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environmental fate and effects data requirements (40 CFR Part 158) are identified. Furthermore, 

this problem formulation describes the preliminary 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 registered in 1974 as a base (CAS No. 79-57-2; PC code 006304) 

and was later registered in 1984 as oxytetracycline 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 term “oxytetracycline” refers collectively to all 

chemical formulations, unless a specific chemical formulation is identified.

To date, no environmental fate data for oxytetracycline have been submitted; however an 

environmental fate bridging proposal for the hydrochloride salt and the 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) for the 2006 Tolerance Reassessment Progress and 

Risk Management Decision (TRED). These submissions, which refer to multiple open literature 

studies and have yet to be evaluated, 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 oxytetracycline chemical formulations that is not 

addressed by the GDCI is a confirmatory batch equilibrium study. 

The ecological effects data set for calcium oxytetracycline and oxytetracycline hydrochloride 

contains a number of gaps for terrestrial and aquatic animals and plants. Data gaps include the 

following: avian reproduction toxicity; 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 aquatic plant toxicity studies for both the calcium complex and the 

hydrochloride salt. In addition, unless the registrant can clearly demonstrate that the ecological 

effects data for calcium oxytetracycline and oxytetracycline 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 hydrochloride that will need to be addressed prior 

to completion of the ecological risk assessment for registration review. 
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Problem Formulation for the 

Environmental Fate, Ecological Risk, Endangered 

Species, and Drinking Water Assessments 

in Support of the Registration Review of 

Oxytetracycline 

O

O

NH2

HO

N

CH3

H3C

OH

OH

OH O

HO CH3

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 
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Table of Contents 

1. Purpose....................................................................................................................................... 3 

2. Problem Formulation ................................................................................................................. 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 and Drinking Water Exposure Assessments for 

Oxytetracycline............................................................................................................................... 3 

Appendix B. Data Call-In Table for Calcium Oxytetracycline and Oxytetracycline 

Hydrochloride ................................................................................................................................. 3 
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1. Purpose 

The purpose of this problem formulation is to provide 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 bacteria, 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 registered in 1974 as oxytetracycline 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)-] (CAS No. 79-57-2; PC code 

006304) and was later registered in 1984 as oxytetracycline hydrochloride salt (CAS No. 2058-

46-0; PC code 006308) and as oxytetracycline 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 term “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 waiver request and a bridging proposal for the 

environmental fate data, it is unclear whether the hydrochloride salt (PC code 006308) and the 

calcium complex (PC code 006321) behave similarly. 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 because comparable data sets on the two chemical 

formulations for the same taxa are not available. 

This document will provide a plan for analyzing data relevant to oxytetracycline chemical 

formulations and for conducting environmental fate, ecological risk, endangered species, and 

drinking water assessments for their registered uses. Additionally, this problem formulation is 

intended to identify data gaps, uncertainties, and 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, Fungicide, and Rodenticide Act (FIFRA), all pesticides distributed 

or sold in the United States generally must be registered by the 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 based on a wide range of environmental and health effects studies. 

In 1996, FIFRA was amended by the Food Quality 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/registration_review/). The registration review program is 
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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 Registration Review program pursuant to Section 3(g) 

of FIFRA, the Agency is beginning its evaluation of oxytetracycline to determine whether it 

continues to meet the FIFRA standard for registration. This problem formulation for the 

environmental fate, ecological risk, endangered 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 Eligibility Decision (TRED) (USEPA, 2006) 

• 1 Section 3 New Use (S3NU) updated ecological 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 first registered, through 1992, 

when ecological effects data were initially submitted, 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 adverse effects to non-target organisms. The 

risk of chronic effects was not estimated in these assessments due to a lack of data. However, 

concern was raised for emergence of antimicrobial 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 the 2006 TRED and the proposed use on apples 

yielded drinking water exposure estimates 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 issued in February 2008 for a complete suite of 

environmental fate data, other than a batch equilibrium 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 requirements included in the GDCI. These waiver 

requests reference multiple studies from the open literature and have yet to be evaluated. If 
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acceptable, the data referenced in the waiver requests may be used in the ecological risk and 

drinking water exposure assessments. 

3. Stressor Source and Distribution 

3.1. Mechanism of Action 

 

Oxytetracycline (also known as terramycin) is a broad spectrum human and animal antibiotic 

produced from the actinomycete Streptomyces rimosus and used to control bacteria, fungi, and 

mycoplasma-like organisms. In humans, oxytetracycline is administered orally or intravenously 

to treat infectious diseases caused by a wide variety of microorganisms. 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 bacteria 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 impair protein synthesis 

in mammalian cells. However, the active transport system found in bacteria is absent in these 

cells and there are differences in sensitivity at the ribosomal level. These differences are likely 

to be important determinants in the selective action of tetracyclines. 

3.2. Overview of Pesticide Usage 

Oxytetracycline was originally registered for agricultural use in the United States in 1974 on 

pears, peaches, and nectarines. Tree injection registrations expanded oxytetracycline use 

patterns to include the non-agricultural uses on forest, ornamental, and non-crop-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 containing 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 hydrochloride 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. 
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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% base1

)

Non-crop-bearing ornamental trees 

Wettable Powders 

55146-89 FiremanTM Calcium 

complex 

31.1% 

(17% base1

)

Pears, peaches, and nectarines 

55146-97 Mycoshield® Calcium 

complex 

31.5% 

(17% base1

)

Apples, pears, peaches, and nectarines 

80990-1 FirelineTM 17 

WP 

Hydrochloride 18.30% 

(17% base1

)

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, and/or flowers of treated trees. 

