vvEPA
United States Prevention, Pesticides EPA 738-R-06-011
Environmental Protection and Toxic Substances June 2006
Agency (7508P)
Report of the Food Quality Protection Act
(FQPA) Tolerance Reassessment
Progress and Risk Management Decision
(TRED) for Oxytetracycline
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
June 30, 2006
CERTIFIED MAIL
Dear Registrant:
This is the Environmental Protection Agency's (hereafter referred to as EPA or
the Agency) "Report of the Food Quality Protection Act (FQPA) Tolerance
Reassessment Progress and Risk Management Decision for Oxytetracycline," which was
approved on June 30, 2006. This document is also known as a Tolerance Reassessment
Decision, or TRED. A Notice of Availability of this tolerance reassessment decision will
be published in the Federal Register. Because of the extensive collaboration with
registrants and other federal agencies prior to and during the 60-day public comment
period and because relatively few comments were received during the 60-day public
comment period, the TRED document and final risk assessments are being issued without
an additional public comment period. The TRED, supporting risk assessments, and
response to comments for oxytetracycline are available to the public in EPA's Pesticide
Docket EPA-HQ-OPP-2005-0492 at: http://www.regulations.gov. EPA issued a
reregistration eligibility decision for oxytetracycline in March 1993.
The oxytetracycline TRED was developed through EPA's public participation
process, published in the Federal Register on May 14, 2004, which provides opportunities
for public involvement in EPA's pesticide tolerance reassessment and reregistration
programs. Developed in partnership with USD A and with input from EPA's advisory
committees and others, the public participation process encourages public involvement
starting early and continuing throughout the pesticide risk assessment and risk mitigation
decision making process. The public participation process encompasses full, modified,
and streamlined versions that enable EPA to tailor the level of review to the level of
refinement of the risk assessments, as well as to the amount of use, risk, public concern,
and complexity associated with each pesticide. Through the public participation process,
EPA is making a commitment to both involve the public and meet statutory deadlines.
Background
The Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA,
requires EPA to reassess all the tolerances in effect on or before the enactment of FQPA
on August 3, 1996. In reassessing these tolerances, EPA must consider, among other
things, aggregate risks from non-occupational sources of pesticide exposure, whether
there is increased susceptibility to infants and children, and the cumulative effects of
pesticides with a common mechanism of toxicity. Once a safety finding has been made,
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the tolerances are considered reassessed. Existing tolerances associated with
oxytetracycline have been reassessed in accordance with FFDCA, as amended by FQPA.
In addition to the assessment of direct risks posed by dietary exposure, EPA also
assessed the potential for pesticidal uses of oxytetracycline to contribute to antibiotic
resistance. In late 2004, EPA held an internal "problem formulation" meeting for the
streptomycin and oxytetracycline TREDs. During this meeting EPA noted that these
chemicals' potential contributions to antibiotic resistance were not fully understood.
Recognizing that pesticidal uses of streptomycin and/or oxytetracycline may possibly
contribute to antibiotic resistance of bacterial pathogens with potential adverse public
health consequences, and that other entities may have more expertise in evaluating
antibiotic resistance, EPA requested input from three other agencies.
In May 2005, EPA hosted two conference calls with U.S. Centers for Disease
Control and Prevention (CDC), U.S. Food and Drug Administration (FDA) Center for
Drug Evaluation and Research and Center (CDER) and Center for Veterinary Medicine
(CVM), and U.S. Department of Agriculture (USD A) to discuss antibiotic resistance.
EPA then met internally to discuss the options for addressing potential concerns resulting
from the continued use of antibiotics as pesticides and evaluate the appropriateness and
feasibility of conducting a qualitative antibiotic resistance risk assessment based on FDA
CVM's Guidance for Industry #152 (Evaluating the Safety of Antimicrobial New Animal
Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health
Concern). Based on the discussion and evaluation, EPA included in its risk assessments a
qualitative assessment of antibiotic resistance modeled on FDA CVM's Guidance for
Industry #152 (see the Streptomycin HED Chapter dated February 7, 2006 and the
Oxytetracycline HED Chapter dated June 19, 2006).
