BAZARS EVALUATION OXVZSZON
STANDARD BVALOATZOM PROCEDURE
QUALITATIVE HATORE OP TKE REStDOEs
FLAHT METAEOLISH
Praparad by
Martin r. Kovaca Jr., Ph.D.
standard Evaluation Proeaduraa Project Manager
Orvill* *. payntac, Ph.D.
Onitad Stataa cnvironmantal Protection Aganct
Offiea of Paaticida Pro^r
Waahington* D.C. 20460
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ITJIT
DVlSXOMi STANDARD EVALUATXOH nOCEDURI
Nature. 4* .the. RaciAie* Plant Metabollan
Martin F. Kovaca Jr.. Ph.D.
1
. 0.8. .BnvironMatal Prectetlon Agency/OPP/HED/TS-769C
401 N Street SH
Washington. D.C. 20460
540/D»-ee-102
-...n •etaboli8» «tudi«8 are designed to characterise the
qualitative i.ature of the total terminal residue in plants.
Specifically, these studies should provide an estimate of total
residues in the treated crop, identify the major components of
SUL!^;1 t?raln*} rwidue thus indicating the components to be
i^?^-f?f in "8ld"e quantification studies, indicate the
distribution of residues in the treated crop, and show the
efficiency of extraction procedures for various components of the
residue. This SEP describes in a detailed, sequential stepwise
manner hew EPA reviewers evaluate plant metabolism studies, and
what type of information is taken into consideration in the
review process. -
Unclassified and freely available.
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STANDARD !VALDATZON PROC!DURE
This Standard Evaluation Procedure (SIP) is on. of a set
of guidance documents which explain the procedures Used to
evaluate environmental and human health effects data submitted
to the Office of Pesticide Programs. The SEPs are designed
to ensir. comprehensive and consistent treatment of major
scientific topics in these revievi and o provide interpretive
policy guidance where appropriate. The Standard Evaluation
Procedures will be used in conjunction with the appropriat.
Pesticide Assessment Guidelines and other Agency Guidelines.
While the documents wers developed to explain specifically
the principles Of scLantifLCivaiuatjonwjthin the Of f Lc of
Pesticide Program$,. they may also be used by other offices in
the Agency in the evaluation of studies and scientific data.
The Sta’idard Evaluation Procedures viii also serve as .sliaabli
internal .fsrence documents inc v i i i inform the public and
r.gulit.d community of important considerations in the
evaluation of test data for determining chemical hazards.
believe the SIPs will improve both the quality of scliice. -
within EPA and in conjunction with the Pesticide Assessment
Guidelines, will lead to more effective us. of both public
and private resources.
Anne 1.. Barton Acting Director
lizard Evaluation Division
•1
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RESIDUE CHEMISTRY BR*$CH
STA1IMRD EVALUATION PROCEDURE
qualitative isature of the Residue: Plant Metabolism
I. I NTRODU cTION
A. Purvose of the Standard Evaluation Pzocedure
This Standard Evaluation Procedure (SEP) is designed to
aid Residue Chemistry Branch (RCB) data reviewers in their
evaluations of plant metabolism studies which qualitatively
determine pesticide residues and their transformation in plants.
This particular SEP document addresses plant metabolism
studies only the topic of animal emtabolism studies will be
addressed in a separate SEP document.
B. Backaround Information
Plant metabolism studies provide residue chemistry
data on the qualitative nature of the reaidu• in plants and are
required by 40 CPR 158.125 to support the registration of my
pesticide intended for use on a food or feed crop under the
amended Federal Insecticide, Fungicide, and Rodenticide Act.
The Pesticide Assessment Guidelines, Subdivision 0,
Chimistr which are nonregulatory companions to 40 CPR
Part 158 descri e in Section 171—4(a)(l) and (2) protocols
which say be used to perform plant metabolism studies. Section
171-4(a)(2) of these Guidelines states in part that: A metabolism
study must be submitted for each type of plant for which use is
proposed and generally one metabolism study will be required for
each a the crop groups defined in 4Q C?R 180.34(f), except for
herbs and spices. If the results of three metabolism studies en
dissimilar crops indicate a sia lar metabolic route in the three
crops, then additional metabolism studies will not be r.quired.
