Antimycin A Human Health Risk Assessment DP No. 0427904 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: July 6, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Antimycin A - Draft Human Health Risk Assessment for Registration Review 

PC Code: 0063 14 

Decision No.: 506169 

Petition No.: NA 

OP Barcode: 427904 

Registration No.: NA 

Regulatory Action: Reg Review 

Risk Assessment Type: Human Health Case No.: NA 

TXR No.: NA CAS No.: 1397-94-0 

MRID No.: NA 40 CFR: NA 

FROM: 

THROUGH: 

Alexandra Gave lek, M.S., Biologist 

William Donovan, PhD, Chemist 

r ~1., 11 L c __ 

UJ $J;J . ~" :;:. :;. 

William Irwin, PhD, DABT, Toxicologist 

Risk Assessment Branch V N II 

Health Effects Division (7509P) 

rJ~~'r 

Michael Metzger, Branch Chief I nJ Q 

Risk Assessment Branch V N TI ~ · 

Hea lth Effects Division (7509P) 

TO: Christina Scheltema 

Pesti cide Reevaluation Divison (PRD) 

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Antimycin A Human Health Risk Assessment DP No. 0 427904 

1.0 Executive Summary .................................................... ........... .... .............. ........... ... ............ 3 

2.0 Introduction and Use Pattern ........... .... ................. ............ ... .... .... ....... ...... .... .... ............... 3 

2.1 Consideration of Environmental Justice .......................... ............................................ 4 

3.0 Hazard Characterization and Dose-Response Assessment .................. .............. ............ 4 

4.0 Dietary Exposure I Residue Chemistry Considerations ..... .... .... .................................... 6 

5.0 Residential (Non-Occupational) Exposure and Risk Assessment ... ..................... ......... 7 

6.0 Aggregate Exposure .............. ................................................ ............................................. 7 

7.0 Cumulative Exposure and Risk Assessment ....... ... ............ ........... ................. ................. 7 

8.0 Occupational Exposure and Risk Assessment .... ....... ..... .... .............. ... ....... ........ ...... ....... 7 

9.0 Incident Reports .......................................................................... .................. ....... .... .......... 8 

10.0 Ref ercnces ............. ................................................................................................ .............. 8 

-Appendix A. Acute Toxicology Profile ..... ........ .... ..... .................... ................. .... ........... ... .......... 9 

Appendix B. Chemical Identity and Physicochernical Properties .... .... .......... ........... ... ......... 10 

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Antimycin A Human Health Risk Assessment DP No. D427904 

1.0 Executive Summary 

This document represents the Health Effects Division's (HED) Draft Human Health Risk 

Assessment in support of Registration Review of antimycin A (CAS Reg. No. I 397-94-0). 

Antimycin A is a restricted use pesticide (RUP) used to eliminate invasive and unwanted scaled 

fish in ponds, lakes, streams, and catfish fanns. Due to the extensive use restrictions for this 

pesticide and acute deactivation methods, residues of antimycin A are not expected in any food 

commodities following treatments, and thus there is no need for tolerances. 

In keeping with its limited uses, the scientific database for antimycin A is also limited. Briefly, 

the toxicology database for antimycin A includes the standard battery of acute toxicity studies 

and a 90-day oral toxicity study in the rat. The open scientific literature contains reports 

concerning neurotoxicity and genotoxicity studies involving antimycin A. Product chemistry 

data have been submitted and reviewed. No exposure studies have been submitted or are 

required to support the restricted use of antimycin A. 

Considering the use restrictions, the low use rate, the short half-life, and the low potential for 

bioconcentration in aquatic organisms, HED concludes that there are no risks of concern 

resulting from the current registered use of antimycin A according to the directions on the 

Fintrol® Concentrate label. However, any expansion of the use for Antimycin A would likely 

require additional studies and an additional human health risk assessment. 

