Document ID: EPA-HQ-OPP-2006-1002-0030
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-13T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

	WASHINGTON, D.C.  20460

	

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

April 18, 2007

Memorandum

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

		Barcode: DP# 338641 

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:

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).  This memorandum has been revised to
address the registrant “error” comments received during Phase I, and
public comments received in March 2007.  The document includes risk
mitigation and label revision proposals that SRRD plans to include in
the RED.  Antimycin A is a restricted use piscicide used to eliminate
invasive/unwanted fish in ponds, lakes, streams and catfish farms. 
Derived from Streptomyces mold, 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 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.  The chemical structure of antimycin A is
shown in Figure 1.

Figure 1:  Chemical Structure of antimycin A

There is currently one active antimycin A registration (Section 3), for
a product called Fintrol® Concentrate that contains 23% active
ingredient (a.i.).  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 9-12 months elapse before
those fish are ready for harvest, the potential for antimycin residues
in harvested fish is considered unlikely. 

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, endocrine,
immunological, 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 several hundred 
pounds per year in the U.S.   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, and according to SRRD the Agency will require additional label
language to preclude significant 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
recommends requiring the submission of data to support a human health
risk assessment.  

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). 

For the catfish farm use, mitigation measures must be put in place to
prevent food exposure.  HED recommends that the label require a  12
month, or greater, harvest prohibition following application of
antimycin A)

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.  

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, lakes, reservoirs 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, for standing bodies of water with similar
pH conditions, 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 hydrolysis and
oxidation following neutralization with potassium permanganate.  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 (KMnO4) 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, several hundred pounds 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 tc \l1 "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 a dermal, eye and respiratory
irritant.     Table 1 presents the acute toxicity data for antimycin A. 

Table 1.  Summary of AcuteToxicity Data for antimycin A

Test	

Species	

Results	

Reference

Oral LD50 	

Rat	

28 mg/kg 

(Toxicity Category I)

(technical)	Tox Record 000684

286 mg/kg (males)

361 mg/kg/ (females)

316 mg/kg  (combined)

 (Toxicity Category II) for 23% 	

MRID 45937201 (Acceptable)

Dermal LD50 	

Rat	>5000 mg/kg

(Toxicity Category IV) for 23%	MRID 46762604 (Acceptable)

 Inhalation LC50	

Rat	<0.166 mg/L 

(Toxicity Category II)

(technical)	1993 EPA Review

D189202

>2.59 mg/L

MMAD-2.8 um; GSD-4.1

 (Toxicity Category IV) for 23%	MRID 46762605

(Acceptable)

Dermal Irritation	

Rabbit	Not a dermal irritant (23% ai)	MRID 46762602

(Acceptable)

Some irritation was noted when 5% antimycin was applied for 3 days	Tox
Record 000684

Eye Irritation	Rabbit	Irritation resolved within 48 hours for a 0.5%
solution	1993 EPA Review

D189202

Opacity: Non washed; at 1 hr, 2/3 scattered diffuse areas of 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%	MRID 46762603

(Acceptable)

	The toxicological database is inadequate to conduct a quantitative risk
assessment.  The Agency lacks information regarding developmental,
reproductive, neurological, endocrine, immunological, dermal, inhalation
and chronic toxicity of antimycin A.  Some limited mutagenicity data and
an oral subchronic toxicity study are available which are discussed
below.  

	No mutagenicity studies are available in our database.  However, based
on the published literature, there was no evidence that antimycin A
induced a mutagenic response in in vitro tests for genetic toxicity. 
The tests employed were mouse lymphoma thymidine kinase locus and DNA
alkaline unwinding assays (Wangenheim and Bolcsfoldi 1988, Garberg et
al. 1988).  

	In the mouse lymphoma thymidine kinase locus assay (in vitro mammalian
cell gene mutation test), no significant 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 S(
activation (Wangenheim and Bolcsfoldi 1988).   

	In the DNA alkaline unwinding assay, no significant mutagenic activity
was produced by antimycin A tested at concentrations in the range of 1.5
X 10-5 to 150 X 10-5 mol/L.  The study was not conducted in the presence
of S( activation. [NOTE:  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).   

	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.  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 were 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 a treatment-related effect.  

	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.

	Neurotoxicity.  Incoordination, impaired reflexes and respiratory
distress have been reported in mice injected intravenously with
antimycin A. (HSDB 2007).  

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 several hundred pounds 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 antimycin A,
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 a very low pressure of 2.31x10-15
mmHg at ambient temperatures, and thus inhalation exposure to antimycin
A vapors 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 a dermal irritant, and eye irritation
in animals was transient.  However, the end use product, Fintrol( is a
severe eye irritant and the label should state that workers not wear
contact lenses.  Fintrol( can melt the contact lenses onto the cornea of
applicators if eye protection is not used.  

	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 (generally less
than 25 ppb) and label restrictions not to harvest fish for 1 yr
following treatment.  In addition, antimycin A appears to have a low
potential to bioaccumulate in aquatic organisms (EFED memo, Young and
Steeger 12/12/06, D310730).  Based on discussions with the risk
management team, SRRD also intends to improve the label language
regarding the 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 A 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 A and the great variability in potential travel
times from the point of application to a reservoir, only first
approximations of antimycin A 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 A are made only to surface
waters, it is possible that antimycin A 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 A 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 animals are not
inadvertently exposed downstream from treatment areas.  

	(2)  Although hydrolysis data are available on antimycin A, 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.    
SEQ CHAPTER \h \r 1  

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 use.   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.   HED also
recommends that workers wear coveralls while handling or mixing the
concentrated liquid.  It is recommended that the applicators should be
certified.  Because the end use product, Fintrol(, is a severe eye
irritant, it is recommended that the label state that workers not wear
contact lenses.  Fintrol( can melt the contact lenses onto the cornea of
applicators if eye protection is not used.  

	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.   Mitigation measures must be put in place to prevent
food exposure (i.e. a 12 month, or greater, harvest prohibition
following application in the absence of fish residue data to ensure that
fish residues will be non-detectable).  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.  

REFERENCES:

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
203:155-176,1988

Hazardous Substances Data Bank (HSDB).  2007.  Antimycin A.    HYPERLINK
"http://toxnet.nlm.nih.gov"  http://toxnet.nlm.nih.gov .  April 17,
2007.

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

Wangenheim, J., Bolcsfoldi G.  Mouse Lymphoma L15178Y Thymidine Kinase
Locus Assay of 50 compounds.   MUTAGENESIS 3:193-205,1988 

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