540/09-90-103
Kepone: Position Document
[OP-66019]
Kepone Working Group
-Environmental Protection Agency
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Section IA. Summary Checklist
CRPAR Checklist - Active Ingredient
decachloro - octahydro - 1,3,4 methano - 2H - cyclobuti (c. u) pentalen -2-one
" ACTIVE INGREDIENT: ' COMMON NAME: PhlnrrWnno APPROX. 1974 PROD. VOL. : 840.000 lb.
TRADE NAME: Kepone
USES: * .
Insecticide x' Fungicide '
Herbicide Disinfectant
Criteria '
Acute Toxicity - llumnns, Domestic Animals
1. Dermal LDjo £ 40 rag/kg (formulated) Dertnal LDen of 20X a
(Dust 1 label 5% active) 410. mg/kg
EC (cone. ) 5% = 1620 mq/kq
(raibblts) .. =
W? (cone. ) i
i
G (cone. ) '
j '.-'
2. Dersul LD5Q < 6 g/kg, (diluted for spray,)
Chlordecone products are not avail-able 1n these formulations
' EC (cone. ) - .
KP (cone. ) . :
'* G '(cone. ) .
' i
3. Inhalntion LC 5Q < 0.01 mg/liter (formulated)
Test at 10S concentration, only chlordecdne dust label
EC (cone. ) at 5% active .
No significant difference
wp (cone. ) in weight gain or liver or
lung -pathology among
c (cone. ) chlordeconfe dust & plaifl dust
exposed mice & controls
Applicable PERS data tl.ice exposed 19 hrs. over- 10
day period.
4.6 cases human. poisoning(primarily children) '
In only one case was the causitive agent confirmed. No
deaths were attributed to acute poisoning.
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* '.* St
Plant Growth Reg y
Other ' .' &&*&
Study Triggers
162.11 Criteria
Yea.
«
Np_
X
X
X
Ref.
Pest Pet
OE0919
Doc *'
08276
'est Pet
)EO 919
Doc. #
091574
No
Study
Found
* *
2nd Verfficastbn
\
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Study Triggers Np_ :
162.11 Criteria Study 2nd Verification
Criteria ' . . ' Yes
Chronic Toxicity
1. Oncogcnic effects - man or mammals
(species: rats & mice : exposure: or!al " )
- *
2.; Mutagenic effects
(tests: ' . . )
3. Other chronic effects man or mammals
a. teratogenic ' ...
effect:
dosage:
' *
b. ncurotoxic
effect: tremors '
dosage:
c. reproduction testicular atr()phy 5Q & 8Q ppM '
- effect: reduced reproduction in rates & mice
dosage: 5 to 37.5 PPM
d. ' other: . '
-.
X.
.
*
a" . '
.' '
*
' ''.
Np_
.«'
.
( '
%
X*
x*
.
Ref.
IB (1)
and' (2}
aiiu \ * /
.
(4) and
(5) -
' .
Found
*
*
*
. ,
.
' '
. _
Needed? '
i
* m
',[
9
i
*
'..''"' i
.... " r*
'".- '
*
*
f *
' . '
*"
".
'
* No trigger at this time. Issue'unresolved.
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Criteria
Chronic Toxicitjf (continued)
°r8anisn
"evidenced
monitoring data '
Mass we amounts destroyed beneficial bacteria1 (sewage treatment)
petition studies (residue, !*!&$$*«&&$
5. Fatality to endangered species
Lack of Emergency Treatment
1. No antidote or first aid treatment . . '
Acute ToxicitY-Wilnlff. (calculation on attached sheet)
Not applicable See Discussion. '
1. Mammal: feed residue > acute oral LD£Q . .
2.1 Avian: feed residue > subacute dietary LC5Q '
3. Aquatics: 6" concentration * 1/2 acute LC50
Applicable PERS data:
Applicable monitoring data: None except these resultino in
USB Of.Oeannt hnttov hafte fnr fiya an*c Tk- « V,
ting ?fiis use? : There are c^fently
Study Trlf.r.orn No
162.11 Criteria
Yes
*.
:
No
'x
x.'
x'
X
1
x
X
X
Ref.
,
.
Study
Found
' X
'
OC
*
2nd Verification
Needed?
. '
..
.
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Monitoring Data
Soil
Water
Air
Data aval labile in Hopewell area
(atypical) .