Although the tree injection uses may result in exposure to non-target wildlife, potential risks 

from these use patterns may not be quantified because 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 spray application directions that may lead to 

environmental exposure. These use patterns are listed in Table 2. The maximum single foliar 

application rate for oxytetracycline is 0.638 pounds of active ingredient per acre (lbs a.i./A) 

(EPA Reg. No. 55146-89 and 80990-1). This application rate may be applied weekly, nine times 

per year, resulting in a maximum annual foliar application rate for oxytetracycline of 5.74 lbs 

a.i./A. 
Table 2. Labeled maximum use patterns for foliar 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, 80990-1 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 Aerial2

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. No. 55146-97, use directions for EPA 

Reg. No. 55146-89 and 80990-1 are ambiguous. 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 their 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 foliar 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 (BEAD) of the Office of Pesticide Programs 

estimates average annual usage 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 oxytetracycline is likely to be greater than these 

estimates for agricultural uses. 
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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 transport characterization because no environmental 

fate (Subdivision N) studies have been submitted for oxytetracycline. The studies were waived 

in the reregistration process (USEPA, 1993) on the basis of limited 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, anaerobic aquatic metabolism, aerobic aquatic 

metabolism, and terrestrial field dissipation. The GDCI applied to each currently registered 

chemical formulation independently, pending bridging 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 transport data from product chemistry studies and the 

open literature. Data from open literature do not fulfill Subdivision N data guideline 
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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 that the water solubility of hydrochloride salt is 1g in 2 mL 

(500,000 mg L-1) and that oxytetracycline base and calcium 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 the water solubility is somewhat near 10 g L-1

(10,000 mg L-1; MRID 44219401). Therefore, these compounds 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 (Kd) for oxytetracycline in 30 eastern U.S. soils representing 

five soil orders and 28 soil series have been published in a peer-reviewed study (Jones et al., 

2005). The study concluded that soil texture, cation exchange capacity, and iron oxide content 

appeared to most influence oxytetracycline sorption in soils with organic carbon content of 0 to 

4%. Soil organic carbon content negatively correlated with compound sorption in those soils, 

but not with a single soil of 9% organic carbon. Kd values ranged from 486 L/kg to 12,047 L/kg 

(pH 5.5), which indicates that oxytetracycline has relatively low mobility and is expected to 

preferentially adsorb to soils with minimal expected 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 Center1

 published a study on the chemical 

degradation of antibiotics in anaerobic swine lagoons, which found that oxytetracycline 

hydrolysis rates generally increase as pH deviates from 7 and as temperature increases in 

synthetic systems (Loftin et al., 2004). A kinetics study of oxytetracycline found that high 

temperatures, light exposure, alkaline conditions, the presence of a substrate, and the presence of 

organic matter each led to decreased concentrations 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 oxytetracycline “might be considered as moderately 

persistent,” displaying first-order half-lives of 31 to 175 days in natural surface 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, these data may not be sufficient for use as model 

inputs for environmental exposure assessment. 

 

1

 Online at: http://ks.water.usgs.gov. 
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4. Receptors 

Consistent with the process described in the Overview Document (USEPA, 2004), the risk 

assessment for oxytetracycline relies on a surrogate species approach. Toxicological data 

generated from surrogate test species, which are intended to be representative of broad 

taxonomic groups, are used to extrapolate to potential effects on a variety of species (receptors) 

included under these taxonomic groupings. 

Acute toxicity data from studies submitted by pesticide registrants along with the available open 

literature are used to evaluate the potential direct and indirect effects of oxytetracycline to 

aquatic and terrestrial receptors. Registrant-submitted chronic data for oxytetracycline are not 

available. Submitted data typically include toxicity information on the technical grade active 

ingredient, degradates, and when available, formulated products (e.g., “Six-Pack” studies). The 

open literature studies are identified through 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 oxytetracycline on biotic communities from 

loss of species that are sensitive to the chemical and from changes in structure and functional 

characteristics of the affected communities. 

Based on an interim ECOTOX open literature search conducted in June 2008, a large number of 

potentially relevant open literature papers for oxytetracycline were identified. A complete search 

of the ECOTOX database for oxytetracycline toxicity data is expected to be completed in August 

2008. Given the number of papers identified for review based on the interim 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 registration review problem 

formulation for oxytetracycline. However, an evaluation of the ECOTOX open literature studies 

for possible quantitative and/or qualitative inclusion in the ecological risk assessment, including 

identification of open literature data that may be used to fill the large number of ecological 

effects data gaps, is expected to be completed prior to the docket opening for oxytetracycline. 

Based on a preliminary review of the interim ECOTOX search, open literature data were 

identified for a number of taxonomic groups, including estuarine/marine fish, 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 used to fulfill these data gaps will be determined 

pending their review and evaluation. 

A summary of the aquatic and terrestrial toxicity data used to derive 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 oxytetracycline 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 only for oxytetracycline hydrochloride (i.e., no aquatic 
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toxicity data are available for the oxytetracycline calcium complex). All submitted acute aquatic 

toxicity studies for freshwater fish and invertebrates are classified as “acceptable”. 

