Document ID: EPA-HQ-OPP-2005-0492-0027
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-16T04:00Z

Page
1
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46
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
19­
JUN­
2006
MEMORANDUM
SUBJECT:
Oxytetracycline:
HED
Chapter
of
the
Tolerance
Reregistration
Eligibility
Decision
Document
(
TRED)
and
Proposed
New
Uses
on
Apples.
Revised
After
Phase
3
Public
Comment
Period.
PC
Codes:
006304,
006308,
and
006321;
DP
Barcode:
D330129;
Case
No.
0655.

Regulatory
Action:
Phase
3
Reregistration
Action
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
William
H.
Donovan,
Ph.
D.,
Chemist
Reregistration
Branch
3
(
RRB3)
Health
Effects
Division
(
HED)
(
7509P)

AND
Kimyata
Morgan,
Ph.
D.,
Toxicologist
RRB3/
HED
(
7509P)

THROUGH:
Danette
Drew,
Branch
Senior
Scientist
RRB3/
HED
(
7509P)

TO:
Lance
Wormell,
CRM
Reregistration
Branch
2
Special
Review
and
Registration
Division
(
7508P)
Page
2
of
46
Table
of
Contents
1.0
Executive
Summary
........................................................................
Page
4
of
45
2.0
Ingredient
Profile
............................................................................
Page
8
of
45
2.1
Summary
of
Supported
Uses..................................................
Page
8
of
45
2.2
Structure
and
Nomenclature
..................................................
Page
9
of
45
2.3
Physical
and
Chemical
Properties..........................................
Page
10
of
45
3.0
Metabolism
Assessment
.................................................................
Page
11
of
45
3.1
Comparative
Metabolic
Profile..............................................
Page
11
of
45
3.2
Nature
of
the
Residue
in
Foods.............................................
Page
11
of
45
3.2.1
Description
of
Primary
Crop
Metabolism...................
Page
11
of
45
3.2.2
Description
of
Livestock
Metabolism........................
Page
11
of
45
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation              
Page
12
of
45
3.3
Environmental
Degradation
..................................................
Page
12
of
45
3.4
Tabular
Summary
of
Metabolites
and
Degradates
.................
Page
12
of
45
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
..........
Page
12
of
45
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
                
Page
12
of
45
3.6.1
Tabular
Summary              .
Page
12
of
45
3.6.2
Rationale
for
Exclusion
of
Metabolites
and
DegradatesPage
13
of
45
4.0
Hazard
Characterization/
Assessment
...........................................
Page
13
of
45
4.1
Hazard
Characterization
.......................................................
Page
13
of
45
4.1.1
Qualitative
Assessment
of
Antimicrobial
Resistance..
Page
17
of
45
4.2
FQPA
Hazard
Considerations
..............................................
Page
24
of
45
4.2.1
Adequacy
of
the
Toxicity
Data
Base..........................
Page
24
of
45
4.2.2
Evidence
of
Neurotoxicity.........................................
Page
25
of
45
4.2.3
Developmental
Toxicity
Studies
................................
Page
25
of
45
4.2.4
Reproductive
Toxicity
Study.....................................
Page
26
of
45
4.2.5
Additional
Information
from
Literature
Sources
........
Page
26
of
45
4.2.6
Pre­
and/
or
Postnatal
Toxicity
...................................
Page
26
of
45
4.2.6.1
Determination
of
Susceptibility......................
Page
26
of
45
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility...............
Page
26
of
45
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study..
Page
26
of
45
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
            
Page
27
of
45
Page
3
of
46
4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
      
Page
27
of
45
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection..........
Page
27
of
45
4.4.1
Acute
Reference
Dose
(
aRfD)
.................................
Page
27
of
45
4.4.2
Chronic
Reference
Dose
(
cRfD)
................................
Page
27
of
45
4.4.3
Recommendation
for
Aggregate
Exposure
Risk
Assessments
             .
Page
28
of
45
4.4.4
Classification
of
Carcinogenic
Potential.....................
Page
29
of
45
4.5
Special
FQPA
Safety
Factor
.................................................
Page
29
of
45
4.6
Endocrine
disruption.............................................................
Page
30
of
45
5.0
Public
Health
Data.........................................................................
Page
30
of
45
6.0
Exposure
Characterization/
Assessment
........................................
Page
30
of
45
6.1
Dietary
Exposure/
Risk
Pathway............................................
Page
30
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45
6.1.1
Residue
Profile..........................................................
Page
31
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45
6.1.2
Chronic
Aggregate
Dietary
Exposure
and
Risk..........
Page
32
of
45
6.2
Water
Exposure/
Risk
Pathway..............................................
Page
34
of
45
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway.......
Page
35
of
45
6.3.1
Home
Uses
...............................................................
Page
35
of
45
6.3.2
Recreational
Uses......................................................
Page
35
of
45
6.3.3
Other
(
Spray
Drift,
etc.)
............................................
Page
35
of
45
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization.............
Page
36
of
45
7.1
Acute
Aggregate
Risk...........................................................
Page
36
of
45
7.2
Chronic
Aggregate
Risk........................................................
Page
36
of
45
8.0
Cumulative
Risk
Characterization/
Assessment
...........................
Page
36
of
45
9.0
Data
Needs
and
Label
Requirements
..........................................
Page
37
of
45
9.1
Toxicology...........................................................................
Page
37
of
45
9.2
Residue
Chemistry................................................................
Page
37
of
45
9.3
Occupational
and
Residential
Exposure.................................
Page
37
of
45
9.4
Recommended
Data
for
Refining
Qualitative
Risk
Assessment
...................................................................
Page
37
of
45
10.0
References
......................................................................................
Page
38
of
45
11.0
APPENDICIES
..............................................................................
Page
42
of
45
1.0
TOXICOLOGY
DATA
REQUIREMENTS
.........................
Page
42
of
45
2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
......................
Page
43
of
45
3.0
TOLERANCE
REASSESSMENT
SUMMARY...................
Page
45
of
45
Page
4
of
46
1.0
Executive
Summary
This
assessment
provides
information
to
support
the
issuance
of
a
risk
management
decision
document
known
as
a
Tolerance
Reregistration
Eligibility
Decision
(
TRED)
Document
for
oxytetracycline.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Use
Profile
Oxytetracycline
is
a
broad­
spectrum
antibiotic
produced
from
the
actinomycete
Streptomyces
rimosus.
Oxytetracycline
is
a
human
and
animal
antibiotic
drug
which,
in
various
forms,
is
used
primarily
to
control
bacteria,
fungi,
and
mycoplasma­
like
organisms.
In
agriculture,
oxytetracycline
is
used
to
help
control
fire
blight
of
pears,
peaches,
and
nectarines.
Nufarm
Americas,
Inc.,
and
IR­
4
have
submitted
a
tolerance
petition
(
PP#
7E4855)
for
use
on
apples.
Oxytetracycline
hydrochloride
and
oxytetracycline
calcium
are
registered
for
use
as
bactericide/
fungicides
to
control
bacterial
diseases
on
nectarines,
peaches
and/
or
pears.
The
current
memo
concerns
oxytetracycline
hydrochloride,
oxytetracycline
calcium,
and
oxytetracycline
(
hereafter
collectively
referred
to
as
"
oxytetracycline").

Oxytetracycline
is
a
FIFRA
List
A
reregistration
chemical.
Under
the
Oxytetracycline
Case
No.
0655,
manufacturing­
use
products
are
registered
under
PC
Codes
006308
(
oxytetracycline
hydrochloride)
and
006321
(
oxytetracycline
calcium).
There
are
currently
no
registered
manufacturing­
use
products
under
PC
code
006304
(
oxytetracycline);
however,
the
agency
has
required
the
registration
of
the
oxytetracycline
TGAI
in
the
form
of
oxytetracycline
dihydrate
in
connection
with
a
number
of
oxytetracycline
calcium
end­
use
product
registrations.

Tolerances
are
currently
established
for
the
residues
of
oxytetracycline
per
se
[
40
CFR
§
180.337],
and
are
set
at
0.35
ppm
for
peach
and
pear.
As
indicated
in
40
CFR
§
180.1(
h),
tolerances
for
peaches
also
cover
nectarines.
There
are
adequate
field
trial
data
available
to
support
the
establishment
of
a
tolerance
for
residues
of
oxytetracycline
per
se
in/
on
apples
at
0.35
ppm.

This
preliminary
risk
assessment
for
oxytetracycline
was
based
on
the
supported
uses
as
outlined
in
the
Use
Closure
Memo
(
L.
Wormell,
31­
MAR­
2005);
in
addition,
a
proposed
new
use
on
apples
is
also
included.

Hazard
Identification
and
Dose
Response
Assessment
Oxytetracyclines
include
oxytetracycline,
oxytetracycline
calcium
and
hydroxyoxytetracycline
monhydrochloride.
The
toxicity
of
all
three
oxytetracyclines
would
be
expected
to
be
similar
and
shall
be
considered
equivalent
in
this
hazard
characterization.
Historically,
all
the
toxicological
data
requirements
for
oxytetracycline
have
been
waived.
The
information
available
on
the
effects
Page
5
of
46
of
oxytetracycline
in
humans,
supplemented
with
the
data
available
on
the
toxicity
of
oxytetracycline
in
laboratory
animals,
is
sufficient
to
evaluate
the
toxicity
of
oxytetracycline
and
related
compounds.
Based
on
the
information
available
from
these
sources,
the
database
is
complete
and
there
are
no
datagaps.

Animals
In
mice,
oxytetracycline
has
a
low
acute
toxicity,
being
a
Category
IV
for
oral
toxicity
(
LD50
>
7200
mg/
kg).
Based
on
the
extensive
availability
of
human
data
from
the
drug
use
of
oxytetracycline,
the
data
requirements
for
the
acute
dermal,
inhalation,
primary
eye
irritation,
and
skin
sensitization
studies
in
animals
have
been
waived.

A
definitive
target
organ
has
not
been
identified.
The
most
common
effect
in
intermediate­
or
long­
term
oral
exposures
was
a
decrease
in
body
weight
and/
or
body
weight
gain.
Clinical
signs
noted
were
increased
incidence
of
respiratory
signs
and
rough
hair
coat
and
decreased
maternal
survival
and
percent
of
treated
dams
found
pregnant.
In
a
chronic
toxicity
study
in
dogs,
a
yellow
discoloration
of
the
thyroid
was
observed
in
all
dosed
animals
at
necropsy.
No
other
changes
in
clinical
signs,
mortality,
body
weight,
food
consumption,
macrosopy,
or
histopathology
were
reported
in
dogs.

In
prenatal
developmental
toxicity
studies,
maternal
toxicity
was
evident
in
rats
as
a
dose­
related
increase
in
mortality.
A
dose­
related
decrease
in
fetal
body
weight
was
observed
in
rats.
No
maternal
or
developmental
toxicity
was
observed
in
mice
treated
up
to
2,100
mg/
kg/
day.
No
treatment­
related
external,
visceral,
or
skeletal
abnormalities
were
found
in
either
species.
In
a
study
citation
that
was
reported
by
a
Joint
FAO/
WHO
committee,
oxytetracycline
did
not
adversely
affect
reproductive
parameters
in
rats
over
two
generations.

There
is
no
evidence
of
increased
sensitivity
in
pups
versus
adults
based
on
rat
and
mice
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
postnatal
toxicity
resulting
from
exposure
to
oxytetracycline
and
the
special
FQPA
safety
factor
can
be
reduced
to
1X
since
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

No
evidence
of
neurotoxicity
was
observed
in
any
study.

There
is
carcinogenic
potential
but
no
evidence
of
carcinogenicity
was
observed
in
rats.
In
F344/
N
rats,
histological
examination
showed
a
dose
related
increase
in
the
incidence
of
benign
phaeochromcytomas
in
the
adrenal
gland
of
male
rats
fed
2,500
mg/
kg/
day.
In
females
an
increase
in
the
incidence
of
adenomas
of
the
pituitary
gland
was
found
in
the
highest
dose
group
(
1,875
mg/
kg/
day).
Mice
fed
up
to
1,875
mg/
kg/
day
exhibited
no
evidence
of
carcinogenicity.
The
bacterial
reverse
mutation
test,
chromosome
aberration
study,
and
sister
chromatid
exchange
assays
were
all
negative,
with
and
without
metabolic
activation.
The
mouse
lymphoma
forward
mutation
assay
revealed
that
oxytetracycline
was
mutagenic
only
with
metabolic
activation,
however,
the
dose
levels
were
close
to
toxic
concentrations
and
the
positive
effect
in
the
in
vivo
Page
6
of
46
micronucleus
assay
in
mice
was
not
dose
related.

The
microbiological
effects
of
oxytetracycline
were
examined
by
studies
examining
the
induction
of
drug­
resistant
organisms
in
dogs.
In
a
6­
week
study
in
dogs,
which
received
oxytetracycline,
there
was
no
increase
in
the
level
of
resistant
fecal
coliforms
at
2
ppm
in
the
diet
(
equivalent
to
0
.05
mg/
kg/
day).
Dogs
receiving
10
ppm
(
equivalent
to
0.25
ppm)
displayed
an
increase
in
a
multiple
antibiotic­
resistant
population
of
enteric
lactose­
fermenting
organisms.

A
relevant
study
on
metabolism
is
available
in
the
open
literature.
After
oral
administration
of
47.6
mg
14C­
labeled
hydroxyoxytetracycline
monohydrochloride/
kg
b.
w.
to
mice,
72%
of
the
applied
dose
was
found
in
the
large
intestine
after
2
hours;
only
5%
was
absorbed,
of
which
the
major
portion
(
3.6%)
was
excreted
in
the
urine.
In
the
liver
1.9%
and
1.1%
of
the
dose
applied
was
recovered
after
1
and
2
hours,
respectively.

Mode
of
Action
Tetracyclines
exert
their
activity
in
bacteria
by
inhibiting
protein
synthesis.
Inhibition
occurs
when
oxytetracycline
binds
to
the
30S
ribosomes,
preventing
aninoacyl
tRNA
from
reading
the
mRNA
ribosome
complex,
thereby
preventing
polypeptide
chain
elongation.
High
concentrations
of
tetracyclines
also
impair
protein
synthesis
in
mammalian
cells.
However,
the
active
transport
system
found
in
bacteria
is
absent
in
these
cells
and
there
are
differences
in
sensitivity
at
the
ribosomal
level.
These
differences
are
likely
to
be
important
determinants
in
the
selective
action
of
tetracyclines.
In
humans,
oxytetracycline
is
administered
orally
or
intravenously
to
treat
infectious
diseases
caused
by
a
wide
variety
of
microorganisms.
The
dose
for
adults
range
from
1000
to
2000
mg
per
day.
The
usual
daily
dose
for
children
is
25
to
50
mg/
kg.