In February 2006, EPA opened a 60-day public comment period for the
preliminary risk assessments. During the public comment period, EPA received 8
comments relating to the use of oxytetracycline. Comments were received from Rutgers
University, U.S. Apple Association, Northwest Horticultural Council, Keep Antibiotics
Working, and 4 plant pathologists from around the U.S. The majority of the respondents
were supportive of the use of oxytetracycline on fruit trees and indicated that it is an
integral and critical component in disease control programs. Another respondent urged
EPA to implement steps to minimize the potential contribution to antibiotic resistance
from the use of oxytetracycline. All of these comments were considered and
incorporated into EPA's risk management decisions and this document represents EPA's
response to public comments.
EPA has completed its review of the dietary risks and is issuing its risk
management decision for oxytetracycline.
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Regulatory Decision
EPA has evaluated the dietary and residential risks from the supported registered
uses and has determined that there is a reasonable certainty that no harm to any
population subgroup will result from exposure to oxytetracycline.
Acute dietary exposure was not estimated because no acute toxicity was identified
in any of the relevant studies in the oxytetracycline database. The chronic dietary
exposure estimate (food + water) for the U.S. population is 32% of the chronic
Population Adjusted Dose (cPAD). The chronic dietary exposure estimate for the most
highly exposed population subgroup, all infants (children <1 year of age), is 95% of the
cPAD using conservative, screening level exposure assumptions. Dietary risk estimates
for food and water are below EPA's level of concern.
The 2 tolerances currently established at 40 CFR 180.337 for residues of
oxytetracycline in/on raw agricultural commodities are now considered reassessed under
section 408(q) of the FFDCA (see Table 6).
Use Profile
Oxytetracycline (Case Number 0655) includes the active ingredients
oxytetracycline (PC Code 006304), hydroxytetracycline monohydrochloride (PC Code
006308), and oxytetracycline calcium (PC Code 006321). In this document, unless
specified otherwise, "oxytetracycline" refers to both oxytetracycline hydrochloride and
oxytetracycline calcium; there is no active product for PC Code 006304.
Table 1. Chemicals in Case Number 0655
PC Code
006304
006308
006321
Chemical Name
oxytetracycline, a.k.a. 2-Naphthacenecarboxamide, 4-(dimethylamino)-
l,4,4a,5,5a,6, 1 l,12a-octahydro-3,5,6, 10, 12, 12a-hexahydroxy-6-methyl-l, 1 1-dioxo-,
(4S-(4.alpha.,4a.alpha.,5.alpha.,5a.alpha.,6.beta.,12a.alpha.))-
oxytetracycline hydrochloride, a.k.a. hydroxytetracycline monohydrochloride
oxytetracycline calcium, a.k.a. calcium oxytetracycline
Oxytetracycline is an antibiotic pesticide used to control bacteria, fungi, and
mycoplasma-like organisms. The majority of oxytetracycline is used on pears. Other
crops treated include peaches, nectarines, and apples. Oxytetracycline use on apples has
been approved under emergency exemption (Section 18) for several years due to the lack
of efficacious alternatives. A full registration (Section 3) is currently under review by
EPA as a separate action. Oxytetracycline is also registered for use on forest trees and
ornamental trees, shrubs, and vines. The estimated total domestic pesticidal use (annual
average) is approximately 15,000 Ibs. active ingredient (ai) per year. Approximately
8,000 Ibs. ai are used annually on pears and 2,000 Ibs. ai are used annually on peaches,
and 2,000 Ibs. ai are used annually on apples. All other uses are less than 500 Ibs. ai
annually. There are no residential pesticidal uses of oxytetracycline. Oxytetracycline is
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also registered with FDA to treat infectious diseases in animals and humans and also as a
food additive to increase animal weight gain. Although firm estimates are not available,
literature studies report that the estimated percentage of antibiotics applied to plants
compared to all other antibiotic use is <0.5% (McManus, 2002).
Oxytetracycline is typically applied to foliage by ground or aerial spray, and is
also used as a tree injection. Oxytetracycline may be used every 4 to 6 days and up to 10
times per season depending on crop type and application method.
Alternative Control Measures:
Oxytetracycline is one of few tools available to combat fire blight, a potentially
devastating disease in fruit trees. Non-antibiotic alternatives include copper,
prohexadione, biological controls, fosetyl-Al, pruning, and planting resistant cultivars.
