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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 preparing 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 re place the instructions that appear in green , i.e., “ [ insert

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

TEMPLATE:

Huntsman Corporation

I N

- 10682

EPA has received a pesticide petition I N

- 10682 from Exponet, Inc., 1150 Connecticut Ave., NW

, Suite 1100

, Washington, DC 20036 on behalf of Huntsman Corp., 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 establi sh an exemption from the requirement of a tolerance for

n

- butyl benzoate (CAS RN 136

- 60

- 7) in 180.910 pre

- and post

- harvest applications, 180.930 animal uses and applications, and 180.940 (a)(b)(c) tolerance exemptions for active and inert ingredients for use in antimicrobial formulations (food

- contact surface sanitizing solutions).

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
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 Chemistry

1. Plant metabolism. Not applicable/Not required for the establish ment of a toler|nce 0 exemption for inert ingredients

.

2. Analytical method. Not applicable/Not required for the establishment of a toler|nce 0 exemption for inert ingredients.

3. Magnitude of residues. There is no specific crop residue information available for

m

- butyl benzoate. This information is typically not available or required for the establishment of a tolerance exemption for inert ingredients.

B. Toxicological Profile2

1. Acute toxicity. Potential human exposure from the use of n

- b utyl b enzoate as pesticide inert ingredient could primarily occur via the oral route through the consumption of food or drinking water. n

- b utyl benzoate was tested in the complete battery of six acute toxicity studies: OPPTS 870.1100 acute oral toxicity; OPPTS 870.1200 acute dermal toxicity; OPPTS 870.1300 nose only acute inhalation toxicity; OPPTS 870.2400 eye irritation; OPPTS 870.2500 primary dermal irritation

, and OPPTS 870.2600 dermal sensitization (Buehler). The testing results indicate that n

- butyl benzoa te exhibits low acute toxicity by oral, dermal and inhalation exposure routes, n

- b utyl b enzoate is also

non

- irritating to the skin and eyes and negative for dermal sensitization

.

2. Genotoxicty. n

- b utyl benzoate was not genotoxic in the OPPTS 870.5100 (OECD 471) Reverse Bacterial Mutation Assay. Neither IARC, NTP

, nor OSHA has
listed n

- butyl benzoate as a carcinogenic chemical.

3. Reproductive and developmental toxicity. OPPTS 870.355 (OECD 422)
Combined Repeated Dose Toxicity S tudy with the Reproductive/Developmental Toxicity Screening Test Study

.

Summary Results: The purpose of this study was to provide information on possible effects on repeated dose toxicity, male and female reproductive performance such as gonadal function, mating behavior, conception and the development of the conceptus and parturition. The study also places emphasis on neurological effects as a specific endpoint.

The test item, JEFFSOL® AG 1700 solvent (n

- butyl benzoate) was administered daily to Wistar H annover rats (12 animals/sex/group and 5 animals/sex/satellite groups) by gavage, on a 7 day per week basis (from 14 days before mating period to 4 days post

delivery). Satellite groups consisted of control (0 mg/kg bw/day) and high dose level (1000 mg/kg bw/day) groups and were administered the test material for 28 days, were not mated, and were kept for 14 days after the treatment period for observation of reversibility of toxic effects. The test item was administered to animals in the main study
at doses of 0 (vehicle control), 250, 500 and 1,000 mg/kg bw/day. The dosage levels were selected in agreement with the Sponsor, based upon the results of a dose range

- finding study (P.T. 3984.329.003.11).

