EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

Isagro, S.p.A.

EPA has received a pesticide petition ( 3E8162 ) from Technology Sciences Group on behalf of Isagro S.p.A.

, 1150 18 th Street NW, Suite 1000, Washington, DC 20036 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180

1. by establishing a tolerance for residues of

Benalaxyl

- M import tolerances for Grape

, 1.1 ppm; Grape , juice 1.1 ppm ; Grape , wine 1.1 ppm ; Grape, raisin 2.2 ppm; Tomato 0.25 ppm and Tomato , processed 0.25 ppm.

EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully ev aluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. In plants and animals, the metabolism of Benalaxyl

- M is adequately understood for the purposes of establishing the proposed tolerances. Based on the available metabolism and toxicology data, Benalaxyl

- M is proposed to be considered as the residue of concern in plant and animal matri ces.

2. Analytical method. In plants and animals, the residue of concern, Benalaxyl

- M, can be determined using Liquid Chromatography (LC) with a Mass Spectrometer (MS) detector for the proposed uses:

For imported commodities : grape, raisins, and grape processed commodities at 10 parts per billion (ppb) , tomato and tomato processed commodities at 10 parts per billion (ppb)

.

Studies to evaluate FDA multi

- residue method testing were performed for plant samples.

3. Magnitude of residues. To support the import tolerance request, the registrant has provided 25 grape and 23 tomato Benalaxyl

- M residue trials that mimic product use conditions and rates to support an import tolerance in the United States. In addition, residue studies were conducted on processed products (i.e., raisins, grape juice, young wine, bottled wine, vegetable (tomato) juice, ketchup, canned tomatoes, pureed tomatoes, and tomato paste). The residue demonstrates that imported commodities treated with Benalaxyl

- M will be below the proposed tolerance s

.

B. Toxicological Profile

1. Acute toxicity. The acute toxicity studies indicated low toxicity for2

technical Benalaxyl

- M, placing it into Toxicity Category III for oral and dermal toxicity, Toxicity Category III for eye irritation, and Toxicity Category IV for skin irritation. Dermal sensitization studies found that Benalaxyl

- M is a nonsensitizer.

2. Genotoxicty. Benalaxyl

- M does not induce gene mutations in bacterial and mammalian cells, chromosome aberrations in mammalian cells or deoxyribonucleic acid (DNA) damage in bacterial cells in in vitro test systems. Similarly, it does not exhibit a clastogenic effect in vivo in the mouse micronucleus test. Therefore, there is no evidence to suggest a genotoxic hazard.

3. Reproductive and developmental toxicity. In the rat developmental toxicity study with Benalaxyl

- M, there was no evidence of teratogenicity or other embryotoxic eff ects at the highest dose levels although maternal toxicity was evident based on decreased body weight gain at 250 mg/kg bw/day, the highest dose level tested A2 05 06 01. In the rabbit study test the maternal NOAEL was 1,000 mg/kg bw/day, the highest dose level tested. The developmental NOAEL in the rabbit developmental toxicity study was found to be 250 mg/kg bw/day based on developmental delays at 1,000 mg/kg bw/day. A two generation reproduction study in the rat found a NOAEL of 55.6 to 81.0 mg/kg bw/d ay in males and 70.7 to 116 mg/kg bw/day in females based on decreased body weight gain in F1 and F2 pups during lactation at the high dose level. Liver effects observed in high dose parents. The effects reported at the dose level were considered to be a daptive in nature.

4. Subchronic toxicity. A 90

- day rat study found a NOAEL of 80 ppm, equal to 6.7 mg/kg bw/day, based on reduced weight gain in females receiving 400 ppm and greater A2 05 03 02. A 90

- day study in the dog reported a NOAEL of 900 ppm, equa l to 32.0 mg/kg bw/day for males and 35.0 mg/kg bw/day for females, based clinical chemistry changes indicative of liver toxicity. A 90

- day rat neurotoxicity study reported a NOAEL above 10000 ppm (highest tested dose), equal to 784 mg/kg bw/day for males and 1139 mg/kg bw/day for females for n eurotoxicological effects. An immunotoxicity study conducted for 28

- days in male rats with diets containing up to 10,000 ppm of Benalaxyl

- M resulted in no evidence of immunotoxicity (ref. A2 05 10 01). The NOEL
was eq ual to 924.6 mg/kg bw/day, the highest dose level tested. A 28

- day dermal toxicity in the rat is available for Benalaxyl

- M. No evidence of adverse effects was observed at any dose level (ref. A2 05 03 08). The NOAEL was determined to be 1,000 mg/kg bw/day, the highest dose level tested.

5. Chronic toxicity. A one year study was conducted with Benalaxyl

- M in the dog. Animals were dosed by capsule for 52 weeks. The NOEL was found to be 100 mg/kg bw/day based upon clinical chemistry changes indicative of liver toxicity at a dose level of 300 mg/kg bw/day. Diffuse hypertrophy of the thyroid was seen at this dose level in females.

A chronic study in the rat was conducted to assess chronic toxicity and oncogenicity (ref. A2 05 05 01). Rats were exposed to Benalaxyl

- M for 52 weeks in chronic phase of the study and for 104 weeks in the oncogenicity assay. The NOEL for chronic toxicity was determined to be 60 ppm (equal to 2.4 mg/kg bw/day for males and3

3.13 mg/kg bw/day for females) based upon treatment

- related effects in liver and thyroid gland of both sexes at higher dose levels. There was no evidence of a neoplastic response at any dietary concentration in the rat study.

