[Federal Register Volume 72, Number 215 (Wednesday, November 7, 2007)]
[Rules and Regulations]
[Pages 62788-62794]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-21796]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2006-0524; FRL-8153-7]


Oxytetracycline; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: This regulation establishes a tolerance for residues of 
oxytetracycline in or on apples. Interregional Research Project 
4 (IR-4) requested this tolerance under the Federal Food, 
Drug, and Cosmetic Act (FFDCA).

DATES: This regulation is effective November 7, 2007. Objections and 
requests for hearings must be received on or before January 7, 2008, 
and must be filed in accordance with the instructions provided in 40 
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: EPA has established a docket for this action under docket 
identification (ID) number EPA-HQ-OPP-2006-0524. To access the 
electronic docket, go to http://www.regulations.gov, select ``Advanced 
Search,'' then ``Docket Search.'' Insert the docket ID number where 
indicated and select the ``Submit'' button. Follow the instructions on 
the regulations.gov website to view the docket index or access 
available documents. All

[[Page 62789]]

documents in the docket are listed in the docket index available in 
regulations.gov. Although listed in the index, some information is not 
publicly available, e.g., Confidential Business Information (CBI) or 
other information whose disclosure is restricted by statute. Certain 
other material, such as copyrighted material, is not placed on the 
Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available in the electronic 
docket at http://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket 
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The Docket Facility telephone number is (703) 
305-5805.

FOR FURTHER INFORMATION CONTACT: Barbara Madden, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 305-6463; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be potentially affected by this action if you are an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
Potentially affected entities may include, but are not limited to those 
engaged in the following activities:
     Crop production (NAICS code 111), e.g., agricultural 
workers; greenhouse, nursery, and floriculture workers; farmers.
     Animal production (NAICS code 112), e.g., cattle ranchers 
and farmers, dairy cattle farmers, livestock farmers.
     Food manufacturing (NAICS code 311), e.g., agricultural 
workers; farmers; greenhouse, nursery, and floriculture workers; 
ranchers; pesticide applicators.
     Pesticide manufacturing (NAICS code 32532), e.g., 
agricultural workers; commercial applicators; farmers; greenhouse, 
nursery, and floriculture workers; residential users.
    This listing is not intended to be exhaustive, but rather to 
provide a guide for readers regarding entities likely to be affected by 
this action. Other types of entities not listed in this unit could also 
be affected. The North American Industrial Classification System 
(NAICS) codes have been provided to assist you and others in 
determining whether this action might apply to certain entities. If you 
have any questions regarding the applicability of this action to a 
particular entity, consult the person listed under FOR FURTHER 
INFORMATION CONTACT.

B. How Can I Access Electronic Copies of this Document?

    In addition to accessing an electronic copy of this Federal 
Register document through the electronic docket at http://www.regulations.gov, you may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at http://www.epa.gov/fedrgstr. You may also access a 
frequently updated electronic version of EPA's tolerance regulations at 
40 CFR part 180 through the Government Printing Office's pilot e-CFR 
site at http://www.gpoaccess.gov/ecfr.

C. Can I File an Objection or Hearing Request?

    Under section 408(g) of FFDCA, any person may file an objection to 
any aspect of this regulation and may also request a hearing on those 
objections. You must file your objection or request a hearing on this 
regulation in accordance with the instructions provided in 40 CFR part 
178. To ensure proper receipt by EPA, you must identify docket ID 
number EPA-HQ-OPP-2006-0524 in the subject line on the first page of 
your submission. All requests must be in writing, and must be mailed or 
delivered to the Hearing Clerk as required by 40 CFR part 178 on or 
before January 7, 2008.
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing that does not contain any CBI for inclusion in the public 
docket that is described in ADDRESSES. Information not marked 
confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA 
without prior notice. Submit this copy, identified by docket ID number 
EPA-HQ-OPP-2006-0524, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public 
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania 
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P), 
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South 
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only 
accepted during the Docket's normal hours of operation (8:30 a.m. to 4 
p.m., Monday through Friday, excluding legal holidays). Special 
arrangements should be made for deliveries of boxed information. The 
Docket Facility telephone number is (703) 305-5805.