Qualitative
Assessment
of
AntiMicrobial
Resistance
The
overall
risk
of
the
development
of
antibiotic
resistance
to
oxytetracycline
in
human
health
and
the
environment
is
medium.
Following
the
recommendation
of
FDA's
Guidance
#
152,
a
medium
concern
for
release
and
exposure
and
a
highly­
important
concern
for
consequence
results
in
an
overall
risk
assessment
rank
as
medium.

Endpoints
used
in
risk
assessment
are
provided
in
Table
1.

Table
1.
Endpoint
Used
for
Oxytetracycline
Risk
Assessment
Dietary
NOAEL
mg/
kg/
day
RfD
mg/
kg/
day
PAD
mg/
kg/
day
chronic
­
all
populations
0.05
0.0005
(
UF=
100;
FQPA
=
1)
0.0005
Exposure
Assessment
Page
7
of
46
An
acute
dietary
and
drinking
water
exposure
analysis
was
not
conducted
because
a
toxic
endpoint
attributable
to
a
single­
dose
effect
was
not
identified
in
the
database.
Analysis
of
chronic
dietary
and
drinking
water
exposure
pathways
were
included
in
the
oxytetracycline
risk
assessment.
Sources
of
dietary
exposure
include
food
from
treated
crops
of
apple,
peach,
nectarine,
and
pears;
as
well
as
from
drinking
water.
The
dietary
exposure
to
oxytetracycline
is
expected
to
be
low
due
to
the
long
PHIs
and
the
limited
number
of
crop
uses.
Drinking
water
exposure
may
occur
due
to
run­
off
from
the
agricultural
uses
of
oxytetracycline
in
orchards.
Occupational
exposures
are
not
assessed
for
TREDs.
Residential
exposures
were
not
assessed
because
no
residential
exposures
are
anticipated.

The
use
of
oxytetracycline
as
a
drug
in
food
animals
is
regulated
by
the
FDA
according
to
21
CFR
556.500.
The
FDA
has
established
the
following
tolerances
for
the
sum
of
residues
of
the
tetracyclines
including
chlortetracycline,
oxytetracycline,
and
tetracycline:
2
ppm
in
muscle
(
meat)
of
cattle,
swine,
sheep,
poultry,
fish
and
lobsters;
6
ppm
in
liver,
12
ppm
in
fat
and
kidney,
and
0.3
ppm
in
milk.
HED
notes
that
the
drug
uses
of
oxytetracycline
in
livestock
and
humans
result
in
considerably
higher
exposure
levels
to
oxytetracycline
residues
than
the
agricultural
uses;
the
estimated
percentage
of
antibiotics
applied
to
plants
compared
to
all
other
antibiotic
use
is
<
0.5%
(
McManus
et
al.).
Wet
apple
pomace
is
a
feedstuff
of
regulatory
interest
associated
with
apples,
while
peaches/
nectarines
and
pears
have
no
livestock
feedstuffs.
Due
to
low
oxytetracycline
residue
levels
in
apples,
quantifiable
residues
of
oxytetracycline
in
livestock
commodities
as
a
result
of
feeding
wet
apple
pomace
from
treated
apples
are
not
expected.
Therefore,
based
on
the
agricultural
uses
of
oxytetracycline,
HED
finds
there
is
no
reasonable
expectation
that
residues
of
concern
will
transfer
to
livestock
tissues
[
40
CFR
§
180.6(
a)(
3)].
However,
to
account
for
the
possibility
of
oxytetracycline
residues
in
livestock
commodities
arising
from
drug
and
subtherapeutic
dosing
of
animals,
HED
included
the
results
of
Food
Safety
and
Inspection
Service
(
FSIS)
livestock
monitoring
data
from
the
years
2002­
2004
in
the
dietary
exposure
analyses
(
see
section
6.1.2).

Risk
Assessment
and
Risk
Characterization
Risk
assessments
were
conducted
for
dietary
and
drinking
water
exposure
pathways
together
as
an
aggregate
assessment
of
risk
from
the
combined
food
and
drinking
water
pathways.
A
cumulative
risk
assessment
considering
risks
from
other
pesticides
or
chemical
compounds
having
a
common
mechanism
of
toxicity
has
not
been
conducted
for
this
TRED.
HED
has
not
yet
determined
that
any
other
chemical
substances
have
a
mechanism
of
toxicity
in
common
with
that
of
oxytetracycline.

Aggregate
Exposures
and
Risks
Since
there
is
potential
for
concurrent
exposure
via
food
and
water,
the
combined
exposures
are
estimated
for
the
aggregate
assessment.
To
assess
aggregate
risk,
drinking
water
model­
based
EDWCs
determined
by
EFED
are
included
in
the
dietary
exposure
assessment
along
with
Page
8
of
46
potential
residue
levels
in
foods.

HED
conducted
a
partially
refined
chronic
dietary
exposure
analyses
using
the
Dietary
Exposure
Evaluation
Model
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
)
.
The
chronic
dietary
analyses
were
conducted
for
the
general
U.
S.
population
and
all
population
subgroups.

Chronic
aggregate
risks
are
expressed
as
a
percentage
of
the
chronic
Population
Adjusted
Dose
(
cPAD).
An
aggregate
risk
of
100%
of
the
PAD
is
the
level
of
exposure
that
should
not
be
exceeded,
(
i.
e.,
estimated
risk
less
than
100%
of
PAD
is
not
of
concern).
The
PAD
is
the
chronic
reference
dose
(
cRfD)
modified
by
the
special
FQPA
Safety
Factor.
The
special
FQPA
safety
factor
for
sensitivity
in
infants
and
children
for
the
chronic
dietary
assessment
in
this
case
is
1X.
Based
on
these
analyses,
the
aggregate
(
food
+
water)
chronic
dietary
risk
from
existing
and
proposed
uses
of
oxytetracycline
are
below
HED's
level
of
concern
for
the
general
US
population
and
all
population
subgroups.
Oxytetracycline
chronic
aggregate
exposure
(
food
+
water)
was
estimated
at
0.000160
mg/
kg/
day
for
the
U.
S.
population
(
32%
of
the
cPAD)
and
0.000473
mg/
kg/
day
(
95%
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
All
Infants
(<
1
year
old)).
These
results
indicate
that
chronic
aggregate
dietary
exposure
to
oxytetracycline
from
food
and
drinking
water
is
below
HED's
level
of
concern
for
all
population
subgroups.

2.0
Ingredient
Profile
Oxytetracycline
is
an
antibiotic
bactericide/
fungicide
registered
for
use
on
pears,
peaches,
and
nectarines.
This
TRED
also
includes
a
requested
new
use
on
apples.

2.1
Summary
of
Supported
Uses
Table
2.1.
Overall
Use
Patterns
for
Oxytetracycline
Oxytetracycline
hydrochloride
Page
9
of
46
Crop
Max
Single
Rate
(
Lbs/
ai/
A)
Applications
per
Yr
Maximum
Seasonal
Rate
(
Lbs
/
A/
Yr)
Retreatment
Interval
(
RTI,
days)
Preharvest
Interval
(
days)

Pear
0.1847
10
1.847
4­
6
60
Peach,
Nectarine
0.6926
9
6.233
7
21
Oxytetracycline
calcium
Crop
Max
Single
Rate
(
Lbs/
ai/
A)
Applications
per
Yr
Maximum
Seasonal
Rate
(
Lbs
/
A/
Yr)
RTI
(
days)
Preharvest
Interval
(
days)

Pear
0.3150
10
3.15
4­
6
60
Peach,
Nectarine
0.6926
9
6.233
7
21
Apple
0.255
6
1.53
3­
6
60
2.2
Structure
and
Nomenclature
TABLE
2.2.
Oxytetracycline
Nomenclature
PC
Code
006304
Chemical
structure
OH
O
OH
O
OH
NH
2
O
OH
H
N
C
H
3
CH
3
CH
3
O
H
H
OH
Common
name
Oxytetracycline
Molecular
Formula
C22H24N2O9
Molecular
Weight
496.47
IUPAC
name
(
4S,
4aR,
5S,
5aR,
6S,
12aS)­
4­
dimethylamino­
1,4,4a,
5,5a,
6,11,12a­
octahydro­
3,5,6,10,12,12a­
hexahydroxy­
6­
methyl­
1,11­
dioxonaphthacene­
2­
carboxamide
CAS
name
4­
Dimethylamino­
3,5,6,10,12,12a­
hexahydroxy­
6­
methyl­
1,11­
dioxo­
1,4,4a,
5,5a,
6,11,12a­
octahydro­
naphthacene­
2­
carboxylic
acid
amide
CAS
#
79­
57­
2
2.3
Physical
and
Chemical
Properties
Page
10
of
46
Oxytetracycline
is
a
non­
volatile
solid
with
low
water
solubility.

TABLE
2.3
Physicochemical
Properties
of
Oxytetracycline
hydrochloride
and
Oxytetracycline
Calcium
Parameter
Value
Reference
Oxytetracycline
hydrochloride
(
PC
Code
006308)

Melting
point
Decomposes
above
180
°
C
RED
12/
29/
92
pH
2.4
(
1%
aqueous
solution)
RED
12/
29/
92
Density,
bulk
density,
or
specific
gravity
5.0
lbs/
ft3
1.98
g/
mL
(
bulk
density)
RD
D289846,
9/
9/
03,
S.
Malak
D167892,
9/
22/
92,
F.
Toghrol
Water
solubility
Freely
soluble
in
water
RD
D289846,
9/
9/
03,
S.
Malak
Solvent
solubility
Sparingly
soluble
in
alcohol
RD
D289846,
9/
9/
03,
S.
Malak
Vapor
pressure
N/
A;
water
soluble
salt
RD
D289846,
9/
9/
03,
S.
Malak
Dissociation
constant,
pK
N/
A;
water
soluble
salt
RD
D289846,
9/
9/
03,
S.
Malak
Octanol/
water
partition
coefficient
N/
A;
water
soluble
salt
RD
D289846,
9/
9/
03,
S.
Malak
UV/
visible
absorption
spectrum
Not
available
Oxytetracycline
calcium
(
PC
Code
006321)

Melting
point
Decomposes
above
180
°
C
RD
D203326,
9/
30/
94,
A.
Smith
pH
8.6
(
1%
aqueous
solution)
RED
12/
29/
92
Density,
bulk
density,
or
specific
gravity
Bulk
density:

0.39
g/
cc
free­
flowing
0.56
g/
cc
compressed
RD
D203326,
9/
30/
94,
A.
Smith
Water
solubility
g/
100
mL
at
23
°
C:

3.14
in
pH
1.2
water
0.05
in
pH
5
water
0.11
in
pH
7
water
3.86
in
pH
9
water
RD
D203326,
9/
30/
94,
A.
Smith
Solvent
solubility
Not
available
Vapor
pressure
Not
available
Dissociation
constant,
pKa
Not
available
Octanol/
water
partition
coefficient
K
=
<
10
RD
D203326,
9/
30/
94,
A.
Smith
Page
11
of
46
TABLE
2.3
Physicochemical
Properties
of
Oxytetracycline
hydrochloride
and
Oxytetracycline
Calcium
Parameter
Value
Reference
UV/
visible
absorption
spectrum
Not
available
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Rat
metabolism:
No
oxytetracycline
rat
metabolism
data
have
been
submitted.

Plant
metabolism:
No
oxytetracycline
plant
metabolism
data
have
been
submitted.

Livestock
metabolism:
No
oxytetracycline
livestock
metabolism
data
have
been
submitted.

Water
degradates:
No
oxytetracycline
water
metabolism
data
have
been
submitted.

No
guideline
metabolism
studies
were
submitted
for
rats,
plants,
or
livestock
due
to
a
data
waiver.
The
only
available
metabolism
data
for
oxytetracycline
involve
human
and
mouse
metabolism
studies
reported
in
the
open
literature.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
Due
to
the
widespread
use
of
oxytetracycline
as
a
drug,
and
the
low
residue
levels
expected
in
or
on
tree
fruit,
no
plant
metabolism
data
are
required
(
see
memo
of
W.
J.
Hazel
dated
4/
12/
88;
memo
of
W.
B.
Greer
dated
4/
19/
88;
and
memo
of
R.
B.
Perfetti
dated
10/
13/
92).
The
residue
of
concern
is
the
parent
compound,
oxytetracycline
per
se,
as
specified
in
40
CFR
180.337.

3.2.2
Description
of
Livestock
Metabolism
Due
to
the
widespread
use
of
oxytetracycline
as
a
drug,
and
the
low
residue
levels
expected
in
or
on
tree
fruit,
no
livestock
metabolism
data
are
required
(
see
memo
of
W.
J.
Hazel
dated
4/
12/
88;
memo
of
W.
B.
Greer
dated
4/
19/
88;
and
memo
of
R.
B.
Perfetti
dated
10/
13/
92).
The
residue
of
Page
12
of
46
concern
is
the
parent
compound,
oxytetracycline
per
se,
as
specified
in
40
CFR
180.337.

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
No
rotational
crop
metabolism
data
are
required
since
orchard
crops
are
not
rotated.

3.3
Environmental
Degradation
No
environmental
fate
studies
have
been
submitted
for
oxytetracycline.
The
studies
were
waived
in
the
reregistration
process
(
USEPA,
1993)
on
the
basis
of
limited
use
patterns
and
low
estimated
risks.
Some
fate
and
transport
data
for
oxytetracycline
were
located
from
product
chemistry
studies
and
the
open
literature.

3.4
Tabular
Summary
of
Metabolites
and
Degradates
Not
applicable
since
no
metabolism
data
were
submitted.

3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Not
applicable
since
no
metabolism
data
were
submitted.

3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Page
13
of
46
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Primary
Crop
oxytetracycline
per
se
oxytetracycline
per
se
Plants
Rotational
Crop
Not
Applicable
­
no
crop
rotation
from
orchard
crops
Not
Applicable
­
no
crop
rotation
from
orchard
crops
Ruminant
Not
Applicable
­
no
residues
expected
Not
Applicable
­
no
tolerances
required
Livestock
Poultry
Not
Applicable
­
no
residues
expected
Not
Applicable
­
no
tolerances
required
Drinking
Water
oxytetracycline
per
se
Not
Applicable
3.6.2
Rationale
for
Exclusion
of
Metabolites
and
Degradates
The
oxytetracycline
risk
assessment
team
has
determined
that
the
regulated
residues
in
apple,
peach,
nectarine,
and
pear
will
include
parent
only
for
the
purpose
of
tolerance
enforcement
and
risk
assessment.
The
basis
for
this
decision
is
that
due
to
the
widespread
use
of
oxytetracycline
as
a
drug,
and
the
low
residue
levels
expected
in
or
on
tree
fruit,
plant
and
livestock
metabolism
studies
were
waived.