The control group received the vehicle alone (corn oil). Animals were checked daily for mortality or morbidity. Body weight of males was recorded on the first day of dosing and weekly thereafter (including mating and post

- mating periods). Females were weighed on the first day of dosing and once a week thereafter; during the premating and mating periods, females w ere weighed on days 0, 7, 14 and 20 of gestation and during
lactation on the s ame days as the weighing of the litters (on day 0 and 4 postnatal). Food consumption w as determine d on t h e same day of body weight determination during premating and lactation periods . During the gestation period, food consumption was determined on days 3, 6, 9, 12, 15, 18 an d 20 . After the mating period, food consumption
of males was deter mined weekly. Animals w ere su bjected to a careful clinical examination prior to the initiation of the treatment and once a week thereafter. Functional3

observation battery (FOB) was performed in 5/animals/sex/group on males at th e end of the dosing period a nd for females during lactation (day 3). At t he end of the treatment period, the animals were submitted for overnight fasting. On the day of necropsy, the
animals were weighed and anesthetized by CO 2 inhalation. Blood samples were collected by cardiac punc ture (from 5/animals/sex/group) for hemogram and clotting analyses, leukogram and clinical chemistry. During necropsy, the animals were subjected to a complete gross examination of organs and tissues. The total number of implantation sites and corpora lute a was counted. The appropriate organs and tissues (from 5/animals/sex/group) were removed, weighed and submitted for histopathological fixation. Full histopathology of the preserved organs and tissues was performed in the high dose and control animals.

JE FFSOL® AG 1700 solvent did not cause any mortality or clinical signs of toxicity during the study. No effects were observed in the functional observational battery, hematology and clotting parameters, clinical chemistry parameters or organ weights. No macr oscopic findings related to the test item were observed. No histopathological effects were reported in neurological tissues (cerebrum, cerebellum, pons, peripheral nerve, spinal cord (cervical, midthoracic and lumbar sections) or any immunological tissues (bone marrow, thymus, spleen, lymph nodes).

Although the study authors stated that no effects on body weight, body weight gain or food consumption were observed or considered to be treatment

- related, large, albeit not uniformly statistically significant b ody weight gain deficits were sporadically observed. Mean body weight gain in the 1000 mg/kg bw/day male parental test group from days 14 to 21 was reduced by 97.7% when compared to the vehicle control mean (no statistical significance). At the intermediate dose of 500 mg/kg bw/day, body weight gain from days 28 to 35 in parental males was reduced by 16%. In maternal females, mean body weight gain in the high dose level (1000 mg/kg bw/day) was decreased (not statistically significant) when compar ed to controls during the last week of gestation (gestation days (GD) 14

- 20; 30.2%), resulting in a 10.6% reduction over the entire gestation period (GD 0

- 20). Mean body weight gain in the high dose group was also non

significantly reduced during the lacta tion period (51.9%) which corresponded to a significant reduction in food consumption during this period . Non

- significant reductions

in mean body weight gain compared to the control group mean were also present at 250 and 500 mg/kg bw/day treatment groups during gestation and lactation. In some, but not all cases, body weight gain deficits showed dose response. In the satellite group females (1000 mg/kg bw/day), body weight gain was significantly reduced from days 0

- 7 (88.2%) of treatment when compared to t he vehicle control mean body weight gain, however this effect corresponded with the statistically significant reductions in food consumption from day 0

- 7 and 14

- 21 and recovered over the next two weeks of treatment. In satellite group males (1000 mg/kg bw/ day) food consumption was significantly decreased from day 0

- 7 and body weight gain was non

- significantly reduced from days 0

- 7 (40%), 7

- 14 (85.7%) resulting in a 4.1% decrease over the entire dosing period (0

- 28).

During the microscopic tissue evaluation s, three males in the high dose group presented slight reduction of germ cells. Despite the presence of this finding, their4

reproductive ability was not affected, since these males produced offspring from their respective females. Similar epid idymis lesion s were observed in treated and control satellites at the end of the recovery period, both cases were unilateral and occurred in two animals per group. Therefore, the study authors considered this finding not test item
related.

