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**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF**

**PREVENTION, PESTICIDES AND**

**TOXIC SUBSTANCES**

September 27, 2006

**[Memorandum]{.underline}**

SUBJECT: Antimycin A: Health Effects Division (HED) Considerations for
the Reregistration Eligibility Decision (RED) Document. Phase I.

Barcode: DP# 310734

FROM: Deborah Smegal, MPH, Toxicologist/Risk Assessor

Re-Registration Branch 1

Health Effects Division (HED) (7509P)

THRU: Michael Metzger, Branch Chief

And

Christine Olinger, Senior Scientist

Reregistration Branch I

Health Effects Division (HED), (7509P)

TO: Lance Wormell, Chemical Review Manager

Reregistration Branch 2

Special Review and Reregistration Division (SRRD) (7508P)

**[Background:]{.underline}**

This document represents the Health Effects Division's (HED) input to
support the Reregistration Eligibility Decision (RED) on Antimycin A
(CAS Reg. No.1397-94-0), which is to be written by the Special Review
and Reregistration Division (SRRD). The document includes risk
mitigation and label revision proposals that SRRD plans to include in
the RED. Antimycin A is a restricted use antibiotic piscicide used to
eliminate invasive/unwanted fish in ponds, lakes, streams and catfish
farms. Derived from *Streptomyces* bacteria, Antimycin A acts by
inhibiting electron transfer in the mitochondria during cell
respiration. Antimycin A is toxic to fish at low concentrations (0.5 to
25 ppb) 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. The chemical structure of antimycin A is
shown in Figure 1.

##### Figure 1: Chemical Structure of Antimycin A

![](media/image2.png)

There is currently one active Antimycin A registration (Section 3).
There is currently no emergency exemption (Section 18) use or special
local need (Section 24c) use. No tolerance exists for commodities
treated with antimycin A although food fish (aquaculture) ponds can be
treated with antimycin A to remove undesirable scaled fish. Because
treatments generally occur before stocking with fingerling catfish and
roughly 9 months elapse before those fish are ready for harvest, the
potential for antimycin residues in harvested fish is considered
unlikely.

1.  **SUMMARY AND CONCLUSIONS**

HED believes that there are insufficient data available at this time to
conduct a quantitative human health risk assessment for Antimycin A.
Currently, HED lacks reliable information on the hazard of Antimycin A
with regard to developmental, reproductive, neurological, dermal,
inhalation and chronic toxicity. However, Antimycin A is a restricted
use pesticide used only by trained and/or certified applicators that is
used in quantities of less than 100 lbs per year in the U.S. There is
currently only one registered product that is used at low application
rates resulting in water concentrations of less than 25 ppb, and
according to SRRD the Agency will require additional label language to
preclude human exposure.

> Based on discussions with the SRRD risk management team, in lieu of
> calling in additional data to perform a risk assessment, the SRRD
> intends to implement mitigation measures though product labels, a use
> manual, and proper training to address the following issues identified
> below. If the following mitigation measures are not adopted, HED will
> require the submission of data to support a human health risk
> assessment.

a)  For the stream/lake use, mitigation measures are necessary to
    prevent food exposure, drinking water, swimming and/or recreational
    exposures (i.e. the dead fish must not be eaten; drinking water must
    be treated with a deactivation agent; the area must be posted to
    keep swimmers out of the area; hikers must be warned not to consume
    fish, drink the water or swim in the treated areas).

b)  For the catfish farm use, mitigation measures must be put in place
    to prevent food exposure (i.e. a 12 month, or greater, harvest
    prohibition following application)

c)  For workers proper personal protective equipment (PPE) should be
    required to prevent dermal exposure. For example, additional label
    language will specify that workers wear long-sleeved shirt and long
    pants and/or coveralls to preclude dermal exposure during
    application.

HED believes that improvements in label language, in addition to other
measures required by SRRD as part of the Re-Registration Eligibility
Decision (RED), will ensure there will be negligible human exposure from
food, swimming and drinking water, and minimal exposure to workers with
the addition of PPE. Thus, HED believes the resulting risks would also
be negligible when the product is used by trained applicators according
to the label instructions.

