vvEPA
          United States
          Environmental Protection
          Agency
            Prevention, Pesticides,
            And Toxic Substances
            (H7508W)
EPA738-B-93-001
February 1993
Pesticide Reregistratipn
Rejection Rate Analysis
Residue Chemistry/
Environmental Fate
Follow Up Guidance For
Conducting Rotational
Crop Studies
                                  Recycled/Recyclable
                                  Printed on paper that contains
                                  at least 50% recycled fiber

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              UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460
                            FEB 2 3 1993
                                                 OFFICE OF
                                            PREVENTION, PESTICIDES AND
                                               TOXIC SUBSTANCES
MEMORANDUM
SUBJECT:

FROM:
Guidance on How to Conduct Studies on Rotational Crops.
Ed Zager, Chief
Chemistry Branch II:  Reregistration
Health Effects Division (H7509C)

           and

Debra Edwards, Ph.D.,  Chief
Chemistry Branch I:  Tolerance Support
Health Effects Division (H7509C)
TO:
Peter Caulkins,  Acting Director
Special Review and Reregistration Division (H7508W)

                 and

Lawrence Culleen,  Acting Director
Registration  Division (H7505C)
THRU:     Penelope A.  F
          Health Effect
                jae^Crisp, Ph.D.
                Division (H7509C)
                                              Director
Earlier  this   year  the  Chemistry  Branches  of  HED  took   over
responsibility for the review of data generated on rotational crops
(Guideline No. 's 165-1 and 165-2) .  The attached paper was prepared
by a  team  consisting  of  Dr.  R. Perfetti, Dr.  R.  Lor anger, Dr.  W.
Hazel,  F.  Suhre,  M.  Rodriguez and R.  Quick in order  to provide
guidance to  Registrants  and  Chemistry Branch  personnel on how  to
conduct and review these  studies. This document will  be  utilized  by
the  Chemistry   Branches   in  future  reviews  of  rotational   crop
studies .

We recommend that this paper  be provided to all interested parties.

cc  (With Attachment): L. Rossi, S. Irene,  RBP, RF, Petition
Review Aids  File and Rotational Crops  File
                                                       Recycled/Recyclable
                                                       Printed with Soy/Canola Ink on paper that
                                                       contains t least 50% recycled fiber

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GUIDANCE ON HOW TO CONDUCT STUDIES ON ROTATIONAL CROPS

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INTRODUCTION

The Chemistry Branches of Health Effects Division (HED) have taken
over  the  responsibility for  review of  studies which  determine
whether pesticide residues of concern result in rotational crops as
a  result  of  uptake  from  soil  of  previously  treated  fields
(Guideline  Nos.  165-1  and  165-2).  This  transfer was  performed
because the  concern  over residues in these situations is chiefly
dietary. The following  paper  is  intended to provide additional
guidance to  HED  personnel and  other interested  parties  as to the
requirements and procedure for review of submitted studies.

HISTORICAL

Studies on "Confined Rotational Crops" (Guideline Number  165-1) and
"Field Rotational Crops" (165-2) are conditionally required under
40 CFR  158  for uses of  pesticides  on terrestrial  food  crops and
aquatic food crops. As stated in Subdivision N,  a rotational crop
use is any field-vegetable crop use, aquatic crop use  or any other
site  use on which it is reasonably foreseeable that  any food or
feed  crop  may be produced after application  of a pesticide. The
purpose of these studies is to determine the nature and amount of
pesticide residue uptake into rotational crops.  The confined study
uses  radioactive   material   applied to   a  small  plot  (often
laboratory/greenhouse).  Results of these "hot" studies are used to
determine whether field  studies (using non-radioactive  pesticide)
are  needed to measure  residues  in rotational  crops  grown under
actual  field conditions.  Based  on these  data appropriate crop
rotation  restrictions   (time  from  application  to   planting  of
rotational crop) may be established and  the need for tolerances on
the rotated  crops determined.

Review  of  these studies has been conducted by the Environmental
Fate  and Ground Water Branch (EFGWB) in  the Environmental Fate and
Effects Division (or its predecessors in earlier organizations of
OPP) .   Presumably this assignment was based on the importance of
soil  residues as a  factor  in determining  levels  of  residues in
rotational  crops.

