),  This  study is not typically required,  but  is an
option available to  registrants.  Biological monitoring is required
for  those exposure scenarios  where  passive  dosimetry  is  not
practical  (i.e.  swimmers exposed to pesticides).   The specific
metabolism  and  pharmacokinetics of  a  pesticide must  be  well
understood before a study of this nature can be conducted.
                                10

-------
V. CURRENT REJECTION RATS

     The small number of studies reviewed in this discipline limit
the scope  and meaningfulness of rejection rates.   There were no
rejected mixer/loader/applicator studies in the database that could
be  used  in   this  rejection   rate  analysis.      For  post-
application/reentry studies (132-1A,  132-1B, 133-3,  and 133-4) our
List A database indicates 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  (e.g. incorrect
calculation of the transfer  coefficient).  Regardless,  since all of
the studies  in this discipline  are  higher tier studies  and are
likely to  be  triggered  late  in the reregistration  process,  any
rejected studies that have to be repeated will likely delay a RED
and therefore is of concern to the Agency.
                                11

-------
 VI. REJECTION FACTORS

     A total of  18  studies were evaluated to  determine  the most
common reasons for rejecting occupational and residential exposure
studies.   By far, the most common cause for rejection is inadequate
or, in some cases,  a complete  lack  of Quality Assurance/Quality
Control (QA/QC) data.  Other reasons included:  failure to provide
meteorological data such as rainfall, wind speed, and temperature;
not using appropriate toxicity end points to determine AELs; using
the wrong  transfer  coefficient;  and,  poor  study  design.   The
majority  of the  studies  evaluated  for this  report were post--
application/reentrystudies.

     Admittedly,   the   Subdivision   K   guidelines   for   post-
application/reentry exposure  (published in October 1984)  provided
minimal guidance to the registrants  regarding QA/QC.  Nor were any
Data Reporting Guidelines  (DRG) or Standard Evaluation Procedures
(SEP)   established  in the  1984 guidelines.   The purpose  of the
guidelines  at that time was to establish an acceptable scientific
approach to these recently developed post-application/ reentry data
requirements.   However,  a general discussion  of Good Laboratory
Practices  (GLP)  was  provided.  The  Subdivision  U guidelines for
mixer/loader/applicator  exposure  (published  in  1987)   provide
thorough  QA/QC  requirements  acceptable  to  EPA.    Since  its
publication,  OREB has  encouraged  registrants  to use the QA/QC
criteria presented in the Subdivision U guidelines when conducting
studies  pursuant to Subdivision  K.     Because  Part   158  data
requirements for mixer/loader/applicator exposure are not currently
in  the 40 CFR, the Subdivision U Guidelines were made available
through the National  Technical Information Service (NTIS), National
Agricultural   Chemicals   Association  (NACA),   and  the  Federal
Register.  To compensate for this and to minimize the submission of
faulty data, OREB has requested that  registrants  submit a protocol
for review  by the Branch prior to the initiation  of a study.  Many
basic flaws such as those discussed above are caught at this stage.
Protocol  submission and  review  is discussed further on page 19 of
this document.

i.   Four Major Rejection  Factors

l. Rejection Factor:     Inadequate  or  completelack of
                         quality assurance/quality control
                         data.

     1PA  Guidance on  this  factor

     -  Subdivision  K:    132-1A, 132-1B, 133-3,  133-4

     -  Subdivision  U:    231,  232

     Guidance  on this topic appears  in the Subdivision U-
Applicator  Exposure  Monitoring  Guidelines  (Appendix A) and covers

                                12

-------
laboratory recovery, field recovery, and storage stability data
and are common causes of rejection. The absence of these types of
data seriously compromise a study.

     Industry Comment:  Guidance is presented only as Quality
Assurance Survey forms to be completed upon the submission of
studies for inclusion in PHED (Pesticide Handlers Exposure
Database). Such guidance should appear in the guidelines, not in
an Appendix, and should clearly delineate the types of QA/QC data
expected by the Agency.

     EPA Response:  QA/QC guidance is provided throughout the
Subdivision U guidelines.  However, the Subdivision K guidelines
do not contain QA/QC requirements.  The Agency is currently
revising the Subdivision K Guidelines which are expected to be
completed by the end of the calendar year.  The revised
Subdivision K guidelines will contain the Agency's requirements
for QA/QC data.


EPA/Industry comments and Responses Regarding Rejection Factor 1
- QA/QC Data Requirements

A. Laboratory recovery data verify the adequacy (accuracy,
precision) of the analytical methods used to measure the residues
in the collected samples. Without knowing the adequacy of the
analytical method, the reviewer is left wondering whether the
reported residue data are valid.  Specific guidance regarding
laboratory recovery is presented on pages 2-6, 2-18, and 2-36 of
the Subdivision U Applicator Exposure Monitoring Guidelines. This
is also referenced on page A-21 of a sample Quality Assurance
form provided with the guidelines, and is identified in the Phase
III Guidance Data Acceptability Criteria Checklist.

     Industry comment:  It is agreed that the laboratory recovery
of analytes from substrates must be tested prior to study
initiation  (page 2-6 of Subdivision U, Section c.3-dermal; and 2-
18, Section h.2- airborne). It is also critical that lab
recoveries be run with each set of experimental samples.

     EPA Response:  No comment necessary.


B. Fi eld re covery data are generated using field spikes and
provide a measure of the amount of the pesticide residue
collected in the field that is found remaining in samples
following transport to the lab and storage prior to analysis.
Specific guidance regarding field recovery data is presented on
pages 2-6 and 2-10 of the Subdivision U Applicator Exposure
Monitoring Guidelines  (Appendix A). This is referenced on page A-
21 of a sample Quality Assurance form provided with the
guidelines and identified in the Phase III Guidance Data

                                13

-------
Acceptability Criteria Checklist,

     Industry Comment:  It is agreed that page 2-10, Section D.4
of Subdivision U adequately describes the requirement for
conducting recoveries on dermal passive dosimeters, and page 2-
23, Section K.4, for respiratory exposure measurements.  However,
the Agency needs to define the number of field spikes required
for particular studies.  Although Subdivision U Guidelines
require one field spike per worker per day, the number of workers
per day has nothing to do with the number of field QA samples
necessary to validate an exposure sample replicate.  The same
number of field QA samples should be generated for an exposure
replicate involving one worker as for a replicate involving 15
workers.

     EPA Response:  One concurrent set of field spike data per
day should be sufficient in most cases to cover multiple exposure
replicates on the sarae day.  However, it should be noted that
more field spikes are needed if field spike samples are also used
to generate storage stability data,


C. Storage stability data provide a measure of the decay rate of
pesticide residues in/on samples if they are stored prior to
analysis. With increased pressure on laboratories for analytical
services, this practice is becoming increasingly common. Specific
guidance regarding storage stability data are presented on page
2-19 of the Subdivision U Applicator Exposure Monitoring
Guidelines (Appendix A). This is also referenced on page A-21 of
a  sample Quality Assurance form provided with the guidelines and
identified in the Phase III Guidance Data Acceptability Criteria
Checklist. Also see pages 31, 37, and 44 of the Subdivision K
Guidelines (Appendix A).

     Industry Comment:  Page 2-19 of Subdivision U addresses
storage stability of pesticides on trapping materials from
respiratory sampling. However, there is no corresponding section
for dermal passive dosimeters. There is also no guidance on
storage stability for biomonitoring samples, e.g., urine. Also,
it is appropriate to test the storage stability before  initiation
of the  study, but it is also useful to include storage  stability
samples with each day's experimental samples to verify  stability
during  pre-shipment, shipment, and storage after receipt by the
analytical laboratory. These storage stability samples  should be
prepared at the experimental site  in order to closely simulate
the conditions to which the experimental samples are exposed.
However, if the field recovery data are adequate,  the storage
stability data  are not used in any of the  calculations  of
estimation of exposure. It does provide assurance  that  losses did
not occur during  shipping and storage.

