Fluoxastrobin is the accepted common name for the pesticidally active E-isomer of (2-[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy phenyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime.

The Z-isomer of fluoxastrobin is typically present at much lower levels (E:Z ratio of approximately 90:10). Additionally, the Z-isomer of fluoxastrobin is considered to be a metabolite (photo-degradate) of
fluoxastrobin. Z isomer: (1Z)-[2-[[6-(2-chlorophenoxy)-5-fluoro-4-pyrimydinyl]oxy]phenyl](5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime

The CAS Number Bayer CropScience initially obtained for fluoxastrobin pertained to both isomers combined. After consultation with the EPA, Bayer CropScience requested that fluoxastrobin (the pesticidally active E-isomer only) be designated as the active ingredient.

The tolerances that EPA established on September 16, 2005, include both fluoxastrobin (i.e. the E-isomer) and the Z-isomer and the risk assessment for these tolerances was based on exposures resulting from both isomers.

Note: For milk and meat tolerances, EPA included the phenoxy-hydroxypyrimidine metabolite,
6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinol.

Reference: US EPA. Pesticide tolerances. Final Rule. September 16, 2005. Federal Register.

Adverse Effects:

Body Weight
Bone
Decrease
Endocrine: Adrenal
Endocrine: Testicular
Endocrine: Thyroid
Endocrine: Uterus
Kidney
Liver
Reproductive
Spleen
Urinary tract

Environmental:
• Moderately to highly persistent in soil
• Moderately toxic to estuarine/marine fish;
• Highly toxic to freshwater fish and invertebrates;
• Very highly toxic to estuarine/marine invertebrates.
• Risks to endangered species. The list of endangered/threatened freshwater fish species where fluoxastrobin is used on potatoes, tomatoes, peppers, and peanuts are grown is comprised of 84 different species representing 36 States. The three States with the largest number of endangered /threatened freshwater fish species include California, Washington, and Oregon.

Applicable from: August 2004

Potato: 0.1 p pm
Wheat (winter), rye (winter: 0.05 ppm

August 10, 2005: Conclusion regarding the peer review of the pesticide risk assessment of the active substance fluoxastrobin. European Food Safety Authority.
• Conclusion - 81 pages
• Summary - 6 pages
• Final addendum to the Draft Assessment Report (July 2005) - 73 pages
• Cover page
• Comments on the draft assessment report - 39 pages
• Reporting Table - 62 pages
• Expert Meeting Reports - 42 pages
• Evaluation Table - 24 pages

May 11, 2005 - First sales of Fluoxastrobin in Europe.
Fluoxastrobin, the new broad spectrum, leaf systemic strobilurin fungicide of Bayer CropScience is about to make its market debut under the brand name of Fandango® in key markets in Europe this year. The active ingredient Fluoxastrobin gained its first global approval in the UK at the end of 2004, where it will be launched for foliar application in cereals this season. First sales will also take place in Germany and Ireland.
Fandango® is an innovative fungicide, combining two molecules with different modes of action – the new strobilurin Fluoxastrobin and Prothioconazole, the first active ingredient of the triazolinthion class of substances...

2004 - Environmental fate of Fluoxastrobin (HEC5725);
by H. Borchers and H.-P. Stupp. Pflanzenschutz-Nachrichten Bayer 57/2004, 3: 337-354

2004 - Fluoxastrobin (HEC5725) – the new dimension in strobilurin fungicides;
by U. Heinemann, J. Benet-Buchholz, W. Etzel and M. Schindler. Pflanzenschutz-Nachrichten Bayer 57/2004, 3: 299-318.

2004 - Behaviour of Fluoxastrobin (HEC 5725) in plants and animals.
by H. Reiner, A. Klempner and J. Koster. Pflanzenschutz-Nachrichten Bayer 57/2004, 3: 391-414.