The total mean number of pu ps born was 6.1 at 1000 mg/kg bw/da y and 7.9 in the control group and the body weight of pups at day 4 postnatal was 9.2 g at 1000 mg/kg bw/day and 10.3 g in the control group. Although each of these metrics was lower in the high dose animals than in contr ols, the study authors considered these findings as not likely to be test item related because the changes were not statistically significant. Additionally the study reported that while the absolute number of dead pups at day 0 in the high dose group (12/6 1) was statistically significantly increased when compared to controls on day 0 (0/71) (resulting in a mean number of live pups of 4.9 and 7.9 at 1000 mg/kg bw/day and control groups, respectively); survival from post

- natal day 0

- 4 in the high dose group w as comparable to controls (4/71 versus 3/49).

To summarize, although the study authors reported that the No Observable
Adverse Effect Level (NOAEL) was 1000 mg/kg bw/day for parental and embryo

- fetal toxicity, assessment of the data reported in the study reveal that the NOAEL of the test item JEFFSOL® AG 1700 solvent in Wistar Hannover rats may be 500 mg/kg bw/day
for parental animals (males and females) and 500 mg/kg bw/day for embryo

- fetal toxicity. The Lowest Observed Adverse Effect Level (LOAEL) can be considered to be 1000 mg/kg bw/day based on decreased mean body weight gain and food consumption in male and female parental animals and embryo

- fetal toxicity at 1000 mg/kg bw/day as evidenced by increased pup mortality at post

- natal day 0.

4. Subchronic toxicity. The general systemic toxicity NOAEL from the 28

- Day
OPPTS 3650.2000 (OECD 422) Combined Repeated Dose Toxicity Study with a Reproduction /Developmental Toxicity Screening Test in rats was 500 mg/kg body weight/day

.

5. Chronic toxicity. No chronic toxicity data for n

- butyl benzoate are available.
Based on the Federal Register Notice (August 9, 2006, Volume 71, Number 153, pages
45415

- 45424), the Agency stated that the preferred test for repeat

- dose toxicity is the "Combined Repe ated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD Test Guideline 422)." Therefore, an OPPTS 3650.2000 (OECD 422) study has been submitted and the results are summarized under the Reproductive and Developmental Toxic ity ( above )

.

6. Animal metabolism. Esterase mediated hydrolysis is a well

- established primary pathway by which all esters are metabolically degraded. The acid and alcohol metabolites

may be excreted and or enter other pathways to be conjugated and excret ed. Classical metabolism pathways indicate, n

- butyl benzoate would be readily hydrolyzed by esterases in the gut to generate one molar equivalent of n

- butanol and one molar equivalent of benzoic acid. Both of thes e metabolites are also important industrial and agrochemicals and the United Nations Environmental Program (UNEP) h as publish ed5

OECD SIDs documents for both n

- butanol and benzoic acid. Both of these primary metabolites are less lipophilic (Log Kow for n

- bu tanol = 0.88 an d Log Kow for benz oic acid = 1.87) than the parent n

- butyl benzoate ester, which has Log Kow = 3.84. Thus,
neither of these metabolites would bioaccumulate. Rather n

- buta n ol and benzoic acid would rapidly enter other pathways and/or be conjugated and excreted.

7. Metaboli te toxicology

. No metabolites of toxicological concern are expected
based on the reported animal metabolic pathway for ester hydrolysis to generate n

- butyl
alcohol and benzoic acid as primary metabolites.

8. Endocrine disruption

. n

- butyl benzoate does not belong to a class of chemicals designated or potentially designated as endocrine disrupters. Although at some future
date EPA may screen n

- butyl benzoate for potential estrogen, androgen, and thyroid ( EAT ) hormonal effects in the Endocri ne Disruptor Screening Program ( EDSP ) assays, the current repeat dose database of mammalian toxicology studies, that includes reproductive and developmental toxicity testing, does not indicate potential adverse EAT
hormonal effect.

C. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs EPA to consider
available information concerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking water from ground water or surface

water and exposure through pesticide use in gardens, lawns, or buildings (residential and
other indoor uses). It is unlikely that humans (adults and children) would be exposed to n

butyl benzoate via potential residues on foods and in drinking water.