2.0 Introduction and Use Pattern 

Antimycin A is a restricted use pesticide (RUP) used to eliminate invasive/ unwanted fish in 

ponds, lakes, streams, and catfish farms. Derived from Streptomyces mold, antimycin A inhibits 

electron transfer in the mitochondria during cell respiration. Antimycin A is toxic to fish at low 

concentrations (0.5 to 25 ppb of active ingredient) with certain species being more sensitive to 

the compound than others. Unlike other registered piscicides, fish are reportedly not able to 

detect and thus avoid antimycin A in treatment areas. Antimycin A is used in fish management 

because low treatment concentrations are required to achieve management objectives and the 

compound is reported to degrade rapidly, making it possible to restock treated areas within a 

short time after treatment. 

Antimycin A is a restricted use pesticide used only by trained and/or certified applicators. There 

is currently only one registered product (Fintrol® Concentrate) that is used at low application 

rates resulting in water concentrations generally less than 25 ppb antimycin A. The labels include 

language to preclude significant human exposure, described below. 

The personal protective equipment (PPE) on the label include long-sleeved shirt, long pants, 

chemical-resistant gloves, shoes plus socks, protective eyewear, dust/mist respirator and 

chemical-resistant apron for all mixers, loaders, and other handlers exposed to the concentrate 

through cleaning equipment or spi lls. The PPE of long-sleeved shirt, long pants, chemicalresistant gloves, shoes plus socks, and protective eyewear are required for a ll applicators and 

other handlers. When using handheld equipment, appli cators must wear coveralls and a dust/mist 

respirator. Only protected handlers may be in the area during application. The certified 

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Antimycin A Human Health Risk Assessment DP No. D427904 

applicator must supervise for the duration of application. Recreational access (i.e .. wading, 

swimming, boating, fishing) is not allowed during treatment or for 7 days after treatment. Where 

practical, dead fish should be buried. Surviving fish must not be harvested for food or feed for 

12 months after treatment. Water must not be restocked with fish for 7 days after treatment or 

until levels are below the limit of detection (LOO). If drinking water intakes are present within 

the treatment area, the certified applicator must notify the public water supply or individual users 

and the intake must be c losed during treatment and until levels are below of the LOD. The 

certified applicator must placard all access to the treatment area. Placards must be placed every 

250 feet along the shoreline of the treated area or at public access points. Placards must restrict 

recreational access to the area for 7 days after treatment, prohibit swimming or wading in the 

treated water, and prohibit consumption of water or dead fish from the treated water. 

The chemical structure and physiochemical properti es of Antimycin A can be found in Appendix 

B. 

2.1 Consideration of Environmental .Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Envirom11ental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doc.gov/oepa/guidance/justice/eo 12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. Tn line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup's food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFlI) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups. 

3.0 Hazard Characterization and Dose-Response Assessment 

Antimycin A is a restricted use piscicidc. Its pesticidal mode of action is to inhibit electron 

transport of the mitochondria at Complex lll, required for energy generation in all eukaryotes. 

The target organ for antimycin A in rats is the gastrointestinal tract, based on a 90-day rat oral 

study on a 23% a.i. formulation, with a study LOA EL of 0.5 mg/kg/day (the lowest dose tested) 

based on diarrhea and soft feces. It should be noted that other components in the formulation (i.e. 

acetone and surfactants) may have contributed to the toxicity reported. 

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Antimycin A Human Health Risk Assessment DP No. 0427904 

The toxicological database is inadequate to conduct a quantitative risk assessment. The only subchronic rat study is an 90-day oral study on the 23% formulation. The Agency lacks information 

regarding developmental, reproductive, neurological, immunological, dermal, inhalation and 

chronic toxicity of antimycin A. There are no guideline mutagenicity studies for antimycin A; 

however, two literature in vitro studies did not detect a mutagenic response. 

90-Day Oral Toxicity Study in Rat 

In a sub-chronic oral toxicity study (MRID 4553330 l , 4676260 I), Fintrol® Concentrate (23% 

active ingredient (a.i.), Batch # 1977) was administered to I 0 Sprague-Dawley rats/sex/dose in 

the diet at dose levels of 0, 0.5, 5 and l 0 mg/kg/day of Antimycin A from Day 0 until Day 41 

and 0, 0.5, I 0 and 20 mg/kg/day from Day 42 until study termination (Groups I, TI , III and IV, 

respectively). The following parameters were examined: clinical signs, body we ight, food 

consumption, functional observational battery, hematology, clinical chemistry, gross lesions, 

selected organ weights, and histopathology o f selected tissues and organs. 

