1 EPA Registration Division contact: Bipin Gandhi ( 703 305 8380)

ExxonMobil Chemical Company [ 4E6937]

EPA has received a pesticide petition [ 4E6937] from ExxonMobil Chemical Company ( ExxonMobil), division of Exxon Mobil Corporation, 13501 Katy Freeway, Houston, TX 77079 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 requirement of a tolerance for C11 12 Rich Aromatic Hydrocarbon Fluid ( Aromatic 200 Fluid), in or on the raw agricultural commodities. EPA has determined that the petition contains data or information regarding the elements set forth in section 408( d)( 2) of the FFDCA; 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 . Due to the inherent physicochemical properties ( volatility) of C11 12 Rich Aromatic Hydrocarbon Fluid, there is little likelihood of C11 12 Rich Aromatic Hydrocarbon Fluid remaining intact in any crop matrix.

B. Toxicological Profile 1. Acute toxicity. C11 12 Rich Aromatic Hydrocarbon Fluid ( Aromatic 200 Fluid) has a low order of acute toxicity based on studies conducted in rats via oral and inhalation exposure, in mice via inhalation exposure, and in rabbits via dermal exposure. In an acute oral rat study, the animals were dosed at 0.5, 1.5 and 5.0 g/ kg ( EMBSI 1991a). All animals in the low and mid dose groups survived to study termination, while 3 females and 2 males ( of a total of 10 animals) died in the high dose group. All deaths occurred between days 2 and 4 following test material administration. Based on the results of this study, the LD50 for female rats is 5.0 g/ kg; the LD50 for male rats is calculated at 10.65 g/ kg and the LD50 for both sexes combined is calculated at 7.05 g/ kg for C11 12 Rich Aromatic Hydrocarbon Fluid. The rabbit dermal LD50 is greater than 3.16 g/ kg for C11 12 Rich Aromatic Hydrocarbon Fluid ( EMBSI 1990). In the acute dermal study, rabbits were dosed at 3.16 g/ kg. All animals survived to study termination and there were no treatment related clinical signs, indicating that the dermal LD50 for C11 12 Rich Aromatic Hydrocarbon Fluid exceeds 3.16 g/ kg. In an acute rat inhalation study, animals were dosed at the maximum attainable vapor concentration of 169 mg/ m3 ( 0.2 mg/ liter or 26 ppm) ( EMBSI 1993). All animals survived to study termination, indicating that the rat inhalation LC50 for 2 C11 12 Rich Aromatic Hydrocarbon Fluid is greater than 169 mg/ m3. Inhalation studies were also performed using combined vapor and aerosol generation. In rats, the LC50 was greater than 4778 mg/ m3 ( 4.8 mg/ liter or 726 ppm) ( 4618 mg/ m aerosol, 160 mg/ m3 vapor) ( EMBSI 1997c). In mice, the LC50 was greater than 1073 mg/ m3 ( 1.1 mg/ liter or 163 ppm) ( 961 mg/ m3 aerosol, 112 mg/ m3 vapor) ( EMBSI 1997a). C11 12 Rich Aromatic Hydrocarbon Fluid is a mild skin and eye irritant in rabbits.

2. Genotoxicity. C11 12 Rich Aromatic Hydrocarbon Fluid ( Aromatic 200 Fluid), showed no evidence of causing mutagenic effects in in vitro and in vivo genotoxicity assays. In an Ames assay, C11 12 Rich Aromatic Hydrocarbon Fluid was not mutagenic in Salmonella strains tested in the presence or absence of metabolic activation ( EMBSI 1991c). It was also non mutagenic when tested in an in vivo mouse bone marrow micronucleus assay using oral gavage doses of 0.25, 0.5, and 1.0 g/ kg ( EMBSI 1991b).