Oxytetracycline is classified as practically non-toxic to freshwater fish and invertebrates on an 

acute exposure basis. Acute data for estuarine/marine fish and invertebrates 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) 

LC50

96 

>94.9 417832-01 

(Murphy and 

Peters, 1981) 

Practically nontoxic 

Oncorhynchus 

mykiss 

(Rainbow Trout) 

Freshwater fish 

and aquaticphase 

amphibians LC50

96 >116 

471832-02 

(Murphy and 

Peters, 1981) 

Practically nontoxic 

Daphnia magna 

(Water Flea) 

Freshwater 

Invertebrates 

EC50 

48 >102 417832-03 

(Bellantoni et 

al., 1991) 

Practically nontoxic 

4.2. Effects to Terrestrial Organisms 

Available data on the toxicity of oxytetracycline to terrestrial 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 oxytetracycline hydrochloride was tested in the chronic 

developmental study, calcium oxytetracycline was used in the terrestrial testing for birds and 

honey bees. Chronic data for birds and terrestrial plant toxicity data are not available for 

oxytetracycline. In addition, no terrestrial toxicity data are available for oxytetracycline 

hydrochloride. 

All submitted terrestrial toxicity studies for mammals, birds, and honey bees are classified as 

“acceptable”. Oxytetracycline is classified as practically non-toxic to mammals and birds on an 

acute oral basis and also practically non-toxic to birds on a sub-acute dietary exposure basis. In 

addition, oxytetracycline is practically non-toxic to honey bees (Apis mellifera) on an acute 

contact exposure basis. 

Despite the lack of mortality observed in the acute studies with mammals, birds, and honey bees, 

it is important to note that reduction in body weight was observed in the mammalian 

developmental study and the acute bobwhite quail oral LD50 test. In the mammalian 
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developmental study, reduction in fetal and maternal body weight was observed relative to the 

control at the lowest oxytetracycline hydrochloride treatment level of 1200 mg a.i./kg,day. In 

addition, a reduction in bobwhite quail body weight was observed in the acute oral LD50 test at 

the three highest test calcium oxytetracycline 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 quail, relative to the control, in the dietary LC50 

test and no change in body weight between the treated groups and the control in the mallard duck 

dietary LC50 test. Therefore, there appears to be variability in the available data with regards to 

oxytetracycline effects on body weight. 

Table 4. Summary of endpoints from submitted terrestrial animal toxicity studies for oxytetracycline1. 

Species 

(common 

name)

Taxa 

Represented

Endpoint Mean 

Concentration 

Test 

Substance 

(% a.i.) 

Citation 

MRID 

Acute 

Toxicity 

Classification 

LD50

>5000 mg/kg BW 17.4 454593-01 

(Moore, 2000) Practically 

non-toxic 

Rattus 

norvegicus 

(Laboratory 

Rat) 

Mammals 

NOAEC 

LOAEC 

<1,200 mg/kg/day2 

1,200 mg/kg/day 

(reduced maternal 

and fetal body 

weight) 

NR 

001323-91 

(Wolkowski et 

al., 1983) 

NA 

Anas 

platyrhynchos

(Mallard Duck) LC50

>5620 mg/kg-diet 

(ppm) 60.4 

417778-03 

(Long et al., 

1991) 

Practically 

non-toxic 

LD50

>2000 mg./kg BW3

60.4 

417778-01 

(Campbell et 

al., 1991) 

Practically 

Colinus non-toxic 

virginianus 

(Northern 

Bobwhite 

Quail) 

Birds, terrestrialphase 

amphibians, and 

reptiles 

 

 

 

LC50 >5620 mg/kg-diet 

(ppm) 

60.4 

417778-02 

(Long et al., 

1991) 

Practically 

non-toxic 

Apis mellifera

(Honey Bee) 

Terrestrial 

invertebrates LD50 >100 μg/bee 60.4 

416273-08 

(Winter et al., 

1991) 

Practically 

non-toxic 

1

 Anhydrous oxytetracycline was tested in acute mammalian study, oxytetracycline 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. 
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4.3. Incident Database Review 

A review of the Ecological Incident Information System (EIIS) maintained by the Agency’s 

Office of Pesticide Programs (OPP) was performed on June 24, 2008 (USEPA, 2008b). Based 

on the results of this query, no ecological incidents have been reported for oxytetracycline 

hydrochloride (PC Code 006308) and calcium oxytetracycline (PC Code 006321). 

Although no incidents associated with oxytetracycline have been reported, 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 reproduction, are rarely received. 

EPA’s changes in the registrant reporting requirements of incidents may also account for the 

reduced number of reported incidents. Registrants are now only required to submit detailed 

information on ‘major’ incidents. Minor incidents are generally reported aggregately and are not 

included in EIIS. In addition, there 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 scope; 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 ecosystems potentially at risk could include the treated 

area and immediately adjacent areas that may receive drift or runoff. Areas adjacent to the 

treated area could include cultivated fields, fencerows and hedgerows, meadows, fallow fields or 

grasslands, woodlands, riparian habitats and other uncultivated areas. 
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Aquatic ecosystems potentially at risk include water 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 actual environmental value that is to be protected, defined by 

an ecological entity (species, community, or other entity) and its attribute or characteristics 

(USEPA, 1998). For oxytetracycline, the ecological entities may include the following: birds, 

mammals, terrestrial-phase amphibians, reptiles, freshwater fish and invertebrates, aquatic-phase 

amphibians, estuarine/marine fish and invertebrates, terrestrial plants, insects, 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 must 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 receptor. 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, and a feasible route of exposure. 