Wet
apple
pomace
is
a
feedstuff
of
regulatory
interest
associated
with
apples,
while
peaches/
nectarines
and
pears
have
no
livestock
feedstuffs.
However,
quantifiable
residues
of
oxytetracycline
in
livestock
commodities
as
a
result
of
feeding
wet
apple
pomace
from
treated
apples
are
not
expected.
Therefore,
based
on
the
agricultural
uses
of
oxytetracycline,
HED
finds
there
is
no
reasonable
expectation
that
residues
of
concern
will
transfer
to
livestock
tissues
[
40
CFR
§
180.6(
a)(
3)].

4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
Oxytetracyclines
include
oxytetracycline,
oxytetracycline
calcium
and
hydroxyoxtetracycline
monhydrochloride.
The
toxicity
of
all
three
oxytetracyclines
would
be
expected
to
be
similar
and
shall
be
considered
equivalent
in
this
hazard
characterization.
Oxytetracycline
is
a
member
of
the
Page
14
of
46
tetracycline
family
of
antibiotics.
It
is
a
broad
spectrum
antibiotic
produced
by
the
actinomycete
Streptomyces
rimousus
and
became
available
for
use
in
1950.
Its
use
as
broad­
spectrum
antibiotic
is
possible
because
of
its
activity
against
a
wide
range
of
disease­
causing
bacteria.
The
chemical
name
of
oxytetracycline
is
2­
napthacenecarboxamide,
4­(
dimethylamino)­
1,
4,
4a,
5,
5a,
6,
11,
12a­
octahydro­
3,
6,
10,
12,
12a­
pentahydroxy­
6­
methyl­
1­
11­
dioxo.
The
information
available
on
the
effects
of
oxytetracycline,
oxytetracycline
calcium,
and
dihydroxy
tetracycline
monohydrochloride
in
laboratory
animals
is
sufficient
to
evaluate
the
toxicity
of
oxytetracycline
and
related
compounds.

Animal
Data
In
mice,
oxytetracycline
has
a
low
acute
toxicity,
being
a
Category
IV
for
oral
toxicity
(
LD50
>
7200
mg/
kg).
Historically,
the
data
requirements
for
the
acute
dermal,
inhalation,
primary
eye
irritation,
and
skin
sensitization
studies
in
animals
have
been
waived.

Oxytetracycline
has
low
toxicity
potential
when
administered
by
the
oral
route
to
animals.
In
the
rat,
the
liver
is
a
potential
target
organ
at
high
dose
levels
(
>
1,
250
mg/
kg/
day).
Long­
term
administration
of
oxytetracycline
to
male
and
female
rats
at
this
dose
led
to
fatty
metamorphosis
of
the
liver.
No
other
signs
of
hepatic
toxicity
were
observed
in
the
13­
week
oral
toxicity
study
or
the
prenatal
developmental
study
in
rats.
However,
the
available
database
did
not
demonstrate
the
potential
for
the
liver
to
be
the
primary
target
organ
in
other
animal
species
(
e.
g.
mice
or
dogs).
Clinical
signs
in
the
rat
included
increased
incidence
of
respiratory
signs
and
rough
hair
coat
and
decreased
maternal
survival.
The
most
common
effect
in
intermediate­
or
long­
term
oral
exposures
was
a
decrease
in
body
weight
and/
or
body
weight
gain.
In
a
13­
week
feeding
study
in
mice,
a
decrease
in
body
weight
was
observed
at
7,500
mg/
kg/
day.
In
a
103­
week
feeding
study
in
mice,
a
slight
decrease
in
body
weight
(
7­
9%)
was
observed
in
males
at
945
mg/
kg/
day.
No
adverse
effects
were
seen
in
mice
at
2,100
mg/
kg/
day
in
a
mouse
prenatal
developmental
study.

Toxicity
in
dogs
was
manifested
as
a
shift
from
a
predominantly
drug­
susceptible
population
of
enteric
lactose­
fermenting
organisms
to
a
multiple
antibiotic
resistant
population
in
intestinal
flora
isolated
from
fecal
samples
in
a
44­
week
feeding
study
(
see
section
4.4.2).
In
a
chronic
toxicity
study
in
dogs,
a
yellow
discoloration
of
the
thyroid
was
observed
in
all
dosed
animals
at
necropsy.
No
other
changes
in
clinical
signs,
mortality,
body
weight,
food
consumption,
macrosopy,
or
histopathology
were
reported
in
either
of
the
two
chronic
toxicity
studies
in
dogs.

No
evidence
of
neurotoxicity
was
observed
in
any
study.

In
developmental
toxicity
studies,
maternal
toxicity
was
evident
in
rats
as
a
dose­
related
increase
in
mortality.
A
dose­
related
decrease
in
fetal
body
weight
was
observed
in
rats.
The
high
incidence
of
maternal
deaths
and
fetotoxicity
noted
at
all
dose
levels
tested
did
not
allow
for
an
establishment
of
a
NOAEL
(
LOAEL
=
1200
mg/
kg/
day;
LDT).
No
maternal
or
developmental
toxicity
was
observed
in
mice
treated
up
to
2,100
mg/
kg/
day.
No
treatment­
related
external,
Page
15
of
46
visceral,
or
skeletal
abnormalities
were
found
in
either
species.
Historically,
the
requirement
for
a
rabbit
prenatal
developmental
toxicity
study
has
been
waived.
Given
the
data
available
on
the
toxicity
of
oxytetracyclines
in
rats,
mice
and
humans
and
the
lack
of
reported
adverse
effects
to
children
and
infants,
further
studies
will
not
provide
additional
information
for
risk
assessment.

In
a
study
citation
that
was
reported
by
a
Joint
FAO/
WHO
committee
in
2000,
reproductive
parameters
in
rats
such
as
litter
size,
litter
and
pup
weight,
and
the
number
and
percent
of
live
or
dead
fetuses
did
not
show
significant
differences
in
the
first
or
second
generations.
Additionally,
growth
rate
was
not
significantly
affected.
The
NOAEL
in
this
study
was
18
mg/
kg/
day
(
note
that
only
1
dose
was
tested).
Historically,
the
data
requirement
for
the
2­
generation
reproductive
study
was
waived.
A
reproductive
study
is
unlikely
to
result
in
a
more
sensitive
endpoint
than
the
one
already
being
used
for
risk
assessment.

Although
benign
tumors
were
observed
in
rats,
HED
has
no
carcinogenicity
concerns
for
this
chemical.
In
F344/
N
rats,
histological
examination
showed
a
dose
related
increase
in
the
incidence
of
benign
phaeochromcytomas
in
the
adrenal
gland
of
male
rats
fed
2,500
mg/
kg/
day.
In
females
an
increase
in
the
incidence
of
adenomas
of
the
pituitary
gland
was
found
in
the
highest
dose
group
(
1,875
mg/
kg/
day).
Mice
fed
up
to
1,875
mg/
kg/
day
exhibited
no
evidence
of
carcinogenicity.
The
bacterial
reverse
mutation
test,
chromosome
aberration
study,
and
sister
chromatid
exchange
assays
were
all
negative,
with
and
without
metabolic
activation.
The
mouse
lymphoma
forward
mutation
assay
revealed
that
oxytetracycline
was
mutagenic
only
with
metabolic
activation,
however,
the
dose
levels
were
close
to
toxic
concentrations
and
the
positive
effect
in
the
in
vivo
micronucleus
assay
in
mice
was
not
dose
related.

The
microbiological
effects
of
oxytetracycline
were
investigated
by
studies
examining
the
induction
of
drug­
resistant
organisms
in
dogs.
In
a
6­
week
study
in
dogs,
there
was
no
increase
in
the
level
of
resistant
fecal
coliforms
at
2
ppm
in
the
diet
(
equivalent
to
0.05
mg/
kg/
day).
Dogs
receiving
10
ppm
(
equivalent
to
0.25
mg/
kg/
day)
displayed
an
increase
in
a
multiple
antibioticresistant
population
of
enteric
lactose­
fermenting
organisms.

There
is
a
relevant
study
on
mice
in
the
open
literature.
After
oral
administration
of
47.6
mg
14Clabeled
hydroxyoxytetracycline
monohydrochloride/
kg
b.
w.
to
mice,
72%
of
the
applied
dose
was
found
in
the
large
intestine
after
2
hours;
only
5%
was
absorbed,
of
which
the
major
portion
(
3.6%)
was
excreted
in
the
urine.
In
the
liver
1.9%
and
1.1%
of
the
dose
applied
was
recovered
after
1
and
2
hours,
respectively.

Mode
of
Action
and
Data
from
Therapeutic
(
Non­
pesticidal)
Uses
Tetracyclines
exert
their
activity
in
bacteria
by
inhibiting
protein
synthesis.
Inhibition
occurs
when
oxytetracycline
binds
to
the
30S
ribosomes,
preventing
aninoacyl
tRNA
from
reading
the
mRNA
ribosome
complex,
thereby
preventing
polypeptide
chain
elongation.
High
concentrations
of
tetracyclines
also
impair
protein
synthesis
in
mammalian
cells.
However,
the
active
transport
Page
16
of
46
system
found
in
bacteria
is
absent
in
these
cells
and
there
are
differences
in
sensitivity
at
the
ribosomal
level.
These
differences
are
likely
to
be
important
determinants
in
the
selective
action
of
tetracyclines.
In
additional
to
the
available
animals
studies
and
reports,
there
is
extensive
data
on
the
toxicity
of
oxytetracyclines
in
humans.
In
humans,
oxytetracycline
is
administered
orally
and
intravenously
to
treat
infectious
diseases
caused
by
a
wide
variety
of
microorganisms
such
as
chlamydia,
rickettsial,
mycoplasma
pneumonia,
spirochetes,
gram­
negative
bacteria
(
Bartonella
bacilliformis,
Pasteurella
pestis,
Brucella
sp.),
and
gram­
positive
bacteria
(
Streptococcus
sp.,
Staphylococcus
aureus,
Neisseria
gonorrhoeae).
Both
the
oral
and
intravenous
dose
for
adults
ranges
from
1
to
2
grams
per
day.
The
daily
oral
dose
for
children
is
25
to
50
mg/
kg
daily
in
two
to
four
divided
doses.

The
antibiotic
may
cause
gastrointestinal
irritation,
mostly
after
oral
administration,
in
some
but
not
in
all
individuals.
Epigastric
burning
and
distress,
abdominal
discomfort,
nausea,
vomiting
and
diarrhea
may
occur
which
may
be
lessened
by
administrating
oxytetracycline
with
a
meal
and/
or
at
more
frequent
intervals
and
smaller
doses.
Intravenous
administration
may
produce
thrombophlebitis.
Oxytetracycline
appears
to
be
one
of
the
least
hepatoxic
among
the
tetracyclines.
Most
hepatic
toxicity
develops
in
humans
receiving
2000
mg
or
more
of
drug
per
day
parenterally.
This
effect
may
occur
when
large
quantities
are
administered
orally.
Pregnant
women
appear
to
be
susceptible
to
severe
tetracycline­
induced
hepatic
damage.
Children
under
7
years
of
age
may
develop
a
brown
discoloration
of
the
teeth.
Treatment
of
pregnant
women
may
also
produce
discoloration
of
the
teeth
of
infants.
Oxytetracycline
is
deposited
in
the
skeleton
of
fetuses
and
children
which
can
produce
depression
of
bone
growth.
However,
this
is
readily
reversible
if
the
period
of
exposure
to
the
drug
is
short.
(
Hardman
et
al.,
10th
ed)

Additionally,
various
skin
reactions
such
as
morbiliform
rashes,
urticaria,
and
generalized
dermatitis
may
occur
following
exposure
to
oxytetracyclines
in
humans,
but
they
are
rare.
Angioedema
and
anaphylaxis
may
develop.
Other
effects
such
as
burning
sensation
of
the
eyes,
cheilosis,
brown
or
black
coating
of
the
tongue,
atrophic
or
hypertrophic
glossitis,
pruritus
ani
or
vulvae
or
vaginitis,
fever
and
eosinophilia
may
persist
for
weeks
after
cessation
of
therapy.
Administration
of
oxytetracycline
to
undernourished
adults
results
in
weight
loss,
increased
urinary
but
not
fecal
nitrogen
excretion,
negative
nitrogen
balance,
and
elevated
serum
nonprotein
nitrogen
concentrations.
Administration
of
oxytetracycline
may
lead
to
development
of
superinfections
by
strains
of
bacteria
or
yeasts
resistant
to
the
agent
(
see
antimicrobial
resistance
section).
(
Hardman
et
al.,
10th
ed)

Tetracyclines
as
a
class
are
incompletely
absorbed
from
the
gastrointestinal
tract.
The
percentage
of
an
oral
dose
of
oxytetracycline
absorbed
by
the
gastrointestinal
tract
is
60
to
80%.
Most
absorption
takes
place
in
the
stomach
and
upper
small
intestine.
Absorption
of
tetracyclines
is
impaired
by
chelation
of
divalent
or
trivalent
cations.
Therefore,
the
absorption
of
oxytetracycline
is
compromised
by
the
concurrent
ingestion
of
dairy
products,
aluminum
hydroxide
gels,
calcium,
magnesium,
iron
and
zinc
salts,
and
bismuth
subsalicylates.
Tetracyclines
are
widely
distributed
through
the
body
and
into
tissues
and
secretions,
particularly
in
the
liver,
kidney,
bones
and
teeth.
Tetracyclines
are
eliminated
primarily
by
the
kidney,
although
they
are
also
concentrated
in
the
Page
17
of
46
liver
and
excreted
by
way
of
the
bile
into
the
intestines.
Renal
clearance
of
tetracyclines
is
by
glomerular
filtration.
From
10­
35%
of
the
dose
of
oxytetracycline
is
excreted
in
active
form
in
the
urine
as
the
parent
drug.
(
Hardman
et
al.,
10th
ed)

4.1.1
Qualitative
Assessment
of
Antimicrobial
Resistance
Bacterial
resistance
to
oxytetracycline
as
a
result
of
drug
use
has
long
been
recognized.
HED
recognizes
that
pesticidal
uses
of
oxytetracycline
may
contribute
to
antibiotic
resistance
of
bacterial
pathogens
with
potential
adverse
public
health
consequences.
This
section
of
the
risk
assessment
is
a
qualitative
assessment
of
the
development
of
antibiotic
resistance
from
pesticidal
uses.
This
is
a
qualitative
assessment
because
not
enough
data
are
available
to
quantitate
development
of
resistance.