3. Reproductive and developmental toxicity. C11 12 Rich Aromatic Hydrocarbon Fluid showed no evidence of causing developmental toxicity and is unlikely to be a selective developmental toxicant. In a Sprague Dawley rat developmental study ( EMBSI 1992), pregnant dams were dosed by oral gavage with 75, 150 or 450 mg/ kg/ day C11 12 Rich Aromatic Hydrocarbon Fluid during gestational days 6 through 15. At 450 mg/ kg/ day, maternal body weight gain and food consumption were significantly decreased during the first three days of treatment. Mean body weight change was comparable between treated animals and controls during the overall study period, and there were no statistically significant differences in organ weights and uterine implantation data between treated groups and controls. There were no differences in mean fetal body weight, nor were there any significant differences in the incidences of fetal variations or malformations in treated groups as compared to controls, either on a per fetus or a per litter basis. Based on the study results, the maternal No Observed Adverse Effect Level ( NOAEL) is 150 mg/ kg/ day and the developmental NOAEL is greater than 450 mg/ kg/ day.

C11 12 Rich Aromatic Hydrocarbon Fluid has not been tested for reproductive toxicity. However, OECD SIDS guidelines expressly provide that chemicals such as C11 12 Rich Aromatic Hydrocarbon Fluid need not be tested for reproductive toxicity to conclude that they are not likely to be reproductive toxicants:

" For health effects testing the reproductive toxicity requirements may be satisfied through the use of data from several studies. . . . Requirements are met when a developmental toxicity study is available together with a 90 day repeated dose study that sufficiently documents that reproductive organs were examined histologically and indicate no effects."

OECD, Manual for Investigation of HPV Chemicals, Chapter 2: SIDS, The SIDS Plan and the SIDS Dossier, p. 11 ( 2002). For C11 12 Rich Aromatic Hydrocarbon Fluid, a developmental toxicity study was conducted ( EMBSI 1992), which was also tested in a 90 day subchronic study 3 ( EMBSI 1991) and histopathology of reproductive organs showed no effects. Together, these studies demonstrate that C11 12 Rich Aromatic Hydrocarbon Fluid is a low concern for reproductive toxicity.

4. Subchronic toxicity. C11 12 Rich Aromatic Hydrocarbon Fluid has low order of subchronic toxicity by the oral route of exposure. In a subchronic oral gavage study, C11 12 Rich Aromatic Hydrocarbon Fluid was administered to Sprague Dawley rats at concentrations of 300, 600 or 1000 mg/ kg/ day, 7 days/ week for 13 weeks ( EMBSI 1991). A satellite group received 1000 mg/ kg/ day for 13 weeks, followed by a 4 week recovery period. Body weights and food consumption were significantly decreased in male rats at 1000 mg/ kg/ day; this effect was not seen in female rats. Hematologic and serum chemistry changes were observed in both male and female rats at 600 and 1000 mg/ kg/ day dose levels and correlated with effects seen in the liver and spleen. Kidney and liver weights increased in both sexes at all dose levels, but the organ weights for animals in the recovery group were similar to those of control animals, indicating that this was a reversible effect. No treatment related histopathological effects were observed in the kidney.

Treatment related microscopic changes were observed in the liver, thyroid, stomach, spleen and urinary bladder of rats. Histopathologic evaluation showed that these effects were decreased and/ or reversed in the recovery group, and/ or also observed in control animals. Inflammation and necrosis of the stomach were observed in some treated animals and were attributed to the effects of intubation of a bolus dose of a locally irritating substance on the gastrointestinal tract. The effects had reversed completely after the 4 week recovery period. The NOAEL for this study is 600 mg/ kg/ day and that the minor effects seen in the study were the result of the gavage dosing mechanism, and the inherent irritating effect of large bolus dosing, rather than toxicity of C11 12 Rich Aromatic Hydrocarbon Fluid. Nonetheless, to maximize conservatism in the analysis, and for purposes of this risk assessment, a NOAEL of 300 mg/ kg/ day was assumed. Based on the results from this study, repeated exposure to very high oral doses of C11 12 Rich Aromatic Hydrocarbon Fluid can result in reversible effects to the liver, thyroid, stomach, spleen, and urinary bladder.