     EPA Response:  As stated in Subdivision U, "At the current

                                14

-------
stage of development, biological monitoring should be considered
a chemical specific method.  Consequently, only general guidance
can be provided to assist in the selection of analytical methods,
sampling collection schedule, and sample storage."  There have
been no major developments in this field of monitoring.  The
Agency will continue to evaluate studies employing biological
monitoring on a case-by-case basis.  Coordination with the
appropriate toxicology branches is essential, particularly when
considering the pharmacokinetics of the substances involved.

     Guidance on dermal storage stability is provided on pages 2-
6 and 2-7 of the Subdivision U guidelines.  Additional
information regarding QA/QC of passive dosimetry samples will be
addressed in the appropriate section of the Subdivision K
Guidelines currently undergoing revision.

D.  Assessment of EPA Guidance on QA/QC Data Requirements;  As
previously mentioned (in the Rejection Rate Analysis document),
Subdivision K provides minimal guidance on QA/QC data
requirements. However,  the new Subdivision K guidelines will
address these requirements more effectively. Please note that the
QA/QC data discussed here are used in all facets of data
reporting to EPA (i.e.  programs such as RCRA, CERCLA, and other
FIFRA-related data reporting requirements).

     Further guidance regarding QA/QC data is also provided in
the Pesticide Handlers Exposure Database  (PHED) which was
developed by a task force composed of representatives of EPA,
Health and Welfare Canada, and the National Agricultural
Chemicals Association (NACA). The guidance provided in PHED
delineates the criteria used for grading the various recovery
data discussed above. The grades range from A to E with A being
the best and E the worst.

     Industry Comment:   The EPA is correct in noting that QA/QC
data are required under FIFRA. The guidance provided by PHED is
helpful and the grading criteria emphasize the importance of
adequate QA/QC data.  However, until the Subdivision K revisions
are completed, interim guidance is needed concerning the number
of field spikes as well as additional QA/QC data that should be
generated for worker exposure studies.

     Good science practitioners understand the importance of
laboratory recoveries to verify the adequacy of the analytical
method and provide a correction factor for losses during the
analytical procedure. Similarly, the generation of sound field
recovery data is absolutely essential to adequately determining
exposures to field workers. This indeed is of such importance
that the Agency should consider giving additional guidance on how
to do field recoveries. For example, it is recommended that
diluted spray solution be used for fortification of sampling
media. But what should be used when a granular product is being

                                15

-------
tested? Also, what procedures should be considered when the
active ingredient is volatile or photolabile and more likely to
dissipate from the sampling medium during a full day of sampling?

     EP1, Response:  The Agency continues to stress the importance
of submitting protocols prior to study initiation as chemical
specific problems are best addressed at that level.  The Agency
agrees that properly conducted field and laboratory recovery
tests are both essential.  Field recovery data should be used to
correct the field residue data, while laboratory recovery data
should only be used to verify the adequacy of the analytical
method.

     The Agency recognizes the need for interim guidance on QA/QC
data requirements, particularly with respect to the following;

     o    the definitions of field recovery and storage stability
          data;
     o    additional guidance for generating field recovery and
          storage stability data;
     o    guidance on how recovery data should be used;
     o    guidance on what data are absolutely necessary and what
          data are optional;
     o    guidance on QA/QC requirements for whole body
          dosimeters.
2. Rejection Factor;     Not providing meteorological data.

     EPA Guidance on this Factor

          Subdivision K: 132-1A, 132-1B, 133-3, 133-4

     Guidance on this topic is presented on pages 11 and 30 of
the Subdivision K guidelines. Since climate and weather
conditions  strongly influence the dissipation of pesticide
residues, absence of these data are grounds for rejection of the
study.

     industry Comment:  Meteorological data are interesting and
may permit  an explanation for variations in data from one day to
the next. However, the weather should have no effect on the
validity of the study unless the study was conducted under
conditions  so adverse that the application or reentry operation
was atypical. A limited amount of weather information is all that
is needed,  i.e., only temperature, wind speed and direction,
humidity, and precipitation during the sampling period. Such data
is not  relevant when conducting studies indoors, though
temperature and humidity should be recorded. The absence of
complete meteorological data should not be cause of rejection as
long as there is enough to provide evidence for the actual

                                16

-------
conduct of the study as described.  The specific types and the
amount of meteorological data required needs to be clarified.

     EPS, Response:  The Agency agrees that, at a minimum,
meteorological data should include site specific rainfall data
(not from the nearest airport),  temperature, wind speed and
direction, and humidity, as well as information on irrigation
practices.  Often, even the most basic meteorological data are
not provided in study reports.  If meteorological data were
collected, but not reported, the study could be upgraded upon
submission of these data.

     If weather conditions are so adverse that they require
lengthy discussions relative to the outcome of the study, the
registrant should consider abandoning the study.  The Agency is
flexible in this regard when granting time extensions.


3.Rejection Factor;     Using inappropriate toxicological end
                         points and tran s fer coefficientg when
                         calculating reentry levels.

     EPA Guidance on this Factor

          Subdivision K: 132-1A, 132-1B, 133-3, 133-4

     Extensive discussion of the use of toxicity end points is
presented on pages 24, 27, 28, and 29 of the Subdivision K
guidelines. A discussion of transfer coefficients for use in the
absence of real passive dosimetry data are provided in the
abstract "The Relationship Between Dermal Pesticide Exposure By
Fruit Harvesters and Dislodgeable Foliar Residues" by G. Zweig,
J. Leffingwell, and W. Popendorf.  OREB will provide registrants
with the appropriate citations and we encourage registrants to
solicit our input regarding transfer coefficients and toxicity
end-points. Studies using unacceptable toxicity end points or
transfer coefficients will be returned to the registrant for
recalculation.

     Industry Comment:  It is not at all certain that the
correlation between the transfer coefficient for a given task and
dislodgeable residues is independent of the nature of the
pesticide. Indeed, it is probable that the dislodgeability of a
pesticide from foliage will vary from one chemical to another;
hence, the use of published transfer coefficients for surrogate
chemicals may not be appropriate for many chemicals. In any case,
the registrant and the Agency should agree on the approach to be
taken and the toxicity end points to be utilized before embarking
on a Subdivision K study. However, the registrant's use of an
inappropriate toxicological endpoint does not compromise the
validity of the dislodgeable residue and worker exposure data and
should not be a cause for the rejection of these data.

                                17

-------
     EPA Response:  If an inappropriate toxicity end point or
transfer coefficient is used, the study must be rejected
initially, but could be upgraded accordingly after receiving the
revised calculations.  The Agency does not have the resources to
devote time to recalculating data when reviewing a study.  The
Agency agrees that the transfer coefficient method may under or
over estimate postapplication exposure.  For this reason, we are
currently requiring that foliar and soil dissipation studies be
conducted concurrently with dermal and inhalation exposure
studies.  We suggest that registrants work together to identify
areas where reentry exposure data and foliar dislodgeable residue
data are needed to develop crop and work specific transfer
coefficients in order to minimize the number of studies that need
to be conducted.  Most studies submitted to date have used
published transfer coefficients to determine exposure from foliar
dissipation data rather than conducting exposure studies to
determine dermal transfer coefficients for the specific crops and
work activities.


4.Rejection Factor;     Insufficient sampling intervals.

