**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460** 

**OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION**  February 14, 2012 **MEMORANDUM SUBJECT:**  Decision Document for Petition Number 1E7893 : 2 - Ethyl - 1 - hexanol;

Human Health Risk Assessment and Ecological Effects Assessment for Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations **PC Code:** 841003 **DP Barcode: N/A**  **Decision No.: N/A Regulatory Action:**  In ert Tolerance Exemption **Petition No** 1E7893 **CAS No and Name :**  104 - 76 - 7; 1 - H exanol, 2 - eth yl **Inert Tracking No: N/A**  **FROM:** John C. Redden, M.S. Team Leader

Janet Whitehurst, M.S. Biologist In ert Ingredient Assessment Branch (IIAB) Registration Division (7505P) **TO:** PV Shah, Ph.D. Branch Chief

In ert Ingredient Assessment Branch (IIAB) Registration Division (7505P)2

**EXECUTIVE SUMMARY** EPA has received a pesticide petition 1E7893 from Cognis Corporation, c/o L ewis & Harrison LLC, 122 C Street NW, Suite 740, Washington DC 20001, proposing pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 USC 346a(d), to amend 40 CFR §180.910 and 180.930 , to set a maximum use - level for 2 - e thyl - 1 - hexanol (CAS No. 104 - 76 - 7) , at 20 % of an inert ingredient, in pesticide formulations. 2 - Ethyl - 1 - hexanol will only be used in inert ingredients used in pesticide formulations applied to pre - and post - harvest and direct application to animals . The purpose of this document is to as sess as required under the Federal Food Drug and Cosmetic Act (FFDCA ) the risk of the use of 2 - e thyl - 1 - hexanol ; and to amend 40 CFR §180.910 and 180.930 to set a maximum use - level of 2 - e thy l - 1 - hexanol (CAS No. 104 - 76 - 7) at 2 0% of inert ingredient in pestic ide formulations. Industriall y, 2 - e thyl - 1 - hexanol is mainly used in the manufacture of ester plasticizers which are used in producing soft poly vinyl chloride. The other major use of 2 - e thyl - 1 - hexanol is in the manufacture of a chemical used in the manufac ture of coating materials, adhesives, printing inks, and impregnating agents. It occurs naturall y in food and is used as a flavor volatile and is approved as an indirect U.S. Food and Drug Administration (FDA) Food Additive under 21 USC 177.1200 and 176.21 0 . In addition, 2 - e thyl - 1 - hexanol is used as a pesticide inert ingredient in pesticide formulations applied to growing crops, raw agricultural commodities (RACs), or animals. The Agency

has reviewed the d ata submitted by the petitioner. EPA expects that exposure to 2 - ethyl - 1 - hexanol would primarily be through the oral route, via consumption of treated foods and exposure through drinking water. Residential use of pesticide products containing 2 - eth yl - 1 - hexanol are not expected based on the use pattern r equested and past use pattern. Therefore, an aggregate risk assessment was not performed. Overall, 2 - ethyl - 1 - hexanol is of low acute toxicity by the oral and dermal routes; however, it is moderatel y irritating to the skin and severel y irritating to the eye. In subchronic repeat dose studies, hepatic effects were noted, including increased liver weights and peroxisome proliferation in rats and mice. To explore this finding and EPA’s concern that it could induce cancer, EPA required oncogenicit y testing un der the Toxic Substances Control Act. After reviewing the studies submitted under the test rule, the Agency concluded that 2 - ethyl - 1 - hexanol is not carcinogenic in the mouse or rat. Based on the results of the rat and mice studies and lack of mutagenicity concerns, it can be reasonably concluded that 2 - ethyl - 1 - hexanol is not likely to be carcinogenic. No evidence of neurotoxicity was identified. The available data indicate that 2 - ethyl - 1 - hexanol is not mutagenic. Further, the available data show that 2 - eth yl - 1 - hexanol is not developmentally toxic. Because exposure to 2 - ethyl - 1 - hexanol is expected to be low and developmental toxicity is not expected , the FQPA factor of 10X was reduced to 1X The metabolic fate of 2 - ethyl - 1 - hexanol has been studied in rats and rabbits. It is readily converted to 2 - eth yl hexanoic acid, which can be oxidized to a hydrox ylacid and a diacid. Within 28 hours following a single oral dose of [14C] 2 - ethyl - 1 - hexanol to rats, about 81% of the radioactivity

was recovered in the urine, about 6% was recovered in the air as CO2, and about 8% was in the feces. The primary metabolites in the urine were 2 - eth yl hexanoic acid, 2 - ethylhexanoic acid glucuronide, 2 - eth yl - 1, 6 - hexanedioic acid and 2 - ethyl - 5 - hydrox yh exanoic acid. In the rabbit give n an oral dose of 2 - ethylhexanol, the major urinary metabolite was 2 - ethylhexanoyl3

glucuronide; 2 - eth yl - 2, 3 - dihydrox yh exanoic acid and a trace of unmetabolized 2 - ethylhexanol were also present. No endpoint of concern for acute exposure was identified in the available database. The NOAEL, from the carcinogenicit y study in rat was 50 mg/kg/day

based on dose - related reduced body weights at the LOAEL of 450 mg/kg/day . The chronic RfD is 0.5 mg/kg/day using 100 fold uncertaint y factor (10X intraspecies and 10X interspecies variation). The population adjusted dose is equal to chronic RfD (0.5 mg/kg/day) since the FQPA factor is reduced from 10X to 1X. This endpoint of concern was used for all exposure durations in order to be conservative in the risk assessment . The chronic dietary

exposure from food and water to 2 - ethyl - 1 - hexanol is 7.7% of the cPAD for the U.S. population and 25 % of the cPAD for children 1 - 2 y rs old, the most highly

exposed population subgroup. The aggregate risk assessment was not performed because r esidential use of pesticide pro ducts containing 2 - eth yl hexanol are not expected based on the use pattern requested and past use pattern. Occupational handler risks are not of concern for all scenarios. RD notes that the occupational handler ass essment assumes that mixer/loaders/applicators wear protective gloves when using open pour in support of aerial, chemigation, airblast and groundboom applications and low pressure handwands. RD believes this is a reasonable assumption given the volume of pesticide handled for these applications. O ccupational post application handler risks are not of concern. The estimated MOEs are greater than 300 based on 100 % dermal absorption. Therefore, the estimated MOEs do not exceed the Agency ’s level of concern. Environmental fate and ecological effects of concern are not expected from the proposed use pattern of 2 - ethyl - 1 - hexanol in pesticide formulations applied to pre - and post - harvest and direct application to animals. . EPA has determined that the availab le data supports a maximum use level of 10% rather than 20% requested b y the registrant . T here is a reasonable certaint y that no harm to any population subgroup will result from 2 - ethyl - 1 - hexanol when used as inert ingredient at a maximum use level of 10%, in pesticide formulations applied pre - and post harvest and direct application to animals , as result of aggregate exposure , considering available dietary and o ther non - occupational pesticide exposure data. T herefore, it is recommended that that the maximum use level of 2 - eth yl - 1 - hexanol in pesticide formulations applied under 180.910 and 180.930 be increased from 2.5% to 10 %. **I. BACKGROUND**  Cognis Corporation submitted a petition to the U.S. Environmental Protection Agency , herein referred to as the Agen cy or EPA, pursuant to Section 408(d) of the Federal Food , Drug and Cosmetic Act (FFDCA) , with respect to the inert ingredient, 2 - eth yl - 1 - hexanol , that the maximum use level of 2 - ethyl - 1 - hexanol in pesticide formulations applied to growing crops be increas ed from 2.5% to 2 0 %.4