Traditionally the  confined  study  has  served  as a  worst-case
indicator of whether residues could  occur in rotational crops. The
study is  often conducted indoors using potted  plants,  conditions
which would  tend to reduce the dissipation of the  pesticide in the
soil. Until  recently, if detectable residues of  concern  were  found
in the crop during the confined study after the proposed  rotational
crop interval,  the field trials would normally  be  required to
assess  whether  residues occur in  rotational  crops  under actual
growing conditions.   In  some cases registrants have volunteered to
perform field studies  to  refute results  of the confined study,
especially  if  the  registrant did not want  a  rotational crop

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 interval  on the label.   If detectable residues were found in the
 field  studies  for crops having a 12 month plantback interval (or
 after  a shorter interval the registrant desired on the  label), the
 registrant  would be directed to seek a tolerance under  the FFD&CA.
 In this case, a tolerance petition was submitted and responsibility
 for review  shifted to the  Chemistry Branch in HED.

 Recently, EFGWB has been using the results of the confined studies
 alone  to  determine whether tolerances  are required for rotational
 crops.    Under  this  revised  process,   EFGWB  has  deferred  to
 Toxicology  Branch when radioactive residues of  the parent compound
 or closely  related metabolites were found in the  crops during the
 hot study.   In other words, the  field  trials have been eliminated
 as  an early step in  determining the need  for  rotational crop
 tolerances.  Under  that procedure,  if  Toxicology  Branch   (TOX)
 concluded that the residues identified in the confined study were
 not toxicologically  significant or,  if they were  toxicologically
 significant,  but  the  levels  present  were  not  toxicologically
 significant,  then no  tolerance was  required.    However,  if TOX
 concluded  the  opposite,  the  registrant was  referred  to  the
 Chemistry Branches in HED.

 Scientific  Considerations

 Confined  Rotational Crop Studies; 165-1

 The protocol for performing the three  required confined rotational
 crop  studies  (small  grain,   leafy  vegetable  and root  crop)  is
 provided  in  Pesticide Assessment  Guidelines   Subdivision  N.
 Acceptance  Criteria  were  discussed  in  the   Agency's  Phase  3
 Technical Guidance Document. Confined  rotational  crop  studies are
 essentially metabolism  studies;  therefore, it is  recommended that
 the publication entitled "Additional Guidance for Conducting Plant
 and Livestock  Metabolism  Studies"  (7/16/92) be consulted before
 conducting  a confined  rotational crop study. (It should be noted
 that,  in the  case  of confined  rotational  crop  studies,  the
 application rate is IX,  not an exaggerated rate.) . This paper will
 refer frequently to that document when discussing various phases of
 the subject experiments. A flow diagram describing  the approach
 discussed in this paper is  provided in Figure 1  at the  end of this
 document.

The following should be considered when a confined rotational crop
 study  is  to be conducted. The  test material should be  the pure
 active ingredient  radiolabeled  (PAIRA)  with  C  in  a  non-labile
position  (e.g.,  in a ring).  The parent compound only should be
applied to the appropriate  soil type (usually a  sandy loam) at the
maximum  label  rate  (IX)  and  the  required  three rotated  crops
 (small grain, leafy vegetable and root crop)  should be planted at
appropriate  soil  aging intervals  (e.g,  1,  4,  7 or  9, and  12
months) .   Sampling  of the  soil  is  not required and  need  only be
performed at the  Registrant's   discretion.  The  crops  should  be

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harvested and the appropriate plant parts (see Pesticide Assessment
Guidelines Subdivision O, Table II) should be sampled and combusted
to determine the total radioactive residue (TRR). At this point, if
each of the three crops demonstrate a TRR of  <0.01  ppm in edible
portions at one of the plantback or soil aging intervals then  the
Chemistry  Branches  will  conclude that  no further  work and  no
tolerances are needed. An appropriate rotational crop restriction
can be set at the shortest interval where no TRR is    >0.01 ppm,
provided that the Registrant is willing to place this interval on
the label. If the TRR  is <0.01 ppm in all three crops at the one
month interval,  then no plantback restriction will  be needed on the
label. If,  however, in the  three confined studies,  the minimum
intervals at which the TRR is <0.01 ppm differ, then the rotational
crop restrictions will be set at the interval appropriate to each
tested crop group with the  longest interval being applied to all
other  (untested)  rotated  crops.  The following  example should be
considered:

     The  TRR for leafy vegetables is  <0.01  ppm  at the  1  month
     plantback  interval, the root  crop  TRR is <0.01  ppm at the 4
     month interval and the grain  crop  TRR is <0.01  ppm at the 9
     month interval. The rotational crop  restrictions would be 1
     month for  leafy  vegetables,   4 months for root  crops  and 9
     months for small grains and all other rotated crops.

