RESIDUE CHEMISTRY BRANCH
STANDARD EVALUATION PROCEDURE
Residues in Meat, Milk, Poultry and Eggs:
Dermal Treatments
Prepared by:
Richard A. Loranger
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REPORT DOCUMENTATION
PAGE -
-HASS®7 EVALUATION DIVISION: STANDARD EVALUATION PROCEDURE
— -fcesJLduis in' Heat',' Milt, Poultry and Eg£s : Dermal -Treatments • •
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'Richard A. Loranger
U.S. Environmental Protection Agency /OP.P/HED/TS-769C
401 M Street SW
Washington, D.C. 20460
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STANDARD EVALT ATION PROCEDURE
PREAMBLE
This Standard Evaluation Procedure (SEP) is one 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 ensure comprehensive and consistent treatment of major
scientific topics in these reviews and to provide interpretive
policy guidance where appropriate. The Standard Evaluation -
Procedures will be used in conjunction with the appropriate
Pesticide Assessment Guidelines and other Agency Guidelines.
While the documents were developed to explain specifically
the principles of scientific evaluation within the Offlce of
Pesticide Programs, they may also be used by other offices in
the Agency in the evaluation of studies and scientific data.
The Standard Evaluation Procedures will also serve as valuable
internal reference documents and will inform the public and
regulated community of important considerations in the
evaluation of test data for determining chemical hazards. 1
believe the SEPs will improve both the quality of science
within EPA and, in conjunction with the Pesticide Assessment
Guidelines, will lead to more effective use of both public
and private resources.
Ac 1 Acting Director
Hazard Evaluation Division
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RESIDUE CHEMISTRY BRANCH
STM DARD E’JALUATION PROCEDURE
Residues in Meat. Milk, Po91 ry and Eggs;
Dermal Treatmentstll
I. IbTTRODUCflON
(A) Purpose of the Standard Evaluation Procedure
This Standard Evaluation Procedure is designed to
aid Residue Chemistry Branch reviewers in their evalua-
tions of residue studies reflecting darmal treatment of
livestock including poultry. The document also informs
pesticide manufacturers and the public of the considerations
involved in review of such data.
(B) Background information
Animal treatment studies are required under 40 CFR
158.125 when a pesticide is requested for registration for
direct application to livestock* under the amended Federal
Insecticide, Fungicide, and Rodenticide Act. The section
of the Residue Chemistry Guidelines (Subdivision 0)
dealing with such studies is 171—4(c)(3).
- These animal studies are also needed to set toler-
ances for residues of pesticides in meat, milk, poultry
and eggs under Section 408 of the Federal Food, Drug and
Cosmetic Act. Exposure of the public to pesticide residues
from ingestion of these raw agricultural commodities can
then be estimated.
( C 1 0bjective of Feeding Studies
As noted in 40 CFR 180.6 a conclusion must be made
whether finite residues of a pesticide and “its conversion
products” will, be found in meat, milk, poultry and eggs
Cl) Livestock feeding studies and feed—through uses of
pesticides will be addressed in a separate Standard
Evaluation Procedure being developed concurrently.
* The term “livestock” refers to cattle, goats, bogs,
horses, poultry and sheep.
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when animals are “fed agricultural products bearing..
pesticide residues.” when pesticides are used “directly
on the animal,” or when pesticides are “administered pur-
posely in the feed or drinking water. To make this con-
clusion direct animal treatment studies and/or feeding
studies (discussed in separate Standard Evaluation
Procedure) are required to determine the extent to which
the pesticide transfers to meat, milk, poultry and eggs.
Such experiments should measure the “total toxic residue”
(parent pesticide plus its degradation products, metabolites
and impurities of toxicological significance) in these com-
modities following oral ingestion and/or dermal treatment
depending on the proposed uses of the chemical. If the
data then show that finite residues are expected from such
Uses, the studies will be used to determine the appropriate
tolerances.
II. INFORMATION TO BE SUPPLIED -
The submitted study should include all the informa-
tion needed to describe completely the handling of the
animals, the actual application of the pesticide (i.e..
the treatment portion of the study), the analyses of the
tissues, milk, and eggs for the residue of concern, and
the handling/storage of samples between collection and
residue analysis. Appendix 1 lists the basic information
required for review of livestock dermal studies. This
list represents a shortened version of the Data Reporting
Guidelines to be developed in FT 87.
Useful Standard Evaluation Procedures and Data Sub-
mission Guidelines related to this document include those
on Analytical Methods, Animal Metabolism, and Storage
Stability (being developed concurrently).
