# Proposed Decision for the Establishment ofan Import Tolerance Under the Federal Food, Drug and Cosmetics Act (FFDCA) for Residues ofthe New Active Ingredient Benalaxyi-M in or on Grapes and Tomatoes

# Proposed Decision for the Establishment ofan Import Tolerance Under the Federal Food, Drug and Cosmetics Act (FFDCA) for Residues ofthe New Active Ingredient Benalaxyl-M in or on Grapes and Tomatoes

Jac o senger, Director Office ofPesticide Programs
Date: 

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**--~ ------------**  Page2of5Proposed Decision for the Establishment ofan Import Tolerance Under the Federal Food, Drug and Cosmetics Act (FFDCA) for Residues ofthe New Active Ingredient Benalaxyl-M in or on Grapes and Tomatoes 

### REGULATORY PROPOSAL
TheAgency isproposing to establish an importtolerance undertheFederal Food, Drug and CosmeticsAct (FFDCA) for residues ofthe new active ingredient Benalaxyl-M (CAS No. 688046-61-9) in oron grapes and tomatoes. 

### I. HUMAN HEALTH RISK
A summary ofthe human healthrisk as assessed in theAgency document entitled "BenalaxylM. Human HealthRisk Assessment for the establishment ofatolerance inion Grape and Tomato, March 3, 2015," is accessible in docket #EPA-HQ-2013-0714. Currently, Benalaxyl-M is not registered for use as a pesticide in the United States

. Based onthe proposed usepattern, exposureto Benalaxyl-M for the general public can occur viadietary exposure to imported grapes and tomatoes (food) only. Thus, the regulatory decision facing EPA was whether, under FFDCA sec. 408, the Agency could find that there is a "reasonable certainty of no harm" from dietary exposure to benalaxyl-M

. To address this issue, the EPA performed a human health risk assessment using the data submitted with the petition. The available toxicity data indicated that Benalaxyl-M has no significant acute toxicity via oral, dermal or inhalation route ofexposure. Itis not a skin irritant and does not cause skin sensitization

. The liver and thyroid are the primary target organs for benalaxyl-M. In rats, increased liver weights, clinical chemistry changes indicative oflivertoxicity, hepatocellular hypertrophy, and thyroid follicular cell hypertrophy were seen following subchronic and chronic exposure. In mice, increased liver weight and microscopic lesions in the liver (hepatocellular hypertrophy, necrosis, eosinophilic foci) were observed following subchronic and chronic exposure. Additionally, chronic exposure in rats and mice led to increases in the incidence ofliver (rat, mouse) and thyroid (rat) tumors. In dogs, increased liver weight, changes in clinical chemistry indicative ofliver toxicity, and hepatocellular hypertrophy were observed following subchronic exposure via the diet, whereas clinical chemistry changes indicative oflivertoxicity, fat vacuolation in the liver, and thyroid follicular cell hypertrophy were observed following chronic exposure via capsules. No evidence of increased quantitative or qualitative susceptibility was seen in the benalaxyl-M hazard database following in utero exposure with rats orrabbits in the prenatal developmental studies or in young rats in the 2-generationreproduction study. No evidence ofmaternal toxicity or developmental effects was observed in the developmental toxicity studies in rabbits or rats. There is no reproductive concern. No neurotoxic effects were observed in the acute and subchronic neurotoxicity studies in rats, and no immunotoxic effects were observed in the immunotoxicity study in rats. Benalaxyl-M was classified as "Likely to be Carcinogenic to Humans". This determination was based onthe treatment-related livertumors observed in male mice, liver tumors observed in male and female rats; and thyroid follicular cell tumors observed in female rats. No treatment-related tumors were observed in female mice. A linear low-dose extrapolation model (Q* 1) was used to estimate cancerrisk, based on the male mouse liver tumors, Q1 *= 5.90 x 10-3 (mg/kg/dayt 1• There is no mutagenicity concern from the in vivo or in vitro genetic toxicity assays. Page3 orsConsequently, pursuant to FFDCA sec. 408(b)(2)(C), EPA applied an additional 1OX "FQPA safety factor" to account for the uncertainty associated with the potential for enhanced sensitivity ofthe developing organism to prenatal or postnatal thyroid toxicity

. As a result ofthe additional 1 OX, the total uncertainty factor for benalaxyl-M was 

### 1 OOOX, including the standard 1

### OX factor for potential animal-to-human variability and 1 OX factor for potential variability within the human population. Using the chronic Population Adjusted Dose (cPAD) values for benalaxyl-M, EPA determined that potential dietary exposure represented no more than 7% ofthe cPAD for the most exposed subgroups. Because an acute endpoint was not selected, no quantitative acute risk assessment is necessary. EPA noted the calculations ofdietary exposure used conservative values that likely overestimated potential exposure. Based on this analysis, EPA concluded that there was reasonable certainty ofno harm from approval ofthe import tolerance for tomato and grapes. II. PROPOSED REGULATORY DECISION Technology Sciences Group on behalfofIsagro S.p.A., submitted a petition to establish tolerances for residues ofthe fungicide Benalaxyi-M, in or on grapes and tomatoes

. Benalaxyi-M is formulated as water-dispersible granules and wettabl e powders for foliar use to control downy mildew (Piasmopara vitacola) in grapes and late blight (Phytophthora infestans) in tomato. Benalaxyi-M is not currently registered in the U.S.
The Agency is proposing to establish an import tolerance for residues ofBenalaxyl-M in oron imported grape at 1

. 1ppm (part per million); grapejuice at 1.1 ppm; grape wine at 1.1 ppm; grape raisin at 2.2 ppm; tomato at 0.25 ppm and tomato processed at 0.25 ppm. The human health risk assessment provides a rationale and presentsacceptable scenarios relative to acute, chronic and cancerrisks.
As required by the FFDCA, the Agency published a notice offiling in response to the petition submitted by Technology Sciences Group on behalfofIsagro S.p.A.. The notice of filing was published in the Federal Register on February 2 1 ,2014. No comments were received in response to the notice of filing.

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