2 - ethyl - 1 - hexanol is a branched, eight - carbon fatty alcohol. After the lighter alcohols (those with one to four carbons such as methanol or butanol), 2 - ethyl - 1 - hexanol is the most important sy nthetic alcohol. Industrially , 2 - eth yl - 1 - hexanol is mainly used in the manufacture of ester plasticizers which are used in producing soft polyvinyl chloride. The other major use of 2 - ethyl - 1 - hexanol is in the manufacture of a chemical used in the manufacture of coating materials, adhesives, pri nting inks, and impregnating agents. EPA expects that exposure to 2 - eth yl - 1 - hexanol is widespread, though not at high concentrations. It occurs naturally in food and is used as a flavor volatile and is approved as an indirect U.S. Food and Drug Administration (FDA) Food Additive. In addition, 2 - eth yl - 1 - hexanol is used as a pesticide inert ingredient in pesticide formulations applied to growing crops, raw agricultural commodities (RACs), or animals. As such, it has three tolerance exemptions: 40 CFR 180.910; 40 CFR 180.920; and 40 CFR 180.930. **II. PHYSICAL AND CHEMICAL PROPERTIES**  The subject of this petition is the i nert ingredient, 2 - ethyl - 1 - hexanol , which is also known as isooctanol. 2 - eth yl - 1 - hexanol is a branched, eight carbon fatty alcohol. The stru cture of 2 - eth yl - 1 - hexanol is shown below.

There are several sy

nthetic pathway s for the manufacture of 2 - ethyl - 1 - hexanol . T he predominant process is the “oxo route” which accounts for >95% of the 2 - eth yl - 1 - hexanol produced. The oxo reaction process for 2 - ethyl - 1 - hexanol production is shown below. The manufacturing process for 2 - ethyl - 1 - hexanol results in high - purit y (>99%). Identifiers and chemical/physical properties for 2 - ethyl - 1 - hexanol are provided in Table 1 on the proceeding page. The chemical/phy sical propert y values are taken from U.S. EPA 2006b.5

**Table 1. Chemical Identit y Information and Chemical/Physical Property Values for**  **2 -**  **ethyl**   ** 1** **- hexanol**  Purity : >99.0 ( 2 - eth yl - 1 - hexanol ) CAS#: 104 - 76 - 7 Empirical Formula: C 8 H 18 O Phy sical Characteristics: Clear colorless liquid Odor: Mild characteristic odor Molecular Weight: 130.23 Density : 6.94 lb/gal at 20 0 C Melting Point: - 76 0 C Boiling Point: 183 - 185 0 C Water Solubility : Nearl y insoluble in water Vapor Pressure: 0.06 at 20 0 C, mmHg Lo g K ow 2.73 (estimated) Henry ’s Law Constant 2.3 x 10 - 5 atm/m 3 /mole Common Names: 2 - ethyl - 1 - hexanol ; 2 - ethylhexyl alcohol; 1 - hexanol **III. HUMAN HEALTH ASSESSMENT**  The Agency has reviewed the data submitted b y the petitioner. The Agency has concluded that the data on 2 - ethyl - 1 - hexanol are adequate to character ize the toxicity 2 - ethyl 1 - hexanol . **A. Summary of Toxicity Data** 6

Acute Toxicity The results of acute toxicity studies conducted with 2 - ethyl - 1 - hexanol and the corresponding toxicity categories are summarized in Table 2 below. The Agency has determined that 2 - eth yl - 1 - hexanol is of low acute toxicity by the oral and dermal routes. Studies in rats and mice have LD50s ranging from 2000 to 6400 mg/kg body weight. 2 - ethyl - 1 - hexanol is moderatel y irritating to the skin and severely

irritating to the eye. **Table 2**  **. Summary of Acute Toxicity Data for**  **2 -**  **ethyl -**  **1 -**  **hexanol Species**  **Route LD**  **50 (m**  **g/kg bw) Toxicity**  **Category Reference**  Rat Oral 2000 - 3,700 III JECFA, 1993 Mouse Oral 3200 - 6400 III JECFA, 1993 Rabbit Dermal 2000 - >2600 III Scala, 1973 Rat Inhalation >227 ppm (1.21 mg/L) @ 6 hours No deaths , III Scala, 1973 Mice Inhalation >227 ppm (1.21 mg/L) @ 6 hours No deaths, III Scala, 1973 Rabbit Ey e Irritation Severe Scala, 1973 Rabbit Skin Irritation Moderate Scala, 1973 Subchronic Toxicity - Mouse and Rat Several sub - chronic oral studies have been performed with 2 - ethyl - 1 - hexanol . The results of these studies are presented below and in Table 3 .  Mice were fed 2 - eth yl - 1 - hexanol in their diet at a dose of approximately 1500 mg/kg/day for four day s. A NOAEL could not be establish ed . The LOAEL is 1500 mg/kg/day based on i ncreases in hepatic peroxisomes (L ington & Bevin, 1991).

 Mice were gavaged with 0; 143; 351; 702; 1053; or 1755 mg/kg/day of 2 - ethyl - 1 - hexanol for 14 day s. A significant increase in liver w eight and number of hepatic peroxisomes were observed at 702 mg/kg and higher. The NOAELis 351 mg/kg/day and the LOAEL is 702 mg/kg/day

based on significant increase in liver weight and number of hepatic peroxisomes . (L ington & Bevin, 1991).

 Rats (strai n unspecified) were fed 0; 100 (10 mg/kg/day) ; 500 (50 mg/kg/day) ; 2500 (250 mg/kg/day) or 12,500 ppm (1250 mg/kg/day) 2 - ethyl - 1 - hexanol for 13 weeks. There were no significant effects on mortality , body weights, food consumption or kidney weights. His topathological lesions included cortical degeneration in the kidney s of the high dose male rats, focal liver congestion or swelling in female rats at 1250 mg/kg/day (LOAEL) . No effects were observed at the NOAELof 250 mg/kg/day group. (L ington & Bevin, 1 991).7

 F344 rats were gavaged with 0; 25; 125; 250 or 500 mg/kg/day of 2 - eth yl - 1 - hexanol 5 day s/week for 13 weeks. The NOAEL is 125 mg/kg/day . The LOAEL is 250 mg/kg/day based on a decrease in b ody weights for both sexes at the high dose group and, r elat ive liver, kidney , and stomach weights increase s at 250 and 500 mg/kg. Gross pathological examination revealed forestomach lesions in the 500 mg/kg animals and peroxiso me proliferation in the liver. (L ington & Bevin, 1991; Astill et al., 1996)

 B6C3F1 mic e were gavaged with 0; 25; 125; 250 or 500 mg/kg/day of 2 - ethyl - 1 - hexanol for 13 weeks. At 500 mg/kg/day , the onl y effects seen in the mouse were increased relative stomach weights in males and a low incidence of gross and microscopic findings in the fore stomach and liver. A NOAEL is 250 mg/kg/day . . The LOAEL is 500 mg/kg/day based on relative stomach weights in males and a low incidence of gross and microscopic findings in the forestomach and liver. (Astill et. al., 1996)

 Rats gavaged with 1,350 mg/kg of 2 - ethyl - 1 - hexanol for seven day s showed increased liver weights and liver peroxisomes. The LOAEL is 1350 mg/kg/day (Lake et al 1975, cited in Lington Bevan 1991)

 Rats fed 2.0% 2 - ethyl - 1 - hexanol (approximately 1,000 mg/kg) in their diet for 14 day s sho wed no significant effects on peroxisome enzymes. The NOAEL is 1000 mg/kg/day (Ganning et al 1982, cited in L ington and Bevan 1991)

 In a dietary

study , rats were fed 2.0% 2 - eth yl - 1 - hexanol in their diet (approx. 1000 mg/kg/day) for 21 day s; a number of ef fects were noted including decreased serum lipids, increased liver weights, and an increase in liver peroxisomes. A NOAELcould not be established. The LOAEL is 1000 mg/kg/day based on decreased serum lipids, increased liver weights, and an increase in li ver peroxisomes. (L ington & Bevin, 1991).