III. THE DATA EVALUATION PROCESS
(A) Determine Need for Study
Animal treatment studies are required whenever a.
registration is requested for direct application of a
pesticide to livestock (including poultry). Such uses
include dusts, sprays, dips, pour—one, dust bags, back—
rubbers, and ear tags. Treatment of livestock premises
(which is an indirect application to animals) will be
covered later in a separate Standard Evaluation
Procedure.
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Separate studies are required for cattle, swine, and
poultry (assuming derinal uses requested for all three) .
Depending on the routes of entry of the chemical (i.e.,
its absorbency through akin versus oral ingestion by
licking/grooming; levels of residues found in cattle and
hogs), additional studies may be required for other
species (goats, sheep, horses).
Data reflecting exaggerated treatments are desirable
but generally not required unless the registrant wants to
show the use falls under Category 3 of 180.6 (i.e., no
reasonable expectation of finite residues in meat/milk/
eggs). In that case (as with feeding studiea) the
registrant has to show that no detectable residues are
incurred following exposure to LOX the desired rate.
(B) Read Study and Identify Data Gaps
Next, the reviewer reads the study to determine
whether the information listed in Appendix 1 has been
submitted. Any omissions which are significant enough
to prevent a complete examination of the study should be
noted in the review. Such data gaps must be clearly
identified so the registrant can be informed by the
Product Manager of the need for additional data and/or
detaiLs on the conduct of the study.
(C) Assess the Appropriateness and Adequacy of the Data
- The reviewer then considers the adequacy of the
supplied data/thformation. In doing so, the reviewer
should keep in mind the following major points:
Did the animals receive the maximum dermal treat-
ment with respect to the types of formulations.
(i.e.. those likely to give highest residues) and
- concentration, number, and frequency of application?
• ‘Were animals sacrificed within the proposed pre—
slaughter interval?
• Were the proper tissues and r.a.c.’a (milk/eggi)
sampled for both control and treated animals?
• Did the registrant provide storage stability data
to show tesidues would not degrade between sample
collection and analysis?
• Was the total toxic residue determined in tissues,
milk and eggs using a validated analytical method?
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For a more detailed list of points the reviewer
should consider, refer to Appendix 2. In addition to the
Latter, the technical guidance available in reviewer aid
materials such as the Residue Chemistry Guidelines and
Bources listed in Appendix 3 should be utilized.
Having considered all the points involved (Appendix 2)
the reviewer writes a summary of the study clearly outlining
(1.) data gaps/omissions (as noted above in (B)) and
(2) deficiencies in the reported data (such as spray/dip
concentrations too low; toxic metabolitee not measured;
preslaughter interval too long).
CD) Make a Regulatory Determination
As noted under the Introduction, a determination must
be made as to whether finite residues of the pesticide will
be found in tissues/milk/eggs and, if found, what tolerances
are appropriate to cover such residues.
If data gaps/deficiencies prevent such a determination,
the reviewer so indicates and outlines what corrective steps
need to be taken. If the study is adequate, the reviewer
categorizes the proposed use of the pesticide under 40 CFR
180.6(a). (In many cases the 14 C metabolism study indicates
whether the chemical transfers to animal products.) For the
use to be placed under Category 3 of 180.6(a) (i.e., no
reasonable expectation of finite residues) no detectable
residues should be found after exposure to the pesticide at
lOX the proposed rate. In that case no tolerances are
required for the chemical in animal products.
The presence of detectable residues from the
lox or lower exposure levels means the use falls un 1er
categories 1 or 2 of 180.6(a) (“finite residues will actually
be incurred” or “there is a reasonable expectation of
finite residues”). In that case the reviewer must determine
what tolerance levels are appropriate. ThiB generally -.
involves using the maximum residues found in animals treated
at the maximum proposed rate. This should reflect multiple
modes of exposure if the label so permits (for example,
dermal. sprays plus backrubber). Also, if residues of the
pesticide are found on feed items, tolerances must be set
high enough to cover both dermal and oral routes of exposure.
For this purpose it is generally assumed that residues from
from oral ingestion and dermal treatments are addItive. It
should also be noted that the tolerances are almost always
set to one significant figure (e.g., 0.01, 0.2, 05 ppm) for
those Ci ppm. On occasion, fractional values greater than
1 ppm may be acceptable, although whole numbers are still
preferrable.
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Although separate tolerances are established for
meat, fat and seat byproducts (latter include liver and
kidney), they are often set at the same numerical value.
