Proposed Decision for the Establishment of an Import 

Tolerance Under the Federal Food, Drug and 

Cosmetics Act (FFDCA) for Residues of the New 

Active Ingredient Benalaxyi-M in or on Grapes and 

Tomatoes 
Proposed Decision for the Establishment of an 

Import Tolerance Under the Federal Food, 

Drug and Cosmetics Act (FFDCA) for 

Residues of the New Active Ingredient 

Benalaxyl-M in or on Grapes and Tomatoes 

Jac o senger, Director 

Office of Pesticide Programs 

Date: fo /t/!5' --~ ------------

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Proposed Decision for the Establishment of an Import Tolerance Under the Federal Food, 

Drug and Cosmetics Act (FFDCA) for Residues of the New Active Ingredient Benalaxyl-M in 

or on Grapes and Tomatoes 

REGULATORY PROPOSAL 

The Agency is proposing to establish an import tolerance under the Federal Food, Drug 

and Cosmetics Act (FFDCA) for residues of the new active ingredient Benalaxyl-M 

(CAS No. 688046-61-9) in or on grapes and tomatoes. 

I. HUMAN HEALTH RISK 

A summary of the human health risk as assessed in the Agency document entitled "BenalaxylM. Human Health Risk Assessment for the establishment of a tolerance 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 on the 

proposed use pattern, exposure to Benalaxyl-M for the general public can occur via dietary 

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 of exposure. It is 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 ofliver toxicity, 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 of liver toxicity, 

and hepatocellular hypertrophy were observed following subchronic exposure via the diet, whereas 

clinical chemistry changes indicative ofliver toxicity, 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 or rabbits in the prenatal developmental studies or in young 

rats in the 2-generation reproduction study. No evidence of maternal 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 on the treatment-related liver tumors 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 cancer risk, 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. 

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Consequently, pursuant to FFDCA sec. 408(b )(2)(C), EPA applied an additional 1 OX "FQPA safety 

factor" to account for the uncertainty associated with the potential for enhanced sensitivity of the 

developing organism to prenatal or postnatal thyroid toxicity. As a result of the 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% of the cP AD for the most exposed 

subgroups. Because an acute endpoint was not selected, no quantitative acute risk assessment is 

necessary. EPA noted the calculations of dietary exposure used conservative values that likely 

overestimated potential exposure. Based on this analysis, EPA concluded that there was 

reasonable certainty of no harm from approval of the import tolerance for tomato and grapes. 

II. PROPOSED REGULATORY DECISION 

Technology Sciences Group on behalf of Isagro S.p.A., submitted a petition to establish tolerances for 

residues of the fungicide Benalaxyi-M, in or on grapes and tomatoes. Benalaxyi-M is formulated as 

water-dispersible granules and wettable 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 of Benalaxyl-M in or on 

imported grape at 1.1 ppm (part per million); grape juice 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 presents acceptable scenarios relative to 

acute, chronic and cancer risks. 

As required by the FFDCA, the Agency published a notice of filing in response to the petition 

submitted by Technology Sciences Group on behalf of Isagro 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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