Antibiotic alternatives include streptomycin.
Copper: Copper provides reasonable protection against fire blight disease if
applied as preventive sprays in combination with use of disease forecasting
models. Copper is effective in reducing the percent of infected blossom cluster
infections on apples. The efficacy of copper is dependent upon many factors such
as disease pressure, application timing, and its persistence on plant surfaces. The
persistence is dependent upon weather conditions. In current disease management,
copper plays an important part in a fire blight management program, but can only
be safely applied in the early spring or autumn when the trees are dormant.
Prohexadione: Prohexadione® has no pesticidal properties. It reduces linear
growth of branches resulting in reduced tree canopy volume. Prohexadione
treatment of trees reduces their susceptibility to fire blight. It may be an additional
tool in the management of fire blight.
Biological Control Agent: BlightBan® (a.i. Pseudomonasfluorescens strain
A506) is used to complement streptomycin (see below); it is not a replacement for
streptomycin and other antibiotics. Commercial use of Blightban is limited due to
poor efficacy and high cost.
Fosetyl-Al: Aliette®, a fungicide, is also registered for fire blight control, but data
supporting this use are not convincing of its efficacy against fire blight. No
practical control activity was observed in experimental trials in Michigan.
Fosetyl-Al is not used commercially for the control of fire blight because it does
not appear to be efficacious.
Pruning: The branches and tree limbs that show fire blight disease symptoms in
the late season are removed from the trees and destroyed to prevent the spread of
disease and source of inoculums for the next year. This practice is effective in
reducing the primary inoculums and tree death.
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Resistant Cultivars: Red Delicious variety of apple has some resistance against
the fire blight disease but it is not grown widely because most consumers prefer
other varieties. All other commercially grown varieties are susceptible.
Streptomycin: Streptomycin is a registered antibiotic for the control of fire blight,
but in some areas the pathogen has developed resistance to the antibiotic.
Human Health Effects
(For a complete discussion, see the Oxytetracycline HED Chapter dated June 19, 2006.)
No acute dietary endpoint was selected because no acute toxicity was identified in
any of the relevant studies in the oxytetracycline database.
The chronic dietary endpoint for all populations is based on microbiological
effects observed in a resistance study in dogs at the lowest observed adverse effect level
(LOAEL) of 0.25 mg/kg/day. The no observed adverse effect level (NOAEL) in this
study was 0.05 mg/kg/day. An uncertainty factor of 100 (10X for intra-species variation
and 10X for inter-species extrapolation) was applied to the NOAEL resulting in a chronic
reference dose (cRfD) of 0.0005 mg/kg/day. A summary of the toxicological dose and
endpoints for oxytetracycline that were used in the dietary risk assessment is shown
below in Table 2.
Table 2. Toxicological Dose and Endpoints used in the Dietary Risk Assessment
Exposure
Scenario
Acute Dietary
Chronic Dietary
(All populations)
Cancer
Dose Used in Risk
Assessment, UF
FQPA SF and Level of
Concern for Risk
Assessment
Study and
Toxicological Effects
N/A - toxicity attributable to acute exposure was not identified
NOAEL= 0.05 mg/kg/day
UF= 100
cRfD1 = 0.0005 mg/kg/day
FQPA SF = IX
cPAD2 = 0.0005 mg/kg/day
Microbial study in dogs
LOAEL = 0.25
mg/kg/day based on
microbial effects
Not Classifiable as to Human Carcinogenicity3
UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level,
LOAEL = lowest observed adverse effect level, chronic RfD = chronic reference dose, N/A = not
applicable
1 cRfD = NOAEL
UF
2 cPAD = cRfD
FQPA SF
3 No evidence of carcinogenicity was found in a literature search of toxicity in animals. In the mouse, there
was no evidence of carcinogenicity at the highest dose tested in the carcinogenicity study. In the rat
carcinogenicity study, only benign tumors were observed. Therefore, there is low concern for
carcinogenicity and no quantitative assessment is required.
The drug oxytetracycline is administered to humans orally or intravenously to
treat infectious diseases caused by a wide variety of microorganisms. The dose for adults
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is approximately 15 to 30 mg/kg. The daily dose for children is approximately 25 to 50
mg/kg.