The conceptual model for oxytetracycline provides a written description and visual 

representation of the predicted relationships between oxytetracycline, potential routes of 

exposure, and the predicted effects for the assessment endpoint. A conceptual model consists of 

two major components: a risk hypothesis and a conceptual diagram, which are discussed below 

(USEPA, 1998). 

6.1. Risk Hypothesis 

A risk hypothesis describes the predicted relationship among the stressor, exposure, and 

assessment endpoint response along with the rationale for their selection. For oxytetracycline, 

the following ecological risk hypothesis is being employed for this ecological risk assessment: 

Based on the available toxicity data, direct acute risks to freshwater fish and 

invertebrates, mammals, birds, and terrestrial insects are possible for oxytetracycline, 

although this hypothesis may be rejected based on the results of previous risk 

assessments. Based on the application methods and lack of available chronic toxicity 

data for non-target aquatic and terrestrial species, in addition to aquatic and terrestrial 

plants, oxytetracycline has the potential to reduce survival, reproduction, and/or growth 

in non-target terrestrial and aquatic 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.
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6.2. Conceptual Diagram 

Based on a lack of environmental fate data for oxytetracycline, runoff, spray drift, volatilization, 

and direct spray represent potential transport mechanisms of oxytetracycline to aquatic and 

terrestrial habitats where 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 oxytetracycline effects on aquatic organisms. 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 

Non-vascular 

Vascular 

Uptake/cell, 

roots, leaves Riparian plant

terrestrial 

exposure 

pathways see 

Figure 3 
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Figure 3. Conceptual model for oxytetracycline effects on terrestrial organisms. 

7. Analysis Plan 

In order to address the risk hypothesis, the potential for adverse effects on the environment is 

estimated. The use, environmental fate, and ecological effects of oxytetracycline are 

characterized and integrated to assess the risks. This is accomplished using a risk quotient (ratio 

of exposure concentration to effects concentration) approach. Although risk is often defined as 

the likelihood and magnitude of adverse ecological effects, the risk quotient-based approach does 

not provide a quantitative estimate of likelihood and/or magnitude of an adverse effect. 

However, as outlined in the Overview Document (USEPA, 2004), the likelihood of effects to 

individual organisms from particular uses of oxytetracycline is estimated using the probit doseresponse slope and either the level of concern (discussed below) or the actual calculated risk 

quotient value. 

This analysis plan will be revisited and may be revised depending upon the review and 

evaluation of data available in the open literature, 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 / 

Amphibians 

Ingestion 
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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 degradates 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 mixtures of multiple active 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 containing more than one active ingredient), each active 

ingredient is subject to an individual risk assessment for regulatory decision regarding the active 

ingredient on a particular use site. It should be noted, however, that no multi-active ingredient 

product formulations are registered for oxytetracycline. 

Available toxicity data for environmental mixtures of oxytetracycline with other pesticides will 

be presented as part of the ecological risk assessment. It is expected that the potential toxic 

effect of oxytetracycline, in combination with other pesticides used in the environment, is likely 

to be a function of many factors including but not necessarily limited to: (1) the exposed species, 

(2) the co-contaminants in the mixture, (3) the ratio of oxytetracycline and co-contaminant 

concentrations, (4) differences in the pattern and duration of exposure among contaminants, and 

(5) the differential effects of other physical/chemical characteristics of the receiving waters (e.g.

organic matter present in sediment and suspended water). Quantitatively predicting the 

combined effects of all these variables on mixture toxicity to any given taxa with confidence is 

beyond the capabilities of the available data and methodologies. However, a qualitative 

discussion of implications of the available pesticide mixture effects data on the confidence of 

risk assessment conclusions will be addressed as part of the uncertainty analysis. 

7.2. Measures of Exposure 

In order to estimate risks of oxytetracycline exposures in aquatic and terrestrial environments, all 

exposure modeling and resulting risk conclusions 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 estimated environmental concentrations (EEC) of 

oxytetracycline using maximum labeled application 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 predict terrestrial EECs on food items is T-REX. 

The model used to derive EECs relevant to terrestrial 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 generate daily exposures and 1-

in-10 year EECs of oxytetracycline that may occur in surface water bodies adjacent to 

application sites receiving oxytetracycline through runoff and spray drift. PRZM simulates 
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pesticide application, movement and transformation on an agricultural field and the resultant 

pesticide loadings to a receiving water body via runoff, erosion and spray drift. EXAMS 

simulates the fate of the pesticide and resulting concentrations in the water body. The standard 

scenario used for ecological pesticide assessments assumes application to a 10-hectare 

agricultural field that drains into an adjacent 1-hectare water body that is 2 meters deep (20,000 

m3 volume) with no outlet. PRZM/EXAMS is used to estimate screening-level exposure of 

aquatic organisms to oxytetracycline. The measure of exposure for aquatic species is the 1-in-10 

year return peak or rolling mean concentration. The 1-in-10-year peak is used for estimating 

acute exposures of direct effects to aquatic organisms. The 1-in-10-year 60-day mean is used for 

assessing chronic exposure to fish and aquatic-phase amphibians. The 1-in-10-year 21-day mean 

is used for assessing aquatic invertebrate chronic exposure. 