     EPA Guidance on this Factor

          Subdivision K: 132-1A, 132-1B, 133-3, 133-3

     Guidance regarding standards for sample collection are
provided on page 30 of the Subdivision K guidelines. An example
of a typical sampling interval provided in the guidance indicates
that samples should be taken as soon as the sprays have dried or
the dusts have settled, and at 1, 2, 5, 7, 14, 21, 28, and 35
days after the final application.

     Industry Comment:  Indeed, these sampling intervals should
be for guidance purposes only.  There are many reasons for
including alternative sampling intervals that are not on the
specific days indicated in the guidelines.  Also, if residues
drop below certain levels, or plateau, registrants should be able
to cease sampling for dislodgeable residues.  While Subdivision K
Guidelines recommend specific sampling intervals for foliar
dissipation studies, the number of different sampling intervals
for concurrent worker exposure studies are not specified in the
guidelines.  Fieldworker exposure on day 1 post-application
should be considered worst case, and one sampling interval post-
application for worker exposure studies should be considered
adequate when the interval is the earliest possible  (or
anticipated) reentry time following application.  However,
conducting exposure  studies  at multiple intervals with the same
workers in the same  fields would provide valuable information
concerning the exposure process and the validity of the generic
transfer  coefficient process.
                                18

-------
     EPA Response:  The Agency agrees with Industry on these
comments.  A sufficient number of sampling intervals should be
considered to establish a decline curve for dislodgeable
residues.  Typically, the intervals are frequent in the beginning
of a study and less so near the end.  The proposed sampling
schedule should be included in the study protocol.
ii.  Protocol Submission and Review

Submission and review of protocols prior to initiation of worker
exposure studies is highly advisable for conducting acceptable
studies.  The design of worker exposure studies is open for
suggestion and discussion, and many issues can be resolved at the
protocol stage.

     Industry Comment:  Timely review by EPA of study protocols
is essential; comments on the design of a study must be received
before the study is scheduled to be initiated.

     An issue that needs to be considered is whether a GLP
protocol must be submitted or if a "study design report" is more
appropriate for worker exposure studies.  The nature of worker
exposure studies makes it difficult to submit formal GLP
protocols for review by the Agency prior to initiation of a
study.  The major parameters being considered in a field study
such as application technique, type of crop and number of
replicates are known in advance and can be provided for Agency
review in a study design outline.  In contrast, many of the minor
details involved in a field study are not finalized until just
prior to study initiation.  The inclusion of these details in a
GLP protocol for Agency review prior to study initiation would
result in numerous protocol amendments and deviations to be
signed and accounted for in the final report.  In addition,
guidance is needed on exactly what information the Agency would
like included in the study design report or protocol.

     EPA Response:  Registrants should refer to the
Reregistration Phase 3 Technical Guidance Document (dated Dec.
24, 1989), specifically the checklists for summarizing studies
under Subdivision K and U, for a summary of what should be
included in a study design report or protocol.  Registrants
should refer to Subdivision K and U for additional details of
information and/or data to include in a protocol.  The Agency
does agree that additional guidance is needed concerning the
minimum amount of information that should be included in these
submissions.

     Concerning GLP protocols, the Agency recognizes that, while
all studies are required to be conducted according to GLP, the
submission of a GLP protocol for review prior to initiation of a

                                19

-------
study may not be feasible in most cases.   The more informal
requirement of a study design report is more practical and is
recommended under Subdivision U.  The Agency, therefore,
recommends that registrants submit study design reports for
review prior to initiation of studies rather than GLP protocols
for Subdivision K and U studies.  It should be noted that the
study design report must include enough information to determine
whether the proposed study will adequately address the worker
exposure issue(s) of concern.  A final GLP protocol must be
signed by the appropriate study investigators prior to
commencement of the study and this protocol should be included in
the final study report submitted to the Agency.
iii.  Examples of "Avoidable Rejection Factors" for Occupational
and Residential Exposure Studies

     Based on a review of the above factors, as well as other
reasons, occupational and residential exposure studies may be
rejected and hence OREB has generated the following list of
avoidable rejection factors on the part of the registrants.
Should these factors cause a future study submission to be
rejected, EPA would likely consider taking appropriate regulatory
actions. This assessment would only be applied to future studies
submitted to EPA. This judgement would not be applied
retroactively.

1)  EPA Rejection Rate Study Comment:  Complete lack of QA/QC
data.

     Industry Comment:  Industry agrees with the Agency
assessment.

     EPA Response:  No comment necessary.
2)  EPA Rejection Rate Study Comment:  Complete lack of weather
data.

     Industry Comment:  Industry agrees with the Agency
assessment, but data does not have to be extensive.

     EPA Response:  The weather data should, at a minimum,
consist of rainfall  (site specific), temperature, humidity, wind
speed and wind direction.
                                20

-------
3)  EPA Rejection Rate Study Comment:  Did not use the maximum
application rate and frequencies of application asper	EPA
a ccepted,. 1abeling.

     Industry Comment:  This is dependent of the type of study.
For foliar dislodgeable residues and associated reentry tasks,
the requirement is probably appropriate. However, for monitoring
reentry during activities such as incorporation, tillage,
installing drainage tile, etc. the requirement should be for the
maximum rate and frequency for the soil type, crop and locale,
not simply the maximum use rate. For example, a fumigant may be
used at one rate on potatoes in Washington, but at a much
different rate on peanuts in North Carolina. The weather
conditions, soil type, and equipment used may play more important
roles than application rate. For measuring exposure to
applicators, it should again be required that the maximum
application rate  (or anticipated maximum rate planned in the case
of new products or label changes for existing products) be used
for the crop and locale being studied, and not necessarily the
maximum permissible rate on the label. For example, a fungicide
may be used on apples in Virginia at the rate, X, but the same
product may be used at only 1/2X in Washington on apples. Yet the
conditions in the two states may be such that exposure under both
sets of conditions should be studied. Additionally, it is the
premise of PHED that exposure is due to physical parameters, and
that exposure data is best normalized to the amount of product
handled. Hence, it should be permissible to use less than maximum
recommended rates as long as sampling is adequate to allow
measurement of exposure. This should not automatically be a cause
for rejection of an exposure study.

     !PA Response:  The important point is that the study,
particularly for reentry, represent the worst case for exposure.
The registrant must convince the Agency that the worst case has
been evaluated.  Industry's comment about PHED and the assumption
that exposure data is best normalized for the amount of product
handled is more appropriate for mixer/loader/applicator studies
than for reentry studies.
4)  EPA Rejection Rate Study Comment:  Poorly organized,
confusing reports.

     Industry Comment:  Industry agrees that the report should be
sent back to the registrant.

     EPA Response:  No comment necessary.
                                21

-------
5)  EPA Rejection Rate Study Comment:  Foliar dissipation and
dermal exposure studies were not conducted concurrently to
establish a transfer coefficient.

     Industry Comment:  Industry agrees that this needs to be
done at minimally one time period after application in order to
calculate a transfer coefficient.

     EPA Response:  The Agency currently believes it is
desireable to include a minimum of two sampling intervals for
dermal and/or inhalation passive dosimetry studies which are to
be conducted concurrently with soil and/or foliar dissipation
studies.
6)  EPA Rejection Rate Study Comment:  Inadequate statistical
methods.

     Industry Comment:  It is not agreed that this should be an
automatic reason for rejection. Often, data from field exposure
studies are so variable that no statistical treatment at all is
the appropriate method. Unless some specific guidance is provided
by the Agency, this should not be reason for rejection.

     EPA Response:  The Agency recognizes that worker exposure
data is often variable.  However, the registrant must attempt to
explain the variability.  The Agency will address this topic in
the revised Subdivision K guidelines.
7)  EPA Rejection Rate Study Comment:  Testing crops orreentry
activities notrepresentative of actual use situations
(activities leading tothe highest exposure should be studied).