 Rats were gavaged with 2 - ethyl - 1 - hexanol at a dose of 130 mg/kg/day for 14 day s. No significant effects were seen on the testes, serum lipids, and various liver endpoints, including peroxisome proliferation. (Lin gton & Bevin, 1991).

 Rats were gavaged with 100; 320 or 950 mg/kg/day for five day s/week for 28 day s. Liver weights and liver peroxisomes were significantly increased at 320 and 950 mg/kg/day . The NOAEL is 100 mg/kg/day based on liver weights and liver p eroxisomes at the L OAEL of 320 mg/kg/day . (Lington & Bevin, 1991)

 Rats were gavaged with 0; 143; 352; 702 or 1053 mg/kg/day of 2 - eth yl - 1 - hexanol for 14 day s. A significant increase in liver weight and number of hepatic peroxisomes were observed at 702 m g/kg and higher. (Lington & Bevin, 1991). The NOAEL is 352 mg/kg/ day

based on a significant increase in liver weights and number hepatic peroxisomes at the LOAEL of 702 mg/kg/day .8

**Table 3**  **. Summary of Oral Subchronic Toxicity Data for**  **2 -**  **ethyl -**  **1 -**  **hexano l**  **Species Study** 

**Duration (days)**  **NO A**  **EL/LOAEL 1**  **Effects Reference**  Mice 4 LOAEL = 1500 mg/kg /day Hepatic peroxisomes increased L ington & Bevin, 199 1 Rats 91 NOAEL = 250 mg/kg/day LOAEL = 1250 mg/kg/day Liver & Kidney toxicity Lington & Bevin. 199 1 Mic e 14 NOAEL = 351 mg/kg/day LOAEL = 702 mg/kg/day Hepatic peroxisomes increased & Liver weights increased Lington & Bevin, 199 1 Rats 91 NOAEL = 125 mg/kg/day LOAEL = 250 mg/kg/day Forestomach lesions & Hepatic peroxisomes increased Lington & Bevin, 1 99 1 Mice 91 LOAEL = 500 mg/kg/day NO AEL =250 Relative stomach weights increased Astill et al. 1996a Rats 7 LOAEL = 1350 mg/kg/day Hepatic peroxisomes increased & Liver weights increased Lington & Bevin, 199 1 Rats 14 NOAEL = 1000 mg/kg/day No signific ant effects on peroxisomes Lington & Bevin, 199 1 Rats 21 LOAEL = 1000 mg/kg/day NOAEL could not be established Hepatic peroxisomes increased Liver weights increased Serum lipids decreased Lington & Bevin, 199 1 Rats 14 130 mg/kg No effects seen ; nongui deline study Lington & Bevin, 199 1 Rats 28 NOAEL = 100 mg/kg/day L OAEL = 320 mg/kg/day Hepatic peroxisomes increased & Liver weights increased Lington & Bevin, 199 1 Rats 14 NOAEL = 352 mg/kg/day LOAEL = 702 mg/kg/day Hepatic peroxisomes increased & Liver we ights increased Lington & Bevin, 199 1

1 NA OEL

– No - Observable Effect Level 1 LOAEL = Lowest Observable Adverse Effect Level Neurotoxicity No pertinent neurotoxicity studies concerning 2 - ethyl - 1 - hexanol were identified in a search of the published literature. However, no neurotoxic effects, even at high doses, were observed in the subchronic or chronic studies, so there is no reason to assume 2 - eth yl - 1 - hexanol has neurotoxic potential.9

Dermal Absorption The rate and extent of dermal uptake of 2 - eth yl - 1 - hexanol appears to be very low. The in vitro dermal flux for 2 - eth yl - 1 - hexanol was calculated to be 0.038 mg/cm 2 /hr in human skin (striatum corneum) and 0.22 mg/cm 2 /hr in full thickness rat skin (Barber, et al., 1992; JECFA, 1993). Metabolism and Pharmacokinetics The metabolic fate of 2 - ethyl - 1 - hexanol has been studied in rats and rabbits. It is readily converted to 2 - eth yl hexanoic acid, which can be oxidized to a hydrox ylacid and a diacid. Within 28 hours following a single oral dose of [ 14 C]ethylhexanol to rats, about 81% of the radioactivity

was recovered in the urine, about 6% was recovered in the air as CO 2 , and about 8% was in the feces (Lington and Bevan, 1994). The primary metabolites in the urine were 2 - ethylhexanoic acid, 2 - ethylhexanoic acid glucuronide, 2 - eth yl - 1 , 6 - hexanedioic acid and 2 - ethyl - 5 - hydrox yh exanoic acid. In the rabbit given an oral dose of 2 - eth yl - 1 - hexanol , the major urinary metabolite was 2 - eth yl hexanoyl glucuronide; 2 - ethyl - 2 , 3 - dihydroxy hexanoic acid and a tr ace of unmetabolized 2 - ethyl - 1 - hexanol were also present (L ington and Bevan, 1994). Carcinogenicit y - Mouse and Rat C arcinogenicit y studies were conducted in both rats and mice with 2 - eth yl - 1 - hexanol . The results of long - term oral carcinogenicity stu dies indicated that 2 - ethyl - 1 - hexanol is not carcinogenic in rats (24 months) or mice (18 months). The incidence of epatocellular carcinomas at 750 mg/kg/day

in female mice was slightl y higher than in historical controls, however this effect was considere d to be incidental and unrelated to the administration of 2 - ethyl - 1 - hexanol. The increase was statistically

significant when compared with the incidence in vehicle control females but not when compared with the incidence in control f emales given distilled water by gavage. In these studies, the 750 mg/kg/day dose of the compound produced a number of statistically significant, non - carcinogenic adverse effects, but these effects were not observed at 50 or 200 mg/kg/day in mice or at 50 mg/kg /day in rats (W HO Food Additives Series 32) . In the mouse 18 - month oral study , male and female mice were gavaged with 2 - ethyl - 1 - hexanol at doses of 0, 50, 200 or 750 mg/kg/day . No substance - related changes were seen at 50 or 200 mg/kg/day . At 750 mg/kg/day , reduced bo dy weight gain related to decreased food consumption and increased mortalit y were noted. In addition, treatment - related hematological changes were seen, and slight but not statistically significant increases were noted in focal hy perplasia of the epitheli um of the forestomach . No statistically significant increases in tumor incidence were observed (Astill, et al., 1996b). In the rat 24 - month study, male and female rats were gavaged five day s/week for 24 months at 0, 50, 150 or 500 mg/kg/day. Dose - related reduced body weight gain was noted at 150 mg/kg/day and higher. Clinical findings included poor general condition, labored breathing, and piloerection. In creased mortalit y occurred in females at 500 mg/kg/day. No increase in tumor incidence was note d . The NOAE L is 50 mg/kg/day based on dose - related reduced body weights at the LOAEL10

