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: Inert 

Tolerance Exemption

Petition No 1E7893 CAS No and Name: 104-

76-7; 1-Hexanol, 2-ethylInert Tracking No: N/A

FROM: John C. Redden, M.S. Team Leader

Janet Whitehurst, M.S. Biologist

Inert Ingredient Assessment Branch (IIAB)

Registration Division (7505P)

TO: PV Shah, Ph.D. Branch Chief

Inert Ingredient Assessment Branch (IIAB)

Registration Division (7505P)
2

EXECUTIVE SUMMARY

EPA has received a pesticide petition 1E7893 from Cognis Corporation, c/o Lewis & 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-ethyl-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 assess as required under the Federal Food Drug and 

Cosmetic Act (FFDCA) the risk of the use of 2-ethyl-1-hexanol; and to amend 40 CFR §180.910 

and 180.930 to set a maximum use-level of 2-ethyl-1-hexanol (CAS No. 104-76-7) at 20% of inert 

ingredient in pesticide formulations.

Industrially, 2-ethyl-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, printing inks, 

and impregnating agents. 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 under 21 USC 177.1200 

and 176.210 . In addition, 2-ethyl-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 data 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-ethyl-1-

hexanol are not expected based on the use pattern requested 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 

moderately irritating to the skin and severely 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 oncogenicity 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-ethyl-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-ethylhexanoic acid, which can be oxidized to a hydroxyl acid 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-ethylhexanoic acid, 2-ethylhexanoic 

acid glucuronide, 2-ethyl-1, 6-hexanedioic acid and 2-ethyl-5-hydroxyhexanoic acid. In the rabbit 

given an oral dose of 2-ethylhexanol, the major urinary metabolite was 2-ethylhexanoyl 
3

glucuronide; 2-ethyl-2, 3-dihydroxyhexanoic 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 carcinogenicity 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 

uncertainty 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 yrs old, the most highly exposed 

population subgroup. The aggregate risk assessment was not performed because residential use of 

pesticide products containing 2-ethylhexanol 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 assessment 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. Occupational 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 available data supports a maximum use level of 10% rather than 20% 

requested by the registrant. There is a reasonable certainty 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 other non-occupational pesticide 

exposure data. Therefore, it is recommended that that the maximum use level of 2-ethyl-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 Agency or EPA, pursuant to Section 408(d) of the Federal Food, Drug and 

Cosmetic Act (FFDCA), with respect to the inert ingredient, 2-ethyl-1-hexanol, that the maximum 

use level of 2-ethyl-1-hexanol in pesticide formulations applied to growing crops be increased 

from 2.5% to 20%. 
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 

synthetic alcohol. Industrially, 2-ethyl-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, printing inks, and impregnating agents. EPA expects that exposure to 2-ethyl-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-ethyl-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 inert ingredient, 2-ethyl-1-hexanol, which is also known as 

isooctanol. 2-ethyl-1-hexanol is a branched, eight carbon fatty alcohol. The structure of 2-ethyl-1-

hexanol is shown below.

 

 

 

There are several synthetic pathways for the manufacture of 2-ethyl-1-hexanol. The predominant 

process is the “oxo route” which accounts for >95% of the 2-ethyl-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-purity (>99%). Identifiers and chemical/physical properties for 

2-ethyl-1-hexanol are provided in Table 1 on the proceeding page. The chemical/physical property 

values are taken from U.S. EPA 2006b.
5

Table 1. Chemical Identity Information and Chemical/Physical Property Values for 2-ethyl1-hexanol

Purity: >99.0 (2-ethyl-1-hexanol)

CAS#: 104-76-7

Empirical Formula: C8H18O

Physical Characteristics: Clear colorless liquid 

Odor: Mild characteristic odor

Molecular Weight: 130.23

Density: 6.94 lb/gal at 200C

Melting Point: -760C

Boiling Point: 183-1850C

Water Solubility: Nearly insoluble in water

Vapor Pressure: 0.06 at 200C, mmHg

Log Kow 2.73 (estimated)

Henry’s Law Constant 2.3 x 10-5atm/m3/mole

Common Names: 2-ethyl-1-hexanol; 2-ethylhexyl alcohol; 1-hexanol

III. HUMAN HEALTH ASSESSMENT

The Agency has reviewed the data submitted by the petitioner. The Agency has 

concluded that the data on 2-ethyl-1-hexanol are adequate to characterize the toxicity 2-ethyl1-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-ethyl-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 moderately irritating to the 

skin and severely irritating to the eye. 