     Industry Comment:  Industry agrees in principle with this,
but there could be some disagreement between registrants and
reviewers on what represents the highest exposure scenario. If
there is disagreement, it should be resolved prior to initiation
of a study. The Agency should also recognize that registrants and
their employees are in the field frequently and through their
experience have the better basis for selecting the scenarios that
are likely to yield the highest exposures. In this regard,
representatives from OREB should be provided more opportunity to
observe the conduct of field exposure studies conducted by
registrants.

     EPA Response:  It is the Agency's hope that the registrants
know their chemical and its uses.  The registrants should also
recognize that the Agency's staff have seen many exposure studies

                                22

-------
and may have some insight regarding particular exposure
scenarios.  The Agency encourages any discussion in this regard
and welcomes the opportunity to witness "first-hand" field
studies conducted by or on behalf of registrants.


8)  EPA Rejection Rate Study Comment:  Inadequatehand1ing or
storage of samples.

     Industry Comment;  Industry agrees with the Agency's
assessment. Samples should be handled and stored according to
GLPs.

     EPA Response:  No comment necessary.
9}  EPA Rejection Rate Study Comment:  Inadequate handling or
m a int e nance of test s ;u b s t a n c e or _ sample storage containers.

     Industry Comment:   The requirement under GLP to maintain
all sample storage containers is only practical for lab studies.
This requirement is not practical for worker exposure studies
because of the large number of field samples generated and stored
separately.  EPA should consider a "blanket waiver" of the
requirement to maintain sample storage containers for field
studies.

     1PA Response:  EPA/OREB agrees that storage of numerous
pesticide containers for the duration of field worker exposure
studies is not practical.  This is not an OREB criterion for
study rejection.  OREB has contacted the Office of Compliance
Monitoring regarding this issue.  OCM verbally affirmed that
container storage is not practical for field studies and has
provided a mechanism for obtaining waivers from that requirement
in the case of field studies.  An OCM Questions and Answers
Document (Attachment 1) contains guidance to that end.  OREB/HED
will cooperate with Special Review and Reregistration Division
and NACA regarding the possibility of obtaining a generic waiver
from OCM relative to field studies.

-------
The following factors may cause a study to be rejected but will
not be a reason to initiate regulatory action;


1)  Additional EPA Comment:  Failure to propose a reentry
interval.

     Industry Comment:  Industry agrees that it is in the
registrant's best interest to propose a reentry interval for its
product.

     EPA Response:  No comment necessary.
2)  Additional EPA Comment:  Failureto report data in terms of
surface areafor foliar dissipation studies (ie. reportingppro
instead of ug/cm2) .

     Industry Comment:  Industry agrees with the Agency's
assessment.

     EPA Response:  No comment necessary.
3)  Additional EPA Comment:  Using personal protective equipment
(PPE) or engineering controls in a study when these mitigating
measureswillnot appear on accepted EPA labeling.

     Industry Comment:  The use of personal protective equipment
by a worker during, for example, mixer/loader studies should be
permitted by the worker providing the passive dosimetry measures
potential exposure if the equipment was not worn. This should be
at the worker's discretion, especially for new chemicals with
which the worker has had no experience. Engineering controls
should be permitted if it is the registrant's intent to require
such controls on the label. In such cases, it should not be
required that registrants conduct studies both with and without
the controls.

     EPA Response:   The Agency agrees with Industry, as long as
the exposure measured reflects the labeled use.
 4)  Additional  EPA Comment:  Didnotuse the TEP for which
 registration/reregistration  is being requested.

      Industry Comment:   Some TEPs  are such that the study of one
                                24

-------
should suffice for others. For example, studying the exposure of
applicators to an active formulated as a wettable powder (WP)
will provide the same information as an aqueous suspension (AS),
suspension concentrate (SC) , or dry flowable (DF),  because they
are all in essentially the same physical form once they have been
dispersed in water in the spray tank. The same could be said for
determining foliar dislodgeable residues for such formulations.

     EPA Response;  The Agency agrees with Industry.  However,
with the growing list of formulation types, it would be helpful
if the registrants informed the Agency which formulations would
be represented in a given study prior to its initiation.
5)  Additional EPA Comment:  Sample contamination (in the field
or laboratory) ...

     Industry Comment:  Industry agrees with the Agency
assessment, such data should not be submitted.

     EPA Response:  No comment necessary.
6}  Additional EPA Comment:  Problems with the analytical method.

     Industry Comment:  Industry agrees with the Agency's
assessment, only data based on validated analytical methodology
should be submitted.

     EPA Response:  No comment necessary.
7}  Additional EPA Comment:  Although highly variable data may be
unavoidable, the registrant should attempt to explain any
variability.

     Industry Comment:  Industry agrees with the Agency
assessment. If studies are conducted using good science, GLPs and
proper record keeping, it is often possible to explain a highly
aberrant result.

     EPA Response:  No comment necessary.
                                25

-------
VII.     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 meteorological data.
                          -Used inappropriate lexicological end points and transfer coefficients when calculating reentry
                          levels.
                          -Insufficient sampling intervals.
                                                        26

-------
VIII. CONCLUSIONS

Despite a very limited sample size, several important points
warrant emphasis here;

1)  EPA Rejection Rate Study Comment:

     All of the studies in this discipline are higher tier
     studies that are triggered by the results of animal toxicity
     studies (81-2,3,7; 82-1,2,3,4,7; 83-2,3,4). Since some of
     these toxicity studies are four year studies (83-2; 83-4),
     it is quite possible that any required occupational and
     residential exposure studies will be triggered late in the
     reregistration process. Consequently, even a low rejection
     rate will likely delay a RED and therefore is of great
     concern to the Agency;


2)  EPA Rejection Rate Study Comment:

     The most common rejection factor is inadequate quality
     assurance/quality control data. The guidelines for post-
     application/reentry exposure provide minimal guidance to
     registrants regarding QA/QC;

     Industry Comment:  It is agreed that guidance is minimal, so
additional guidance is needed before more studies are rejected
for this reason.

     EPA Response:  Every effort will be made to determine if the
registrant made a "good faith effort" to follow accepted QA/QC
procedures when conducting a study.  If the Agency determines
that the registrant has made such an effort, the study may be
considered suitable for determining a reentry interval.  However,
if it is evident that QA/QC procedures were inadequate, the study
must be rejected.  If QA/QC data are not provided or discussed at
all in the study report, the study must be initially rejected but
the registrant will be given the opportunity to provide
additional data to upgrade the study.


3)  EPA Rejection Rate Study Comment:

     Adequate QA/QC guidance does exist for the
     mixer/loader/applicator exposure studies and can be used for
     the post-application/reentry exposure studies.

     Industry Comment:  As indicated earlier, this guidance is
only presented as the QA form for submission of data into PHED. A
more detailed discussion of this topic in the body of the
guidance documents is needed.
                                27

-------
     EPA Response:  No comment necessary.
4)   EPA Rejection Rate Study Comment:

     The available studies evaluated for this report focus almost
     exclusively on the post-application/reentry exposure
     guidelines. At this time little is known about the rejection
     factors associated with the mixer/loader/applicator exposure
     guidelines.

     Industry Comment:  One reason for little being known about
the rejection factors for M/L/A studies is that few thorough
reviews have been conducted by Agency personnel and returned to
registrants.  Many registrants are simply not getting Agency
reviews which would allow them to "fix" any problems with the
studies.  In addition, the review of protocols by Agency
personnel has often been so slow that registrants have commenced
studies and, in some cases, even completed the field monitoring
portions of studies without having received formal comments or
approval of the protocols. This puts registrants in tenable
situations when studies are submitted in support of registrations
or reregistrations.