It is the Registrant's prerogative to perform additional confined
rotational  crop  studies  on  other  crops   to  establish  less
restrictive intervals based on levels of radioactivity.

In rare cases,  TOX  may have  concerns regarding the presence of a
pesticide or metabolite at levels <0.01 ppm. Determination of the
presence  (or absence)  of specific  metabolites  of concern at levels
<0.01 ppm may be required in these cases.

If any of the  plants  in the confined studies exceed the trigger
value (0.01 ppm) at the 12 month interval, then the nature of the
residue  in  those  test crops  having  a  TRR  >0.01  ppm  must  be
determined.  The Registrant is referred to the  7/16/92 guidance
document  discussed  above  (see also  the  comment regarding the
application  rate for  confined rotational crop  studies)  for a
description  of  the procedures  which  need  to  be   followed  to
accomplish this determination.  If  any one  of the three  crops shows
<0.01 ppm at a given interval but  the Registrant desires a shorter
interval  on  the label for that crop where the  TRR  is >0.01 ppm,
then  the  composition  of  the TRR in that rotated crop  (at the
desired interval) should be determined as  described above for the
crop parts where the trigger value (i.e.,  0.01 ppm) was exceeded.
If  several  samples of the  crop  are  available  at  the desired
interval, the sample having the highest  TRR should be utilized. In
either of the above  cases, this information is  needed  in order that

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the Agency can make  a  conclusion  as to whether the residue is an
inadvertent residue of no concern  or whether cold field trials are
needed to make that determination.

If the metabolism in rotated crops  appears to be  different than
that  in  the  primary crop, that is,  if different  metabolites are
observed in rotated  crops than  in primary crops,  the Agency will
make  a determination as  to whether the different  rotational crop
metabolites are of concern at the levels observed. If necessary,
the HED  Metabolism Committee will be  consulted to expedite this
decision.

The following are examples of the situations described above;

The primary  (target)  crop  metabolism studies  indicate  that the
parent and metabolites A, B, C,  D and E are present in the plant.
The Agency decides that only the parent and metabolite B need to be
regulated  in  the  tolerance  expression.  The  following  three
scenarios might be encountered regarding rotational crops:

1) The confined rotational crop studies indicate  that the TRR is
>0.01 ppm  and that  parent  and  metabolites  A, B,  C and  D are
present. Limited  rotational crop  field trials will  normally be
required with analysis  for  parent and  metabolite  B  if  it is
determined that  these residues  could  be present  at detectable
levels.   If, however, metabolites  A, C and D  are present at much
higher levels in the rotational crops than in the primary crop, the
HED Metabolism Committee may be consulted as to whether the other
metabolites need to be quantitated.

2) The confined rotational crop  studies show that the  TRR is >0.01
ppm and  that the radioactive residue consists of  no parent and
metabolites  D and  E.  In this case the  Agency   would  normally
conclude  that this  is   an  inadvertent  residue   of  no  concern
situation and no field trials would be required. A rotational crop
restriction may be necessary. As  above however, if metabolites D
and E are  present at much higher  levels  in the rotational crops
than  in  the primary  crop, the HED Metabolism Committee  may be
consulted as to whether these metabolites need to be quantitated.

3) The confined rotational crop studies indicate  that the TRR is
>0.01 ppm and that there is no  parent present but  that the major
portion  of  the TRR  consists of  a  new  metabolite F. This will
require a decision, as to whether  there is toxicological concern
over the new metabolite. At this point the HED Metabolism Committee
may be consulted for an expedited decision. If  it is concluded that
the metabolite is of concern  at the levels likely to be present,
then F should be  analyzed for in the limited rotational crop field
trials.   If it  is  decided that F  is of no concern  then,  as in 2
above, this is an inadvertent residue of no concern situation and
no  field  trials    are  necessary.  However,   a rotational  crop
restriction may be necessary.