II. Petition for Tolerance

    In the Federal Register of October 11, 2006 (71 FR 59783) (FRL-
8097-6), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 
U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 
7E4855) by Interregional Research Project 4 (IR-4), 500 
College Rd., East, Suite 201 W, Princeton, NJ 08540. The petition 
requested that 40 CFR 180.337 be amended by establishing a tolerance 
for residues of the fungicide oxytetracycline, in or on apple at 0.35 
parts per million (ppm). That notice referenced a summary of the 
petition prepared by Nufarm Americas Inc., the registrant, which is 
available to the public in the docket, http://www.regulations.gov. 
Comments were received on the notice of filing. EPA's response to these 
comments is discussed in Unit IV.C.
    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.

III. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a 
reasonable certainty that no harm will result from aggregate exposure 
to the pesticide chemical residue, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information.'' This includes exposure through drinking water and in 
residential settings, but does not include occupational exposure. 
Section 408(b)(2)(C) of FFDCA requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance and to ``ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue. . . 
.'' These provisions

[[Page 62790]]

were added to FFDCA by the Food Quality Protection Act (FQPA) of 1996.
    Consistent with section 408(b)(2)(D) of FFDCA, and the factors 
specified in section 408(b)(2)(D) of FFDCA, EPA has reviewed the 
available scientific data and other relevant information in support of 
this action. EPA has sufficient data to assess the hazards of and to 
make a determination on aggregate exposure for the petitioned-for 
tolerance for residues of oxytetracycline on apple at 0.35 ppm. EPA's 
assessment of exposures and risks associated with establishing the 
tolerance follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
children. Specific information on the studies received and the nature 
of the adverse effects caused by oxytetracycline as well as the no-
observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse-
effect-level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov. The referenced document is available in the docket 
established by this action, which is described under ADDRESSES, and is 
identified as document 0027 (pages 20 thru 24) in Docket ID EPA-HQ-OPP-
2005-0492.
    For oxytetracycline 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 
milligrams/kilograms/day (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 2-generation study, there was no toxicity 
identified in pups at the highest dose tested. The degree of concern is 
low for prenatal and/or postnatal toxicity resulting from exposure to 
oxytetracycline. No evidence of neurotoxicity was observed in any 
study.
    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.
    The mechanisms of action of antimicrobials, such as 
oxytetracycline, are based on affecting 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 1,000 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.

B. Toxicological Endpoints

    For hazards that have a threshold below which there is no 
appreciable risk, the toxicological level of concern (LOC) is derived 
from the highest dose at which no adverse effects are observed (the 
NOAEL) in the toxicology study identified as appropriate for use in 
risk assessment. However, if a NOAEL cannot be determined, the lowest 
dose at which adverse effects of concern are identified (the LOAEL) is 
sometimes used for risk assessment. Uncertainty/safety factors (UFs) 
are used in conjunction with the LOC to take into account uncertainties 
inherent in the extrapolation from laboratory animal data to humans and 
in the variations in sensitivity among members of the human population 
as well as other unknowns. Safety is assessed for acute and chronic 
risks by comparing aggregate exposure to the pesticide to the acute 
population adjusted dose (aPAD) and chronic population adjusted dose 
(cPAD). The aPAD and cPAD are calculated by dividing the LOC by all 
applicable UFs. Short-, intermediate-, and long-term risks are 
evaluated by comparing aggregate exposure to the LOC to ensure that the 
margin of exposure (MOE) called for by the product of all applicable 
UFs is not exceeded.
    For non-threshold risks, the Agency assumes that any amount of 
exposure will lead to some degree of risk and estimates risk in terms 
of the probability of occurrence of additional adverse cases. 
Generally, cancer risks are considered non-threshold. For more 
information on the general principles EPA uses in risk characterization 
and a complete description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm. A summary of the 
toxicological endpoints for oxytetracycline used for human risk 
assessment can be found at www.regulations.gov in document 0027 (pages 
27 thru 29) in Docket ID EPA-HQ-OPP-2005-0492.
    No appropriate acute dietary endpoint attributable to a single 
exposure was identified for females age 13-49 or for the general 
population. A chronic dietary endpoint (cPAD) was identified for all 
populations based on the microbiological study in dogs with a NOAEL of 
0.05 mg/kg/day based on a shift from a predominantly drug-susceptible 
population of enteric lactose-fermenting organisms to a multiple 
antibiotic-resistant population at 0.25 mg/kg/day (LOAEL) in mature 
beagle dogs. This chronic endpoint is considered 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 1,000 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 cPAD 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.