     EPA Response:  The Agency has been open to holding meetings
with registrants to discuss solutions to this situation. The
Agency continues to encourage registrants to submit protocols as
early as feasible, request meetings, or request time extensions
until the protocols have been reviewed.

     The Agency encourages registrants to revisit the Subdivision
U guidelines as well as the Reregistration Criteria for
Acceptability as these documents do provide guidance on QA/QC
data.  The Agency also encourages registrants to continue
investigating the state-of-the-art of exposure methodology and
ensure their protocols get to the Agency in a timely fashion.
                                28

-------
IX.  RECOMMENDATIONS

     Solutions to many of the factors leading to the rejection of
occupational and residential exposure studies were identified as
a result of this rejection rate analysis and subsequent
discussions with industry.  The need for additional guidance on
occupational and residential data requirements is evident.  The
Agency plans to issue revised Subdivision K Guidelines as well as
Standard Evaluation Procedures (SEPs) for studies conducted under
Subdivision K.  Draft copies of these documents should be
available by December, 1993.

     In the interim, the Agency recommends that industry develop
a proposal for Agency review that includes QA/QC requirements for
particular studies and specific information that should be
provided in protocols or study design reports that are submitted
to the Agency prior to initiation of studies.

     The development of the above documents should reduce the
rejection rate for occupational and residential exposure studies.

     With respect to protocol submission, the Agency recommends
that registrants submit "study design reports" rather than formal
GLP protocols prior to initiation of Subdivision K and U studies.
The Agency recognizes that variations in study design for
Subdivision K and U studies are necessary to ensure that the
studies adequately address the worker exposure issue(s) of
concern.  Many issues that could potentially result in the
rejection of a study, including requirements for meteorological
data collection, number and timing of sampling intervals, and
maximum vs. typical application rates, can be resolved at the
protocol or study design stage.

     Concerning Good Laboratory Practices (GLP) requirements, the
Agency recognizes that the requirement under GLP to maintain all
sample storage containers is not practical for field studies such
as foliar and soil dissipation and worker exposure studies
because of the large number of samples generated in these
studies.  A proposal to waive this GLP requirement for field
studies should be drafted for consideration by the GLP
Program/OCM.

     The Agency continues to recommend that foliar and/or soil
dissipation studies and postapplication worker exposure studies
be conducted concurrently in order to calculate crop and task
specific transfer coefficients; the Agency does not recommend the
use of generic transfer coefficients.  The Agency further
recommends that industry, with the assistance of NACA, make a
coordinated effort to determine crop groups based on the exposure
data generated, i.e. crops should be grouped according to the
postapplication worker exposure associated with each crop.
                                29

-------
     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 upgrade the study.

     Finally, SRRD intends to continue tracking rejection rates
for occupational and residential exposure guideline studies,
particularly Subdivision K studies.  If a significant reduction
in the rejection rates for these studies is not observed, further
regulatory action may be required.
                                30

-------
X.  APPENDIX A - EPA GUIDANCE DOCUMENTS

     EPA distributed the following documents to guide registrants
on the correct procedures for conducting occupational and
residential exposure studies.  Specific references to these
materials are made under each of the rejection factors listed.

          Subdivision K: Exposure: Reentry Protection (1984)

     -    Subdivision U: Applicator Exposure Monitoring (1986)

     -    "The Relationship Between Dermal Pesticide Exposure By
          Fruit Harvesters and Dislodgeable Foliar Residues", G.
          Zweig, J. Leffingwell, and W. Popendorf, 1985.

          FIFRA Accelerated Reregistration - Phase 3 Guidance
          (1989)
                                31

-------
APPENDIXB -Actions taken by ORES to reduce the rejection rate

     To ensure that registrants develop and submit acceptable
studies to the EPA, OREB has been carrying out the following
actions for the last several years:

     o    sponsored and participated in American Chemical Society
          (ACS), American Society for Testing of Materials
          (ASTM), and the Society of Environmental Toxicology and
          Chemistry (SETAC) symposiums and conferences with
          National Agricultural Chemicals Association (NACA),
          federal agencies, and private industries on EPA
          reentry/worker exposure guideline requirements;

     o    participated with NACA, California Department of Food
          and Agriculture  (CDFA), and Health and Welfare Canada
          on joint projects concerning indoor and turf reentry
          exposure methodology;

     o    created a task force with Health and Welfare Canada,
          CDFA, and NACA on the Pesticide Handlers Exposure Data
          Base  (PHED) in regard to handler exposure data
          acceptability/availability (including a QA/QC grading
          criteria for data);

     o    presented talks to both national and international
          organizations outside EPA and published relevant
          reentry/worker exposure papers in ACS, American
          Industrial Hygiene Association (AIHA), ASTM, and other
          professional journals;

     o    published Federal Register notices as guidelines became
          available through the National Technical Information
          Service  (NTIS);

     o    participated in updates of 40 CFR 158 Data Requirements
          for Registration;

     o    reviewed reentry study protocols submitted by the
          registrants before they were conducted;

     o    conducted face-to-face meetings and phone conferences
          with registrants regarding submitted study protocols;

     o    conducted meetings regarding data/protocol requirements
          with consultants and  contractors that conduct
          reentry/exposure studies for registrants;

     o    provided Summaries of Guidance Data Acceptability
          Criteria in the  Phase III Guidance Packages for
          Reregistration  (it should be noted that it is our
          belief that registrants, in some cases, submit studies

                                32

-------
          knowing they are unacceptable,  as demonstrated when
          they fill-out the Acceptability Criteria Summaries for
          Reregistration);

     o    EPA funded exposure methodology research through
          university cooperative agreements and the Office of
          Research and Development/EPA-Pesticides Research
          Committee;

     o    encouraged registrants to research new exposure
          methodologies as well as to pool their resources to do
          more comprehensive/acceptable studies.

     Most recently, OREB has drafted an SEP for Subdivision K -
Agricultural Crops and is currently revising the Subdivision K
Guidelines.
                                33

-------
                                     TT A~ H M -t NT
FEDERAL INSECTICIDE FUNGICIDE, AND RODENTICIDE ACT (FIFRA)

       GOOD LABORATORY PRACTICE STANDARDS (GLPS)

                   QUESTIONS AND ANSWERS
                        Prepared by the
                Pesticides Enforcement Policy Branch
                     Policy and Grants Division
                  Office of Compliance Monitoring
          Office of Prevention, Pesticides, and Toxic Substances
                UJ. Environmental Protection Agency

                          May'l2, 1992

-------
                                                            FFFRA CLP Q'$ & A's
                                                                     May 12, 1992
                                                                      Page 1 of 14
                                 INTRODUCTION
       On August 17, 1989, EPA published In the Federal Register revisions to the
 Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Good Laboratory Practice
 standards (GLPS) (54 FR 34052). This revision included changes that the Food and
 Dnjg Administration made to its GLPS (September 4, 1987; 52 FR 33768) and expanded
 the scope of the regulations to include data submissions which had previously not been
 under GLPS.  The expansion of GLPS to include Geld studies has brought many facilities
 under GLPS for the first time while also making the standards applicable to entirely
 different types of testing environments than had previously been the case.

       Since the publication of the revised rule in 1989, EPA lias received many
 questions  from persons who wish clarification regarding the applicability of the rule to
 their activities.  These questions have ranged  from limply asking whether the work they
 are doing is  required to comply to technical questions regarding  how the standards
 should be applied in the context of field as opposed to laboratory studies,  Many written
 replies have been made to persons who hive  submitted specific questions in writing to
 EPA.  Copies of specific correspondence have been provided upon request.