of 450 mg/kg/day . (Astill, et. al., 1996b). The chronic RfD is 0.5 mg/kg/day (10X intrspecies and 10X intersepcies variation **.** Mutagenicity and Genotoxicity Table 4 summarizes the available genotoxicity studies on 2 - eth yl - 1 - hexanol . This table has been taken from the WHO JECFA 1993 report. All the reported results were negative except a study b y Seed (1982). Therefore, the “weight - of - evidence” shows that 2 - eth yl - 1 - hexanol is not a mutagen. **Table 4**  **. Results of Genotoxicity Assays on**  **2 -**  **ethyl -**  **1 -**  **hexanol Test**  **Test Subject 2**  **- ethyl**  **- 1**  **- hexanol**  **conc. Result**  **Reference 7**  Ames test 1 S - typhimurium TA 98 TA 100 TA1535 TA1537 0 - 1.0  L/plate Neg. Kirby et al., 1983 Ames test 1 S. ty phimurium TA 98 TA 100 TA1535 TA1537 0 - 220  g/plate Neg. Zeiger et al., 1985 Ames test 1 S. typhimurium TA 98 TA 100 TA1535 TA1537 TA 1538 TA2367 0 - 2000  g/plate Neg. 3 Agarwal et al., 1985 Ames test 1 S .typhimurium TA 98 Ta100 TA1537 TA1535 TA 1538 0 - 1.8  l/plate Neg. Litton Bionetics Inc. 1982a Ames test 1 S. typhimurium TA 98 TA 100 TA1535 TA1537 TA 1538 Urine from rats gavaged with 1 gm/kg bw/day 2 - ethyl - 1 - hexanol for 15 days Neg. DiVincenzo et al., 1983

In vitro cell transformation 1 BALB/3T3 cells 0 - 162  g/plate Neg. 4 Litton Bionetics Inc. 1982b 8 - Azaguanine resistance assay2 S. typhimurium TA 100 0 - 1.5 mM Pos. 5 Seed, 1982 Mouse micronucleus test B6C3F1 mouse bone 456 mg/kg bw /day i.p. for 1 or 2 days Neg. 6 Litton Bionetics Inc. 1982c Mouse lymphoma assay 1 L527 8Y/TK+/ - mo use lymphoma cells 0.01 - 0.24  L/ml Neg. Kirby et al., 1983 Rec - assay Bacillus subtilis 500  g/disk Neg. Tomita et al., 1982 CHO mutation assay Chinese hamster ovary cells (CHO) 1.5 - 2.8 mM Neg. Phillips et al., 1982 Unscheduled DNA synthesis a ssay Primary rat hepatocytes Not given Neg. Hodgson et al., 1982 In vivo dominant lethal assay ICR/SIM mice 250, 500, 1000 mg/kg bw/day for 5 days Neg. Rushbrook, et al., 1982 In vivo chromosomal aberration assay F344 rat bone marrow cells 0.02, 0.07, 0 .21 g/kg bw/day for 5 days Neg. Putnam et al., 1983 (1) Both with and without metabolic activation (2) Without metabolic activation (3) Moderate cytotoxicity reported in most cultures11 (4) Negative from 0 - 225  l/ml without metabolic activation; negative from 0.0162  l/ml with rat hepatocytes for metabolic activation (5) Small dose - related increase (maximum increase was approximately 3.5 times background) in mutation frequency accompanied by decreased survival (cytotoxicity) (6) Negative with and without activation with S9 and with an without  - glucuronidase/arylsulfatase (7) All references cited in the JECFA 1993 report In addition to the reports in JECFA (1993), a chromosome aberration study was sponsored b y NTP (1989) in which CHO cells were exposed in vitro to concentrations of 2 - ethyl - 1 - hexanol of 50, 108, or 233  g/ml, with and without activation. There was no increase in chromosome aberrations reported for an y concentration of the test material, with or without activation. This study is negative for mutagenicity. Developmenta l and Reproductive Toxicity

– Mice and Rat In a developmental toxicity study p regnant mice were gavaged with 2 - eth yl - 1 - hexanol in corn oil at a dose level of 1525 mg/kg/day over gestation day s (GD) 6 through 13. Control mice were gavaged with corn oil, and dams were allowed to litter. Administration of 2 - ethyl - 1 - hexanol caused statisticall y significant decreased maternal body weight gain, decreased number of viable litters, decreased liveborn per litter, decreased percentage survival of pups and decrease d birth weight and weight gain for pups (Hardin et al., 1987). The maternal and developmental NOAEL s for this study are less than 1525 mg/kg/day (limit dose for developmental toxicity studies is 1000 mg/kg/day) based on decreased maternal body weight gain, decreased number of viable litters, decreased liveborn per litter, decreased percentage survival of pups and decreased birth weight and weight gain for pups respectivel y . In a developmental toxicity study conducted in the rat, pregnant rats were gavaged with 2 - ethyl - 1 - hexanol at approximately 800 and 1600 mg/kg bw (6.25 or 12.5 mmol/kg bw) on GD 12. On GD 20, the rats were killed. Following cesarean section implantation sites were determined in situ and the number of dead or resorbed fetuses was determ ined. L ive fetuses were removed and examined; internal and external soft tissue and skeletal malformations were recorded. At the high dose, statistically significant effects were seen in the live fetuses. These effects include hydronephrosis (8%), tail defects (5%), and limb defects (10%). No maternal effects associated with the test compound were reported (Ritter et al., 1987; JECFA 1993; EPA Memo 2006b). The developmental NOAEL is 800 mg/kg/day based on a LOAEL of 1600 mg/kg/day ( hydronephrosis (8%) , tail defects (5%), and limb defects (10%) . The National Toxicology Program has conducted a developmental toxicity study on 2 - eth yl - 1 - hexanol in pregnant Swiss mice (NTP 1991). Microencapsulated 2 - eth yl - 1 - hexanol was provided to mice on GD 0 to 17 at 0, 90, 300 or 900 ppm in feed. These doses are equivalent to 0, 13.5, 45.0, or 135 mg/kg/day . At sacrifice (GD 17) the number of ovarian corpora lutea and uterine implantation sites, including resorptions, and dead or live fetuses, were recorded. Live f etuses were sexed and examined for external, visceral and skeletal malformations and variations. No dams diet, delivered early or were removed from study . Pregnancy rate was high (93 - 96%) and equivalent across all groups. One control litter at 0% was ful ly resorbed; all other pregnant animals had live litters at scheduled necrops y. The numbers of live litters evaluated were 27 at12

