vvEPA
Eiwfonmnal Protection
A9»«Y
Offici of Pvttodfl Proqrwnt (TS-766C)
Wwfitfigton. OC 20460
540/FS-90-094
Pesticide
Fact Sheet
Name of Chemical:
Reason for Issuance:
Date Issued:
Fact Sheet Number:
*olr>et
Registration Standard
June 25, 1987
215
1. DESCRIPTION OF CHEMICAL
Generic Name:
Common Names:
Trade Names:
N-(trichloromethylthlo)
phthallmlde
Folpet
Folpan, Folpex, Phaltan and
Thlophal
081601
133-07-3
19^2
Fungicide
Dlcarboxlmldes or chlorinated
Organosulfur compounds
Chevron Chemical Company
Stauffer Chemical Company
Makteshlm Beer Sheva
Chemical Works, Ltd.
Calhlo Chemicals, Inc.
2. USE PATTERNS AND FORMULATIONS
Application sites: Terrestrial food crops, ornamental
plants, In Interior and exterior paints and coatings,
and In plastics.
EPA Shaughnessy Code:
Chemical Abstracts
Service (CAS) Number:
Year of« Initial
ReglstratIon:
Pesticide Type:
Chemical Family:
U.S. Producer:
Types of formulations: Formulation Intermediates containing
1.42 to 882 folpet, dusts containing 42 to 882 folpetj
wettable powders containing 14.52 to 852 folpet, wettable
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powder/dust containing 5% to 8.82* folpet, impregnated
materials containing 0.0616% to 0.2288% folpet, flowable
concentrates containing 13% and 44% folpet, liquid
ready-to-use products containing 0.27% to 1.0% folpet,
pressurized liquids containing 0.5% to 0.75% folpet,
a pressurized dust containing 4.0% folpet and a 14.18%
water soluble pellet (tablet).
Types and methods of applications Foliar spraying and
dusting with hand, ground, and aerial equipment, dipping,
drenching, brushing, rolling, padding, spraying and
incorporat ing.
Usual carrier: Water, oil based paints and coatings, and
vinyl plastics.
3 * SCIENCE FINDINGS
Summary Science Statements Folpet is classified as a Group B2
oncogen {probable human carcinogen): it causes developmental
effects in laboratory animals? and it is a mutagen based on
studies with bacteria and mouse lymphoma cells, and based on
an i_n vivo Drosophila sex-linked recessive lethal assay.
Folpet caused a dose-related oncogenic effect, adenocarcinoma
of the duodenum, an uncommon tumor in mice. Technical
folpet is a Category II pesticide based on reversible
eye damage observed in studies with rabbits. Folpet
is very highly toxic to fish and invertebrates. Available
data are insuf f ic ient to assess the env ironmental fate
of folpet. Plant and animal metabolism data and residue
chemistry data are insufficient to support established
tolerances for residues of folpet in or on 30 raw agri-
cultural commodities.
Chemical characteristics:
Physical state:
Crystalline solid
White
Color:
Melting point
177 #C
Boiling point
150 #C at 0.02 mm Hg
Solubi1ity:
Insoluble in water, very low in
aliphatic hydrocarbon solvents:
low in aromatic polar, oxygenated
and halocarbon solvents.
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Vapor Dressure:
Stability:
No appreciable volatility at
ordinary temperatures.
Stable when stored in dry
conditions at ambient or lower
temperatures; not stable under
alkaline conditions.
Acute toxicological characteristics:
Acute oral toxicity (rat): Males - 43.8 g/kg
Females - 19.5 q/kg
Acute oral toxicity (mouse): 2440 mg/kg
Acute dermal toxicity
(rabbi t):
Acute inhalation toxicity
(rat and mouse):
Primary eye irritation
(rabbit):
Primary dermal irritation
(rabbit):
Dermal sensitization
(guinea pig):
> 5.0 g/kg
Inconclusive, inadequate to
determine the acute inhalation
toxic i ty.
Reversible corneal opacity,
prevented by immediately
washing the exposed eye
Folpet is a Toxicity Category II
pest icide.
Not a skin irritant to rabbits
Sensitizer
Chronic toxicological characteristics:
2-Gen. reproduction (rat): Parental NOEL = 34.5 mg/kg/day
Decreased weight gain in Fi offspring. Reproductive
NOEL in F2 matings was 800 ppm (40 mg/kg/day) based on
decreased body weight gain, decreased fertility of males
and a lowest effect level (LEL) of 3600 ppm (180 mg/kg/day)
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Rats - 90-Day feeding:
NOEL = 3000 ppm
LEL = 10,000 ppm
(Effects: decreased brain
we iqht, total blood protein
including albumin).