Exposure estimates for terrestrial animals assumed to be in the target area or in an area exposed 

to spray drift are derived using the T-REX model (v1.3.1; Dec. 7, 2006). This model 

incorporates the Kenega nomograph, 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 

95th 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, including information on 118 species of plants, 121 

pesticides, and 17 chemical classes. 

EECs for terrestrial plants inhabiting dry and wetland areas are derived using TerrPlant (v1.2.2; 

Dec. 26, 2006). This model uses estimates of pesticides in runoff and in spray drift to calculate 

EECs. EECs are based upon solubility, application rate and minimum incorporation depth. 

The AgDRIFT spray drift model (v2.01; May 24, 2001) is used to assess exposures of terrestrial 

plants to oxytetracycline deposited on terrestrial habitats by spray drift. 

7.3. Measures of Effect 

 

Ecological effects data are used as measures of direct 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 ecological 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 USEPA, Office of Research and Development, 

and the National Health and Environmental Effects Research Laboratory's Mid-Continent 

Ecology Division. 

Information on the potential effects of oxytetracycline on non-target animals is also collected 

from the Ecological Incident Information System (EIIS; USEPA, 2008b). The EIIS is a database 

containing adverse effect (typically mortality) reports on non-target organisms where such 

effects have been associated with the use of pesticides. 
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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 coloration). Quantitative assessments of risks, though, are limited to 

those endpoints that can be directly 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 amphibians and reptiles. The 

same assumption is made for fish and aquatic-phase amphibians. 

The acute measures of effect used for animals in this assessment are the LD50, LC50 and EC50. 

LD stands for "Lethal Dose", and LD50 is the amount of a material, given all at once, that is 

estimated to cause the death of 50% of the test organisms. LC stands for “Lethal Concentration” 

and LC50 is the concentration of a chemical that is estimated to kill 50% of the test organisms. 

EC stands for “Effective Concentration” and the EC50 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-listed animals are the NOAEL/NOAEC and NOEC. 

NOAEL stands for “No Observed-Adverse-Effect-Level” and refers to the highest tested dose of 

a substance that has been reported to have no harmful (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 from the control. The NOEC is 

the No-Observed-Effects-Concentration. For non-listed plants, only acute exposures are 

assessed (i.e., EC25 for terrestrial plants and EC50 for aquatic plants); for listed plants either the 

NOAEC or EC05 is used. 

 

7.4. Integration of Exposure and Effects 

Risk characterization is the integration of exposure and ecological effects characterization to 

determine the potential ecological risk from the use of oxytetracycline on apples, peaches, 

nectarines, and pears and the likelihood of direct and indirect effects to non-target organisms in 

aquatic and terrestrial habitats. The exposure and toxicity effects data 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) method is used to compare exposure and measured 

toxicity values. EECs are divided by acute and chronic toxicity values. The resulting RQs are 

then compared to the Agency’s Levels of Concern (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 effects to non-target organisms. In addition, incident data from the 

EIIS will be considered as part of the risk characterization. 

 

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 risk assessment. If possible, an effort will be made to further 

qualitatively describe risk using probabilistic tools that the Agency has developed. These tools 
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have been reviewed by FIFRA Scientific Advisory Panels 

(http://www.epa.gov/scipoly/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 threatened and/or endangered (listed) species from 

registered uses of oxytetracycline. This assessment will be conducted in accordance with the 

Overview Document (USEPA, 2004), provisions 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 area directly or indirectly affected by the federal 

action, as indicated by the exceedance of Agency Levels of Concern (LOCs) used to evaluate 

direct or indirect effects. The Agency’s approach to defining the action area under the provisions 

of the Overview Document (USEPA, 2004) considers the results of the risk 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 the 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 LOCs. Specific measures of ecological effect 

that define the action area for listed species include any direct and indirect effects and/or 

potential modification of its critical habitat, including reduction in survival, growth, and 

reproduction as well as the full suite of sublethal 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 assessment will incorporate model estimates of 

oxytetracycline in surface and ground waters. These estimates will reflect environmental fate 

data recently called-in and a determination by the Agency’s Residues of Concern 

Knowledgebase Subcommittee (ROCKS) on which residues are of risk concern. Concentrations 

of oxytetracycline residues in surface waters 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 labeled maximum use pattern that may lead to 
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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 oxytetracycline have been submitted that fulfill 40 CFR Part 

158.1300 guideline data requirements. 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 environmental fate data that fulfill most data 

requirements. An environmental fate bridging 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 formulations and to assess exposure, if they are 

acceptable. However, data from the open literature typically do not report complete mass 

balances, including identification of all major degradates. Therefore, regardless of whether the 

data from the open literature are useful for exposure 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 confirmatory 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 oxytetracycline contains a number of gaps for terrestrial and 

aquatic animals and plants (Tables 5 – 7). Data gaps include the following: avian reproduction 

toxicity; 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 aquatic 

plant toxicity studies. In addition, unless the registrant can clearly demonstrate that the 

ecological effects data for calcium oxytetracycline and oxytetracycline 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 hydrochloride. Further 

information on ecological effects data required to fulfill the Agency’s guideline requirements for 

oxytetracycline is presented as the 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 
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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. 

As previously discussed in Section 4, a completed review of the ECOTOX open literature data is 

not available for this draft of the registration review problem formulation for oxytetracycline. 