No adverse neurological effects were observed in any groups as assessed by the functional 

observational battery (FOB) conducted at 3 months. Also, survival, gross lesions, and 

microscopic pathology findings were not affected by treatment with the test material and no eye 

abnormalities were observed during ophthalmoscopic examinations. No treatment-related 

hematology findings were observed except for neutrophils in the Group IV females. The 

neutrophil in the females was significantly higher (145%) than that of the control group, but this 

finding was not corroborated by gross or microscopic pathology, thus was not considered 

toxicologically significant. 

No treatment-related clinical chemistry findings were observed except for two serum parameters, 

total protein and calcium. Total protein in the Group III males and Group IV females and 

calcium in the Group IV fema les were significantly less (15-18%) than those of the control 

group; however, these findings were not corroborated by gross or microscopic pathology and 

were not considered toxicologically significant. At 0.5 mg/kg, animals had diarrhea in one male 

on days 3 1 and 32, and soft feces in 3 females on eight days (Days 33, 40, 4 1, 86-90) were 

observed. In both Groups III and IV (5 and I 0 mg/kg) animals, increasing incidence of diarrhea 

or soft feces were observed when compared to the control or Group II animals. Group IV male 

and female rats gained 2 1 % less weight than the control anjmals, however, no treatment-re lated 

effects were observed on absolute body weights and food consumption at all doses. Increased 

incidence of diarrhea and soft stool was considered as a treatment-related effect of the 

form ulation. 

The LOA EL was 0.5 mg/kg/day based on occurrence of increased incidence of diarrhea or soft 

feces. The NOAEL was not established. 

This study is classified as acceptable/guideline and satisfies the guide line requirements (OPPTS 

870.31 OOa ; OECD 408) for a sub-chronic oral toxicity study in the rat. 

Neurotoxicity 

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Antimycin A Human Health Risk Assessment DP No. 0427904 

Incoordination, impaired reflexes and respiratory distress have been reported in mice inj ected 

intravenously with antimycin A (HSDB 2007); however, this exposure route is not expected for 

humans. 

Genotoxicity 

In the mouse lymphoma thymidine kinase locus assay (in vitro mammalian cell gene mutation 

test), no signifi cant mutagenic activity was produced by antimycin A tested at concentrations in 

the range of 0.526 X 10·

5 to 5.26 X 10·5 mol/L. The study was not conducted in the presence of 

S9 activation (Wangenheim and Bolcsfoldi 1988). 

In the DNA a lka line unwi nding assay, no significant mutagenic acti vity was produced by 

antimycin A tested at concentrations in the range of 1.5 X I 0·5 to 150 X I 0·5 mol/ L. The study 

was not conducted in the presence of S9 activation. The DNA alkaline unwinding assay is based 

on the measurement of the proportions of single- to double-stranded DNA by alkaline unwinding 

and hydroxyapatite elution in mouse lymphoma cells treated in vitro with various chemicals. 

(Garberg et al. 1988). 

Acute Toxicity 

The acute toxicity of antimycin A that indicates that it has a high oral toxicity (Category I) for 

the technical grade acti ve ingredient (TGAI) pesticide, but lower toxicity concern (Category II) 

for the one actively registered end-use pesticide product containing 23% a.i .. The 23% 

formulation is a Category II eye irritant, but the irritation with a 0.5% solution of the technical 

antimycin is a Category Ill eye irritant (i.e., resolved in 2 days). Conversely, the 23% 

formulation of antimycin is not a dermal irritant while the TGAI is a Category llI demrnl irritant. 

The acute toxicity data for antimycin A in presented in Appendix A. 

4.0 Dietary Exposure I Residue Chemistry Considerations 

For aquatic use pesticides, there is a potential for human exposure through drinking water and 

fish consumption. However, in the case of antimycin A, sufficient use restrictions are included 

on the Fintrol® Fish Toxicant Kit label to eliminate human dietary exposures. 

For water, the use instructions specify that flowing water (including outflow from standing water 

such as lakes and aquaculture ponds) from treatment areas must be deactivated with potassium 

permanganate. When drinking water intakes are present within treatment areas, the intakes must 

be closed during treatment and until monitoring samples demonstrate antimycin A levels are 

below the limit of detection of 0.0 15 ppb. 