C. Objective of Plant Metabolism Studies
Plant metabolism studies are designed to charact.ris.
the qualitative nature Cf the total terminal residue in plants and
answer the question. vhat is the chemical residue? S cit ically
these studies should U) provide an estimate of o residues
in the treated crops, (2) identify the major components of the
total terminal residue, thus indicating the components to be
looked for in residue quantification studies (3) indibat. the
distribution of residues, e.g., whether translocation ocours, or
whether the residues ar. entirely aurf ce residues and (4) show the
efficiency of extiaction procedures for various components of the
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residue. Requirements of these studies should be extended to
also include characterization of residues in all plant parts
used for food or teed. Par example, if residues of concern
(i.e., of toxicological significance) are found in animal feed
it..s or in plant parts which can be converted to processed
commodities, then animal metabolism and processed commodity
studies respectively will be required.
In the final analysis, plant metabolis, studies should
answer the following question; What is the qualitative nature
of tl e total terminal residue that will result in or on the raw
food or feed cv ’undity as a result of application of the pesticide
formulated product according to the proposed label directions
for use? Plant metabolism studies by characterising the qualitative
nature of the total terminal residue thereby facilitates a chomical
definition of the ‘total toxic tesidue’.
The term ‘total toxic residue’ is defined as th. sue
of the parent pesticide and its degradation products, tabolites
(free or bound), and impurities, that are considered to he of
toxicological significance, and therefore warrant regulation.
II. NF9RMA?XON 9,B! PPL D
The petitioner/registrantes report on plant metabolism
studies should include all information necessary to provide a
complete and acourate description of treatments and procedures:
radiolabeling techniques to include rate, method, and time of
radiolabel application in relation to the development and growth
cycle of the treated raw agricultural commodity (Rlc) extraction,
fractionation, and characterization techniques omployed for the
identification of residue components whether free or bound at.
each spling intervals definition of total terminal residues, to
include data for all •a or components of the total terminal
residue reflecting their distribution within the RAC (including
animal feed ite or plant parts which can be converted to
processed commodities) expressed as both percentage Cf the total
recovered plant radioactivity and quantity (ppm) found, at time
of harvest or when utilized for animal feeds reporting of data to
include a delineation, preferably in a flowshi.t, of possible
routes of degradation or metabolism in plants,(and when enforconent
analytical methodology has been developed, validation of these
method. with radiolabeled sples derived from the plant metabolism
study, accompanied by a statement aide as to their capability to
determine all components of the total toxic residue, whether free
or bound/cOfljugst.d in the SAC) and quality control asures/
precautions taken to ensure validity of all aspects Cf -the plant
metabolism study.
($ot.: If the specified bracketed ststent Jnforeation
is provided elsewhere within the overall data submission package
it need not be reiterated in the plant metabolism study but
referenced a. to location in the data submission package.]
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III . THE DATA EVALUATION PROCESS
A. Determine the Need for the StudY
The reviewer should initially determine whether the
study is required under 40 CPR Part 158. Normally, a plant
metabolism study is required to support the registration of any
pesticide intended for use on a food or feed crap and accordingly
must be submitted for each type of plant for which use is proposed.
Exception. to the latter requirement are clearly delineated in
Section 171-4(a) (2) if the Pesticide Assessment Guidelines, Sub-
division 0, Residu .
8. Read the ReDort and Identify Data Gaps
Using the Data Reporting Guidelines on atu e of the
esidue: P ants, the reviewer should look for data gaps—cm asions
n t e ormation supplied by the petitioner/registrant in his
report. These should be duly noted in the reviewer’s report, and
a judgment made as to which are considered significant enough to
adversely affect the review process. Those so identified should
be cammunicated back to the petitioner/registrant by the Product
Nanager for corrective action.