Mice - Oncogenici ty:
Folpet was a positive carcinogen
with a dose-related increased inci-
dence of adenocarcinomas in the
duodenum (a rare neoplasma in
CD-I mice in all dose groups
(1,000, 5,000 and 12,000 ppm; or
142.9, 714.3 and 1714.2 mg/kq/day ) .
Mice - Oncogenicity:
Folpet was a positive carcinogen
with a dose-related statistically
increased incidence of adeno-
carcinomas in the duodenum (a
rare neoplasma in B6C3F1 mice)
in all dose groups (1,000, 5,000
and 10,000 ppm,- or 142.9, 714.3
1428.6 mg/kq/day).
Rats - Spraque-Dawley rats
fed a diet of 200, 800, and
3200 ppm folpet did not cause
an oncogenic response.
Dogs - 60 and 120 mg/kg/day caused
non-significant reduction in
mean body weight gains and decreased
cholesterol, total protein, albumin
and globulin. Lowest observed effect
level (LOEL) was 60 mg/kq/day
and the NOEL was 10 mg/kg/day.
Developmental effect: Folpet was positive for
developmental effects in both
rabbits and rats.
Rabbits - Developmental
NOEL - 10 mg/kg
Developmental LEL = 20 mq/kg
(hydrocephalus, domed skull,
and irregularly shaped
fontanelles)
Subchromc feeding:
Chronic feeding/dosing
Oncogenicity:
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Rats - Developmental NOEL
= 60 mg/kg. Developmental LEL =
360 mg/kg (possible incomplete
ossification of one or both pubes
and/or eschia ).
Mutagenicity: E. coli, WP 2 her, reverse mutation,
"positive direct-acting mutaqen.
S» typhimurium, TA 1535, reverse
mutation, positive direct-acting
mutagen.
Mouse lymphoma cells - Positive
in L5178Y/TK mouse lymphoma
cells.
In vivo, Drosophila sex-linked
recessive assay. Positive for
sex-linked recessive lethals.
Dominant Lethal in mice -
negative for mutations.
Unscheduled DNA Synthesis -
Positive in the presence of
metabolic activation.
DNA Repair Assay - in B. subt i1 is
and E. coli, Positive for DNA
damage without metabolic activation.
Mitotic Recombination - Positive
for recombinants, with or
without metabolic activation
in S. cerevisiae D3.
Mouse Somatic Cell Mutation
Assay - negative for mutations
Significant pup mortality
at all dose levels: NOEL
for survival not established.
Metabolism: I_n vitro stabi 1 ity in human
blood - Half life of folpet
in human blood is about 1
minute, degrades rapidly to
Dhthalimide.
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Physiological and Biochemical Behavioral Characteristics:
Foliar absorption: There are no data to characterize
the absorption of folpet, its metabolites and
degradates by roots and shoots of plants.
Translocation: There are no data to characterize the
translocation of folpet, its metabolites and
degradates in plants.
Mechanism of Pesticidal Action: Folpet inhibits normal
cell division of a broad spectrum of microorganisms,
however the precise mechanism of this effect is
not understood.
Metabolism and Persistence in Plants and Animals: The
metabolism and accumulation of folpet, its
metabolites and degradates, are not understood.
Environmental Characteristics: Data gap.
Ecological Characteristics:
Hazards to Fish and Wildlife
Bluegill sunfish
Rainbow trout
Characterized as "highly tox;
and warmwater fish.
Daphnia magna:
Avian Toxicity:
Avian Reproduction:
96
hr
LC50
96
hr
LC50
c*
to
both
= 675 ppb
« 185 ppb
coldwater
48 hr LC50 « 0.60 ppm Very highly
toxic to aquatic invertebrates.
SIightly toxic:
LC50 * Bobwhite quail > 2510 mg/kg
LC50 * Mallard duck > 5000 ppm
Available data indicate that folpet
does not impair avian reproduction
Potential problems related to endangered species:
Based on data on similar pesticides, the Agency is
concerned about the effect of folpet exposure on
endangered birds, fish, and insect species. The Agency
will consult with the Office of Endangered Species
regarding the potential of folpet use to jeopardize
endangered species and may, pending the results of that
consultation, require labeling restrictions to ensure
protection of these species.