However, if residues concentrate in fat, the latter may
receive a higher tolerance. Likewise, when silk residues
are found to partition mostly into the milk fat, the
tolerance is generally set on the latter with the equiva-
lent whole milk value (l/25x milk fat tolerance) expressed
parenthetically (e.g., milk fat (reflecting 0.02 ppm in
whole milk]........ 0.5 ppm’s). If liver or kidney has
significantly higher levels than other tissues, a separate
tolerance is established for that organ. The meat bypro-
duct tolerance is then qualified to show the separation of
that tissue as in the following example: meat byproducts
(except kidney) ........ 0.1 ppm; kidney ........ 2 ppm.
For dermal uses on swine and chickens it is likely that
separate higher tolerances will be required for hog and
poultry skin.
Unlike the situation with residues on feed iteme
(wherein cattle tolerances are automatically extended to
goats, horses and sheep), tolerances are established only
for those species to be listed on product labels.
Having completed the various considerations discussed
above, the reviewer states whether the meat/milk/egg toler-
ances (existing or proposed depending on the type of regis-
tration action) are appropriate. If they are not, the
proper ones are listed so the Product Manager can inform
the registrant of the requirement for revised tolerances
(i.e., a new tolerance petition or a revised Section F in a
pending petition). In some cases, efficacy considerations
permitting, the reviewer may also be able to suggest changes
in the use pattern (application rate, number and timing of
treatments) so that revision of tolerances is not necessary.
IV. REVIEWER AIDS
There are a large number and variety of source
materials that are available to assist the data reviewer in
the evaluation process. A listing of some of the more useful
references that reside within the Branch is provided in
Appendix 3 to this document. -
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— APPENDIX 1 -
INFORMATION REQUESTED OF PETITIONER
— FOR DERMAL LIVESTOCK STUDIES
1. Identity of active ingredient (a.i.) and relative levels
of a.i. and impurities.
2. Type of formulation ( 4P, EC, duBt. pour—on), % active
ingredient, amount of a.i. per gallon for liquids, and
% of each inert ingredient.
3. Mode of application (high pressure spray, ULV spray, dip,
- backrubber, pour—on, dust, ear tag).
4. Treatment rates—concentration and time for dips: spray
concentration plus Volume per animal; quantity of pour—
on formulation per animal.
5. Number and frequency of treatments.
6. Identity of solvent/diluent and any spray adjuvants.
7. Identity of animals and number per treatment level.
8. Housing, diet composition, and feeding/milking schedules
during acclimation and treatment periods.
9. Sampling dates for milk and eggs; sample compositing
technique if applicable.
10. General health, body weights, feed consumption, and egg/
milk production prior to and during treatment period.
11. Mode and date of sacrifice (time in hours fr m final
application of pesticide) and organs sampled (compositing
of latter if applicable).
12. Conditions and length of sample storage (including
shipping if applicable) prior to extraction/analysis.
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13. Detailed description of analytical method and chemical
species determined.
14. Recovery data demonstrating validity of analytical
method.
15. Dates of sample extraction and analysis of extract (also
storage conditions of extract if applicable).
16. Data demonstrating stability of residues under observed
storage of samples (and extracts if applicable).
17. Measured residue levels in muscle, fat, liver, kidney
(except poultry), poultry and hog skins, milk, and
eggs.
18. Representative raw data and chromatograms of control,
spiked, and treated samples supporting reported residues
and recoveries.
19. Names/addresses of organizations/personnel involved in
the feeding and analytical portions of the study.
20. Quality assurance procedures — measures/precautions to
- ensure fidelity of study and analyses (such as animal
identification, proper labeling/coding of samples,
record keeping procedures, high quality equipment and
reagents, etc.). -
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-APPENDIX 2—
POINTS TO CONSIDER IN EVALUATING DIRECT ANIMAL TREATMENT STUDIES
Application of Pesticide to Animals
• Was the material applied clearly identified as to its
chemical structure and purity? Is there any impurity of
concern (such as hexachlorobenzene)7
• Were the proper animals treated with the pesticide?
Cattle, swine and poultry each require a separate study
for dermal uses. Healthy animals should be chosen with
dairy cows in mid—Lactation and chickens in full lay.
For sheep the data should reflect use on shorn and un—
shorn animals unless the label specifies treatment at
only one of these stages. Data may not be required for
goats and horses (and perhaps sheep) if the cattle study
shows low residue accumulation for similar uses.
• Did each treatment level involve an adequate number of
animals? A poultry study should include 10 birds per
level (allowing 3—4 samples per composite), while Only
3 individuals are needed for cattle and other livestock
(swine, goats, horses, sheep). Each study should also
include untreated (control) animals (10 for poultry, 3
for larger animals).
• Did feed consumption, body weights, and milk/egg pro-
duction decrease drastically after treatment started?