Aquaculture Treatment Areas 

Surviving fish from selective kills at aquaculture sites must not be harvested for food or feed for 

a minimum of 12 months after treatment. Following complete kill treatments, restocking is 

permitted only after a minimum of 7 days or once three consecutive monitoring samples taken no 

less than 4 hours apart demonstrate the antimycin A levels are below the limit of detection of 

0.015 ppb. 

Treatment Areas Other Than Aquaculture 

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Antimycin A Human Health Risk Assessment OP No. D427904 

The use instructions require the placement of warning placards at treatment sites prohibiting 

recreational access (e.g., wading, swimming, boating, fishing, etc.) within the treatment area 

while antimycin A is being appli ed and for 7 days after treatment, and the consumption of dead 

fish or treated water. The signs are to be removed no earlier than 7 days after treatment and no 

later than 14 days after treatment. 

Conclusions. Considering these use restrictions together with the low use rate (~ 25 ppb), the 

short half-life of antimycin A under typical outdoor aquatic conditions (half-life < 12 hours), and 

low potential for bioconcentration in aquatic organisms, HED concludes that there is no 

reasonable expectation of antimycin A residues in aquatic organisms or drinking water; thus, 

tolerances are not required for fish, mollusks, or crustaceans, and a dietary risk assessment is not 

required. 

5.0 Residential (Non-Occupational) Exposure and Risk Assessment 

Recreational access (i.e., wading, swimming, boating, and fishing) is not allowed during 

treatment or for 7 clays after treatment. Depending on environmental conditions, the expected 

half-life of antimycin A ranges from several minutes to approximately 12 hours. Assuming a 12 

hour half-life, the Agency estimates that at least 99% of the compound will have degraded after 7 

days (Antimycin A RED, 5/2007). No residential exposure is expected based on the registered 

uses and label restrictions and a residential exposure assessment is not required. 

6.0 Aggregate Exposure 

There is minimal exposure expected for antimycin A; therefore. a quantitative aggregate 

assessment is not required for anrimycin A. 

7.0 Cumulative Exposure and Risk Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

antimycin A and any other substances and antimycin A does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that antimycin A has a common mechanism of toxicity with other 

substances. For information regarding EPA 's efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA 's Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/. 

8.0 Occupational Exposure and Risk Assessment 

Occupational exposure is expected to be negligible for the registered uses of Antimycin A. 

Exposure to trained appli cators during antimycin A application is likely to be low, based on the 

low volume use, physical & chemical characteristics, and required PPE. 

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Antirnycin A Human Health Risk Assessment DP No. D427904 

9.0 Incident Reports 

There were no incident cases reported for antimycin A to either IDS or SENSOR-Pesticides. 

There does not appear to be a concern at this time that would warrant further investigation (S. 

Recore, 4/ 15/ 15, DP426688). 

10.0 References 

Antimycin A: Tier l Review of Human Incidents. DP#426688. April 15, 2015. S. Recore. 

Antimycin A: Revised Health Effects Division Considerations for the Reregistration Eligibility 

Decision (RED) Document. DP#33864 1. April 18, 2007. D. Smegal. 

Product Chemistry Review of Fintrol Concentrate (Antimycin A). DP#389850. June 6, 2011. 

M. Rivera Piansay. 

Reregistration Eligibility Decision for Antimycin A. EPA 738-R-07-007. May, 2007. 

Garberg, P, Akerblom E.L., Bolcsfoldi, G. 1988. Evaluation of a Genotoxicity Test Measuring 

DNA-Strand Breaks in Mouse Lymphoma Cells by Alkaline Unwinding and Hydroxyapatite 

Elution. MUTAT RES 203 :1 55-176,1988 

Hazardous Substances Data Bank (HSDB). 2007. Antimycin A. http://toxnet.nlm.nih.gov. 

April l 7, 2007. 

Kuhn, J (200 I) Fintrol Concentrate (Antimycin): 90-day oral toxicity study in rat (diet). 

Stillmeadow, Inc., Sugar Land, TX. Laboratory Study No. 6024-00, August 28, 200 I. 

