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Cymoxanil

Publication Date: 10/97

TRADE OR OTHER NAMES

Some trade names for products containing cymoxanil include Curzate, Sygan, and Syphal. In addition, there are many premix formulations with various trade names (3, 4).

REGULATORY STATUS

Cymoxanil is a fungicide used on crops including potatoes, tomatoes, and grapes. Cymoxanil is not registered for non-crop use in any country. In December 1996, DuPont submitted an application for Section 3 Registration in the U.S. for cymoxanil and a tolerance on potatoes (6). The product Curzate M-8, a formulation of 8% cymoxanil and 64% mancozeb, is currently being used as a Section 18 emergency exemption material to control late blight on potatoes in the U.S. (2, 6).

INTRODUCTION

Cymoxanil was first introduced in 1977. It is an acetimide compound used as both a curative and preventative foliar fungicide. In Europe it is being sold for use on grapes, potatoes, tomatoes, hops, sugarbeets and other vegetable crops. Cymoxanil is currently not registered in the U.S. (3, 4).

Cymoxanil's mode of action is as a local systemic. It penetrates rapidly and when inside the plant, it cannot be washed off by rain. It controls diseases during the incubation period and prevents the appearance of damage on the crop. The fungicide is primarily active on fungi belonging to the Peronosporales order: Phytophthora, Plasmopara, and Peronospora (2).

TOXICOLOGICAL EFFECTS

ACUTE TOXICITY

Technical cymoxanil has low acute toxicity. The acute oral LD50 is 960 mg/kg in rats. The acute dermal LD50 is >2,000 mg/kg in rabbits. The 4-hour rat inhalation LC50 is >5.06 mg/L. Minimal transient irritation of the skin and eyes was observed in rabbits. Cymoxanil did not cause skin sensitization in guinea pigs. Cymoxanil should be classified as Toxicity Category III for oral and dermal toxicity and Toxicity Category IV for inhalation toxicity and skin and eye irritation potential (1).

CHRONIC TOXICITY

A 12-month chronic feeding study was conducted in male dogs at dietary levels of 0, 50, 100 and 200 ppm and in female dogs at 0, 25, 50 and 100 ppm. The no- observable-effect-levels (NOEL) for chronic toxicity were 100 ppm in male dogs (3.0 mg/kg/day) and 50 ppm in female dogs (1.6 mg/kg/day), based on body weight and food consumption effects in both sexes and decreased red cell parameters in males. No gross or histopathological effects were observed (1).

A 90-day feeding study was conducted in rats at dietary levels of 0, 100, 750, 1500 or 3000 ppm. Body weight effects, increased food consumption, decreased food efficiency, increased mean relative organ weights, and testicular (elongate spermatid degeneration) and epididymal histo-pathologic effects were observed at 1500 and 3000 ppm. The NOEL was 750 ppm (47.6 mg/kg/day males; 59.9 mg/kg/day females) (1).

The potential neurotoxicity of cymoxanil was evaluated in rats as part of the 90-day feeding study at dietary levels of 0, 100, 750, 1,500 or 3,000 ppm. The NOEL for neurotoxicity was the highest dietary level tested, 3000 ppm for male (224 mg/kg/day) and female (333 mg/kg/day) rats. Cymoxanil is considered not to be a neurotoxicant (1).

A 90-day feeding study was conducted in mice at dietary levels of 0, 50, 500 and 1,750, 3,500 or 7,000 ppm. The highest dietary level was terminated by the third week of the study due to severe toxicity. The NOEL was established at 50 ppm for female mice (11.3 mg/kg/day) based on body weight effects at 500 ppm; no NOEL was established for male mice due to body weight effects and increased liver weights at all dietary levels. Liver weight increases were observed in female mice at 1,750 and 3,500 ppm. No histopathologic alterations were found in male or female mice at levels up to 3,500 ppm (1).

A 90-day feeding study was conducted in dogs at dietary levels of 0, 100, 200 or 250/500 ppm (250 ppm for weeks 1 and 2; 500 ppm for the remainder of the study). No NOEL was established for female dogs due to lower body weight gain, food consumption and food efficiency at all dietary levels. The NOEL in males was 100 ppm (3 mg/kg/day) based on decreased body weight gain (1).

A 28-day repeated dose dermal study was conducted with rats at dosages of 50, 500 or 1,000 mg/kg with daily 6-hour exposures. No toxicologically significant effects were observed in any treatment group. The NOEL is considered to be 1,000 mg/kg/day (1).

