Document ID: EPA-HQ-OPP-2006-1002-0031
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 23, 2007

Memorandum

SUBJECT:	Antimycin A:  Response to Public Comments on the Health Effects
Division (HED) Considerations for the Reregistration Eligibility
Decision (RED) Document 

		Barcode: DP# 338642 

FROM:	Deborah Smegal, MPH, Toxicologist/Risk Assessor

		Byong-Han Chin, Toxicologist

		Timothy Dole, Industrial Hygienist

		Christine Olinger, Senior Scientist

		Re-Registration Branch 1 

		Health Effects Division (HED) (7509P)

	

THRU:		Michael Metzger, Branch Chief 

		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) response
to public comments received in March 2007

GENERAL COMMENTS:  

Comment:  

There are uncertainties regarding effects to humans due to an incomplete
database.

EPA Response:  

The HED memorandum acknowledges a lack of toxicity data for antimycin A.
 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 the Agency will require additional label
language to preclude significant human exposure.  Given these
considerations, HED believes there are minimal risks to human health
from antimycin A.

Comment:  

Based on the potential for residues, a tolerance should be established
for antimycin A in fish (see Gilderhus et al. 1969, Ritter et al. 1966).

EPA Response:  

The catfish farm use is considered to be a non-food use because the
Agency intends to require label restrictions not to harvest fish for 1
year following treatment with antimycin A to ensure that fish residues
will be non-detectable.  In addition, antimycin A appears to have a low
potential to bioaccumulate in aquatic organisms (EFED memo, Young and
Steeger 12/12/06, D310730).  Thus, a food tolerance is not necessary
under these use conditions.  

COMMENTS FROM ANN MCCAMPBELL, MARCH 19, 2007

Comment:  

I do not agree that sub-chronic impacts of antimycin can be dismissed
because

there was no ?gross or microscopic? pathology demonstrated (p. 6). This
ignores the possibility of functional impacts, such as on the endocrine
or immune systems, which can be significantly impacted without showing
structural

abnormalities. Microscopic analysis would also miss abnormalities that
are too

small to be seen with a standard microscope.

EPA Response:  

The document was revised to add that the Agency lacks toxicology
information regarding endocrine and immunological toxicity of antimycin
A.  

Comment:  

I also disagree that because antimycin has a low vapor pressure and
because it

will preferentially partition into acetone rather than air that this
means that antimycin will not become airborne (p. 8). My experience with
chlorpyrifos, which is also relatively non-volatile, was that when mixed
with petroleum solvents in the product Dursban, it contaminated my house
when fumes entered open windows. I believe the volatile component of
Dursban acted as a carrier to volatilize the otherwise less volatile
chlorpyrifos. In any case, the claim that antimycin is not expected to
become airborne should be recognized as only theoretical and until this
hypothesis is empirically tested, should not be given much weight.

EPA Response:  

The memorandum was revised to state the following:  “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…. 
Backpack applications, however, may result in significant aerosols
exposures if high concentrations are applied, and it is therefore
recommended that the label be clarify to specify the solution strength
for backpack application.”  

HED believes the comments related to chlorpyrifos (dursban) are not
directly relevant to antimycin A.  

Comment:  

An assumption is made that antimycin affected the intestinal flora of
rats who

developed diarrhea after consuming antimycin (p.7). Is there any
documentation

of this? How likely is this explanation given the fact that antimycin
has no

effect on bacteria?

EPA Response:  

The document was modified to state the following:  “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.” 

Comment:  

The worst case scenario is described as drinking water contamination at
the

application concentration (p. 9), but the worst case would actually be a

misapplication or spill scenario, which were not, but should be,
analyzed.

EPA Response:  

It is current Agency policy to conduct assessments assuming that
individuals follow the label instructions.  

Comment:  

More attention should be paid to evidence that antimycin causes DNA
strand

breaks and is a mutagen.

EPA Response:  

No mutagenicity studies are available in our database to indicate that
antimycin A is mutagenic.  However, the published literature including
the ToxNet/Environmental Mutagen Information Center (EMIC), did not show
evidence that antimycin A by itself is a mutagen.  Many references used
antimycin A with other chemicals to study a mutation.  

COMMENTS FROM ANN MCCAMPBELL, MARCH 19, 2007 RELATED TO THE WATER
QUALITY CONTROL COMMISSION HEARING ON NEW MEXICO DEPARTMENT OF GAME AND
FISH PETITION DATED SEPTEMBER 12, 2002  

Comment:  

Antimycin A is a highly toxic pesticide and poison. It is not an
antibiotic (Exhibit 1) or a

pharmaceutical agent. Although antimycin A is derived from bacteria, it
has more in

common with cyanide than penicillin. Like cyanide, antimycin A blocks
electron

transport in mitochondria causing cellular anoxia.

EPA Response:  

The HED memorandum was revised to remove reference to antimycin A as an
antibiotic.  

Comment:  

Fintrol concentrate carries the highest acute toxicity rating given by
the U.S.

