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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 replace the instructions that appear in green, i.e., “[insert 

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

TEMPLATE:

Huntsman Corporation

IN-10682

EPA has received a pesticide petition IN-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, requesting, 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

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 establishment of a toler|nce0

exemption for inert ingredients.

2. Analytical method. Not applicable/Not required for the establishment of a 

toler|nce0 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 Profile
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1. Acute toxicity. Potential human exposure from the use of n-butyl benzoate as 

pesticide inert ingredient could primarily occur via the oral route through the consumption of 

food or drinking water. n- butyl 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 benzoate exhibits low 

acute toxicity by oral, dermal and inhalation exposure routes, n-butyl benzoate is also 

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

2. Genotoxicty. n-butyl 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 Study 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 Hannover 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 postdelivery). 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 were weighed on days 0, 7, 14 and 20 of gestation and during 

lactation on the same days as the weighing of the litters (on day 0 and 4 postnatal). Food 

consumption was determined on the 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 and 20. After the mating period, food consumption 

of males was determined weekly. Animals were subjected to a careful clinical 

examination prior to the initiation of the treatment and once a week thereafter. Functional 
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observation battery (FOB) was performed in 5/animals/sex/group on males at the end of 

the dosing period and for females during lactation (day 3). At the end of the treatment 

period, the animals were submitted for overnight fasting. On the day of necropsy, the 

animals were weighed and anesthetized by CO2 inhalation. Blood samples were collected 

by cardiac puncture (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 lutea 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.

JEFFSOL® 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 macroscopic 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 body 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 compared 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 nonsignificantly reduced during the lactation 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 the 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 evaluations, three males in the high dose group 

presented slight reduction of germ cells. Despite the presence of this finding, their 
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reproductive ability was not affected, since these males produced offspring from their 

respective females. Similar epididymis lesions 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 pups born was 6.1 at 1000 mg/kg bw/day 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 controls, 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 (12/61) 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 was 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 Repeated 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 Toxicity (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 excreted. 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 these metabolites are also important industrial and

agrochemicals and the United Nations Environmental Program (UNEP) has published 
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OECD SIDs documents for both n-butanol and benzoic acid. Both of these primary 

metabolites are less lipophilic (Log Kow for n-butanol= 0.88 and Log Kow for benzoic 

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-butanol and benzoic acid 

would rapidly enter other pathways and/or be conjugated and excreted.

7. Metabolite 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 Endocrine 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 nbutyl benzoate via potential residues on foods and in drinking water.

1. Dietary exposure. 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 that 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 IDEEM. The model, 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 drinking 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 

reproductive/developmental effects for n-butyl benzoate may be assigned as 500 mg/kg 
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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 Population Adjusted dose (cPAD) is also 5 mg/kg/day. 

The 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. population and 

children 1-2 years old, Based on I-DEEM screening 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. Cumulative 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 benzoate. Moreover nbutyl 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 evaluate the cumulative effects of such chemicals, 

see the policy statements released by EPA's Office of Pesticide Programs concerning 

common mechanism 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 inert

screening level methodology (I-DEEM) was conducted. Based on the conservative I-
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DEEM dietary exposure estimates, there is a reasonable certainty that no harm will result 

to the US population from the aggregate exposure to n-butyl benzoate.

2. Infants and children. The FFDCA Section 408 requires an additional tenfold 

margin 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 for 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.

Completeness 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 for 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-butyl 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) assessments 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 maternal 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 significant decreases in food consumption but nonstatistically significant decreased body weight gain in male parental animals.

Body weight gain decreases for maternal animals were also reported but these

were not statistically significant. Significant offspring effects were limited to 

increased pup mortality on post-natal day 0. All effects to the pups and parental 
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generation animals were reported only at the high dose level and a clear NOAEL 

(500 mg/kg bw/day) was identified for all effects.

Considering 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-butyl 

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-butyl 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

residual 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 significant crop

residues and resultant dietary exposures to sensitive populations are unlikely. n –

butyl 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 also 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.