Unrt«d St««t Offio* of P«tkad« and Toxic Subttmnca*
Environmental Protection O«Je» of Pwtfaide Programs (TS-766CI
Agency Wuhington, DC 20460
- 54Q/FS-88-116
x>EPA Pesticide
Fact Sheet
Name of Chemical: METALAXYL
Reason for Issuance: REGISTRATION STANDARD
Date Issued: September 1988
Fact Sheet Number: 155.1
DESCRIPTION OF CHEMICAL
Generic Name: N-(2,6-Dimethylphenyl)-N-(Methoxyacetyl) Alanine
Methyl ester.
Common Name: Metalaxyl
Trade Names: Ridomil, Subdue, Apron, Proturf.
EPA Shaughnessy Code: 113501
Chemical Abstracts Service (CAS) Number: 57837-19-1
Year of Initial Registration: 1979
Date of Initial Registration Standard: December 1981
Pesticide Type: Systemic Fungicide
U.S. and Foreign Producers: Ciba-Geigy, O.M. Scott and Son, Co.~
Wilbur-Ellis, and Gustafson.
USE PATTERNS AND FORMULATIONS
Application Sites: Metalaxyl is registered for use on over 100
agricultural crops (including more than 30
seed treatment uses). Metalaxyl is also
registered for ornamental and turf uses.
Major Uses: More than 90% of the total poundage of metalaxyl
used domestically is used in the foll'wing ten
crops/sites: tobacco, turf, potatoes, ornamentals,
soybean (seed treatment), onions, citrus, cucurbits,
tomatoes, and cotton.
Application Rates: Metalaxyl is applied to soil or foliage.
Application rates range from 0.135 to 8.0 Ib
ai/acre for agricultural crops, from 0.25 to
1.12 oz ai/100 Ib seed for agricultural seed
treated, from 0.33 to 1.35 Ib/ai/acre for
ornamental turf, and from 0.90 to 7.20 Ib/ai
acre for ornamental trees and plants. Multi-
ple applications (varying with use) are
approved.
Method of Application: Foliar application; soil application by
incorporation, surface spraying (broadcast
or band), drenching, sprinkler or drip
irrigation; soil mixing; trunk spraying.
For agricultural seed treatment metalaxyl
is applied with conventional slurry or
mist seed treating equipment.
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Types Registered: Single active ingredient products containing
metalaxyl are formulated as a granular (G),
pelleted/tableted (P/T) (in fertilizer spikes),
wettable powder (WP), emulsifiable concentrate
(EC), and flowable liquid concentrate (F1C),
as well as a 90% technical product. The
granular, wettable powder and emuisifiable
concentrate formulations are also formulated
as multiple active ingredient products. In
addition, metalaxyl is sold in a combination
with mancozeb, chlorothalonil, pentachloroni-
trobenzene, captan, and triadimefon.
SCIENCE FINDINGS
Summary of Science Statements
Studies indicate that metalaxyl is not oncogenic or terato-
genic. Studies also indicate that metalaxyl does not cause in-
creased incidence of tumors or cause embryotoxic, fetotoxic or
teratogenic effects. Metalaxyl also does not cause reproductive
effects nor did it induce gene mutations in bacteria, yeast, and
mouse lymphoma cells and does not cause chromosomal aberrations
in tests with yeast, hamsters, and mice.
Metalaxyl was found to be practically nontoxic acutely and
subacutely to avian species and to present no adverse effects to
avian and mammalian populations. Metalaxyl poses no hazard to
endangered terrestrial or aquatic animal species or to plant
species.
