- -2 of 38- environmental fate and effects data requirements (40 CFR Part 158) are identified. Furthermore, this problem formulation describes the prelimin ary ecological risk hypothesis and analysis plan for evaluating and characterizing risk to non-target species and the environment in support of the registration of oxytetracycline.

Oxytetracycline was originally re gistered in 1974 as a base (C AS No. 79-57-2; PC code 006304) and was later registered in 1984 as oxytetracy cline hydrochloride salt (CAS No. 2058-46-0; PC code 006308) and as oxytetracycline calcium complex (CAS No. 7179-50-2; PC code 006321). The original chemical formulation (PC code 006304) is no longer registered; therefore, only the hydrochloride salt (PC code 006308) and calcium complex (PC code 006321) are subject to registration review. In this document, the te rm “oxytetracycline” refers collectively to all chemical formulations, unless a specific chemical formulation is identified.

To date, no environmental fate data for oxytet racycline have been submitted; however an environmental fate bridging proposal for the hydrochloride salt and th e calcium complex and waiver requests for the calcium complex were submitted by the registrant in July 2008 in response to a Generic Data Call-In (GDCI) fo r the 2006 Tolerance Reassessment Progress and Risk Management Decision (TRED). These submi ssions, which refer to multiple open literature studies and have yet to be evalua ted, may be used to bridge the environmental fate of the two currently registered chemical formulations and to assess exposure, if they are acceptable. The only remaining environmental fate data gap for oxyt etracycline chemical formulations that is not addressed by the GDCI is a confirmatory batch equilibrium study.

The ecological effects data set for calcium oxyt etracycline and oxytetr acycline hydrochloride contains a number of gaps for terrestrial and aq uatic animals and plants. Data gaps include the following: avian reproduction toxi city; acute toxicity to saltwater fish, invertebrates, and mollusks; early-life stage freshwater fish toxicity ; full life cycle freshwater invertebrate toxicity; and Tier I terrestrial and aqua tic plant toxicity studies for both the calcium complex and the hydrochloride salt. In addition, unless the registra nt can clearly demonstrate that the ecological effects data for calcium oxytetracycline and oxyt etracycline hydrochloride can be bridged, there are a number of gaps associated with the lack of aquatic toxicity data for calcium oxytetracycline and terrestrial toxicity data for oxytetracycline h ydrochloride that will need to be addressed prior to completion of the ecological risk assessment for registration review.- -3 of 38- 

# Problem Formulation for the Environmental Fate, Ecological Risk, Endangered Species, and Drinking Water Assessments

in Support of the Registration Review of Oxytetracycline

O O

NH 2 

### O H N CH 3 

### C H 3 

### OH

OH OH O O H CH 3



### OH

Oxytetracycline (CAS 79-57-2)

Prepared by: Greg Orrick, Environmental Scientist Anita Pease, Senior Biologist

Reviewed by: Melissa Panger, Ph.D., Biologist Brian Anderson, Acting Risk Assessment Process Leader Elizabeth Behl, Branch Chief U. S. Environmental Protection Agency Office of Pesticide Programs Environmental Fate and Effects Division
Environmental Risk Branch IV 1200 Pennsylvania Ave., NW
Mail Code 7507P Washington, DC 20460

August 13, 2008- -4 of 38- Table of Contents

1. Purpose.................................................................................................................... ................... 3
2. Problem Fo rmulation ........................................................................................................ ......... 3 2.1. Nature of Regulatory Action............................................................................................... . 3
2.2. Previous Risk Assessments................................................................................................. . 3
3. Stressor Source and Distribution ........................................................................................... .... 3
3.1. Mechanism of Action....................................................................................................... .... 3 3.2. Overview of Pesticide Usage............................................................................................... 3 3.3. Environmental Fate and Transport....................................................................................... 3 3.3.1. Solubility.............................................................................................................. ......... 3 3.3.2. Mobility................................................................................................................ ......... 3 3.3.3. Degradation............................................................................................................. ...... 3 4. Receptors.................................................................................................................. .................. 3 4.1. Effects to Aquatic Organisms .............................................................................................. 3 4.2. Effects to Terrestrial Organisms .......................................................................................... 3
4.3. Incident Database Review.................................................................................................. .. 3 4.4. Ecosystems Potentially at Risk ............................................................................................ 3 5. Assessment Endpoints ....................................................................................................... ........ 3 6. Conceptual Model........................................................................................................... ........... 3 6.1. Risk Hypothesis ........................................................................................................... ........ 3 6.2. Conceptual Diagram ........................................................................................................ .... 3 7. Analysis Plan .............................................................................................................. ............... 3
7.1. Stressors of Concern ...................................................................................................... ...... 3 7.2. Measures of Exposure...................................................................................................... .... 3
7.3. Measures of Effect ........................................................................................................ ....... 3 7.4. Integration of Exposure and Effects .................................................................................... 3
7.5. Deterministic and Probabilistic Assessment Methods......................................................... 3 7.6. Endangered Species Assessments........................................................................................ 3 7.7. Drinking Water Assessment ................................................................................................ 3 7.8. Preliminary Identification of Data Gaps.............................................................................. 3

7.8.1. Fate.................................................................................................................... ............ 3
7.8.2. Effects ................................................................................................................. .......... 3
8. References................................................................................................................. ................. 3 8.1. Submitted Product Chemistry Studies ................................................................................. 3
8.2. Submitted Effects Studies................................................................................................. ... 3 Appendix A. Past Ecological Risk a nd Drinking Water Exposure Assessments for Oxytetracycline................................................................................................................ ............... 3 Appendix B. Data Call-In Table for Calc ium Oxytetracycline and Oxytetracycline Hydrochloride .................................................................................................................. ............... 3- -5 of 38- 1. Purpose

The purpose of this problem formulation is to pr ovide an understanding of what is known about the environmental fate and ecological effects of the registered uses of oxytetracycline. Oxytetracycline is a broad spectrum human and animal antibiotic produced from the actinomycete Streptomyces rimosus and used to control bacter ia, fungi, and mycoplasma-like organisms. In agriculture, the compound is mainly used to control fire blight ( Erwinia amylovora ) in apples and pears and bacterial spot ( Xanthomonas campestris pv. pruni ) in peaches and nectarines.

Oxytetracycline was originally register ed in 1974 as oxytet racycline base [2-naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,5,6,10,12,12ahexahydroxy-6-methyl-1,11-dioxo-, (4S,4aR,5S,5aR,6S,12aS)-] (C AS No. 79-57-2; PC code 006304) and was later registered in 1984 as oxyt etracycline hydrochlor ide salt (CAS No. 2058- 46-0; PC code 006308) and as oxyt etracycline calcium complex (CAS No. 7179-50-2; PC code 006321). The oxytetracycline base (PC code 006304) is no longer registered; therefore, only the hydrochloride salt (PC code 006308) and calcium complex (PC code 006321) are subject to registration review. In this document, the te rm “oxytetracycline” refers collectively to all chemical formulations, unless a specific chemical formulation is identified. Pending review of a July 2008 submission by the registrant for a wa iver request and a br idging proposal for the environmental fate data, it is unclear whethe r the hydrochloride salt (PC code 006308) and the calcium complex (PC code 006321) behave simila rly. In addition, it is unclear whether the hydrochloride salt and the calcium complex share similar ecotoxicological effects to non-target aquatic and terrestrial animals and plants becau se comparable data sets on the two chemical
formulations for the same taxa are not available.

This document will provide a plan for analyzi ng data relevant to oxytetracycline chemical formulations and for conducting environmental fa te, ecological risk, endangered species, and drinking water assessments for their registered us es. Additionally, this problem formulation is intended to identify data gaps, uncertainties, a nd potential assumptions used to address those uncertainties relative to characterizing the ecological risk associated with the registered uses of oxytetracycline.

2. Problem Formulation

2.1. Nature of Regulatory Action

Under the Federal Insecticide, F ungicide, and Rodenticide Act (FIF RA), all pesticid es distributed or sold in the United States ge nerally must be registered by th e U.S. Environmental Protection Agency. In determining whether a pesticide can be registered in the U.S., the Agency evaluates its safety to non-target species ba sed on a wide range of environmen tal and health effects studies. In 1996, FIFRA was amended by the Food Qualit y Protection Act, and the Agency was mandated to implement a new program for the periodic review of pesticides, i.e ., registration review (http://www.epa.gov/oppsrrd1/re gistration_review/). The re gistration review program is- -6 of 38- intended to ensure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse
effects to human health and the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the new registration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely.

As part of the implementation of the new Regist ration Review program purs uant to Section 3(g) of FIFRA, the Agency is beginning its evalua tion of oxytetracycline to determine whether it
continues to meet the FIFRA standard for re gistration. This problem formulation for the environmental fate, ecological risk, endangere d species, and drinking water assessments in support of the registration review will be posted in the initial docket on December 17, 2008, which will open the public phase of the review process.

2.2. Previous Risk Assessments

Previous risk assessments that serve as the basis for this problem formulation include the following (for details, see Appendix A ):

• 5 Section 18 (S18) risk assessments for uses on apples from 1991 to 1994

• 1 Reregistration Eligibility Decision (RED) (USEPA, 1993)

• 1 Tolerance Reassessment and Eligibili ty Decision (TRED) (USEPA, 2006)

• 1 Section 3 New Use (S3NU) updated ecologica l risk assessment of proposed use on apples (USEPA, 2007a)

• 1 S3NU Drinking Water Assessment of proposed use on apples (USEPA, 2007)

Risk could not be assessed from 1974, when oxytetracycline was firs t registered, through 1992, when ecological effects data were initially subm itted, due to a lack of data. Ecological risk assessments in support of the 1993 RED (USEPA, 1993) and for the proposed use on apples (USEPA, 2007a) did not identify potential acute a dverse effects to non-target organisms. The
risk of chronic effects was not estimated in thes e assessments due to a lack of data. However, concern was raised for emergence of antimicrobi al drug resistance due to agricultural use of oxytetracycline, which could pose a threat to the public health. For registration review, chronic ecotoxicity data requirements will be pursued in order to conduct a national-level ecological risk

assessment.

