Document ID: EPA-HQ-OPP-2006-0524-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-11T04:00Z

Summary of Petitions

PP#  7E4855

EPA has received a pesticide petition [7E4855] from the Interregional
Research Project #4 (IR-4), Rutgers, The State University of New Jersey,
500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C.346a(d), to amend 40 CDR part 180.337 by establishing
a tolerance for residues of oxytetracycline in or on the raw
agricultural commodity apples at 0.35 parts per million (ppm).

EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data supports granting of the petition.
Additional data may be needed before EPA rules on this petition.

This summary was prepared by Nufarm Americas Inc., the registrant and
EPA has not fully evaluated the merits of the pesticide petition. The
summary may have been edited by EPA if the terminology used was unclear,
the summary contained extraneous material, or the summary
unintentionally made the reader conclude that the findings reflected
EPA’s position and not the position of the petitioner. 

In addition, to the new data summarized below, however, Nufarm Americas
Inc. is also relying on a summary of information, data and arguments
previously submitted by Merck, Syngenta and IR-4, pursuant to section
408(d)(2)(A)(i) of the FFDCA as amended. It is the original summary of
information previously submitted by IR-4, and previously relied upon by
Merck and Syngenta that Nufarm Americas Inc. once again is relying on in
connection with this new pesticide petition. EPA has not republished the
summary of information initially submitted, except where EPA believes
such information would be helpful in understanding the new data.     

Oxytetracycline is an antibiotic used to control fire blight in apples
at a rate up to 200 ppm concentration. Up to 6 applications may be made
beginning at 10% bloom and continuing at 3-6 day intervals. 
Oxytetracycline severs an unmet need as the only alternative antibiotic
control of fireblight where resistance to Erwinia amylovora has occurred
and as a resistance management tool for streptomycin.

A.	Residue Chemistry

Analytical Method

The nature of the residues is adequately understood and an adequate
method is available for enforcement purposes with a limit of detection
(LOD) that allows monitoring with residues at or above the levels set in
these proposed tolerances. 

Plant Metabolism and Magnitude of Residues.

Residue data are available from studies conducted by IR-4. These studies
were carried out in Michigan, New York, Virginia, Washington, and
California. Only a single sample in the Michigan trial reported greater
residues than 0.1 ppm. In the second phase of this study, 100 pounds of
fruit was collected from both an untreated plot and one treated with
1,528 ppm oxytetracycline. The fruit was separated into juice, wet
pomace, and dry pomace, and all fractions had oxytetracycline residues
less than 0.05 ppm. In another study, the maximum residues detected in
all samples (including analyses of juice and whole apple) were less than
0.2 ppm. It is unlikely that residues of oxytetracycline in or on apples
will exceed the proposed tolerance of 0.35 ppm.

Oxytetracycline Residue Data

Trial	Applications	Spray Rate (gallon/acre)	Max. Residue detected ppm

	ppm/acre	oz. product/acre

Virginia	558	44	

100	0.065

	1115	88

0.028

Washington	151	54	

450	0.026

	302	108

0.047

Michigan	191	12	

80	<0.013

	382	24

0.252

New York	305	24	

100	0.013

	1528	120

0.032

Dry pomace	1528	120	100	<0.05

Wet pomace	1528	120	100	<0.05

Juice	1528	120	100	<0.05

California	200	16	100	<0.2

New York	611	58	

117	<0.2

	3050	280

<0.2

Juice	3050	280	117	<0.2

Whole apple	3050	280	117	<0.2

Wet pomace	3050	280	117	NA

B.	Toxicological Profile

	

Acute Toxicity

Oxytetracycline has been designated as a Toxicity Category IV substance,
indicating low toxicity. The acute oral LD50 of the hydrochloride in
Swiss mice was reported to be 7,200 mg/kg. 

Oxytetracycline has been used as a drug extensively for over 50 years in
animals and in man. It is one of a group of broad-spectrum antibiotics
known as tetracyclines, which were developed for control of bacterial
diseases in man and animals. As a result of its human drug use, there is
an extensive body of toxicological and clinical data available on
oxytetracycline. Due to this large body of data, EPA waived acute
toxicity data requirements for oxytetracycline in the 1993 RED. 

Reproductive and Developmental Toxicity

No evidence of teratogenicity was observed in CD-1 Mice or CD rats.
Charles River CD rats were administered 1,200, 1,350, or 1,500 mg/kg/day
hydrochloride (gavage) during gestation days 6 through 15. Decreased
maternal and fetal body weights, maternal survival, and a dose-related
decrease in the percent of pregnant dams were reported. As a result, a
NOEL was not established, and the LEL was 1,200 mg/kg/day. In a CD-1
mouse study, the dams were administered 0, 1,350, 1,670, or 2,100
mg/kg/day hydrochloride (gavage) during gestation days 6 through 15. No
effects were observed and the NOEL was 2,100 mg/kg/day, the highest dose
tested. 