Physical/Chemical Characteristics
Technical
Physical State: Crystalline
Color: White to beige
Odor: Odorless
Solubility: Water - 00.7%
Benzene - 55.0%
Hexane - 00.9%
Methanol - 65.0%
Isopropanol - 27.0%
Methylene Chloride - 75.0%
Stability: Stable up to 300°C? slight exothermic reaction
up to 450°C
Melting Point: 71 - 72°C
Vapor Pressure: 2.2 x 10"6 Torr at 20°C
Density: 1.21 g/cm3 at 20°C
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Toxicology Profile
Acute Toxicity:
o Acute Oral Toxicity
(Rat): 669 mg/kg
(Mice) : 788 mg/kg
(Hamster): 7120 mg/kg
o Acute Dermal Toxicity
(Rabbit): >6000 mg/kg
(Rat): >3170 mg/kg
o Primary Eye Irritation
(Rabbit): No effect
o Prim?.y Skin Sensitization
(Rabbit): slight effect
o Primary Dermal Sensitization
(Guinea Pig): No effect
Toxicity Categoty III
(moderate acute oral)
Toxicity Category III
(moderate acute dermal)
Toxicity Category II
(moderate eye irritant)
Toxicity Category IV
(slight skin irritant)
Toxicity Category IV
(not a sensitizer)
Subchronic Feeding Studies
Rodent Feeding Studies
In 90-day feeding studies in rats and mice the liver was
the target organ for metalaxyl toxicity.
In female rats a NOEL of 250 ppm (12.5 mg/kg/day) and a
lowest-observed effect level (LOEL) of 1250 ppm (6.25 mg/
kg/day) were observed.
In male mice, a NOEL of <1250 ppm (187.5 mg/kg/day), and
a LOEL of 1250 ppm (6.25 mg/kg/day) were observed.
Non-Rodent Feeding Study
A 90-day feeding study in dogs showed no toxicity up to
1250 ppm in their diet (31.25 mg/kg/day; highest dose tested)
Subchronic Dermal Toxicity
Metalaxyl had no effect on rabbits when applied to intact
or abraded skin for 21 days at doses up to 1000 mg/kg/day.
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Subchronic Inhalation Toxicity
No effects were observed in rats exposed to smoke from ciga-
rettes containing metalaxyl. The NOEL in this study is
greater than 13,000 ppm (highest dose tested).
Chronic Toxicity
Metalaxyl had minimal effects in chronic feeding studies
with rats and dogs. The NOEL established in rats was 250 ppm
(12.5 mg/kg/day), and the LOEL was 1250 ppm (62.5 mg/kg/day).
In dogs the LOEL was established at 1000 pppm (250 mg/kg/day),
and the NOEL was 250 ppm (62.5 mg/kg/day).
Oncogenicity
The long-term feeding studies in rats and mice showed no in-
crease in the incidence of tumors as a result of metalaxyl.
Teratology
In pregnant rats, NOEL's for maternal and developmental toxicity
were established at 50 mg/kg/day,. and LOEL's for both types of
toxicity were established at 250 mg/kg/day.
Metalaxyl caused no embryotoxic, fetotoxic, or teratogenic
effects in treated rabbits. The NOEL for maternal toxicity
was 300 to 500 mg/kg/day, and the developmental toxicity was
greater than 300 mg/kg/day (highest dose tested in the main
study).
Reproduction
In a multi-generation reproduction study with rats, no dose-
related effects were observed throughout the three generations
with respect to toxicity or reproductive parameters. The NOEL
for reproductive and developmental toxicity is greater than
1250 ppm (12.5 mg/kg/day).
Mutagenicity
Metalaxyl did not induce gene mutations in bacteria, yeast and
mouse lymphoma cells in vit;ro with or without metabolic activa-
tion. The fungicide also caused no structural or numerical
chromosomal aberrations as indicated by yeast, hamsters or mice.
No DNA damage was observed in bacteria and no unscheduled DNA
synthesis was noted in rat primary hepatocytes or human fibro-
blasts in vitro as the result of exposure to metalaxyl. These
results suggest that metalaxyl is not genotoxic.
Metabolism
Metabolism studies in rats showed that single oral doses of
metalaxyl are readily absorbed. Approximately 62 to 65% of
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the administered radioactivity is recovered in the urine and
feces within 24 hours after dosing, and 96% is recovered during
the 48 hours after dosing. The major route of excretion in
males was the feces after oral and dermal doses, while that
for females was the urine for both routes of administration.
