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Azoxystrobin

Publication Date: 10/97

TRADE OR OTHER NAMES

The active ingredient azoxystrobin is a methoxyacrylate compound used as a preventive and curative systemic fungicide. Some trade names for products containing azoxystrobin include Abound, Amistar, Bankit, Heritage, and Quadris. Formulations come as a wettable granule (4, 5).

REGULATORY STATUS

Azoxystrobin is an experimental compound. The data package has been submitted to register the active ingredient with the U.S. Environmental Protection Agency (EPA). Outside the U.S., the active ingredient is used on cereals, cucurbits, vegetables, fruit crops, peanuts, turf, ornamentals, stone fruit, bananas, rice, apples, grapes, potatoes and other crops (4, 5).

INTRODUCTION

Azoxystrobin is a broad spectrum fungicide with activity against several diseases on many edible crops and ornamental plants. Some diseases controlled or prevented are rice blast, rusts, downy mildew, powdery mildew, late blight, apple scab, and Septoria (1, 4).

TOXICOLOGICAL EFFECTS

ACUTE TOXICITY

The acute rat oral LD50 was >5,000 mg/kg. The acute rat dermal LD50 was >2,000 mg/kg. The acute inhalation LC50 in rats was 962 mg/l for males and 698 mg/l for females. Azoxystrobin was not a skin sensitizer in guinea pigs. The active ingredient was found to be a slight irritant in rabbits for both eyes and skin. There were no corneal effects. Based on these results, azoxystrobin was classified as Toxicity Category IV for acute oral toxicity and skin irritation, and Category III for acute dermal, inhalation and eye irritation (4).

CHRONIC TOXICITY

Azoxystrobin is non-oncogenic in the rat. Based on a study which administered azoxystrobin in the diets of rats the following values were recorded: male rat 3.6 mg/kg/day, female rat 3.6 mg/kg/day at 60 ppm diet; male rat 18.2 mg/kg/day, female rat 22.3 mg/kg/day at 300 ppm diet; male rat 82.4 mg/kg/day, female rat 117.6 mg/kg/day at 1500/750 ppm diet, respectively.

The No Observed Effect Level (NOEL/NOAEL) for azoxystrobin in the rat is 18 mg/kg bwt/day. The Reference Dose (RfD) for azoxystrobin should be based upon the NOAEL of 18 mg/kg bwt/day with an uncertainty factor of 100, RfD = 0.18 mg/kg bwt/day.

A dietary inclusion level of 1,500 ppm was established as a Maximum Tolerated Dose (MTD) in female rats, where decrements in body weight gain relative to control of approximately 19 percent at week 53 and 11 percent at week 105 were observed. The maximum reduction relative to control was seen at week 73 (approximately 20 percent). In male rats, this dose level was in excess of an MTD (biliary toxicity), resulting in a reduction in the top dose level from 1,500 ppm to 750 ppm for the second year of the study. Reductions in male body weight gain relative to control animals were seen throughout the duration of the study with a maximum reduction of approximately 11 percent in the first year (at week 45), continuing into the second year (maximum reduction of approximately 13 percent at week 99).

In the rat, there was no statistical increase in the number of tumor- bearing animals, animals with malignant tumors, benign tumors, multiple tumors, single tumors or metastic tumors in animals treated with azoxystrobin at dose levels of up to 1,500 ppm (up to 117.1 mg azoxystrobin/kg bwt/day) for 2 years.

Azoxystrobin is of low subchronic toxicity in 21-day dermal testing (6).

Reproductive Effects

Azoxystrobin showed no evidence of reproductive toxicity. The NOEL for toxicity was judged to be 300 ppm azoxystrobin which, for the premating period, translates into a daily dose of 32 mg azoxystrobin/kg body weight/day based on body weight reductions relative to control and liver toxicity in adult males.