C. Assess the kDBropriateneas and Adeauacv of the Data
The data reviewer then considers the appropriateness
(i.e., the relevancy of both the test crap selected and the
Submitted radiolabel protocol to the intended use pattern of the
pesticide) of the study including the adequacy of all supporting
data/informsticn that have been supplied. Appendix 1 of this
document discusses specific aspects of testing parameters that
warrant consideration.
As an adjunct to these, the reviewer •houl5 draw upon
the technical guidance in the reviewer aids materials that are
available to him, such as the Residue Chemistry Guidelines (a.k.a.
Subdivision 0 of the Pesticide Assessment Guidelines). A listing
of some suggested source materials is located in Appendix 2 to
this document.
Any perceived deficiencies in the data/information
supplied should be identified and explained, with a statement as
to what IteDs should be taken to resolve the deficiencies, so
that this information can be relayed back to the petitioner/
registrant by the Product Nan ger f,r appropriate action.
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B. Deçermine the Need for Deference/Reference to Other
BED Branches
In considering the apprapriateness and adequacy of the
data/information that hay, been supplied in support of a plant
metabolism study, the data reviewer must also determine if
deference/reference(s) to other BED Branch(es) is/are germane to
reaching that decision.
In the case of plant metabolism studies, specific
deference/reference(s) may be made to Toxicology Branch (TB)
to elicit their apimion regarding the toxicological significance
of all characterised/ident ified components, whether free or
bound, of the total terminal residue in the subject crcp (including
processed fractions derived therefrom) at time of harvest or when
utUised for animal feed.
Situations in which deferences to TB are apprcpriate
have been described in the SEP on t be am. (
paragraph under of that ocument
In the interim period until the response(s) to such
teferencs/reference(s) is/are received, final judgment by the
data reviewer on the issues(s) in questions should be withheld.
I. Bake a Reaulatorv Recomaen ....... . .
If thi submitted plant metabolism study adequately
defines the qualitative nature of the total terminal residue in the
subject crop, then the data reviewer should decide which components
of this residue are in need of regulation, i.e., those considered
as comprising the total toxic residue in plants, in need of
enforcewent methodology and furthermore to be included in the
tolerance expresaior. ?or a detailed discussion of helpful
criteria for determining whether a metabolite should be included
in the tolerance expression see Item 10 , x ression o a lerance
under ata P uirement in tbiSBP on A -. e , nc u rig
the flowsheet agram ncluded as Append x I to t at ocument.
These recommendations on the part of the data reviewer may require
the assistance of TB through their responses to RCB’a def.r.nce/
reference(s) described mD, above.
IV. REVIEWER AIDS
There are a large number and variety of source materials
that are available to assist tho data reviewer in the tvaluation
process. a listing f some of the sore useful references that
reside within the Branch are provided in Appendix 2 to this
document.
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APPENDIX 1
Major points to consider in evaluating plant metabolism data
includ, the following;
A. Overall Protocoiconsideration. :
1. Conduct of the Test
Has the petitioner/registrant adequately described
the overall testing environment including environr.ental controls
imposed, if any, during the conduct of the plant metabolism study
(i.e. ,envircnmentally uncontrolled outdoor test plot, semi—controlled
greenhouse environment, or completely controlled and menitored
growth chamber)?
The reviewer should be aware that if any of the
reported environmental conditions, including testing media
selected, are atypical or at great variance with the .zpected
cultural practices or environments under which the selected test
crap is grown, then the resultant metabolism data obtained may be
suspect and therefore not reflective of the proposed use.
2. The Test Crop
las the test crap been adequately described in the
submitted metabolism study? If so, is it the same crop for which
use is proposed? If not, consult Section 171.4(a) (2) of the
Pesticide Assessment Guidelines, Subdivision 0, Residue Chemistr
and 40 C?RI 1 10.34(f) regarding criteria for traniflTI ra Lo abeled
metabolism ata bet en crop species.