There is no evidence of increased sensitivity in pups versus adults based on rat
and mouse developmental studies and the rat multi-generation reproduction study. In
prenatal developmental studies in both rats and mice treated with oxytetracycline, there
was no toxicity identified in the pups at any dose tested. In the two-generation study,
there was no toxicity identified in pups at the highest dose tested (18 mg/kg/day). The
degree of concern is low for pre- and/or post-natal toxicity resulting from exposure to
oxytetracycline and the special FQPA SF can be reduced (IX) since there are no residual
uncertainties for pre- and/or post-natal toxicity.
The dose used in human medicine ranges from 1000 mg to 2000 mg per day
(orally or intravenously). Based on the dose used in human medicine, a theoretical
NOAEL of 16.7 mg/kg/day could be calculated by dividing the dose (1000 mg/day) by
the approximate weight of an adult (60 kg). This theoretical NOAEL could then be used
to derive a cRfD to estimate dietary risk. Instead of deriving the cRfD from a theoretical
NOAEL based on human drug use, EPA used the NOAEL of 0.05 mg/kg/day in dogs to
derive the cRfD and cPAD of 0.0005 mg/kg/day. Since the cPAD derived from the
chronic RfD is several orders of magnitude lower than the dose that would be derived
from using the theoretical human NOAEL, the cRfD is protective for all effects and is not
likely to underestimate exposure. There are no further residual uncertainties and the
FQPA safety factor can be removed (IX).
Oxytetracycline has a low acute toxicity (Category IV) for oral toxicity in mice
(LDso > 7200 mg/kg). Based on the availability of extensive information from
oxytetracycline use as a human drug, the data requirements for the acute dermal,
inhalation, primary eye irritation, and skin sensitization studies in animals have been
waived.
No evidence of carcinogenicity was found in a literature search of toxicity in
animals. However, in accordance with EPA's Guidelines for Carcinogen Risk
Assessment, oxytetracycline is classified as "Not Classifiable as to Human
Carcinogenicity" due to the lack of guideline carcinogenicity studies.
EPA's use of information derived from the pharmaceutical uses of streptomycin is
in accordance with EPA's Final Rule promulgated on January 26, 2006 related to
Protection for Subjects in Human Research, which is codified in 40 CFR Part 26.
Drinking Water Exposure and Risk Assessment
(For a complete discussion, see the Oxytetracycline Tier 1 Drinking Water Assessment
dated May 22, 2006.)
Drinking water exposure to pesticides can occur through ground and surface
water contamination. EPA considers both acute (one day) and chronic (lifetime) drinking
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water risks and uses either modeling or actual monitoring data, if available, to estimate
those risks. Since available water monitoring data are considered inadequate to
determine surface and ground water drinking water exposure estimates, estimated
drinking water concentrations (EDWCs) are calculated from surface and ground water
models FIRST V 1.0 and SCI-GROW V 2.3, respectively. The EDWCs are based on
application methods, rates, and use sites that would likely yield the highest drinking
water concentrations.
Table 3 presents Tier 1 (screening level) chronic EDWCs for surface water and
groundwater assuming nine separate applications of oxytetracycline calcium to peaches
and/or nectarines at a rate of 0.64 Ib ai/A with a 7-day retreatment interval.
Table 3. Highest surface/ground water EDWCs for oxytetracycline
Exposure Duration
Chronic
Surface Water Chronic EDWC
4.6 ppb
Ground Water EDWC
0.033 ppb
Concentrations in surface water (4.6 ppb) and ground water (0.033 ppb) represent
upper-bound estimates of the concentrations that might be found in surface water and
groundwater due to the use of oxytetracycline calcium on peaches/nectarines. These
drinking water exposure estimates are incorporated into an aggregate chronic dietary
assessment using both food and water concentrations.
Acute and Chronic Dietary (Food + Water) Exposure and Risk Assessment
(For a complete discussion, see the Oxytetracycline Chronic Dietary Exposure
Assessment dated February 6, 2006.)
Acute dietary risk assessments were not conducted because no toxicity
attributable to acute exposure could be identified based on the data currently available for
oxytetracycline.