An oncogenicity study of Benalaxyl

- M in the mouse was conducted for 78 weeks. An increased incidence of hepatocellular adenomas was observed in males and females of the high dose level of 7,000 ppm (equivalent to 962.23 and 1180 mg/kg bw/day in males and females respectively). A mode

- of

- action study conducted subsequent to the mous e oncogenicity study indicated that the tumor response in mice was associated with CYP 2b induction and a pattern of cell proliferation and enzyme induction similar to phenobarbital (ref. A2 05 05 03). The weight of the evidence indicates that Benalaxyl

- M is not likely to be a human carcinogen.

6. Animal metabolism. A metabolism study in rats found the same metabolic pathway for the R and S enantiomers. This pathway consists of oxidation of the methyl group of the aniline ring to hydroxymethyl and then to carboxylic acid. Hydroxylation of the phenyl ring and hydro lysis of the carboxylmethyl group also occurs.

7. Metabolite toxicology

. Two of the soil metabolites have been tested in genotoxicity batteries and 90

- day studies in rats. The methyl

- N

- malonyl

- N (2,6

- xylyl)

- D,L

- alaninate metabolite was negative for ge notoxicity in the reverse mutation, mouse lymphoma, and micronucleus assays. This metabolite was clastogenic only in the absence of S9

- activation in the chromosomal aberration assay. The NOAELs in a 90

- day study in the rat by dietary incorporation were 922.8 and 1072.6 mg/kg bw/day for males and females respectively. The N

- malonyl

- N

- (2,6

- xylyl)

- D,L

- alanine metabolite was negative for genotoxicity in the reverse mutation, mouse lymphoma and chromosomal aberration assays. The NOAELs in a 90

- day rat study by dietary incorporation were 819.2 and 978.1 mg/kg bw/day for males and females, respectively.

8. Endocrine disruption

. To date there is no evidence to suggest that Benalaxyl

- M functions in a manner similar to any known hormone, or that it acts as an en docrine disrupter.

C. Aggregate Exposure

1. Dietary exposure. Estimates of chronic dietary exposure were calculated using Dietary Exposure Evaluation Module Food Commodity Intake Database (DEEM TM

FCID TM) software from the US EPA. The database was used to determine chronic exposure estimates for the overall U.S. pop ulation and 24 population subgroups. The resulting dietary exposures were compared to a chronic reference dose (RfD) of 0.024 mg/kg bw/day. The RfD is based on the NOAEL of 2.4 mg/kg bw/day from the rat chronic toxicity study (52 week) and the rat carcin ogenicity feeding study (104

- week) with a 100

- fold uncertainty factor to account for intra

- species and inter

- species variations.

i. Food. Chronic dietary exposure estimates for the overall U.S. population and 24 population subgroups, including infants and children, are well below the chronic RfD.4

Estimated daily exposures from tolerance level residues and a 100% CT assumption for all crops were 15.8% of the RfD or less for all populations examined. The assumption of 100% crop treated is a worst case f or Benalaxyl

- M.

ii. Drinking water

. No exposures via drinking water are expected based on the proposed import tolerances

.

2. Non

- dietary exposure

. No exposures via residential uses are expected based on the proposed import tolerances

. There are currently no residential uses for Benalaxyl

- M.

D. Cumulative Effects

. Consideration of a common mechanism of toxicity is not necessary at this time because there is no indication that toxic effects of Benalaxyl

- M would be cumulative with thos e of any other chemical compound.

E. Safety Determination

1. U.S. population. Benalaxyl

- M is a new active ingredient that is proposed for import tolerances on grape, raisin, and tomato . It is the R isomer of the racemic mixture, Benalaxyl , which was evaluated by the Joint Meeting on Pesticide Residues (JMPR) in 2009. JMPR proposed Maximum Residue Limits for Benalaxyl on tomatoes, grapes, melons, onions, potatoes, lettuce and meat milk and offal. Using the chronic exposure assumptions for the proposed tolerances and the proposed RfD described above, the dietary exposure for the U.S. population was calculated to be 3.4% of the RfD. The maximum dietary exposure to a population subgroup in the United States is calculated to be 15.8% for chil dren 1

- 2 years old if it is assumed that 100% of the each of the crops are treated and all grapes and tomatoes consumed in the U.S. are imported. No residential or drinking water exposure is anticipated. Therefore, taking into account the proposed uses, i t can be concluded with reasonable certainty that residues of Benalaxyl

- M in food and drinking water will not result in unacceptable levels of human health risk.

2. Infants and children

. FFDCA section 407 provides that EPA shall apply an additional safet y factor for infants and children to account for prenatal and postnatal toxicity and the lack of completeness of the database. Only when there is no indication of increased sensitivity of infants and children and when the data base is complete , the extra

s afety factor may be removed by the EPA. In the case of Benalaxyl

- M, the toxicology database is complete and there is no indication of increased sensitivity in the developmental and multi

- generation reproductive toxicity studies. Therefore, it can be concluded that there is no need for an additional safety factor and a safety factor of 100

can be used for the assessment. Chronic and multigenerational studies on mammals, aquatic organisms and wildlife did not reveal any immune or endocrine effects. Any endocrine related effects would have been detected in this array of required tests.

F. International Tolerances

. A Codex Alimentarium Commission Maximum Residue Level (MRL) has not been set for Bena lax yl

- M.