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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

TEMPLATE:

Huntsman Corporation

IN-10683

EPA has received a pesticide petition IN-10683 from Exponent, Inc., 1150 

Connecticut Ave., NW, Suite 1100, Washington, DC, 20036 on behalf of Huntsman 

Corporation, 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 di-n-butyl carbonate, CAS RN 542-52-9, as an inert ingredient in non-food and 

food use pesticide in 40 CFR §180.910 for pre- and post-harvest applications; 40 CFR 

§180.930 for animal uses and applications; and 40 CFR §180.940 (a)(b)(c) for tolerance 

exemptions for active and inert ingredients for use in antimicrobial formulations (foodcontact 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 tolerance 

exemption for inert ingredients.

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

tolerance exemption for inert ingredients.

3. Magnitude of residues. There is not any specific crop residue information 

available for di-n-butyl carbonate. This information is typically not available or required for 

the establishment of a tolerance exemption for inert ingredients.

B. Toxicological Profile

1. Acute toxicity. Potential human exposure from the use of di-n-butyl carbonate as 

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

food or drinking water. Di-n-butyl carbonate was tested in six acute toxicity studies. The 
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testing results indicate that the product exhibits low acute toxicity by oral, dermal and 

inhalation exposure routes. The product is moderately irritating to the eyes and was 

negative for dermal sensitization. Di-n-butyl carbonate was however, irritating to the skin 

producing moderate to severe erythema from Days 1 to 8 with 4 hours of exposure. The 

irritation, however, subsides by Day 9.

2. Genotoxicty. Di n-butyl carbonate was negative in a Bacterial Reverse Mutation 

Assay (OPPTS 870.5100/OECD guideline 471) using Salmonella typhimurium tester 

strains TA98, TA100, TA1535 and TA1537 and Escherichia coli tester strain WP2 uvrA 

in the presence and absence of Aroclor-induced rat liver S9 [8]. At concentrations 

ranging from 1.5 to 5000 ug per plate, no positive mutagenic response was observed.

3. Reproductive and developmental toxicity. Results reported from OPPTS 

870.3650 (OECD 422) Combined Repeated Dose Toxicity Study with the Reproductive 

and Developmental Toxicity Screening Test.

EDSA 09/12 (di-n-butyl carbonate) 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 post-delivery). Satellite groups 

consisted of control (0 mg/kg bw/day) and high dose level (750 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 750 mg/kg bw/day. The control group received the vehicle alone (deionized 

water). The dosage levels (in mg/body weight/day) were selected in agreement with the 

Sponsor, based upon the results of a dose range-finding study (P.T. 3984.329.004.11).

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 postmating periods). Females were weighed on first day of dosing and once a week 

thereafter; during the premating and mating periods, 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 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 
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high dose and control animals and in selected tissues of other animals in other dose 

groups, which presented findings in macroscopic observations.

The di-n-butyl carbonate test material (EDSA 09/12) did not result in any test 

material-related mortality or clinical observations in 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. Differences in body weights and body weight gains were observed in treated 

males and females compared to the control group. In the main study, female body weight 

gain premating from day 0-7 was reduced by 26.6% in the 750 mg/kg bw/day dose level 

(no statistical significance) and was reduced by 56.2% in the 500 mg/kg bw/day dose 

group (no statistical significance) when compared to the control group. These deficits in 

body weight gain premating from day 0-7 did not show any dose-response relationship. A 

similar not statistically significant decrease in body weight gain from days 0-7 in the 

satellite females occurred at 750 mg/kg bw/day (11.9%) when compared to controls. 

Body weight gain during gestation days 14-20 was statistically significantly reduced in 

the 750 mg/kg bw/day treatment group by 38.5% when compared to the control group 

and overall gestation body weight gain (gestation days 0-20) was reduced by 21.3% (not 

statistically significant) when compared to control. Body weight gain during lactation 

(Days 0-4) was also reduced (not statistically significant) by 71.5% in the high dose

females. In the satellite group females, body weight gain was non-significantly reduced 

from Days 14-21 by 59.5% when compared to the control. Food consumption in the main 

study females in the 750 mg/kg bw/day group was slightly reduced throughout the study 

(premating through gestation) without statistical significance when compared to the 

control group females. The exception was for lactation (Days 0-4) where the food 

consumption was statistically significantly reduced (22.5%), corresponding with the 

decreased body weight gain in this group. In the satellite study females, the food 

consumption in the 750 mg/kg bw/day group was generally less than controls throughout 

the study period for females without statistical significance. A similar non-statistically 

significant reduction in body weight gain was observed in the males. Overall body weight 

gain in the males during the entire treatment period was reduced by 11.2% in the main 

study and 37.3% in the satellite animals compared to respective controls. The largest 

difference was during study days 0-7 (-32.7% for the main study), study days 7-14 (-