Were all specific crop parts harvested and subjected
to 14 C residue analysis for a determination of the total terminal
:esidue clearly identified? Do they conform to Ref. Table II of
Subdivision 0, Guidelines?
Was the treated test crap grown to harvest (maturity)
and/or to a developmental (immature) stage when normally utilized
for animal feed, and are all the important dates relative to the
growing and harvesting of the test crop reported?
Is there any other unpublished or published information
known to us regarding the aetetolism of this pesticide on the
subject or botanically—related crap that mast be taken into
consideration?
3. The Radiolabled Pesticide
Was the original source of radiolabel report d
including the purity and specific activity of the prepared
radiolabled pesticide product in Curies/mole or disintegrations
per minute per gram (dpm/g)?
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f radiolabela other than 1¼ ware employed (i.e.,
3 , Up, and was rationale given for their.use?
Was radiolabeling in a potentially labile sid.
chain or other potentially unstable position in the molecule
avoided?
Was pesticide chemical labeled in a strategically
important place in the molecule (L..., preferably in ring nuclei
if present) or if not present, at secondary or tertiary branching
locations in the molecule?
Was multiple radiolab.ling attempted for complex
pesticide molecules cortaining multiple ring structures that may
be cleaved or readily Beparated as a result of metabolism?
4. Application of the Pesticide
Overall, did the plant metabolism protocol reflect
or mimic, to the extent possible, the intended use pattern
(proposed labeling) of the pesticide on the test crop (i.e.,
preplant soil incorporated, over—the—tap postemergent foliar
application, bait application, lay—by application, etc.)?
In what formulation (i.e., solvent, carrier, bait,
adjuvant or other matrix) was the radiolabeled pesticide applied,
and by what means (i.e., hand sprayer, topical application, soil
injection, etc.)?
- Did the total rate of application to the test crop
reflect g east the maximum allowable rate depending on the
chemical an t e test conditions employed? Exaggerated doses may
be needed to ensure sufficient radioactivity for the purposes of
residue identificationjcharactetization. -
Were the timing and frequency of radiolabel applications
reported and ware treated plants harvested at maturity or when
normally utilized for animal feed?
was an explanation or rationale provided hy the
petitioner/registrant for any significant deviation in either the
rate or mode of application to the test crop from the intended
use pattern? -
B. AnalYses to Determine Total Terminal Residues
1. Total Accountability of Radioactive Residue in Test Crop
Did the petitioner/registrant dete ine total recovered
(i.e., combustible) radioactivity remaining in the plant at time
of sampling or harvest?
Per the analysis of total recn,ered radioactive
residues, ware plant parts sampled including those which may be
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prøcegs.d into food or feed items at time of harvest or at a
stags of development ihen normally utilized for animal feed,
subjected to ozidative combustion analy. 3 and subsequent Liquid
Scintillation Counting of the resultant CO 2 formed?
Were experimental details of sample harvest and
preparation provided prior to oxidative combustion analysis (i.e.,
dis iect ion, grinding, lyophilisation)?
It samples ware not combusted as soon as possible
after preparation, how long were samples stored and under what
conditions? If stored, did the petitioner/registrant adequately
describe sample collection, preparation and storage condition.-
to enable the reviewer to evaluste sample integrity?
as a result of oxidative combustion analyses of
radiolabeled comp nents in plant parts end fractions examined,
did the petitioner/registrant account for a majority of the total
radioactivity in or on the test crop at time of sampling or
ba vest?
Did the petitioner/registrant detezzine what percentage
of total recovered radioactivity was determined by subsequently
developed enforcement methodology? t preceding Note under II]
Pot each samole analyzed (olant mart or aamola fraction) ,
was total radioactivity reported asz
(1) total radioact±ve counts, (2) percentage of the
total recovered plant radioacti4t3. at the time of
sampling or harvest, and (3) ppm (;axpresaed as
equivalents of parent compound) of total recovered
plant radioactivity at the time of sampling or
harvest? If not, then the petitioner/registrant
must recalculate and resubmit his radiolebeled
residue data in this format.