0.009%, and 0.03%, and 26 at 0) and 0.09% 2 - ethyl - 1 - hexanol . There was no treatment - related maternal toxicity

observed in thi s study . Maternal body weights, weight gains (absolute or corrected for gravid uterine weight), gravid uterine weight and liver weight (absolute or relative to body weight) were unaffected. Food consumption (g/kg/day and g/day) was significantl y increased for GD 0 to 3 at 0.09% and unaffected for all other time points evaluated. There were no effects of exposure to dietary 2 - ethyl - 1 - hexanol on any gestational parameters. The number of corpora lutea, uterine implantation sites (live, dead resorbed), pre - and postimplantation loss, sex ratio (% males) and live fetal body weight per litter (all fetuses or separately b y s ex) were all equivalent across all groups. There were also no treatment - related changes in the incidence of individual, external, visceral , skeletal or total malformations or variations. In conclusion, there were no maternal or developmental toxic effects of 2 - eth yl - 1 - hexanol dietary exposure throughout gestation at a concentration up to 135 mg/kg/day (EPA memo, 2006b). In a submission t o USEPA in 2003 (“Distillation By - Products from Manufacture of 2 - eth yl - 1 - hexanol”, HPV submission, 2003), BASF submitted the results of a surrogate chemical for assessing the reproductive toxicity of 2 - eth yl - 1 - hexanol . Diethylhexyl adipate (DEHA; the dies ter of adipic acid with 2 - ethyl - 1 - hexanol ) is known to be well absorbed b y rodents and primates and rapidly converted (both in the gut and after sy stemic absorption) to 2 - eth yl - 1 - hexanol and adipic acid (Anon. 1997). Li ke 2 - ethyl - 1 - hexanol , adipic acid is metabolized via beta - oxidation but metabolized to succinic and acetic acids, and subsequently to other normal intermediary metabolites (Clay

ton, et al., 1993). In a one - generation reproduction study (I CI1988), groups of Wistar - derived rats (15 males/dos e; 30 females/dose) were administered DEHA in their diets at a level of 0, 28, 170 or 1080 mg/kg/day . After 10 weeks on the diet, the animals were mated to produce one - generation of offspring that was reared to day 36 post partum. Test substance was admi nistered continuously throughout the study (approximately 1 - 19 weeks of exposure). No effects were seen on male or female fertility . At the highest dose, however, there was a reduction in the body

weight gain of the dams during gestation; an increase in liver weight in both male and female parents; and reductions in offspring weight gain, total litter weight and litter size. The NOAEL and LOAEL for this study were also 170 and 1080 mg/kg/day DEHA (about 120 and 760 mg/kg/day 2 - eth yl - 1 - hexanol ), respectiv el y. In summary, DEHA administration to male and female rats did not interfere with fertility , even at parentall y toxic dose and the same results would be expected for 2 - eth yl - 1 - hexanol . Inhalation Studies An inhalation developmental study was performe d by

Nelson et al., (1988) in which groups of approximately

15 pregnant Sprague - Dawley rats were exposed for 7 hours/day to air saturated with 2 - ethyl - 1 - hexanol vapor (approximately 850 mg/m 3 2 - ethyl - 1 - hexanol ) throughout gestation (GD 1 - 19). Dams were we ighed dail y during the first week of exposure, then weekl y. Dams were killed on Gestation day

20. Fetuses were removed, sexed, weighed and examined for external, visceral and skeletal defects. 2 - eth yl - 1 - hexanol reduced maternal feed intake (10 - 15%) but did not produce significant maternal toxicity . No developmental toxicity was observed.13

Dermal Toxicity

Studies The American Chemistry Council (ACC) submitted two dermal studies conducted with 2 - eth yl - 1 - hexanol : Eleven (11) day dermal probe study i n male and female B6C3F1 mice, and 11 day dermal probe study in male and female Fischer F344 rats. In the rat study , 25 mated females were dosed (via occluded dermal patch) for six hours/day over GD 6 through 15 at levels of 0.3, 1.0, or 3.0 ml /kg/day

(ne at) equivalent to 0, 420, 840, 1680 or 2520 mg/kg /day 2 - ethyl - 1 - hexanol (undiluted). Maternal toxicity (reduced weight gain during GD 6 - 9) was noted at 3.0 ml /kg/day . Exfoliation and crusting were seen at all dose levels and ery thema seen at the application site was found at 1.0 and 3.0 ml/kg/day . No evidence of embryotoxicity , fetotoxicity , or teratogenicit y was noted at an y dose level. The NOAEL for maternal toxicity was 1.0 ml /kg/day equivalent to 1680 mg/kg/day , based on reduced body we ight seen at the L OAEL of 3.0 ml /kg/day , equivalent to 2520 mg/kg/day . A NOAEL for developmental toxicity is greater than 3.0 mL/kg/day . The LOAEL for developmental toxicity was not observed (T yl , et al., 1992; US EPA 2006b ). **B . Toxicity Endpoint Selection**  In the r at 24 - month study, male and female rats were gavaged five day s/week for 24 months at 0, 50, 150 or 500 mg/kg/day. Dose - related reduced body weight gain was noted at 150 mg/kg/day and higher. Clinical findings included poor general condition, labored breathing, and piloerection. In creased mortalit y occurred in females at 500 mg/kg/day. No increase in tumor incidence was noted . The NOAE L is 50 mg/kg/day based on dose - related reduced body weights at the LOAEL of 450 mg/kg/day . (Astill, et al., 1996b). T he chronic RfD is 0.5 mg/kg/day (10X intr aspecies and 10X inters p e cies variation. The population adjusted dose is equal to chronic RfD (0.5 mg/kg/day) since the FQPA factor is reduced from 10X to 1X. This endpoint of concern was used for all exposure durations in order to be conservative in the risk assessment. **C . Special Considerations for Infants and Children**  There are several developmental toxicity studies available in mice and rats by the gavage route. One developmental toxicity study in rats via i nhalation and a dermal developmental toxicity study in mice are also available. In one developmental toxicity study in mice via oral route, no developmental toxicity

was observed at the highest dose of 1525 mg/kg/day. In a separate developmental to xicity

s tudy in mice oral route, no developmental effects were observed at doses up to 135 mg/kg/day (the highest dose tested) . In a rat developmental toxicity study via oral routes, developmental and maternal toxicity the NOAEL was 800 mg/kg/day based on hydronep hrosis and tail abnormalities seen at the L OAEL of 1600 mg/kg/day above the limit dose of 1000 mg/kg/day . No developmental toxicity was seen in rats (inhalation) and mice (dermal) at doses up to 850 mg/m3 and 2520 mg/kg/day , respectivel y. The available dat a on developmental toxicity studies with 2 - ethyl - 1 - hexanol clearl y suggest no evide nce of increased susceptibility for infants and children. No two generation reproduction study is available in the database for 2 - eth yl - 1 - hexanol , however, no effects on spe rm and other reproductive parameters were observed in rats at doses up to 1080 mg/kg/day

when fed on diets containing d iethylhex yladipate (DEHA ). In mammals, DEHA is readily

metabolized to 2 - ethyl - 1 - hexanol .14

Section 408 of the FFDCA provides that EPA s hall apply an additional margin of safet y for infants and children in the case of threshold effects to account for prenatal and post natal toxicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety

will be safe for infants and children. EPA concludes that the FQPA safet y factor could be removed (i.e. reduced to 1X ) for 2 - eth yl - 1 - hexanol for the following reasons : i. The database that includes the developmental studies described above is considered adequate for FQPA assessment . ii. No evidence of increased susceptibility was observed in developmental toxicity studies and the reproduction study

described above. iii. No neurotoxicity

studies are available in the database, however, no cl inical signs of neurotoxicity

were observed in the available subchronic and chronic studies. Therefore, the developmental toxicity

study is not necessary

at this time. iv. N o evidence of immunotoxicity was seen in the database; therefore, an immunotoxic ity study is not required. v. There are no residual uncertainties identified in the exposure databases. The food and drinking water assessment is not likely to underestimate exposure to any subpopulation, including those comprised of infants and children. The food exposure assessments are considered to be highl y conservative as they are based on the use of the highest tolerance level from the surrogate pesticides for every food and 100% crop treated is assumed for all crops. EPA also made conservative (p rotective) assumptions in the ground and surface water modeling (100 ppb) used to assess exposure to 2 - ethyl - 1 - hexanol in drinking water . Taking into consideration the available information, EPA concludes the additional 10X FQPA safet y factor can be re duced to 1X. **IV . Exposure**  **Assessment** In eva luating dietary

exposure to 2 - eth yl - 1 - hexanol , EPA considered exposure under the petitioned for exemptions from the requirement of a tolerance. EPA assessed dietary exposures from 2 - eth yl - 1 - hexanol in food as f ollows: i . Acute and Chronic exposures . Inconducting the acute and chronic dietary exposure assessment s , EPA used food consumption information from the U.S. Department of Agriculture (USDA) [1994