5. First Evaluation for UK Provisional Approval of Fluoxastrobin (HEC 5725), in the products 'Bayer UK831' and 'Bayer UKA 148' and First Consideration of the Inclusion of Fluoxastrobin in Annex I of Directive 91/414/EEC. [ACP 18 (301/2003)]

5.1 Fluoxastrobin is a new strobilurin fungicide, developed by Bayer CropScience. Approval was requested for two formulations, an emulsifiable concentrate (EC) foliar spray and a seed treatment. This is the first application for a seed treatment containing a strobilurin. Fluoxastrobin is also being considered for inclusion in Annex I of Directive 91/414/EEC with the UK acting as Rapporteur.

5.2 The Committee was asked to consider whether Ministers should be advised to grant provisional approval for these formulations. They were also asked to comment on the evaluation and the conclusions reached, ahead of the evaluation being submitted to the EU Commission and the start of the Annex I peer review process.

5.3 Members sought some confirmatory information on the mode of toxicological action of fluoxastrobin, but confirmed that this would not affect the human health risk assessment, which was acceptable

5.4 It was agreed that a risk to aquatic invertebrates from the spray could be addressed by a 15 metre buffer zone. Further data would be required to refine this aspect of the risk assessment. Concerns about risks to non-target arthropods were also discussed. It was thought that there was inconsistency in the data which should be examined outside the meeting. The concerns could be addressed by appropriate labelling.

5.5 The Committee agreed that provisional approval could not be granted for use of the product as a seed treatment at present as this contained prothioconazole (which would not be commercially approved - see minute 4 above). As buffer zones larger than 5m are not acceptable in UK for use on arable crops, the foliar spray could not be recommended for approval in the UK either.
Ref: Final minutes of the 301st meeting of the Advisory Committee on Pesticides held on 10 July 2003.

BAYER. Pesticide Tolerances. FINAL RULE.

• Reproduction and fertility - rats. Offspring systemic: decreased body weights, delayed preputial separation, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
• Chronic toxicity-dogs. LOAEL was 8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on body weight reductions and hepatocytomegaly and cytoplasmic changes associated with increased serum liver alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra;
• 90-Day oral toxicity-dogs. dose-related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
• 90-Day oral toxicity-mice. There was a dose related increase in liver weight in both sexes and in kidney weight in females, in addition to other effects whose toxicological relevance was considered uncertain. Among these effects were increased hepatocellular hypertrophy with cytoplasmic changes in the high-dose males and minimal to moderate kidney tubular hypertrophy in mid- and high-dose females.
• Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
• 90-Day Subchronic Oral Toxicology-Dog. dose-related reductions in net body weight gain and food efficiency; toxicity findings in the liver (cholestasis) in both sexes; and toxicity findings in the kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males)

• Thyroid. FAN suggested that a 14-week feeding study using dogs showed an effect on the thyroid, which seems to conflict with the statement that ``...There is no evidence to suggest that fluoxastrobin has any primary endocrine disruptive potential.'' FAN stated that a ``discussion or rationale'' addressing this should have been provided. EPA does believe that the thyroid effects seen in the dog study indicated that fluoxastrobin is an endocrine disruptor. An effect on the thyroid gland, even though this gland is part of the endocrine system, does not necessarily mean that endocrine disruption has or will occur. In this case, the effects observed in the thyroid gland were induced by effects fluoxastrobin had on liver enzymes and are therefore considered secondary.

• CONDITIONS
The following conditions are being imposed on Bayer CropScience (the petitioner) for the registration of fluoxastrobin.
1. Submit additional information concerning weather conditions, confirmatory raw data, and soil characteristics data for the crop field trial and field rotational crop studies.
2. Submit additional data concerning the chromatograms and chromatography in the goat metabolism study.
3. The enforcement methods must be rewritten to include instructions for the analysis of all crops, and to specify the
additional ions to be monitored for quantitation.
4. A new peanut processing study must be submitted.
5. Submit reference standard materials for fluoxastrobin and several molecules related to it, including isotopically labeled
internal standard reference materials, to the EPA National Pesticide Standards Repository.
6. Submit additional information concerning the grass forage and hay rotational crop field trials.
7. Submit confirmatory data and additional information concerning the storage stability data.
8. Submit additional information concerning the mouse immunotoxicity subacute feeding study.