2. haracterizatjon/Identificption of Extractable
Radioactivity
Did the petitioner/registrant describe the conditions
employed for the acidic, basic and/or enzymatic hydrolysis of the
filter cake or residue remaining from previously extracted plant
tissue and/or water soluble plant extracts to facilitate release
of conjugated residues from these samples? If so, was the ratio
and/or amounts of total free vs conjugated parent compound and/or
metabolite reported in each extracted sample matrix?
Did the petiti rner/registrant utilize appropriate
solvents/extraction technique, to quantitatively recover radiolabeled
moieties from all sample matrices? Por example, for complex
bound radiolabeled matrices were exhaustive sequential Soxhlet
extractions with a series of both nonpolar and polar solvents
employed including additional extractions with deccmplèxing
reagents (i.e., Na 2 —EDTA or mild detergents), rather than simple
extractions with or partitioning into nonpolar organic solvents
which may not have captured all polar radiolabeled moieties present?
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Did the petitioner/registrant provide a quantitative estimate
of residual radioactivity (i.e.. reported as ‘nenextractable,
unidentified or bound’) remainir’ in the extracted sample matrix
following exhaustive solvent extractions? If so, see item (3)
below for procedures to characterize these residues and assess
their significance.
(Note: In many instances, the petitioner/registrant
may report significant levels of ‘nonextractable, unidentified
or bound’ residues in the RAC examined, however, these residues
do not reflect ‘bound residues’ in the context of the IUPAC (1981)
definition cited in Appendix 2, but in reality represent conjugated
or complex bound radiolabeled residues not extractable followiviq
the inefficient or incomplete sample treatment/extraction proceàures
employed by the investigator.]
Overall, did the petitioner/registrant clearly
demonstrate and report that the extraction protocols utilized in
the plant metabolism study would have released essentially all of
the conjugated or bound forms of the metabolites formed, and
were radiochemical extraction efficiencies for all harvested
plant tissues determined and reported?
wer. adequate protocols used and results reported
for fractionation and isolation of the radioactivity extracted
from the sampl. matrices?. Pot example, wore .t.chniques such as
i solvent partitioning, high voltage electrcphoresis, ion—exchange
column chromatography, IIPLC using gradient elution with a radio-
active detector and thin layer radioautography employed?
During sample fractionation, wes total radioactivity
monitored and reported in representative sample fractions isolated
and was any loss of radioactivity accounted for? -
In the reviewers judgment were all major iietabolite
components (i.e., those generally comprising .10 percent of
total recovered radioactive residue) ultimately separated and
purified to the extent possible in preparative radio—EPLC fractions
and in radio—TIC spots or zones to permit subsequent low—level
characterization/identification by the determinative methods
employed? -
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Were the isolated and pvrified tabolites
characterized via U values by a leapt two different solvent
systems on TLC run as a single or tvo’diaen.ional chromatogrem,
and by their relative r.temtion times on BPLC and OC colusos
•luted with different solvents or employing various column packings
and equipped with radioactiv, detectors? Were all Mown or
suspected metabolLtes of the parent compound synthemised and
cochromatographed on the same TLC plates and on the same EPIC or
G’ columns to facilitate in the identification of unkn n sample
.2tabolites7
If available, did the petitioner/registrant employ
mass spectral analyse. in the CI and/or SI mode . coupled with
the same IPz.c or CC systems employed for th, separation end
characterization of metabolites described above for ultimate
metabolite identification? If mass spectral analyses wore employed
were scans in the CI and/or II modes obtained for all known and
suspected metabolites of the parent compound and compared to
those obtained for the sample metabolites to insure identification?