Oxytetracycline
has
two
major
agricultural
uses.
It
is
used
to
treat
plant
and
animal
disease
and
at
subtherapeutic
doses
in
animals
to
promote
growth.
Clinically,
oxytetracycline
is
a
second­
line
of
defense
against
a
host
of
infections.
The
pesticidal
use
of
oxytetracycline
on
plants
is
small
compared
to
the
animal
and
human
usage;
it
has
been
estimated
as
<
0.5%
of
all
antibiotic
uses
(
McManus
et
al.).
The
mechanisms
of
action
of
antimicrobials
is
based
on
effecting
the
pathogenic
organism
and
not
the
host.
The
database
for
oxytetracycline
demonstrates
that
it
is
indeed
of
low
toxicological
concern
as
most
adverse
effects
seen
following
oral
oxytetracycline
treatment
in
animals
are
observed
at
very
high
dosages
(
e.
g,
near
or
above
1000
mg/
kg/
day
in
animals).
In
humans,
there
are
demonstrated
toxicological
concerns
associated
with
the
use
of
oxytetracycline,
although
the
risk
of
adverse
effects
are
low.

Of
more
recent
concern
are
the
documented
cases
of
tetracycline
resistance
and
a
marked
potential
for
multi­
drug
resistance
and
the
development
of
super
infections
that
may
result
from
this
resistance.
Resistance
to
antibiotics
has
reduced
the
clinical
effectiveness
of
the
tetracyclines
over
the
past
few
decades.
Microorganisms
often
display
cross­
resistance
across
the
tetracycline
family
of
compounds,
that
is
microorganisms
that
become
resistant
to
one
tetracycline
frequently
exhibit
resistance
to
others.
Of
the
microorganisms
which
cause
human
disease,
bacteria
have
and
continue
to
develop
resistance
to
antibiotics
in
general,
particularly
to
enterobacters,
enterococci
and
pseudomonads.
Specifically,
most
strains
of
gram­
positive
bacteria
which
cause
human
diseases
are
resistant
to
tetracyclines.
Many
of
the
enterobacteriaceae
(
aerobic
gram­
negative
bacilli)
have
also
developed
resistance
to
tetracyclines.
However,
there
are
other
alternatives
to
treatment
with
oxytetracycline.
These
alternatives
include
but
are
not
limited
to
(
usually
first­
line
agents)
gentamicin,
penicillins,
and
others.

Although
oxytetracycline
has
been
used
in
plant
agriculture
for
over
30
years
without
any
documented
evidence
of
human
health
effects,
it
is
imperative
that
its
potential
impact
on
human
health
and
the
environment
be
further
assessed
based
on
the
potential
for
the
development
of
antibiotic
resistance.
Page
18
of
46
Given
that
the
development
of
antibiotic
resistance
could
pose
a
major
threat
to
human
health,
that
increased
application
of
antibiotics
in
the
environment
has
the
potential
to
impact
the
acquisition
of
human­
pathogen
resistance
to
antibiotics
and
the
general
lack
of
substantial
data,
the
HED
has
adopted
a
qualitative
risk
assessment
process
similar
to
that
of
the
Food
and
Drug
Administration's
Center
for
Veterinary
Medicine
in
evaluating
animal
drugs
Guidance
for
Industry
#
152
(
URL:
http://
www.
fda.
gov/
cvm/
Documents/
fguide152.
doc)
As
a
part
of
the
hazard
assessment/
characterization
of
oxytetracycline,
the
risk
assessment
team
will
qualitatively
consider
the
potential
impact
on
human
health
that
the
pesticidal
uses
of
oxytetracycline
might
pose
focusing
on
the
following
assessments:
1)
Release
Assessment:
the
probability
that
resistant
bacteria
are
present
in
the
commodity
as
a
consequence
of
pesticidal
use,
2)
Exposure
Assessment:
the
probability
for
humans
to
ingest
bacteria
in
question
from
a
relevant
food
commodity,
and
3)
Consequence
assessment:
the
probability
that
human
exposure
to
resistant
bacteria
results
in
an
adverse
health
consequence.
Criteria
1
&
2
will
be
assigned
either
a
high,
medium
or
low
classification
and
criteria
3
will
be
assigned
as
important,
highly
important
or
critically
important
classification.
The
overall
risk
estimate,
which
integrates
the
components
of
risk
assessment
into
an
overall
conclusion,
provides
a
qualitative
indication
of
the
potential
to
human
health
of
the
proposed
use
of
this
antimicrobial
pesticide
and
is
ranked
as
high,
medium,
or
low.
The
qualitative
assessment
is
outlined
below:

Release
Assessment
The
probability
that
tetracycline
resistant
bacteria
are
present
in
the
commodity
as
a
consequence
of
the
pesticidal
use
of
oxytetracycline
use
is
of
medium
concern.
Application
of
antibiotics
by
occupational
handlers
to
commodities
in
the
orchard
is
of
concern
not
only
because
of
resistance
pressure,
but
because
of
its
potential
to
affect
microorganisms
in
the
orchard,
whether
they
are
beneficial,
innocuous,
pathogenic
or
otherwise.
Orchards
are
treated
prophylactically
with
antibiotics
in
the
early
spring
when
trees
are
most
susceptible
to
infection.
It
is
believed
that
by
harvest,
these
antibiotics
have
fully
degraded
into
the
environment.
In
the
US,
oxytetracycline
has
been
used
on
pear
and
apple
for
control
of
E.
amylovora
and
on
peach
and
nectarine
for
control
of
X.
arboricola.
There
have
been
reports
of
tetracycline
resistant
strains
of
E.
amylovora
in
apple
orchards,
however,
the
extent
of
this
resistance
is
unknown
at
present
time
(
McManus
et
al).
What
is
known
is
that
these
resistance
genes
are
carried
on
mobile
genetic
elements
such
as
plasmids
and
transposons
identical
or
similar
to
those
described
in
tetracycline
resistant
bacteria
of
environmental,
animal
and
human
origins.
Transmission
of
resistant
genes
on
mobile
elements
makes
them
easier
to
transmit
between
bacterial
species
than
chromosomally
mediated
resistance
mechanisms.
Genes
coding
for
antibiotic
resistance
can
be
transferred
between
bacteria
and
it
is
possible
for
bacteria
never
exposed
to
the
antibiotic
to
acquire
resistance
from
those
which
have.
Additionally,
tetracyclines
can
select
for
multi­
drug
efflux
pumps
in
bacteria
that
are
capable
of
conveying
resistance
to
other
classes
of
antimicrobials.
Considering
these
factors,
there
is
a
moderate
concern
that
resistant
genes
present
in
the
commodity
and
orchards
can
be
released
into
the
environment
based
on
oxytetracycline's
pesticidal
uses.
The
default
of
medium
concern
is
justified
based
on
the
confirmed
presence
of
resistant
genes
in
the
orchards
and
the
residual
uncertainty
related
to
the
extent
of
the
resistance
present.
Since,
to
date,
there
are
no
reports
available
regarding
the
quantitative
amounts
of
tetracycline
resistant
bacteria
on
the
plant
commodities,
it
is
possible
to
further
refine
this
assessment
by
consideration
of
monitoring
data
Page
19
of
46
for
antimicrobial
resistance
among
bacteria
isolated
from
fruits
that
are
commonly
treated
with
antibiotic
pesticides.
We
recommend
that
the
registrants
supply
monitoring
data
for
antimicrobial
resistance
to
oxytetracycline
in
the
orchards.
In
addition,
when
additional
appropriate
screening
and/
or
testing
protocols
have
been
developed,
oxytetracycline
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
the
release
of
tetracycline
resistant
bacteria
into
the
environment.

Exposure
Assessment
The
probability
of
humans
ingesting
resistant
bacteria
in
question
from
a
relevant
food
commodity
(
peaches,
pears,
apples,
and/
or
nectarines)
is
of
medium
concern.
There
is
a
possibility
of
the
oxytetracycline
resistant
plant
pathogens
being
ingested
by
humans
and
transferring
that
resistance
to
bacteria
that
are
responsible
for
causing
broad­
spectrum
human
infections.
The
default
ranking
as
a
medium
risk
for
exposure
is
justified
by
the
fact
that
there
is
a
medium
probability
that
resistant
plant
pathogens
are
ingested.
Although
there
is
a
medium
concern
that
humans
will
ingest
resistant
bacteria
present
on
food
commodities,
it
is
possible
to
further
refine
the
assessment
if
the
pesticidal
use
is
significantly
much
less
than
the
human
and
animal
therapeutic
uses
and
animal
non­
therapeutic
uses
(
e.
g.,
as
a
growth
promoter).
Accurate
information
on
oxytetracycline
use
on
plants
vs.
its
therapeutic
human
and
animal
uses
and
non­
therapeutic
animal
uses
would
give
further
insight
to
the
scope
of
the
exposure
and
assist
HED
scientists
in
refining
the
assessment
in
order
to
modify
our
default
characterization.
We
recommend
that
the
registrants
supply
usage
data
for
oxytetracycline
on
fruit
trees
currently
used
in
order
to
incorporate
the
level
of
oxytetracycline
pesticidal
uses
verses
human
and
animal
agricultural
uses
into
the
risk
assessment.
In
addition,
when
additional
appropriate
screening
and/
or
testing
protocols
have
been
developed,
oxytetracycline
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
exposure
of
tetracycline
resistant
bacteria
to
humans
via
its
plant
agricultural
use.

Consequence
Assessment
The
probability
that
human
exposure
to
resistant
bacteria
results
in
an
adverse
health
consequence
is
highly­
important.
Naturally
occurring
host
flora
in
the
intestine
are
a
potential
reservoir
of
genes
that
may
become
resistant
to
oxytetracycline
and
which
may
confer
that
resistance
to
pathogenic
bacteria.
Since
many
of
the
tetracyclines
are
incompletely
absorbed
from
the
gastrointestinal
tract,
high
concentrations
are
reached
in
the
intestinal
contents
and
enteric
flora
are
markedly
altered.
After
repeated
exposures,
it
is
possible
for
resistant
strains
of
aerobic
and
anaerobic
coliform
microorganisms
and
gram­
positive
spore­
forming
bacteria
to
appear.
This
could
increase
the
potential
for
two
human
health
consequences
of
antimicrobial
resistance,
an
increase
in
food
borne
illnesses
and
an
increase
in
the
number
of
treatment
failures.
Tetracyclines
are
utilized
for
treatment
of
a
variety
of
diseases
and
infections.
Tetracyclines
are
a
first
choice
for
the
control
of
diseases
caused
by
microorganisms
other
than
bacteria
including
chlamydiae,
rickettsiae,
mycoplasmas,
and
spirochetes.
It
is
important
to
note
that
the
CDC
has
indicated
that
resistance
to
the
tetracyclines
by
chlamydia,
mycoplasmas,
rickettsiae
and
spirochetes
has
not
occurred
in
approximately
50
years
of
clinical
use.
Oxytetracyclines
are
also
broad­
spectrum
antibiotics
that
are
used
for
treating
a
wide
variety
of
bacterial
infections
including
infections
of
Page
20
of
46
the
lungs,
urinary
system,
respiratory
system,
skin,
and
eyes.
They
are
also
used
as
a
prophylactic
treatment
following
surgery
or
injury.
Broad­
spectrum
antibiotics
are
used
in
a
variety
of
clinical
situations.
They
are
often
used
empirically
prior
to
identifying
the
causative
bacteria
for
an
infection.
Moreover,
they
are
used
when
drug
resistant
bacteria
do
not
respond
to
narrow­
spectrum
antibiotics
or
in
the
case
of
superinfections,
where
there
are
multiple
types
of
bacteria
causing
illness.
It
should
be
noted,
however,
that
although
oxytetracyclines
are
broadspectrum
antibiotics,
they
are
primarily
used
as
second­
line
agents
for
the
control
of
most
diseases
and
infections
caused
by
bacteria
and
there
are
other
alternatives
to
treatment
with
oxytetracycline.
There
is
already
a
moderate
level
of
resistance
to
these
antibiotics
by
bacteria.
Gentamicin
and
penicillins
are
often
the
first­
line
agents
against
bacteria.
However,
oxytetracycline
has
recently
been
used
as
a
second­
line
agent
for
bacteria
which
pose
significant
health
threats
such
as
anthrax.
Given
the
far­
reaching
use
of
oxytetracycline
and
its
use
as
a
second­
line
of
defense
against
potentially
deleterious
microorganisms,
the
classification
of
highlyimportant
is
justified.
When
additional
appropriate
screening
and/
or
testing
protocols
have
been
developed,
oxytetracycline
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
human
exposure
of
tetracycline
resistant
bacteria
to
humans
via
its
plant
agricultural
use.

Overall
Risk
Estimate
The
overall
risk
of
the
development
of
antibiotic
resistance
to
oxytetracycline
in
human
health
and
the
environment
is
medium.
Following
the
recommendation
of
FDA's
Guidance
#
152,
a
medium
concern
for
release
and
exposure
and
a
highly­
important
concern
for
consequence
results
in
an
overall
risk
assessment
rank
as
medium.
Please
note
that
the
overall
risk
estimate
can
be
impacted
by
submission
of
monitoring
data
and
usage
data.
While
there
are
no
monitoring
data
available,
the
estimated
percentage
of
antibiotics
applied
to
plants
compared
to
all
other
antibiotic
use
is
<
0.5%
(
McManus
et
al).
Monitoring
studies
(
see
data
needs
[
Section
9.4]
for
suggestions)
and
accurate
information
on
the
usage
of
oxytetracycline
on
plants
would
allow
for
refinements
of
default
assumptions.

Table
4.1a
Acute
Toxicity
Profile
­
Test
Substance
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.11
Acute
oral
[
mice]
No
MRID
LD50
=
7,200
mg/
kg
IV
Page
21
of
46
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
(
mice)
No
MRID
National
Toxicology
Program
(
NTP)
study
0,
3100,
6300,
12500,
25000,
or
50,000
ppm
M
&
F:
0,
465,
945,
1875,
3750,
7500
mg/
kg/
d
NOAEL
=
3750
mg/
kg/
day
LOAEL
=
7500
mg/
kg/
day
based
on
decreases
in
body
weight.

870.3150
90­
Day
oral
toxicity
(
rats)
No
MRID
National
Toxicology
Program
(
NTP)
study
0,
3100,
6300,
12500,
25000,
or
50,000
ppm
0,
155,
315,
625,
1250,
2500
mg/
kg/
day
NOAEL
=
2500
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

870.3700a
Prenatal
developmental
in
(
rats)
00932391
Oxytetracycline
hydrochloride
0,
1200,
1350,
or
1500
mg/
kg/
day
Maternal
NOAEL
=
not
identified
LOAEL
 
1200
mg/
kg/
day
based
on
increased
incidence
of
respiratory
signs
and
rough
hair
coat
and
decreased
body
weight
gain,
mortality,
and
percent
of
treated
dams
found
pregnant
(
LDT).