Kepone generally not looked for is
monitoring programs
Yes
No
FDA Market Basket Not examined for Kepone residues
USDA Aphis
Incident Reports
Tolerances '.005 PPM bananas
.01'PPM banana peels(Pet. OE0919)
Agency currently revising
^Formulations/Products
References:
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Section I.B Data Supporting Kepone RPAR Triggers
Data
Oncogenicity (1) Report on Technical Grade Chlordecone.
Carcinogenesis Program, Division of Cancer
Cause & Prevention, National Center
Institute, January 1976
(2) lexicological Studies on Decachloro-
Octahydro - 1, 3, 4- metheno-2H-cyclobuta
(cd) pentalen-2-one. Data submitted in
conjunction with Pesticide Tolerance
Petition OE0919. Allied Chemical Co.
July 1. 1961
Test
RATS
(Osborne-
Mendel)
MICE
(B6C3F1)
RATS
(Albino)
Length of Test
112 weeks
90 weeks
Periods between
one & two years
Dosages Resulting
in Observed Effects
Ural
Males 24 ppm
Females 26 ppm
Males
Females
20 ppm
23 ppm
20 ppm
40 ppn
Oral
Males
(one)
Males
(one)
Females
(three)
Females
(one)
25 ppm
25 ppro
10 ppm
25 ppm
Results
Statistically
significant
Increase over
controls
(P<.05) of
Incidence of
hepatocellular
carcinomas
Differences of
opinion by four
examining clinical
pathologists
existed as to the
nature of observed
hepatocellular
carcinomas, the
most serious diagnosis
by an examining
pathologist, is
listed below:
Hepatocellular
carcinoma
Evolving
carcinoma
Hepatocellular
carcinomas
Evolving
carcinoma
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Trigger
Data
Test
Length of Test Dosages Resulting
Reproduction (3) Good, Ernest E., George W. Ware
and David F. Miller, Effects of
Insecticides on Reproduction in the
Laboratory House: I. Kepone,
Journal of Economic Entomology,
Vol 58, p. 754 (1965)
(4) Toxicological Studies on
Decachloro-Octahydro-1,3,4- metheno-
2H -cyclobuta (cd) pentalen-2-one.
Data submitted in conjunction with
Pesticide Tolerance Petition OE0919.
A11 i ed .Ghent i ca 1 Compa ny.
(5) Huber. James J., Some
Physiological Effects of the
Insecticide Kepone in the
Laboratory Mouse, Toxicology
- and Applied Pharacology, Vol. 7,
p. 516 (1965)
MICE
(mixed lot
used in
initial test
subsequent 3
tests BALB/C)
RATS
120 days
3 months
MICE
(BALB/C)
130 days
160-days
in Observed Effects
BraT
5 ppm to 37.5 ppm
Oral
Males
50 ppm
80 ppm
Oral
10 to 37.5 ppm
40 ppm
Results
Reduced reproduction rate
in chlordecone-fed mice
and in their progeny
Testicular
atrophy
Reduced reproduction rate
No reproduction
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Acute Toxicity to Humans and"Domestic Animals
Discussion: Available data indicate chlordecone does not meet
the criteria for RPAR trigger.
Does Chlordecone Meet or Exceed the Criteria
for Oncogenic Effects on Man or other Mammals
Discussions: .
Part 162. ll(a)(3)(ii)(A) specifies that if the compound induces
oncogenic effects in experimental mammalian species or in man
as a result of oral, inhalation or dermal exposure; or induces
mutagenic effects, as determined by multitest evidence; a
rebuttable presumption shall arise. Available data indicate that
chlordecone induces oncogenic effects in both sexes of mice and
rats as a result of oral exposure. "The Report on Carcinogensis
Program, Division of Cancer Cause and Prevention, National Cancer
Institute, released in January 1976, reports the results of a long-term
study on the oncogenic effects chlordecone on both sexes of Osborne-Mendel
rats and B6C3F1 mice. Chlordecone was administered orally
-for -a- -pa-riod-of -SO-weeks. - Ttie miee-we-r-e-sa-cri-fi-ced-after -9-0
weeks and the rats after 112 weeks; moribund animals were sacrificed
and necropsied. None of the control rats developed hepatocellular
carcinomas. For the mice 16% of the male controls and none
of the female controls developed heptacellular carcinomas. Pathological
diagnosis revealed a statistically significant increase (P< .05)
in the incidence of hepatocellular carcinomas in rats fed an average
24 ppm (males) and 26 ppm (females) and in mice fed an average
of 20 and 23 ppm (males) and 20 and 40 ppm (females). Extensive
hyperplasia of the liver was also reported in both species.