[[Page 62791]]

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to oxytetracycline, EPA considered exposure under the 
petitioned-for tolerances as well as all existing oxytetracycline 
tolerances in (40 CFR 180.337). EPA assessed dietary exposures from 
oxytetracycline in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk 
assessments are performed for a food-use pesticide, if a toxicological 
study has indicated the possibility of an effect of concern occurring 
as a result of a 1-day or single exposure.
    No such effects were identified in the toxicological studies for 
oxytetracycline; therefore, a quantitative acute dietary exposure 
assessment is unnecessary.
    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment, EPA used the food consumption data from the USDA 1994-1996 
and 1998 Nationwide Continuing Surveys of Food Intake by Individuals 
(CSFII). As to residue levels in food, EPA relied upon anticipated 
residues and percent crop treated (PCT) information for all 
commodities. Anticipated residue levels for apples, peaches 
(nectarines), and pears, percent crop treated information, default 
processing factors, and Food Safety and Inspection Service (FSIS) 
monitoring data from 2002, 2003, and 2004 to estimate residue levels in 
livestock commodities were used. Tolerances are currently established 
under 40 CFR 180.337 for residues of oxytetracycline per se in/on peach 
and pears at 0.35 ppm. As indicated in 40 CFR 180.1(h), tolerances for 
peaches also cover nectarines. Therefore, nectarines were included in 
the analysis using the peach residue data. For apples, an anticipated 
residue level of 0.033 ppm was used, based on the mean residue level 
measured in the field trial studies reflecting a total oxytetracycline 
application rate of 1.53 lb ai/A. For peach, nectarine, and pears, an 
anticipated residue level of 0.20 ppm was used, based on average 
residue levels from the available field trial data.
    Based on the registered uses of oxytetracycline on pears, peaches, 
and nectarines, and the proposed use on apples, no quantifiable 
residues in meat, milk, poultry, and eggs (MMPE) are expected. However, 
the Food and Drug Administration (FDA) has established tolerances in 
MMPE commodities for the sum of the residues of the tetracyclines 
including chlortetracycline, oxytetracycline, and tetracycline as 
listed in 21 CFR 556.500. Accordingly, the analysis includes estimates 
of possible oxytetracycline residues in livestock commodities making 
use of monitoring data from the FSIS collected in 2002, 2003, and 2004. 
These data were taken from the FSIS National Residue Program Data 
publications (Red Books).
    The relevant FSIS data sampled kidney tissue from a variety of 
livestock (cattle, swine, poultry, goats, etc), analyzing for 
oxytetracycline residues. As tetracycline residues partition 
preferentially into fat and kidney, measured oxytetracycline residues 
in kidney were used as worst-case level for all other livestock 
tissues. In 2004 and 2002, no oxytetracycline residues were detected in 
4,270 and 6,942 samples, respectively. In 2003, three kidney samples 
had finite oxytetracycline residue levels out of 5,260 samples. To 
compute an estimated residue level for use in Dietary Exposure 
Evaluation Model-Food Consumption Intake Database (DEEM-FCID), an 
average residue level was calculated using [frac12] level of detection 
(LOD) for nondetects (0.005 ppm) together with the three detected 
levels of 2.5, 5.0, and 5.0 ppm. This provided an estimated residue 
level of oxytetracycline in livestock commodities of 0.0058 ppm. This 
value was used for all livestock commodities in the DEEM-FCID analyses.
    iii. Cancer There was no evidence of carcinogenicity for male or 