Developmental
NOAEL
=
not
identified
LOAEL
 
1200
mg/
kg/
day
based
on
decreased
fetal
body
weights
(
LDT).
Page
22
of
46
870.3700b
Prenatal
developmental
in
(
mice)
00132392
Oxytetracycline
hydrochloride
0,
1325,
1670,
and
2100
mg/
kg/
day
Maternal
NOAEL
 
2100
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

Developmental
NOAEL
 
2100
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

870.3800
Reproduction
and
fertility
effects
(
rat)
No
MRID
Oxytetracycline
hydrochloride
0
or
360
ppm
0
or
18
mg/
kg/
day
Parental/
Systemic
NOAEL=
18
mg/
kg/
day
LOAEL
=
not
identified.

Reproductive
NOAEL
and
LOAEL
>
18
mg/
kg/
day.
No
effects
at
the
highest
dose
tested.

Offspring
NOAEL
=
18
mg/
kg/
day
LOAEL
=
not
identified.

870.4100a
Chronic
toxicity
(
rat:
Osborne­
Mendel)
No
MRID
0,
1000
or
3000
ppm
0,
5,
50
or
150
mg/
kg/
day
NOAEL
=
150
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

870.4100b
Chronic
toxicity
(
rat:
Sprague­
Dawley)
No
MRID
0,
100,
or
1000
ppm
0,
5,
or
50
mg/
kg/
day
NOAEL
=
50
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

870.4100c
Chronic
toxicity
(
dog)
00132394
0,
100,
3000,
or
10000
ppm
0,
2.5,
75,
or
250
mg/
kg/
day
NOAEL
=
250
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.
Page
23
of
46
870.4100d
Chronic
toxicity
(
dog)
00132395
0,
5000,
10000
ppm
0,
125,
or
250
mg/
kg/
day
NOAEL
=
125
mg/
kg/
day
(
HDT)

LOAEL
=
not
identified.

870.4200
Carcinogenicity
(
mice)
00159856
Oxytetracycline
hydrochloride
0,
6300,
12500
ppm
0,
945,
1875
mg/
kg/
day
NOAEL
=
945
mg/
kg/
day
LOAEL
=
1875
mg/
kg/
day
based
on
decreased
body
weight
in
male
mice.

No
evidence
of
carcinogenicity
870.4300
Combined
chronic
toxicity/
carcinogeni
city
(
rat)
00159856
Oxytetracycline
hydrochloride
0,
25000,
50000
ppm
0,
1250,
or
2500
mg/
kg/
day
NOAEL
=
not
identified.

LOAEL
=
1250
mg/
kg/
day
based
on
fatty
metamorphosis
of
the
liver.

No
evidence
of
carcinogenicity
Bacterial
reverse
mutation
test
870.5100
No
MRID
NTP
Study
Oxytetracycline
hydrochloride
0­
1
µ
g/
ml
in
DMSO
Negative
up
to
1
µ
g/
plate
with
or
without
metabolic
activation.

Mouse
Lymphoma
forward
mutation
assay
870.5195
No
MRID
NTP
Study
Oxytetracycline
hydrochloride
12.5­
800
µ
g/
ml
Concentrations
of
100
and
200
mg/
ml
were
mutagenic
in
L5178Y/
TK+/­
mouse
lymphoma
cells,
only
with
metabolic
activation.

Chromosome
aberration
assay
(
CHO
cells)

870.5375
No
MRID
NTP
Study
Oxytetracycline
hydrochloride
80­
200
µ
g/
ml
700­
900
µ
g/
ml
Negative
up
to
900
µ
g/
ml
with
or
without
metabolic
activation
Page
24
of
46
Sister
chromatid
exchange
assay
(
CHO
cells)

870.5900
No
MRID
NTP
Study
Oxytetracycline
hydrochloride
60,
70
and
80
µ
g/
ml
400,
500
and
700
µ
g/
ml
Negative
up
to
700
µ
g/
ml
with
or
without
metabolic
activation.

870.6200a
Acute
neurotoxicity
screening
battery
NA
870.6200b
Subchronic
neurotoxicity
screening
battery
NA
870.6300
Developmental
neurotoxicity
NA
870.7485
Metabolism
and
pharmacokinetics
(
species)
Data
requirement
historically
waived.
However
a
study
from
open
literature
is
available.
Oral
administration
of
47.6
mg
14C­
labeled
hydroxyoxytetracycline
monohydrochloride/
kg
b.
w.
to
mice,
72%
of
the
applied
dose
was
found
in
the
large
intestine
after
2
hours;
only
5%
was
absorbed,
of
which
the
major
portion
(
3.6%)
was
excreted
in
the
urine.
In
the
liver
1.9%
and
1.1%
of
the
dose
applied
was
recovered
after
1
and
2
hours,
respectively.

Special
studies:

Antimicrobial
resistance
(
dogs)
40840101
NTP
Oxytetracycline
0,
2,
or
10
ppm
0,
0.05
or
0.25
mg/
kg/
day
NOAEL
=
0.05
mg/
kg/
day
LOAEL
=
0.25
mg/
kg/
day
based
on
a
shift
from
a
predominantly
drug­
susceptible
population
of
enteric
lactose­
fermenting
organisms
to
a
multiple
antibioticresistant
population
in
intestinal
flora.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
Historically,
all
the
toxicological
data
requirements
for
oxytetracycline
have
been
waived.
The
prenatal
developmental
and
carcinogenicity
studies
in
rats
and
mice
were
the
only
acceptable
studies
submitted
to
the
agency.
However,
given
the
extensive
literature
and
study
reports
Page
25
of
46
available
on
the
oxytetracyclines,
this
risk
assessment
takes
a
weight­
of­
the­
evidence
approach,
considering
the
available
data
from
a
variety
of
sources,
including
studies
submitted
and
reviewed
by
the
agency,
the
National
Toxicology
Program,
the
WHO,
the
FDA,
and
open
literature
studies.
The
information
available
on
the
effects
of
oxytetracycline
in
laboratory
animals
is
sufficient
to
evaluate
the
toxicity
of
oxytetracycline
and
related
compounds.
Based
on
the
information
available
from
these
sources,
the
database
is
complete
and
there
are
no
datagaps.

4.2.2
Evidence
of
Neurotoxicity
Neurotoxicity
studies
have
not
been
conducted
with
oxytetracycline.
However,
no
evidence
of
neurotoxicity
was
observed
in
any
study.
No
clinical
signs
indicative
of
toxicity
were
noted
in
subchronic
and
chronic
studies
in
dogs,
rats,
or
mice.

4.2.3
Developmental
Toxicity
Studies
Rat
Developmental
Studies
In
a
rat
prenatal
developmental
study
(
MRID
00932391),
thirty­
six
female
Charles
River
CD
(
COBS)
rats
were
dosed
by
gavage
during
days
6
through
15
of
gestation
with
1,200,
1,350,
or
1,500
mg/
kg/
day
of
oxytetracycline
hydrochloride.
Thirty­
seven
control
dams
received
corn
oil
during
the
same
time
period.
There
were
dose­
related
decreases
in
maternal
survival
and
body
weight
gain,
and
increases
in
incidence
of
breathing
difficulties
and
rough
coat.
In
addition,
there
were
significant
dose­
related
decreases
in
the
percent
of
treated
dams
found
pregnant.
There
was
also
a
dose­
related
decrease
in
fetal
body
weight.
The
high
incidence
of
maternal
deaths
and
the
fetotoxicity
noted
at
all
dose
levels
tested
did
not
allow
for
an
establishment
of
a
NOAEL.
The
LOAEL
was
1,200
mg/
kg/
day
(
lowest
dose
tested).
The
significant
findings
discussed
in
this
study
can
be
attributed
to
the
excessive
dose
levels
used,
thereby
overly
stressing
the
treated
dams.

In
a
mouse
prenatal
developmental
study
(
MRID
00132392),
groups
of
42
female
CD­
1
mice
were
dosed
by
gavage
during
days
6
through
15
of
gestation
with
0,
1,350,
1,670,
or
2,100
mg/
kg/
day
of
oxytetracycline
hydrochloride.
No
adverse
effects
were
demonstrated.
The
NOAEL
for
maternal
and
developmental
toxicity
in
this
study
was
2,100
mg/
kg/
day
(
highest
dose
tested).

Rabbit
Development
Study
Historically,
the
requirement
for
a
rabbit
prenatal
developmental
toxicity
study
has
been
waived.
Given
the
data
available
on
the
toxicity
of
oxytetracycline
in
rats
and
mice
and
the
lack
of
reported
adverse
effects
to
children
and
infants,
further
studies
will
not
provide
additional
information
for
risk
assessment.
Page
26
of
46
4.2.4
Reproductive
Toxicity
Study
Historically,
the
data
requirement
for
the
2­
generation
reproductive
study
was
waived.
The
cRfD
derived
from
the
resistance
study
in
mature
beagles
will
be
protective
for
all
effects.
Data
gathered
from
further
studies
will
not
provide
additional
information
for
risk
assessment.

Although
the
data
requirement
was
waived
by
the
agency,
a
literature
study
conducted
in
1954
and
cited
by
the
WHO
is
available.
In
a
reproduction
study,
groups
of
female
and
10
male
Wistar
rats
were
fed
diets
containing
0
or
360
ppm
oxytetracycline
hydrochloride
beginning
at
weaning
(
23
days
of
age).
Animals
were
first
mated
at
120
days
of
age.
A
second
mating
was
performed
one
month
after
the
weaning
of
the
first
litter.
One
male
and
one
female
of
these
second
litters
were
mated
and
effects
on
reproduction
and
lactation
were
determined
in
the
second
generation.
Growth
rate
was
not
significantly
affected.
Reproductive
parameters
such
as
litter
size,
litter
and
pup
weight,
and
the
number
and
percent
of
live
or
dead
fetuses
did
not
show
significant
differences
in
the
first
or
second
generations.
Dosed
pups
of
both
generations
gained
significantly
more
weight
from
days
3­
21
post
partum
compared
to
controls.
The
NOAEL
in
this
study
was
360
ppm
oxytetracycline
hydrochloride,
equivalent
to
18
mg/
kg/
day.

4.2.5
Additional
Information
from
Literature
Sources
Extensive
information
is
available
from
literature
sources
and
have
been
cited
where
appropriate
in
the
risk
assessment.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
No
quantitative
or
qualitative
evidence
supports
increased
susceptibility
of
rat
or
mouse
fetuses
from
in
utero
exposure
to
oxytetracycline
in
the
developmental
toxicity
studies.
Effects
on
offspring
body
weight
were
seen
in
the
presence
of
systemic
effects
in
the
dam.
The
data
requirement
for
the
2­
generation
reproduction
study
has
been
waived
but
a
study
available
in
literature
demonstrates
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
rats.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
There
is
a
low
degree
of
concern
and
no
residual
uncertainties;
therefore,
the
FQPA
safety
factor
can
be
adjusted
to
1X.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
Page
27
of
46
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
The
available
data
on
the
toxicity
of
oxytetracycline
do
not
support
the
recommendation
for
a
developmental
neurotoxicity
study.

4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
The
available
data
on
the
toxicity
of
oxytetracycline
do
not
support
the
recommendation
for
a
developmental
neurotoxicity
study.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
and
the
General
Population
No
appropriate
endpoint
for
females
age
13­
49
or
for
the
general
population
attributable
to
a
single
exposure.

4.4.2
Chronic
Reference
Dose
(
cRfD)

Studies
Selected:
Microbiological
effects
in
dogs.

MRID
No.:
40840101(
dog;
NTP
study)

Executive
Summary:
Study
1­
Microbiological
Effects
in
Dogs
Mature
beagles
were
fed
a
ground­
meal
diet
containing
0,
2,
or
10
ppm
of
oxytetracycline
for
44
days
(
equivalent
to
0,
0.05,
or
0.25
mg/
kg/
day).
Fecal
samples
from
individual
animals
were
collected
during
the
experimental
period
and
examined
for
resistant
coliforms
by
a
comparative
plate
counting
technique.
The
10
ppm
(
0.25
mg/
kg/
day)
diet
resulted
in
a
shift
from
a
predominantly
drug­
susceptible
population
of
enteric
lactose­
fermenting
organisms
to
a
multiple
antibiotic­
resistant
population.
A
shift
to
resistance
did
not
occur
in
the
group
fed
2
ppm
(
0.05
mg/
kg/
day).

Dose
and
Endpoint:
The
NOAEL
of
0.05
mg/
kg/
day
based
on
a
shift
from
a
predominantly
drugsusceptible
population
of
enteric
lactose­
fermenting
organisms
to
a
multiple
antibiotic­
resistant
population
at
0.25
mg/
kg/
day
(
LOAEL)
in
mature
beagle
dogs.
Page
28
of
46
Comments
about
Study/
Endpoint/
UF:
The
selection
of
the
chronic
endpoint
was
based
on
the
microbiological
study
in
dogs.
The
endpoint
is
conservative
and
protective
for
the
entire
toxicological
database
and
was
selected
based
on
the
qualitative
classification
of
overall
risk
of
resistance
being
medium.
Other
studies
in
the
toxicological
database
demonstrated
NOAELs
near
or
above
1000
mg/
kg/
day
with
the
exception
of
a
cited
2­
generation
reproductive
study
which
had
a
NOAEL
of
18
mg/
kg/
day.
Based
on
the
data
available,
the
UF
for
the
dog
study
is
10X
for
intraspecies
variations
and
10X
for
interspecies
extrapolation.
The
cRfD
was
selected
using
an
animal
resistance
endpoint
in
mature
beagle
dogs.
The
risk
assessment
team
acknowledges
that
this
study
is
not
a
precise
description
of
antibiotic
resistance
in
animals
or
humans.
It
is,
however,
a
good
indicator
of
the
selective
pressure
of
antibiotic
usage
and
recognizes
the
potential
for
resistance
in
future
infections.

Chronic
RfD
=
0.05
mg/
kg/
day
=
0.0005
mg/
kg/
day
(
dog
study)

100
4.4.3
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
1996
FQPA,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
requirement
of
occupational
or
residential
exposure
monitoring
data
is
not
required
by
the
agency
therefore
the
dermal
and
inhalation
routes
were
not
considered
in
this
risk
assessment.
The
oral
route
of
exposure
is
the
only
route
of
concern
and
is
addressed
in
this
risk
assessment.