Drinking water assessments in support of th e 2006 TRED and the proposed use on apples yielded drinking water exposure esti mates that were similar to each other and that were based on conservative assumptions in the absence of submitted environmental fate data. These assessments relied on batch equilibrium data from a study in the open literature by Jones et al. (2005). A Generic Data Call-In (GDCI) was issu ed in February 2008 for a complete suite of environmental fate data, other than a batch equ ilibrium study, in order to fulfill registration data requirements (40 CFR Part 158.1300). In response , waiver requests were submitted in July 2008 for each of the environmental fate guideline requ irements included in the GDCI. These waiver requests reference multiple studies from the open literature and have yet to be evaluated. If- -7 of 38- acceptable, the data referenced in the waiver re quests may be used in the ecological risk and drinking water exposure assessments.

3. Stressor Source and Distribution

3.1. Mechanism of Action

Oxytetracycline (also kn own as terramycin) is a broad spec trum human and animal antibiotic produced from the actinomycete Streptomyces rimosus and used to control bacteria, fungi, and mycoplasma-like organisms. In humans, oxytetracycline is administ ered orally or intravenously
to treat infectious diseases cau sed by a wide variety of microor ganisms. In agriculture, the compound is mainly used to control fire blight ( Erwinia amylovora ) in apples and pears and bacterial spot ( Xanthomonas campestris pv. pruni ) in peaches and nectarines.

Tetracyclines inhibit protein synthesis in ba cteria by binding to the 30S ribosomes. This prevents aninoacyl tRNA from reading the mRNA ribosome complex, which prevents polypeptide chain elongation. High concentrations of tetracyclines also im pair 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.

3.2. Overview of Pesticide Usage

Oxytetracycline was originally registered for ag ricultural use in the Un ited States in 1974 on pears, peaches, and nectarines. Tree injec tion registrations expa nded oxytetracycline use patterns to include the n on-agricultural uses on forest, orna mental, and non-cr op-bearing trees, woody shrubs, and palms. Oxytetracycline was also registered for use as a marine anti-foulant additive for barnacle control; however, this use was cancelled in 2005. There are currently six active Section 3 end-use products containi ng oxytetracycline (EPA Reg. No. 7946-18, 55146-89, 55146-97, 64014-11, 74779-2, and 80990-1) as well as 39 Section 18 registrations and 3 Section 24(c) registrations that are active or under review. The hydr ochloride salt and calcium complex chemical formulations of oxytetracycline are both currently formulated in solution for tree injection and as a wettable powder for foliar spray. Table 1 lists the current uses of oxytetracycline per label and chemical formulation.- -8 of 38- Table 1. Currently labeled uses of oxytetracycline. EPA Reg.

No. Product
Name Chemical
Formulation Percent
Active Ingredient Uses

Injection Solutions 7946-18 MycojectTM Calcium complex 4.22% Ornamental and non-bearing trees

64014-11 Tree Tech®

OTC-Ca Calcium complex 4.57% Forest, ornamental, crop-bearing and noncrop-bearing trees, woody shrubs, and palms

74779-2 Bacastat TM Tree Injection Hydrochloride 18.30% (17% base 1 ) Non-crop-bearing ornamental trees

Wettable Powders

55146-89 FiremanTM Calcium complex 31.1% (17% base 1 ) Pears, peaches, and nectarines

55146-97 Mycoshield® Calcium complex 31.5% (17% base 1 ) Apples, pears, peaches, and nectarines

80990-1 FirelineTM 17

WP Hydrochloride 18.30% (17% base 1 ) Apples, pears, peaches, and nectarines

1 The percent active ingredient in each of these product formulations is equivalent to 17% oxytetracycline base.

Given that oxytetracycline is a systemic pesticide, it is possible that tree injection uses may result in exposure to terrestrial wildlife via ingestion of leaves, fruits, a nd/or flowers of treated trees. Although the tree injection uses may result in ex posure to non-target w ildlife, potential risks from these use patterns may not be quantified b ecause aerial applications of oxytetracycline are expected to result in higher oxytetracycline residues on treated tree foliage and a greater potential for dietary exposure to wildlife. The wettable powder use patterns from currently registered labels will be assessed, as they have foliar sp ray application directions that may lead to environmental exposure. These use patterns are listed in Table 2 . The maximum single foliar application rate for oxytetracyc line is 0.638 pounds of active ingred ient per acre (lbs a.i./A) (EPA Reg. No. 55146-89 and 80990-1). This applicati on rate may be applied weekly, nine times per year, resulting in a maximum annual foliar application rate for oxyt etracycline of 5.74 lbs
a.i./A.Table 2. Labeled maximum use patterns for fo liar spray applications (overall maximum use pattern in bold). 1
Use Pattern EPA Reg. No. App. Rate (lbs a.i./A) App.

per Year Annual App. Rate (lbs a.i./A) App.

Interval (days) App.

Method

Apple 80990-1 0.255 6 1.53 3 Air-blast Apple 55146-97 0.170 5 0.850 3 Aerial Peach & Nectarine 55146-89, 80 990-1 0.638 9 5.74 7 Air-blast

Peach & Nectarine 55146-97 0.255 8 2.04 7 Air-blast Pear 55146-89, 55146- 97, 80990-1 0.170 10 1.70 4 Aerial 2

Pear 55146-97 WA050006 0.085 10 0.850 4 Aerial

Pear 55146-97 WA050011 0.170 10 1.70 4 Aerial

1. Maximum use patterns reflect the maximum application rate, maximum number of applications per year, the

minimum application interval, and the application method of maximum exposure. 2. Aerial application is assumed in the absence of labeled directions.

In contrast to clearly stated use directions for EPA Reg. N o. 55146-97, use directions for EPA Reg. No. 55146-89 and 80990-1 are am biguous. For example, the number of applications per year for the latter two labels are not clearly limited, but “may involve up to 8 or 9 applications.” Furthermore, applications rates and th eir limits for EPA Reg. No. 80990-1 are only recommended. The use patterns listed in Table 2 reflect the assumption that these recommended label directions will be followed as directives. However, applicators may potentially apply oxytetracycline at higher rates. Because a folia r application method is not specified for use on pears on any label, aerial application is assumed to occur.

In 2002, the U.S. Geological Survey estimated 33,000 pounds of oxytetracycline were applied on agriculture in the United States ( Figure 1 ; USGS, 2008). The majority of usage was on pears (59%), followed by apples (28%), via emergency exemptions, and peaches (13%). The Biological and Economic Analysis Division (BE AD) of the Office of Pesticide Programs estimates average annual usag e of oxytetracycline from 2001- 2006 at 10,000 lbs a.i. on pears, 5,000 lbs a.i. on peaches, and 3,000 lbs a.i. on apples (USEPA, 2008c). Because non-agricultural usage is not reported, the total annual usage of oxytet racycline is likely to be greater than these estimates for agricultural uses.- -10 of 38- Figure 1. Estimated annual agricultural usage of oxytetracycline in 2002 (USGS, 2008).

3.3. Environmental Fate and Transport

Currently, many data gaps exist for fate and tr ansport characterization because no environmental fate (Subdivision N) studies have been submitted for oxytetracycline. The studies were waived in the reregistration process (U SEPA, 1993) on the basis of limite d use patterns at the time and
low estimated risks. A Generic Data Call-In (GDCI) was issued in February 2008 for the following studies: soil column leaching, hydrolysis , aqueous photolysis, soil photolysis, aerobic soil metabolism, anaerobic soil metabolism, an aerobic aquatic metabolism, aerobic aquatic metabolism, and terrestrial field dissipation. The GDCI applied to each currently registered chemical formulation independently, pending br idging of the environmental fate of the hydrochloride salt and the calcium complex. In response, waiver requests and a bridging proposal were submitted in July, 2008. These submissions reference multiple studies from the open literature and have yet to be evaluated. If acceptable, the data submitted in the waiver requests and bridging proposal may be used in the ecological risk and drinking water exposure

assessments.

The following are a selection of fate and transp ort data from product chemistry studies and the open literature. Data from open literature do not fulfill Subdivision N data guideline- -11 of 38- requirements, but were used in prior assessments in the absence of data that do fulfill guideline requirements.

3.3.1. Solubility

Product chemistry studies indicate th at the water solubility of hydr ochloride salt is 1g in 2 mL (500,000 mg L -1 ) and that oxytetracycline base and cal cium salt are slightly soluble (MRID 41602001, 46109401, 43262301, 44219401). They also report that the 0.1% solution pH of calcium salt is 7.5 to 10.0, which implies that th e water solubility is somewhat near 10 g L -1
(10,000 mg L -1 ; MRID 44219401). Therefore, these comp ounds are soluble enough to dissolve in surface water and groundwater; however, their exact solubilities in water are not well defined.

3.3.2. Mobility

Soil to water partition coefficients (K d ) for oxytetracycline in 30 easte rn U.S. soils representing
five soil orders and 28 soil series have b een published in a pee r-reviewed study (Jones et al.

, 2005). The study concluded that soil texture, cation exchange capacity, and iron oxide content appeared to most influence oxytet racycline sorption in soils with organic carbon content of 0 to 4%. Soil organic carbon content negatively co rrelated with compound sorption in those soils, but not with a single soil of 9% organic carbon. K d values ranged from 486 L/kg to 12,047 L/kg (pH 5.5), which indicates that oxytetracycline ha s relatively low mobility and is expected to preferentially adsorb to soils with minimal expect ed transport in the dissolved phase in runoff or
leachate.