1. Dietary ex

posure. EPA assesses potential dietary exposures to inert ingredients used in agricultural pesticide formulations using a screening

- level model referred to as "IDEEM," in which the "I" stands for inerts and "DEEM" is the dietary exposure
evaluation model t hat is used by EPA to assess dietary exposures to active ingredients in pesticide products. EPA's Inert Ingredients Assessment Branch and residue chemists in the Health Effects Division of the office of pesticide programs jointly developed I

DEEM. The mode l, as developed by EPA, uses crop

- specific residue data (i.e., maximum tolerances) for 57 active ingredients as surrogates for potential inert ingredient residue
levels. I

- DEEM estimates that inert ingredients are used on all crops, and that 100 percent
of all crops are assumed to be "treated" with the inert ingredient(s). I

- DEEM assumes that the inert is present at a concentration of 50% in all the pesticide formulations. In addition, EPA includes potential residues of 100 ppb in water for potential drinki ng water exposures. Using these assumptions, and including no cap for use as an inert ingredient in the food use pesticide formulations supported by way of this petition, the chronic dietary exposure is estimated to be 0. 1 89 mg/kg/day for the general U.S . population 0.706 mg/kg/day for children 1

- 2 years of age (i.e., the most highly exposed subpopulation.

On the basis of the OPPTS 870.355 (OECD 422) study Repeated Dose and Reproductive/Developmental Toxicity Screening, a NOAEL for systemic and reproduct ive/developmental effects for n

- butyl benzoate may be assigned as 500 mg/kg6

bw/day. The chronic reference dose (cRfD) is therefore 5 mg/kg based on 500 mg/kg bw/day ÷ 100 . Based on the removal of the FQPA Safety Factor (below), the resulting
chronic P opula tion A djusted d ose (cPAD) is also 5 mg/kg/day

.

T he dietary (food plus drinking water) exposures for n

- butyl benzoate should be expressed as a percentage of the proposed cPAD for the general U.S. populat ion and
children 1

- 2 years old, Based on I

- DEEM scre ening level calculations, the chronic dietary exposures are estimated to be 3.78% of the cPAD for the general U.S. population and
14.2% of the cPAD for children 1

- 2 years old.

These data demonstrate that the I

- DEEM screening

- level chronic dietary (food and drinking water) exposures are below the cPAD and are therefore below EPA's
established level of concern for all U.S. subpopulations.

i. Food. The available data demonstrate that the I

- DEEM screening level chronic dietary (food and drinking water) exposures are well below 100% of the cPAD, and are
therefore below EPA's established level of concern for all U.S. subpopulations.

ii. Drinking water

. Drinking water is included in the I

- DEEM exposure

assessment. Exposure to n

- butyl benzoate via drinking water is expected to be negligible.

2. Non

- dietary exposure

. Given the low estimate of dietary exposure, there is ample room in the overall aggregate MOE for non

- dietary uses including potential
residential exposures

.

D. Cu mulative Effects

Section 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether

to establish, modify, or revoke a tolerance, the Agency considers "available information" concerning the cumulative effects of a particular pesticide's residues and "other
substances that have a common mechanism of toxicity." Unlike pesticides for which EPA
has followed a cumulative risk approach based on a common mechanism of toxicity, EPA
has not conducted a common mechanism evaluation for n

- butyl benzo ate. Moreover n

butyl benzoate does not produce a toxic metabolite(s) that may have a common mechanism of toxicity with other substances.

For information regarding EPA's efforts to determine which chemicals have a

common mechanism of toxicity and to evalu ate the cumulative effects of such chemicals, see the p o licy statements released by EPA's Office of Pesticide Programs concerning

common me chanism determinations and procedures for cumulating effects from
substances found to have a mechanism ( http://www.epa.gov/pesticides/cumulative/ ).

E. Safety Determination

1. U.S. population

. [ A dietary exposure assessment using current EPA i n ert screening level methodology (I

- DEEM) was conducted. Based on the conservative I

-7

DEE M d ietary exposure estimates, there is a reasonable certainty that no harm will result to the US popul ation from the aggregate exposure to n

- butyl benzoate.