4.4.4
Classification
of
Carcinogenic
Potential
The
RfD/
Peer
Review
Committee
(
File
R058617,
dated
12/
18/
92)
concluded
that
the
doses
tested
in
the
rat
and
mice
are
adequate
for
carcinogenicity
testing,
and
the
data
evaluation
records
for
these
two
studies
are
adequate.
The
chemical
was
tested
in
rats
up
to
50,000
ppm
(
2500
mg/
kg/
day)
and
in
mice
up
to
12,500
ppm
(
1875
mg/
kg/
day).
On
the
basis
of
these
two
studies,
the
chemical
was
classified
as
a
"
Group
D."

This
classification
is
in
agreement
with
the
conclusion
made
by
the
National
Toxicology
Program's
(
NTP)
Peer
Review
Committee.
In
their
report,
the
NTP
Peer
Review
Committee
concluded
that
"
.
.
there
was
equivocal
evidence
of
carcinogenicity
for
male
F344/
N
rats
(
the
high
dose
group)
as
indicated
by
increased
incidences
of
pheochromocytomas
of
the
adrenal
gland
[
with
a
statistically
significant
positive
trend,
not
significant
in
pairwise
comparison
with
concurrent
controls,
and
was
outside
the
historical
control
range].
There
was
equivocal
evidence
of
carcinogenicity
for
females
F
344/
N
rats
as
indicated
by
increased
incidences
of
adenomas
of
the
pituitary
gland
[
to
have
a
high
background
rate]
in
the
high
dose
group".
With
respect
to
the
Page
29
of
46
mouse
study,
the
NTP
report
concluded
that
"....
there
was
no
evidence
of
carcinogenicity
for
male
or
female
B6C3F1
mice
fed
oxytetracycline
hydrochloride
for
two
years."

Given
the
equivocal
nature
of
the
carcinogenic
response
in
the
rat
study
at
an
extremely
high
dose
level
(
especially
when
the
actual
dietary
exposure
to
man
is
taken
into
consideration),
and
the
fact
that
mutagenicity
data
were
somewhat
inconclusive,
the
RED
cRFD/
Peer
Review
Committee
felt
that
the
"
D
Group"
classification
is
appropriate.
It
should
be
emphasized,
however,
that
this
classification
is
based
on
adequate
studies
in
two
animal
species.
Therefore,
new
carcinogenicity
studies
are
not
needed
at
this
time.
The
Committee
indicated
that
the
carcinogenicity
issue
may
be
revisited
if
the
exposure
changes.

Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
females
13­
49
and
the
general
population)
None
selected
No
appropriate
endpoint
for
females
age
13­
49
or
for
the
general
population
attributable
to
a
single
exposure.

Chronic
Dietary
(
all
populations)
NOAEL
=
0.05
mg/
kg/
day
(
dogs)

UF
=
100
cRfD
=
0.0005
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=

chronic
RfD
FQPA
SF
=
0.0005
mg/
kg/
day
Microbiological
Study
in
Dogs
LOAEL
=
0.25
mg/
kg/
day
based
on
a
shift
from
a
predominantly
drugsusceptible
population
of
enteric
lactose­
fermenting
organisms
to
a
multiple
antibiotic­
resistant
population.

Cancer
(
oral,
dermal,
inhalation)
Classification:
The
Agency's
Peer
Review
Committee
has
classified
oxytetracycline
as
a
"
Group
D"
carcinogen
("
Not
Classifiable
as
to
Human
Carcinogenicity").

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RFD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
4.5
Special
FQPA
Safety
Factor
Based
on
the
hazard
data,
the
risk
assessment
team
recommended
the
special
FQPA
safety
factor
be
reduced
to
1x
because
there
is
a
low
degree
of
concern
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.
The
oxytetracycline
risk
assessment
team
evaluated
the
quality
of
the
exposure
data;
and,
based
on
these
data,
recommended
that
the
special
FQPA
safety
factor
be
reduced
to
1x.
The
recommendation
is
based
on
the
following:

°
The
dietary
food
exposure
assessment
utilizes
mean
residue
levels
and
percent
crop
treated
Page
30
of
46
information
for
all
relevant
commodities,
and
monitoring
data
to
estimate
possible
livestock
residue
levels.
By
using
these
refined
assessments,
chronic
exposures
are
not
likely
to
be
underestimated.

°
The
dietary
drinking
water
assessment
(
Tier
1
estimates)
yields
values
generated
by
modeling
methods
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.

4.6
Endocrine
disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).
In
the
available
toxicity
studies
on
oxytetracycline,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.

When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
oxytetracycline
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
Reference:
Review
of
Oxytetracycline
Incident
Reports.
Monica
Hawkins.
D315687.
22­
AUG­
2005.

There
were
almost
no
reports
of
ill
effects
from
exposure
to
oxytetracycline
in
the
available
data
bases.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
Page
31
of
46
Reference:
Oxytetracycline
Reassessment
Eligibility
Decision
(
TRED).
Summary
of
Product
Chemistry
and
Residue
Data.
William
Donovan.
D315689.
15­
AUG­
2005.

6.1.1
Residue
Profile
Due
to
the
widespread
use
of
oxytetracycline
as
a
drug,
and
the
low
residue
levels
expected
in
or
on
tree
fruit,
no
plant
or
livestock
metabolism
data
are
required
(
see
memo
of
W.
J.
Hazel
dated
4/
12/
88;
memo
of
W.
B.
Greer
dated
4/
19/
88;
and
memo
of
R.
B.
Perfetti
dated
10/
13/
92).
Permanent
tolerances
are
established
for
residues
of
oxytetracycline
per
se
in/
on
peaches,
pears
at
0.35
ppm
[
40
CFR
§
180.337].
IR­
4
has
submitted
a
tolerance
petition
(
PP#
7E4855)
proposing
residues
of
oxytetracycline
per
se
in/
on
apples
at
0.35
ppm.
There
are
currently
no
tolerances
for
oxytetracycline
residues
in
livestock
commodities
or
for
inadvertent
residues
in
rotational
crops.

As
noted
in
the
oxytetracycline
Registration
Standard
(
4/
14/
1988),
the
available
microbiological
assay
method
for
the
determination
of
oxytetracycline
residues
in
or
on
tree
fruit
is
inadequate
for
tolerance
enforcement;
however,
this
method
was
used
for
data
collection
purposes.
The
method
is
similar
to
Final
Action
Microbiological
Methods
I
and
II
in
the
AOAC
Official
methods
of
Analysis
(
1984;
42.293­
42.298).
This
method
is
nonspecific
and
insufficiently
sensitive
for
quantitative
determination
of
oxytetracycline
because
it
does
not
distinguish
oxytetracycline
from
other
compounds
that
may
alter
the
response
of
the
bioassay
test
organism.
The
available
data
indicate
that
recoveries
are
generally
low
and
markedly
variable.
In
a
12/
15/
04
meeting
of
the
HED
Chemistry
Science
Advisory
Council
(
ChemSAC),
the
Council
reaffirmed
that
the
described
method
is
not
acceptable
for
tolerance
enforcement
purposes,
and
recommended
that
the
registrant
develop
a
validated
enforcement
method
based
on
HPLC,
similar
to
AOAC
methods
995.09
and
995.04,
which
use
HPLC
to
determine
tetracycline
levels
in
animal
tissues
and
milk,
respectively.

The
use
of
oxytetracycline
as
a
drug
in
food
animals
is
regulated
by
the
FDA
according
to
21
CFR
556.500.
The
FDA
has
established
the
following
tolerances
for
the
sum
of
residues
of
the
tetracyclines
including
chlortetracycline,
oxytetracycline,
and
tetracycline:
2
ppm
in
muscle
(
meat)
of
cattle,
swine,
sheep,
poultry,
fish
and
lobsters;
6
ppm
in
liver,
12
ppm
in
fat
and
kidney,
and
0.3
ppm
in
milk.
HED
notes
that
the
drug
uses
of
oxytetracycline
in
livestock
result
in
considerably
higher
exposure
levels
to
oxytetracycline
residues
than
the
agricultural
uses;
the
estimated
percentage
of
antibiotics
applied
to
plants
compared
to
all
other
antibiotic
use
is
<
0.5%
(
McManus
et
al.).
Wet
apple
pomace
is
a
feedstuff
of
regulatory
interest
associated
with
apples,
while
peaches/
nectarines
and
pears
have
no
livestock
feedstuffs.
Due
to
low
oxytetracycline
residue
levels
in
apples,
quantifiable
residues
of
oxytetracycline
in
livestock
commodities
as
a
result
of
feeding
wet
apple
pomace
from
treated
apples
are
not
expected.
Therefore,
based
on
the
agricultural
uses
of
oxytetracycline,
HED
finds
there
is
no
reasonable
expectation
that
residues
of
concern
will
transfer
to
livestock
tissues
[
40
CFR
§
180.6(
a)(
3)].
However,
to
account
for
the
possibility
of
oxytetracycline
residues
in
livestock
commodities
arising
from
drug
and
sub
Page
32
of
46
therapeutic
dosing
of
animals,
HED
included
the
results
of
FSIS
livestock
monitoring
data
from
the
years
2002­
2004
in
the
dietary
exposure
analyses
(
see
section
6.1.2).

Adequate
field
trial
data
are
available
to
support
the
use
of
oxytetracycline
in/
on
peach
and
pear.
An
adequate
number
of
field
trials
were
conducted
in
the
appropriate
geographical
regions
using
the
appropriate
formulation
applied
at
the
maximum
use
rate.

Crop
field
trials
for
apples
were
conducted
from
0.5
to
11.6x
the
proposed
seasonal
rate
of
1.53
lb
ai/
A
and
from
49
to
61
days
PHI
as
compared
to
the
proposed
PHI
of
60
days.
Residues
were
largely
at
the
limit
of
quantitation
(
LOQ)
of
0.013
and
0.2
ppm
up
to
0.252
ppm.
The
mean
apple
residue
level
found
at
a
1x
treatment
rate
was
0.033
ppm
(
D298424,
W.
Cutchin,
03­
JAN­
2005).
Considering
the
wide
range
of
application
rates,
up
to
11.6x
the
recommended
rate,
the
general
lack
of
detectable
oxytetracycline
residues,
and
the
existence
of
the
data
on
a
similar
crop
(
pear),
HED
tentatively
concludes
that
adequate
field
trial
data
are
available
to
support
the
establishment
of
a
tolerance
for
residues
of
oxytetracycline
per
se
in/
on
apples
at
0.35
ppm,
provided
that
an
adequate
analytical
enforcement
method
is
developed
and
submitted.

No
data
have
been
submitted
for
processed
food
uses
of
oxytetracycline,
as
no
processed
commodity
data
are
required
for
peaches
or
pears.
Apple
processed
commodities
were
produced
from
apples
treated
at
5
and
11.6x
the
proposed
use
rate.
Residues
were
below
LOQ
on
the
apple
RACs
and
apple
processed
commodities.
As
the
maximum
theoretical
concentration
factor
for
apple
pomace
is
14x,
the
processing
studies
indicate
that
concentration
of
oxytetracycline
would
not
be
expected
in
processed
apple
commodities.
Tolerances
are
not
required
on
apple
processed
commodities.

Data
were
not
submitted
for
confined
accumulation
in
rotational
crops.
The
use
sites
will
not
involve
rotated
crops;
therefore,
data
are
not
required
for
rotational
crops.

6.1.2
Chronic
Aggregate
Dietary
Exposure
and
Risk
Reference:
Oxytetracycline
Chronic
Dietary
Exposure
Assessments
for
the
Tolerance
Reregistration
Eligibility
Decision
(
TRED).
Revised
After
Phase
1­
Error
Only
Corrections.
DP
Barcode:
D315686,
William
Donovan,
06­
FEB­
2006.

Chronic
aggregate
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
­
Food
Consumption
Intake
Database
(
DEEM­
FCID
 
,
Version
2.0)
model.
This
model
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analyses
were
performed
to
support
the
tolerance
reregistration
eligibility
decision
for
oxytetracycline.
Page
33
of
46
The
chronic
analysis
used
anticipated
residue
levels
for
apples,
peaches
(
and
nectarines),
and
pears,
percent
crop
treated
information
as
supplied
by
BEAD
together
with
default
processing
factors,
and
monitoring
data
from
the
Food
Safety
Inspection
Service
(
FSIS)
collected
during
the
years
2002­
2004
to
estimate
residue
levels
in
livestock
commodities.
Thus,
the
following
average
residue
values
were
used
for
apples;
peaches
and
pears;
and
livestock
commodities:
0.033,
0.20,
and
0.0058
ppm,
respectively.
Drinking
water
was
incorporated
directly
in
the
dietary
assessment
using
the
highest
relevant
chronic
estimated
drinking
water
concentration
(
EDWC)
for
surface
water
generated
by
the
FIRST
model:
4.6
ppb.
Table
6.1.2a
summarizes
the
results
of
the
chronic
dietary
analyses.

Table
6.1.2a.
Results
of
Chronic
Dietary
(
Food
+
Water)
Exposure
Analysis
Using
DEEM
FCID
DEEM­
FCID
 
Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.0005
0.000160
32
All
Infants
(<
1
year
old)
0.0005
0.000473
95
Children
1­
2
years
old
0.0005
0.000441
88
Children
3­
5
years
old
0.0005
0.000329
66
Children
6­
12
years
old
0.0005
0.000205
41
Youth
13­
19
years
old
0.0005
0.000121
24
Adults
20­
49
years
old
0.0005
0.000127
25
Adults
50+
years
old
0.0005
0.000132
26
Females
13­
49
years
old
0.0005
0.000126
25
The
resulting
chronic
aggregate
dietary
exposure
estimates
using
the
DEEM­
FCID
model
were
less
than
100%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups.
Oxytetracycline
chronic
aggregate
exposure
(
food
+
water)
was
estimated
at
0.000160
mg/
kg/
day
for
the
U.
S.
population
(
32%
of
the
cPAD)
and
0.000473
mg/
kg/
day
(
95%
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
All
Infants
(<
1
year
old)).
These
results
indicate
that
chronic
aggregate
dietary
exposure
to
oxytetracycline
from
food
and
drinking
water
is
below
HED's
level
of
concern
for
all
population
subgroups.

For
comparison
purposes,
a
second
chronic
dietary
analysis
was
conducted
to
depict
exposure
levels
resulting
from
food
uses
only.
Table
6.1.2b
summarizes
the
results
of
the
food
only
analysis,
which,
when
compared
to
the
food
+
water
results
in
Table
6.1.2a,
shows
the
relative
Page
34
of
46
contributions
of
water
and
food
sources
to
the
total
exposure
level
to
residues
of
oxytetracycline.