2.  **USE INFORMATION**

According to the Use Closure Memo (US EPA, 2005), Antimycin A is applied
to water by drip-feed device as part of a drip station, backpack
sprayer, boat bailer, and sprayer. Drip stations are typically used in
streams and rivers inaccessible to boat traffic. Backpack sprayers may
be used to supplement drip stations or other application devices in
areas with poor water circulation (e.g., stagnant pools that the
chemical may not reach through natural stream flow). The Fintrol® label
recommends that backpack sprayers be used in areas where water depth is
1 foot or less. Boat bailers are used in larger water bodies such as
ponds and rivers. Deeper water bodies may require the use of a pump
mechanism (to ensure adequate mixing throughout the water column) where
Antimycin A is dispensed through a perforated hose stretching the length
of the water column or is delivered through the propeller wash.

Environmental factors such as water body size, flow rate, pH,
temperature, and gradient affect the quantity of Antimycin A and how
many application sites/stations must be used to achieve the desired
concentration. For example, Antimycin A is more effective in warm water;
thus, less Antimycin A may be required during the summer months than the
winter months for the same treatment site, assuming other factors remain
constant.

### There are two broad uses for Antimycin A as a piscicide: Complete kill and selective kill. In a complete kill, the water body is treated at 5 to 25 ppb of Antimycin A to eliminate all fish in the treatment area. A common objective of a complete kill is to eliminate invasive or non-native species in an area to restore threatened or indigenous species.

In a selective kill, the water body is treated at 0.5 to 1.0 ppb of
Antimycin A to eliminate only small, scaled fish. A common objective of
a selective kill is to eliminate smaller fish to free up food and other
resources for larger fish. Selective kills at higher concentrations are
also used in catfish farming to eliminate scaled fish that commonly
reduce the catfish yields of commercial catfish farmers. According to
the Fintrol® label, scaled fish in catfish farms succumb to treatment at
5 to 10 ppb of Antimycin A whereas catfish generally tolerate up to 20
ppb.

According to the Fintrol® label, in complete and selective kills, dead
fish may be collected and disposed of or left to biodegrade. Areas
downstream of the treatment area may or may not be neutralized with an
oxidizing agent such as potassium permanganate to intentionally
inactivate Antimycin A.

**Detoxification:**

It is believed that Antimycin A is broken down by oxidation. For
situations where fish kills cannot extend beyond a certain point
downstream, the Fintrol® label provides instructions for how to detoxify
Antimycin A with potassium permanganate (KMnO~4~) at 1 ppm. Potassium
permanganate is a strong oxidizing agent commonly used to purify
drinking water and kill pond algae. According to the product label,
water may be considered detoxified when fingerling rainbow trout or
fingerling bluegills survive for at least 48 hours in livecars placed
100 yards downstream from the site of potassium permanganate
introduction.

**Usage and Use Rates:**

According to the registrant, less than 100 lbs. of Antimycin A are used
annually in the US. EPA's Screening Level Usage Analysis returned no
data on agricultural or non-agricultural uses of Antimycin A. Antimycin
A is available as a soluble concentrate/liquid. Retreatment and reentry
intervals are not specified on the current label.

**3.0 HAZARD CHARACTERIZATION**

The Agency has some limited information on acute toxicity of Antimycin A
that indicate a high toxicity concern (toxicity category I) for the
active ingredient (AI) pesticide, but lower toxicity concern (Toxicity
category II) for the one actively registered end-use pesticide product
containing 23% ai. Antimycin A is not a dermal irritant, and eye
irritation resolved within 48 hours following exposure. Table 1 presents
the acute toxicity data for Antimycin A.