Table 2. Summary of Acute Toxicity Data for 2-ethyl-1-hexanol

Species Route LD50 (mg/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 Eye 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-ethyl-1-hexanol in their diet at a dose of approximately 1500 mg/kg/day

for four days. A NOAEL could not be established. The LOAEL is 1500 mg/kg/day based 

on increases in hepatic peroxisomes (Lington & Bevin, 1991).

 Mice were gavaged with 0; 143; 351; 702; 1053; or 1755 mg/kg/day of 2-ethyl-1-hexanol

for 14 days. A significant increase in liver weight and number of hepatic peroxisomes 

were observed at 702 mg/kg and higher. The NOAEL is 351 mg/kg/day and the LOAEL is 

702 mg/kg/day based on significant increase in liver weight and number of hepatic 

peroxisomes. (Lington & Bevin, 1991).

 Rats (strain 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. Histopathological lesions included cortical degeneration in the kidneys 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 NOAEL of 250 mg/kg/day group. (Lington & 

Bevin, 1991).
7

 F344 rats were gavaged with 0; 25; 125; 250 or 500 mg/kg/day of 2-ethyl-1-hexanol 5 

days/week for 13 weeks. The NOAEL is 125 mg/kg/day. The LOAEL is 250 mg/kg/day

based on a decrease in body weights for both sexes at the high dose group and, relative 

liver, kidney, and stomach weights increases at 250 and 500 mg/kg. Gross pathological 

examination revealed forestomach lesions in the 500 mg/kg animals and peroxisome 

proliferation in the liver. (Lington & Bevin, 1991; Astill et al., 1996)

 B6C3F1 mice 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 only effects seen in the mouse were increased relative 

stomach weights in males and a low incidence of gross and microscopic findings in the 

forestomach 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 days 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 days 

showed no significant effects on peroxisome enzymes. The NOAEL is 1000 mg/kg/day

(Ganning et al 1982, cited in Lington and Bevan 1991)

 In a dietary study, rats were fed 2.0% 2-ethyl-1-hexanol in their diet (approx. 1000 

mg/kg/day) for 21 days; a number of effects were noted including decreased serum lipids, 

increased liver weights, and an increase in liver peroxisomes. A NOAEL could not be 

established. The LOAEL is 1000 mg/kg/day based on decreased serum lipids, increased 

liver weights, and an increase in liver peroxisomes. (Lington & Bevin, 1991).

 Rats were gavaged with 2-ethyl-1-hexanol at a dose of 130 mg/kg/day for 14 days. No 

significant effects were seen on the testes, serum lipids, and various liver endpoints, 

including peroxisome proliferation. (Lington & Bevin, 1991).

 Rats were gavaged with 100; 320 or 950 mg/kg/day for five days/week for 28 days. 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 peroxisomes at the LOAEL of 

320 mg/kg/day. (Lington & Bevin, 1991)

 Rats were gavaged with 0; 143; 352; 702 or 1053 mg/kg/day of 2-ethyl-1-hexanol for 14 

days. A significant increase in liver weight and number of hepatic peroxisomes were 

observed at 702 mg/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-hexanol

Species Study 

Duration 

(days)

NOAEL/LOAEL1 Effects Reference

Mice 4 LOAEL = 1500 

mg/kg /day

Hepatic peroxisomes

increased

Lington & Bevin, 

1991

Rats 91 NOAEL = 250 

mg/kg/day

LOAEL = 1250 

mg/kg/day

Liver & Kidney toxicity Lington & Bevin.