female mice fed oxytetracycline hydrochloride for two years. Results 
from carcinogenicity studies in rats were less clear cut (equivaocal); 
however, based on the weight of the evidence, the EPA has classified 
oxytetracycline as a ``Group D'' carcinogen (``Not Classifiable as to 
Human Carcinogenicity''). Therefore, a cancer risk assessment was not 
conducted.
    iv. Anticipated residue and percent crop treated (PCT) information. 
Section 408(b)(2)(E) of FFDCA authorizes EPA to use available data and 
information on the anticipated residue levels of pesticide residues in 
food and the actual levels of pesticide residues that have been 
measured in food. If EPA relies on such information, EPA must pursuant 
to section 408(f)(1) of FFDCA require that data be provided 5 years 
after the tolerance is established, modified, or left in effect, 
demonstrating that the levels in food are not above the levels 
anticipated. For the present action, EPA will issue such Data Call-Ins 
as are required by section 408(b)(2)(E) of FFDCA and authorized under 
section 408(f)(1) of FFDCA. Data will be required to be submitted no 
later than 5 years from the date of issuance of this tolerance.
    Section 408(b)(2)(F) of FFDCA states that the Agency may use data 
on the actual percent of food treated for assessing chronic dietary 
risk only if:
    a. The data used are reliable and provide a valid basis to show 
what percentage of the food derived from such crop is likely to contain 
such pesticide residue.
    b. The exposure estimate does not underestimate exposure for any 
significant subpopulation group.
    c. Data are available on pesticide use and food consumption in a 
particular area, the exposure estimate does not understate exposure for 
the population in such area. In addition, the Agency must provide for 
periodic evaluation of any estimates used. To provide for the periodic 
evaluation of the estimate of PCT as required by section 408(b)(2)(F) 
of FFDCA, EPA may require registrants to submit data on PCT.
    The Agency used PCT information as follows: 5% peaches, 5% 
nectarines, and 25% pears. The Agency used projected percent crop 
treated (PPCT) information for apples assuming 10% of apples are 
treated.
    EPA uses an average PCT for chronic dietary risk analysis. The 
average PCT figure for each existing use is derived by combining 
available federal, state, and private market survey data for that use, 
averaging by year, averaging across all years, and rounding up to the 
nearest multiple of five percent except for those situations in which 
the average PCT is less than one. In those cases <1% is used as the 
average and <2.5% is used as the maximum. EPA uses a maximum PCT for 
acute dietary risk analysis. The maximum PCT figure is the single 
maximum value reported overall from available federal, state, and 
private market survey data on the existing use, across all years, and 
rounded up to the nearest multiple of five percent. In most cases, EPA 
uses available data from United States Department of Agriculture/
National Agricultural Statistics Service (USDA/NASS), Proprietary 
Market Surveys, and the National Center for Food and Agriculture Policy 
(NCFAP) for the most recent 6 years.
    Generally, estimated PCT at the national level for a given crop/
year may be equated to the average of all corresponding state PCTs 
weighted by their state acres grown. Such estimates take account of 
usage (or lack of usage) in all states for which the crop is grown and 
for which data are available. However, for a new use with previous 
usage occurring only under Section 18s, estimated PCT calculated over 
all growing states may understate what PCT would be upon Section 3 
registration