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Efficacy Review Results: Folpet product registrations with
EPA have been supported with efficacy data. Tolerant
strains of target plant pathogens have not been reported
Tolerance Assessments: List of Crops and Tolerances: The
following table lists the present status for tolerances
in parts per million (ppm) for residues of folpet:
Parts Per
Mill ion
of Folpet
Residue
Raw Agricultural Commodity
U.S.
Canada
Mexico
Codex
Apples
25
25
25
10
Avocados
25
25
25
-
Blackberries
25
25
-
-
Blueberries
25
25
_
25
Boysenberries
25
25
-
-
Celery
50
30
50
-
Cherries
50
25
-
15
Citrus Fruits
15
15
15
10
Crabapple
25
25
_
-
Cranberries
25
25
-
-
Cucumbers
15
15
15
2
Currants
25
25
-
_
Dewberries
25
25
-
-
Garlic
15
15
15
-
Gooseberries
25
25
-
-
Grapes
25
25
25
25
Huckleberries •
25
25
—
—
Leeks
50
25
-
-
Lettuce
50
25
50
15
Loganberries
25
25
-
-
Melons
15
15
15
2
Onions (dry bulb)
15
25
15
2
Onions {green)
50
25
50
2
Pumpkins
15
15
—
Raspberries
25
25
—
15
Shallots
50
—
—
Squash (Summer)
15
15
15
•
Squash (Winter)
15
15
15
-
Strawberries
25
25
25
20
Tomatoes
25
25
3
5
Results of tolerance assessment: Using the NOEL of
10 mg/kg/day from the chronic dog study and a 100 fold
uncertainty factor to account for data gaps and the
extrapolation of animal data to humans, the Provisional
Acceptable Daily Intake (PADI) is 0.10 mg/kg/day. The
Maximum Permissible Intake (MPI) for a 60 kg person is
therefore 6.0 mg/day. Using this value existing tolerances
utilize 123 % percent of the PADI based on nononcogenic
effects. This calculation is conservative and is
likely to decrease when based on actual residue data.
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SUMMARY OF REGULATORY POSITIONS
o Folpet is a carcinogen in two strains of mice; however
folpet was not carcinogenic in rats in a chronic feeding
study. A second rat oncogenicity study is currently
under review. Based on the oncogenicity data from
studies with two strains of mice, mutagenicity data
and structural similarity to captan, which is also an
oncogen; the Agency has classified folpet as a B2 or
probable human carcinogen.
Based on a Oj* of 3.49 x 10"^ and estimated exposure
levels from residues at tolerance levels (obtained
under the "Food Factor" system), and assuming 100% of
all foods have tolerance level residues, the cancer
risk from dietary exposure to folpet is calculated as
3.1 x 10~*. Due to the lack of folpet residue data,
dietary risk estimates are based on 100% tolerance
levels. When residue data required by the Registration
Standard are received and reviewed, these risk estimates
may be lower. Oncogenic risks from dermal exposure are
not considered likely because folpet's half-life in blood
is only 1 minute.
o Folpet causes developmental effects (toxicity) in rabbits
and may be a potential human teratogenic pesticide.
A teratology study with folpet in rabbits indicated de-
velopmental toxicity in the form of hydrocephalus and
altered.development of skull bones.
The Agency calculated a dietary MOS of 90 (for females
aged 13 and older) based on an acute single-day exposure
to folpet as a result of consumption of food containing
tolerance level residues, and the NOEL of 10 mg/kg/day
for maternal and developmental toxicity. However, when
the distribution of food consumption is considered,
exposures for the upper 15 and 5 percent of the
subpopulation yield MOS' s of 50 and 33, respectively.
When residue data required by the Registration Standard
are received and reviewed, dietary MOS's are likely to
be significantly higher.
The Agency also calculated dermal MOS's for mixers/
loaders/applicators on agricultural and home/garden
sites. Based on the NOEL of 10 mg/kg/day for maternal
and developmental toxicity, acute dermal exposures, and
an estimated dermal absorption of 0.4%, MOS's for
agricultural and home/garden sites are 340 and 47,000,
respect ively.