1991

Mice 14 NOAEL = 351 

mg/kg/day 

LOAEL = 702 

mg/kg/day

Hepatic peroxisomes 

increased &

Liver weights increased

Lington & Bevin,

1991

Rats 91 NOAEL = 125 

mg/kg/day 

LOAEL = 250 

mg/kg/day

Forestomach lesions &

Hepatic peroxisomes 

increased

Lington & Bevin,

1991

Mice 91 LOAEL = 500 

mg/kg/day

 NOAEL=250

Relative stomach 

weights increased

Astill et al. 1996a

Rats 7 LOAEL = 1350 

mg/kg/day

Hepatic peroxisomes 

increased &

Liver weights increased

Lington & Bevin,

1991

Rats 14 NOAEL = 1000 

mg/kg/day

No significant effects on 

peroxisomes

Lington & Bevin,

1991

Rats 21 LOAEL = 1000

mg/kg/day

NOAEL could not be 

established

Hepatic peroxisomes 

increased

Liver weights increased

Serum lipids decreased

Lington & Bevin,

1991

Rats 14 130 mg/kg No effects seen; 

nonguideline study

Lington & Bevin,

1991

Rats 28 NOAEL = 100 

mg/kg/day

LOAEL = 320 

mg/kg/day

Hepatic peroxisomes 

increased & Liver 

weights increased

Lington & Bevin,

1991

Rats 14 NOAEL = 352 

mg/kg/day

LOAEL = 702 

mg/kg/day

Hepatic peroxisomes 

increased &

Liver weights increased

Lington & Bevin,

1991

1NAOEL – 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-ethyl-1-hexanol has neurotoxic 

potential.
9

Dermal Absorption

The rate and extent of dermal uptake of 2-ethyl-1-hexanol appears to be very low. The in vitro

dermal flux for 2-ethyl-1-hexanol was calculated to be 0.038 mg/cm2/hr in human skin (striatum 

corneum) and 0.22 mg/cm2/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-ethylhexanoic acid, which can be oxidized to a hydroxyl acid and a diacid. 

Within 28 hours following a single oral dose of [

14C]ethylhexanol 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 (Lington and Bevan, 1994). The primary metabolites in the urine were 2-

ethylhexanoic acid, 2-ethylhexanoic acid glucuronide, 2-ethyl-1, 6-hexanedioic acid and 2-ethyl-5-

hydroxyhexanoic acid. In the rabbit given an oral dose of 2-ethyl-1-hexanol, the major urinary

metabolite was 2-ethylhexanoyl glucuronide; 2-ethyl-2, 3-dihydroxyhexanoic acid and a trace of 

unmetabolized 2-ethyl-1-hexanol were also present (Lington and Bevan, 1994).

Carcinogenicity-Mouse and Rat

Carcinogenicity studies were conducted in both rats and mice with 2-ethyl-1-hexanol. The results 

of long-term oral carcinogenicity studies 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 slightly higher than in historical controls, however this effect was 

considered 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 females 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 (WHO 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 body weight gain related to decreased food consumption 

and increased mortality were noted. In addition, treatment-related hematological changes were 

seen, and slight but not statistically significant increases were noted in focal hyperplasia of the 

epithelium 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 days/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. 

Increased mortality occurred in females at 500 mg/kg/day. No increase in tumor incidence was 

noted. The NOAEL is 50 mg/kg/day based on dose-related reduced body weights at the LOAEL
10

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-ethyl-1-hexanol. This table has been 

taken from the WHO JECFA 1993 report. All the reported results were negative except a study by 

Seed (1982). Therefore, the “weight-of-evidence” shows that 2-ethyl-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 Reference7