Chronic dietary risk assessments were conducted using the Dietary Exposure
Evaluation Model (DEEM-FCID™), Version 2.03, which used food consumption data
from the United States Department of Agriculture's (USDA's) Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. Based on the registered
uses of oxytetracycline on pears, peaches, and nectarines, and the proposed Section 3 use
on apples, no quantifiable residues in meat, milk, poultry, and eggs (MMPE) are
expected. However, FDA has established tolerances in MMPE commodities for the sum
of the residues of the tetracyclines including chlortetracycline, oxytetracycline, and
tetracycline as listed in 21 CFR 556.500. Accordingly, EPA's dietary analysis includes
estimates of possible oxytetracycline residues in livestock commodities making use of
monitoring data from the Food Safety and Inspection Service (FSIS) collected in 2002,
2003, and 2004. These data were taken from the FSIS National Residue Program Data
publications (Red Books).
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The relevant FSIS data sampled kidney tissue from a variety of livestock (cattle,
swine, poultry, goats, etc), analyzing for oxytetracycline residues. As tetracycline
residues partition preferentially into fat and kidney, measured oxytetracycline residues in
kidney were used as worst-case level for all other livestock tissues. In 2004 and 2002, no
oxytetracycline residues were detected in 4270 and 6942 samples, respectively. In 2003,
three kidney samples had finite oxytetracycline residue levels out of 5260 samples. To
compute an estimated residue level for use in DEEM-FCID, an average residue level was
calculated using /^ level of detection for nondetects (0.005 ppm) together with the three
detected levels of 2.5, 5.0, and 5.0 ppm. This provided a conservative estimated residue
level of oxytetracycline in livestock commodities of 0.0058 ppm and this value was used
for all livestock commodities in the DEEM-FCID analyses.
The chronic dietary assessments assumed tolerance level residues on treated crops
and incorporated percent crop treated information. Modeled EDWCs for surface water
sources were also included. The highest exposure and risk estimates were for all infants
(<1 year old) using surface water as the drinking water source. The exposure for all
infants was 0.000473 mg/kg/day, which utilized 95% of the cPAD. The chronic dietary
exposure estimates for food and water are below EPA's level of concern (see Table 4).
Table 4. Summary of Dietary (Food + Water) Exposure and Risk
Population Subgroup
General U.S. Population
All Infants (< 1 year old)
cPAD
(mg/kg/day)
0.0005
0.0005
Surface Water
EDWC (ppb)
4.6
4.6
Total (Food + Water)
Exposure (mg/kg/day)
0.000160
0.000473
% cPAD
32
95
EDWC = estimated drinking water concentration, cPAD = chronic population adjusted dose
Residential Risk
At this time, no product containing oxytetracycline is registered for residential use
and there is no anticipated exposure in or around homes or recreational areas.
Aggregate Risk
(For a complete discussion, see the Oxytetracycline HED Chapter dated June 19, 2006.)
In accordance with the FQPA, EPA must consider and aggregate pesticide
exposures and risks from all potential sources including food, drinking water, and
residential exposures. Since no product containing oxytetracycline is registered for
residential use, only food and drinking water were considered in the aggregate
assessment. In an aggregate assessment, exposures are combined and compared to
quantitative estimates of hazard (e.g., aNOAEL). When aggregating exposures and risks
from various sources, EPA considers both the route and duration of exposure. In general,
exposures from various sources are aggregated only when the toxic effect determined by
the endpoint selected for each route is the same. In the case of oxytetracycline, an
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aggregate assessment was performed using high-end exposures and conservative
endpoints. Further refinements would have been incorporated into the risk assessment if
exposures of concern had been identified. Since the screening level aggregate assessment
did not show risks of concern, EPA concludes with reasonable certainty that combined
residues of oxytetracycline from food and drinking water exposures will not result in an
aggregate risk of concern to any population subgroup.
An acute aggregate assessment was not conducted because acute toxicological
effects attributable to oxytetracycline could not be identified. Short-term and
intermediate-term aggregate risk assessments were not conducted because there are no
existing or proposed residential uses for oxytetracycline.