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o Folpet is a mutagen in Salmonella, E. coli, mouse
L5178Y/TK lymphoma cells and in the i_n vivo Drosophila
sex-linked recessive lethal assay with metabolic
activation. Folpet is positive in B. subtilis and
E. coli DNA repair assays and in yeast for mitotic
recombination. An in vitro study of chromosome
aberration must be submitted.
o No new food uses will be registered until additional
residue chemistry and chronic toxicology data are
submitted and found to be acceptable for assessing
the proposed use.
o Until product-specific data indicate otherwise, all
folpet products must bear labeling with the signal
word "WARNING" and the appropriate precautions for
potential risk of hazard from eye exposure. Technical
folpet caused corneal opacity that was present up to
7 days in a rabbit eye study.
o An interim 24 hour reentry interval is being imposed
for agricultural crop uses of folpet until reentry data
have been submitted, evaluated and found to support a
different reentry interval. This reentry requirement
reflects concern for the potential risk that may be
associated with expected human exposure that could
result from repeated entry into treated sites.
o The Agency is requiring the following studies to support
all existing tolerances in agricultural commodities:
plant and animal metabolism, storage stability, and
analytical methodology. Metabolism of folpet in plants
and animals has not been adequately defined. Plant
and animal metabolites have not been quantified. No
storage stability data are available for residues in
plant and animal tissues.
o The Agency is requiring additional residue chemistry
data for all established tolerances for folpet. Processing
studies are required for tomato pomace, grape pomace,
citrus fruit pulp and apple pomace. If animal metabolism
data demostrate that detectable residues of concern may
occur in animals from registered uses, then data quant-
itating the magnitude of the residue in animal tissues
will be required to quantify human dietary exposure and
for regulating the use of folpet to protect the public.
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o While data gaps are being filled, currently registered
folpet products may be sold, distributed, formulated
and used in the United States. Registrants must provide
or agree to develop additional data, as specified in
the Data Appendix of the Folpet Registration Standard.
o The Agency is imposing precautionary labeling for all
folpet products. The precautionary labeling requirements
will provide information that will increase the awareness
of users and promote proper use of folpet products.
o The Agency is requiring the use of certain protective
clothing (long sleeve shirt and pants) and equipment
(goggles or face shield) for all folpet products.
The protective clothing and equipment requirements
will reduce exposure to folpet products and decrease
the risks associated with use of these products.
The Agency is requiring labeling of all products to
reflect the high toxicity of folpet to fish. Studies
with ra inbow trout and blueg ill sunfish indicate that
folpet is highly toxic to fish. The required labeling
will warn users of the hazard of discharging folpet into
lakes, streams, ponds, estuaries, oceans or public
water.
o The Agency is requiring the use of a dust mask or
similar protection against particle inhalation
during (nixing and loading of agricultural use and
commercial ornamental plant use products and when
reentering these treated sites within 24-hours •
after application to reduce the potential risk of
hazards associated with the use of folpet products.
o The Agency is requiring the labels of industrial products
to clearly state on the front panel "For Industrial
Use Only", in order to avoid use of these products in
non-industrial settings where workplace exposure is not
well regulated.
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Required Labeling:
Required labeling reflects use restrictions needed to
reduce exposure to folpet. Submission of modified
labeling addressing the following areas will be
required within 90 days from the receipt of the
Standard:
1. Ingredient Statements
2. Precautionary Statements
3. Environmental Hazards Statements
4. Use of Water from Treated Cranberry Bogs
5. Applicator Restriction for Greenhouse Uses
6. Use Precaution Statements
7. Reentry Interval
8. Signal Word Revision
SUMMARY OF MAJOR DATA GAPS
Product Chemistry
Tox icology:
Acute Testing
Subchronic Testing
Chronic Testing
Special Testing
Environmental Fate:
Photodegradation
Metabolism Studies - Laboratory
Mobility Studies
Dissipation Studies Field
Accumulation Studies
Subdivision K, Reentry Studies
Ecological Effects:
Aquatic Organism Testing
Nontarget Insect Testing - Aquatic Insects
Residue Chemistry:
Metabolism in plants and livestock
Residue analytical methods, for plant and animal residues
Storage stablity data for raw agricultural commodities
Magnitude of residues in food commodities
6. CONTACT PERSON AT EPA
Richard F. Mountfort
Product Manager (23)
Fungicide-Herbicide Branch
Registration Division (TS-767C)
Office of Pesticide Programs
Washington, DC 20460
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DISCLAIMER: The information presented in this Pesticide Fact
Sheet is for informational purposes only and may not be used
to fulfill data requirements for pesticide registration and
rereg istration.
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