Ames test1S-typhimurium TA98 

TA100 TA1535 TA1537

0-1.0 L/plate Neg. Kirby et al., 1983

Ames test1S.typhimurium TA98 

TA100 TA1535 TA1537

0-220 g/plate Neg. Zeiger et al., 1985

Ames test1S.typhimurium TA98 

TA100 TA1535 TA1537 

TA1538 TA2367

0-2000 g/plate Neg.3 Agarwal et al., 

1985

Ames test1S.typhimurium TA98 

Ta100 TA1537 TA1535 

TA1538

0-1.8 l/plate Neg. Litton Bionetics 

Inc. 1982a

Ames test1S. typhimurium TA98 

TA100 TA1535 TA1537 

TA1538

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 

transformation1

BALB/3T3 cells 0-162 g/plate Neg.4 Litton Bionetics 

Inc. 1982b

8-Azaguanine 

resistance assay2

S. typhimurium TA100 0-1.5 mM Pos.5Seed, 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 

assay1

L5278Y/TK+/- mouse 

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 assay

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 cultures
11

(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 by 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 any concentration of the test material, with or without activation. This study is 

negative for mutagenicity.

Developmental and Reproductive Toxicity – Mice and Rat

In a developmental toxicity study pregnant mice were gavaged with 2-ethyl-1-hexanol in corn oil 

at a dose level of 1525 mg/kg/day over gestation days (GD) 6 through 13. Control mice were 

gavaged with corn oil, and dams were allowed to litter. Administration of 2-ethyl-1-hexanol

caused statistically significant 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 (Hardin et al., 1987). The maternal and developmental NOAELs

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 respectively. 

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 determined. Live 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-ethyl-1-

hexanol in pregnant Swiss mice (NTP 1991). Microencapsulated 2-ethyl-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 fetuses 

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 fully resorbed; all other pregnant 

animals had live litters at scheduled necropsy. The numbers of live litters evaluated were 27 at 
12

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 this 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 significantly 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 by sex) 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-ethyl-1-hexanol dietary exposure throughout gestation at a 

concentration up to 135 mg/kg/day (EPA memo, 2006b). 

In a submission to USEPA in 2003 (“Distillation By-Products from Manufacture of 2-ethyl-1-

hexanol”, HPV submission, 2003), BASF submitted the results of a surrogate chemical for 

assessing the reproductive toxicity of 2-ethyl-1-hexanol. Diethylhexyl adipate (DEHA; the diester 

of adipic acid with 2-ethyl-1-hexanol) is known to be well absorbed by rodents and primates and 

rapidly converted (both in the gut and after systemic absorption) to 2-ethyl-1-hexanol and adipic 

acid (Anon. 1997). Like 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 (Clayton, et al., 1993). In a one-generation reproduction study (ICI 1988), groups of 

Wistar-derived rats (15 males/dose; 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 

administered 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-ethyl-1-hexanol), respectively. In summary, DEHA administration to male and 

female rats did not interfere with fertility, even at parentally toxic dose and the same results would 

be expected for 2-ethyl-1-hexanol.

Inhalation Studies

An inhalation developmental study was performed 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/m32-ethyl-1-hexanol) throughout gestation 

(GD 1-19). Dams were weighed daily during the first week of exposure, then weekly. Dams were 

killed on Gestation day 20. Fetuses were removed, sexed, weighed and examined for external, 

visceral and skeletal defects. 2-ethyl-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-ethyl-1-

hexanol: Eleven (11) day dermal probe study in 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 (neat) 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 erythema seen at the application site was 

found at 1.0 and 3.0 ml/kg/day. No evidence of embryotoxicity, fetotoxicity, or teratogenicity was 

noted at any dose level. The NOAEL for maternal toxicity was 1.0 ml/kg/day equivalent to 1680 

mg/kg/day, based on reduced body weight seen at the LOAEL 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 (Tyl, et al., 1992; US EPA 2006b).

B. Toxicity Endpoint Selection

In the rat 24-month study, male and female rats were gavaged five days/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. 

Increased mortality occurred in females at 500 mg/kg/day. No increase in tumor incidence was 

noted. The NOAEL is 50 mg/kg/day based on dose-related reduced body weights at the LOAEL 

of 450 mg/kg/day. (Astill, et al., 1996b). The chronic RfD is 0.5 mg/kg/day (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.