       Notwithstanding, the correspondence file U of limited usefulness to other persons
since the issues addressed are often specific to a particular situation.  There have been
requests for a general guidance document regarding EPA'i FIFRA GLP policy.  The
following questions and answers have  been prepared by the Policy and Grants Division of
the Office of Compliance Monitoring  to serve as official written policy for the regulate U
community,

-------
                                                           FIFRA CLP Q's & A's
                                                                    May 12, 1992
                                                                    Page 2 of 14
                          QUESTIONS AND ANSWERS
APPLICABILITY
 1.    Whit is the applicability of GLPS to work in progress it the time that the rule
      became effective?

      The GLPS apply to all study-related work which it performed on or after the
      effective date of the rule.  Studies in progress must be in compliance with GLPS
      from the effective date onward. A statement of compliance or non-compliance
      must accompany the final study report for such a ftudy.  This statement must
      either (1) state that the study was in compliance with GLPS, (2) describe in detail
      how it did not comply with GLPS, or (3) itate that the submitter did not sponsor
      or conduct the study and does not know its compliance status.  The statement
      must account for compliance or deviations with both the previous GLP rule
      (effective 1984), and the current rule (effective 1989), as applicable,

2.    If i study was in prop-cat on October 16,1989, mutt it have a protocol?  What
      pans of the study would the protocol address?

      All portions of the  study performed on or after the effective date must be
      performed according to a  written protocol as provided at 40 CFR 160.120. That
      protocol need only address those parts of the study performed on or after the
      effective date. Please note that if a study wts subject to the 1984 GLPS, a
      protocol was required for  all parts of the study conducted after the effective  date
      of that rule. The compliance statement submitted  with that study's report must
      specify in detail those study  activities which were not performed in accordance
      with GLPS.

3.    Cuntpl reiegisiratxMi procedures involve submission of data that resulted from
      studm performed prior to the effective date of GLPS.  Do GLPS apply to such
      data, md tf so, bow?

      Any data presently submitted in support of a pestJdde research or marketing
      permit must be accompanied by a trut and correct compliance statement as
      described at 40 CFR 160,12 regardless of when the study was performed.
      Therefore, data submitted to meet rcregistration requirements are required to he
      accompanied with a true and correct compliance statement informing P^ in
      detail of all differences between the practices used in the study and those required
      by GLPS.  It is not unlawful to truthfully admit that studies supporting such

-------
                                                            FIFRA GLF Q's & A's
                                                                     May 12.  1992
                                                                      Page 3 of 14


       submissions did not comply with OLPS, cor would such an admission necessarily
       lead to rejection of the data.  The compliance statement will help the Agency to
       determine the reliability of !he data based on current data requirements.  Note
       that such art admission may nevertheless result in an enforcement action if they
       indicate that an unlawful act lias occurred, For example, other regulations, i.e.,
       books and records as stated at 40 CFR 169.2(k), require retention of raw data
       generated in support of registered pesticides prior to the effective date of GLPS,
       Admitting to destruction of recordi would not exclude the Agency from taking
       enforcement actions for the books and records violation.

 4.     Do GLPS apply to data used to support tolcraace petitions?

       Yes. The scope of the regulations as stated at 40 CFR 160.1  require that itudies
       conducted to develop data pursuant to sections 408 and 409 of the Federal Food,
       Drug, and Cosmetic Act be performed in accordance with GLPS,

5.     Are ttudiea conducted uader the Interregional Research Project Number 4 (IR-4)
       program to support the regfetratioa of minor usei subject to the OLPS?

       Yet,

6.     Do GLPS apply to weather data and son analytii data?

       Any data which are collected u part of a study listed in 40 CFR 160.1 must be
       collected according to GLPS.  This includes weather data and soil analyses which
       are collected as part of & larger study which must comply with GLPS. II non-study
       data such as local weather data are cited In a study report, and the study report
       clearly indicates  thai such data were noi gathered as part of ibe study, GLPS
       would not apply to such  data.

7.     What appUcabflity do GLPS have when State, Federal, or independent
       labonrtortei are used to provide soil or weather data for GLP studies?

      GLPS ire applicable in luch circumstances if such data are gathered as part of a
      FIFRA study.  Only where such data are gathered indepcndemry of the study, and
      the study report clearly indicates  that such data were not pthered as part of the
      study, would GLPS not apply,

-------
                                                            FIFRA GLP Q's & A's
                                                                     May 12, 1992
                                                                      Page 4 of 14
 DEFINITIONS
8.     WOJ EPA issue separate GLP standards for field testing as opposed to laboratory
       testing?

       The expansion of GLPS to cover field studies was based on the need to assure
       identical standards for til data submitted to EPA under FIFRA, and on the
       determination that the GLPS are technically general enough to cover virtually any
       type of research environment.  EPA docs not intend to Issue separate standards.

9.     Can an experiment be divided  into more than one study, based on where or when
       the work is performed, or the phase of the experimental work?

       Under GLPS, the term "study" refers to an experiment to determine or predict the
       effects or characteristics of a test substance. EPA considers a study to be
       composed of all  of the necessary elements of research which are performed in
       order to obtain the reported results.  If the dementi of research consist of several
       phases of work which must be  taken in the context of each  other to get
       meaningful results, they are all considered to be elements of the same itudy. An
       example of this would be where one laboratory treats  a test system with a test
       substance and sends the treated test system to another laboratory for analysis.

       If the experiment involves treatment of test systems in several different locations,
       the experiment may be considered to be composed of either one study
       encompassing all locations or several studies each involving one or more locations.
       In the latter case, however, It would be necessary that each separate study stand
       entirely by itself, I.e., meet all of the criteria of a study.  There would have to be
       separate compliance statements for each, separate tracking on master schedules,
       separate quality assurance inspections, etc.  Each study would have to have a
       study director (and only one study director), although it may be possible for the
       same study director to oversee  several of such studies  at the same time.  Finally,
       where fevtral studies are compiled for submission, the submission must include
       tnie and correct compliance statements for each study involved in the submission.

10.     What is EPA'i forma] policy on certifying copies of raw data?  Muit each page be
      rigned and dated?

      EPA stated in the preamble to the  August 17, 1989 rule (54 FR 34066) that
      acceptable alternatives to signing and dating each page may be devised anc}
      incorporated  into standard operating procedures.  EPA did not further elaborate
      in order to allow each testing facility flexibility in implementing SOPs that would

-------
                                                             FIFRA GLP Q's & A's
                                                                      May 12, 1992
                                                                       Page 5 of 14


       provide adequate assurances within its facilities.  Note that EPA may inspect the
       original records, which must be maintained by the registrant as provided at 40
       CFR 169.2(k), to  assure that they have been kept and shat the copies are  correct.
                                *f
 11.    Is It permissible to discard originaj raw data worksheets after exact copiei have
       been made?

       Destruction of original raw data is prohibited.  The registrant  is responsible for
       maintaining all original raw data as specified at 40 CFR  169,2(k).  Copies of data
       may be used to assure compliance with GLPS  at the level of the testing facility,
       but EPA requires that the registrant maintain all original data that support a
       study.

 12.    What type of sponsor-testing facility communication ii considered  to be raw data
       which mult be archived at the end of the study?

       All record! of sponsor-testing facility communication which occur as  pan of the
       activities of a itudy are considered to be raw data, as defined  at 40 CFR 160,3.
       This Includes memoranda, letters, and records of telephone conversations  which
       occur during the course of the study.  Communication conducted prior to  the
       study (i.e., before  the protocol is signed) or following the completion of the study
       (i.e., after the report is signed) would not normal])* be considered to  be raw data.
       Note that certain records not specific to a particular study which ire generated
       when the study is not in progress still  need to be retained to prove that study's
       compliance with GLPS. Examples include records of a sponsor1! notifying a
       facility of the need to comply with GLPS is required at 40 CFR 160.10, and
       records of facility documents such as standard operating  procedures.
STUDY DIRECTOR

13.    Many field studies involve more than one technical            involving different
      personnel and different methodologiei, often by different contractors.  Concern
      has been raised over the difficulty for a single individual to phytkaHy oversee all
      phases and to be expert in all techniques Involved. Within the same study, is it
      acceptable to assign a different study director to different phtsct?