A chronic aggregate assessment for food and water exposure was conducted
because a chronic toxicological endpoint was identified for oxytetracycline. EPA's
aggregate assessment for food includes estimates of possible oxytetracycline residues in
livestock commodities making use of monitoring data from the Food Safety and
Inspection Service (FSIS) National Residue Program Data collected in 2002, 2003, and
2004. The highest aggregate exposure and risk estimates were for all infants (<1 year old)
using surface water as the drinking water source, which utilized 95% of the cPAD. The
chronic dietary exposure estimates for food and water are below EPA's level of concern.
Results of the dietary (food + drinking water) exposure and risk assessment are presented
in Table 4.
Pharmaceutical Aggregate Risk
Section 408 of the FFDCA requires EPA to consider potential sources of exposure
to a pesticide and related substances in addition to the dietary sources expected to result
from a pesticide use subject to the tolerance. In order to determine whether to maintain a
pesticide tolerance, EPA must "determine that there is a reasonable certainty of no harm."
Under FFDCA section 505, the Food and Drug Administration reviews human drugs for
safety and effectiveness and may approve a drug notwithstanding the possibility that
some users may experience adverse side effects. EPA does not believe that, for purposes
of the section 408 dietary risk assessment, it is compelled to treat a pharmaceutical user
the same as a non-user, or to assume that combined exposures to pesticide and
pharmaceutical residues that lead to a physiological effect in the user constitutes "harm"
under the meaning of section 408 of the FFDCA.
Rather, EPA believes the appropriate way to consider the pharmaceutical use of
oxytetracycline in its risk assessment is to examine the impact that the additional non-
occupational pesticide exposures would have to a pharmaceutical user exposed to a
related (or, in some cases, the same) compound. Where the additional pesticide exposure
has no more than a minimal impact on the pharmaceutical user, EPA could make a
reasonable certainty of no harm finding for the pesticide tolerances of that compound
under section 408 of the FFDCA. If the potential impact on the pharmaceutical user as a
result of co-exposure from pesticide use is more than minimal, then EPA would not be
able to conclude that dietary residues were safe, and would need to discuss with FDA
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appropriate measures to reduce exposure from one or both sources. EPA provided its
findings with respect to oxytetracycline to FDA in a letter dated May 24, 2006, which is
available in the public docket (EPA-HQ-OPP-2005-0492).
The pesticidal exposure estimates described in the May 24, 2006 letter reflect the
dietary dose from pesticidal uses of oxytetracycline that a user treated with a
pharmaceutical oxytetracycline product would receive in a reasonable worst-case
scenario. EPA's pesticide exposure assessment has taken into consideration the
appropriate population, exposure route, and exposure duration for comparison with
exposure to the pharmaceutical use of oxytetracycline.
EPA estimates that the pharmaceutical oxytetracycline exposure a user is
expected to receive from a typical therapeutic dose (25 mg/kg/day for children) is 50,000
to 200,000 times greater than the estimated dietary exposure from the pesticidal sources
of oxytetracycline (0.000121 mg/kg/day to 0.000473 mg/kg/day). Therefore, because the
pesticide exposure has no more than a minimal impact on the total dose to a
pharmaceutical user, EPA believes that there is a reasonable certainty that the potential
dietary pesticide exposure will result in no harm to a user being treated therapeutically
with oxytetracycline. FDA is aware of EPA's conclusions regarding pesticide exposure
in users receiving treatment with a pharmaceutical oxytetracycline drug product and
FDA's June 7, 2006 response to EPA is available the public docket (EPA-HQ-OPP-2005-
0492).
Cumulative Risk Assessment
FQPA requires that EPA consider "available information" concerning the
cumulative effects of a particular pesticide's residues and "other substances that have a
common mechanism of toxicity." The Agency considers other substances because low-
level exposures to multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect, as would a higher level
of exposure to any of the other substances individually.
Unlike other pesticides for which EPA has followed a cumulative risk approach
based on a common mechanism of toxicity, EPA has not made a common mechanism of
toxicity finding as to oxytetracycline and any other substances, and oxytetracycline does
not appear to produce a toxic metabolite that is also produced by other substances. For
the purposes of this tolerance action, therefore, EPA has not assumed that oxytetracycline
has a common mechanism of toxicity with other substances. For information regarding
EPA's efforts to determine which chemicals have a common mechanism of toxicity and
to evaluate the cumulative effects of such chemicals, see the policy statements released
by EPA's Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a common
mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.