Environmental Protection Agency (EPA), Toxicity Category I. The label
contains the

warning “DANGER POISON” next to a skull and crossbones. Under
“hazards to

humans and domestic animals” it says this product is “FATAL IF
SWALLOWED” and

“MAY BE FATAL IF ABSORBED THROUGH THE SKIN”.

According to its Material Safety Data Sheet (Exhibit 2), the oral LD 50
of antimycin A in

rats is 30 mg/kg, that is, it takes 30 mg/kg of ingested antimycin A to
kill half the test

animals. According to an EPA Chemical Profile (Exhibit 3), the LD 50 for
guinea pigs is

even lower at an extraordinary 1.8 mg/kg. Pesticides with an oral LD 50
less than 50

mg/kg meet the criteria for EPA Toxicity Category I. To put this in
perspective, pesticides in the other three EPA toxicity categories have
much higher oral LD 50 values.

The oral LD 50 for Category II pesticides is 50-500 mg/kg, for Category
III pesticides it

is 500-5000 mg/kg, and is greater than 5000 mg/kg for Category IV
pesticides (1).

EPA Response:  

The HED memorandum indicates that antimycin A technical is in toxicity
category 1 for acute oral toxicity.  The document was revised to include
the LD50 of 28 mg/kg.  The recent acute toxicity study for the end-use
product that contains 23% antimycin A (fintrol concentrate; MRID
45937201)  produced a higher LD50 of 316 mg/kg (combined sexes), which
is considered to be toxicity category 2.  

Comment:  

The Hazards Information section of the Material Safety Data Sheet
(Exhibit 2) states that

routes of entry for antimycin A include the skin, inhalation, and
ingestion. The ingestion

hazard rating is “highly toxic”. Antimycin A is also noted to be an
eye, skin and

respiratory irritant. Target organs include eyes, skin, respiratory
tract, cardiovascular

system, nervous system, kidneys, and possibly fetus. Inhalation of
vapors or aerosol can

irritate the eyes, nose, and respiratory tract. Direct contact with skin
or eyes can produce

severe irritation. And systemic intake can produce a decrease in blood
pressure, nausea,

light headedness, dizziness, excitement, incoordination, weakness, loss
of coordinated

speech and drowsiness. Medical conditions said to be aggravated by
antimycin A

exposure are pre-existing eye, skin, respiratory, kidney, nervous system
or cardiovascular

ailments.

A University of California at Santa Cruz Laboratory Standard Operating
Procedure guide

on antimycin A (Exhibit 4) states that this material is considered a
Particularly Hazardous

Substance by the CAL OSHA Lab Standard. It also says that antimycin A is
“highly

toxic” and “may be fatal if swallowed, absorbed through skin, or
inhaled”. It notes that

“respiratory distress, impaired reflexes, incoordination, and terminal
symptoms consistent

with CNS (central nervous system) depression have been reported in
experimental

animals poisoned by the oral or parenteral route.”  

ToxNet Hazardous Substance Databank Information on antimycin A, which
includes data

from PoisonDex (Exhibit 5), states that respiratory distress,
incoordination, impaired

reflexes, and CNS (central nervous system) depression have occurred in
animals. It

further notes that the minimum lethal human exposure level is unknown.

EPA Response:  

The HED memorandum was revised to more clearly indicate that antimycin A
is a dermal, eye and respiratory irritant.  

The following text was added to the HED memorandum:  “Neurotoxicity: 
Incoordination, impaired reflexes and respiratory distress have been
reported in mice injected intravenously with antimycin A. (HSDB
2007).”  

Comment:  

Besides its extreme acute toxicity, ToxNet also states that antimycin A
is an experimental

MUTAGEN. The NIOSH Registry of Toxic Effects of Chemical Substances
(RTECS)

(Exhibit 6) also includes “mutation data” on antimycin A. And there
are 36 references

regarding antimycin on the ToxNet Environmental Mutagen Information
Center (EMIC)

web page (2). At least one study describes antimycin-induced DNA
fragmentation and

strand breaks (Exhibit 7).

EPA Response:  

No mutagenicity studies are available in our database to indicate that
antimycin A is mutagenic.  Although RTECS indicates that antimycin A is
a mutagen, no citations are provided to support this conclusion (RTECS
2006).  However, the published literatures including the
ToxNet/Environmental Mutagen Information Center (EMIC), did not show
evidence that Antimycin A by itself (i.e., when tested alone) is a
mutagen.  Many of the references cited by the commentor appeared to test
antimycin A with other chemicals.   Regarding one study which involves
antimycin A with DNA fragmentation and strand breaks (Exhibit 7, Garberg
et al. 1988)), genotoxic activity was also not demonstrated by antimycin
A by itself.   In this study (Garberg et al. 1988) that employed the DNA
alkaline unwinding assay (see reference), genotoxic activity was not
demonstrated by antimycin A tested at concentrations in the range of 1.5
X 10-5 to 150 X 10-5 mol/L.  [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.]    

Reference

GARBERG P; AKERBLOM EL; BOLCSFOLDI G.  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 

Comment:  

Perhaps most importantly, there is a disturbing lack of knowledge about
the full range of

toxicity of antimycin A. Fintrol was initially registered in 1977 (3)
before the EPA

adopted more stringent registration requirements. In a 1987 EPA Chemical
Profile on

Antimycin A (Exhibit 3) data was “not found” in most categories
evaluated -- from

physical and chemical properties to health hazards -- despite a search
of 15 data sources.