An evaluation of the ECOTOX open literature studies for oxytetracycline, which will include 

identification of data that may be used to fulfill the ecological effects data gaps, is expected to be 

completed prior to the opening of the docket for this chemical. Based on a preliminary review of 

the interim ECOTOX search, open literature data were identified for a number of taxonomic 

groups, including estuarine/marine fish, 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 used to fulfill these data gaps will be determined 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 terrestrial animals exposed to oxytetracycline 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 

850.2200 Avian dietary 417778-02 (Ca OTC) Acceptable

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. 
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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 

850.1075 Freshwater fish 417832-01 (OTC HCl) Acceptable 

– 

Acute toxicity 

417832-02 (OTC HCl) Acceptable 

Yes Data for calcium 

oxytetracycline or

bridging rationale 

required 

850.1075 Saltwater fish – 

Acute toxicity 

None NA Yes2 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 Yes2 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 
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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 effects data for plants exposed to oxytetracycline 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 Yes1 

850.4500 Aquatic plant toxicity 

with algae 

None NA Yes1 

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. 

8. References 

Capone, D. G., D. P. Weston, V. Miller, C. Shoemaker. 1996. Antibacterial Residues in Marine 

Sediments and Invertebrates Following Chemotherapy in Aquaculture. Aquaculture 

145(1-4): 55-75. 

Doi, A. M., M. K. Stoskopf. 2000. The Kinetics of Oxytetracycline Degradation in Deionized 

Water under Varying Temperature, pH, Light, Substrate, and Organic Matter. Journal of 

Aquatic Animal Health 12(3): 246-253. 

Effland, W. R., N. C. Thurman, I. Kennedy. 1999. Proposed Methods for Determining 

Watershed-derived Percent Crop Areas and Considerations for Applying Crop Area 

Adjustments to Surface Water Screening Models. Presentation to the FIFRA Science 

Advisory Panel, May 27, 1999. Online at: 

http://www.epa.gov/scipoly/sap/1999/index.htm. 

Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeger. 1994. Literature review and evaluation of the 

EPA food-chain (Kenaga) nomogram, an instrument for estimating pesticide residues on 

plants. Environ. Tox. Chem. 13:1383-1391. 
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Hoerger, F. and E. E. Kenaga, 1972. Pesticide Residues on Plants: Correlation of Representative 

Data as a Basis for Estimation of their Magnitude in the Environment. In F. Coulston and 

F. Korte, eds., Environmental Quality and Safety: Chemistry, Toxicology, and 

Technology, Georg Thieme Publ., Stuttgart, West Germany, pp. 9-28. 

Ingerslev, F., L. Torang, M. Loke, B. Halling-Sorensen, N. Nyholm. 2001. Primary 

Biodegradation of Veterinary Antibiotics in Aerobic and Anaerobic Surface Water 

Simulation Systems. Chemosphere 44: 865-872. 

Jones, A. D., G. L. Bruland, S. G. Agrawal, D. Vasudevan. 2005. Factors Influencing the 

Sorption of Oxytetracycline to Soils. Environmental Toxicology and Chemistry 24(4): 

761-770. 

Jones, R. D., S. Abel, W. R. Effland, R. Matzner, R. Parker. 1998. An Index Reservoir for Use 

in Assessing Drinking Water Exposure. Proposed Methods for Basin-scale Estimation of 

Pesticide Concentrations in Flowing Water and Reservoirs for Tolerance Reassessment. 

Presentation to FIFRA Science Advisory Panel, June 29-30, 1998. Online at: 

http://www.epa.gov/scipoly/sap/1998/index.htm. 

Kolpin, D., E. Furlong, M. Meyer, E. Thurman, S. Zaugg, L. Barber, H. Buxton. 2002. 

Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. 

Streams, 1999-2000: A National Reconnaissance. Environmental Science & Technology 

36(6): 1202-1211. 

Loftin, K., C. Adams, M. Meyer, R. Surampali. 2004. Hydrolysis of Selected Veterinary 

Antibiotics and Their Chemical Degradation in Anaerobic Swine Lagoons. The Ninth 

Symposium on the Chemistry & Fate of Modern Pesticides, Vail, Colorado. August 16-

19, 2004. Abstract online at: 

http://ks.water.usgs.gov/Kansas/pubs/abstracts/chemfate.kl.2004.htm. 

Milewski, I; Tlusty, M. F., D. A. Bengston, H. O. Halvorson, S. D. Oktay, J. B. Pearce, R. B. 

Rheault, Jr. (eds.). 2001. Impacts of Salmon Aquaculture on the Coastal Environment: 

A Review. Marine Aquaculture and the Environment; A meeting for Stakeholders in the 

Northeast. 166 - 197 pp. Cape Cod Press, Falmouth, Massachusetts. 324 p. 

U.S. Environmental Protection Agency (USEPA). 1992. Pesticides in Ground Water Database: 

A Compilation of Monitoring Studies: 1971-1991: National Summary. U.S. 

Environmental Protection Agency. Washington DC. 

USEPA. 1993. Reregistration Eligibility Document for Hydroxytetracycline 

Monohydrochloride and Calcium Oxytetracycline, List A, Case 0020. U.S. 

Environmental Protection Agency, Office of Pesticide Programs. Mar. 31, 1993. 

USEPA. 1998. Guidelines for Ecological Risk Assessment. Risk Assessment Forum, Office of 

Research and Development, Washington, D.C. EPA/630/R-95/002F. April 1998. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=30759 
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-28 of 38- 

USEPA. 2002. Guidance for Selecting Input Parameters in Modeling the Environmental Fate 

and Transport of Pesticides. U.S. Environmental Protection Agency, Office of 

Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, 

Environmental Fate and Effects Division. Feb. 28, 2002. Online at: 

http://www.epa.gov/oppefed1/models/water/input_guidance2_28_02.htm. 