3.3.3. Degradation

The following studies from open literature may offer insight regarding the degradation of oxytetracycline. The USGS Kansas Water Science Center 1 published a study on the chemical degradation of antibiotics in anaerobic sw ine lagoons, which found that oxytetracycline hydrolysis rates generally increase as pH devi ates from 7 and as temperature increases in synthetic systems (Loftin et al. , 2004). A kinetics study of oxytetracycline found that high temperatures, light exposu re, alkaline conditions, the presence of a substrate, and the presence of organic matter each led to decreased concentr ations of the compound in deionized water as compared to contrasting conditions (Doi and Stoskopf, 2000). An aerobic aquatic dissipation study performed in diffuse light found that oxytetr acycline “might be considered as moderately persistent,” displaying first-or der half-lives of 31 to 175 days in natural su rface water and sediment (Ingerslev et al. , 2001). These data are not acceptable according to 40 CFR Part 158 data requirements mainly because they do not include complete material balances and identification of major degradates. Therefore, th ese data may not be sufficient for use as model inputs for environmental exposure assessment.

1 Online at: http://ks.water.usgs.gov.- -12 of 38- 4. Receptors

Consistent with the process described in th e Overview Document (USEPA, 2004), the risk assessment for oxytetracycline relies on a surroga te species approach. Toxicological data generated from surrogate test species, which are intended to be representative of broad taxonomic groups, are used to extrapolate to poten tial effects on a variety of species (receptors)
included under these taxonomic groupings.

Acute toxicity data from studies submitted by pe sticide registrants along with the available open literature are used to evaluate the potential dir ect and indirect effect s of oxytetracycline to aquatic and terrestrial receptors. Registrant -submitted chronic data for oxytetracycline are not available. Submitted data typically include to xicity information on the technical grade active ingredient, degradates, and when available, formulated products ( e.g. , “Six-Pack” studies). The open literature studies are identified th rough EPA’s ECOTOXicology (ECOTOX) database (USEPA 2008a), which employs a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The evaluation of both sources of data may also provide insight into the direct and indirect effects of oxytetracy cline on biotic communities from loss of species that are sensitiv e to the chemical and from cha nges in structure and functional
characteristics of the affected communities.

Based on an interim ECOTOX open literature search conducted in June 2 008, a large number of potentially relevant open literature papers for oxyt etracycline were identifie d. A complete search of the ECOTOX database for oxytetr acycline toxicity data is expected to be completed in August 2008. Given the number of papers identified for review based on the in terim search and the likelihood that additional papers may be located based on the completed ECOTOX search, an evaluation of the open literature is not provided as part of this draft re gistration review problem formulation for oxytetracycline. However, an evaluation of the ECOTOX open literature studies for possible quantitative and/or qua litative inclusion in the ecological risk assessment, including identification of open literature da ta that may be used to fill the large number of ecological effects data gaps, is expected to be completed prior to the doc ket opening for oxytetracycline. Based on a preliminary review of the interim ECOTOX search, open literature data were identified for a number of taxonomic groups, includi ng estuarine/marine fis h, invertebrates, and mollusks, as well as aquatic plants, for which no registrant-submitted data are available. The extent to which the open literature data can be us ed to fulfill these data gaps will be determined pending their review and evaluation.

A summary of the aquatic and terrest rial toxicity data used to de rive a preliminary evaluation of risk for oxytetracycline is provided in Sections 4.1 and 4.2, respectively. In addition, a summary of ecological incidents associated with oxyt etracycline and a description of ecosystems potentially at risk are provided in Sections 4.3 and 4.4, respectively.

4.1. Effects to Aquatic Organisms

A summary of the aquatic toxicity data from registrant-submitted studies is provided in Table 3

. Aquatic toxicity data are available on ly for oxytetracyclin e hydrochloride ( i.e. , no aquatic- -13 of 38- toxicity data are available for the oxytetracyclin e calcium complex). All submitted acute aquatic toxicity studies for freshwater fish and inve rtebrates are classified as “acceptable”. Oxytetracycline is classi fied as practically non-toxic to fres hwater fish and invertebrates on an acute exposure basis. Acute data for estuarine/ma rine fish and invertebra tes and chronic data for aquatic animals are not available. In addition, toxicity data for aquatic vascular and non-vascular plants are also not available.

Table 3. Summary of submitted aquatic toxicity studies for oxytetracycline hydrochloride.

Species

(common name) Taxa Represented Endpoint Duration (hours) Measured
concentration

(mg a.i./L) Citation

MRID Acute Toxicity
Classification

Lepomis
macrochirus (Bluegill Sunfish) LC 50 96 >94.9 417832-01

(Murphy and Peters, 1981) Practically nontoxic

Oncorhynchus mykiss

(Rainbow Trout) Freshwater fishand aquaticphase amphibians LC 50 96 >116 471832-02 (Murphy and Peters, 1981) Practically nontoxic

Daphnia magna

(Water Flea) Freshwater
Invertebrates EC 50 48 >102 417832-03

(Bellantoni et

al. , 1991) Practically nontoxic

4.2. Effects to Terrestrial Organisms

Available data on the toxicity of oxytetracycline to terrestr ial animals are summarized in Table
4 . With the exception of the mammalian toxicity test in rats, in which anhydrous oxytetracycline was tested in acute studies and oxytetracyclin e hydrochloride was tested in the chronic developmental study, calcium oxytetracycline was us ed in the terrestrial testing for birds and honey bees. Chronic data for birds and terrestr ial plant toxicity data are not available for oxytetracycline. In addition, no terrestrial toxicity data are available for oxytetracycline hydrochloride.

All submitted terrestrial t oxicity studies for mammals, birds, and honey bees are classified as “acceptable”. Oxytetracycline is classified as pr actically non-toxic to mammals and birds on an acute oral basis and also practica lly non-toxic to birds on a sub-acute dietary exposure basis. In addition, oxytetracycline is prac tically non-toxic to honey bees ( Apis mellifera ) on an acute contact exposure basis.

Despite the lack of mortality observed in the acut e studies with mammals, birds, and honey bees, it is important to note that reduction in body weight wa s observed in the mammalian developmental study and the acute bobwhite quail oral LD 50 test. In the mammalian- -14 of 38- developmental study, reduction in fetal and matern al body weight was observed relative to the control at the lowest oxytetracy cline hydrochloride treatment leve l of 1200 mg a.i./kg,day. In addition, a reduction in bobwhite quail body we ight was observed in the acute oral LD 50 test at the three highest test calcium oxytetracyclin e concentrations of 500, 1000, and 2000 mg a.i./kg, with a corresponding NOAEC value of 250 mg a.i./ kg. Although these studies show reduction in body weight, the results of the other avian acute studies show that calcium oxytetracycline resulted in increased weight gain of bobwhite qu ail, relative to the control, in the dietary LC 50 test and no change in body weight between the treated groups and the control in the mallard duck dietary LC 50 test. Therefore, there appears to be variab ility in the available data with regards to oxytetracycline effects on body weight.

Table 4. Summary of endpoints fr om submitted terrestrial animal to xicity studies for oxytetracycline 1

. Species (common

name) Taxa Represented Endpoint Mean
Concentration Test
Substance

(% a.i.) Citation

MRID Acute Toxicity
Classification

LD 50 >5000 mg/kg BW 17.4 454593-01 (Moore, 2000) Practically
non-toxic
Rattus norvegicus (Laboratory Rat) Mammals

NOAEC
LOAEC <1,200 mg/kg/day 2 1,200 mg/kg/day (reduced maternal

and fetal body weight) NR 001323-91 (Wolkowski et

al. , 1983) NA

Anas platyrhynchos (Mallard Duck) LC 50 >5620 mg/kg-diet (ppm) 60.4 417778-03 (Long et al.

, 1991) Practically
non-toxic

LD 50 >2000 mg./kg BW 3 60.4 417778-01 (Campbell et

al. , 1991) Practically
non-toxic Colinus virginianus (Northern
Bobwhite

Quail) Birds, terrestrialphase amphibians, and reptiles

LC 50 >5620 mg/kg-diet (ppm) 60.4 417778-02 (Long et al.

, 1991) Practically
non-toxic

Apis mellifera (Honey Bee) Terrestrial
invertebrates LD 50 >100 μg/bee 60.4 416273-08 (Winter et al.

, 1991) Practically
non-toxic

1 Anhydrous oxytetracycline was tested in acute mammalian study, oxytetracyc line hydrochloride was tested in the chronic mammalian developmental study, and calcium oxytetracycline was used in the terrestrial testing for birds and honey bees.

2 Based on reduction in fetal body weight in a rat developmental toxicity study.

3 Sublethal effects ( i.e. , reduction in body weight) relative to control observed at treatment levels of 500, 1000, and 2000 mg/kg-BW; corresponding NOAEL = 250 mg/kg-BW.- -15 of 38- 4.3. Incident Database Review

A review of the Ecological Incident Informa tion System (EIIS) maintained by the Agency’s Office of Pesticide Programs (OPP) was perf ormed on June 24, 2008 (USEPA, 2008b). Based on the results of this query, no ecological incidents have b een reported for oxytetracycline hydrochloride (PC Code 006308) and calcium oxytetracycline (PC Code 006321).

Although no incidents associated with oxytetracy cline have been repo rted, the absence of reported incidents should not be construed as the absence of incidents. Incident reports for nontarget plants and animals typically provide information on mortality events only. Reports for other adverse effects, such as reduced growth or impaired re production, are rarely received. EPA’s changes in the registrant reporting requirements of inci dents may also account for the reduced number of reported incidents. Regist rants are now only required to submit detailed information on ‘major’ incidents. Minor incident s are generally reported aggregately and are not included in EIIS. In addition, ther e have been changes in state monitoring efforts due to lack of

resources.