The neurotoxicity of C11 12 Rich Aromatic Hydrocarbon Fluid was assessed as part of a neurobehavioral testing program on aliphatic, cycloaliphatic and aromatic hydrocarbon solvents. This study suggests that C11 12 Rich Aromatic Hydrocarbon Fluid can cause slight, transient central nervous system depression   with related, minor neurobehavioral effects which are known to occur under conditions of very high exposures to hydrocarbon solvents  but that C11 12 Rich Aromatic Hydrocarbon Fluid is not expected to cause any nervous system damage. This test program was jointly sponsored by the Dutch government and the CEFIC Hydrocarbon Solvent Producers Association ( HSPA) ( Nessel et al. 2000; TNO Nutrition and Food Research Institute 2001). The purpose of this testing program was to develop data on the neurobehavioral effects of hydrocarbon solvent constituents on the central nervous system. Most representative for purposes of evaluating the toxicity of C11 12 Rich Aromatic Hydrocarbon Fluid was the test on C10 C11 Aromatics. Male rats were exposed by inhalation, 8 hours per day for 3 consecutive days to 0, 35, 110 or 365 ppm ( 0, 0.2, 0.6 and 2.0 g/ m3). Animals were tested for effects on motor 4 activity, functional observation measures ( FOB), and learned performance of a visual discrimination task. No remarkable clinical signs were observed during the testing period. Some low to moderate gait abnormalities were observed during the 3 day exposure period in rats exposed at the maximum concentration level. In the learned performance test, the high dose rats had increased latencies to make a correct choice and latencies to obtain water reinforcement, as well as increases in the variability of the speed of responding. A small, but statistically significant, decrease in the number of collected reinforcements also was observed in the high dose group. Effects of exposure were most clearly observed after the first eight hour exposure period. The LOAEL for this test was 365 ppm ( 2.0 g/ m3), and the NOAEL was 110 ppm ( 0.6 g/ m3).

5. Chronic toxicity. C11 12 Rich Aromatic Hydrocarbon Fluid has not been tested specifically for carcinogenicity because data on its structure and metabolism, subchronic health effects, and genotoxicity indicate that C11 12 Rich Aromatic Hydrocarbon Fluid is not likely to have carcinogenic properties. C11 12 Rich Aromatic Hydrocarbon Fluid does not belong to a class of chemicals known to react with DNA, nor is it metabolized to materials that are likely to react with DNA. The data available for C11 12 Rich Aromatic Hydrocarbon Fluid indicate that this compound is not genotoxic and also does not produce significant cumulative toxicity. Therefore, C11 12 Rich Aromatic Hydrocarbon Fluid is unlikely to be carcinogenic either by genetic or epigenetic mechanisms and is unlikely to be either an inducer or promoter of carcinogenicity.

6. Animal metabolism. Due to the complex, multi constituent nature of these types of aromatic hydrocarbon solvents, absorption, metabolism, distribution and excretion studies are not conducted specifically on C11 12 Rich Aromatic Hydrocarbon Fluid. However, sufficient data on other aromatic solvents   such as alkylbenzenes and alkylnaphthalenes   exist to describe the absorption, distribution, metabolism and excretion of C11 12 Rich Aromatic Hydrocarbon Fluid ( Hissink, et al. 1999; Snyder 1987; Patty's Toxicology 2001; European Union, 1999). Typically, aromatic hydrocarbons are well absorbed, widely distributed between tissues, extensively metabolized and rapidly excreted. Heavy aromatic hydrocarbon solvents are generally well absorbed by most routes of exposure. They are rapidly absorbed into the blood from oral, dermal or inhalation routes of exposure, although the efficiency of dermal absorption varies depending on the molecular weight and structure of the compounds. Following absorption, heavy aromatic hydrocarbon solvents distribute throughout the body and are extensively metabolized and eliminated. Typically, these solvents will be found at higher levels in the organs of metabolism and excretion, although they can distribute to other tissues as well, particularly those with high lipid content. The most common metabolic pathway for heavy aromatic hydrocarbon solvents is oxidation followed by conjugation. Cytochrome P450 catalyzes the oxidation of the solvents to alcohol or acidic forms. For compounds with side chains   including many constituents of C11 12 Rich Aromatic Hydrocarbon Fluid   side chain oxidation is the first step in metabolism. Glucuronidation and sulfation are both common Phase II reactions in the metabolism of heavy aromatic hydrocarbon solvents, and these reactions typically occur in the liver. Other conjugation reactions may also occur. This conjugation typically serves to detoxify the heavy aromatic hydrocarbon solvent metabolites, and the conjugates often can be found excreted in the urine. 5 Heavy aromatic hydrocarbon solvents are rapidly excreted. Both rodents and humans show similar clearance kinetics of hydrocarbons from blood. Typically, they are excreted as various metabolites in the urine, although some parent compound may still be present. Urine is the primary route of excretion for hydrophilic conjugates from both oral and inhalation exposure to heavy aromatic hydrocarbon solvents, although a much smaller fraction of metabolite excretion can also occur through the feces. Some lower molecular weight components of heavy aromatic hydrocarbon solvents   including a few of the constituents in C11 12 Rich Aromatic Hydrocarbon Fluid   may also be excreted through the lung. In radiotracer experiments, most heavy aromatic hydrocarbon solvents are almost completely eliminated from the body within 48 hours, although small amounts may reside in organs with high lipid content for slightly longer periods of time.