If so, animals did not receive an adequate acclimation
period or the pesticide is producing deleterious effects.
Toxicology Branch should be alerted as to the possible
hazard of dermal use of the pesticide.
• What formulations and modes of application were employed?
Generally, each formulation and application technique
.should be tested. However, data from dips and high
pressure wetting -sprays can cover use of dusts (but not
vice versa) and pour—one (provided ca the same amount of
active ingredient is applied per anTi al). If a product
can be diluted with an organic solvent, data using the
proper diluent wil]. be required (i.e., data using water
as the solvent will not cover uses of other diluents).
Data are often not required for ear tag uses as long as
studies are available on full body treatments (sprays,
dips) or backrubbers.
• How many separate studies or trials were conducted?
For dermal uses it is advisable to perform several
unrilated tests or at least allow applications by
various individuals to see if applicator differences
affect residue levels.
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Were adequate quantities of pesticide applied per treat-
ment? At a minimum animals should receive the highest
exposure to pesticide permitted by the label. For sprays
this entails the maximum solution concöntration and spray
volume per animal. For dips the most concentrated solution
and longest exposure time in the tank should be employed.
Pour—on studies must use the maximum amount of solution
permitted per animal. Free access should be given to back—
rubbers and dust bags. Studies at exaggerated concentra-
tions/doses are desirable, but only required if the
registrant wants to prove the use can be classified under
Category 3 of 40 CFR 180.6 (a).
• How many applications were made to the animals? What was
the frequency of treatment? Animals should receive the max-
imum number of applications with the minimum retreatment
interval specified on the label. However, if the petitioner
can demonstrate that milk residues have declined to non—
detectable levels within the minimum retreatment period,
data for multiple applications to dairy animals would not
be necessary. For-meat animals biopsy samples of fat tissue
could be used for the same purpose. In those cases where
daily exposure is involved (dust bags, backrubbere, ear tags)
data is required to show that residues plateaued in milk or
tissues by the time of sacrifice.
• Were treated and control animals housed separately? Since
animals (especially cattle) often groom and lick each other,
the controls should be kept separate from treated animals.
The latter should be allowed free access to each other to
simulate actual animal husbandry. However, in some cases it
maybe useful to restrain a few additional treated animals
in harnesses to demonstrate the extent of absorption through
the skin (versus oral ingestion by licking the fur).
Sample Collection and Analysis
• What sampling procedure was utilized for milk and eggs?
Milk and eggs should be collected and analyzed daily until
residues have plateaued. This procedure should be repeated
after each dermal application unless the residues have de-
clined to non—detectable levels within the retreatment
interval (in which case multiple applications do not have
to be examined at all). Milk samples from different cows
should not be pooled, although up to 3 eggs may be compos—
ited. Analyses must be conducted on whole milk and eggs
(yolk and white). In addition, several milk samples should
be analyzed to determine how residues partition into milk
fat. Sometimes information on the latter may be found in
the metabolism study.
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Were animals sacrificed within the proposed preslaughter
interval? Generally, we do not accept PSI’s longer than 3
days as being practical. (although we have accepted 5 days and
longer in certain cases). In any case, the animals should be
sacrificed within the PSI on the label (provided it is a
practical one). However, with dermal treatments residues may
not peak until a week or so after treatment. Therefore, if
the label PSI is short (1—3 days), additional data reflecting
longer intervals are advisable to establish the true maximum
residue level. for tolerance calculations.
Which organs were sampled? Were samples composited?
For cattle, goats, hogs, horses and sheep, analyses are
required for muscle, fat, liver and kidney. Hog skin should
also be analyzed after dehairing and steaming as in commercial
slaughterhouses. Data on fried pork skins are also needed.
although the tolerance is set on the uncooked commodity as
the raw agricultural commodity. If residues concentrate upon
frying, a food additive tolerance will be required for the
fried skins. For poultry, samples include muscle (breast,
thigh), liver, skin, and fat. Tissues should not be composited
except in the case of poultry where it is acceptable if at
least 3 unique samples are analyzed per feeding level (i.e.,
3—4 tissues per composite if 10 hens per level).
• Were all samples frozen as soon as possible after collec-
tion/sacrifice? Is storage stability data available
reflecting intervals from collection to extraction and
from extraction to residue quantitation? --Refer to separate
Standard Evaluation Procedure on Storage Stability for more
details.
• Wasthe total toxic residue measured by a validated method?
Has the method been tested by EPA and published in the FDA
Pesticide Analytical Manual? Parent compound plus all
metabolites and impurities of toxicological concern should
be determined in milk/eggs/tissues. Recoveries 3hould be
> 70%. For more details on analytical methodology refer
to .the Standard Evaluation Procedure (SEP) on that topic.