Reproductive Effects

A two-generation reproduction study in rats fed diets containing 0, 100, 500, or 1,500 ppm resulted in no-observable-adverse-effect-levels (NOAEL) of 100 ppm for both parental rats (equivalent to 6.50 and 7.85 mg/kg/day for P1 males and females, respectively) and offspring (equivalent to 7.39 and 8.85 mg/kg/day for F1 males and females, respectively). The NOAELs were based on alterations in body weight parameters, food consumption and food efficiency in the parents at 500 ppm, and decreases in pup weights and viability in the offspring at 500 ppm. Based on these results, cymoxanil is not considered a reproductive toxin (1).

Teratogenic Effects

A developmental toxicity study was conducted with cymoxanil in rats at 0, 10, 25, 75, or 150 mg/kg/day on days 7-16 of gestation. The NOELs for maternal and developmental effects were considered to be 10 mg/kg/day for both maternal toxicity (based on reduced weight gain and food consumption at 25 ppm and above) and developmental toxicity (based on effects that included fetal variations in ossification at 25 ppm and above) (1).

A developmental toxicity study was conducted in rabbits at dose levels of 0, 4, 8 and 16 mg/kg/day. Cymoxanil was not considered maternally or fetally toxic at any dose level. A second rabbit study at 0, 8, 16 and 32 mg/kg/day demonstrated toxicity to the doe at 16 mg/kg/day. Changes in axial skeleton of the fetus were observed at all dose levels, but without direct relation to dosage. A third rabbit study was conducted at 0, 1, 4, 8, and 32 mg/kg/day.

Maternal toxicity was observed at 8 mg/kg/day. Although skeletal variations were seen in some fetal groups, they were not considered related to cymoxanil since they were not statistically increased or dose related. A reevaluation of the combined results of all three rabbit studies using current statistical methods demonstrated NOAELs of 8 mg/kg/day for the doe and 4 mg/kg/day for the fetus (1).

In the absence of significant differences between maternal and fetal effect levels (revealed in both the rat and combined rabbit studies), cymoxanil was not considered a developmental toxin (1).

Mutagenic Effects

A battery of in vitro and in vivo tests were conducted to determine the genotoxic potential of cymoxanil. Cymoxanil was negative for mutagenicity in in vitro bacterial (Salmonella typhimurium or Escherichia coli tester strains) and mammalian cell assays (Chinese hamster ovary (CHO) cells) and is therefore considered not mutagenic. Cymoxanil was positive for induction of chromosome aberrations in in vitro assays (CHO cells and human Iymphocytes), but negative in two species of in vivo assays (rat clastogenicity and mouse micronucleus). The weight-of evidence indicates that cymoxanil is not clastogenic. Cymoxanil was negative for induction of unscheduled DNA synthesis (UDS) in one in vitro assay but positive in another; however, it was negative for induction of UDS in both hepatocytes and spermatocytes when evaluated in in vivo assays. Therefore, the weight-of-evidence indicates that cymoxanil does not produce DNA damage. In summary, cymoxanil is not considered genotoxic, nor does it have the potential to induce heritable effects (1).

Carcinogenic Effects

An 18-month oncogenicity study was conducted in mice at dietary levels of 0, 30, 300, 1,500 or 3,000 ppm. The NOEL was 30 ppm (4.19 and 5.83 mg/kg/day for males and females, respectively) based on histopathological effects in testis and liver for males and the mucosal lining of the gastrointestinal tract for females at 300 ppm. Cymoxanil is not considered oncogenic (1).

A two-year combined chronic toxicity/oncogenicity study was conducted in rats at dietary levels of 0, 50, 100, 700 or 2,000 ppm. The NOEL for chronic effects was 100 ppm (4.08 and 5.36 mg/kg/day for male and female rats, respectively), based on decreased mean body weights, mean body weight gains, food consumption, and food efficiency; and gross and/or histopathological alterations of the retina, Iymph nodes, lung, intestine, testes, and sciatic nerve at 700 ppm. Cymoxanil is not considered oncogenic (1).

No cancer risks have been identified in the available cymoxanil data evaluation records (2).

Organ Toxicity

No evidence of endocrine effects were observed upon comprehensive evaluation of data from the standard battery of EPA required toxicology studies. These animal studies were conducted at exposure levels that far exceed those likely to be experienced by a human. Thus, adverse endocrine effects are not expected to occur in humans (general population or sub-groups, including nursing infants and children) (1).