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide 

Programs. U.S. Environmental Protection Agency, Office of Prevention, Pesticides and 

Toxic Substances, Office of Pesticide Programs, Washington DC. January 23, 2004. 

USEPA. 2006. Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment 

Progress and Risk Management Decision (TRED) for Oxytetracycline. EPA 738-R-06-

011. U.S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic 

Substances. June 30, 2006. 

USEPA. 2007a. McKinnon, A. Oxytetracycline: Updated Ecological Risk Assessment of 

Oxytetracycline for the New Use on Apples. DP Barcode 335758. U.S. Environmental 

Protection Agency, Office of Pesticide Programs, Environmental Fate and Effects 

Division, Memorandum to RD. Aug. 27, 2007. 

USEPA. 2007b. McKinnon, A. Oxytetracycline: Updated Tier I Drinking Water Exposure 

Assessment of Oxytetracycline for the New Use on Apples. DP Barcode 343090. U.S. 

Environmental Protection Agency, Office of Pesticide Programs, Environmental Fate and 

Effects Division, Memorandum to RD. Aug. 27, 2007. 

USEPA. 2008a. ECOTOXicology Database. Office of Research and Development National 

Health and Environmental Effects Research Laboratory’s (NHEERL’s) Mid-Continent 

Ecology Division (MED). June 30, 2008. http://cfpub.epa.gov/ecotox/ 

USEPA. 2008b. Ecological Incident Information System. June 24, 2008. 

http://www.epa.gov/espp/consultation/ecorisk-overview.pdf 

USEPA. 2008c. The Case Oxytetracycline: Screening Level Usage Analysis (SLUA). U.S. 

Environmental Protection Agency, Office of Prevention, Pesticides and Toxic 

Substances, Office of Pesticide Programs, Biological and Economic Analysis Division. 

May 29, 2008. 

U.S. Fish and Wildlife Service (USFWS) and National Marine Fisheries Service (NMFS). 1998. 

Endangered Species Consultation Handbook: Procedures for Conducting Consultation 

and Conference Activities Under Section 7 of the Endangered Species Act. Final Draft. 

March 1998. 
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U.S. Geological Survey (USGS). 2008. 2002 Pesticide 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 Hydrochloride and Oxytetracycline Calcium 

Complex – Product Chemistry Data. Performed and submitted by Pfizer Inc. 

MRID 44219401. McKay, Ph.D., B. M. 1997. Determination 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 fingerlings. 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. 
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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- ist 31(? ):27-32. (Also~In~unpublished submission received Aug 20, 

1976 under 39445-1; submitted by American Carbonyl, Inc., Tenafly, N.J.; CDL:228232-C) 
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Appendix A. Past Ecological Risk and Drinking Water 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 mortality 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 mortality for non-target animals is not likely. 

Risk to plants and risk of chronic 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 mortality 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 mortality 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 
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Appendix B. Data Call-In Table for Calcium Oxytetracycline and Oxytetracycline 

Hydrochloride 

The following sample Data Call-In (DCI) table includes rationales for requiring the data 

requested in this problem formulation, 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 terrestrial toxicity data for oxytetracycline hydrochloride, unless 

the registrant can clearly demonstrate that the available data for calcium 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, Avian Dietary Toxicity, and Honeybee Acute 

Contact Toxicity 

Rationale for Requiring the Data 

Although acute oral and dietary 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 registrant 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 application of oxytetracycline 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 risk to listed and non-listed birds exceeds the 

Agency’s concern levels for the oxytetracycline hydrochloride formulation. 

How could the data change the Agency’s decision or impact the Agency’s future 

decision-making? 

If future endangered species risk assessments are performed without these data, the 

Agency would have to assume that oxytetracycline hydrochloride “may affect” birds and 

honey bees, which are used as a surrogate for terrestrial insects, directly via acute effects 

(and listed species from other taxa indirectly), and use of oxytetracycline hydrochloride 

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 for 

oxytetracycline hydrochloride which are unnecessarily severe. In addition, the lack of 

these data may result in assumed risk and potential mitigation of oxytetracycline 
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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 potential risk of chronic 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 can provide a rationale for bridging the oxytetracycline calcium 

complex and hydrochloride salt data, avian reproduction studies should be submitted only 

for calcium oxytetracycline. If such bridging rationale cannot be provided, avian 

reproduction data 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 extent of potential risk to avian species through 

chronic exposure via application of calcium 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 birds exceeds the Agency’s concern levels. 

How could the data change the Agency’s decision or impact the Agency’s future 

decision-making? 

If future endangered species risk assessments are performed without these data, the 

Agency would have to assume that calcium oxytetracycline and oxytetracycline 

hydrochloride “may affect” birds directly via chronic effects (and listed species from 

other taxa indirectly), and use of these oxytetracycline chemical formulations 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 for oxytetracycline 

chemical formulations which are unnecessarily severe. In addition, the lack of these data 

may result in assumed risk and potential mitigation of the oxytetracycline chemical 

formulations under FIFRA. 
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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 invertebrate data have been submitted for 

oxytetracycline hydrochloride, no data specific for calcium oxytetracycline are available 

for these taxa. Unless the registrant can clearly 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 calcium oxytetracycline data or justification of 

data bridging for the two chemical formulations, the Agency would presume that acute 

risk to listed and non-listed freshwater fish and invertebrates exceeds the Agency’s 

concern levels for the calcium oxytetracycline formulation. 