– 1996 and 1998] Nationwide Continuing Survey s of Food Intake b y Individuals (CSFII). As to residue levels in food, no residue data were submitted for 2 - ethyl - 1 - hexanol . In the absence of specific residue data, EPA has developed an approach which uses surrogate information to derive upper bound exposure estimate s for the subject inert ingredient. Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of high use insecticides, herbicides, and fungicides. A complete description of the general approach taken to assess i nert ingredient risks in the absence of residue data is contained in the memorandum entitled15

‘‘AlkylAmines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary

Exposure and Risk Assessments for the Inerts,’’ (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

–HQ

– OPP

–2008

– 0738. In the dietary

exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest tolera nce for a given commodity . Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentration of inert ingredient in the scenarios leading to these highest levels of tolerances would be no higher than the concentration of the active ingredient. The Agency

believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded conservatism s. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate exposure. The concentrations of active ingredient in agricultural products are generall y at least 50 percent of the product and often can be much higher. Further, pesticide products rarel y have a single inert ingredient; rather there is generally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingre dient in the pesticide product in relation to that of the active ingredient. In the case of 2 - ethyl - 1 - hexanol , EPA used the aforementioned assumptions to conduct the dietary exposure assessment. Second, the conservatism of this methodology is compounded by

EPA’s decision to assume that, for each commodity , the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the active ingredient with the highest tolerance level. This assumption overstates residue value s because it would be highly unlikel y, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would be present at the level of the active ingredient in the highest tolerance for every commodity . Finall y, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of all foods are treated with the inert ingredient at the rate and manner necessary to produc e the highest residue legally possible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, and then used this methodology to choose the highest possible residue that could be found on food and assumed that all food contained this residue. No consideration was given to potential degradation between harvest and consumption even though monitoring data shows that tolerance level residues are t ypicall y one to two orders of magn itude higher than actual residues in food when distributed in commerce. Accordingl y, although sufficient information to quantify actual residue levels in food is not available, the compounding of these conservative assumptions will lead to a significant e xaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data. ii. Cancer. 2 - ethyl - 1 - hexanol is not expected to be carcinogenic since it was negative for carcinogenicity

in mice and rats in the available studies and there was a negative response for mutagenicity . Since the Agency has not identified any

concerns for carcinogenicity relating to 2 - ethyl - 1 - hexanol , a cancer dietary exposure assessment to evaluate cancer risk was not performe d.16

iii . Dietary exposure from drinking water. For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for 2 - ethyl - 1 - hexanol , a conservative drinking water concentration v alue of 100 parts per billion (ppb) based on screening level modeling was used to assess the contribution to drinking water for chronic dietary

risk assessments for 2 - eth yl - 1 - hexanol . These values were directly entered into the dietary exposure model. iv . From non - dietary exposure . The term ‘‘residential exposure’’ is used in this document to refer to non - occupational, non - dietary exposure . **V. Aggregate Risk and Determination of Safety** EPA determines whether acute and chronic pesticide exposures a re safe b y comparing aggregate exposure estimates to the acute population - adjusted dose ( aPAD ) and chronic population - adjusted Dose ( cPAD ) . The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safet y factors (SFs). EPA calculates the aPAD and cPAD by dividing the points of departure ( POD ) by

all applicable uncertainty factors ( UFs ) . For linear cancer risks, Short - , intermediate - , and chronic - term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the margin of exposure ( MOE ) called for by the product of all applicable UFs is not exceeded. **As 2**  **- ethyl**  **- 1**  **- hexanol**  **will only be used in insecticide formulations applied to**  **agricultural growing crops**  **and a nimals**  **there is no residential exposure, therefore aggregate risk was not done**  **.** a. Acute risk

. A cute dietary risk assessment was not conducted since an endpoint of concern following single or few doses was not identified in the available database. b. Ch ronic risk. A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary

consumption of food and drinking water u sing the exposure assumptions discussed in section IV for chronic exposure and the use limitations of not mor e than 50% by weight in pesticide formulations . The chronic dietary exposure from food and water to 2 - ethyl - 1 - hexanol is 7.7 % of the cPAD for the U.S. population and 25 % of the cPAD for children 1 - 2 y rs old, the most highl y exposed population subgroup. c. Aggregate cancer risk for U.S. population . The Agency has not identified any

concerns for carcinogenicity

relating to 2 - ethyl - 1 - hexanol . d. Short- term risk . Short - term aggregate exposure takes into account short - term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). There are no residential uses for this compound. Therefore an aggregate short - term risk assessment was not done. e. Intermediate - term risk . There are no residential u ses for this compound. Therefore an aggregate intermediate - term risk assessment was not performed. **VI. Occupational Exposure/Risk Pathway** 17

ORE ASSESSMENT FOR 2 - EH AGRI CUL TURAL USES The Agency

conducted an assessment of occupational exposures and risks that might result from the proposed use of 2 - EH as proposed b y the registrant. The default assumption utilized in the occupational exposure estimates were taken exposure handbook and HED Standard Operating Procedure to assess exposure and risk. The fol lowing algorithm was used: Unit Exposure * rate of application * units treated/day * rate of absorption * body weight (mg/lb handled) (lb ai/unit ie Acre) (acres) (100 %) (70 kg) In this case, to err on the “protective side” it was assumed that absorption via the dermal and inhalation routes of exposure is 100 %. The Point of Departure (No Observed Adverse Effect Level or NOAEL) is identified as 50 mg/kg bw/day for dermal and inhalation routes of exposure. The Level of Concern (LOC) is for Margins of Exposure (MOE) < 100. Margin of Exposure is calculated as NOAEL (mg/kg bw/day) ÷ Dose (mg/kg bw/day). The concentration of 2 - ethyl - 1 - hexanol in an end - use product is assumed to be 10 % (0.10). T he rates of application per crop/use site are described by HED as “t ypical” after comparisons of numerous materials used in a similar manner. The resulting estimates of exposure and risk are considered conservative, that is, protective. The estimates are based on the assumption of 100 % absorption via the dermal and inhalation routes of exposure. In addition, the units treated per day per method of application are considered to be “high end” i.e., tending towards the maximum capabilities per method. S ince the NOAELs identified for short - term, intermediate - term and long - term duration exposures, are the same, onl y the short - term MOEs are shown herein, since they are the same for intermediate - term and long - term exposures. All Margins of Exposure are greater than 100 therefore the proposed uses on agricultural crops do not exceed the Agency ’ s level of concern. See Table 5 for a summary of exposures and risks.Table 5: Asssessment for Agricultural Uses **Occupational Handler Risk**  **Assessment** Insecticides LOC 100 **Scenario Representative**  **Application Parameters Dose**  **Short -**  **Term MOEs**