Fate in Animals and Humans

An oral dose of radiolabelled cymoxanil was extensively metabolized and rapidly eliminated in the rat. More than 85% of the dosed radioactivity is eliminated in the excrete, mostly in the urine, within 48 hours. After 96 hours, less than 1% of the administered dose remained in the tissues. The major excretory products were polar metabolites such as 2-cyano-2-methoxyimino acetic acid, glycine and other amino acid conjugates. These metabolites are rapidly metabolized to other natural products. A minor metabolite, 1-ethyl-5,6-di-2,4(1H,3H)pyridinedione, was also identified and is postulated as an intermediate metabolite (1).

Cymoxanil degrades rapidly and extensively in ruminants to natural products, including fatty acids, glycerol, glycine and other amino acids, lactose, and acid hydrolyzable formyl and acetyl groups (1).

ECOLOGICAL EFFECTS

Effects on Birds

Cymoxanil is not acutely toxic to birds. The acute LD50 for both the bobwhite quail and the mallard duck are greater than 2,250 mg/kg. The dietary LC50 for the same two species was greater than 5,620 ppm. In an avian reproduction study with bobwhites, cymoxanil had no effect at 300 ppm; decreases in weight and hatchling viability were observed at 1,200 ppm. In a reproduction study with mallards, the no observable effect concentration (NOEC) was 100 ppm. At 300 ppm in this study, egg production and hatchling viability were reduced (5, 6).

Effects on Aquatic Organisms

Cymoxanil is slightly toxic to fish and other estuarine and marine organisms on an acute basis. The 96-hour LC50 for various species (in mg/L) were: 91 for common carp; 61 for rainbow trout; 29 for bluegill sunfish; >47.5 for sheepshead minnow; and >44.4 for mysid shrimp. The NOEC for various species (in mg/L) were: 47 for common carp; 28 for rainbow trout; 17 for bluegill sunfish; 11.3 for sheepshead minnow; and 17.6 for mysid shrimp.

In addition, the 48-hour LC50 and NOEC for Daphnia were 27 mg/L and 15 mg/L, respectively. The 96-hour EC50 and NOEC for shell growth in oysters were 46.9 mg/L and 28.2 mg/L, respectively.

In the early life stage test using rainbow trout, a treatment-related decrease in percent hatchling survival was observed at 0.25 mg/L. In this study, the NOEC was less than 0.031 mg/L, and the EC50 for percent hatch was greater than 1.5 mg/L, the highest concentration tested. In chronic toxicity testing of cymoxanil with other aquatic species, the NOEC results (in mg/L) were: 0.067 for Daphnia magna; 0.094 for sheepshead minnow and 1.70 for mysid shrimp. The LOEC results (in mg/L) were: 0.15 for Daphnia magna; 0.178 for sheepshead minnow and 3.77 for mysid shrimp (5, 6).

Effects on Nontarget Species

Cymoxanil is relatively non-toxic to aquatic plants. Lemna gibba, Skeletonema costatum and Selenastrum capricornutum, when exposed directly to the maximum labeled use rate of cymoxanil, all exhibited less than 25% growth inhibition. Five-days exposure period to a freshwater diatom and a blue-green algae resulted in EC25 levels (in ug/L) of 101 for Navicula pellicosa and 119 for Anabaena flos-aquae; EC50 levels (in ug/L) of 202 for Navicula pellicosa and 231 for Anabaena flos-aquae; and NOEC levels (in ug/L) of 63.3 for Navicula pellicosa and 65.2 for Anabaena flos- aquae.

Cymoxanil is not acutely toxic to beneficial organisms. The 48-hour acute contact LD50 to honeybees, as well as the NOEL, was greater than 25 ug/bee. The 48- hour dietary LC50 and the NOEC for honeybees was greater than 1,000 ppm. The 14-day LC50 value for earthworms was calculated at greater than 2,208 ppm (6).

ENVIRONMENTAL FATE

Breakdown of Chemical in Soil and Groundwater

Cymoxanil degrades rapidly in the environment. In sterile, aquaeous environments it degrades rapidly at pH7 or above; at lower pHs it is stable. Photolysis is a significant degradation pathway. Soil metabolism studies indicate cymoxanil degrades very rapidly under both aerobic and anaerobic conditions with half-lives of two days or less. Both aerobic and anaerobic metabolism occur via a similar degradation pathway. Aerobic metabolism was studied in a wide variety of soil types and cymoxanil degraded rapidly in all soil types. Soil degradates also declined rapidly in soil with half-lives less than 7 days. Carbon dioxide is the terminal degradation product. While cymoxanil and its degradates are weakly absorbed to soil, they degrade so rapidly that movement into groundwater is unlikely. The half-life of cymoxanil under field conditions was 1-9 days (1, 6).