How could the data change the Agency’s decision or impact the Agency’s future 

decision-making? 

If future endangered species risk assessments are performed without 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 for 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 acute effects of calcium oxytetracycline 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 application to food crops which are located in close proximity to 

estuarine/marine environments. If the registrant can provide a rationale for bridging the 
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oxytetracycline calcium complex and hydrochloride 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 data 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 extent of potential risk to estuarine/marine 

organisms including fish, invertebrates, and mollusks, through acute exposure imposed 

by the application of calcium oxytetracycline and oxytetracycline hydrochloride 

according to the label. In the absence of data, 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 decision or impact the Agency’s future 

decision-making? 

If future risk assessments are performed without these data, the Agency would have to 

assume that calcium oxytetracycline and oxytetracycline hydrochloride “may affect” 

estuarine/marine fish, invertebrates, and mollusks directly via acute effects (and listed 

species from other taxa indirectly), and use of these oxytetracycline chemical 

formulations 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 for oxytetracycline chemical formulations which are unnecessarily 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 chronic effects of calcium oxytetracycline and oxytetracycline 

hydrochloride to freshwater fish and invertebrates. 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 

freshwater fish and invertebrate chronic studies. The 40 CFR Part 158 data requirements 

specify that a full life cycle freshwater invertebrate test and an early life stage test for 

freshwater fish be submitted. If the registrant can provide a rationale for bridging the 

oxytetracycline calcium complex and hydrochloride salt data, freshwater fish and 

invertebrate chronic studies should be submitted only for oxytetracycline hydrochloride. 

If such bridging data cannot be provided, freshwater fish and invertebrate chronic data 

should be submitted for both the oxytetracycline calcium complex and hydrochloride salt 

formulations. 
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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 the application of calcium 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 decision or impact the Agency’s future 

decision-making? 

If future endangered species risk assessments are performed without these data, the 

Agency would have to assume that calcium oxytetracycline and oxytetracycline 

hydrochloride “may affect” freshwater fish and invertebrates directly via chronic effects 

(and listed species from other taxa indirectly), and use of these oxytetracycline chemical 

formulations 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 for oxytetracycline chemical formulations which are unnecessarily 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 terrestrial plants are not available. Based on 

the 40 CFR Part 158 data requirements, Tier I level seedling emergence 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 studies will be used to estimate potential risks to 

terrestrial plants associated with the use of oxytetracycline. The data will reduce 

uncertainties associated with the current risk assessment for terrestrial plants and will 

improve the Agency’s understanding of the 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 terrestrial habitats and 

significantly contribute to overall 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 
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if the current application rates of oxytetracycline may result in direct adverse effects to 

terrestrial 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 “may affect” 

terrestrial plants directly (and listed species from other taxa indirectly via reduction in 

prey base and/or habitat), and use of oxytetracycline may need to be restricted in areas 

where listed species could be exposed and/or critical habitat is present. The lack of these 

data will limit the flexibility the Agency and registrants have in coming into compliance 

with the Endangered Species Act and could result in use restrictions for oxytetracycline 

which are unnecessarily 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: 850.4400 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 oxytetracycline hydrochloride. Based on the 40 CFR Part 158 data 

requirements, Tier I level non-target aquatic plant data are required for all fungicides. If 

the registrant can provide a rationale for bridging the oxytetracycline calcium complex 

and hydrochloride salt data, Tier I aquatic plant studies should be submitted only for 

oxytetracycline hydrochloride. If such bridging rationale cannot be provided, aquatic 

plant toxicity data should be submitted for 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 oxytetracycline hydrochloride. The data will reduce uncertainties 

associated with the current risk assessment for aquatic plants and will improve the 

Agency’s understanding of the potential effects 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 plants form the basis of the food chain for 

aquatic habitats and significantly contribute to overall water quality, a solid 

understanding of the potential risks to aquatic plants is essential for sound environmental 

risk management decision-making. Without aquatic plant data for oxytetracycline, the 

Agency cannot determine if the current application rates of oxytetracycline 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 affect” aquatic plants directly (and listed 
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species from other taxa indirectly 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 flexibility the Agency and 

registrants have in coming into compliance with the Endangered Species Act and could 

result in use restrictions for oxytetracycline chemical formulations which are 

unnecessarily 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: 835.1230 

Study Title: Adsorption/Desorption 

Rationale for Requiring the Data 

The Agency has a limited understanding of how oxytetracycline (hydrochloride salt and 

calcium complex) behaves in the environment once applied. Depending on the mobility 

of the compound in the environment, oxytetracycline 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 concentrations 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 resulting from labeled application 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 oxytetracycline 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 compound is mobile at 

concentrations resulting from labeled application rates, then the Agency could not 

necessarily conclude that environmental exposure or the risk of oxytetracycline 

contributing to antibiotic resistance in human pathogens is negligible and further study 

and/or restrictions would be required. 

How could the data impact the Agency’s future decision-making? 

In the absence of the required data, data from the open literature based on high 

concentrations will be used for ecological risk and drinking water exposure assessment. 

If the required data indicate that oxytetracycline is mobile in the environment at 

concentrations resulting from labeled application 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.