The distribution of radiolabel observed six days after dosing
did not indicate that metalaxyl residues were-stored in tissues
following a single dose.
Dermal, Absorption
The absorption T]_/2 values for metalaxyl in tetrahydrofuran
(THF) ranged from 12 hours (in male rats receiving a 1 mg/kg
dermal dose) to 20 hours (male rats given a dermal dose of 10
mg/kg). The value for females was 13 hours for both doses.
ECOLOGICAL CHARACTERISTICS
Metalaxyl has been found to be practically nontoxic acutely
and subacutely co avian species and to present no adverse effects
to avian and mammalian populations. There is no indication of
detrimental effects on aquatic plant species and the technical
pesticide is practically nontoxic to freshwater aquatic animal
species. The most sensitive organism appears to be Daphnia maj
having LCsQS of 28 and 12.5 ppm with technical and formulated
pesticides, respectively.
Chronic toxicity assays on aquatic species and fish accumula-
tion testing do not suggest that metalaxyl presents a long-term
risk in the aquatic environment. It appears very unlikely that
metalaxyl could accumulate in water or sediments to concentra-
tions that would pose a risk to aquatic populations.
Although use of metalaxyl presents little risk to freshwater
populations it cannot be assumed that the same holds true for
marine/estuarine species which may be exposed in connection with
several of the registered uses. The Agency is requesting data
on marine/estuarine species such as oysters and shrimp.
Endangered Species
The registered uses of technical metalaxyl and a widely used
formulation, Ridomil® 27.9% ai EC (which appears to be more
toxic to aquatic species than the technical), do not present a
hazard to endangered terrestrial or aquatic animal species or
plant species.
Environmental Fate
Metalaxyl was found to be moderately stable under normal en-
vironmental conditions. Fish accumulation was found not to exceed
7X when fish were exposed to metalaxyl at 1 ppm in water, and the
residues were found to accumulate in the nonedible portions over
the edible portions. Residues declined rapidly during depuration.
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The rotational crop data demonstrated the need for a 12-
month rotational crop restriction because some crops will take
up metalaxyl residues of concern when planted 12 months or more
after treatment of a prior crop. Confined studies are needed to
identify all residues of concern plus field tests are necessary
to determine the need for additional tolerances.
In addition, ground water monitoring studies were required
early in the registration process for metalaxyl. While subsequent
submissions were judged to be sufficient at the time, these studies
are no longer adequate and further data are required.
TOLERANCE REASSESSMENT
Tolerances have been established for residues of metalaxyl in
numerous varieties of raw agricultural commodities (40 CFR 180.408)
and also in food and feed commodities (21 CFR 193.277 and 21 CFR
561.273, respectively). In addition, tolerances have also been
established for indirect or inadvertant residues of metalaxyl.
The acceptable daily intake (ADI) is based on the six month
feeding study in dogs (NOEL of 6.3 mg/kg/of body weight/day) and a
100-fold safety factor. Therefore, the ADI is calculated to be
0.063 mg/kg/day.
REGULATORY POSITION
This review of metalaxyl is the second intensive evaluation
of the compound. A Registration Standard was developed in 1981
in conjunction with its initial registration. At that time
metalaxyl was registered for non-food uses on tobacco, conifers,
ornamentals, and turf and was not registered for any food or feed
uses. The only additional data needed to support the registered
non-food uses in 1981 were groundwater monitoring, subchronic
inhalation toxicity, phytotoxicity and storage stability. Since
the issuance of the 1981 Registration Standard, registrations
have been approved for use on over 100 agricultural crops. These
registrations were granted based on adequate supporting data
(including residue, acute and chronic data) at the time of
application for registration.