This report presents a clear indication of chlordecone1 s oncogenicity.
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Data submitted by Allied Chemical Company in conjunction
with Pesticide Tolerance Petition OE0919, entitled "Toxicological
Studies on Decachloro-Otahydro- 1, 3, 4-metheno-2H-cyclobuta(cd)
pentalen-2-one" (Document No. 108253. July 1, 19&1) also indicates
that chlordecone is oncogenic in rats. Six groups of male and female
albino rats were fed 0, 5, 10, 25, 50, and 80 ppm chlordecone
respectively for periods of up to two years. Only seven male rats
were examined at the 25 ppm dose level. Four clinical pathological
examined the slides made from the liver tissue of these treated rats.
Liver lesions in one rat were diagnosed as hepatocellular carcinoma
by 2 pathologists and "evolving carcinoma" by one pathologist who also
found "evolving carcinoma" in a second male rat at this feeding
level. Of the sixteen female rats surviving at the 10 ppm feeding
level, liver lesions in three were diagnosed as hepatocellular carcinoma
by one pathologist. Of the nine female rats surviving at the 25 ppm level,
liver lesions in one was diagnosed as "evolving carcinoma" by one
pathologist. None of'the 23 control rats developed heptocellular
carcinomas.
The primary supportive data for this trigger is from NCI. The
Allied Chemical Company test, which also indicates oncogenic effects,
may not of itself be definitive enough to trigger for oncogenicity. The
method of conducting the latter test, however, may have minimized
the possibility of discovering heptocellular lesions. In the Allied
test mice were numbered and survivors of a given numerical
sequence were sacrificed and examined on selected dates. Examinations
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were made only of rats surviving to these selected dates. Rats
which died in the interim were not examined. It is probable
that rats not surviving to a given examining date may have exhibited
a higher incidence of hepatocellular lesions.
It must be observed that liver biopsies of humans suffering from
chlordecone poisoning have shown this organ to have the highest
content of chlordecone of any tissue in the body. Some samples
have shown a mild toxic hepatitis on light microscopy.
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Other Chronic or Delayed Toxic Effects
Discussion:
40 C.F.R. 162. ll(a)(3)(ii)(B) provides that "(a) rebuttable
presumption shall arise if a pesticide's ingredients . . . produces
any other dosa'ge up to a level, as determined by the Administrator,
which is substantially higher than that to which humans can
reasonably be anticipated to be exposed taking into account ample
margins of safety "
There may be difficulty in relating many pesticide uses to human
exposure. The use of chlordecone baits is a case in point. The
major use of kepone in the continental United States is as a roach
and ant bait in houses and on lawns and gardens. Several registrations
for kepone bait formulation enclosed or not enclosed in traps provide
for general applications along baseboards, shelves, sills, or wherever
ants may-appear. Label directions do not always limit the amount of kepone
bait that can be applied to a single room. Although these labels also
provide a warning not to apply in areas accessible to children or domestic
animals, the direction to apply where ants appear could result in
application in areas clearly accessible. This is contradictory to the
warning and could be followed before a warning is read.
\
Another use in which a certain amount of human exposure is entailed
is the use of 5% chlordecone dust on banana plants in Puerto Rico. As
noted on the CRPAR checklist (Section IA), there is only one registered
product having this use. Directions call for surface application of 8 Ibs.
of active ingredient per acre and allow for application at six month intervals.
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The direct hazard to humans would be a chronic dermal or inhalation . '"
effect. The acute toxic effects of chlordecone for these routes of
exposure are, as noted, insufficient to trigger a RPAR.
The registered product label specifying this use prescribes a
respirator for workers. The hazard of this use depends upon the
degree of compliance with label directions. Label revisions might
reduce neurological and reproductive hazards of chlordecone use.
The words "might reduce the hazards" are used in connection with
label revision because we obviously cannot insure that directions will
be followed by all users nor do we currently know if they are being
followed. Should we assume that label directions, if clear and precise
and accompanied by adequate restrictions and warnings which if followed
would mitigate or eliminate the human or wildlife exposure, are adequate
to achieve those ends regardless of the nature of the given pesticide?