4.4. Ecosystems Potentially at Risk

The ecosystems at risk are often extensive in scop e; therefore, it may not be possible to identify specific ecosystems during the development of a nation-wide ecological risk assessment. However, in general terms, terrestrial ecosystem s potentially at risk could include the treated area and immediately adjacent areas that may recei ve drift or runoff. Areas adjacent to the treated area could include cultivated fields, fenc erows and hedgerows, meadows, fallow fields or grasslands, woodlands, riparian habita ts and other uncultivated areas.- -16 of 38- Aquatic ecosystems potentially at risk include wa ter bodies adjacent to, or down stream from, the treated area and could include impounded bodies such as ponds, lakes and reservoirs, or flowing waterways such as streams or rivers. For uses in coastal areas, aquatic habitat also includes marine ecosystems, including estuaries.

5. Assessment Endpoints

Assessment endpoints represent the ac tual environmental value that is to be protected, defined by an ecological entity (species, community, or othe r entity) and its attri bute or characteristics (USEPA, 1998). For oxytetracyclin e, the ecological entities may include the following: birds, mammals, terrestrial-phase amphibian s, reptiles, freshwater fish a nd invertebrates, aquatic-phase amphibians, estuarine/marine fish and invertebrates, terrestrial plants, inse cts, and aquatic plants and algae. The attributes for each of these entities may include growth, reproduction, and
survival.

6. Conceptual Model

For a pesticide to pose an ecological risk, it mu st reach ecological receptors in biologically significant concentrations. An exposure pathway is the means by which a pesticide moves in the environment from a source to an ecological recepto r. For an ecological pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptors, an d a feasible route of exposure.

The conceptual model for oxytetracycline pr ovides a written desc ription and visual representation of the predicted relationships between oxytetracy cline, potential routes of exposure, and the predicted effects for the assess ment endpoint. A conceptual model consists of two major components: a risk hypo thesis and a conceptual diagram, which are discussed below (USEPA, 1998).

6.1. Risk Hypothesis

A risk hypothesis describes the predicted re lationship among the stre ssor, exposure, and assessment endpoint response along with the rationa le for their selection. For oxytetracycline, the following ecological risk hypothesis is bei ng employed for this ecological risk assessment:

Based on the available toxicity data, di rect acute risks to freshwater fish and invertebrates, mammals, birds, and terrestrial insects are possible for oxytetracycline, although this hypothesis may be rejected bas ed on the results of previous risk assessments. Based on the application methods and lack of available chronic toxicity data for non-target aquatic and te rrestrial species, in additi on to aquatic and terrestrial plants, oxytetracycline has the potential to reduce survival, reproduction, and/or growth in non-target terrestrial and aqua tic organisms when used in accordance with the current label. These non-target organisms include Federally listed threatened and endangered species as well as non-listed species.- -17 of 38- 6.2. Conceptual Diagram

Based on a lack of environmental fate data for ox ytetracycline, runoff, sp ray drift, volatilization, and direct spray represent poten tial transport mechanisms of o xytetracycline to aquatic and
terrestrial habitats wh ere non-target organisms may be exposed. These transport mechanisms ( i.e ., sources) are depicted in the conceptual models below ( Figures 2 and 3 ) along with the receptors of concern and the potential attribute changes in the receptors due to exposures of oxytetracycline.

Figure 2. Conceptual model for oxytet racycline effects on aquatic organism s. Dotted lines indicate exposure pathways that have a low likelihood of contributing to ecological risk. 

### Stressor

Source

Receptors

Attribute Change Oxytetracycline applied to use site (apple, peach, nectarine, and pear)

Spray drift

Fish/aquatic-phase amphibians Eggs

Larvae
Juveniles / Adults

Individual organisms
Reduced survival Reduced growth Reduced reproduction Food chain Reduction in algae Reduction in prey Habitat integrity Reduction in primary productivity
Reduced cover Community change Surface water/

Sediment Runoff

Aquatic Animals
Invertebrates

Vertebrates 

### Exposure
Media

Uptake/gills or integument

Ingestion Ingestion Long range atmospheric

transport

Wet/dry deposition Soil Ground water

Uptake/gills or integument

Aquatic Plants

N on-vascular

Vascular Uptake/cell, roots, leaves Riparian plant
terrestrial

exposure pathways see

Figure 3- -18 of 38- Figure 3. Conceptual model for oxytetracycline eff ects on terrestrial organisms.

7. Analysis Plan

In order to address the risk hypot hesis, the potential for adverse effects on the environment is estimated. The use, environmental fate, a nd ecological effects of oxytetracycline are characterized and integrated to assess the risks. This is accomplished using a risk quotient (ratio of exposure concentration to eff ects concentration) approach. A lthough risk is often defined as the likelihood and magnitude of adverse ecological effects, the risk quotient-based approach does not provide a quantitative estima te of likelihood and/or magnitude of an adverse effect. However, as outlined in the Overview Docume nt (USEPA, 2004), the likelihood of effects to individual organisms from partic ular uses of oxytetracycline is estimated using the probit doseresponse slope and either the level of concern (d iscussed below) or the actual calculated risk quotient value.

This analysis plan will be revisited and may be revise d depending upon the review and evaluation of data available in the open literatu re, data submitted by the registrant(s) as part of the data call-in, and information submitted by the public in response to the opening of the Registration Review docket. 

### Stressor

Source

Receptors

Attribute Change Oxytetracycline applied to use site (apple, peach, nectarine, and pear)

Direct application Spray drift

Birds / Terrestrialphase amphibians / reptiles /

mammals Terrestrial

insects

Individual organisms
Reduced survival Reduced growth Reduced reproduction Food chain Reduction in prey Habitat integrity Reduction in primary productivity
Reduced cover Community change Terrestrial/riparian plants grasses/forbs, fruit, seeds (trees, shrubs) Runoff

Mammals 

### Exposure
Media Soil

Ingestion Ingestion

Ingestion Ingestion Dermal uptake/Ingestion Long range atmospheric

transport

Root uptake
Wet/dry deposition

Birds /

Am p hibians

Ingestion- -19 of 38- 7.1. Stressors of Concern

The focus of this assessment is oxytetracycline, which includes the currently registered chemical formulations, oxytetracycline hydrochloride salt (PC code 006308) and oxytetracycline calcium complex (PC code 006321). Environmental degradat es will be screened for ecological risk concern using the available data.

In its ecological risk assessments, the Agency does not routinely include an evaluation of mixtures of active ingredients, either those mi xtures of multiple activ e ingredients in product formulations or those in the applicator’s tank. In the case of the product formulations of active ingredients (that is, a registered product contai ning more than one active ingredient), each active ingredient is subject to an indi vidual risk assessment for regula tory decision regarding the active ingredient on a particular use site. It should be noted, however, that no multi-active ingredient product formulations are regist ered for oxytetracycline.

Available toxicity data for environmental mixtur es of oxytetracycline with other pesticides will be presented as part of the ecological risk assessm ent. It is expected that the potential toxic effect of oxytetracycline, in combination with othe r pesticides used in th e environment, is likely to be a function of many factors including but not necessarily lim ited to: (1) the exposed species, (2) the co-contaminants in the mixture, (3) the ratio of oxytetracycl ine and co-contaminant concentrations, (4) differences in the pattern and duration of exposure among contaminants, and (5) the differential effects of ot her physical/chemical characterist ics of the receiving waters ( e.g. organic matter present in sediment and susp ended water). Quantitatively predicting the
combined effects of all these variables on mixture toxicity to any given ta xa with confidence is beyond the capabilities of the available data and methodologies. However, a qualitative discussion of implications of th e available pesticide mixture eff ects data on the confidence of
risk assessment conclusions will be addresse d as part of the uncertainty analysis.

7.2. Measures of Exposure

In order to estimate risks of oxyt etracycline exposures in aquatic and terrestrial environments, all exposure modeling and resulting risk conclusion s will be made based on maximum application rates for the foliar spray use patterns listed in Table 2 . Measures of exposure are based on aquatic and terrestrial models that predict es timated environmental concentrations (EEC) of oxytetracycline using maximum labeled applicati on rates and methods, as well as any mitigation measures specifically indicated on the label ( e.g. spray drift buffers). The models used to predict aquatic EECs are the Pesticide Root Zone Model coupled with the Exposure Analysis Model System (PRZM/EXAMS). The model used to pred ict terrestrial EECs on food items is T-REX.
The model used to derive EECs relevant to terr estrial and wetland plants is TerrPlant. These models are parameterized using relevant reviewed registrant-submitted environmental fate data.

PRZM (v3.12.2; May 12, 2005) and EXAMS (v2.98.4.6; Apr. 25, 2005) are screening simulation models coupled with the input shell PE (v5.0; Nov. 15, 2006) to ge nerate daily exposures and 1- in-10 year EECs of oxytetracycline that may occur in surface water bodies adjacent to application sites receiv ing oxytetracycline throug h runoff and spray drift. PRZM simulates- -20 of 38- pesticide application, movement and transforma tion on an agricultural field and the resultant pesticide loadings to a recei ving water body via runoff, erosion and spray drift. EXAMS simulates the fate of the pestic ide and resulting concentrations in the water body. The standard scenario used for ecological pesticide asse ssments assumes application to a 10-hectare agricultural field that drains into an adjacent 1-hectare water body that is 2 meters deep (20,000

m 3 volume) with no outlet. PRZM/EXAMS is us ed to estimate screen ing-level exposure of aquatic organisms to oxytetracyclin e. The measure of exposure for aquatic species is the 1-in-10 year return peak or ro lling mean concentration. The 1-in-1 0-year peak is used for estimating acute exposures of direct effects to aquatic organisms. The 1-in-1 0-year 60-day mean is used for assessing chronic exposure to fish and aquatic-ph ase amphibians. The 1-in-10-year 21-day mean is used for assessing aquatic i nvertebrate chronic exposure.