+------------+----------+--------------------------+-------------------+
| **Table 1. |          |                          |                   |
| Summary of |          |                          |                   |
| Acu        |          |                          |                   |
| teToxicity |          |                          |                   |
| Data for   |          |                          |                   |
| Antimycin  |          |                          |                   |
| A**        |          |                          |                   |
+============+==========+==========================+===================+
| Test       | Species  | Results                  | Reference         |
+------------+----------+--------------------------+-------------------+
| Oral       | Rat      | Toxicity Category I      | 1993 EPA Review   |
| LD~50~     |          |                          |                   |
|            |          | (technical)              | D189202           |
+------------+----------+--------------------------+-------------------+
|            |          | 286 mg/kg (males)        | MRID 45937201     |
|            |          |                          | (Acceptable)      |
|            |          | 361 mg/kg/ (females)     |                   |
|            |          |                          |                   |
|            |          | 316 mg/kg (combined)     |                   |
|            |          |                          |                   |
|            |          | (Toxicity Category II)   |                   |
|            |          | for 23%                  |                   |
+------------+----------+--------------------------+-------------------+
| Dermal     | Ratt     | \>5000 mg/kg             | MRID 46762604     |
| LD~50~     |          |                          | (Acceptable)      |
|            |          | (Toxicity Category IV)   |                   |
|            |          | for 23%                  |                   |
+------------+----------+--------------------------+-------------------+
| Inhalation | Rat      | \<0.166 mg/L             | 1993 EPA Review   |
| LC~50~     |          |                          |                   |
|            |          | (Toxicity Category II)   | D189202           |
|            |          |                          |                   |
|            |          | (technical)              |                   |
+------------+----------+--------------------------+-------------------+
|            |          | \>2.59 mg/L              | MRID 46762605     |
|            |          |                          |                   |
|            |          | MMAD-2.8 um; GSD-4.1     | (Acceptable)      |
|            |          |                          |                   |
|            |          | (Toxicity Category IV)   |                   |
|            |          | for 23%                  |                   |
+------------+----------+--------------------------+-------------------+
| Dermal     | Rabbit   | Not a dermal irritant    | MRID 46762602     |
| Irritation |          |                          |                   |
|            |          |                          | (Acceptable       |
+------------+----------+--------------------------+-------------------+
| Eye        | Rabbit   | Irritation resolved      | 1993 EPA Review   |
| Irritation |          | within 48 hours for a    |                   |
|            |          | 0.5% solution            | D189202           |
+------------+----------+--------------------------+-------------------+
|            |          | Opacity: Non washed; at  | MRID 46762603     |
|            |          | 1 hr, 2/3 scattered      |                   |
|            |          | diffuse areas of         | (Acceptable)      |
|            |          | opacity, 1/3 easily      |                   |
|            |          | discernible translucent  |                   |
|            |          | areas of opacity. At 24  |                   |
|            |          | hrs, 1/3 scattered       |                   |
|            |          | diffuse areas of         |                   |
|            |          | opacity. Form 48 to 72   |                   |
|            |          | hrs, 2/3 scattered       |                   |
|            |          | diffuse areas of         |                   |
|            |          | opacity. Washed: at 1    |                   |
|            |          | hr, 1/3 scattered        |                   |
|            |          | diffuse areas of         |                   |
|            |          | opacity, 2/3 easily      |                   |
|            |          | discernible translucent  |                   |
|            |          | areas of opacity, 1/3    |                   |
|            |          | scattered diffuse areas  |                   |
|            |          | of opacity.              |                   |
|            |          |                          |                   |
|            |          | (Toxicity Category II)   |                   |
|            |          | for 23%                  |                   |
+------------+----------+--------------------------+-------------------+

\(a\) Contains 23% Antimycin A

The toxicological database is inadequate to conduct a quantitative risk
assessment. The Agency lacks information regarding developmental,
reproductive, neurological, dermal, inhalation and chronic toxicity of
Antimycin A. Only one oral subchronic toxicity study is available which
is discussed below.

**Subhronic Toxicity.** In a subchronic study, rats exposed to the end
use product containing Antimycin A (23% ai) exhibited an increased
incidence of diarrhea or soft feces at the lowest dose tested of 0.5
mg/kg/day. A NOAEL was not established. A detailed summary of the study
is provided below.

[90-Day Oral Toxicity Study in Rat.]{.underline} In a subchronic oral
toxicity study (MRID 45533301, 46762601), Fintrol® Concentrate (23%
a.i., Batch \# 1977) was administered to 10 Sprague-Dawley rats/sex/dose
in the diet at **active ingredient dose levels** of 0, 0.5, 5 and 10
mg/kg/day from Day 0 until Day 41 and 0, 0.5, 10 and 20 mg/kg/day from
Day 42 until study termination.

The following parameters were examined: clinical signs, body weight,
food consumption, functional observational battery, hematology, clinical
chemistry, gross lesions, selected organ weights, and histopathology of
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 and was
not considered toxicologically significant.

No treatment-related clinical chemistry findings were observed except
for two parameters. Total protein in the Group III males and Group IV
females and calcium in the Group IV females were significantly less
(15-18%) than those of the control group. But these findings were not
corroborated by gross or microscopic pathology and was not considered
toxicologically significant.

In Group II (0.5 mg/kg) animals, diarrhea in one male on days 31 and 32
and soft feces in 3 females on eight days (Days 33, 40, 41, 86-90) were
observed. In both Groups III and IV (5 and 10 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 21% less weight than the control
animals, however, no treatment-related effects were observed on absolute
body weights and food consumption at all doses. Increased incidence of
diarrhea and soft stool was considered as treatment related effects due
to Antimycin effect on the intestinal flora leading to diarrhea and soft
feces.