**Application Targets/Crops**  **Application Area**  **(m g/k**  **g/day) Dermal**  **Inhalation Combined**  **Rate Treated**  **Absorbed Baseline**  **Inhalation Dermal**  **Mixer Loaders** Li quids: Aerial / Chemigation Corn (avg/IT) 0.07 1200 0.02040 0.0014400 2450.98 34722.2 2289.4

Corn (Max/ST) 0.2 1200 0.05829 0.0041143 857.84 12152.8 801.3 Li qu ids: Airblast Nut Trees (avg/IT) 0.25 40 0.00243 0.0001714 20588.24 291666.7 19230.8 Nut Trees (Max/ ST) 0.9 40 0.00874 0.0006171 5718.95 81018.5 5341.9 Li quids: Groundboom Corn (avg/IT) 0.07 200 0.00340 0.0002400 14705.88 208333.3 13736.3 Corn (Max/ST) 0.2 200 0.00971 0.0006857 5147.06 72916.7 4807.7 Turf/Golf Courses (avg/IT) 0.07 40 0.00068 0.0000480 73529.41 1041666.7 68681.3 Turf/Golf Courses (Max/ST) 0.2 40 0.00194 0.0001371 25735.29 364583.3 24038.5 Li quids: L ow Press./High Vol. Turfgun L CO Use on

Turf (avg/IT) 0.72 5 0.00087 0.0000617 57189.54 810185.2 53418.8 LC O Use on Turf (Max/ST) 0.72 5 0.00087 0.0000617 57189.54 810185.2 53418.8 Wettable Powders: Airblast Nut Trees

(avg/IT) 0.3 40 0.02229 0.0073714 2243.59 6782.9 1685.9 Nut Tr ees (Max/ ST) 0.6 40 0.04457 0.0147429 1121.79 3391.5 843.0 Wettable Powders: Gr oundboom Corn (avg/IT) 0.07 200 0.02600 0.0086000 1923.08 5814.0 1445.1

Corn (Max/ST) 0.16 200 0.05943 0.0196571 841.35 2543.6 632.2 Turf/Golf Courses 0.07 40 0. 00520 0.0017200 9615.38 29069.8 7225.419 (avg/IT) Turf/Golf Courses (Max/ST) 0.16 40 0.01189 0.0039314 4206.73 12718.0 3161.1 Wet. Powdr.: Low Press./High Vol. Turfgun LC O Use on

Turf (avg/IT) 0.72 5 0.00669 0.0022114 7478.63 22609.8 5619.8 LC O Use on Turf (Max/ ST) 0.72 5 0.00669 0.0022114 7478.63 22609.8 5619.8 Aerial Liquid Application Corn (avg/IT) 0.07 1200 NA NA NA NA NA

Corn (Max/ST) 0.2 1200 NA NA NA NA NA Airblast Nut Trees

(avg/IT) 0.25 40 0.01857 0.0006429 2692.31 77777.8 2 602.2 Nut Trees (Max/ST) 0.9 40 0.06686 0.0023143 747.86 21604.9 722.8 Gr oundboom Corn (avg/IT) 0.07 200 0.00220 0.0001480 22727.27 337837.8 21294.7

Corn (Max/ST) 0.2 200 0.00629 0.0004229 7954.55 118243.2 7453.2 Turf/Golf Courses (avg/IT) 0.07 40 0 .00044 0.0000296 113636.36 1689189.2 106473.6 Turf/Golf Courses (Max/ST) 0.2 40 0.00126 0.0000846 39772.73 591216.2 37265.8 Low Pressure/High Volume Turfgun LC O Use on

Turf (avg/IT) 0.72 5 0.01851 0.0003394 2700.62 147306.4 265 2.0 LC O Use on Turf (Max/ST) 0.72 5 0.01851 0.0003394 2700.62 147306.4 2652.0 Wettable Powder: Low Pressure Handwand Ornamentals

(avg/IT) 0.72 5 0.31886 0.0565714 156.81 883.8 133.2 Ornamentals (Max/ST) 0.72 5 0.31886 0.0565714 156.81 883.8 133.2 Li quid: L ow Pressure Handwand Ornamentals

(avg/IT) 0.72 5 0.01903 0.0015429 2627.63 32407.4 2430.6 Ornamentals (Max/ST) 0.72 5 0.01903 0.0015429 2627.63 32407.4 2430.6**VI I**  **. Cumulative Exposure** 

Cumulative effects from substances with a common mechanism of toxicity , Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency

consider “available information” concerning the cumulative effects of a particular pesticide's residues and “othe r substances that have a common mechanism of toxicity .” EPA has not found to share a common mechanism of toxicity with an y other substances, and does not appear to produce a toxic metabolite produced by other substances. For the purposes of this toleranc e action, therefore, EPA has assumed that does not 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 o f such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative . **VIII . Environmental Justice Statement**  Potential areas of environmental justice concerns, to the extent possible, wer e considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variet y of consumer subgroups according to well - established procedures. In line with OPP policy , RD estimates risk s to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patt erns are compiled by the USDA under CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the y ear, ethnic group, and region of the country. Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the de velopment of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups **I X.**  **Environmental Fate and Drinking Water**  **Considerations** In 2002 (U.S. EP A, 2002), the Environmental Fate and Effects Division (EFED) evaluated the environmental fate of the aliphatic alcohols b y reviewing the available data and considering Structure Activity

Relationships (SAR). According to the review, the C6 through C8 alco hols,21

which includes 2 - eth yl - 1 - hexanol , are water soluble and mobile in terrestrial and aquatic environments, moving mainly with the water phase to surface and ground water receptors. Volatility from soil (vapor pressure 0.36 mm Hg), and water (Henry ’s law constant of 2.3 x 10 - 5 atm/m 3 /mole) and microbially - mediated degradation are expected to limit transport to surface and ground water from applications or releases to land, with biodegradation being the major route of environmental dissipation. Fugaci ty modeling predicts approximately 50% to 55% of releases will be associated with the water phase and 40% with soils. Predicted dissipation half - lives range from 1.0 to 1.5 day s in rivers and 15 to 20 day s in lakes. These data suggest that 2 - eth yl - 1 - hexanol is not very persistent in the environment. In addition, biologicall y - mediated degradation, in both aerobic and anaerobic conditions, will limit leaching of 2 - eth yl - 1 - hexanol . Based on the high volatility of most aliphatic alcohols and aeration seque nces used in many

drinking water utilities, it is unlikely that most of these compounds, including 2 - eth yl - 1 - hexanol , will be found in treated water at concentrations equivalent to those in the environment. **X. Ecotoxicity**  The Agency

finds that, bas ed on ecotoxicity estimates, 2 - eth yl - 1 - hexanol is practicall y nontoxic on an acute basis. For freshwater and marine/estuarine fish, the acute toxicity estimates range from 6.5 to 19.5 mg/Land for Daphnia magna, 22.4 mg/L . For m ys id shrimp, acute toxicity is estimated to be 3.4 mg/L and for algae 14.6 mgIL . (U.S EPA 2002) **XII. Risk Characterization**  Overall, 2 - ethyl - 1 - hexanol is of low acute toxicity by the oral and dermal routes; however, it is moderatel y irritating to the skin and severel y irritat ing to the eye. In subchronic repeat dose studies, hepatic effects were noted, including increased liver weights and peroxisome proliferation in rats and mice. To explore this finding and EPA’s concern that it could induce cancer, EPA required oncogenicit y testing under the Toxic Substances Control Act. After reviewing the studies submitted under the test rule, the Agency concluded that 2 - ethyl - 1 - hexanol is not carcinogenic in the mouse or rat. Based on the results of the rat and mice studies and lack of mutagenicity concerns, it can be reasonably concluded that 2 - ethyl - 1 - hexanol is not likely to be carcinogenic. No evidence of neurotoxicity was identified. The available data indicate that 2 - ethyl - 1 - hexanol is not mutagenic. Further, the available data show that 2 - eth yl - 1 - hexanol is not developmentally toxic. Because exposure to 2 - ethyl - 1 - hexanol is expected to be low and developmental toxicity is not expected, the FQPA factor of 10X was reduced to 1X The metabolic fate of 2 - ethyl - 1 - hexanol has been studied in rats and rabbits. It is readily converted to 2 - eth yl hexanoic acid, which can be oxidized to a hydrox ylacid and a diacid.22