Exposure estimates for terrestrial an imals assumed to be in the target area or in an area exposed to spray drift are derived using the T-RE X model (v1.3.1; Dec. 7, 2006). This model incorporates the Kenega nomogr aph, as modified by Fletcher et al. (1994), which is based on a large set of actual field residue data. The upper limit values from the nomograph represent the
95 th percentile of residue values from actual field measurements (Hoerger and Kenega, 1972).
The Fletcher et al. (1994) modifications to the Kenega nomograph are based on measured field residues from 249 published research papers, incl uding information on 118 species of plants, 121 pesticides, and 17 chemical classes.

EECs for terrestrial plants inha biting dry and wetland areas are derived using TerrPlant (v1.2.2; Dec. 26, 2006). This model uses estimates of pestic ides in runoff and in sp ray drift to calculate EECs. EECs are based upon solubility, applicati on rate and minimum incorporation depth.

The AgDRIFT spray drift model (v2.01; May 24, 2001) is used to assess exposures of terrestrial plants to oxytetracyclin e deposited on terrestrial habitats by spray drift.

7.3. Measures of Effect

Ecological effects data are used as measures of di rect and indirect effects to biological receptors. Data are obtained from registrant-submitted studies or from literature studies identified by
ECOTOX. The ECOTOX database (USEPA, 2008a) provides more eco logical effects data in an attempt to bridge existing data gaps. ECOTOX is a source for locating single chemical toxicity data and potential chemical mixture toxicity data for aquatic life, terrestrial plants, and wildlife. ECOTOX was created and is maintained by the US EPA, Office of Research and Development,
and the National Health and Environmental Ef fects Research Laboratory's Mid-Continent Ecology Division.

Information on the potential effects of oxytetracy cline on non-target animal s is also collected from the Ecological Incident Information System (EIIS; USEPA, 2008b). Th e EIIS is a database containing adverse effect (typic ally mortality) reports on non -target organisms where such
effects have been associated w ith the use of pesticides.- -21 of 38- Where available, sublethal effects observed in both registrant-submitted and open literature studies will be evaluated qualitatively. Such effects may include behavioral changes ( e.g. , lethargy and changes in colora tion). Quantitative assessments of risks, though, are limited to those endpoints that can be di rectly linked to the Agency’s assessment endpoints of impaired survival, growth and reproduction.

The assessment of risk for direct effects to non-target organisms makes the assumption that toxicity of oxytetracycline to birds is similar to terrestrial-phase amphibi ans and reptiles. The same assumption is made for fish and aquatic-phase amphibians.

The acute measures of effect used fo r animals in this assessment are the LD 50 , LC 50 and EC 50

. LD stands for "Lethal Dose", and LD 50 is the amount of a material, given all at once, that is
estimated to cause the death of 50% of the test organisms. LC st ands for “Lethal Concentration”
and LC 50 is the concentration of a chemical that is estimated to kill 50% of the test organisms.
EC stands for “Effective Concentration” and the EC 50 is the concentration of a chemical that is estimated to produce a specific effect in 50% of the test organisms. Endpoints for chronic measures of exposure for listed and non-lis ted animals are the NOAEL/NOAEC and NOEC.
NOAEL stands for “No Observed-Adverse-Effect-Level ” and refers to the hi ghest tested dose of a substance that has been reported to have no harm ful (adverse) effects on test organisms. The NOAEC ( i.e. , “No-Observed-Adverse-Effect-Concentration” ) is the highest test concentration at
which none of the observed effects were statistically different fr om the control. The NOEC is
the No-Observed-Effects-Concentration. Fo r non-listed plants, only acute exposures are assessed ( i.e. , EC 25 for terrestrial plants and EC 50 for aquatic plants); for listed plants either the

NOAEC or EC 05 is used.

7.4. Integration of Exposure and Effects

Risk characterization is the integration of e xposure and ecological effects characterization to determine the potential ecological risk from the use of oxytetracyclin e on apples, peaches, nectarines, and pears and the likeli hood of direct and indi rect effects to non-target organisms in aquatic and terrestrial habitats. The exposure and toxicity effects da ta are integrated in order to
evaluate the risks of adverse ecological effects on non-target species. For the assessment of oxytetracycline risks, the risk quotient (RQ) me thod is used to compare exposure and measured toxicity values. EECs are divide d by acute and chronic toxicity values. The resulting RQs are then compared to the Agency’s Levels of Con cern (LOCs) (USEPA, 2004). These criteria are used to indicate when oxytetracycline’s uses, as directed on the label, have the potential to cause
adverse direct or indirect effect s to non-target organisms. In addition, incident data from the EIIS will be considered as part of the risk char acterization.

7.5. Deterministic and Probabilistic Assessment Methods

The quantitative assessment of risk will primarily depend on the deterministic point-estimate based approach described in the ri sk assessment. If possible, an effort will be made to further qualitatively describe risk using probabilistic to ols that the Agency has developed. These tools- -22 of 38- have been reviewed by FIFRA Scientific Advisory Panels (http://www.epa.gov/scipol y/sap/index.htm) and have been deemed as appropriate means of refining assessments where deterministic approaches have identified risks.

7.6. Endangered Species Assessments

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), the Agency will evaluate risks to Federally-listed th reatened and/or endangere d (listed) species from registered uses of oxytetracycline. This asse ssment will be conducted in accordance with the Overview Document (USEPA, 2004), provi sions of the ESA, and the Services’ Endangered Species Consultation Handbook (USFWS/NMFS, 1998).

The assessment of effects associated with the registration of oxytetracycline is based on an action
area. The action area is considered to be the ar ea directly or indirectly affected by the federal action, as indicated by the exceedance of Agency Le vels of Concern (LOCs) used to evaluate
direct or indirect eff ects. The Agency’s approach to defi ning the action area under the provisions of the Overview Document (USEPA, 2004) consider s the results of the ri sk assessment process
to establish boundaries for that action area with the understanding that exposures below the Agency’s defined LOCs constitute a no-effect threshold. For th e purposes of this assessment,
attention will be focused on the footprint of the action ( i.e. , the area where oxytetracycline application occurs), plus all areas where offsite transport ( i.e. , spray drift, runoff, etc.) may result in potential exposure that exceeds the Agency’s LO Cs. Specific measures of ecological effect that define the action area for listed species in clude any direct and in direct effects and/or potential modification of its critical habitat, including reduction in survival, growth, and reproduction as well as the full suite of subletha l effects available in the effects literature. Therefore, the action area extends to a point where environmental exposures are below any
measured lethal or sublethal effect threshold for any biological entity at the whole organism, organ, tissue, and cellular level of organization. In situations where it is not possible to determine the threshold for an observed effect, the action area is not spatially limited and is
assumed to be the entire United States.

7.7. Drinking Water Assessment

A drinking water assessment will be conducted to support future human health risk assessments of oxytetracycline. The drinking water asse ssment will incorporate model estimates of oxytetracycline in surface and ground waters. Th ese estimates will reflect environmental fate data recently called-in and a determina tion by the Agency’s Residues of Concern Knowledgebase Subcommittee (ROCKS) on which resi dues are of risk con cern. Concentrations of oxytetracycline residues in surface wate rs will be estimated using PRZM/EXAMS (see description above). Ground water estimates of oxytetracycline residue concentrations will be estimated using the Screening Concentration in Ground Water (SCI-GROW) model (v.2.3, Jul. 29, 2003). The drinking water assessment will also include a summary of available surface and ground water monitoring data. The currently la beled maximum use pattern that may lead to- -23 of 38- drinking water exposure is air-blast spray on peaches and nectarines ( i.e. , nine applications per year at 0.638 lbs a.i./A).

7.8. Preliminary Identification of Data Gaps

7.8.1. Fate

The national-level assessment will be conducted based on the available, acceptable data. To date, no environmental fate data for oxytetracyclin e have been submitted that fulfill 40 CFR Part 158.1300 guideline data requirement s. Based on the results of the 2006 TRED (USEPA, 2006), a Generic Data Call-In (GDCI) was issued in February 2008 for both currently registered
chemical formulations in order to collect e nvironmental fate data that fulfill most data requirements. An environmental fate brid ging proposal for the hydrochloride salt and the calcium complex and waiver requests for the calcium complex were submitted in July 2008 in response to the GDCI. These submissions refer to multiple studies from the open literature and have yet to be evaluated. The open literature data may be used to bridge the environmental fate of the two currently registered chemical form ulations and to assess exposure, if they are acceptable. However, data from the open lite rature typically do not report complete mass balances, including identific ation of all major degradates. Ther efore, regardless of whether the data from the open literature are useful for expos ure assessment, they are not likely to fulfill data guideline requirements.

Assuming that the data called in will be received and found acceptable for both currently registered chemical formulations, the only remaining environmental fate data gap for oxytetracycline chemical formulations is a c onfirmatory batch equilibrium study. The GDCI
table in Appendix B requires this study in order to fill the data gap and includes a rationale for requiring the data, an explanation of how the data will be used, and a brief description of the how the data could impact the Agency’s future decision-making.

7.8.2. Effects

The ecological effects data set for oxytetracyclin e contains a number of ga ps for terrestrial and aquatic animals and plants ( Tables 5 – 7 ). Data gaps include th e following: avian reproduction toxicity; acute toxicity to saltwater fish, invert ebrates, and mollusks; early-life stage freshwater fish toxicity; full life cycle freshwater invertebra te toxicity; and Tier I terrestrial and aquatic plant toxicity studies. In a ddition, unless the registrant can clearly demonstrate that the ecological effects data for calcium oxytetracy cline and oxytetracycline hydrochloride can be bridged, there are a number of gaps associated with the lack of aquatic to xicity data for calcium oxytetracycline and terrestrial toxicity data for oxytetracy cline hydrochloride. Further information on ecological effects data required to fulfill the Agency’s guideline requirements for oxytetracycline is presented as th e Data Call-in (DCI) table in Appendix B . In addition to providing the guideline number and study title for required data , the DCI table provides a- -24 of 38- rationale for requiring the data, an explanation of how the data will be used, and a brief description of the how the data could im pact the Agency’s future decision-making.