A three-generation reproduction study in CD rats was conducted with the
hydrochloride at 0, 1, 20, and 100 mg/kg/day (diet). A possible decrease
in the survival of the second and third generation of pups from the high
dose group (measured as the 21-day survival index) was noted. It was not
possible to determine if this was a true treatment-related effect
because individual data were not presented plus dosing was not
confirmed. Due to these deficiencies and others, EPA concluded that the
study was invalid, but the data requirement was waived based upon the
availability of human data. 

Chronic Feeding Toxicity

Two, 2-year studies were conducted in rats. In the first study, 20 SD
rats/sex/group were fed diets containing approximately 0, 5, or 50
mg/kg/day oxytetracycline for 2 years. Survival and body weights were
greater in the treated rats as compared to controls. A decrease in the
weight of the testes and an increased incidence of histological changes
of the testes was reported; however, only summary data was presented.
These effects were not considered treatment related but were thought to
be related to the difference in the mean age of surviving treated rats
compared to the control group. The NOEL was 50 mg/kg/day, the highest
dose tested. In the second study, male Osborne Mendel rats were treated
with 0, 5, 50, or 150 mg/kg/day oxytetracycline or the hydrochloride in
the diet. Survival and body weights were greater in the treated rats.
There was no effect of oxytetracycline on the mean weight of the testes
and epididymides, nor were there any histological changes reported in
the testes. The NOEL was 150 mg/kg/day, the highest dose tested. 

To address the long-term effects of oxytetracycline, two chronic studies
were also conducted in dogs. In the first study 2 mongrel dogs/sex
received diets containing 0, 5,000, or 10,000 ppm oxytetracycline for 12
months. No effects were noted except testicular degeneration and
disrupted spermatogenesis in 2 males from the high dose group. However,
these effects were not observed in a follow-up 2-year dog study. In the
second dog study, groups of eight male dogs (4 beagles and 4 mongrels)
were fed diets containing 0, 100, 3,000, or 10,000 ppm oxytetracycline
or the hydrochloride for a period of 2 years. The only effect observed
in this study was a discoloration of the long bones and the thyroid. No
effects on the testes or epididymides were reported. The NOEL for this
study was 10,000 ppm (approximately 250 mg/kg/day). 

Carcinogenicity

In an oncogenicity study by the National Toxicology Program (NRP),
groups of F344N rats were administered 0, 25,000, or 50,000 ppm (0,
1,250, or 2,500 mg/kg/day oxytetracycline in their diet for 103 weeks.
The NTP’s Peer Review Committee concluded that “…there was
equivocal evidence of carcinogenicity for the male rats as indicated by
increased incidences of pheochromocytomas of the adrenal gland. There
was equivocal evidence of carcinogenicity in female rats as indicated by
increase incidences of adenomas of the pituitary gland in the high dose
group.” 

In a second NTP oncogenicity study, B6C3F1 mice fed oxytetracycline at
0, 6,300, or 12,000 ppm in their diet for 2 years, showed no evidence of
nonneoplastic or neoplastic lesions in either female of male mice. The
NTP’s Peer Review Committee concluded that there was no evidence of
carcinogenicity in female or male B6C3F1 mice.

In December of 1988, EPA completed a review of the data for
oxytetracycline and concluded that there is no evidence of carcinogenic
effects in either the rat or the mouse. The EPA Peer Review Committee
determined that oxytetracycline should receive a “Group D”
classification (“Not Classifiable as to Human Carcinogenicity”).

Human Data

The major side effects associated with oxytetracycline use in humans are
summarized below. After oral administration, oxytetracycline can cause
gastrointestinal irritation characterized by epigastric distress,
abdominal discomfort, nausea, vomiting and diarrhea in some individuals.
Taking oxytetracycline with a meal minimizes the side effects.
Intravenous use has been reported to product thrombophlebitis. Side
effects associated with long-term use may include changes in blood
parameters (leucocytosis, atypical lymphocytes, etc.). Liver injury
especially in pregnant women has been observed with large doses
administered either orally or parenterally. Skin reactions and
dermatitis have been reported to occur rarely as side effects to
treatment. With therapeutic doses of oxytetracycline, discoloration of
the teeth has been observed in treated children under the age of seven
and in infants whose mothers were treated during pregnancy.
Oxytetracycline may deposit in the skeleton of fetuses and children,
which may lead to a depression of bone growth. This effect is readily
reversible when the duration of exposure is short. 