For background on how to determine the “total toxic
residue” refer to the S.E.P. on Animal Metabolism.
• Was the method sufficiently sensitive? The sensitivity
should be 0.01—0.05 ppm or less.
• Were control values less than the method sensitivity?
If samples from untreated animals are found to contain
apparent residues, the validity of the study I. question-
able. Keeping controls and treated animals in the same
enclosed area may lead to such results due to grooming
between individuals.
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Did the submitter provide raw data and chromatograms to
support the reported residue levels? Representative -
chromatograms should be presented for control, fortified
and treated samples of each commodity. Actual values
should be reported for each sample rather than an average
for an entire group.
• Was there reasonable agreement between samples from the
same exposure level? If one value is considerably higher
than the others, can it be discarded as an outlier?
Other Considerations
• Are the results of the cold derinal study consistent with
the radiolabeled metabolism study? The levels of the
residue of concern should be similar provided comparable
amounts of active ingredient were applied per animal
using the same mode of treatment, pre—slaughter intervals
and numbers of applications.
• Has a Registration Standard been issued for this chemical
and, if so, is it.being used in evaluation of the dermal
study?
• Is the pesticide undergoing Special Review? If so, has
any relevant information been submitted under that pro—
ce S
• is there any other unpublished (such as data submitted in
earlier petitions, Section 18 and 24(c) requests) or
published information (such as Codex/FAO Monographs) known
to us about feeding of this pesticide to livestock? If so,
this information should be consistent with the results of
the new study.
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— APPENDIX 3
REVIEWER AIDS MATERIALS
Following is a listing of some of the more useful
source materials within the Residue Chemistry Branch that
could prove helpful in reviewing livestock dermal studies:
(1) Federal Food, Drug, and Cosmetic Act, as amended,
5 , 408—409. -
(2) Federal Insecticide, Fungicide, and Rodenticide
Act, as amended.
(3) Subdivision 0 (Residue Chemistry] of the Pesticide
Assessment Guidelines, 5 171-3 and 5 171-4, prepared by OPTS,
EPA, 1982.
(4) Subdivision D (Product Chemistry] of the Pesticide
Assessment Guidelines, prepared by OPTSIEPA, 1982.
(5) Code of Federal Regulations (40 CFR 158 and 180;
2]. CFR 193 and 561), General Services Administration Wash-
ington, D.C., update i annually.
(6) Pesticide Chemical News Guide , R. E. Duggan.
editor, Food Chemical News, Inc., Washington, D.C., 1982,
updated monthly.
- (7) “Guidelines for Data Acquisition and Data Quality
Evaluation in Environmental Chemistry,” Anal. Chem . 52, 2242-
2248 (1980). —
(8) Acceptable Common Names and Chemical Names for
the Ingredient Statement on Pesticide Labels , 4th ed., C. R.
Blalock, et al., editors, OPPIEPA, 1979, available from
National Technical In-formation Service, Springfield, VA.
(9) ParaChemicals Handbook , t4eister Publishing Co.,
Willoughby, OH, updated annually.
(10) Nanogen Index: A Dictionary of Pesticides and
Chemical Pollutants , K. Packer, editor, Nanogens Inter—
natonal, Freedom, CA, 1975 (updated periodically by supple-
ments).
(11) F.D.A. Pesticide Analytical Manual , Volumes I
and II, available from the National Technical Information
Service, Springfield, VA. -
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(32) Guidelines on Supervised Studies to Provide bata
on the nature and Amount of Pesticide Residues in Products
of Animal Origin , Codex Committee on Pesticide Residues,
draft dated Nov. 5, 1984.
(13) Statistical Methods Applied to Experiments in
Agriculture and Bioloqy , 7th. ed., G. W. Snedecor, Iowa
State College Press 1 l980.
(14) Registration Standards on various individual.
pesticides, prepared by OPTS/EPA, (several issued each
fiscal year).
(15) Directory of Professional Workers in State
Agricultural Experiment Stations and Other Cooperating
State Institutions , published by U.S. Dept. of Agriculture.
(16) Various reference texts and journal publications
of a scientific or agricultural nature, including PAO/Codex
Monographs; Residue Reviews (assorted volumes); Analytical
j str ( assorted issues); Journal of Agricultural and
Food Chemistry (assorted issues); Journal of the Association
of Official Analytical Chemists ( assorted issues) .
(17) Residue Chemistry Branch files: petition and
registration files; reviewer aids; policies; subject files;
reading files: cultural practices files (cattle, poultry,
swine); et al.
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