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metalaxyl (Apron, Ridomil, Subdue) Chemical Fact Sheet 9/88

EPA Pesticide Fact Sheet
Name of Chemical: METALAXYL
Reason for Issuance: REGISTRATION STANDARD
Date Issued: September 1988
Fact Sheet Number: 155.1


                         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.

                      2. 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 following 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 lb ai/acre for agricultural
  crops, from 0.25 to 1.12 oz ai/100 lb seed for agricultural seed
  treated, from 0.33 to 1.35 lb/ai/acre for ornamental turf, and from
  0.90 to 7.20 lb/ai acre for ornamental trees and plants.  Multiple
  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.

- 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 (FLC), as well as a 90%
  technical product.  The granular, wettable powder and emulsifiable
  concentrate formulations are also formulated as multiple active
  ingredient products.  In addition, metalaxyl is sold in a combination
  with mancozeb, chlorothalonil, pentachloronitrobenzene, captan, and
  triadimefon.


                           3. SCIENCE FINDINGS

Summary of Science Statements

    Studies indicate that metalaxyl is not oncogenic or teratogenic.  
Studies also indicate that metalaxyl does not cause increased 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 more 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 degrees C; slight exothermic reaction up
  to 450 degrees C
- Melting Point:  71 - 72 degrees C
- Vapor Pressure:  2.2 x 10 minus 6 Torr at 20 degrees C
- Density:  1.21 g/cm3 at 20 degrees C


Toxicology Profile

Acute Toxicity:
- Acute Oral Toxicity               Toxicity Category III
                                    (moderate acute oral)
        (Rat): 669 mg/kg
       (Mice): 788 mg/kg
    (Hamster): 7120 mg/kg

- Acute Dermal Toxicity             Toxicity Category III
                                    (moderate acute dermal)
     (Rabbit): >6000 mg/kg
        (Rat): >3170 mg/kg

- Primary Eye Irritation            Toxicity Category II
                                    (moderate eye irritant)
      (Rabbit): No effect

- Primary Skin Sensitization        Toxicity Category IV
                                    (slight skin irritant)
      (Rabbit): slight effect

- Primary Dermal Sensitization      Toxicity Category IV
                                    (not a sensitizer)
  (Guinea Pig): No effect


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.

Subchronic Inhalation Toxicity

     No effects were observed in rats exposed to smoke from cigarettes 
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 increase 
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 vitro with or without metabolic activation.  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 fibroblasts 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 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 Tl/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 to 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 magna, having LC50s of 28 and 
12.5 ppm with technical and formulated pesticides, respectively.

     Chronic toxicity assays on aquatic species and fish accumulation 
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 concentrations 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 
environmental 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.

     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 lOO-fold 
safety factor.  Therefore, the ADI is calculated to be 0.063 mg/kg/day.


                        4. 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 requirement, 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 fulfill 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.

     The following Agency positions are based on the substantially 
complete data base currently available for metalaxyl:

- 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.

- The Agency is requesting rotational crop studies and, in order to meet
  the statutory standard for continued registration, product labeling
  must bear a 12-month rotational crop restriction as an interim
  measure.
- Additional ground water monitoring and laboratory leaching studies are
  being required.  The Agency has determined that data submitted on
  ground water monitoring are inadequate.
- 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.
- 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.
- While data gaps are being filled currently registered manufacturing-
  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.


                          5. 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 specifications of the standard.

     In addition to the above, in order to remain in compliance with 
FIFRA, the Agency is requiring:

- Revised environmental hazard labeling
- 12-month rotational crop statement

                      6. SUMMARY OF MAJOR DATA GAPS

40CFR Section 158.120 - Product Chemistry
- Description of Beginning Materials and Manufacturing Process
- Discussion of the Formation of Impurities
- Preliminary Analysis
- Certification of Ingredient Limits
- Analytical Methods to Verify Certified Limits

40CFR Section158.125 - Residue Chemistry
- Nature of the Residue in Livestock
- Residue Analytical Method
- Storage Stability Data
- Magnitude of the Residue (potatoes; sugar beet roots; soy beans;
  cereal grains; forage, fodder and straw of cereal grains; cottonseed;
  hops; peanuts; pineapples; sunflower seeds

40CFR Section158.130 - Environmental Fate
- Photodegradation Studies in Water
- Terrestrial Field Dissipation Studies
- Confined Accumulation Studies on Rotational Crops
- Ground Water Monitoring and Laboratory Leaching Studies

40CFR Section158.135 - Toxicology
- Acute Inhalation Toxicity
- Metabolism Studies

40CFR Section158.145 - Ecological Effects
- Acute LC50 Estuarine/Marine Organisms (shrimp and oyster)

                     7. 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.