7. Metabolite toxicology. There are no known metabolites of toxicological concern.

8. Endocrine disruption. There are no significant findings in other relevant toxicity tests, i. e., developmental toxicity, which would suggest that C11 12 Rich Aromatic Hydrocarbon Fluid produces effects characteristic of the disruption of endocrine function. In addition, the absence of any endocrinerelated structural alerts suggest that C11 12 Rich Aromatic Hydrocarbon Fluid is not likely to have endocrine distrupting properties.

C. Aggregate Exposure 1. Dietary exposure. For Tier 1 " generic inert" acute and chronic estimates, a conservative approach was taken which did not account for considerations of inert ingredient specific weight fractions and effective application rates, or for evaporative loss, an important physical property of the C11 C12 Rich Aromatic Hydrocarbon Fluid. In addition, actual application rates are lower than the tolerance based residue data used in the Tier 1 assessment. Therefore, Tier 1 estimates on C11 12 Rich Aromatic Hydrocarbon Fluid represent a conservative assessment. Physicochemical properties of the C11 12 Rich Aromatic Hydrocarbon Fluid, e. g., volatility, which directly impacts bioavailability, was considered using a tiered approach to assess potential dietary exposure. Evaporative loss experiments were conducted using ASTM Method D3539 ( Section 16.2) with C11 12 Rich Aromatic Hydrocarbon Fluid ( Aromatic 200 Fluid) to show that there was significant potential for evaporative loss from treated agricultural surfaces. These studies showed that the evaporative loss rate for C11 12 Rich Aromatic Hydrocarbon Fluid far exceeded the realistic application rate. These data represent a conservative evaporative loss rate estimates since environmental conditions, e. g., air movement and variable temperature, were not taken into consideration. To further explore the potential for evaporative loss and the impact on dietary exposure to C11 12 Rich Aromatic Hydrocarbon Fluid, a refined Tier 2 and 3 dietary exposure analysis was developed based on selection of publicly available surrogate food residue data for volatile pesticide active ingredients. These volatile active ingredients, which have vapor pressures less than or equal to that of C11 12 Rich Aromatic Hydrocarbon Fluid and 6 associated " relative diffusion" or loss to air that are generally much lower than those for C11 12 Rich Aromatic Hydrocarbon Fluid, have extensive food residue data reported in the USDA Pesticide Data Program ( PDP). The extensive, multiyear PDP data for these two volatile surrogates were all below the detection limit therefore, these data clearly demonstrate the low potential for food residues associated with relatively volatile chemicals used on a variety of fruits and vegetables. For the health benchmark, a review of the dataset suggested that the most sensitive acute endpoint is the reduced weight gain in maternal animals in the developmental toxicity study with a NOAEL of 150 mg/ kg/ day and a NOAEL for developmental effects of greater than 450 mg/ kg/ day. Consistent with EPA practice, a 100 fold safety factor ( or Margin of Exposure, MOE) was applied to these NOAELs to determine the level at which adverse effects would not be anticipated. For the chronic endpoint, a NOAEL of 300 mg/ kg/ day was applied based on the subchronic toxicity study on C11 12 Rich Aromatic Hydrocarbon Fluid. In addition, to ensure a highly conservative risk assessment, an additional 10 fold safety factor to the usual 100 fold safety factor was applied, resulting in a chronic safety factor of 1000. No additional database uncertainty factors were warranted since C11 12 Rich Aromatic Hydrocarbon Fluid has been tested for all major toxicological endpoints with the exception of reproductive toxicity and carcinogenicity, and the available data show that neither of these endpoints is likely to be of concern.