Table
6.1.2b.
Results
of
Chronic
Dietary
(
Food
Only)
Exposure
Analysis
Using
DEEM
FCID
DEEM­
FCID
 
Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.0005
0.000063
13
All
Infants
(<
1
year
old)
0.0005
0.000155
31
Children
1­
2
years
old
0.0005
0.000297
59
Children
3­
5
years
old
0.0005
0.000194
39
Children
6­
12
years
old
0.0005
0.000112
23
Youth
13­
19
years
old
0.0005
0.000051
10
Adults
20­
49
years
old
0.0005
0.000036
7.2
Adults
50+
years
old
0.0005
0.000037
7.3
Females
13­
49
years
old
0.0005
0.000036
7.2
Based
on
these
analyses,
the
food
only
chronic
dietary
risk
from
existing
and
proposed
uses
of
oxytetracycline
are
below
HED's
level
of
concern
for
the
general
US
population
and
all
population
subgroups.
The
highest
food
only
chronic
dietary
exposure
(
0.000297
mg/
kg/
day)
was
found
for
Children
1­
2
years
old
(
59%
cPAD),
while
that
for
the
US
population
was
0.000063
mg/
kg/
day
(
13%
cPAD).
The
results
presented
in
Tables
6.1.2a
and
6.1.2b
clearly
indicate
that
water
consumption
is
a
large
contributor
to
chronic
dietary
exposure
of
oxytetracycline
residues.

6.2
Water
Exposure/
Risk
Pathway
Reference:
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.
Greg
Orrick,
D315690,
04­
AUG­
2005.

Tier
I
Estimated
Drinking
Water
Concentrations
(
EDWCs)
were
calculated
for
oxytetracycline
using
the
surface
and
ground
water
models
FIRST
V
1.0
and
SCI­
GROW
V
2.3,
respectively.
The
highest
resulting
EDWC
values
reflecting
the
maximum
use
pattern
for
oxytetracycline
(
on
Page
35
of
46
peaches
and
nectarines)
are
presented
in
Table
6.2.

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Oxytetracycline.

Oxytetracycline
Exposure
Duration
Surface
Water
EDWC,
ppb
a
Ground
Water
EDWC.,
ppb
b
Chronic
4.6
0.033
a
From
the
Tier
1
FIRST
model.
Input
parameters
are
based
on
the
physical
properties
of
oxytetracycline,
and
assuming
9
separate
applications
of
oxytetracycline
calcium
to
peaches
and/
or
nectarines
at
a
rate
of
0.642
lb
ai/
A
with
a
7­
day
retreatment
interval.

b
From
the
SCI­
GROW
model
assuming
9
separate
applications
of
oxytetracycline
calcium
to
peaches
and/
or
nectarines
at
a
rate
of
0.642
lb
ai/
A
with
a
7­
day
retreatment
interval.

Because
the
highest
EDWC
value
was
obtained
for
surface
water
(
4.6
ppb),
this
level
was
selected
for
use
a
point
estimate
in
the
aggregate
dietary
analysis
of
oxytetracycline.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Oxytetracycline
uses
are
being
supported
only
for
the
following
agricultural
crops:
apples,
peach,
pear,
and
nectarine.
There
are
no
anticipated
exposures
in
or
around
homes
or
recreational
areas.

6.3.1
Home
Uses
­
Not
applicable.

6.3.2
Recreational
Uses
­
Not
applicable.

6.3.3
Other
(
Spray
Drift,
etc.)

Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
ground
application
method
employed
for
oxytetracycline.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
On
a
chemical
by
chemical
basis,
the
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
Page
36
of
46
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
with
specific
products
with
significant
risks
associated
with
drift.
Page
37
of
46
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
various
sources
including
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.

For
most
pesticide
active
ingredients,
water
monitoring
data
are
considered
inadequate
to
determine
surface
and
ground
water
drinking
water
exposure
estimates,
so
model
calculations
have
been
used
to
determine
estimated
drinking
water
concentrations
(
EDWCs).
FDA­
approved
uses
of
oxytetracycline
were
included
in
the
chronic
aggregate
risk
assessment
through
the
use
of
Food
Safety
Inspection
Service
(
FSIS)
monitoring
data
of
livestock
commodities
in
the
dietary
analyses.

7.1
Acute
Aggregate
Risk
An
acute
aggregate
risk
assessment
was
not
conducted
because
no
endpoint
of
concern
attributable
to
a
single
dose
was
identified.

7.2
Chronic
Aggregate
Risk
A
chronic
aggregate
risk
assessment
was
conducted
for
oxytetracycline,
as
presented
in
Section
6.1.2.
In
summary,
chronic
aggregate
exposures
to
oxytetracycline
in
food
and
drinking
water
are
not
of
concern
from
a
risk
perspective.

8.0
Cumulative
Risk
Characterization/
Assessment
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
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
38
of
46
9.0
Data
Needs
and
Label
Requirements
9.1
Toxicology
None
9.2
Residue
Chemistry
The
registrant
should
submit
a
validated
analytical
enforcement
method
(
Guideline
#
860.1340)
for
oxytetracycline.
This
should
include
an
independent
laboratory
validation
(
ILV),
and
an
acceptable
confirmatory
method.
Once
these
are
received,
BEAD/
ACL
will
be
requested
to
conduct
a
petition
method
validation
(
PMV)
of
the
enforcement
method.
Note
that
the
tolerance
reassessment
summary
presented
in
Appendix
3.0
of
this
document
is
contingent
upon
successful
Agency
completion
of
PMV
of
the
analytical
enforcement
method.

9.3
Occupational
and
Residential
Exposure
None
9.4
Recommended
Data
for
Refining
Qualitative
Risk
Assessment
(
Note
that
submission
of
this
data
is
recommended
to
further
refine
the
qualitative
assessment
but
is
not
required)

°
Since
oxytetracycline's
potential
contributions
to
antibiotic
resistance
are
not
fully
understood,
monitoring
for
antimicrobial
resistance
among
bacteria
isolated
from
fruits
that
are
commonly
treated
with
antibiotic
pesticides
is
suggested
(
possibly
through
the
National
Antimicrobial
Resistance
Monitoring
System
or
by
expanding
a
CDC
pilot
study
of
antibiotic
resistance
in
orchards).

°
Additional
usage
data
specific
to
pesticidal
use
of
oxytetracycline
(
or
tetracyclines)
relative
to
human
and
animal
therapeutic
uses
and
animal
non­
therapeutic
use
(
e.
g.,
as
a
growth
promoter).
Page
39
of
46
10.0
References
Regulatory
Documents
on
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.
Greg
Orrick,
D315690.
04­
AUG­
2005.

Oxytetracycline
Chronic
Dietary
Exposure
Assessment
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED).
Revised
After
Phase
1­
Error
Only
Corrections.
William
Donovan.
D315686.
06­
FEB­
2006.

Oxytetracycline
Reassessment
Eligibility
Decision
(
TRED).
Summary
of
Product
Chemistry
and
Residue
Data.
William
Donovan.
D315689.
15­
AUG­
2005.

Screening
Level
Usage
Analysis
(
SLUA)
for
Oxytetracycline.
Alan
Halvorson.
1/
3/
05.

Hydroxytetracycline
Monohydrochloride
and
Oxytetracycline
Calcium
Reregistration
Eligibility
Document
(
RED).
3/
30/
93.

Review
of
Oxytetracycline
Incident
Reports.
Monica
Hawkins.
D315687.
22­
AUG­
2005.

Oxytetracycline.
Section
3
Use
on
Apples.
Summary
of
Analytical
Chemistry
and
Residue
Data.
Petition
Number
7E4855.
William
Cutchin.
D298424.
03­
JAN­
2005.

Articles
on
Oxytetracycline
from
the
Open
Literature:

ABBITT,
B.,
BERNDTSON,
W.
E.
&
SEIDEL,
G.
E.
(
1984).
Effect
dihydrostreptomycin
or
oxytetracycline
on
reproductive
capacity
of
bulls.
Am.
J.
Vet.
Res.,
45,
2242­
2246.

ANDREWS,
A.
W.,
FORNWALD,
J.
A.
&
LIJINSKY,
W.
(
1980).
Nitrosation
and
mutagenicity
of
some
amine
drugs.
Toxicol.
Appl.
Pharmacol.,
52,
237­
244.
Page
40
of
46
BLACK,
W.
D.
&
GENTRY,
R.
D.
(
1984).
The
distribution
of
oxytetracycline
in
the
tissues
of
swine
following
a
single
oral
dose.
Can.
Vet.
J.,
25,
158­
161.

BURROWS,
G.
E.,
BARTO,
P.
B.
&
MARTIN,
B.
(
1987).
Comparative
pharmacokinetics
of
gentamicin,
neomycin
and
oxytetracycline
in
newborn
calves.
J.
Vet.
Pharmacol.
Therap.,
10,
54­
63.

CORPET,
D.
&
LUMEAU,
S.
(
1987).
Effect
of
low
levels
of
antimicrobials
on
drug
resistant
populations
of
intestinal
bacteria
in
gnotobiotic
mice.
In
Fedesa
report:
Rational
view
of
antimicrobial
residues.
An
assessment
of
human
safety.
Abstracts
of
a
seminar
held
in
Zurich,
March
24.

DEICHMANN,
W.
B.,
BERNAL,
E.,
ANDERSON,
W.
A.
D.,
KEPLINGER,
M.,
LANDEEN,
K.,
MCDONALD,
W.,
MAHON,
R.
&
STEBBINS,
R.
(
1964).
The
chronic
oral
toxicity
of
oxytetracycline
HCl
and
tetracycline
HCl
in
the
rat,
dog
and
pig.
Ind.
Med.
Surg.,
787­
806.

EPA
(
1988).
Guidance
for
the
registration
of
pesticide
product
containing
oxytetracycline,
oxytetracycline
hydrochloride
and
oxytetracycline
calcium
complex
as
the
active
ingredient.
OMB
control
no.
2070­
0057.
Submitted
to
WHO
by
Pfizer
Central
Research,
Groton,
CT,
USA.

GYRD­
HANSEN,
N.
(
1980).
The
effect
of
tetracyclines
on
the
rabbit
heart.
Zbl.
Vet
Med.
A.,
27,
288­
237.

HARDMAN,
J.
G.,
LIMBIRD,
L.
E.,
GILMAN,
A.
G.
(
2001)
Goodman
and
Gilman's
the
pharmacological
basis
of
therapeutics.
10th
ed.
New
York:
McGraw­
Hill.

IMMELMAN,
A.
(
1977).
Blood
levels
of
oxytetracycline
in
dogs
after
oral
administration.
J.
South
African
Vet.
Assoc.,
48
(
3),
183­
186.

LEBEK,
G.
&
EGGER,
R.
(
1983).
The
effect
of
low
levels
of
antibiotics
on
the
selection
of
resistance
in
intestinal
bacteria
in
vitro
observations.
Cited
in
Fedesa
report:
Rational
view
of
antimicrobial
residues.
An
assessment
of
human
safety.
Abstract
of
a
seminar
held
in
Zurich,
March
24.

LEVY,
J.,
ORNOY,
A.
&
ATKIN,
I.
(
1980).
Influence
of
tetracycline
on
the
calcification
of
epiphyseal
rat
cartilage.
Transmission
and
scanning
electron­
microscopic
studies.
Acta
Anat.,
106,
360­
369.

LIKINS,
R.
C.
&
PAKIS,
G.
A.
(
1965).
Fetal
uptake
of
radiocalcium
in
tetracycline­
treated
rats.
Nature,
5004,
1394­
1395.

MCMANUS,
PS;
STOCKWELL,
VO;
SUNDIN,
GW;
JONES,
AL
(
2002)
Antibiotic
Use
in
Page
41
of
46
Plant
Agriculture,
Annu
Rev
Phytopathol,
40:
443­
65
MEVIUS,
D.
J.,
VELLENGA,
L.,
BREUKINK,
H.
J.,
NOUWS,
J.
F.
M.,
VREE,
T.
B.,
&
DRIESSENS,
F.
(
1986a).
Pharmacokinetics
and
renal
clearance
of
oxytetracycline
in
piglets
following
intravenous
and
oral
administration.
The
Vet.
Quart.,
8(
4)
274­
284.

MEVIUS,
D.
J.,
Nouws,
J.
F.
M.,
Breukink,
H.
J.,
Vree,
T.
B.,
Driessens,
F.&
Verkaik,
R.
(
1986b).
Comparative
pharmacokinetics,
bioavailability
and
renal
clearance
of
five
parenteral
oxytetracycline
­
20%
formulations
in
diary
cows.
The
Vet.
Quart.,
8(
4)
285­
294.

MORRISSEY,
R.
E.,
TYL,
R.
W.,
PRICE,
C.
J.,
LEDOUX,
T.
A.,
REEL.,
J.
R.,
PASCHKE,
L.
L.,
MARR,
M.
C.
&
KIMMEL,
C.
A.
(
1986).
The
developmental
toxicity
of
orally
administered
oxytetracycline
in
rats
and
mice.
Fund.
Appl.
Toxicol.,
7,
434­
443.

NOUWS,
J.
F.
M.,
VAN
GINNIKEN,
C.
A.
M.
&
ZIV,
G.
(
1983).
Age­
dependent
pharmacokinetics
of
oxytetracycline
in
ruminants.
J.
Vet.
Pharmacol.
Therap.,
6,
59­
66.

NOUWS,
J.
F.,
VREE,
T.
B.,
TERMOND,
E.,
LOHUIS,
J.,
VAN
LITH,
P.,
BINKHORST,
G.
J.
&
BREUKINK,
H.
J.
(
1985).
Pharmacokinetics
and
renal
clearance
of
oxytetracycline
after
intravenous
and
intramuscular
administration
to
diary
cows.
The
Vet.
Quart.,
7(
4),
296­
305.

NTP
(
1987).
Toxicology
and
carcinogenesis
studies
of
oxytetracycline
hydrochloride
in
F344/
N
rats
and
B6C3F1
mice.
(
feed
studies).
National
Toxicology
Program,
Technical
reports
series
No.
315.
Submitted
to
WHO
by
NTP,
Research
Triangle
Park,
NC,
U.
S.
A.

PRASAD,
S.,
JAYACHANDRAN,
C.
&
SINGH,
M.
K.
(
1987).
Pharmacokinetics
of
oxytetracycline
in
dairy
cows.
Ind.
J.
Anim.
Sciences,
157(
2),
106­
110.

ROLLINS,
L.
D.,
GAINES,
S.
A.,
POCURULL,
D.
W.,
&
MESEAR,
H.
D.
(
1975).
Animal
model
for
determining
the
no
effect
level
of
an
antimicrobial
drug
on
drug
resistance
in
the
lactose
fermenting
enteric
flora.
Antimicrob.
Agents
Chemother.,
7,
661­
665.