2. Infants and children

. The FFDCA Section 408 requires an additional tenfold margi n of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence fo r increased susceptibility, the FQPA safety factor may be reduced or removed. An evaluation of susceptibility and uncertainty issues associated with the proposed uses and tolerance exemptions for n

- butyl benzoate has been performed.

Based on available information discussed thus far and below in Special
Consideration for Infants and Children, Huntsman requests reduction of the FQPA safety
factor to IX and that the additional tenfold safety factor for the protection of infants and
children be removed.

Co mpleteness of the Toxicological Database A scientifically sound and robust mammalian toxicology database that includes acute toxicity, subchronic toxicity, reproductive toxicity, developmental toxicity and genotoxicity data is available and is adequate fo r characterizing the toxicity of

n

- butyl benzoate and for the quantification of hazard for dietary exposure assessment. No immunotoxicological or neurotoxicological findings were reported in the database. There are no residual uncertainties for pre

- and/or postnatal toxicity.

n

- b utyl benzoate does not belong to a class of chemicals that is known or suspected to affect the estrogen receptor or have any adverse effects on the endocrine system.

Evidence of Neurotoxicitv
There is no evidence of neurotoxicity in the toxicological database for n

- butyl benzoate. In the OECD 422 study (Martell 2013), no clinical effects indicative of neurotoxicity were reported, no adverse findings were reported from the functional observational battery (FOB) assessm ents conducted in the study, and no neuropathological findings were reported in the study.

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal Offspring effects at the limit dose of 1000 mg/kg bw/day were associated with
minor materna l toxicity in the form of decreased body weight gain. The same dose level (1000 mg/kg bw/day) resulted in statistically significant body weight, gain and concomitant food consumption decreases in satellite (nulliparous) females as well as statistically sig nificant decreases in food consumption b ut non

statistically significant decreased body weight gain in male pare ntal ani mals. Body weight gain decreases for maternal animals were also rep orted b ut these were not statistically significant. Significant offspring effects wer e limited to increased pup mortality on post

- natal day 0. All effects to the pup s and parent al8

generation animals were reported only at the high dose level and a c lear NOAE L (500 mg/kg bw/day) was identified for all effects.

Consider ing the overall toxicity profile and the endpoints and doses selected for

n

- butyl benzoate, the degree of concern for the effects observed in the n

- buty l benzoate reproductive and developmental toxicity screening study is low; noting
that there is a clear NOAEL for the offspring effects and regulatory doses were selected to be protective of these effects. No other residual uncertainties were identified with respect to susceptibility. The endpoints and doses selected for the dietary risk assessment of n

- buty l benzoate are protective of adverse effects in both offspring and adults.

Residual Uncertainty in the Exposure Database The dietary risk assessment for n

- butyl benzoate is based on conservative, highend assumptions (overestimates) of dietary exposures. Estimated dietary exposure is based on assumed residues from the foliar application of pesticide products in which the inert ingredient would be present at a concentration of 50%. As such, the exposure assessment is likely to overestimate actual exposures . With the standard application of intra

- and inter

- species variability uncertainty factors, the clear NOAEL for the offspring effect from the study by Martell (2013) is protective of potential effects to potentially exposed human populations. No other

res idual uncertainties were identified with respect to susceptibility. The endpoints
and doses selected for n

- butyl benzoate are protective of adverse effects in both offspring and adults.

The physicochemical/environmental properties indicate that significa nt crop residues and resultant dietary exposures to sensitive populations are unlikely. n

– b utyl benzoate is a volatile compound and will degrade both the atmosphere and soil environmental compartments. Thus, it is unlikely that there would be residues
of n

- butyl benzoate on crops or through its use in anti

- microbial application.

I

- DEEM modeling als o supported that the estimated dietary exposures to n

- butyl
benzoate for children 1

- 2 years of age, the potentially most exposed population, is
14.2% and thus below the 100% of the cPAD.

F. International Tolerances

There are no known international tolerances for n

- butyl benzoate.