      No.  Each study must have a single stuf;y direco-  *-l',s represents ihe single source
      of study control. This is explicitly stated in the GLPS at 40 CFR 160,33. A sinuk
      point of control is necessary to the integrity of the udy and to       the poiemuil
      for conflicting instructions and confusion m study ;r-;d?mematien..

-------
                                                             FIFRA GLP Q'I & A's
                                                                      May 12, 1992
                                                                       Page 6 of 14
14.    If there can only be ooc study director assigned to a study, is it acceptable to
       assign "field directors" and "analytical directors" to manage the work which
       involves different phases and/or locations?

       "Die assignment of responsibility for the study to the study director need not
       interfere with ordinary delegation of authority necessary for the performance of
       study duties.  Any authority accepted by persons other than the study  director
       does not reduce the study director's overall responsibility for the study.
QUALITY ASSURANCE UNITS fQALM

15,    Is it acceptable to Inspect study-related procedures it a time other than when the
      study b ongoing?

      The GLPS state as 40 CFR 160.35(a) that a testing facility shall      a Quality
      Assurance Unit (QAU) that shaM monitor each study to assure management that
      the facilities, equipment, personnel, method*, practices, records, and controls are
      in confonnance with the GLPS.  The GLPS further state at  40 CFR 16035(b)(3)
      that the QAU shall inspect each study at intervals adequate to ensure the integrity
      of the study.

      Clearly, the  QAU must conduct inspections adequate to provide the assurances
      required it 40 CFR 160J3(i) and, in the course of so doing, must Inspect each
      study at least once,  All parameters roust be verified adequate for each site, but it
      is acceptable to use inspections conducted during other studies to provide
      necessary assurances. It is also acceptable to use inspections conducted when no
      study ia in progress to assure that methods, personnel, etc. at a particular site are
      in confonnance with GLPS,  However, acceptability of such  inspections is
      contingent on assuring that the facilities, personnel, methods, etc., which  are
      inspected art representative of those used in the study. Note  that it Is necessary
      to reimpect facilities periodically to account for changes in personnel, equipment,
      etc.  Finally, no matter how complete QAU inspectkmal coverage is regarding the
      sites involved In a study, it Is still necessary to conduct at least one inspection of
      study activities while the study is in progress.

-------
                                                            FIFRA GLP Q's & A'$
                                                                     May 12,  1992
                                                                      Page 7 of 14


 16.    .What would constitute adequate inspection of the ongoing study?  Would an audit
       of the protocol or of data records be adequate?

       At least one inspection must be conducted while the study is in progress,  Under
       GLPS, the QAU monitoring of protocols, data records, or other documentation
       phases of a itudy are important just as is directly observing the experimental
       phase of the study. However, the GLPS state it 40 CFR 160J5(b)(3) that
       inspections must be done at intervals adequate to ensure the Integrity of the study,
       and further, at 40 CFR 160.35(b)(4), that periodic status reports noting problems
       and corrective actions be submitted  to management

       An audit of a study protocol would be of very limited utility since the subsequent
       reporting would be to management which, in all likelihood, has already reviewed
       the protocol. Data record audits wduld also be of very limited utility since they
       may occur  after all experimental work is corapleted-in  short, too late for any
       corrective actions to  be taken.  This problem also applies to protocol audits
       conducted  after the experimental phase is completed. Thus, reliance solely on
       such types  of audits would not meet the GLP requirements as stated at 40 CFR
       16035.
FACILITIES

17.   Is it permissible to store mixed feeds containing toe tat substance in the same
      room with the test system during feeding studies?

      As discussed at 40 CFR 160.47(b) test substance mixture storage areas must be
      stored in separate areas from the areas where test systems are kept. However,
      working quantities of test substance mixtures need not be stored in separate
      rooms from test systems. Separate areas within the same room may be designated
      for test substance mixture storage and test systems as long as the separation is
      adequate to preserve the integrity of the study and the identity, strength, purity
      and stability of the mixture.

-------
                                                            FIFRA GLP Q's 
-------
                                                             FIFRA GLP Q'I & A'$
                                                                      May 12,  1992
                                                                       Page 9 of 14


       concerns may be made to the Director, Policy and Grants Division (see question
       #23).

 22.    If a large number of containers ire involved in a study and/or unusual safety
       problems are caused by the storage of such containers, is there any alternative to
       storage?

       Yes, but only if written permission is obtained from tht Director, Policy and
       Grants Division (see question # 23).  The written letter authorizing disposal of
       container! will impose certain requirements that will ensure that the intent of  the
       GLP standards are met

 23.    How doe* one obtain such permission?

       A request for permission must be submitted in writing to the Director, Policy and
       Grants Division, Office of Compliance Monitoring (EN-342), U.S. Environmental
       Protection Agency, 401 M Street, SW, Washington, DC 2046G. The request must
       identify the study for which permission is requested, the testing facility, the nature
       and quantity of containers involved, and the time and location(s) of the study.
       The request should also identify any special storage burdens or safety hazards
       -which retention of the containers may pose.

 24.    What type* of condidom would be imposed by EPA fa granting fudi permission?

       EPA will request that sufficient documentation be available to assure that any
       containers which have  been used for test substance storage during the course of a
       study are thoroughly accounted for from  the time of receipt to disposal.  This
       documentation would generally include such items as bills of lading, inventory
       records, receipts, use togs, and any other supportive records.  In addition, the
       letter will itipulate that the Director of the Laboratory Data Integrity Assurance
       Division of OCM be notified of the location of such records in order that they be
       available for inspection.

25.     Can "generic" permission be obtained  to cover multiple studies and/or test
       substances?

       No.  Each case will be evaluated individually. However,  more than'one study
       and/or test substance may be included in  given request, as long as each study and
       test substance is specifically identified.

-------
                                                             FIFRA GLP Q's &. A's
                                                                      May 12, 1992
                                                                      Page 10 of 14
26.    Can t "generic protocol" be used for obtaining iponsor approval?

       The GLPS require that the protocol be approved by the sponsor, and the date of
       approval must be  Included with the protocol; however the GLPS also provide
       flexibility in how this approval is obtained. A "generic protocol" approach may be
       acceptable for obtaining sponsor approval of certain protocol elements. In such s
       case, the testing facility which is drafting the protocol for a study would only need
       to obtain approval of those elements which wore not included in the generic
       protocol. Please note that since the GLPS require  protocols to include certain
       information that would  not be included in a generic protocol, such as the test
       substance or the proposed start and termination dates, it would still be necessary
       to obtain sponsor  approval for such Information in  addition to the approval of the
       generic protocol.

27.    What records of seeds or transplants of cropi or plants nsed in field studies must
       be
      Where crops or plants are the test system or a component of the test system, all
      GLP standards relating to test system records are applicable. These include
      protocol provisions given at 40 CFR  160,120(a)(6) and (7), as applicable.
      Included, for example, would be the source of the test system supply, species,
      method of identification, etc.  Lot numbers of seeds, brand names, and other
      information uniquely identifying the test system would be relevant
REPORTINg

28.    The GLPS at 40 CFR 160.1SS(aX12) require that signed and dated reports of
      each acieptiu or other professional in the study be included in the final report.
      Can these reports be combined into one report, with all of the scientists and
      profeaJonaJs dating and signing that report?

