Page
1
of
15
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
Page
2
of
15
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
USDA
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,
Page
3
of
15
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
(
USDA)
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.
Page
4
of
15
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
Chemical
Name
006304
oxytetracycline,
a.
k.
a.
2­
Naphthacenecarboxamide,
4­(
dimethylamino)­
1,4,4a,
5,5a,
6,11,12a­
octahydro­
3,5,6,10,12,12a­
hexahydroxy­
6­
methyl­
1,11­
dioxo­,
(
4S­(
4.
alpha.,
4a.
alpha.,
5.
alpha.,
5a.
alpha.,
6.
beta.,
12a.
alpha.))­

006308
oxytetracycline
hydrochloride,
a.
k.
a.
hydroxytetracycline
monohydrochloride
006321
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
lbs.
active
ingredient
(
ai)
per
year.
Approximately
8,000
lbs.
ai
are
used
annually
on
pears
and
2,000
lbs.
ai
are
used
annually
on
peaches,
and
2,000
lbs.
ai
are
used
annually
on
apples.
All
other
uses
are
less
than
500
lbs.
ai
annually.
There
are
no
residential
pesticidal
uses
of
oxytetracycline.
Oxytetracycline
is
Page
5
of
15
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.
Pseudomonas
fluorescens
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.
Page
6
of
15
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
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
N/
A
­
toxicity
attributable
to
acute
exposure
was
not
identified
Chronic
Dietary
(
All
populations)
NOAEL=
0.05
mg/
kg/
day
UF
=
100
cRfD1
=
0.0005
mg/
kg/
day
FQPA
SF
=
1X
cPAD2
=
0.0005
mg/
kg/
day
Microbial
study
in
dogs
LOAEL
=
0.25
mg/
kg/
day
based
on
microbial
effects
Cancer
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
Page
7
of
15
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
(
1X)
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
(
1X).

Oxytetracycline
has
a
low
acute
toxicity
(
Category
IV)
for
oral
toxicity
in
mice
(
LD50
>
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
Page
8
of
15
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
lb
ai/
A
with
a
7­
day
retreatment
interval.

Table
3.
Highest
surface/
ground
water
EDWCs
for
oxytetracycline
Exposure
Duration
Surface
Water
Chronic
EDWC
Ground
Water
EDWC
Chronic
4.6
ppb
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).
Page
9
of
15
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
½
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
Surface
Water
Population
Subgroup
cPAD
(
mg/
kg/
day)
EDWC
(
ppb)
Total
(
Food
+
Water)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.0005
4.6
0.000160
32
All
Infants
(<
1
year
old)
0.0005
4.6
0.000473
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.,
a
NOAEL).
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
Page
10
of
15
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
nonoccupational
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
Page
11
of
15
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
lowlevel
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/.
Page
12
of
15
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
0.35
0.35
Pear
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,
finfish,
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
HED
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
USDA,
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
Page
13
of
15
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
Study
Title
810.1000
Use
and
Usage
Information
810.1000
Antibiotic
Resistance
in
Orchards1
835.2120
Hydrolysis
of
Parent
and
Degradates
as
a
Function
of
pH
at
25oC
835.2240
Direct
Photolysis
Rate
of
Parent
and
Degradates
in
Water
835.2410
Photodegradation
of
Parent
and
Degradates
in
Soil
835.4100
Aerobic
Soil
Metabolism
835.4200
Anaerobic
Soil
Metabolism
835.4400
Anaerobic
Aquatic
Metabolism
835.4300
Aerobic
Aquatic
Metabolism
835.1240
Soil
Column
Leaching
835.1410
Laboratory
Volatilization
from
Soil
Page
14
of
15
Guideline
Study
Title
835.6100
Terrestrial
Field
Dissipation
850.1730
Fish
BCF
860.1340
Analytical
Enforcement
Method
1
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
Amended
Labeling
Language
Placement
on
Label
General
Application
Restrictions
"
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."
Directions
for
Use
General
Application
Restrictions
"
This
material
is
not
to
be
used
for
medical
or
veterinary
purposes."
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
15
of
15
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.