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Tolerance Reassessment Summary
Tolerances for the pesticidal residues of oxytetracycline are established under 40
CFR 180.337. A summary of the oxytetracycline tolerance reassessment is presented in
Table 5.
Table 5. Tolerance Reassessment Summary for Oxytetracycline
Commodity
Current Tolerance (ppm)
Reassessed Tolerances (ppm)
Comments
Tolerances Under 40 CFR §180.337
Peach
Pear
0.35
0.35
0.35
0.35
Tolerances To Be Proposed Under 40 CFR §180.337
Apple
None
0.35
EPA has adequate data
to support apple.
FDA has established tolerances for the sum of the tetracyclines (chlortetracycline,
oxytetracycline, tetracycline) residues for beef cattle, dairy cattle, calves, swine, sheep,
chickens, turkeys, fmfish, and lobster as listed under 21 CFR Part 556.500. These
tolerances are regulated by FDA and are not included in this tolerance reassessment
decision; however, the residues from these uses were included in EPA's dietary risk
assessment.
Antibiotic Resistance
(For a complete discussion, see the Oxytetracycline FED Chapter dated June 19, 2006.)
Bacterial resistance to oxytetracycline as a result of drug use has long been
recognized. EPA recognizes that pesticidal uses of oxytetracycline may contribute to
antibiotic resistance of bacterial pathogens with potential adverse public health
consequences. After evaluating available data and consulting with CDC, FDA CDER,
FDA CVM, and USD A, EPA determined that insufficient data were available to conduct
a quantitative antibiotic resistance assessment and instead conducted a qualitative
antibiotic resistance assessment based on FDA CVM's Guidance for Industry #152.
Because anticipated dietary residues are extremely low (conservatively estimated
at 0.000160 mg/kg/day for the General U.S. Population), it is unlikely that antibiotic
resistance from pesticidal use of oxytetracycline would result from food exposure.
Bacterial resistance to oxytetracycline from pesticidal use of oxytetracycline with adverse
public health consequences could theoretically occur from (1) development of resistance
in bacterial pathogens present in orchards or (2) from development of resistance from
non-pathogenic bacteria in orchards which later transferred their resistance to human
bacterial pathogens.
The possibility of antibiotic resistance resulting in adverse human health
consequences is determined principally by the likelihood of non-pathogenic organisms in
orchards transferring their resistance to pathogens in the human environment. Antibiotic
resistance from pesticidal use of oxytetracycline is unlikely to result directly from dietary
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residues of oxytetracycline because dietary residues are very low. The maximum
aggregate dietary exposure was 0.000473 mg/kg/day which is very small when compared
to a 25 mg/kg/day drug dose. The drug dose is 50,000 times greater than the estimated
pesticidal dietary exposure. The small dose from pesticidal exposure would not be
expected to select for resistant bacteria because very few bacteria would be killed by this
small dose. If bacterial resistance to oxytetracycline from pesticidal use occurs, it is most
likely that it would be caused by development of resistance from non-pathogenic bacteria
in orchards which later transferred their resistance to human bacterial pathogens.
In setting or revising tolerances under section 408 of the FFDCA, EPA must
determine that "there is a reasonable certainty that no harm will result from aggregate
exposure to the pesticide chemical residue." Because the risk of antibiotic resistance
does not arise from the ingestion of pesticide residues, the risk has not been aggregated
for the purposes of this action. EPA may consider the risk of antibiotic resistance in
future actions such as registration review or approval of new uses for oxytetracycline.
EPA is requiring use and usage information as well as additional environmental fate data
to address the uncertainties regarding potential antibiotic resistance from the pesticidal
uses (see Table 6). Based on these new data, EPA may also require an antibiotic
resistance monitoring study to be conducted in orchards or other high use areas. This
study is held in reserve and, if deemed appropriate, will be required through a separate
data call-in. Additional label statements will also be required that will ensure judicious
use of oxytetracycline.