The LOAEL 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
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the rat. Although there was a change in dosage from 5
and 10 to 10 and 20 mg/kg on day 42 onward, the effect of the chemical
on the intestinal flora occurred prior to the changes in dosages.

**4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION**

There are insufficient data available at this time to conduct a
quantitative human health risk assessment for Antimycin A. Currently,
HED lacks reliable information on the hazard of Antimycin A with regard
to developmental, reproductive, neurological, dermal, inhalation and
chronic toxicity. However, Antimycin A is a restricted use pesticide
used only by trained and/or certified applicators that is used in
quantities of less than 100 lbs per year in the U.S. There is currently
only one registered product that is used at low application rates
resulting in water concentrations of less than 25 ppb, and SRRD will
require additional label language to preclude human exposure.

Based on its use pattern there are potential exposures for workers
during application, children or adult recreational users of treated
lakes/streams via swimming, anglers harvesting fish after treatment, and
dietary exposures from the catfish farm use, and potential drinking
water exposures from the treatment of lakes/streams/reservoirs that
could be used as a drinking water source. Each is briefly discussed
below.

**Worker Exposure**. HED believes that exposure to trained applicators
during Antimycin A application is likely to be low, based on the low
volume use, physical & chemical characteristics, and recommended label
language for PPE. Antimycin A has no appreciable vapor pressure
(2.31x10^-15^ mmHg) at ambient temperatures, and thus inhalation
exposure is expected to be minimal. In addition, most of the application
equipment recommended on the label such as boat bailer, and drip-feed
devices are not expected to result in significant aerosol exposure.
Backpack applications, however, may result in significant aerosols
exposures if high concentrations are applied, and it is therefore
recommended that the label be clarified to specify the solution strength
for backpack application. Currently, the label indicates that one
container of product can be applied in five gallons of water, which is
equivalent to a solution strength of 2900 ppm. The aerosol exposures
could also be reduced by specifying the application of coarse spray
droplets.

The current label requires the use of gloves and goggles, and SRRD
intends to also require that applicators wear a long sleeved shirt, and
long pants and/or coveralls to minimize potential dermal exposure. As
noted previously, Antimycin A is not a dermal irritant, and eye
irritation in animals was transient.

**Residential/Recreational Exposure**. HED believes that exposure to
Antimycin A can be prevented through improved label language. The label
needs to clearly state that dead fish must not be eaten, drinking water
must be treated with a deactivation agent; the area must be posted to
keep swimmers out of the area; hikers/fisherman must be warned not to
consume fish, drink the water or swim in the treated areas for a period
of time (time to be specified later but at least 1 week after treatment
and possibly longer).

**Dietary.** No tolerance exists for commodities treated with antimycin
A although food fish (aquaculture) ponds can be treated with antimycin A
to remove undesirable scaled fish. Because treatments generally occur
before stocking with fingerling catfish and roughly 9 months elapse
before those fish are ready for harvest, the potential for antimycin
residues in harvested fish is considered unlikely. Residues in catfish
are expected to be low based on the low application rate (less than 25
ppb) and label restrictions not to harvest fish for 1 yr following
treatment. Based on discussions with the risk management team, SRRD also
intends to improve the label language regarding timeframe required for
sport fishing in water bodies treated with Antimycin A.

**Estimates of Water Concentrations for Drinking Water.** The Agency
estimated drinking water concentrations from the use of Antimycin A.
Details of this assessment are provided in the Environmental Fate and
Effects Division (EFED) memo from D. Young, June 21, 2006, D310732. A
brief summary is provided in this section. When antimycin is applied to
a water body (whether a lake, pond, or stream) the most conservative
acute concentration that could be used for drinking water assessments is
the application concentration. The maximum application concentration is
ambiguous but is "roughly" 25 ppb. However, because of the significant
uncertainties regarding the persistence and sorption properties of
Antimycin A, temporal concentrations trends and chronic concentrations
prediction are also full of uncertainty. With this regard, ranges of
estimates of chronic concentrations can be made by using the full range
of possible degradation rates. The Agency (EFED) provided a range of
chronic concentrations that may result following a 25 ppb application of
Antimycin to a water body and shows that chronic concentrations vary
considerably depending on the half life assumed for Antimycin A, with a
value of 4.6 ppb the most conservative based on the longest reported
half life (47 days). A chronic concentration of 0.0013 ppb was estimated
based on a half-life of 20 minutes.