The liver toxicity observed in the reproductive toxicity study was manifest as gross distension of the common bile duct accompanied by histological change. The histological changes in the intraduodenal bile duct were characterized by an increase (a hyperplasia) in the number of lining (epithelial) cells and bile duct inflammation (cholangitis). In the liver, there was an increased severity of hepatic proliferative cholangitis. The increased severity of the microscopic liver effects were confined to those animals showing gross bile duct changes, suggesting that these effects were secondary to biliary toxicity.

These observations were confined to male F0 and F1 adult rats and were not detected in female animals or in pups (6).

Teratogenic Effects

There were no adverse effects in the rat or rabbit on the number, survival and growth of the fetuses in utero. Azoxystrobin caused no developmental toxicity in the rat or in the rabbit up to and including dose levels shown to be maternally toxic (6).

Mutagenic Effects

Azoxystrobin gave a weak clastogenic response in mammalian cells in vitro at cytotoxic doses. In the whole animal azoxystrobin was negative in established assays for chromosomal damage (clastogenicity) and general DNA damage, at high dose levels (greater than or equal to 2,000 mg/kg). The weak clastogenic effects seen in vitro are not expressed in the whole animal and azoxystrobin is considered to have no genotoxicity in vivo (6).

Carcinogenic Effects

No information was found.

Organ Toxicity

Azoxystrobin is non-oncogenic in the mouse. There was no increased tumor incidence or early onset of tumors in mice receiving up to 2,000 ppm azoxystrobin for up to 2 years. Dietary administration of 2,000 ppm Azoxystrobin was associated with reduced growth and food utilization.

An MTD was established in the mouse oncogenicity study based on body weight gain depression and decreased food utilization seen at the highest dose test of 2000 ppm. At this dose level body weight gain was depressed 20 percent at week 13 and 28 percent at week 53 in males, and 11 percent at week 13 and 19 percent at week 53 in females.

There was no statistically significant change or alteration in tumor incidence in the mouse attributable to treatment with azoxystrobin at dose levels of up to 2,000 ppm (up to 363.3 mg azoxystrobin/kg bwt/day) for 2 years.

A 1-year feeding study on dogs was conducted. Azoxystrobin was administered to groups of 4 beagle dogs at dose levels of 0, 3, 25 and 200 mg/kg bwt/ day, as a daily oral dose.

Adaptive liver responses were observed at 25 and 200 mg/kg bwt/day which were not considered to be toxicologically significant. The adaptive liver responses were increased liver weights and increased serum liver enzyme activities in the absence of any liver histopathology. Liver weights were increased in both sexes at 200 mg/kg bwt/day, and in females at 25 mg/kg bwt/day. Plasma alkaline phosphatase, cholesterol and triglyceride levels were elevated at the top dose in both sexes, with plasma albumin elevated at 200 mg/kg/day in males only. Plasma triglycerides were also elevated at 25 mg/kg bwt/ day in males only. No such effects were observed at 3 mg/kg bwt/day.

These changes were not accompanied by any histopathological change in the liver. Such changes in the absence of signs of a toxic lesion are generally considered to reflect the liver compensating for the increased work it must perform in metabolizing the test compound. While they can be considered to be effects of azoxystrobin treatment, these changes are of no toxicological significance.

The NOEL in this study was 200 mg/kg bwt/day (6).

Fate in Animals and Humans

Azoxystrobin is well absorbed and completely metabolized in the rat. Excretion is rapid and there is no accumulation of azoxystrobin or metabolites. There are no significant plant metabolites that are not animal metabolites.

Toxicity testing results on the azoxystrobin parent compound are indicative of the toxicity of all significant metabolites seen in either plants or mammals (6).

ECOLOGICAL EFFECTS

Effects on Birds

Azoxystrobin exhibited low ecological risks to birds, mammals and fish (1, 2, 3).

Effects on Aquatic Organisms

Azoxystrobin exhibited low ecological risks to birds, mammals and fish (1, 2, 3).

Effects on Other Animals (Nontarget species)

Azoxystrobin exhibited low ecological risks to birds, mammals and fish (1, 2, 3).