SANDE,
M.
A.
&
MANDELL,
G.
L.
(
1985).
Tetracyclines,
Chloramphenicol,
Erythromycin
and
miscellaneous
antibacterial
agents.
In:
Goodman
and
Gilman's,
The
Pharmacological
Basis
of
Therapeutics.
7th
edition,
Macmillan
Publishing
Company,
New
York.
1170­
1176.

SNELL,
J.
F.,
GARKUSCHA,
R.,
&
ALLEN,
E.
L.
(
1957).
Radioactive
Oxytetracycline
II.
Distribution
in
C­
57
BL
Mice
(
preliminary
experiments).
Antibiot.
Ann.,
502­
506.

SWEZEY,
J.
L.,
BALDWIN,
B.
B.
&
BROMEL,
M.
C.
(
1981).
Environment
and
health.
Effect
of
oxytetracycline
as
a
turkey
feed
additive.
Poultry
Science,
60,
738­
743.

SZUMIGOWSKA­
SZEAJBER,
G.
&
JESKE,
J.
(
1970).
Influence
of
tetracycline
base,
tetracycline
hydrochloride
and
oxytetracycline
base
on
development
of
metatarsal
bones
in
the
rat
fetus.
Acta
Polon.
Pharm.,
27(
1),
78­
83.
Page
42
of
46
TARARA,
R.
P.,
HANSEN,
L.
G.
&
SIMON,
J.
(
1976).
Effects
of
repeated
administration
of
oxytetracycline
on
kidney,
liver
and
liver
mixed­
function
oxidases
in
the
rat.
Toxicol.
Appl.
Pharmacol.,
35,
321­
331.

TAYLOR,
H.
W.
&
LIJINSKY,
W.
(
1975).
Tumor
induction
in
rats
by
feeding
aminopyrine
or
oxytetracycline
with
nitrite.
Int.
J.
Cancer,
16,
211­
215.

URAM,
J.
A.,
FRENCH
C.
E.,
BARRON,
G.
P.,
&
SWIFT,
R.
W.
(
1954).
The
effect
of
high
levels
of
terramycin
or
streptomycin
on
growth,
reproduction
and
lactation
of
the
rat.
J.
Nutr.,
481­
492.

XIA,
W.,
GYRD­
HANSEN,
N
&
NIELSEN,
P.
(
1983).
Comparison
of
pharmacokinetic
parameters
for
oxytetracycline
preparations
in
pigs.
J.
Vet
Pharmacol.
Therap.,
113­
120.
Page
43
of
46
11.0
APPENDICIES
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
uses
of
oxytetracycline
are
listed
in
the
table
below.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
The
prenatal
developmental
and
carcinogenicity
studies
in
rodents
are
the
only
acceptable
submitted
studies
in
the
oxytetracycline
database.
Historically,
all
database
requirements
were
waived
based
on
animal
data
that
are
available
from
various
sources
(
open
literature,
NTP,
etc).
Thus,
the
agency
did
not
require
any
toxicity
studies
on
the
technical
grade
ingredient.
This
waiver
is
justified
based
on
the
current
availability
of
animal
data.
Therefore,
none
of
the
studies
are
required
but
all
of
the
study
requirements
are
satisfied
by
the
plethora
of
information
available
on
oxytetracycline
in
animals.
The
data
obtained
from
various
sources
are
listed
in
Tables
4.1a
and
4.1b.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity..........................................................
870.1200
Acute
Dermal
Toxicity
.....................................................
870.1300
Acute
Inhalation
Toxicity.................................................
870.2400
Primary
Eye
Irritation.......................................................
870.2500
Primary
Dermal
Irritation.................................................
870.2600
Dermal
Sensitization
........................................................
Yes
Yes
No
No
No
No
yes
waived
­­
­­
­­
­­

870.3100
Oral
Subchronic
(
rodent)
..................................................
870.3150
Oral
Subchronic
(
nonrodent)
............................................
870.3200
21­
Day
Dermal................................................................
870.3250
90­
Day
Dermal................................................................
870.3465
90­
Day
Inhalation.............................................................
Yes
Yes
No
No
No
waived
waived
 
 
­­

870.3700a
Developmental
Toxicity
(
rodent).....................................
870.3700b
Developmental
Toxicity
(
nonrodent)...............................
870.3800
Reproduction
....................................................................
Yes
Yes
Yes
waived
waived
waived
870.4100a
Chronic
Toxicity
(
rodent)
...............................................
870.4100b
Chronic
Toxicity
(
nonrodent)
.........................................
870.4200a
Oncogenicity
(
rat)...........................................................
870.4200b
Oncogenicity
(
mouse)
.....................................................
Yes
Yes
Yes
Yes
waived
waived
waived
waived
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.........................
870.5195
Mutagenicity 
Gene
Mutation
­
mammalian....................
870.5375
Mutagenicity 
Structural
Chromosomal
Aberrations........
870.5900
Mutagenicity 
Other
Genotoxic
Effects
...........................
Yes
Yes
Yes
Yes
waived
waived
waived
waived
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.......................................
870.6100b
90­
Day
Neurotoxicity
(
hen)
............................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.........................
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
............................
870.6300
Develop.
Neuro................................................................
No
No
No
No
No
 
 
 
 
­­
Page
44
of
46
Technical
Test
Required
Satisfied
870.7485
General
Metabolism
.........................................................
870.7600
Dermal
Penetration...........................................................
Yes
No
waived
­­

Special
Studies
for
Ocular
Effects
No
­­

2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
Subchronic
Mouse
Feeding
Study
In
a
range
finding
study
groups
of
B6C3F1
mice
(
10/
sex/
group)
were
fed
diets
containing
0,
3100,
6300,
12500,
25000
or
50000
ppm
OTC­
HCl
for
13
weeks.
These
dose
levels
are
approximately
equal
to
an
intake
of
0,
465,
945,
1875,
3750,
or
7500
mg/
kg/
day.
No
dose
related
effects
were
observed
on
mortality,
food
consumption,
macroscopy
and
histology.
Body
weights
were
decreased
from
3
to
15%
at
25000
ppm
and
at
50000
ppm.
OTC
concentrations
in
bone
were
measurable
fluorometrically
in
high­
dosed
females
(
NTP,
1987).

Subchronic
Rat
Feeding
Study
In
a
range
finding
study,
groups
of
F344/
N
rats
(
10/
sex/
group)
were
fed
diets
containing
0,
3100,
6300,
12500,
25000
or
50000
ppm
OTC­
HCl
for
13
weeks.
These
dose
levels
were
approximately
equal
to
intakes
of
0,
1200,
1350
or
1500
mg/
kg/
day.
No
dose
related
effects
were
observed
on
mortality,
food
consumption,
body
weight
or
macroscopy.
Minimal
periacinar
fatty
metamorphosis
in
the
liver
of
male
rats
was
observed
at
all
dose
levels
(
no
dose
relation,
control
values
not
given).
Measurable
OTC
concentrations
in
bones
were
detected
in
both
sexes
and
increased
with
the
dose.
The
OTC
concentration
in
bone
was
significantly
increased
in
females
from
12500
ppm
and
up
and
in
males
at
50000
ppm
only
(
NTP,
1987).

Chronic
Rat
Feeding
Study
Groups
of
Osborne­
Mendel
male
rats
were
fed
diets
containing
0
(
180
rats),
100
(
100
rats),
1000
(
130
rats)
or
3000
ppm
(
100
rats)
OTC­
HCl
for
24
months.
Observations
included
clinical
signs,
mortality,
food
consumption,
body
weight,
haematology,
macroscopy,
and
histopathology.
After
24
months
the
mortality
rates
were
43,
23,
23
and
13%
for
the
control
and
experimental
groups,
respectively.
Treated
rats
gained
weight
more
rapidly
than
controls.
Body
weight
and
haematology
were
not
affected.
At
macroscopy
pale
kidneys
were
observed
in
4,
7,
16
and
16%
in
the
control
and
treated
groups,
respectively.
A
slight
to
moderate
brownish
pigmentation
of
the
thyroid
gland
was
seen
in
treated
rats,
but
it
was
not
dose­
related.
Tumour
incidences
were
not
enhanced.
The
NOAEL
in
this
study
was
3000
ppm
(
highest
dose
tested),
equivalent
to
150
mg/
kg
b.
w.
(
Diechmann
et
al.,
1964).
In
a
second
study,
groups
of
Sprague­
Dawley
rats
were
fed
diets
containing
0,
100,
or
1,000pm
(
approximately
0,
5,
or
50
mg/
kg/
day)
hydroxytetracycline
monohydrochlorate.
Observations
included
clinical
signs,
mortality,
body
weight,
food
consumption,
haematology,
organ
weights,
macroscopy
and
histopathology.
No
dose
related
effects
were
observed.
The
NOAEL
was
50
mg/
kg/
day,
the
highest
dose
tested.
Page
45
of
46
Chronic
Dog
Feeding
Studies
Groups
of
mongrel
dogs
(
2/
sex/
group)
were
fed
diets
containing
0,
5000
or
10000
ppm
OTC­
HCl
for
12
months.
Observations
included
clinical
signs,
mortality,
body
weight,
food
consumption,
haematology,
organ
weights,
macroscopy
and
histopathology.
No
dose
related
effects
were
observed
except
for
a
degenerating
germinal
epithelium
in
the
testicular
tubules
in
high­
dosed
male
dogs.
The
NOAEL
in
this
study
was
5000
ppm
in
the
diet,
equivalent
to
125
mg/
kg/
day.

In
a
second
study,
groups
of
8
male
dogs,
four
beagle
dogs
and
four
mongrel
dogs
per
group,
were
fed
diets
containing
0,
1000,
3000
or
10000
ppm
OTC­
HCl
for
24
months.
An
interim
sacrifice
of
1
beagle
and
1
mongrel
dog/
group
was
performed
after
12
months.
Observations
included
clinical
signs,
mortality,
body
weight,
food
consumption,
haematology,
alkaline
phosphatase
(
ALP),
bromosulphophthalein
(
BSP)
clearance,
urea
nitrogen
determinations,
organ
weight
macroscopy,
histopathology
and
semen
examination.
Two
dogs
died
after
12
and
24
months,
respectively
(
1
because
of
filaria
and
1
because
of
gastroenteritis).
No
dose­
related
effects
were
observed.
Atrophy
of
testes
and
epididymus
occurred
more
frequently
in
control
dogs
than
in
treated
ones.
The
NOAEL
was
10000
ppm
in
the
diet
(
the
highest
dose
tested),
equivalent
to
250
mg/
kg
b.
w.
(
Deichmann
et
al.,
1964).

Combined
Chronic
Toxicity/
Carcinogencity
(
Rats)
Groups
of
F344/
N
rats
(
50/
sex/
group)
were
fed
diets
containing
0,
25000,
or
50000
ppm
OTCHCl
(
purity
98.8%)
for
103
weeks.
Observations
included
clinical
signs,
mortality,
body
weight,
food
consumption,
macroscopy
and
histopathology.
Mean
male
body
weights
were
5­
8%
lower
during
the
first
year
of
the
study
at
50000
ppm.
Histological
examination
showed
a
dose
related
increase
in
the
incidence
of
benign
phaeochromocytomas
in
the
adrenal
gland
of
male
rats.
In
females
an
increase
in
the
incidence
of
adenomas
of
the
pituitary
gland
was
found
in
the
highest
dose
group
(
see
Tables
2
and
3,
respectively)
(
NTP,
1987).

Combined
Chronic
Toxicity/
Carcinogencity
(
Mice)
Groups
of
B6C3F1
mice
(
50/
sex/
group)
were
fed
diets
containing
0,
6300
or
12500
ppm
OTCHCl
(
purity
98.8%)
for
103
weeks.
Observations
included
clinical
signs,
mortality,
body
weight,
food
consumption,
macroscopy
and
histopathology.
Mean
body
weights
of
high
dosed
mice
were
5­
9%
lower
than
those
in
the
control
group
only
after
the
first
half
year
of
the
study.
The
tumour
incidence
was
not
significantly
increased
in
either
sex.
The
NOAEL
in
this
study
was
12500
ppm
in
the
diet
(
the
highest
dose
tested),
equal
to
1372
mg/
kg
b.
w.
(
NTP,
1987).

Metabolism
(
Mice)
After
oral
administration
of
47.6
mg
14C­
labelled
OTC­
HCl/
kg
b.
w.
to
mice,
72%
of
the
applied
dose
was
found
in
the
large
intestine
after
2
hours;
only
5%
was
absorbed,
of
which
the
major
portion
(
3.6%)
was
excreted
in
the
urine.
In
the
liver
1.9%
and
1.1%
of
the
dose
applied
was
recovered
after
1
and
2
hours,
respectively
(
Snell
et
al.,
1957).
Page
46
of
46
3.0
TOLERANCE
REASSESSMENT
SUMMARY
Tolerance
Reassessments
for
Oxytetracycline
The
tolerances
listed
in
40
CFR
§
180.337
are
currently
expressed
in
terms
of
oxytetracycline
per
se.
The
oxytetracycline
risk
assessment
team
has
determined
that
the
residues
of
concern
for
the
tolerance
expression
consists
of
oxytetracycline
per
se.
A
summary
of
oxytetracycline
tolerance
reassessments
is
presented
in
Table
A.
3.0.

Tolerances
Listed
Under
40
CFR
§
180.337:

Contingent
on
submission
of
an
adequate
analytical
enforcement
method
and
successful
Agency
petition
method
validation
(
PMV),
residue
data
are
available
to
reassess
the
established
tolerances
on
peach
and
pear.
The
available
residue
data
indicate
that
the
established
tolerances
are
appropriate
and
can
be
retained
at
their
present
levels
(
see
Table
A.
3.0).
Also,
contingent
on
submission
of
an
adequate
analytical
enforcement
method
and
successful
Agency
PMV,
residue
data
are
available
to
support
a
tolerance
for
apple.
The
available
residue
data
indicate
that
the
proposed
tolerance
of
0.35
ppm
is
appropriate
(
see
Table
A.
3.0.).

TABLE
A.
3.0.
Tolerance
Reassessment
Summary
for
Oxytetracycline.

Commodity
Current
Tolerance
(
ppm)
Tolerance
Reassessment
(
ppm)
Comments
Tolerances
Listed
in
40
CFR
§
180.337
Peach
0.35
0.35
Contingent
on
an
adequate
enforcement
method.

Pear
0.35
0.35
Contingent
on
an
adequate
enforcement
method.

Tolerances
To
Be
Proposed
Under
40
CFR
§
180.337
Apple
N/
A
0.35
Contingent
on
an
adequate
enforcement
method.