22.7% and -143% (statistically significant)), for the main study and satellite study,

respectively) and study days 14-21 (-88.2% for the satellite study). Food consumption

was slightly reduced in the satellite group males and was generally comparable to 

controls in the main group (males).
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The study authors stated in the final report that high dose dams showed higher 

pre- and postimplantation losses, lower fertility and lower gestation index when 

compared to the control animals. These findings were considered test item related with 

slight toxicological relevance.

BioAgri historical control data were not included in the final report; control data 

from a recent n-butyl benzoate OPPTS 870.3650 (OECD 422) study is available (Martell 

2013b) and was used to analyze the data for this study (Martell 2013a). This study was 

submitted to EPA by Huntsman in support of a separate tolerance exemption petition 

(MRID not yet assigned). Further analysis of the fertility index did not indicate a 

decrease in the index based on data from a recent study (Martell, 2013b). The current 

study reports 11 pregnant out of 12 mated animals (92.3%) in the control, 250 and 500 

mg/kg bw/day and 10/12 mated animals (83.3%) for the 750 mg/kg bw/day groups. 

However, in the recent n-butyl benzoate study, the control group fertility index was 75%. 

(Martell 2013b). Therefore, the fertility index finding in the di-n-butyl carbonate study is

not attributable to the test material. Similar evaluation of the gestation index data was

performed. In the same recent study by Martell (2013b), the gestation index of the control

animals was reported as 77.7% for n-butyl benzoate. Therefore, the gestation index 

finding of 80% for di-n-butyl carbonate was within controls reported for BioAgri and 

therefore is not attributable to the test material. In Martell (2013b), the pre-implantation 

loss for the control group in the butyl benzoate study was 44.3%, which is higher than the 

42.2% reported in the high dose group for this study. In addition to pre-implantation and 

post-implantation losses in this study (Martell 2013a), total pups (pups born live) were 

statistically lower at 750 mg/kg bw/day (5.7) when compared to the control group (11.7). 

No alterations on pup body weights were observed between control and treated groups 

between days 0 to 4 postnatal and no macroscopic findings were observed in treated or 

control groups.

Although the study authors reported that the No Observed Adverse Effect Level 

(NOAEL) was 750 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 n-di-butyl carbonate 

(EC 09/12) in Wistar Hannover rats may be 500 mg/kg bw/day for parental animals 

(males and females) and 500 mg/kg bw/day based upon embryo-fetal toxicity.

The Lowest Observed Adverse Effect Level (LOAEL) should be considered to be 

750 mg/kg bw/day based on decreased body weight gain in male and female paternal 

animals and embryo-fetal toxicity at 750 mg/kg bw/day as evidenced by increased preand post-implantation losses and decreased total number of pups (Martell 2013a).]

4. Subchronic toxicity. The general systemic NOAEL from the 28-Day OPPTS

3650.2000 (OECD 422) Combined Repeated Dose Toxicity Study with a Reproduction

/Developmental Toxicity Screening Test in rats is 500 mg/kg body weight/day.

5. Chronic toxicity. No chronic toxicity data for di-n-butyl carbonate 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 
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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, Section 3, of this

document.

6. Animal metabolism. Esterase mediated hydrolysis is a well-established primary

pathway by which all esters are metabolically degraded. If ingested di-n-butyl carbonate 

would be readily hydrolyzed by esterases in the gut to generate two molar equivalents of 

n-butyl alcohol and one molar equivalent of carbonic acid (aqueous CO2 solution). The nbutanol log Kow = 0.88 and as such, is considerably less than the parent carbonate ester, 

which has a log Kow = 3.18. Thus, the n-butanol metabolite would be rapidly excreted 

and/or be oxidized sequentially by alcohol dehydrogenase and aldehyde dehydrogenase 

to generate butanoic acid, which is degraded through p-oxidation to generate CO2 and

H2O

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 carbonic acid (CO2) as the primary metabolites.

8. Endocrine disruption. Di-n-butyl carbonate does not belong to a class of 

chemicals designated or potentially designated as endocrine disrupters. Although at some 

future date EPA may screen di-n-butyl carbonate 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 

di-n-butyl carbonate via potential residues on foods and in drinking water.

