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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: PV Shah, (703) 308

- 1846

Huntsman Corporation

.

IN

- 10748

EPA has received a pes ticide petition ( [ IN

- 10748) Huntsman Corporation, 8600 Gosling Road, The Woodlands, TX, 77381 request ing, 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 requirement of a

tolerance for benzyl acetate

, CAS No.: 140

- 11

- 4

, when used in pesticide formulatio ns applied to growing crops under 40 CFR 180.920 . EPA has determined that the petition

contains data or information regarding the elements set for th in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated 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 C

hemistry NA Remove

.

1. Plant metabolism. NA Remove

2. Analytical method. NA Remove

3. Magnitude of residues. NA Remove

B. Toxicological Profile

1. Acute toxicity. Benzyl acetate is low in acute toxicity following exposure of rats by the oral rout e. The acute oral LD50 is 2,490 to 3,690 mg/kg. Benzyl acetate is also low in toxicity by the dermal route. The acute dermal LD50 in rabbits is > 5,000 mg/kg

. Rats exposed by the inhalation route to the maximum attainable vapor

concentration of 766 μg/L benzyl acetate for 4 hours exhibited no clinical signs of toxicity on the day of exposure or during the two week follow

- up period. The LC50 was greater than 766 μg/L. Well

- defined erythema was seen following a four

- hour dermal exposure of rabbit s to 0.5 ml of benzyl acetate that cleared by the end of the 7

- day study

. Benzyl acetate is minimally irritating to the eyes. The potential for benzyl acetate to cause skin sensitization was evaluated in guinea pigs using a variety of test methods, and

w as determined not to be a sensitizer.

2. Genotoxicty. Benzyl acetate has been studied in a variety of bacterial and2

mammalian cell genotoxicity studies as well as in vivo genotoxicity studies. Most of the genotoxicity studies on benzyl acetate have bee n negative, though a few positive results

have been observed. Negative in vivo studies include two micronucleus assays, a sister chromatid exchange assay, and an unscheduled DNA synthesis assay

. The weight of the evidence from all of the available genoto xicity studies indicates that benzyl acetate is not a genotoxic agent.

3. Reproductive and developmental toxicity. The potential for developmental toxicity from exposure to benzyl acetate was evaluated in rat dams. Groups of dams received doses of 0, 10, 100, 500 or 1000 mg/kg/day benzyl acetate by gavage days 6 through 15 of gestation. The data show a decrease in body weight gain of 9.9% occurred in the high dose dams compared to vehicle controls throughout exposure from gestation day 6 through 20

. There were no effects of treatment on corpora lutea, live fetuses, pre

or post

- implantation loss, resorptions, sex ratio, or the mean number of fetuses per dam. Fetal body weights were significantly reduced in the high dose group compared to

controls. Th e authors concluded that benzyl ace tate is not a teratogen, and increased incidences of skeletal and internal variations were due to reduced growth and r eflected

th e decreased fetal body weight. The maternal and fetal NOAELs for this study were

both 500 m g/kg/day based on a decrease in body weight in dams and offspring at 1000 mg/kg/day

.

4. Subchronic toxicity. Ten male and ten female rats per dose were fed benzyl acetate in the diet at concentrations that corresponded to 0, 230, 460, 900, 1750, or 3900 mg/kg/day for male rats or 0, 240, 480, 930, 1870, or 4500 mg/kg/day for female rats for

13 weeks

. Eighteen of the 20 rats in the high dose groups died between weeks 2 and 8 of the study. There was a significant decrease in body weight and food consumpt ion compared to controls in the 1750 mg/kg/day group males and the high dose males and females. There was a benzyl acetate associated decrease in cholesterol level in female

rats in the 1870 and 930 mg/kg/day groups compared to controls . Testicular semin iferous tubular atrophy of mild severity was reported in one male rat in the 900 mg/kg/day group

and with greater severity in two males the 1750 group.

5. Chronic toxicity. Benzyl acetate has been evaluated for carcinogenicity by

IARC and was found to b e “not classifiable as to its carcinogenicity to humans (Group 3).” The evaluation was largely based on the results of bioassays conducted by the National Toxicology program (NTP). The NTP conducted two 2

- year studies on benzyl

acetate in both rats and m ice. The first study was a gavage exposure study and the second was a dietary exposure study

. In the second NTP bioassay of benzyl acetate, groups of 60 male and female F344/N rats received benzyl acetate in the diet at concentrations that provided doses of 0, 130, 260 and 510 mg/kg/day for males and 0, 145, 290, and 575 mg/kg/day for females. After the chronic exposures, the average body weights of the high dose males and females were approximately 5% below the controls, and there were no clinical signs of toxicity in any of the groups. There were no significant neoplastic or non

- neoplastic lesions associated with test article treatment in any dose group. A similar chronic dietary exposure study was conducted in B6C3F1 mice that received 0, 35, 110 or 345 mg/kg/day benzyl acetate for males and 0, 40, 130, and 375 mg/kg/day for females

. Throughout the study the high dose male and female3

mouse body weights were 10 to 16% lower than controls, but subjects exhibited no clinical signs of toxicity. There we re no significant neoplastic or non

- neoplastic lesions associated with test article treatment in any dose group.