As previously discussed in Section 4, a completed review of the ECOTOX ope n literature data is
not available for this draft of the registration review problem fo rmulation for oxytetracycline. An evaluation of the ECOTOX open literature studi es for oxytetracycline, which will include identification of data that may be used to fulfill th e ecological effects data gaps, is expected to be completed prior to the opening of the docket for th is chemical. Based on a preliminary review of the interim ECOTOX search, open literature data were identifi ed for a number of taxonomic groups, including estuarine/marine fi sh, invertebrates, and mollusks, as well as aquatic plants, for which no registrant-submitted data are available. Th e extent to which the open literature data can be used to fulfill these data gaps will be de termined pending its review and evaluation. For guideline requirements with data gaps, the information provided in Tables 5 through 7 indicates instances where open literature data, which may fulfill the data gap pending review, have been identified. In the event that the open literature data are deemed sufficient to fulfill the identified data gaps, following technical review and evaluation, the information provided in Tables 5 through 7 and Appendix B will be revised to reflect the updated information.

Table 5. Available ecological effects data for terrestria l animals exposed to oxytetra cycline and remaining data

gaps. Guideline Description MRID (Chemical Formulation Tested) 1 Classification Data Gap? Comments

850.2100 Avian oral toxicity 417778-01 (Ca OTC) Acceptable Yes Data for oxtetracycline hydrochloride or bridging rationale required 417778-02 (Ca OTC) Acceptable 850.2200 Avian dietary toxicity 417778-03 (Ca OTC) Acceptable Yes Data for oxtetracycline hydrochloride or bridging rationale required 850.2300 Avian reproduction None NA Yes Data for both chemical
formulations or bridging
rationale and data for calcium oxytetracycline are required on waterfowl

and upland game bird species 850.3020 Honeybee acute contact toxicity 417778-04 (Ca OTC) Acceptable Yes Data for oxytetracycline hydrochloride or bridging rationale required

1 Ca OTE = Calcium oxytetracycline.- -25 of 38- Table 6. Available ecological effects data for aquatic animals exposed to oxytetracycline and remaining data

gaps. Guideline Description MRID (Chemical Formulation Tested) 1 Classification Data Gap? Comments

417832-01 (OTC HCl) Acceptable 850.1075 Freshwater fish

– Acute toxicity 417832-02 (OTC HCl) Acceptable Yes Data for calcium oxytetracycline or bridging rationale required

850.1075 Saltwater fish – Acute toxicity None NA Yes 2 Data for both chemical
formulations or bridging
rationale and data for oxytetracycline hydrochloride are

required on one
estuarine/marine fish species

850.1010 Freshwater
invertebrates – Acute toxicity 417832-03 (OTC HCl) Acceptable Yes Data for calcium oxytetracyline or bridging rationale required

850.1025
850.1035
850.1045
850.1055 Saltwater
invertebrates – Acute toxicity None NA Yes 2 Data for both chemical
formulations or bridging
rationale and data for oxytetracycline hydrochloride are

required on one
estuarine/marine mollusk
and one estuarine/marine
invertebrate

850.1300 Freshwater
invertebrate – life cycle test None NA Yes Data for both chemical
formulations or bridging
rationale and data for oxytetracycline hydrochloride are

required on one
freshwater invertebrate

850.1350 Saltwater
invertebrates – life cycle test None NA CR Conditional data requirement based on the
results of the acute
saltwater invertebrate toxicity test

850.1400 Freshwater fish

– early life stage

test None NA Yes Data for both chemical
formulations or bridging
rationale and data for oxytetracycline hydrochloride are required on one of the freshwater fish species
for which acute data are
available

850.1400 Saltwater fish – early life stage

test None NA CR Conditional data requirement based on the
results of the acute saltwater fish toxicity

test- -26 of 38- 850.1500 Fish – life cycle test None NA CR Conditional data requirement based on the

results of the early life stage toxicity test CR = Conditionally required.

1 OTC HCl = oxytetracycline hydrochloride

2 Open literature data may be used to fulfill this data gap, pending review of the available data.

Table 7. Available ecological effect s data for plants exposed to oxytet racycline and remaining data gaps.

Guideline Description MRID/
Accession Classification Data Gap? Comments

850.4100 Terrestrial plant toxicity: Tier I seedling emergence None NA Yes

850.4150 Terrestrial plant toxicity: Tier I vegetative vigor None NA Yes Non-target terrestrial plant data are required at the Tier I level

850.4400 Aquatic plant toxicity
with Lemna spp. None NA Yes 1

850.4500 Aquatic plant toxicity with algae None NA Yes 1 Non-target aquatic vascular and non-vascular plant data are required at the Tier I level.

Data for both chemical
formulations or bridging
rationale and data for oxytetracycline hydrochloride are required for aquatic plants.

1 Open literature data may be used to fulfill this data gap, pending review of the available data.

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U.S. Fish and Wildlife Service (USFWS) and Na tional Marine Fisheries Service (NMFS). 1998. Endangered Species Consultation Handbook: Procedures for Conducting Consultation
and Conference Activities Under Section 7 of the Endangered Sp ecies Act. Final Draft.
March 1998.- -29 of 38- U.S. Geological Survey (USGS). 2008. 2002 Pe sticide Use Maps. U.S. Geological Survey, National Water-Quality Assessment (NAWQA) Program, Pesticide National Synthesis Project. Accessed June 16, 2008. http://water.usgs.gov/nawqa/pnsp/ usage/maps/compound_listing.php?year=02

8.1. Submitted Product Chemistry Studies

MRID 41602001. Dowd, N. E., J. D. DeFoe. 1990. Oxytetracycline Hydr ochloride and Oxytetracycline Calcium Complex – Product Chemistry Data. Performed and submitted by Pfizer Inc.

MRID 44219401. McKay, Ph.D., B. M. 1997. Determ ination of Physical-Chemical Characteristics of 4% w/w Propylene Glycol Solution of the Calcium Salt of Oxytetracycline. Performed by Formulogics, Inc. Submitted by Tree Tech Microinjection System.

MRID 43262301. Johnson, Ph.D., N. A. 1994. Product Chemistry Data for the End Use Product Mycoshield® Brand of Agricultural Terramysin®. Performed by Merck Research Laboratories. Submitted by Merck & Co., Inc.

MRID 46109401. Irrig, H. 2003. Manufacturing Process Description and Supporting Data for Oxytetracycline Calcium Technical (ASF793), Addendum to MRID: 41602001. Performed and submitted by Syngenta Crop Protection, Inc.

8.2. Submitted Effects Studies

MRID: 41777801. Campbell, S.; Hoxter, K.; Smith, G. (1991) Oxytetracycline Calcium Complex: An Acute Oral Toxicity Study with the Northern Bob- white: Lab Project Number: 260-103A. Unpublished study prepared by Wildlife International Ltd. 18 p.

MRID: 41777802. Campbell, S.; Hoxter, K.; Smith, G. (1991) Oxytetracycline Calcium Complex: An Acute Oral Toxicity Study with the Northern Bob- white: Lab Project Number: 260-103A. Unpublished study prepared by Wildlife International Ltd. 18 p.

MRID: 41777803. Long, R.; Hoxter, K.; Smith, G. (1991) Oxytetracycline Calcium Complex: A Dietary LC50 Study with the Mallard: Lab Project Number: 260- 102. Unpublished study prepared by Wildlife International Ltd. 17 p.

MRID: 41777804. Winter, P.; Hoxter, K.; Smith, G. (1991) Oxytetracycline Calcium Complex: An Acute Contact Toxicity Study with the Honey Bee: Lab Project Number: 260-107. Unpublished study prepared by Wildlife International Ltd. 14 p.

MRID: 75075. Scott, M.L.; Holm, E.R.; Reynolds, R.E. (1954) Studies on pheasant nutrition. 3. Effect of antibiotics, arsenicals and thyroactive compounds upon growth and feathering in pheasant chicks. Poultry Science 33:1261-1265. (Also~In~unpublished submission re- ceived Sep 3, 1976 under 1007-82; submitted by Pfipharmecs, Div. of Pfizer, Inc., New York, N.Y.; CDL:238097-F)

MRID: 156311. Wellborn, T. (1971) Toxicity of some compounds to striped bass fi ngerlings. The Progresive
Fish-Culturist:32-36.

MRID: 41783201. Murphy, D. (1991) Oxytetracycline Hydrochloride: A 96-hour Static Acute Toxicity Test with the Bluegill (Lepomes macrochirus): Final Report: Lab Project Number: 260A-102. Unpublished study prepared by Wildlife International Ltd. 42 p.- -30 of 38- MRID: 41783202. Murphy, D. (1991) Oxytetracycline Hydrochloride: A 96-hour Static Acute Toxicity Test with the Rainbow Trout (Onchrhynchus mykiss) Final Rept: Lab Project Number: 260A-103. Unpublished study prepared by Wildlife International Ltd. 43 p.

MRID: 41783203. Bellantoni, D.; Holmes, C.; Peters, G. (1991) Oxytetracycline Hydrochloride: A 48-hour Static Acute Toxicity Test with the Cladoceran (Daphnia magna): Final Rept: Lab Project Number: 260A-101. Unpublished study prepared by Wildlife International Ltd. 47 p.