[[Page 62792]]

because that calculation may include states with no usage because they 
were not granted Section 18s. (However, this may not hold if all states 
where the product is efficacious were granted Section 18 emergency 
exemptions.)
    Therefore, to provide conservative PPCT estimates based on 
historical usage under Section 18s, only states with Section 18s are 
included in the PCT computations for each year. That is, for each year, 
estimated PCT for states with Section 18s is computed as the weighted 
average of state PCTs taken over only states with Section 18s. This 
extrapolates Section 18 usage to the national level. The computation 
utilizes data from the U.S. Department of Agriculture National 
Agricultural Statistics Service (USDA/NASS) because such data are 
readily available and are not proprietary. For risk assessment, the 
average over years of the weighted average state PCTs is appropriate to 
use as the PPCT estimate for use in chronic dietary risk assessment, 
and maximum over years is appropriate for use in acute dietary risk 
assessment. This approach is conservative because use is likely to be 
higher in states which requested emergency exemptions as compared to 
states which did not have such a severe need that they relied on the 
emergency exemption route.
    Predominant factors that bear on whether the estimated PPCTs for 
oxytetracycline on apples could be exceeded may include the history and 
scope of the relevant Section 18s, the presence or lack of alternatives 
and other factors. All relevant information currently available for 
predominant factors has been considered for oxytetracycline on apples.
    The Agency believes that the three conditions listed in Unit 
III.D.iv. have been met. With respect to Condition 1, PCT estimates are 
derived from Federal and private market survey data, which are reliable 
and have a valid basis. The Agency is reasonably certain that the 
percentage of the food treated is not likely to be an underestimation. 
As to Conditions 2 and 3, regional consumption information and 
consumption information for significant subpopulations is taken into 
account through EPA's computer-based model for evaluating the exposure 
of significant subpopulations including several regional groups. Use of 
this consumption information in EPA's risk assessment process ensures 
that EPA's exposure estimate does not understate exposure for any 
significant subpopulation group and allows the Agency to be reasonably 
certain that no regional population is exposed to residue levels higher 
than those estimated by the Agency. Other than the data available 
through national food consumption surveys, EPA does not have available 
information on the regional consumption of food to which 
oxytetracycline may be applied in a particular area.
    2. Dietary exposure from drinking water. The Agency lacks 
sufficient monitoring data to complete a comprehensive dietary exposure 
analysis and risk assessment for oxytetracycline in drinking water. 
Because the Agency does not have comprehensive monitoring data, 
drinking water concentration estimates are made by reliance on 
simulation or modeling taking into account data on the environmental 
fate characteristics of oxytetracycline. Further information regarding 
EPA drinking water models used in pesticide exposure assessment can be 
found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the First Index Reservoir Screening Tool (FIRST) and 
Screening Concentration in Ground Water (SCI-GROW) models, the 
estimated environmental concentrations (EECs) of oxytetracycline for 
chronic exposures are estimated to be 4.6 parts per billion (ppb) for 
surface water and 0.33 ppb for ground water.
    Modeled estimates of drinking water concentrations were directly 
entered into the dietary exposure model. The estimates were calculated 
based on the maximum use pattern for oxytetracycline 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. For chronic dietary risk assessment, the annual average 
concentration of 4.6 ppb was used to assess the contribution to 
drinking water.
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., for lawn and garden pest control, indoor pest control, 
termiticides, and flea and tick control on pets).
    Oxytetracycline is not registered for use on any sites that would 
result in residential exposure.
    4. Cumulative effects from substances with a common mechanism of 
toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when 
considering whether to establish, modify, or revoke a tolerance, the 
Agency consider ``available information'' concerning the cumulative 
effects of a particular pesticide's residues and ``other substances 
that have a common mechanism of toxicity.''
    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 EPA's website at http://www.epa.gov/pesticides/cumulative.