6. Animal metabolism. Benzyl acetate is readily absorbed from the gastrointestinal tract, lungs, and skin, in experimental animals and is r apidly hydrolyzed to benzyl alcohol and acetate. Benzyl alcohol is further oxidized to benzoic acid and after conjugation with glycine is excreted in the urine as hippuric acid. Minor amounts of benzyl alcohol and benzyl mercapturic acid (N

- acetyl

- S

- benz yl

- L

- cysteine) have been detected in the urine, but more than 90% of the urinary metabolite is hippuric acid. Approximately 1 to 1.5 % of benzyl acetate is eliminated in the feces. No parent compound is detected in experimental animals after exposure. S ince metabolism of the primary hydrolysis product of benzyl acetate, benzyl alcohol, is very similar in humans and rodents it is expected that the metabolism of benzyl acetate in humans is very similar to that in

rodents

7. Metabolite toxicology

. N/A Rem ove

8. Endocrine disruption

. In the available toxicity studies on benzyl acetate, there was no toxicologically significant evidence of endocrine disruptor effects. In the 13

- week NTP study

, m ild to moderate aspermatogenesis was identified in two male ra ts of the 3,900 mg/kg group . Atrophy of the seminiferous tubules was reported in two of ten 1,750 mg/kg/day males and mild atrophy occurred in one of the 900 mg/kg/day dose males. These effects occurred at high doses and decreased in incidence and severi ty with decreasing dose.

C. Aggregate Exposure

1. Dietary exposure. The estimated dietary exposure to benzyl acetate and its salts was determined using methods to estimate chronic dietary exposure for a generic inert ingredient. This assessment conside rs drinking water and crop

- specific residues from

pre

- harvest applications of agricultural insecticides, herbicides and fungicides, assuming the highest established tolerance level residue for each commodity. The assessment assumes that the inert ingredie nt is used on all crops, and that 100% of all crops are treated with the inert. The inert ingredient is assumed to be present in all commodities treated with 57 of the most significant active ingredients at the maximum tolerance level as identified by the U.S. EPA for the default assessment. Chronic dietary exposure estimates were derived for the general US population and sub

- groups of the population using the Dietary Exposure Evaluation Model, DEEMTM. The I

- DEEM residue data set developed by EPA was used for the analysis. The estimated chronic exposure for the total US population is 0.189 mg/kg/day, 3.8% of the chronic Population Adjusted Dose ( cPAD ) . Children age 1 to 2 years old have the highest estimated exposure at 0.706 mg/kg/day, 14.1% of the cPAD.

i. Food. Benzyl acetate is a direct food additive approved by the U.S Food and Drug Administration (21 CFR 172.515), and it is a naturally

- occurring component of a variety of fruits and vegetables and other foods. D ietary exposure may occur from use a s4

direct food additive and from consumption of foods that contain naturally

- occurring benzyl acetate. The maximum likely ingestion from use as a direct food additive is 14 μg/kg/day (0.014 mg/kg/day).

ii. Drinking water

. Benzyl acetate e xposure via dri nking water from use as an inert ingredient is not expected to be significant. Based on the physical chemical

characteristics of benzyl acetate , the compound is expected to partition primarily to the soil, and the comparatively small amounts that enter the water will readily biodegrade

. Exposure via the drinking water was estimated in the DEEM dietary exposure assessment assuming a concentration of 100 ppb

.

2. Non

- dietary exposure

. Dermal exposure to consumers is common as a result of use of benzyl ac etate in cosmetic products, particularly in perfumes, lotions, and soaps.

B enzyl acetate is generally added as a fragrance ingredient. Most cosmetic products contain only a very small amount of benzyl acetate as a fragrance.

D. Cumulative Effects

S ection 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other

substan ces that have a common mechanism of toxicity.” EPA has not made a common mechanism of toxicity finding as to benzyl acetate and other compounds. Benzyl acetate does not appear to produce toxic metabolites in common with other substances. For the

purpose of the tolerance exemption actions proposed, it is assumed that benzyl acetate does not share a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. There is a reasonable certainty that no harm to humans will

result from the use of benzyl acetate as an inert ingredient in pesticide products

. A

NOAEL of 500 mg/kg/day in a developmental toxicity study of rats exposed to benzyl

acetate was used to derive the chronic population adjusted dose (cPAD). Intraspecies a nd interspecies uncertainty factors were combined for a total uncertainty factor of 100. The resulting benzyl acetate cPAD is 5 mg/kg/day. For the total US population, the estimated chronic dietary exposure from food and drinking water for benzyl acetate , calculated as

5 0% of all agricultural formulations, is 3.8 % of cPAD. This estimated exposure to benzyl acetate is well below any level of potential concern.

2. Infants and children

. There is a reasonable certainty that no harm to infants and

chil dren will result from the use of benzyl acetate as an inert ingredient in pesticide products. A developmental toxicity study in rats demonstrate d that developmental delay secondary to decreased fetal body weight occurred only at a matern ally toxic dose. A

cPAD of 5 mg/kg/day derived for benzyl acetate was based on this endpoint that is protective of infants and children

. The estimated chronic dietary exposure from food and drinking water was highest ( 14 % of cPAD) for children aged 1 to 2 years old. Esti mated5

exposure of all infants to benzyl acetate , assuming that benzyl acetate makes up 5 0% of all agricultural formulations, is 7.9 % of the cPAD. These estimated exposures to benzyl acetate are well below any level of potential concern.

F. International Tolerances

N/A Remove