In addition, the California Department of Pesticide Regulation recently
rejected the

registration of Fintrol in that state because of insufficient data
regarding its toxicity and

environmental fate (Exhibit 8). There are as well concerns among fish
managers that

Fintrol may lose its federal EPA registration (Exhibits 1 & 9).

EPA Response:  

The HED memorandum acknowledges a lack of toxicity data for antimycin A.
 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 the Agency will require additional label
language to preclude significant human exposure.  Given these
considerations, HED believes there are minimal risks to human health
from antimycin A. 

Comments from Food and Water Watch, Washington D.C.  March 16, 2007.  

Comment:  

The document submitted by the EPA’s Health Effects Division (HED)
states, “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.”iii

The Food Quality Protection Act of 1996 requires that during the
registration process, the

EPA establish a tolerance for pesticides (the level of the pesticide
residue that can be

allowed in food products) based on risk assessment methods to ensure
that the pesticide

can be used with “reasonable certainty of no harm.”iv

However, the HED analysis states, “No tolerance exists for commodities
treated with

antimycin A…HED believes that there are insufficient data 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.”v Additionally,
the Food and Drug

Administration does not test for residues of antimycin A during the
Total Diet Study, a

program that tests for pesticide resides in food.vi

This is unacceptable. The EPA must not allow a food product such as
catfish to be

exposed to a toxic substance without determining the level of residue
that persists in the

edible portion of the fish, and also studying the potential human health
impacts of

consuming the contaminated fish.

Although the level of antimycin A residue in the edible portion of
catfish exposed to the

pisicide has not been studied, it is reasonable to assume the presence
of residue in the

flesh. While catfish can survive comparably higher concentrations of
antimycin A, it can

kill them at concentrations of 20 ppb. In a Bureau of Sport Fisheries
and Wildlife study,

28 out of 30 catfish died in the presence of antimycin A at
concentrations of 20 ppb in the

water.vii

Additionally, a 1966 study, published in Journal of Agricultural and
Food Chemistry,

that measured antimycin A residues in carp and trout provides some basis
for comparison

as to the possible level of antimycin A residue in farmed catfish. Trout
and carp were

exposed to 5 ppb and 10 ppb, levels fatal to both types of fish.viii The
residues in the

edible portions of the fish averaged from 76 to 201 ppm, concentrations
significantly

higher than the 5-10 ppb in the water. The carp, which survived longer
in the presence of

the pisicide, had concentrations of antimycin A residue two to three
times greater than in

the trout.

Since catfish survive longer in the presence of antimycin A at
commercial levels than do

carp, we reasonably conjecture that concentrations of the residue in the
edible portion of

catfish could be even higher than the concentrations in the edible
portion of carp.

Furthermore, another Bureau of Sport Fisheries and Wildlife study
determined that the

effects of antimycin A on fish are likely irreversible, even if the fish
is placed in water

that does not contain any of the pisicide.ix If it is the case that
antimycin A persists in the

flesh of catfish, then the proposed mitigation measure that catfish not
be harvested before

12 months following pisicide application would not do anything to reduce
the risk to

consumers. Pure supposition is not sufficient.

The above studies reinforce the point in the HED analysis about the
potential for dietary

exposure to antimycin A, based on its use in catfish aquaculture.
Indeed, in the face of

such lack of scientific investigation, the EPA cannot conclude that
there is “reasonable

certainty of no harm,” as required by the Food Quality Protection Act.
It is reckless and

unacceptable for the EPA to expose consumers to a chemical whose human
health effects

are simply not known.

EPA Response:  

The catfish farm use is considered to be a non-food use because the
Agency intends to require label restrictions not to harvest fish for 1
year following treatment with antimycin A to ensure that fish residues
will be non-detectable.  In addition, antimycin A appears to have a low
potential to bioaccumulate in aquatic organisms (EFED memo, Young and
Steeger 12/12/06, D310730).  Thus, a food tolerance is not necessary
under these use conditions.  

The commenter cites a study conducted in 1966 on high concentrations of
antimycin A in fish tissues.  However, the study did not identify the
composition of the residues (i.e., whether they are the parent or
breakdown products).  Also, this study used a tritium label, and our
metabolism guidance (860.1300) states "the use of tritium is strongly
discouraged".  Finally, the EFED chapter states (Page 12…  D. Young
and T. Steeger , 12/12/06, D310730) "Antimycin a…appears to have a low
potential to bioaccumulate in aquatic organisms". Therefore, catfish may
have been present at the time of application, but by the time they are
harvested a year later residues in tissues should have dissipated.

GAME AND FISH DEPARTMENT.  STATE OF ARIZONA.  MARCH 18, 2007.  

Comment:  

EPA Response:  

The HED memorandum has been revised to recommend the following:  “…
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.”

Comment:  

EPA Response:  

No revisions are considered necessary to address these comments because
they generally support the HED recommendations.  The Agency will
consider these comments in revising the label language.  

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