ENVIRONMENTAL FATE

Breakdown of Chemical in Soil and Groundwater

Azoxystrobin is degraded rapidly under agricultural field conditions with a soil half-life of less than 2 weeks. The compound is non-volatile and does not leach, but it is very susceptible to photolysis. Photolysis accounts for the majority of the initial loss of the compound, the remainder being degraded microbially.

Based on laboratory data, the predicted mobility of azoxystrobin in soil is relatively low. The soil adsorption coefficient corrected for soil organic matter (Koc) ranges from 300 to 1690. Consequently, the potential mobility is low to medium. As a measure of possible mobility, the standard GUS index value is 1.0; which equates to a non-leacher.

Results from field trials support these laboratory data. After using 14C- labeled azoxystrobin as a "worst case" field application - bare surface, irrigated and poorly retentive soil (light texture and low organic matter content), the compound was retained in the upper 2 inches or so of the soil throughout its lifetime.

Azoxystrobin does not leach. It is unlikely that azoxystrobin would be present in drinking water or groundwater (6).

Breakdown of Chemical in Surface Water

As azoxystrobin does not leach it is very unlikely to enter into water bodies except by accidental, direct over-spray. However, the compound in laboratory tests degrades with a half-life of approximately 7 weeks in flooded anaerobic soils. There is also potential for photolytic degradation in natural aqueous environments; the aqueous photolysis half-life is 11-17 days (6).

Breakdown of Chemical in Vegetation

Plant metabolism has been evaluated in three diverse crops--grapes, wheat and peanuts--which should serve to define the metabolism of azoxystrobin in a wide range of crops. Parent azoxystrobin is the major component found in crops. Azoxystrobin does not accumulate in crop seeds or fruits; very low residues are found in wheat grain, banana pulp, pecan nutmeat, and peanut (nuts). Metabolism of azoxystrobin plants is complex with more than 15 metabolites identified. These metabolites are present at low levels, typically much less than 5 percent of the Total Recoverable Residue (TRR) (6).

PHYSICAL PROPERTIES AND GUIDELINES

Technical azoxystrobin is a white crystalline solid (7).

Physical Properties:

CAS #: 131860-33-8
Chemical name: Methyl (E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate) (1, 2, 3)
Chemical Class/Use: Methoxyacrylate compound used as a preventive and curative systemic fungicide (4)
Solubility in water: 10 mg/l at 25 degrees C (7)
Melting point: 118-119 degrees C
Vapor pressure: <10-5 Pa at 20 degrees C (7)
Partition Coefficient (Kow): 440 (logP = 2.64) (7)

BASIC MANUFACTURER

Zeneca Ag Products
1800 Concord Pike
Wilmington, DE 19850-5458
Telephone: 800-759-4500
Emergency Telephone: 800-327-8633
Fax: 302-886-1552

Review by Basic Manufacturer:

Comments solicited: June, 1997
Comments received: None Received

REFERENCES

  1. Technical Information Bulletin for Heritage Fungicide. 1996. Zeneca Professional Products. Wilmington, DE. 4 pp.
  2. Technical Information Bulletin for Abound Fungicide. 1996. Zeneca Ag Products. Wilmington, DE. 4 pp.
  3. Technical Information Bulletin for Quadris Fungicide. 1996. Zeneca Ag Products. Wilmington, DE. 4 pp.
  4. Thomson, W. T. 1997. Agricultural Chemicals. Book IV: Fungicides. 12th edition. Thomson Publications, Fresno, CA.
  5. Farm Chemicals Handbook. 1997. Meister Publishing Co. Willoughby, OH.
  6. U.S. Environmental Protection Agency. Pesticide Tolerance Petition Filing for Azoxystrobin. Federal Register Document 97-5683. Tuesday, March 11, 1997.
  7. Goodwin, J.R., V.M. Anthony, J.M. Clough, C.R.A. Godfrey. 1992. A novel, broad spectrum, systemic B-methoxyacrylate fungicide. ICI Agrochemicals. Brighton Crop Protection Conference: Pests and Diseases. 9 pp.