At a minimum, did the petitioner/registrant attempt
to classify or categorize, based on the evidence at hand, all
discrete extractable radiolabeled entities which could not be
characterized via the chromatographic techniques employed? In the
aggregate and individually what percentage of the total recovered
plant radiolabeled residue and ppm (expressed a. equivalents of
parent compound) did these unidentified and/or uncharacterized
entities represent?
If these aforementiontd unidentjfied/uncharacteris,d
radiolabeled entities represent a significant portion of the total
recovered radiolabeled residue in plants then TB should be given
as much information a. is available about these entities and
asked whether tn Lr “ncern warrants identification or whether
partial characterization will suffice.
Did the petitioner/registrant identify all s or
metabolite components where each generally comprised , 10 percent
‘of the total recovered radiolabeled residue accounted for in the
submitted plant metabolism study? If so, then TB should be dsked
whether these metabolites are to be included in the tolerance
expression. -
Did the petitioner/registrant, if possible, provide
inforsation on the chemical nature of discrete (minor) metabolite
ccmponents? -
Were individual free minor aetabolite components
each generally comprising C 10 percent of the total recovered
radiolabeled residue identified as extractable/ bioavailable
and pesticidally derived (execon) components of the bound residues
characterized under Item (3) below? If so, arid if their
radioactive concentration (tree + bound) generally comprised ) 10
percent of the total recovered radioactive residue accounted For in
the submitted plant metabolism study then those minor metabolite
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components also b• id.ntif ted. t Not..: (1) in the .aapl.s
given abovetbe percentages provided ar. merely guidelines to be
uses by the Agency’s data reviewers and at. .odif Lad upwerd or
downwerd based on th• importance of the tr•ated crep as a food or
feed and on the toxicity of the minor metabolite c peaest.
(2) The r.quir.msnts of this paragraph are not applicable to minor
metabolit. components which have been irreversibly converted to
complex bound residues which are subsequently released ‘as recycled
radiolabeled (endocon) fragments, of no toxicological concern,
following hydrolytic characterization procedures.]
at a minimum, did the petitioner/registrant provid.
adequate representations of radio—TLC plates and samples of
NPLC/GC chromatogrs as well as mass spectral scans, including a
description of all equipment (and operating parameters) used for
the extraction, fractionation, characterisation, and identification
of radiolabeled residues?
Por each characterized/identified residue component
(metabolite) did the petitioner/registrant report its concentration
both on a ppm (expressed as equivalents of parent compound) basis
and as a percentage of: (1) the total recovered radioactivity in
the treated plant at harvest or when utilized as an animal feed 1
and (2) the total radioactivity recovered fro, the particular
plant part or sample fraction analysed? if not, then the petitioner/
registrant must recalculate and resubmit his metabolite data in
this format. -
3. Characterization and Requlatory Sianificance of
Noneitractable or Bound Residues - - - -
Were the ‘unidentified. nonestractabi. or bamnd ’
residues reported in itme (2) above by the petitioner/registrant
located is edible plant parts used for food or animal feed? If
not, and provided that bound residues are also not expected in
these sam. food or feed its. then no further regulatory action
is required.
If bound’ residues were found in these plant parts.
did they generally compris, less than 10 percent g when normalized
to use conditions less than 0.1 pps (expressed as equivalents of
parent compound) of the total radioactivity recovered from the
treated plant? If so, and furthermore provided that in response
to RCB’s deference/ref.rence(s) ( j itso III (D) of this S )
TI expresses no concern regarding the presence of these low
levels of uncbaracterized bound residues then no further regulatory
action is required. lowever, if TB does express concern over the
presence of these latter tesidues if bound residues generally
exceed 10 percent or 0.1 pp. then these residues must be further
characterized b the petitioner/registrant to enable the Agency
to determine, their regulatory significance.