Submitted by Aquabiotics Corp. MRID 4553330 I . Unpublished. 

USEPA 2005. Antimycin A Use Closure Memo. Case No. 4121. Memo from L. Wom1ell 

(SRRD) to Antimycin A RED Team. October 26, 2005. 

USEPA 2006. Antimycin A Drinking Water Characterization Memo from D. Young 

Environmental Fate and Effects Division (EFED), to L. Wom1ell/T. Myers (SRRD) and C. 

Olinger (HED). June 2 1, 2006, 0 3 10732 

Wangcnheim, J., Bolcsfoldi G. Mouse Lymphoma Ll5178Y Thymidine Kinase Locus Assay of 

50 compounds. MUTAGENESIS 3:193-205,1988 

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Antimycin A Human Health Risk Assessment DP No. 0427904 

Appendix A. Acute Toxicology Profile 

Guideline Study Title Results Toxicity Category 

IOCSPPI 

870.1100 Acute Rat Oral Tox icity Study Technical I 

LDso = 28 mg/kg 

(Tox Record 000684) 

23% Fonnulation II 

LDso = 286 mg/kg (males) 

LDso = 36 1 mg/kg (females) 

LDso = 316 mg/kg (combined) 

(MRID 4593720 I, Acceptable) 

870.1 200 Acute Rat Dermal Toxicity 23% Formulation IV 

LDso > 5000 mg/kg 

(MRID 46762604, Acceptable) 

870.1300 Acute Rat Inhalation Technical II 

Toxicity Study LCso < 0.166 rng/L 

(D I 89202) 

23% Formulation IV 

LCso >2.59 mg/L 

(MMAD-2.8 um; GSD-4. 1) 

(MRID 46762605, Acceptable) 

870.2400 Primary Rabbit Eye Technical 111 

Irritation Study lnitation resolved within 48 hours for a 

0.5% solution 

0189202 

23% Formulation II 

Eye Opacity Findings: 

In non-washed assay: at I hr, 2/3 animals 

had scat1ered di IT use areas of opacity, I /3 

had easily discernible translucent areas of 

opacity. At 24 hrs, I /3 had scanered 

ditTuse areas of opacity. From 48 to 72 hrs, 

2/3 had scattered diffuse areas of opacity. 

In washed assay: at I hr, 1/3 animals had 

scattered ditTuse areas of opacity, 2/3 had 

easily discernible translucent areas of 

opacity, 1/3 had scanered diffuse areas of 

opacity. 

(MRJD 46762603, Acceptable) 

870.2500 Primary Rabbit Skin Technical 111 

Irritation Study Some irritation was noted when 5% 

antimycin was applied for 3 days 

(Tox Record 000684) 

23% Formulation - Not a dem1al irritant 

(MRID 46762602, Acceptable) 

870.2600 Local Lymph Node Assay, Mouse NA NA 

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Antimycin A Human Health Risk Assessment DP No. 0427904 

Appendix B. Chemical Identity and Physicochemical Properties 

Ta ble 8.1. Antimycin A Nomenclature. 

Structure CH3 

0 0 

0 

... 11111NH 

0 

HO 

NH CHO 

0 

Common name Antimycin A 

PC Code 006314 

IUP/\C name (2R.3S.6S. 7 R,8R)-3-[ (3-formamido-2- hydroxybcnzoyl)amino ]-8-hexyl- 2.6-dimcthyl-4. 9-

dioxo- I ,5-dioxonan-7-yl 3-methylbutanoate 

CAS registry number 1397-94-0 

Molecular Formula 

Molecular Weight 548.63 g/mol 

Chemical Class Nitrosalicylanilide 

End-use product (EP) Fintrol® concentrate (EPA Reg. No. 39096-2) 

Table 8.2. Physicochemical Properties of Antimycin A. 

Parameter Value R..:ference 

Melting point/range I 33-I 35°C 

Physical State White to yellowish solid 

Stability Stable if stored at 0°C and protected from light. 0389850. M. Rivera Pianscy. 

Solubility Low 06-J VN-2011 

Vapor pressure 2.3 1 X I Q·

1S@ 24.3°C (mm I lg) 

Octanol/wat..:r panition coefficient. (log 4.21 

Kow) 

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