1. Dietary exposure. The dietary (food plus drinking water) exposures for di nbutyl carbonate are expressed as a percentage of the proposed chronic population 

adjusted dose (cPAD) for the general US population and children 1-2 years old, the 

subpopulation with the highest potential exposures.

Although the NOAEL for di-n-butyl carbonate in OPPTS 870.3650.2000 (OECD 

422) study is reported as 750 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 n-dibutyl carbonate (EC 09/12) 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. 
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The Level (LOAEL) should be considered to b 750 mg/kg bw/day based on 

decreased body weight gain in male and female paternal animals and embryo-fetal 

toxicity at 750 mg/kg bw/day as evidenced by increased pre- and post-implantation losses

and decreased total number of pups. The chronic reference dose (cRfD) is therefore

conservatively proposed to be 5 mg/kg/day (500 mg/kg bw/day ÷ 100).

The available data for the proposed non-food and food use patterns of use support 

that the FQPA safety factor for di-n-butyl carbonate should be reduced from 10X to IX 

(Section E. Safety Determination). Therefore, only the 10X factors for intra- and interspecies variability should be included in calculating the chronic population adjusted dose 

(cPAD = cRfD).

EPA assesses potential dietary exposures to inert ingredients used in agricultural 

pesticide formulations using a screening-level model referred to as "I-DEEM," 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 I-DEEM. 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 will assume 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 0.189 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).

Thus, 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 14.12% 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 di n-butyl carbonate via drinking water is expected to be 

negligible.
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2. Non-dietary exposure. Given the low estimate of dietary exposure, there is 

ample room in the overall aggregate margin of exposure (MOE) for non-dietary uses.

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 di-n-butyl carbonate. Moreover, 

di-n-butyl carbonate 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 common 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 IDEEM dietary exposure estimates, there is a reasonable certainty that no harm will result 

to the U.S. population from the aggregate exposure to di-n-butyl carbonate.

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.

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 di-n-butyl carbonate and for the 

quantification of hazard for dietary exposure assessment. No 

immunotoxicological or neurotoxicity findings were reported in the 
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database. There are no residual uncertainties for pre- and/or post-natal 

toxicity. 

Di-n-butyl carbonate 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 Neurotoxicity

There is no evidence of neurotoxicity in the toxicological database for din-butyl carbonate. In the OPPTS 870.3650 (OECD 422) Combined 

Repeated Dose Toxicity Study with the Reproductive and Developmental 

Toxicity Screening Test, 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 

neuro-pathological findings were reported in the study.

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Offspring effects at the high dose levels of 750 mg/kg bw/day were 

associated with maternal toxicity in the form of statistically significant 

body weight gain during gestation. Significant offspring effects at 750 

mg/kg bw/day were limited to increased pre-and post-implantation 

mortality with decreased number of pups on Day 0. All effects to the pups 

and parental 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 di-n-butyl carbonate, the degree of concern for the effects 

observed in the di-nbutyl carbonate 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 di-n-butyl carbonate are protective of adverse effects in both 

offspring and adults.

In conjunction with the n-butanol tolerance reassessment, EPA (2005) has 

not expressed concern that n-butanol, the major metabolite for di-n-butyl 

carbonate, may cause adverse effects in sensitive populations, infants and 

children.

"Thus based on the available information there is no concern at this

time for increased sensitivity to infants and children to n-butanol 

and isobutyl alcohol when used as an inert ingredient in pesticide 

formulations. For the same reason, a safety factor analysis has not 

been used to assess risk and, therefore, the additional tenfold safety 
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factor for the protection of infants and children is also 

unnecessary."

Residual Uncertainty in the Exposure Database

The dietary risk assessment for di-n-butyl carbonate is based on 

conservative high-end assumptions (over-estimates) of dietary exposures. 

Estimated dietary exposure is based on assumed residues from the foliar 

application of pesticides products in which the inert ingredient is assumed 

to be present in 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, 

500 mg/kg/bw/day, for the offspring effect from the OPPTS 870.3650 

(OECD 422) Combined Repeated Dose Toxicity Study with the 

Reproductive and Developmental Toxicity Screening Test by 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 di-n-butyl carbonate 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.

Additionally, I-DEEM modeling supported that the estimated dietary 

exposures to di-n-butyl carbonate for children 1-2 years of age, the potentially 

most exposed population, is 14.2%, and therefore, below the 100% of the 

cPAD.

F. International Tolerances

There are no known international tolerances for di-n-butyl carbonate.