Endocrine Disruption

No significant evidence of endocrine disruption has been observed with
human therapeutic use of oxytetracycline, nor is there substantial
animal data suggesting any such effect. In a chronic toxicity study,
testicular atrophy/degeneration was observed in rats (20/sex/group)
treated with 100 or 1,000 ppm oxytetracycline; however, these effects
were not attributed to treatment and were not observed in a second
chronic rat study (>100 males/group). Testicular degeneration and
disrupted spermatogenesis was noted in a one-year chronic dog study,
where mongrel dogs (2/sex/group) were fed diets containing 10,000 ppm
oxytetracycline. In a larger and longer second dog study, no effects on
testes or epididymal weight, or semen concentration and morphology were
observed in male dogs (4 beagles and 4 mongrels/group) fed diets
containing 100, 3,000, 10,000 ppm oxytetracycline or the hydrochloride
for 2 years. The reproductive effects observed in the chronic studies
were attributed to differences in the mean age of the surviving treated
animal compared to that of control. When the ages were similar
reproductive effects were not observed. As such, it seems unlikely that
oxytetracycline is a direct endocrine disruptor. Furthermore,
reproductive effects have not been reported with over 30 years of use as
a human drug.

C.	Aggregate Exposure

	1.	Dietary Exposure

i. Food

Three Tier 1 chronic dietary exposure assessments were conducted for
oxytetracycline based on the percent reference dose (%RfD) utilized. In
the most refined of these assessments, the impact of adding apples to
the present registered uses was determined using oxytetracycline field
trial residue data on apples. The initial assessment incorporating
existing tolerance level residues in peaches, pears, and nectarines, was
referred to as the “baseline” assessment. Subsequent assessments
added the commodity apples, first at proposed tolerance level residues
and then using average field trial residues. The difference between the
chronic dietary risk values derived from the baseline assessment and
those inclusive of apple use represent the contribution of apples to the
total chronic dietary risk from oxytetracycline agricultural uses. 

The chronic RfD for oxytetracycline is 0.005 mg/kg/body weight/day,
based on a chronic NOAEL of 0.05 mg/kg body weight/day from a 44-day
feeding study in dogs and an uncertainty factor of 10x to account for
intraspecies variability. An additional uncertainty factor of 10x for
intraspecies variability was not required due to the extensive human
clinical experience with oxytetracycline. The residue data used in the
assessments included published oxytetracycline tolerances for peaches
(0.35 ppm), nectarines (0.35 ppm), and apples (0.35 ppm proposed) and an
average field trial residue value of 0.069 ppm.

In these assessments, a conservative assumption of 100% crop treated
(worst case scenario) was incorporated. In comparison, current percent
of crop treated estimates are that only 1% of the total apple acreage is
treated at least once with oxytetracycline in the US. Additionally,
empirically derived processing factors for apple juice (0.6x) and apple
juice concentrate (1.8x) were applied. The USDA’s continuing survey of
food intakes by individuals (CSFII) 1994-1996 database with the
supplemental CSFII 1998 children’s survey consumption data was used in
all assessments. Exposure modeling was conducted using the dietary
exposure evaluation model (DEEM) from Exponent.

The results from these assessments included the population subgroups:

All Infants (<1 year old)

Nursing Infants (<1 year old)

Non-nursing infants (<1 year old)

Children (1-6 years)

Children (7-12 years)

Females (13-19 years/not pregnant or nursing)

Females (20+ years/not pregnant or nursing)

Females (13-50 years)

Females (13+ years/pregnant, not nursing

Females (13+ years/nursing)

Males (13-19 years)

Males (20+ years)

Seniors (55+ Years)

Overall the chronic %RfD based risk analyses revealed that the dietary
consumption of oxytetracycline treated commodities, including apples,
resulted in acceptable safety margins. 

ii. Drinking Water

The exposure to drinking water in considered minimal. Formulations
containing oxytetracycline will not be applied directly to water. It is
not likely that the potential exposure from residues of oxytetracycline
in drinking water added to the current dietary exposure will result in
an exposure, which exceeds the RfD. Based on its limited use (up to 6
applications) and conservative estimations of environmental
concentrations (5% runoff to 1-acre, 6-inch deep farm pond), potential
drinking water residue exposure is expected to be low. 

	2.	Non-Dietary Exposure

There are no known residential uses of oxytetracycline. Due to the
extensive therapeutic use of this compound and the supporting toxicity
studies, the Agency has not required occupational nor residential
exposure data of oxytetracycline, its hydrochloride, or the calcium
complex.