C Note: These percentage or residue levels are merely
guidelines to be used by the agency’s data reviewers and are
modified upisrd or downwerd based on the importance of the treated
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crop as a food or feed and the toxicity of the •xtractab le/
bioavailable and pesticidally derived (ezocon) cOmponents of the
bound residue.)
mien significant levels of nonextractabl. or b ind
residues mere pr.seat (i.e., generally greater than 10 percent
when normalized to use conditions greater than 0.1 pp. (expressid
as equivalents of parent compound) of the total radioactivity
recovered from th, treated plant) mere beam fide attompta aids by
the petitioner/r.gistrant to further characterize these residues?
r. essentially all of the conjugated or complex bound
chemical species originating from the parent pesticide (.xocons)
extracted from the bound residu. and chically characterized?
During the course of the radiolabeled plant metabolism
study, did the petitioner/r.gistrant conduct interval sampling of
protein, starch, lignin, and cellulose frictions d ich would
indicate if significant levels of unidentified radioactivity are
entering those fractions? The foregoing observations would
indicate that the bound residue does not consist of discrete
moieties (exocons) originating from the parent pesticide (and
possibly of toxicological significance) but rather of recycled
radiolabeled fragnts that have been incorporated into natural
products (endocons) of the plant and therefore are clearly of no
toxicological concern.
(Note: The publication by N. Kovacs (1986) in Appendix
2, should be consulted regarding the characterization and fraction-
ation procedures for plant natural products (eadocons).)
As a result of these fractionation and characterization
procedures, did the pstitioner/r.gistrant clearly domonstrate
that the bound residues consisted primarily of recycled radiolabeled
fragments that mere incorporated into natural plant products? If
so, then no further rcgulatory action is r.quired: if not, then
the exocon components of the bound residua must be characterized.
In response to ACB’s deference/reference(s) to TB
( see it UI (D) of this SIP) mere the extractable and characterized
•xocon components of the bound residue judged to be of toxicological
concern? If not, then no further r.gulatory action is required
if so, then the petitioner/registrant must develop and validate
modified enforcoment analytical thodology to extract and detect
these bound excoon components of toxicological concern.
(Note: The data reviewer is also advised to consult
the publication by N. lovacs (1986) cited in Appendix 2, concerning
further details on bound residue classification, nomenclature,
and i haracteriution strategies, including a proposed tabular
sequential testing approach for determining the regulatory significance
of bound pesticide residues.)
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C. Residue Nethodoloav and Xnstrumenta,j1g
Refer to the SEP on Analytical Nothods for guidance on
this subject area.
D. Ouslity Control
Rofer to the SEP an Naanityd, o( t ie e iditei 1
1 • ad , Item (!)(4) Quality Control for gui ac. on
t S sub Ct area.
I. Evaluation and lr,ortine Peauir.aents
In the data reviewer’s judgment, were .11 component. of
the total terminal residue. whether fre, or bound/conjugated
charactez i s.d to the extent necessary to permit the *g.ncy to
conclude that as a result of the proposed use that the nature of
the total terminal r.sidu. has bean adequately characterisd or
delin.atd in the subject SAC?
W.r. all cpon.nts of th. total terminal residu.,
whether fre. or bound/conjugated characterized to the extent that
E R could render an opinion r.garding the toxicological significance
of each major component and thereby allow the Agency to define
the total toxic residue? -
Did the petitioner/registrant delineate, preferably in a
floweh..t, the possible routes of degradation or pathway of
metabolism in the subject SAC? - -
When enforcament analytical thodology we. developed
did the petitioner/registrant validate these methods with radio-
labeled samples derived from the p’ant metabolism study and
provide a statement as to their capability to determine co.po
neat. of the total toxic residue whether free or boun4/cOfl ugat.d?