i. Food. A conservative tiered dietary exposure assessment was conducted. Exposure values were expressed in terms of margin of exposure ( MOE) which was calculated by dividing the NOAEL by the exposure for each population subgroup. The acute MOEs focused on the lowest NOAELs developmental/ maternal toxicity, and therefore, are based on upper percentile ( 99.9th) exposures for the subpopulations of females in reproductive age, i. e., 13 to 49 years, and children 1 to 2 years ( the highest exposed subgroup). Tier I screening level analysis for a generic inert, adjusted for evaporative loss, as experimentally demonstrated for neat C11 12 Rich Aromatic Hydrocarbon Fluid, resulted in acceptable acute and chronic MOEs. When a conservative evaporative loss rate of 98% was adopted, while retaining all other conservative assumptions in the exposure assessment, the calculated MOE far exceeded the acceptable MOE of 100. Chronic dietary MOEs, even with no evaporative loss, far exceeded the acceptable MOE of 1000. In sum, these data support a conclusion that any dietary exposures to C11 12 Rich Aromatic Hydrocarbon Fluid satisfy the statute's " reasonable certainty of no harm" standard, based on worst case exposure assumptions about how C11 12 Rich Aromatic Hydrocarbon Fluid is used and conservative health benchmarks.

ii. Drinking water. An exposure assessment for drinking water is not necessary due to the volatile nature of this product, lack of water solubility, and the proposed use patterns.

2. Non dietary exposure. C11 12 Rich Aromatic Hydrocarbon Fluid is not typically suitable for indoor use in consumer products due to its inherent characteristic odor which cannot be masked by fragrances. Three outdoor residential application scenarios with the greatest potential for human exposure were modeled to determine whether these uses also satisfy the statue's " reasonable certainty of no harm" standard. Maximum weight percentages of C11 12 Rich Aromatic Hydrocarbon Fluid in 7 residential use products were assumed based on federal and state Volatile Organic Compound ( VOC) limits for consumer product formulations. OPP recommended values for applicator dermal and inhalation unit exposure values, specific to method of application, were used for estimating potential exposures during application. And based on a weight of empirical evidence, an upper bound dermal absorption value was assumed for C11 12 Rich Aromatic Hydrocarbon Fluid. Chronic residential exposures were not considered plausible given the seasonal and intermittent application events , and the rapid evaporative loss of the relatively volatile C11 12 Rich Aromatic Hydrocarbon Fluid. Based on the health benchmarks and foregoing exposure analysis described for the dietary exposure, non dietary exposure showed that in all cases, the calculated MOEs were met even using the most conservative Tier 1 exposure assessment, with maximum possible concentrations of C11 12 Rich Aromatic Hydrocarbon Fluid allowable in the product formulation and with no evaporative loss. Calculated MOEs for female adults and for children far exceeded the acceptable MOE of 100. No further analysis was warranted. Thus, the results of this conservative risk assessments support the conclusion that typical residential exposures to C11 12 Rich Aromatic Hydrocarbon Fluid satisfy the statute's " reasonable certainty of no harm" standard, based on worst case exposure assumptions about how C11 12 Rich Aromatic Hydrocarbon Fluid is used.

D. Cumulative Effects There are currently no available data or other reliable information to indicate that any toxic effects produced by C11 12 Rich Aromatic Hydrocarbon Fluid would be cumulative with those of other chemical compounds.

E. Safety Determination 1. U. S. population. Based on the inherent characteristic odor property, low toxicity, high volatility resulting in rapid evaporative loss, lack of water solubility, and the conservatism applied in the dietary and non dietary ( residential) risk assessments, C11 12 Rich Aromatic Hydrocarbon Fluid meets the statute's " reasonable certainty of no harm" standard and a tolerance exemption should be granted.

2. Infants and children. The potential aggregate exposure of C11 12 Rich Aromatic Hydrocarbon Fluid was considered from dietary and non dietary exposure routes to infants and children and based on this risk assessment, aggregate exposure is not expected to exceed the acceptable MOEs, even when infants and children are considered.

F. International Tolerances There are no known international tolerances for residues of C11 12 Rich Aromatic Hydrocarbon Fluid in food or animal feed.