D. Safety Factor for Infants and Children

    1. In general. Section 408 of FFDCA provides that EPA shall apply 
an additional (``10X'') tenfold margin of safety for infants and 
children in the case of threshold effects to account for prenatal and 
postnatal toxicity and the completeness of the database on toxicity and 
exposure unless EPA determines based on reliable data that a different 
margin of safety will be safe for infants and children. This additional 
margin of safety is commonly referred to as the FQPA safety factor. In 
applying this provision, EPA either retains the default value of 10X 
when reliable data do not support the choice of a different factor, or, 
if reliable data are available, EPA uses a different additional FQPA 
safety factor value based on the use of traditional UFs and/or special 
FQPA safety factors, as appropriate.
    2. Prenatal and postnatal sensitivity. No quantitative or 
qualitative evidence suggests 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.
    3. Conclusion. 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 EPA. However, given the 
extensive literature and study reports available on oxytetracycline, 
the risk assessment takes a weight-of-the-evidence approach, 
considering the

[[Page 62793]]

available data from a variety of sources, including studies submitted 
and reviewed by the EPA, the National Toxicology Program, the World 
Health Organization (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. EPA has 
determined that reliable data show that it would be safe for infants 
and children to reduce the FQPA safety factor to 1X. The decision is 
based on the following findings:
    i. The toxicity database is complete.
    ii There is a low degree of concern and no residual uncertainties 
with regard to pre- and/or postnatal toxicity.
    iii. A developmental neurotoxicity study is not required because 
there was no evidence of neurotoxicity in the current toxicity 
database.
    iv. The dietary food exposure assessment utilizes mean residue 
levels and percent crop treated 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.
    v. In the previous risk assessments for oxytetracycline the 1993 
Reregistration Eligibility Decisision (http://www.epa.gov/pesticides/reregistration/status_page_o.htm) the reference dose was established 
at 0.005 mg/kg/body weight per day based on a NOAEL of 0.05 mg/kg body 
weight per day from the microbiological study in dogs. However, only an 
UF of 10 to account for intraspecies variability was used since it was 
determined that the dog gut is similar to that of humans. For this 
current assessment, EPA has used an UF of 100 to account for 
intraspecies and interspecies variablility. Though the reduction of the 
FQPA safety factor from 10x to 1x does not explicitly address the 
bacterial resistance issue, the chronic dietary endpoint (cPAD) is 
based on this effect. Therefore, the current risk assessment is 
sufficiently conservative and protective of infants and children.