Additional Generic Data Requirements
Toxicity for oxytetracycline was assessed using the extensive database for
oxytetracycline from its use as a human drug and using animal toxicity studies submitted
to FDA. Toxicological and environmental fate data requirements were waived for
oxytetracycline in the 1993 RED. Since the RED, EPA has become aware of the
increasing importance of antibiotic resistance. Therefore, the following environmental
fate and use data requirements presented in Table 6 are necessary to better understand the
fate of pesticidal oxytetracycline in the environment and to support the continued
registration of oxytetracycline.
Table 6. Oxytetracycline Generic Data Requirements
Guideline
810.1000
810.1000
835.2120
835.2240
835.2410
835.4100
835.4200
835.4400
835.4300
835.1240
835.1410
Study Title
Use and Usage Information
Antibiotic Resistance in Orchards1
Hydrolysis of Parent and Degradates as a Function of pH at 25°C
Direct Photolysis Rate of Parent and Degradates in Water
Photodegradation of Parent and Degradates in Soil
Aerobic Soil Metabolism
Anaerobic Soil Metabolism
Anaerobic Aquatic Metabolism
Aerobic Aquatic Metabolism
Soil Column Leaching
Laboratory Volatilization from Soil
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Guideline
835.6100
850.1730
860.1340
Study Title
Terrestrial Field Dissipation
Fish BCF
Analytical Enforcement Method
Based on the results of the required environmental fate data, EPA may require a special study to be
conducted on antibiotic resistance in orchards. This study is being held in reserve and, if deemed
appropriate, will be required through a separate data call-in.
Required Label Changes
Table 7 presents the label amendments required for all products containing
oxytetracycline.
Table 7. Oxytetracycline Label Changes Summary Table
Description
General
Application
Restrictions
General
Application
Restrictions
Amended Labeling Language
"This product contains the antibiotic oxytetracycline. To
reduce the development of drug-resistant bacteria and
maintain the effectiveness of this and other antibacterial
products, this product should be used only to treat or
prevent infections that are proven or strongly suspected to
be caused by bacteria."
"This material is not to be used for medical or veterinary
purposes."
Placement on Label
Directions for Use
Directions for Use
Conclusions
EPA has evaluated the dietary risks from the supported registered uses and has
determined that there is a reasonable certainty that no harm to any population subgroup
will result from chronic exposure to oxytetracycline and considers the existing tolerances
reassessed. Although not related to the FQPA safety finding, there are uncertainties
about the pesticidal contributions to antibiotic resistance. To better understand the fate of
pesticidal oxytetracycline in the environment and its potential contribution to antibiotic
resistance, EPA is requiring additional use and environmental fate data. EPA is also
requiring label amendments that will ensure judicious use of oxytetracycline.
Please contact Lance Wormell of my staff with any questions regarding this
decision. He may be reached by phone at (703) 603-0523 or by e-mail at
wormell. lance@epa. gov.
Sincerely,
Debra Edwards, Ph.D., Director
Special Review and Reregistration Division
Page 14 of 15
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Technical Support Documents for the Oxytetracycline TRED
1. William Donovan and Kimyata Morgan (USEPA/OPPTS/OPP/HED).
Oxytetracycline: HED Chapter of the Tolerance Reregistration Eligibility
Decision Document (TRED) and Proposed New Uses on Apples. Revised After
Phase 3 Public Comments. DP Barcode D330129. June 19, 2006.
2. William H. Donovan (USEPA/OPPTS/OPP/HED). Oxytetracycline Tolerance
Reregistration Eligibility Decision (TRED). Summary of Product Chemistry and
Residue Data. DP Barcode D315689. September 27, 2005.
3. William H. Donovan (USEPA/OPPTS/OPP/HED). Oxytetracycline Chronic
Dietary Exposure Assessment for the Tolerance Reregistration Eligibility
Decision (TRED). Revised After Phase 1-Error Only Corrections. DP Barcode
D315686. February 6, 2006.
4. Greg Orrick (USEPA/OPPTS/OPP/EFED). Oxytetracycline: Tier I Drinking
Water Exposure Assessment of Oxytetracycline Supporting the Reassessment
Under FQPA of Pear and Peach & Nectarine Use Patterns and the Assessment of
the New Use Pattern, Apple. DP Barcode D315682. May 22, 2006.
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