Within 28 hours following a single oral dose of [14C] 2 - ethyl - 1 - hexanol to rats, about 81% of the radioactivity

was recovered in the urine, about 6% was recovered in the air as CO2, and about 8% was in the feces. The primary metabolites in the urine were 2 - eth yl hexanoic acid, 2 - ethylhexanoic acid glucuronide, 2 - eth yl - 1, 6 - hexanedioic acid and 2 - ethyl - 5 - hydrox yh exanoic acid. In the rabbit given an oral dose of 2 - ethylhexanol, the major urinary metabolite was 2 - ethylhexanoyl glucuronide; 2 - eth yl - 2, 3 - dihydrox yh exanoic acid and a trace of unmetabolized 2 - ethylhexanol were also present. Further, the Agency

believes that any

exposure to 2 - ethyl - 1 - hexanol used as an inert ingredient in pesticide formulations would occur at a level much lower than the levels where any effects were noted in animal studies. Individuals are exposed to 2 - ethylhexanol naturally

— it has been found as a flavor vo latile in a number of fruits. The WHO has approved its use as a flavoring agent (JECFA 1993) and FDA allows it as an indirect food additive, which means that 2 - ethylhexanol may come in contact with food through its use in paper products. Thus, any residue s on food resulting from 2 - EH’s use as an inert ingredient in a pesticide formulation are expected to be low because 2 - ethyl - 1 - hexanol is biodegradable, and levels are not expected to be greater than what occurs naturall y in foods consumed. EPA has determ ined that the available data supports a maximum use level of 10% rather than 20% requested b y the registrant. T here is a reasonable certaint y that no harm to any population subgroup will result from 2 - ethyl - 1 - hexanol when used as inert ingredient at a maxi mum use level of 10%, in pesticide formulations applied pre - and post harvest and direct application to animals, as result of aggregate exposure, considering available dietary and o ther non - occupational pesticide exposure data. T herefore, it is recommended that that the maximum use level of 2 - eth yl - 1 - hexanol in pesticide formulations applied under 180.910 and 180.930 be increased from 2.5% to 10 %. **APPENDIX 1** U.S. Environmental Protection Agency Ver. 2.00 DEEM - FCID Chron ic analysis for 2 - ethyl - 1 - hexanol (1994 - 98 data) Residue file name: C: \ Documents and Settings \ jredden \ My Documents \ INERTSDEEM \ 2 - ethyl - 1 - hexanol 10%.R98 Adjustment factor #2 used. Analysi s Date 11 - 16 - 2011/09:54:16 Residue file dated: 11 - 16 - 2011/09:31:16/8 Reference dose (RfD, Chronic) = .5 mg/kg bw/day COMMENT 1: **Inert 57 active ingredients + drinking water (100ppb) @ 10%**

=============================================================== ================ Total exposure by population subgroup

------------------------------------------------------------------------------- Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- --------------- U.S. Population (total) 0.038302 7.7%23

U.S. Population (spring season) 0.039102 7.8% U.S. Population (summer season) 0.038747 7.7% U.S. Populatio n (autumn season) 0.037629 7.5% U.S. Population (winter season) 0.037748 7.5% Northeast region 0.041650 8.3% Midwest region 0.0 38092 7.6% Southern region 0.034296 6.9% Western region 0.041883 8.4% Hispanics 0.040340 8.1% Non - hi spanic whites 0.037545 7.5% Non - hispanic blacks 0.037058 7.4% Non - hisp/non - white/non - black 0.049393 9.9% All infants (< 1 year) 0.079416 15.9% Nursing infants 0.042542 8.5% Non - nursing infants 0.093415 18.7% Children 1 - 6 yrs 0.099167 19.8% C hildren 7 - 12 yrs 0.047968 9.6% Females 13 - 19 (not preg or nursing) 0.027788 5.6% Females 20+ (not preg or nursing) 0.029858 6.0% Females 13 - 50 yrs 0.030905 6.2% Females 13+ (preg/not nursing) 0.032768 6.6% Females 13+ (nursing) 0.038518 7.7% Males 13 - 19 yrs 0.029639 5.9% Males 20+ yrs 0.028828 5.8% Seniors 55+ 0.030486 6.1% Children 1 - 2 yrs 0.124801 25.0% Children 3 - 5 yrs 0.092392 18.5% Children 6 - 12 yrs 0.051062 10.2% Youth 13 - 19 yrs 0.028824 5.8% Adults 20 - 49 yrs 0.028880 5.8% Adults 50+ yrs 0.030415 6.1% Females 13 - 49 yrs 0.029078 5.8%

------------------------------------------------------------------------------- **REFERENCE S**  Agarwal, D.K., Lawrence, W.H., Nunez, L .J., et al., 1985. Mutagenicit y evaluation of phthalic acid esters and metabolites in Salmonella typhimurium cultures. J. Toxicol. Environ. Health 16; 61 - 69. Anony mous. 1997. Di - (2 - ethylhexyl)adipat. Beratergrem ium fuer umweltrelevante Alstoffe (BUA vol. 196. Astill, B.D., Deckardt, K., Gembhart, C., et al., 1996a. Prechronic toxicity studies on 2 - ethylhexanol in F344 rats and B6C3F1 mice. Fundam Appl. Toxicol. 29: 31 - 9.24

Astill, B.D., Gingell, R., Gest, D., et al., 1996b. Oncogenicit y testing of 2 - ethylhexanol in Fischer 344 rats and B6C3F1 mice. Fundam. And Appl. Toxicol. 31: 29 - 41. Barber, E.D., Teetsel, N.M., Kolberg, K.F., Guest, D., 1992. A comparative study of the rates of in vitro percutaneous abso rption of eight chemicals using rat and human skin. Fundam. Appl. Toxicol. 19(4): 493 - 7. Elvers, B., Rounsaville, J.F., Schulz, G., Ullman, F., 1989. Ullman’s Encyclopedia of Industrial Chemistry , 5 th ed. Wiley - VCH. Gomez, E., L edbetter, C.A., Hartsel l, P.A., 1993. Volatile compounds in apricot, plum and their interspecific h yb rids. J. Agric. Food Chem.;41(10: 1669 - 1676. Hardin, B.D., Schuler, R.L., Burg, J.R., et al., 1987. Evaluation of 60 chemicals in a preliminary developmental toxicity

test. Teratogen. Carcinog. Mutagen. 7(1): 29 - 48. Hodgson, J.R., My

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