In 1984, the Agency promulgated general rules at 40 CFR Part
158, which set forth the range of data which must be submitted to
EPA to support the registration or reregistration of each pesticide
under FIFRA. Based on these revised and expanded data requirements,
the toxicity data base for metalaxyl is still virtually complete
and in most cases is adequate to support continued registration
of existing uses. However, some data determined to support
registration in the past only partially fullfill current data
requirements. As a result, several studies primarily in the
disciplines of residue chemistry and environmental fate, must be
conducted and submitted to the Agency. In addition, several new
data requirements are being imposed to characterize potential
adverse effects to marine/estuarine species.
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The following Agency positions are based on the substantially
complete data base currently available for metalaxyl:
o Metalaxyl is not being placed in Special Review at this time
because none of the risk criteria listed in 40 CFR 154.7
prescribing a Special Review have been met.
o The Agency is requesting rotational crop studies and, in
order to meet the statutory standard for continued registra-
tion, product labeling must bear a 12-month rotational crop
restriction as an interim measure.
o Additional ground water monitoring and laboratory leaching
studies are being required. The Agency has determined that
data submitted on ground water monitoring are inadequate.
o Ground water monitoring data will be reviewed when submitted
in order for the Agency to determine whether further regulatory
action is warranted based on this concern.
o The Agency is requiring further data on potential adverse
effects to marine/estuarine species to determine if currently
registered uses will result in exposure levels of concern to
these populations.
o While data gaps are being filled, currently registered manu-
facturing-use products (MP's) and end use products (EP's)
containing metalaxyl as the sole active ingredient may be
sold, distributed, formulated, and used, subject to the
terms and conditions specified in this Standard. However,
registrants must provide or agree to develop additional data,
as specified in the Data Appendices, in order to maintain
existing registrations.
LABELING REQUIREMENTS
All metalaxyl products must bear appropriate labeling as
specified in 40 CFR 156.10. Appendix II of the Standard contains
information on label requirements.
In order to remain in compliance with FIFRA, no pesticide
product containing metalaxyl may be released for shipment by
the registrant after October 30, 1989, unless the product bears
amended labeling which complies with the specifications in the
Standard.
In order to remain in compliance with FIFRA, no pesticide
product containing metalaxyl may be distributed, sold, offered
for sale, held for sale, shipped, delivered for shipment, or
received and (having been so received) delivered or offered to
be delivered by any person after October 30, 1990, unless the
product bears amended labeling which complies with the speci-
fications of the standard.
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In addition to the above, in order to remain in compliance
with FIFRA, the Agency is requiring:
o Revised environmental hazard labeling
o 12-month rotational crop statement
SUMMARY OF MAJOR DATA GAPS
40CFRS158.120 - Product Chemistry
o Description of Beginning Materials and
Manufacturing Process
o Discussion of the Formation of Impurities
o Preliminary Analysis
o Certification of Ingredient Limits
o Analytical Methods to Verify Certified Limits
40CFRS158.125 - Residue Chemistry
o Nature of the Residue in Livestock
o Residue Analytical Method
o Storage Stability Data
o Magnitude of the Residue (potatoes; sugar beet roots;
soy beans; cereal grains; forage, fodder and straw of
cereal grains; cottonseed; hops; peanuts; pineapples;
sunflower seed)
40CFRS158.130 - Environmental Fate
o Photodegradation Studies in Water
o Terrestrial Field Dissipation Studies
o Confined Accumulation Studies on Rotational Crops
o Ground Water Monitoring and Laboratory Leaching Studies
40CFRS158.135 - Toxicology
o Acute Inhalation Toxicity
o Metabolism Studies
40CFRS158.145 - Ecological Effects
o Acute LCso Estuarine/Marine Organisms (shrimp and oyster)
CONTACT PERSON AT EPA; Lois A. Rossi
Product Manager (21)
Fungicide-Herbicide Branch
Registration Division (TS-767C)
Office of Pesticide Programs, EPA
Washington, D.C. 20460
Telephone: (703) 557-1900
DISCLAIMER: The information in this Pesticide Fact Sheet is a
summary only and is not to be used to satisfy data requirements
for pesticide registration and reregistration. The complete
Registration Standard for the pesticide may be obtained from the
contact person listed above. A
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