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
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REJECTION RATE ANALYSIS
OCCUPATIONAL AND RESIDENTIAL EXPOSURE
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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
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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.
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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
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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.
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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.
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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
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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
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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).
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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
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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.
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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)
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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
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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.
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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
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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,
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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
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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,
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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
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FIFRA GLP Q's & A's
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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..
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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.
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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.
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FIFRA GLP Q's
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FIFRA GLP Q'I & A'$
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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.
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FIFRA GLP Q's &. A's
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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.
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FfFRA GLP Q's & A's
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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
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FIFRA GLP Q's &. A's
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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
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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
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FIFRA GLP Q's &. A's
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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.
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