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 inhalation 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 toxicity study 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 hydronephrosis and 

tail abnormalities seen at the LOAEL 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, respectively. The available data on developmental toxicity studies 

with 2-ethyl-1-hexanol clearly suggest no evidence of increased susceptibility for infants and 

children. No two generation reproduction study is available in the database for 2-ethyl-1-hexanol, 

however, no effects on sperm and other reproductive parameters were observed in rats at doses up 

to 1080 mg/kg/day when fed on diets containing diethylhexyl adipate (DEHA). In mammals, 

DEHA is readily metabolized to 2-ethyl-1-hexanol. 
14

Section 408 of the FFDCA provides that EPA shall apply an additional margin of safety 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 safety factor 

could be removed (i.e. reduced to 1X) for 2-ethyl-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 clinical signs of 

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

developmental toxicity study is not necessary at this time. 

iv. No evidence of immunotoxicity was seen in the database; therefore, an immunotoxicity

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 highly 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 (protective) 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 

safety factor can be reduced to 1X.

IV. Exposure Assessment

In evaluating dietary exposure to 2-ethyl-1-hexanol, EPA considered exposure under the 

petitioned for exemptions from the requirement of a tolerance. EPA assessed dietary exposures 

from 2-ethyl-1-hexanol in food as follows:

i. Acute and Chronic exposures. In conducting the acute and chronic dietary exposure 

assessments, EPA used food consumption information from the U.S. Department of Agriculture 

(USDA) [1994–1996 and 1998] Nationwide Continuing Surveys of Food Intake by 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 estimates 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 inert ingredient risks in the absence of residue data is contained in the memorandum entitled 
15

‘‘Alkyl Amines 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 tolerance 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 conservatisms. 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 generally at least 50 percent of the product and often can be much higher. Further, 

pesticide products rarely 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 

ingredient 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 values because it would be highly unlikely, 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. Finally, 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 produce 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 typically one to two orders of magnitude 

higher than actual residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not 

available, the compounding of these conservative assumptions will lead to a significant 

exaggeration 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 performed.
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 value 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-ethyl-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 are safe by 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 safety 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 animals there is no 

residential exposure, therefore aggregate risk was not done.

a. Acute risk. Acute dietary risk assessment was not conducted since an endpoint of concern 

following single or few doses was not identified in the available database.

b. Chronic risk. A chronic aggregate risk assessment takes into account exposure estimates from 

chronic dietary consumption of food and drinking water using the exposure assumptions discussed 

in section IV for chronic exposure and the use limitations of not more 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 yrs old, the most 

highly 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 uses for this compound. Therefore an aggregate 

intermediate-term risk assessment was not performed.

VI. Occupational Exposure/Risk Pathway
17

ORE ASSESSMENT FOR 2-EH AGRICULTURAL USES

The Agency conducted an assessment of occupational exposures and risks that might result from 

the proposed use of 2-EH as proposed by 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 following 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). The 

rates of application per crop/use site are described by HED as “typical” 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. 

Since the NOAELs identified for short-term, intermediate-term and long-term duration exposures, 

are the same, only 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 (mg/kg/day) Dermal Inhalation Combined

Rate Treated Absorbed

Baseline 

Inhalation

Dermal

 

Mixer Loaders

Liquids: 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

Liquids: 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

Liquids: 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

Liquids: Low 

Press./High Vol. 

Turfgun

LCO Use on 

Turf (avg/IT) 0.72 5 0.00087 0.0000617 57189.54 810185.2 53418.8

LCO 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 Trees 

(Max/ ST) 0.6 40 0.04457 0.0147429 1121.79 3391.5 843.0

Wettable Powders: 

Groundboom 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 7225.4
19

(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

LCO Use on 

Turf (avg/IT) 0.725 0.00669 0.0022114 7478.63 22609.8 5619.8

LCO Use on 

Turf (Max/ST) 0.725 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 77777.82602.2

Nut Trees 

(Max/ST) 0.9 40 0.06686 0.0023143 747.86 21604.9 722.8

Groundboom 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) 0.07 400.00044 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