E. Aggregate Risks and Determination of Safety

    Safety is assessed for acute and chronic risks by comparing 
aggregate exposure to the pesticide to the aPAD and cPAD. The aPAD and 
cPAD are calculated by dividing the LOC by all applicable UFs. For 
linear cancer risks, EPA calculates the probability of additional 
cancer cases given aggregate exposure. Short-, intermediate-, and long-
term risks are evaluated by comparing aggregate exposure to the LOC to 
ensure that the MOE called for by the product of all applicable UFs is 
not exceeded.
    1. Acute risk. There were no toxic effects attributable to a single 
dose. An endpoint of concern was not identified to quantitate an acute-
dietary risk to the U.S. general population or to the subpopulation 
females 13-50 years old. Therefore, oxytetracycline is not expected to 
pose an acute risk.
    2. Chronic risk. Using the exposure assumptions described in this 
unit for chronic exposure, EPA has concluded that exposure to 
oxytetracycline from food and water will utilize 32% of the chronic 
population adjusted dose (cPAD) for the U.S. population, 97% of the 
cPAD for all infants less than 1 year old, the subpopulation at 
greatest exposure, and 92% of the cPAD for children 1-2 years old. 
There are no residential uses for oxytetracycline that result in 
chronic residential exposure to oxytetracyline.
    3. Short-term and intermediate-term risk. Short-term and 
intermediate-term aggregate exposure takes into account residential 
exposure plus chronic exposure to food and water (considered to be a 
background exposure level).
    Oxytetracycline is not registered for use on any sites that would 
result in residential exposure. Therefore, the aggregate risk is the 
sum of the risk from food and water.
    4. Aggregate cancer risk for U.S. population. As discussed in Unit 
III.D.iii., EPA has classified oxytetracycline as a ``Group D'' 
carcinogen (``Not Classifiable as to Human Carcinogenicity''). 
Therefore, a cancer risk assessment was not conducted.
    5. Pharmaceutical aggregate risk. Section 408 of the FFDCA requires 
EPA to consider potential sources of exposure to a pesticide and 
related substances in addition to the dietary sources expected to 
result from a pesticide use subject to the tolerance. In order to 
determine whether to maintain a pesticide tolerance, EPA must 
``determine that there is a reasonable certainty of no harm.'' Under 
FFDCA section 505, the Food and Drug Administration reviews human drugs 
for safety and effectiveness and may approve a drug notwithstanding the 
possibility that some users may experience adverse side effects. EPA 
does not believe that, for purposes of the section 408 dietary risk 
assessment, it is compelled to treat a pharmaceutical user the same as 
a non-user, or to assume that combined exposures to pesticide and 
pharmaceutical residues that lead to a physiological effect in the user 
constitutes ``harm'' under the meaning of section 408 of the FFDCA.
    Rather, EPA believes the appropriate way to consider the 
pharmaceutical use of oxytetracycline in its risk assessment is to 
examine the impact that the additional nonoccupational pesticide 
exposures would have to a pharmaceutical user exposed to a related (or, 
in some cases, the same) compound. Where the additional pesticide 
exposure has no more than a minimal impact on the pharmaceutical user, 
EPA could make a reasonable certainty of no harm finding for the 
pesticide tolerances of that compound under section 408 of the FFDCA. 
If the potential impact on the pharmaceutical user as a result of co-
exposure from pesticide use is more than minimal, then EPA would not be 
able to conclude that dietary residues were safe, and would need to 
discuss with FDA appropriate measures to reduce exposure from one or 
both sources. EPA provided its findings with respect to oxytetracycline 
to FDA in a letter dated May 24, 2006, which is available in the public 
docket (EPA-HQ-OPP-2005-0492).
    The pesticidal exposure estimates described in the May 24, 2006 
letter reflect the dietary dose from pesticidal uses of oxytetracycline 
that a user treated with a pharmaceutical oxytetracycline product would 
receive in a reasonable worst-case scenario. EPA's pesticide exposure 
assessment has taken into consideration the appropriate population, 
exposure route, and exposure duration for comparison with exposure to 
the pharmaceutical use of oxytetracycline.
    EPA estimates that the pharmaceutical oxytetracycline exposure a 
user is expected to receive from a typical therapeutic dose (25 mg/kg/
day for children) is 50,000 to 200,000 times greater than the estimated 
dietary exposure from the pesticidal sources of oxytetracycline 
(0.000121 mg/kg/day to 0.000473 mg/kg/day). Therefore, because the 
pesticide exposure has no more than a minimal impact on the total dose 
to a pharmaceutical user, EPA believes that there is a reasonable 
certainty that the potential dietary pesticide exposure will result in 
no harm to a user being treated therapeutically with oxytetracycline. 
FDA is aware of EPA's conclusions regarding pesticide exposure in users

[[Page 62794]]

receiving treatment with a pharmaceutical oxytetracycline drug product 
and FDA's June 7, 2006 response to EPA is available the public docket 
(EPA-HQ-OPP-2005-0492).
    6. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
to the general population, or to infants and children from aggregate 
exposure to oxytetracycline residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

    HWI Method MR-OPAP-MA with modifications is used to measure and 
evaluate oxytetracycline residues. The method is adapted from Pfizer 
Method STP No. 012.14 entitled Microbiological Agar Diffusion Assay for 
Oxytetracycline in Fruit Extract and Hazelton Method OTCF entitled 
Oxytetracycline in Feeds which is published in Official Methods of 
Analysis of the AOAC, 15th Edition as Method 968.50. The method is 
similar to Final Action Microbiological Methods I and II in the AOAC 
Official Methods of Analysis (1984; 42.293-42.298).
    Although there is an enforcement method for oxytetracycline, it 
could be improved. The available method is nonspecific and the data 
generated by the method indicate that recoveries are generally low and 
markedly variable. As a condition of registration, EPA has required 
that the registrant develop an improved 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.

B. International Residue Limits

    There are currently no Codex maximum residue levels (MRLs) for 
oxytetracycline.

