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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: William Cutchin, 703

- 305

- 7990

INSTRUCTIONS: Please utilize this outline in prep aring the pesticide petition. In cases where the outline element does not apply, please insert “NA

- Remove” and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [ insert

company name ] ,” with the information specific to your action.

TEMPLATE:

Bayer Healthcare LLC, Animal Health Division

I N

- 10 838

EPA has received a pesticide petition ( IN

- 10 838 ) from Bayer Healthca re, LLC,

Animal Health Division

, P.O Box 390 Shawnee Mission, KS 6620 1

, 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 to establish an exemption from the re quirement of a

tolerance for di

- N

- butyl adip ate (DNBA, CAS # 105

- 99

- 7) under 40 CFR 180.9 10 when

used in plastic container strips containing pesticides that are placed at the entrance to bee

hives intended to control varroa mites.

EPA has determined that the petition contains data or information re garding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted d a ta 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 NA

B. Toxicological Profile

1. Acute toxicity. DNBA is low in toxicity following acute exposure, with a n oral

LD 50 in rats of 1.52 g/kg body weight. An 8

- hour inhalation exposure to air saturated

with DNBA caused no deaths in a group o f 6 albino rats. DNBA was not toxic to rabbits by the dermal route, with a dermal LD 50 of 19.24 g/kg. DNBA is a dermal irritant. Eye irritation studies in rabbits indicated minor eye irritation with recovery in a few days.

DNBA is not a dermal sensitizer in guinea pigs.

2. Genotoxicty. In two separate Ames Assays, no mutations were induced in any bacterial strain at any concentration of DNBA with or without metabolic activation. A chromosomal aberration assay was conducted on DNBA acco rding to OECD Test2

Guideline 473 using cultured Chinese Hamster lung (CHL/IU) cells. Structural chromosome aberrations were reported in this study with metabolic activation. In an in vivo micronucleus assay, no cytotoxic effects were identified in the bone marrow cells, and there was no significant increase in the number of cells with micronuclei at any dose or time after dosing.

3. Reproductive and developmental toxicity

. In a reproduction study, Male and female rats received DNBA at oral doses of 0,100, 300 and 1,000 mg/kg/day. There was no effect of DNBA exposure on any of the reproductive parameters measured. Pup body weight in the 1,000 mg/kg/day group was slightly reduced compared to controls at birth and on postnatal day 4. The authors identified th e study NOAEL for general toxicity in the parental generation of 300 mg/kg/day based on the increase in kidney weights in males and females at 1,000 mg/kg/day. The NOAEL for reproduction in male and female rats was 1,000 mg/kg. The NOAEL for the F1 generat ion was 300 mg/kg/day.

In a developmental study, groups of 5 female rats received intraperitoneal (IP) injections of DNBA on the 5th, 10th and 15th days of gestation. The dose levels were: 168 mg/kg, 504 mg/kg, 1,009 mg/kg, and 1,682 mg/kg. Four differen t control groups were included in the study, one needle control and three groups that received different vehicles; the DNBA was administered neat with no vehicle. Dams were sacrificed on gestation day 20 and the numbers of corpra lutea, resorption sites, a nd dead and live fetuses were counted. Fetuses were evaluated for gross, skeletal a nti visceral abnormalities. The NOAEL dose for developme ntal effects was 504 mg/kg based on a significant decrease in pup body weight compared to the needle control at the ne xt highest dose of 1,009 mg/kg. No other significant adverse effects were reported at that

LOAEL dose.

4. Subchronic toxicity. The potential effects of repeated oral exposure to DNBA were evaluated in Sprague

- Dawley rats in a 28

- day toxicity test. Male a nd female rats received gavage doses of DNBA of 0, 20,140, or 1000 mg/kg/day. No test substance

related changes were seen in any of the monitored endpoints. The NOAEL in both males and females was 1,000 mg/kg/day.

5. Chronic toxicity. The results of a pr edictive Quantitative Structure Activity Relationship (QSAR) model indicate there is only a marginal concern that DNBP could be an active carcinogen.

6. Animal metabolism. DNBA metabolism can be characterized based on the common structural groups that ma ke up DNBA, the known enzymes that interact with these structural groups, and the metabolites that result from these interactions. DNBA is a linear fatty acid diester that has an n

- butyl group bound to the oxygen atom on each end

of the molecule. Given the se structural groups, DNBA metabolism is catalyzed by carboxylesterase enzymes that are ubiquitous throughout the body, to produce butyl alcohol and adipic acid in a molar ratio of 1:2. N

- butanol is metabolized by alcohol dehydrogenase, and adipic acid is metabolized by beta oxidation.3

7. Metabolite toxicology

. Neither butyl alcohol or adipic acid is of toxicological

concern.

8. Endocrine disruption

. Toxicity related to endocrine disruption was not

observed in the DNBA database.

C. Aggregate Exposure

1. Dietary exposure

. The estimated chronic dietary exposure to DNBA was determined using the Dietary Exposure Evaluation Model (DEEM) software with the Food Commodity Intake Database. The assessment assumes that the inert ingredient, is used on only hone y from bee hives, that 100% of hives are treated with the inert, and

100% of the inert is transferred to the hone y. The maximum exposure was 0.2% of the Population Adjusted Dose.

i. Food . The food commodities included in the assessment were honey, and

h oney, baby food.

ii. Drinking water . [No drinking water exposure from the use of DNBA in honey

bee hives to co ntrol varroa mites is expected.

2. Non

- dietary exposure

. The only non

- dietary exposure to DNBA from use of the bee hive strips would be dermal exposure to workers that apply the strips to the hives if they do not wear gloves.

D. Cumulative Effects

DNBA has been used for many years in personal care products. DNBA is reported to be incorporated in suntan gels, creams and liquids at a concentr ation of 8%, and in nail enamel at 5%. The additional exposure to 0.2% of the population adjusted dose of DNBA is not expected to increase the current exposures significantly.

E. Safety Determination

1. U.S. population. The low toxicity of DNBA and the exaggerated dietary exposure assessment suggest that the total aggregate exposures will be well below the acceptable exposure. Thus, a safety finding for DNBA can be concluded for aggregate exposures from dieta ry and non

- dietary uses.

2. Infants and chi ldren

. The low toxicity of DNBA and the exaggerated diet ary exposure assessment suggest that the total aggregate exposures for infants and children will be well below the acceptable exposure. Thus, a safety finding for DNBA can be

concluded for infant and child exposures from dietary uses.

F. International Tolerances NA

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