For human drinking water, Antimycin may move downstream from the point
of application (outflow from a lake or a stream) and could enter a
drinking water reservoir. Because of the uncertainties surrounding the
degradation of Antimycin and the great variability in potential travel
times from the point of application to a reservoir, only first
approximations of Antimycin concentrations in human drinking water can
be made. The worst possible case would be the concentration of Antimycin
at the point of application---an acute concentration of "roughly" 25
ppb. The worst possible case for a chronic concentration would be the
concentration derived using the longest reported aquatic half
life---"roughly" 4.6 ppb, depending on actual application rate. **These
"rough" estimates of 25 ppb and 4.6 ppb chronic are the EFED-recommended
acute and chronic concentrations for use in human drinking water
exposure assessments.**

The above recommended concentrations apply to both surface water and
groundwater. While applications of Antimycin are made only to surface
waters, it is possible that Antimycin could migrate to groundwater
(e.g., by leaching beneath a pond or stream); however, the resulting
groundwater concentrations would be no higher than the source surface
water concentration. Thus, the above recommendations are also
conservative estimates of groundwater concentrations.

Note that these recommended concentrations are conservative with regard
to what is likely to actually occur as drinking water concentrations. In
actual situations, Antimycin likely will dissipate due to hydrodynamic
dispersion, mixing with side channels, and ultimate dilution into a
larger water body, however these factors are not readily determined and
would be highly localized.

Based on discussions with the risk management team, the Agency intends
to require that drinking water must be treated with a deactivation agent
to preclude human exposure to Antimycin A.

**5.0 DATA NEEDS:**

Environmental fate data gaps have been identified, and efforts are
underway by the U. S. Geological Survey, the EPA Office of Research and
Development and the Office of Pesticide Programs' Biologic and Economic
Assessment Division laboratories to address some of the uncertainties
regarding analytical method development and potential routes of
degradation.

\(1\) An analytical detection method for this compound in water is
currently not available, and needs to be developed. A detection method
would be a useful tool to ensure that humans and are not inadvertently
exposed downstream from treatment areas.

\(2\) Although hydrolysis data are available on Antimycin, there is
considerable variability in the data and degradation half-lives range
from 30 minutes to 47 days. Additional information on Antimycin A
degradation would be helpful.

\(3\) Additionally, while there are anecdotal data suggesting that
Antimycin A is inactivated through the use of an oxidant, *e.g.*
potassium permanganate, there are no data to identify the reaction
products.

**6.0 RECOMMENDED LABEL REVISIONS:**

The label should more clearly state the maximum application rates, as
the current label provides "rough estimates".

Disposal methods for unused pesticide need to be clearly stated.

The label should restrict aerial applications.

> **[Stream/lake]{.underline}** **[use]{.underline}**. Mitigation
> measures are necessary to prevent food exposure, drinking water,
> swimming and/or recreational exposures. The label needs to clearly
> state that dead fish must not be eaten, drinking water must be treated
> with a deactivation agent; the area must be posted to keep swimmers
> out of the area; hikers/fisherman must be warned not to consume fish,
> drink the water or swim in the treated areas.

For workers proper personal protective equipment (PPE) should be
required to prevent dermal exposure. For example, additional label
language should specify that workers wear long-sleeved shirt and long
pants to preclude dermal exposure during application. It is recommended
that the applicators should be certified.

Retreatment and reentry intervals are not specified on the current
label. The language for re-entry of treated areas or fishing of treated
lakes/streams needs to be improved to more clearly specify a time limit
(time to be specified later but at least 1 week after treatment and
possibly longer), or concentration level (\< 1 ppb) in addition to the
current criteria of survival of sensitive species for 48 hours.

> The label should be improved to provide more guidance on when the
> deactivation agent is required.

**[Catfish farm use.]{.underline}** Mitigation measures must be put in
place to prevent food exposure (i.e. a 12 month, or greater, harvest
prohibition following application). The use rate should be reduced to 10
ppb as a maximum concentration since catfish are sensitive to 20 ppb,
and this use is meant to control undesirable scaled fish.

**7.0 REFERENCES**:

Kuhn, J (2001) Fintrol Concentrate (Antimycin): 90-day oral toxicity
study in rat (diet). Stillmeadow, Inc., Sugar Land, TX. Laboratory Study
No. 6024-00, August 28, 2001. Submitted by Aquabiotics Corp. MRID
45533301. Unpublished.

USEPA 2005. Antimycin A Use Closure Memo. Case No. 4121. Memo from
L.Wormell (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. Wormell/T.
Myers (SRRD) and C. Olinger (HED). June 21, 2006, D310732