C. Response to Comments

    Several comments were received from a private citizen objecting to 
IR-4 Rutgers University increasing the use of this pesticide and 
establishment of tolerances. The Agency has received these same 
comments from this commenter on numerous previous occasions. Refer to 
Federal Register 70 FR 37686 (June 30, 2005), 70 FR 1354 (January 7, 
2005), 69 FR 63096-63098 (October 29, 2004) for the Agency's response 
to these objections.

V. Conclusion

    Therefore, the tolerance is established for residues of 
oxytetracycline in or on apple at 0.35 ppm

VI. Statutory and Executive Order Reviews

    This final rule establishes a tolerance under section 408(d) of 
FFDCA in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993). Because this rule has been 
exempted from review under Executive Order 12866, this rule is not 
subject to Executive Order 13211, Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, 
May 22, 2001) or Executive Order 13045, entitled Protection of Children 
from Environmental Health Risks and Safety Risks (62 FR 19885, April 
23, 1997). This final rule does not contain any information collections 
subject to OMB approval under the Paperwork Reduction Act (PRA), 44 
U.S.C. 3501 et seq., nor does it require any special considerations 
under Executive Order 12898, entitled Federal Actions to Address 
Environmental Justice in Minority Populations and Low-Income 
Populations (59 FR 7629, February 16, 1994).
    Since tolerances and exemptions that are established on the basis 
of a petition under section 408(d) of FFDCA, such as the tolerance in 
this final rule, do not require the issuance of a proposed rule, the 
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et 
seq.) do not apply.
    This final rule directly regulates growers, food processors, food 
handlers, and food retailers, not States or tribes, nor does this 
action alter the relationships or distribution of power and 
responsibilities established by Congress in the preemption provisions 
of section 408(n)(4) of FFDCA. As such, the Agency has determined that 
this action will not have a substantial direct effect on States or 
tribal governments, on the relationship between the national government 
and the States or tribal governments, or on the distribution of power 
and responsibilities among the various levels of government or between 
the Federal Government and Indian tribes. Thus, the Agency has 
determined that Executive Order 13132, entitled Federalism (64 FR 
43255, August 10, 1999) and Executive Order 13175, entitled 
Consultation and Coordination with Indian Tribal Governments (65 FR 
67249, November 6, 2000) do not apply to this rule. In addition, This 
rule does not impose any enforceable duty or contain any unfunded 
mandate as described under Title II of the Unfunded Mandates Reform Act 
of 1995 (UMRA) (Public Law 104-4).
    This action does not involve any technical standards that would 
require Agency consideration of voluntary consensus standards pursuant 
to section 12(d) of the National Technology Transfer and Advancement 
Act of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272 
note).

VII. Congressional Review Act

    The Congressional Review Act, 5 U.S.C. 801 et seq., generally 
provides that before a rule may take effect, the agency promulgating 
the rule must submit a rule report to each House of the Congress and to 
the Comptroller General of the United States. EPA will submit a report 
containing this rule and other required information to the U.S. Senate, 
the U.S. House of Representatives, and the Comptroller General of the 
United States prior to publication of this final rule in the Federal 
Register. This final rule is not a ``major rule'' as defined by 5 
U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: October 29, 2007.
Donald R. Stubbs,
Acting Director, Registration Division, Office of Pesticide Programs.

0
Therefore, 40 CFR chapter I is amended as follows:

PART 180--AMENDED

0
1. The authority citation for part 180 continues to read as follows:

    Authority: 21 U.S.C. 321(q), 346a and 371.


0
2. Section 180.337 is amended by alphabetically adding the following 
commodity to the table to read as follows:


Sec.  180.337  Oxytetracycline; tolerance for residues.

     * * *

------------------------------------------------------------------------
                                                              Parts per
                         Commodity                             million
------------------------------------------------------------------------
Apple......................................................         0.35
                                * * * * *
------------------------------------------------------------------------

[FR Doc. E7-21796 Filed 11-6-07; 8:45 am]
BILLING CODE 6560-50-S