      This requirement is intended to ensure that all Information related to the study is
      included in the final  report.  Specifically", when individual scientists findings are
      pan of the study effort, they are required to be included separately: Combined
      reports may in effect be consensus documents, and that would defeat the purpose
      of this requirement,  Note that this requirement is not intended  to require, 
      separate reports of all scientists participating in a  study if such scientists are not.

-------
                                                              FfFRA GLP Q's & A's
                                                                       May 12, 1992
                                                                       Page 11 of 14
       hi fact, providing individual findings or opinions,  For example, pathologist'*
       reports are considered to be separate findings which must be reported separately.
 29,    The GUPS Mate that the study director must assure that raw data are transferred
       to archive* duffing or tt the close of the study,  Is there i "grace* period allowed
            the end of the study to allow this to be done?

       Under GLPS, the study director is required to assure that ill raw daw,
       documentation, the protocol, specimen*, and final reports  are transferred to the
       arcfarvej during or at the dose of the study (40 CFR 16U33(f)),  Thus, there is no
       grace period. The study director must comply with this requirement prior to
       siping the compliance statement. This ensured that data are fully accounted  for
       at the completion of the study.
30.    How doe* EPA define "ck*e of study" la regard to trehjvingl

       The term "at the close of the study" is strictly interpreted to mean  that point of
       time at which the study director signs the final study report The act of signing
       the final report is one of assurance by the study director that the report is a true
       representation of the data that support  the report  At or prior to  the time that
       the study report is signed, the study director must pass control of the raw data to
       the archive*  where their integrity will be maintained. Any delay in the transfer of
       data beyond the dote of the study creates a lapse between the iime that the study
       director assures that the raw data support the study report and the time that  the
       data ajre secured from damage, misuse,  or loss.

31.    Given that data must be transferred to archives at tbe ck*e of the study, is it
       possible to use temporary archive* prior to transfer to a central archive?

       There ii flexibility In the location of the archives of raw data and specimens,  At
       40 CFR 160490(b), the GLPS state that retention of records at alternate locations
       is acceptable, provided that there is specific reference to those locations in the
       archives. Such off-location archives must still meet the full requirements of 40
       CFR  160.190.  Whether records are archived at the registrant's facility, at a
       contractor's central location, or at separate contractors' locations, the study
       director must assure that all raw data and specimens have been archived before
       the study report is signed.  If the study director cannot assure that records ft  a
       particular location are archived correctly, he should not sign a  compliance  '
       statement that indicates that this standard has been met,  Note that, for the

-------
                                                              FIFRA GLP Q's &. A's
                                                                       May 12, 1992
                                                                       Page 12 of 14


       purpose of complying with GLPS, true copies may be archived at the close of the
       study.  The original records will have to be maintained aa well but need not  be
       archived at the end of the study if this is impractical, for example where the
       original data constitutes a facility record shared by other studies still  in progress at
       the close of the study,

 32.    Is h necessary to retain  frozen tissue samples in archive*, or may these be
       discarded after quality assurance verification?

       Under FIFRA GLPS, 40 CFR 160.195, frozen tissue samples are required to be
       retained in archives, and there are no specific allowances for their being discarded
       as there are for "specimens obtained from mutagenicity tests, specimens of soil,
       water, and plants, and wet specimens of blood, urine, feces, and biological fluids."
       The GLPS do not require specially prepared material to be retained  beyond the
       period that it affords evaluation if such material is relatively fragile and differs
       markedly in stability or quality during storage.  EPA does not believe that this is
       the case for many types  of frozen tissues.  The reason that  tissues are frozen is to
       retain their utility for evaluation. Please note that, as provided at 40 CFR
       160.195(h), non-documentary material such as samples and specimens may be
       discarded after EPA has notified the sponsor or testing facility in writing that
       retention is no longer required.

 33.    Must field notebooks be archived during or at the dote of a study?

       If a notebook contains raw data,  the notebook or the raw data must  be archived
       at  the close of the study. Note that  the registrant is responsible for the origina)
       records under 40 CFR 169.2
-------
                                                             FIFRA GLF Q's & A's
                                                                      May 12,  1992
                                                                     Page 13 of 14
        requirements in addition to and independent of GLP requirements.  Failure to
        retain such samples may result in rejection cf data by EPA or enforcement actions
        independently of whether a GLP violation has occurred.
 GLP VIOLATIONS

 36.   Can EPA assets penalties for GLP violations?

       Yes.  FIFRA section 14 states the EPA's authority to assess penalties far
       violations of the Act.

 37.   What arc the possible violations under the statute?

       Violations of OLPS may constitute unlawful acts under FIFRA. Under section
       12(a)(2)(M) h if unlawful to knowingly falsify all or pan of airy application for
       registration, application for experimental use permit, any information submitted to
       the Administrator pursuant to section 7, any record! required to be maintained
       pursuant to this Act, any report filed under this Act, or any information marked as
       confidential and submitted to the Administrator under any provision of this Act to
       be lubmitted to EPA or of records required to be maintained Under  section
       12(a)(2)(Q) of FIFRA it is unlawful to falsify ill or pan of any information
       relating to the  testing of any pesticide (or my ingredient, metabolite, or
       degradation product thereof), including the nature of any protocol, procedure,
       substance, organism, or equipment used, observation made, or conclusion or
       opinion formed, submitted to the Administrator, or that the person knowi will be
       furaihftd to the Administrator, or will become  part of any records required to
       be maintained  by this Act  Under section 12(a)(2)(R) of FIFRA it is unlawful to
       submit to the Administrator  data known to be raise in support of a registration.
       Finally, It is unlawful under FIFRA section 12(a)(2)(B)(i) of FIFRA to refuse to
       prepare, maintain or submit  any records required by or under sections  5, 7, 8, 11,
38.    Whit are the maximum penalties that can be Imposed?

      Section 14(a) of FIFRA provides for maximum civil penalties of not more than
      $5000 per offense for violations of the Act by registrants, commercial applicators,
      wholesalers, dealers, retailers, or other distributors, and of not more than $1000
      per offense for other persons,  For knowing violations of the Act, FIFRA section
      14(b) provides for maximum criminal  penalties of not more  than $50,000 and/or  1

-------
                                                              FIFRA GLP Q's &. A's
                                                                       May 12,  1992
                                                                       Page 14 of 14
       year imprisonment for producers, registrants, or applicants  fcr registration and of
       net more than $20,000 and/or 1 year imprisonment for other knowing violators.
 39,    Wfll dvfl or criminal penalties be imposed for all GLP violations?

       No, Section 9(c)(3) of FIFRA allows a written notice of warning to be issued for
       a minor violation, if such warning is determined  to be adequate to serve the public
       interest.  Section 14(a)(4) of the Act further provides that  in determining the size
       of a penalty EPA may issue a warning in the case that a violation occurred despite
       exercise of due caution or did not cause significant harm to health or the
       environment.  Finally, section, 14(a)(2) of FTFRA provides that persons other than
       registrants, commercial applicators, wholesalers,  dealers, retailers or other
       distributors  who violate any provision of the Act may be assessed a civil penalty
       only subsequent to receiving a written warning for a prior violation. Thus, persons
       who only perform testing and are not engaged in the distribution and sale of
       pesticides will not be assessed crvil penalties for  their first offense. This does not
       extend to criminal penalties as described at section 14(b)(2) of FIFRA

40,     Can EPA reject studies not conducted in accordance with GLPS?

       Yes. The regulations specifically provide for this at 40 CFR 160,17(a), which
       states that "EPA may refuse to consider reliable  ... any data from  a study which
       [is] not conducted in accordance with (GLPS],"   GLP violations associated with a
       study submitted to EPA may also result in enforcement actions whether or not a
       study is rejected.

-------