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It is recommended  that the confined studies be  submitted  to the
Agency as soon after completion as possible,  so that the Agency can
make a conclusion  as to whether  there  is a  potential inadvertent
residue of concern  (i.e., will limited field  trials be needed ?) as
expediently as possible. This will allow the Registrant to design
the field trials in a more efficient manner  (i.e., what compounds
require analysis in the field trials).

Field Rotational Crop Studies (Limited and/or Extensive!;  165-2

If the  level  of the  total radioactive  residue  in  the confined
rotational  crops  exceeds  0.01  ppm  at  the  desired  rotational
interval or at 12 months, and once the nature of  the residue in the
rotational crops is understood, then the Registrant should consider
the Agency's position regarding the residue  to be  regulated in the
primary  crop  (see  discussion above) to  decide  whether  the first
tier  of  field trials should  be  initiated.   That  is,  if  the
composition  of the  TRR in  the  rotational crops  is   such  that
residues which are regulated  in  the primary crop are observed at
levels 0.01 ppm in the rotational crop (following the criteria set
forth in the 7/16/92  document with  the  exception of exaggerated
application  rates),  then field  trials should be performed.  For
further guidance on the protocols for carrying out these  trials see
Pesticide Assessment Guidelines Subdivisions N and O as well as the
following comments.

The limited  field  trials should  be conducted on a representative
crop  (as defined in 40  CFR 180.34  (f))  at two  sites  per crop for
the following 3 crop  groups:  root and  tuber vegetables  ,  leafy
vegetables and cereal grains for  a total  of  6 trials. The 6 trials
should be conducted on  a specific  crop in each of the three crop
groups which the Registrant intends to have as a  rotational crop on
the label. The soil should be treated at the  maximum label rate and
the maximum number  of applications and the appropriate crops should
be planted after the minimum aging interval.  The crops should be
'harvested and  all  of the plant parts prescribed in Subdivision O,
Table II should be  analyzed for the residues  of concern observed in
primary crops as well as any other  residues  of concern specific to
rotational  crops  which  fulfill  the criteria  set  forth  in the
Confined Rotational Crop section of this paper. Detection limits
for rotational crops should  be  comparable  to  those for primary
crops.

If  no   detectable residue  are   observed  in  raw  agricultural
commodities in the  limited  field trials, then no tolerances will be
needed.  However plantback  restrictions  will normally  be needed
unless confined or field studies  show no detectable residues of
concern  at a  30 day plantback interval.

If  the  limited field studies  above  indicate  that   detectable
residues  will  occur,  then  rotational  crop  tolerances  will be
required. The requirement for number of trials would be the same as

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that to establish primary tolerances on all crops  (or crop groups)
which the  Registrant intends to have  as rotational  crops on the
label. If the Registrant desires to allow the "universe" of crops
to be rotated, then  magnitude  of  the residue data is required on
representative crops  (see  40 CFR  180.34 (f))  for all crop groups
which could be planted  in  a typical crop rotation sequence. With
respect to treatment, these trials should be conducted in the same
manner as discussed above for the limited trials.  If the Registrant
believes that a lesser number of crops would be rotated because of
the nature  of the pesticide or due to the way  it  is  used, then
guidance should be obtained from the Agency regarding specific data
requirements in that case.  If tolerances exist on the crops to be
rotated as a result of a primary use, then rotational data on these
crops would be required only  if  residues  in rotated  crops are
significant in comparison to those in the primary crop.

Regulatory Considerations

It  is the  Agency's  position   that data waivers or  agreements
concerning  rotational  crop requirements granted previously  by
EFGWB/EFED should continue to be effective under this new guidance
and  therefore  HED  will  not   reactivate  rotational  crop  data
requirements in these cases.

In  the  future,   under  revised  Guidelines,  the  limited  field
rotational  crop requirement may be altered so  that  an increased
number of limited field trials will be required. This requirement
will not be applied retroactively.

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