It is difficult to obtain information on the degree of label compliance
for the multitude of users. The degree of compliance will obviously
depend upon education and a "host" of s'ocio-economicfactors." Label
directions of pesticides are one method the Agency possesses for
controlling end use of pesticides. Many hazards to man, wildlife, and
non-target species are possible through noncompliance with label
k
directions of most pesticides.
To set a precedent of triggering an RPAR on this basis may be
to insert an unnecessary stumbling block to an effective and necessarily
expeditious review of the many possibly hazardous pesticides on the market
and scheduled for Agency review. On the other hand, a RPAR is a mechanism
through which information may be elicited. Because a presumption may be
rebutted through the submission of exposure data or data showing that the Agency
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presumption was erroneous, it does not constitute the Agency's
final determination.
In addition, the effects of chlordecone exposure on many plant
workers as well as the oncogenic and reproductive effects in laboratory
mammals indicate that this compound is capable of extreme harm to
man. Another pesticide compound may not trigger an oncogenic or
mutagenic effect, yet may have other chronic effects which also
indicate its potential harm to man. The triggering of RPAR by these
other chronic effects is dependent upon human exposure. Can
we always assume that adequate label precautions attempting
to minimize human or wildlife exposure will always eliminate
\
the hazard? .' " . , '
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Reproduction
Discussion:
Several available studies on the effects of chlordecone on
mammalian species indicate that chlordecone produces chronic
effects on reproduction at levels ranging from 5-80 ppm. A
' i
1965 experiment performed at Ohio State University on the effects
of chlordecone on mouse reproduction revealed significant reductions
in reproduction in mice fed chlordecone at dosages ranging
!/
from 5 ppm to 37. 5 ppm. The progeny of the chlordecone-fed
mice also suffered reductions in reproduction at the 5 ppm feeding
level.
Another study performed at Ohio State University in 1965 revealed
reduced numbers of progeny in mice fed chlordecone at 10-37. 5 ppm
I/
dosages. At 40 ppm reproduction was entirely eliminated.
In addition, a 3 month rat study reported in Allied Chemical
Company's Pesticide Tolerance Petition revealed testicular atrophy
in male rats at dosage levels of 25, 50 and 80 ppm. Document
No. 108285 pp. 16-17 (April 11, I960).
Sperm analysis of chlordecone production workers exposed
to extremely high levels showed absent or decreased sperm count
with markedly decreased motility.
±/ Good, Ernest E., George W. Ware, and David F. Miller, Effects
of Insecticides on Reproduction in the Laboratory Mouse: I.
Kepone, 8 Journal of Economic Entomology 754 (1965).
7J Huber, James J., Some Physiological Effects of the Insecticide
Kepone in the Laboratory Mouse, 7 Toxicology and Applied
Pharmacology 516 (1965).
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Neurological Effects
Discussion:
Available studies on the effects of chlordecone on mammalian
species indicates that chlordecone produces neurological effects
at levels of
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Fatality to Endangered. Species
Discussion:
There appears to be no labeled use which would permit large
scale use against fire ants. Except for the use against banana
. . ' .-'.'.'...'. v
root borers, all other uses appear to be for homeowner use
inside or outside the home. There is little or no possibility of
hazard to endangered species from chlordecone in this regard.
The hazard to an endangered species or any species from the
banana use, which is a surface application to the base of the
banana stem, would appear to be primarily from runoff. We
have no data on the extent of this runoff nor on residue levels
in streams or in aquatic organisms. The extent of feeding by
any wildlife at the base of banana plants is an unknown. There
is no information presently available to the Agency that suggests
that a species' survival is endangered by this use.
Acute Toxicity to Wildlife
Discussion:
There are currently no registered label directions permitting
large scale use of chlordecone against fire ants. This would be the only
possible use which might result in application to areas frequented
by wildlife. As noted, the banana use is an unknown in this regard.
This criteria for RPAR is specifically triggered only by application
of pesticides to the feed crop of birds and mammals or by an
aquatic use.
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KtfUKl
PHBE
4. TJH» Md SubtttU
KEPONE: Position Document 1
S. Report Date
January 1976
7.
EPA, OPP, REGISTRATION DIVISION
ft. Performing Organization Rept. No:
540/09-90-103
». Pa«loiii»lin Organization Name and Address
EtJVIRCNMENTAL PPOIBCTICN AGENCY
OFFIQ?; OF PESTICIDE PROGRAMS
WASHINGTON, D.C. 20460
10. Prof*ct/TMk/Work Unit No.
11. Contract
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