MRID: 28002. Wellborn, T.L.; Jr. (1969) The toxicity of nine therapeutic and herbicidal compounds to striped bass. Progessive Fish-Cultur- is t 31(? ):27-32. (Also~In~unpub lished submission received Aug 20, 1976 under 39445-1; submitted by American Carbonyl, Inc., Tenafly, N.J.; CDL:228232-C)- -31 of 38- Appendix A. Past Ecologi cal Risk and Drinking Wat er Exposure Assessments for Oxytetracycline

Table A.1. Past Ecological Risk Assessments for Oxytetracycline.

Date Assessment Type Uses Assessed Potential
Risk
Identified? Summarized Ecological Conclusions

3/25/1991 S18 RA Apples in MI No Risk assessment could not be completed in the absence of toxicity data.
4/8/1992 S18 RA Apples in WA No Risk assessment could not be completed because submitted toxicity data were not reviewed.
4/9/1992 S18 RA Apples in MI No Risk assessment could not be completed because submitted toxicity data were not reviewed.

11/17/1992 RED Chapter All Yes Risk is unlikely to avian or aquatic organisms, as well as honey bees.
2/12/1993 S18 RA Apples in WA Yes No unnecessary risk to non-target organisms, including endangered species.
3/1/1993 RED All Yes Risk is unlikely to avian or aquatic organisms, as well as honey bees.
4/15/1994 S18 RA Apples in OR No (no conclusions)
5/24/2004 IR-4 ERA Apples Yes Risk of acute mo rtality for non-target animals is not likely.
Risk of chronic effects could not be estimated due to lack of data. There is concern for emergence of antimicrobial drug resistance that could pose a threat to the public health.
10/7/2005 IR-4 ESA Apples Yes Risk of acute mo rtality for non-target animals is not likely. Risk to plants and risk of ch ronic effects to animals could
not be estimated due to lack of data. There is concern for emergence of antimicrobial drug resistance that could pose a threat to the public health.
11/4/2006 IR-4 ERA Apples Yes Risk of acute mo rtality for non-target animals is considered
low. Risk of chronic effects could not be estimated due to lack of data. There is concern for emergence of antimicrobial drug resistance that could pose a threat to the public health.
8/27/2007 S3NU ERA Apples Yes Risk of acute mo rtality for non-target animals is considered
low. Risk of chronic effects could not be estimated due to lack of data. There is concern for emergence of antimicrobial drug resistance that could pose a threat to the public health.

Table A.2. Past Drinking Water Exposure Assessments for Oxytetracycline.

Date Assessment Type Summarized Exposure Conclusions
8/4/2005 TRED DWA EDWCs: peak 157 ppb, chronic 8.0 ppb, GW 0.0579 ppb
10/26/2005 TRED Phase I DWA EDWCs: peak 157 ppb, chronic 8.0 ppb, GW 0.0579 ppb
5/22/2006 TRED Phase III DWA EDWCs: peak 89.4 ppb, chronic 4.6 ppb, GW 0.033 ppb
6/1/2006 TRED EDWCs: chronic 4.6 ppb, GW 0.033 ppb (acute risk was not assessed)
8/27/2007 DWA EDWCs: peak 89.2 ppb, chronic 4.53 ppb, GW 0.033 ppb- -32 of 38- Appendix B. Data Call-In Table for Calc ium Oxytetracycline and Oxytetracycline Hydrochloride

The following sample Data Call-In (DCI) tabl e includes rationales for requiring the data requested in this problem formula tion, explanations of the utility of the data, and explanations for how the data might impact risk assessment. As previously stated in Section 7.8.2, ecological effects data submittal will be required to address the lack of aquatic toxicity data for calcium oxytetracycline and the lack of te rrestrial toxicity data for oxy tetracycline hydrochloride, unless the registrant can clearly demonstrate that th e available data for cal cium oxytetracycline and oxytetracycline hydrochloride can be bridged. In the event that the open literature data are
deemed sufficient to fulfill the identified data gaps, following technical review and evaluation, the data requested in the following tables may be waived.

Guideline Number: 850.2100, 850.2200, and 850.3020 Study Title: Avian Oral Toxicity, Av ian Dietary Toxicity, and Honeybee Acute Contact Toxicity Rationale for Requiring the Data

Although acute oral and dietar y avian and acute contact honey bee data have been submitted for calcium oxytetracycline, no data specific for oxytetracycline hydrochloride
are available for these taxa. Unless the re gistrant can clearly demonstrate that the available acute avian and honey bee data for calcium oxytetracycline can be used as a surrogate for oxytetracycline hydrochloride , data specific for the oxytetracycline hydrochloride salt must be submitted. Practical Utility of the Data

How will the data be used? These data are necessary to evaluate the extent of potential acute risk to avian and honey bee species through acute exposure via appl ication of oxytetracy cline hydrochloride according to the label. In the absence of oxytetracycline hydrochloride data or justification of data bridging for the two chemical formulations, the Agency would presume risk to honey bees and that acute ri sk to listed and non-lis ted birds exceeds the Agency’s concern levels for the oxytetr acycline hydrochloride formulation.

How could the data change the Agency’s d ecision or impact the Agency’s future decision-making? If future endangered species risk assessmen ts are performed wit hout these data, the Agency would have to assume that oxytetr acycline hydrochloride “m ay affect” birds and honey bees, which are used as a surrogate for te rrestrial insects, dire ctly via acute effects (and listed species from othe r taxa indirectly), and use of oxytetr acycline hydrochloride may need to be restricted in areas where li sted species could be exposed. The lack of these data will limit the flexibility that the Agency and registrants have in coming into compliance with the Endangered Species Act an d could result in use restrictions for oxytetracycline hydrochloride which are unnecessar ily severe. In addition, the lack of these data may result in assumed risk and potential mitigation of oxytetracycline- -33 of 38- hydrochloride under FIFRA.

Guideline Number: 850.2300 Study Title: Avian Reproduction Rationale for Requiring the Data

There are no avian reproduction studies available for calcium oxytetracycline or oxytetracycline hydrochloride; therefore, the po tential risk of chr onic effects to birds
from the use of these chemical formulations cannot be discounted. Given the available mammalian developmental and bobwhite quail acute oral data, both of which report reduction in body weight, it is possible that similar adverse sublethal effects may be observed in the avian reproduction studies. The 40 CFR Part 158 data requirements specify that avian reproduction studies be submitted for the mallard duck and bobwhite quail. If the registrant ca n provide a rationale for brid ging the oxytetracycline calcium complex and hydrochloride salt data, avian reproduction studies should be submitted only for calcium oxytetracycline. If such br idging rationale cannot be provided, avian reproduction data should be submitted for bot h the oxytetracycline calcium complex and hydrochloride salt formulations. Practical Utility of the Data

How will the data be used? These data are necessary to evaluate the extent of potential risk to avian species through chronic exposure via app lication of calcium oxytetr acycline and oxytetracycline hydrochloride according to the label. In the absence of data, the Agency would presume
that chronic risk to listed and non-listed birds exceeds th e Agency’s concern levels.

How could the data change the Agency’s d ecision or impact the Agency’s future decision-making? If future endangered species risk assessmen ts are performed wit hout these data, the Agency would have to assume that cal cium oxytetracycline and oxytetracycline hydrochloride “may affect” birds directly vi a chronic effects (and listed species from other taxa indirectly), and use of these oxytet racycline chemical formulations may need
to be restricted in areas wh ere listed species could be expos ed. The lack of these data will limit the flexibility that the Agency and registrants have in coming into compliance with the Endangered Species Act and could resu lt in use restrictions for oxytetracycline
chemical formulations which ar e unnecessarily severe. In add ition, the lack of these data may result in assumed risk and potential m itigation of the oxytetracycline chemical
formulations under FIFRA.- -34 of 38- Guideline Number: 850.1075 and 850.1010 Study Title: Freshwater fish – Acute Toxicity and Freshwater Invertebrates - Acute Toxicity Rationale for Requiring the Data

Although acute freshwater fish and invert ebrate data have been submitted for oxytetracycline hydrochloride, no data specific for calcium oxytetracy cline are available for these taxa. Unless the registrant can clea rly demonstrate that the available freshwater fish and invertebrate data for oxytetracycline hydrochloride can be used as a surrogate for calcium oxytetracycline, data specific for the calcium complex salt must be submitted for
these taxa. Practical Utility of the Data

How will the data be used? These data are necessary to evaluate the extent of potential risk to freshwater fish and invertebrates through acute exposure via application of calcium oxytetracycline according to the label. In the absence of cal cium oxytetracycline data or justification of data bridging for the two chemical formula tions, the Agency would presume that acute
risk to listed and non-listed freshwater fi sh and invertebrates exceeds the Agency’s concern levels for the calcium oxytetracycline formulation.

How could the data change the Agency’s d ecision or impact the Agency’s future decision-making? If future endangered species risk assessmen ts are performed wit hout these data, the Agency would have to assume that calcium oxytetracycline “may affect” freshwater fish and invertebrates directly via acute effects (and listed species from other taxa indirectly), and use of calcium oxytetracycline may need to be restricted in areas where listed species could be exposed. The lack of these data will limit the flexibility that the Agency and registrants have in coming into compliance with the Endangered Species Act and could
result in use restrictions fo r calcium oxytetracycline which are unnecessarily severe. In addition, the lack of these data may result in assumed risk and potential mitigation of calcium oxytetracycline under FIFRA.