( See preceding Rote under IX Also Note: The publication by m.
zovacs and C. Trichilo (l9S7) in Appendix 2, should be consulted
for a discussion of procedures to integrate the conduct of
radiolabeled plant metabOlism studies with the subsequent development
and validation of proposed analytical enforcement methodologies)
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APPENDIX 2
REVI ER AIDS MATERIALS
relieving is a listing of some of the more useful rsferenc.
citations within the Residue Chemistry Branch that could prove
helpful in reviewing plant stabolisa studies:
a
(1) borough, H.W., Biological activity of pesticide conjugates.
1n: Kaufman, D., Still, a., Paulson, 0., Sandal, S.
(.ds) Bound and con yated pesticide residues. Washington,
D.C.; American Chemical Society Svmoosium Series It:
10.34, (1976);
(2) borough, H.W., Classification of radioactive pesticide
residues in food—producing animals. Environ. Path
. nL.li!1: 11—19, (1980);
(3) Baurd Evaluation Division, Standard Evaluation Procedure,
Analytical Methods (1988);
(4) laurd Evaluation Division, Standard Evaluation Procedure,
Animal Metabolism (1988);
(S) Basard Evaluation Division, standard Evaluation Procedure,
Naonitude of the Residue: Cram Pield Trials (1985);
(6) International Union of Pure and A mlied Chemistry (xuP 5c)
1981 definition of bound residues in plants: ‘Non—
extractable residues (sometimes referred to as uboundu
or non—extracted residues) in plants are defined as
chemical species originating from pesticides, used
according to good agrioultural practice, that are
unextracted by methods which do not significantly
Change the chemical nature of th.se residues. These
non—extractable residues are considered to exclude
fragments recycled through pathways leading to natural
products.
chemical smecies in this context refers either to the
parent material or to derivatives or fragments of it.
Methods in this context refer to any procedures, such
as solvent extraction and distillation, used to
exhaustively remove chemical species from a plant
mitrix. In each reference to a non—extractable residue,
the extraction procedure must be given.’;
(7) Kaufman, U., Still, C., Paulson, C., Sandal, S. (eds) Bound
and conjugated pesticide residues, Washington, U. C.:
Ari nCbemica1rpecietY vmngsium S jiei2j:(l976),
(8) Ehan SD., Bound pesticide residues in soil and
plants. Residue Reviews li: 1—25, (1982),
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(9) elein, V., Scheunert I., bound pesticide residues
in soil, plants, and food with particular emphesis on
the application of nuclear techniques. In: M!2 :
Pate rood Environ., Proc. mt. Even . ZAEk Vienna,
Austria : pp.177—205, (1982k ;
(10) Eov.cs, R.P., Regulatory aspects of bound residues
(chemistry). R sidue ev1ew! 2.!: 1—17. (1386);
(11) Rovacs, NP., Trichilo, C.L., Regulatory perspective of
pesticide analytical enforcement methodology in the
United States. J.Assoc.Off.Anal.Che . 3J : No.6
937—940 (1987);
(12) Nenlie, C.N., M tabo1isa of pesticides (including three
updates) Special Scientific Reports , United States
Department of the Xnterior, Pish and Wildlife Service;
(13) Pauls’n, C., Caldw.ll, .7.. Iutaon, D., Neme, .7. ( cd i)
Zenobiotic conjugation chemistry. Washington, D.C.;
Amer ican Chemica1 3oeietv Symnosium SerieR an:
(14) Pesticide Assessment Guidelines, Subdivision 0, Addendum 3
Natur. of the Residue: prepared by OPTS/SPA
(15) Pesticide Assessment Guidelines, Subdivision 0, idu
hem r , I 171 —4(a)(1)and(2) . prepared by OPT EPA,
Wash ngton. D.C. ( 19f2) ; -
(16) Registration Standards on various individual pesticides,
prepared by OPTS/EPA (several issued each fiscal year);
(17) Sanderuann, .7. 1., $.taboli of •nviroia.ntal chemicals
by plants — copolymerination into lignth. In: g
Appi. Poly. Sd: Lonlied Polymer iiim 37. John
Wiley a Sons, Inc., New york, pp. - —2011 ) 13) .
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