D. 	Cumulative Effects

Oxytetracycline is a broad-spectrum antibiotic that is used against gram
negative and to a lesser extent gram-positive bacteria. Oxytetracycline
has a common mechanism of action with other tetracycline drugs such as
chlortetracycline, demeclocycline, methacycline, deoxycycline,
minocycline, but not with other pesticides. The tetracyclines elicit
their effects by binding to bacterial ribosomes and thus inhibiting
bacteria protein synthesis. There are no known common modes of toxicity
with other pesticides. Therefore no cumulative exposure through use of
other pesticides with a common mode of action is likely and Nufarm
Americas Inc. believes it is appropriate to consider only the potential
risks of oxytetracycline in an aggregate risk assessment.

E.	Safety Determination

∆

%RfDd	∆ %RfDe

US Population (48 states, all seasons)	1.6	11.1	2.8	9.5	1.2

All Infants (<1 year old)	13	55.4	18.2	42.4	5.2

Nursing Infants (<1 year old)	8.4	31.3	11.4	22.9	3.0

Non-nursing infants (<1 year old)	14.7	64.5	20.8	49.8	6.1

Children (1-6 years)	4.9	56.9	10.9	52.0	6.0

Children (7-12 years)	1.9	14.2	3.7	12.3	1.8

Females (13-19 years/not preg. or nursing)	0.8	6.9	1.5	6.1	0.7

Females (20+ years/not preg. or nursing)	1.1	4.4	1.6	3.3	0.5

Females (13-50 years)	0.8	4.8	1.4	4.0	0.6

Females (13+ years/preg. not nursing	1.6	10.8	2.8	9.2	1.2

Females (13+ years/nursing)	1.4	7.9	2.3	6.5	0.9

Males (13-19 years)	0.4	5.0	1.0	4.6	0.6

Males (20+ years)	0.8	4.1	1.3	3.3	0.5

Seniors (55+ Years)	1.5	5.2	2.1	3.7	0.6

Average Increase (All subgroups) =	16.4	2.1

† 	RfD = 0.005 mg/kg body weight/day

a	Base line assessment

b	Base line assessment + apples (tolerance value)

c	Base line assessment + apples (average field trial value)

d∆	Shows the increase in %RfD attributed to apples (∆ = {baseline +
apple (tolerance)} – baseline)

e∆	Shows the increase in %RfD attributed to apples (∆ = {baseline +
apple (field trial)} – baseline)

Oxytetracycline has been used for over 50 years to treat a variety of
infectious diseases in humans and animals. Although adverse effects have
been reported such as hypersensitivity, discoloration of teeth, bone
deposition, or epigastric distress, these effects are usually associated
with prolonged treatment at high doses. The pesticidal use of
oxytetracycline on pears, peaches, and apples is very limited.
Oxytetracycline residues resulting from these uses are very low,
practically non-detectible. Since maximum oxytetracycline residues
resulting from crop uses are significantly less than the therapeutic
dose (approximately 5-fold less), and do not represent normal consumer
practices, such as washing, oxytetracycline crop use should not pose a
significant risk to the general US population or to infants and
children. 

In a dietary risk assessment, the drug resistance issue was discussed in
detail. In summary, residue levels on or in apples, dietary exposure
data, available toxicological data, usage patterns (i.e., limited
acreage), and limited exposure (i.e., up to 6 applications per year) for
oxytetracycline suggest that there is reasonable certainty of no harm
for the human population and adequate protection for drugs that are
considered essential human therapeutic agents. 

Available data suggest that issue of antimicrobial resistance to
oxytetracycline would not	 pose an increased health risk to humans. The
addition of apples to the chronic dietary risk assessment (using a
conservative average field trial residue value) yielded only minimal
increases in the % RfD for non-nursing infants). Also based on a NASS
survey of up to 5 states, the overall percent of apple acreage treated
was considered low (i.e., <10%), with estimates of the total apple
acreage in the US treated with oxytetracycline thought to be around 1%.
Therefore, a permanent tolerance for oxytetracycline on or in apples
would not have an adverse impact on human health.  

F.	Existing Tolerances

Tolerances are established under 40 CFR § 180.337 for residues of the
pesticide oxytetracycline in or on the following raw agricultural
commodities:

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0.35 ppm

Pear	0.35 ppm

Use of oxytetracycline as a drug in food animals is regulated by the FDA
under: 

21 CFR §520.1660 

21 CFR §520.1660a

21 CFR §520.1660b

21 CFR §520.1660c

21 CFR §520.1660d

21 CFR §522.1660

21 CFR §522.1662

21 CFR §522.1662a

21 CFR §522.1662b

21 CFR §524.1662

21 CFR §524.1662a

21 CFR §524.1662b

21 CFR §558.450

The FDA approved uses in or on beef cattle, dairy cattle, calves, swine,
sheep, chickens, turkeys, catfish, lobster, and salmonids. Tolerances
are established for residues in tissues (muscle, liver, fat, kidney) and
milk under 21 CFR § 556.500.  

There are no codex maximum residue limits for use of oxytetracycline on
apples or any other crop. 

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