Guideline Numbers: 850.1025, 850.1035, 850.1075 Study Title: Oyster Acute Toxicity Test (Shell Deposition), Mysid Acute Toxicity Test, Saltwater Fish Acute Toxicity Test Rationale for Requiring the Data

There are no data on the acu te effects of calcium oxytet racycline or oxytetracycline hydrochloride to estuarine/marine fish, invertebrates, and mollusks, all of which are required based on the 40 CFR Part 158 data requirements because use patterns for oxytetracycline include applica tion to food crops which are lo cated in close proximity to estuarine/marine environments. If the regist rant can provide a rati onale for bridging the- -35 of 38- oxytetracycline calcium complex and hydrochlorid e salt data, acute studies for the oyster, mysid, and saltwater fish should be submitted only for oxytetracycline hydrochloride. If such bridging rationale cannot be provided, acute toxicity da ta for these taxa should be submitted for both the oxytetracycline calcium complex and hydrochloride salt
formulations. Practical Utility of the Data

How will the data be used? These data are necessary to evaluate the exte nt of potential risk to estuarine/marine organisms including fish, invertebrates, and mollusks, through acute exposure imposed by the application of calcium oxytetracy cline and oxytetracycline hydrochloride according to the label. In the absence of da ta, the Agency would presume acute risk to
listed and non-listed estuarine/marine fish, invertebrates, and mollusks.

How could the data change the Agency’s d ecision or impact the Agency’s future decision-making? If future risk assessments are performed w ithout these data, the Agency would have to assume that calcium oxytetracycline and oxytetracycline hydrochloride “may affect” estuarine/marine fish, invertebrates, and mo llusks directly via acute effects (and listed species from other taxa indirectly), a nd use of these oxytetracycline chemical formulations may need to be restricted in areas where listed specie s could be exposed.
The lack of these data will limit the flexibi lity that the Agency and registrants have in coming into compliance with the Endangered Species Act and could result in use restrictions for oxytetracycline chemical form ulations which are unnece ssarily severe. In addition, the lack of these data may result in assumed risk and potential mitigation of the oxytetracycline chemical formulations under FIFRA.

Guideline Numbers: 850.1300, 850.1400 Study Title: Freshwater Invertebrate Life Cycle Test, Freshwater Fish Early Life Stage Test Rationale for Requiring the Data

There are no data on the chr onic effects of calcium oxytetra cycline and oxytetracycline hydrochloride to freshwater fish and invertebrates. Given the available mammalian developmental and bobwhite quail acute oral data, both of which re port reduction in body weight, it is possible that similar advers e sublethal effects may be observed in the
freshwater fish and invertebrate chronic st udies. The 40 CFR Part 158 data requirements specify that a full life cycle fr eshwater invertebrate test a nd an early life stage test for freshwater fish be submitted. If the regist rant can provide a rationale for bridging the oxytetracycline calcium complex and hydrochl oride salt data, freshwater fish and
invertebrate chronic studies should be subm itted only for oxytetracycline hydrochloride. If such bridging data cannot be provided, fres hwater fish and invert ebrate chronic data should be submitted for both the oxytetracyc line calcium complex and hydrochloride salt
formulations.- -36 of 38- Practical Utility of the Data

How will the data be used? These data are necessary to evaluate the extent of potential risk to freshwater fish and invertebrates via chronic exposure based on th e application of calc ium oxytetracycline and oxytetracycline hydrochloride according to the label. In the absence of data, the Agency would presume that chronic risk to listed and non-listed freshwater fish and invertebrates exceeds the Agency’s LOCs.

How could the data change the Agency’s d ecision or impact the Agency’s future decision-making? If future endangered species risk assessmen ts are performed wit hout these data, the Agency would have to assume that cal cium oxytetracycline and oxytetracycline hydrochloride “may affect” freshwater fish a nd invertebrates directly via chronic effects (and listed species from other taxa indirectly), an d use of these oxytet racycline chemical formulations may need to be restricted in areas where listed specie s could be exposed.
The lack of these data will limit the flexibi lity that the Agency and registrants have in coming into compliance with the Endangered Species Act and could result in use restrictions for oxytetracycline chemical form ulations which are unnece ssarily severe. In addition, the lack of these data may result in assumed risk and potential mitigation of the oxytetracycline chemical formulations under FIFRA.

Guideline Number: 850.4100 and 850.4150 Study Title: Terrestrial Plant Toxicity: Tier I Seedling Emergence and Vegetative Vigor Rationale for Requiring the Data

Oxytetracycline toxicity data for non-target te rrestrial plants are not available. Based on the 40 CFR Part 158 data requirements, Tier I level seedling emer gence and vegetative vigor non-target terrestrial plant data are required for all fungicides. Practical Utility of the Data

How will the data be used? Data from Tier I terrestrial plant toxicity studi es will be used to estimate potential risks to terrestrial plants associated with the use of oxytetracyc line. The data will reduce
uncertainties associated with the current risk assessment for terrestrial plants and will improve the Agency’s understanding of th e potential effects of oxytetracycline on terrestrial plants. In the absence of Tier I data, risks for terrestrial plants will be presumed.

How could the data impact the Agency’s future decision-making? Because terrestrial plants form the basis of the food chain for terr estrial habitats and significantly contribute to overa ll habitat quality, a solid understanding of the potential risks to terrestrial plants is essential for sound environmental risk management decisionmaking. Without terrestrial plant data for oxytetracycline, the Agency cannot determine- -37 of 38- if the current application rates of oxytetracyc line may result in direct adverse effects to terrestrial plants and/or indirect effects resu lting from reduction in the prey base and/or loss of habitat/cover. If future endanger ed species risk assessments are performed without these data, the Agency would have to assume that oxytetracycline “may affect” terrestrial plants directly (and listed species from other taxa indirectly via reduction in prey base and/or hab itat), and use of oxytetracycline may need to be restricted in areas where listed species could be expos ed and/or critical ha bitat is present. The lack of these data will limit the flexibility the Agency a nd registrants have in coming into compliance with the Endangered Species Act and could resu lt in use restrictions for oxytetracycline which are unnecessarily severe. In addition, the lack of thes e data may result in assumed risk and potential mitigation of the oxytetr acycline chemical formulations under FIFRA.

Guideline Number: 850.4400 and 850.4500 Study Title: Aquatic plant toxicity (Tier I) Rationale for Requiring the Data

Toxicity data for vascular and non-vascular aquatic plants are not available for calcium oxytetracycline or oxytetracyc line hydrochloride. Based on the 40 CFR Part 158 data requirements, Tier I level non-ta rget aquatic plant data are re quired for all fungicides. If the registrant can provide a rationale for bridging the oxyt etracycline calcium complex and hydrochloride salt data, Tier I aquatic plant studies should be submitted only for oxytetracycline hydrochloride. If such bri dging rationale cannot be provided, aquatic plant toxicity data should be submitted fo r both the oxytetracycline calcium complex and hydrochloride salt formulations. Practical Utility of the Data

How will the data be used? Data from Tier I aquatic plant toxicity studies will be used to estimate potential risks to aquatic vascular and non-vascular plants associated with the use of calcium oxytetracycline and oxytetracycl ine hydrochloride. The data will reduce uncertainties
associated with the current risk assessme nt for aquatic plants and will improve the Agency’s understanding of the potential eff ects of oxytetracycline chemical formulations on aquatic plants. In the absence of Tier I data, risks for both listed and non-listed vascular and non-vascular aquatic plants will be presumed.

How could the data impact the Agency’s future decision-making? Because aquatic vascular and non-vascular pl ants form the basis of the food chain for aquatic habitats and significantly contri bute to overall water quality, a solid understanding of the potential ri sks to aquatic plants is essential for sound environmental risk management decision-making. Without aquatic plant data fo r oxytetracycline, the Agency cannot determine if the current appli cation rates of oxytetr acycline formulations may result in direct adverse effects to aquatic plants and/or indirect effects resulting from reduction in the prey base and/or loss of habitat/cover. If future endangered species risk assessments are performed without these data , the Agency would have to assume that oxytetracycline chemical formulations “may af fect” aquatic plants directly (and listed- -38 of 38- species from other taxa indire ctly via reduction in prey base and/or habitat), and use of oxytetracycline chemical formulations may need to be restricted in areas where listed species could be exposed. The lack of these data will limit the flex ibility the Agency and registrants have in coming into compliance with the Endangered Species Act and could result in use restrictions for oxytetracy cline chemical formulations which are unnecessarily severe. In additi on, the lack of these data may result in assumed risk and potential mitigation of the oxytetracyclin e chemical formulations under FIFRA.

Guideline Number: 835.1230 Study Title: Adsorption/Desorption Rationale for Requiring the Data

The Agency has a limited understanding of how oxytetracycline (hydr ochloride salt and calcium complex) behaves in the environment once applied. Depending on the mobility of the compound in the environment, oxytetracy cline may or may not be transported to surface water and/or ground water bodies used by organisms in the environment and/or by humans for drinking water, contributing to antibiotic resistance in human pathogens present in drinking water. Batch equilibrium data are available in the open literature for a range of conditions and at high concentrations . Because oxytetracycline mobility in the
environment is not well understood at con centrations less than and including that resulting from the highest labeled application rate, the Agency is requiring confirmatory batch equilibrium data. Practical Utility of the Data

How will the data be used? Batch equilibrium data at concentrations re sulting from labeled a pplication rates will facilitate a better understanding of oxytetracycline mobility in the environment. If data confirm that the compound has low mobility at these concentrations, then the Agency could potentially determine that oxytetrac ycline would not likely contribute to environmental exposure or to antibiotic resistance in human pathogens present in water bodies used for drinking water. If data indicate that the co mpound is mobile at concentrations resulting from labeled app lication rates, then the Agency could not necessarily conclude that environmental exposure or the risk of oxytetracycline contributing to antibiotic resi stance in human pathogens is negligible and further study and/or restrictions would be required.

How could the data impact the Ag ency’s future decision-making? In the absence of the required data, da ta from the open literature based on high concentrations will be used for ecological ri sk and drinking water exposure assessment. If the required data indica te that oxytetracycline is mobile in the environment at concentrations resulting from labeled applic ation rates, then antibiotic resistance in potable water may be a public health risk of concern and environmental exposure may be of concern and additional use precautions and/or restrictions may be necessary.