Studies with the formulated product Curzate have shown that the fungicide is quickly degraded under greenhouse conditions, and that the half-life is about three days. In field conditions, the half-life is less than two weeks. Curzate does not move into deep soil layers, but remains near the surface. Leaching studies have shown that Curzate is unlikely to move laterally in soil (5).

Breakdown of Chemical in Surface Water

The formulated product Curzate is stable in water with a pH of 6 or less. under basic conditions, the product hydrolyses. The speed of hydrolysis increases with increasing basicity and temperature (5).

Breakdown of Chemical in Vegetation

Cymoxanil degrades rapidly and extensively in potatoes to natural products. The primary metabolite is glycine (a natural amino acid), which is reincorporated into other naturally occurring products (1, 5).

Field residue trials were conducted with cymoxanil on potatoes at 19 test sites in the U.S. at rates equal to or higher than (up to 5X) the proposed maximum use rate with pre-harvest intervals as short as 0 days. No detectable cymoxanil residue (detection limit = 0.02 ppm) was found in any sample at any of the tested sites or rates (1).

PHYSICAL PROPERTIES AND GUIDELINES

Technical cymoxanil is a peach colored crystalline, odorless solid (4, 6).

Exposure Guidelines:

The following Codex Alimentarius Commission (Codex) Maximum Residue Levels (MRL's) for cymoxanil on potatoes have been established: Belgium, Germany, Indonesia, Mexico, Netherlands, Portugal, Spain, Switzerland - 0.05 ppm, Austria, Brazil, Japan, Italy - 0.10 ppm, Hungary - 0.50 ppm, and Luxembourg - 2.0 ppm (1).

RfD: 0.02 mg/kg/day (2)

Physical Properties:

CAS #: 57966-95-7
Chemical name: 2-cyano-N-[(ethylamino) carbonyl]-2-(methoxyimino)acetamide (4)
Chemical Class/Use: acetimide compound used as both a curative and preventative foliar fungicide (3)
Specific gravity: At 18 C, absolute density is 1.32g/cm3; bulk density is 0.39 g/ml (24.5 lb/ft3) (6)
Solubility in water: 0.1g/100g solvent at 25C (5)
Solubility in other solvents: Aqueous buffers at 20 C: 890 ppm at pH5; 780 at pH7; unstable at pH9 (6)
Organic Solvents at 20 C: 62.4 mg/ml in acetone; 133 mg/ml in methylene chloride; 57.0 mg/ml in acetonitrile; 28 mg/ml in ethyl acetate; 22.9 mg/ml in methanol; 5.29 mg/ml in toulene; 1.43 mg/ml in 1-octanol; and 37 ppm in n-hexane (6)
Melting point: 159-160C (6)
Boiling point: not a liquid
Vapor pressure: 1.50 x 10-4 Pascals at 20C (1.1 x 10-6 mm/Hg)
Octanol/Water Partition Coefficient (Kow): 3.9 in pH5 buffer pH5 at 20C; 4.7 in pH7 buffer pH5.8 at 25 C (6)

The Henry's Law constant at pH7 and 20 C is calculated to be 3.8 x 10-10 atm- m3/mol. (6)

BASIC MANUFACTURER

DuPont Agricultural Products
P.O. Box 80038
Walker's Mill, Barley Mill Plaza
Wilmington, DE 19880-0038
Telephone: 800-441-7515
Emergency Telephone: 800-441-3637
Fax: 302-992-2276

Review by Basic Manufacturer:

Comments solicited: June, 1997
Comments received: July, 1997

REFERENCES

  1. U.S. Environmental Protection Agency. Cymoxanil; Pesticide Tolerance Petition. Federal Register Document.
  2. U.S. Environmental Protection Agency. Cymoxanil; Pesticide Tolerances for Emergency Exemptions. Federal Register Document 97-12475. May 13, 1997.
  3. W. T. Thomson. 1997. Agricultural Chemicals. Book IV: Fungicides. 12th edition. Thomson Publications, Fresno, CA 93791.
  4. Farm Chemicals Handbook. 1997. Meister Publishing Co. Willoughby, OH 44094.
  5. Technical Information Bulletin for Curzate. 1983. E.I. duPont de Nemours and Co., Biochemicals Department, Wilmington, DE 19898. 12 pp.
  6. Review by DuPont Agricultural Products. June 30, 1997.