LCO Use on 

Turf (avg/IT) 0.725 0.01851 0.0003394 2700.62 147306.4 2652.0

LCO Use on 

Turf (Max/ST) 0.725 0.01851 0.0003394 2700.62 147306.4 2652.0

Wettable Powder: 

Low Pressure 

Handwand

Ornamentals 

(avg/IT) 0.725 0.31886 0.0565714 156.81 883.8 133.2

Ornamentals 

(Max/ST) 0.725 0.31886 0.0565714 156.81 883.8 133.2

Liquid: Low Pressure 

Handwand

Ornamentals 

(avg/IT) 0.725 0.01903 0.0015429 2627.63 32407.4 2430.6

Ornamentals 

(Max/ST) 0.725 0.01903 0.0015429 2627.63 32407.4 2430.6
VII. 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 “other substances that have a common mechanism of toxicity.”

EPA has not found to share a common mechanism of toxicity with any other substances, and does 

not appear to produce a toxic metabolite produced by other substances. For the purposes of this 

tolerance 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 of 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, were 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 Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

according to well-established procedures. In line with OPP policy, RD estimates risks 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 patterns 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 analyzed and categorized by subgroups based on age, season of the year, 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 development of specialized software and 

models that consider exposure to bystanders and farm workers as well as lifestyle and traditional 

dietary patterns among specific subgroups

IX. Environmental Fate and Drinking Water Considerations 

In 2002 (U.S. EPA, 2002), the Environmental Fate and Effects Division (EFED) evaluated the 

environmental fate of the aliphatic alcohols by reviewing the available data and considering 

Structure Activity Relationships (SAR). According to the review, the C6 through C8 alcohols, 
21

which includes 2-ethyl-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/m3/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. 

Fugacity 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 days in 

rivers and 15 to 20 days in lakes. These data suggest that 2-ethyl-1-hexanol is not very persistent 

in the environment.

In addition, biologically-mediated degradation, in both aerobic and anaerobic conditions, will limit 

leaching of 2-ethyl-1-hexanol. Based on the high volatility of most aliphatic alcohols and aeration 

sequences used in many drinking water utilities, it is unlikely that most of these compounds, 

including 2-ethyl-1-hexanol, will be found in treated water at concentrations equivalent to those in 

the environment. 

X. Ecotoxicity 

The Agency finds that, based on ecotoxicity estimates, 2-ethyl-1-hexanol is practically nontoxic on 

an acute basis. For freshwater and marine/estuarine fish, the acute toxicity estimates range from 

6.5 to 19.5 mg/L and for Daphnia magna, 22.4 mg/L. For mysid 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 

moderately irritating to the skin and severely 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 oncogenicity 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-ethyl-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-ethylhexanoic acid, which can be oxidized to a hydroxyl acid 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-ethylhexanoic acid, 2-ethylhexanoic 

acid glucuronide, 2-ethyl-1, 6-hexanedioic acid and 2-ethyl-5-hydroxyhexanoic acid. In the rabbit 

given an oral dose of 2-ethylhexanol, the major urinary metabolite was 2-ethylhexanoyl 

glucuronide; 2-ethyl-2, 3-dihydroxyhexanoic 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 volatile 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 residues 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 naturally in 

foods consumed.

EPA has determined that the available data supports a maximum use level of 10% rather than 20% 

requested by the registrant. There is a reasonable certainty 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 other non-occupational pesticide 

exposure data. Therefore, it is recommended that that the maximum use level of 2-ethyl-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 Chronic analysis for 2-ethyl-1-hexanol (1994-98 

data)

Residue file name: C:\Documents and Settings\jredden\My Documents\INERTSDEEM\2-

ethyl-1-hexanol10%.R98

 Adjustment factor #2 used.

Analysis 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. Population (autumn season) 0.037629 7.5%

U.S. Population (winter season) 0.037748 7.5%

Northeast region 0.041650 8.3%

Midwest region 0.038092 7.6%

Southern region 0.034296 6.9%

Western region 0.041883 8.4%

Hispanics 0.040340 8.1%

Non-hispanic 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%

Children 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%

-------------------------------------------------------------------------------

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