 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-ethyl-

Inert 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)

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
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%.

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%.

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.

Table 1.  Chemical Identity Information and Chemical/Physical Property
Values for 2-ethyl-1-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 10-5 atm/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-ethyl-1-hexanol.

Summary of Toxicity Data

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).

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.

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.

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 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 test1	S-typhimurium TA98 TA100 TA1535 TA1537	0-1.0 (L/plate	Neg.
Kirby et al., 1983

Ames test1	S.typhimurium TA98 TA100 TA1535 TA1537	0-220 (g/plate	Neg.
Zeiger et al., 1985

Ames test1	S.typhimurium TA98 TA100 TA1535 TA1537 TA1538 TA2367	0-2000
(g/plate	Neg.3	Agarwal et al., 1985

Ames test1	S.typhimurium TA98 Ta100 TA1537 TA1535 TA1538	0-1.8 (l/plate
Neg.	Litton Bionetics Inc. 1982a

Ames test1	S. 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.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 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

Both with and without metabolic activation

Without metabolic activation

Moderate cytotoxicity reported in most cultures

Negative from 0-225 (l/ml without metabolic activation; negative from
0.0162 (l/ml with rat hepatocytes for metabolic activation

Small dose-related increase (maximum increase was approximately 3.5
times background) in mutation frequency accompanied by decreased
survival (cytotoxicity)

Negative with and without activation with S9 and with an without
(-glucuronidase/arylsulfatase

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 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/m3 2-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.

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.

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 ‘‘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.

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

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 (avg/IT)	0.07	40	0.00520	0.0017200	9615.38	29069.8
7225.4

	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)	0.72
5	0.00669	0.0022114	7478.63	22609.8	5619.8

	LCO 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
2602.2

	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	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	LCO Use on Turf (avg/IT)	0.72	5	0.01851
0.0003394	2700.62	147306.4	2652.0

	LCO 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

Liquid: Low 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

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
HYPERLINK "http://www.epa.gov/pesticides/cumulative"
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,"  HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
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, 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.

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%

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%

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

REFERENCES

Agarwal, D.K., Lawrence, W.H., Nunez, L.J., et al., 1985.  Mutagenicity
evaluation of phthalic acid esters and metabolites in Salmonella
typhimurium cultures.  J. Toxicol. Environ. Health 16; 61-69.

Anonymous. 1997. Di-(2-ethylhexyl)adipat. Beratergremium 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.

Astill, B.D., Gingell, R., Gest, D., et al., 1996b.  Oncogenicity
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 absorption 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, 5th ed.  Wiley-VCH.

Gomez, E., Ledbetter, C.A., Hartsell, P.A., 1993.  Volatile compounds in
apricot, plum and their interspecific hybrids.  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., Myhr, B.C., Mckeon, M., Brusick, D.J., 1982.  Evaluation
of di-(2-ethylhexyl)phthalate an its major metabolites in the primary
rat hepatocyte unscheduled DNA synthesis assay.  Environ. Mutagen. 4(3),
388.  Abstract only.

HPV Submission to USEPA.  Distillation by-products from manufacture of
2-ethyl-1-hexanol.  U.S. EPA HPV Challenge Program Submission by BASF
Corporation , December 31, 2003.

ICI 1988.  ICI Central Toxicology Laboratory.  Di-(2-ethylhexyl)adipate
(DEHA):  Fertility study in rats.  Report CTL/P/2229 (unpublished study)
as cited in IRIS, U.S. EPA.

JECFA 1993.  Safety Evaluation of Certain Food Additives and
Contaminants.  WHO Food Additives Series 32.  2-Ethyl-1-hexanol.  United
Nations Environment Programme.  International Programme on Chemical
Safety.  World Health Organization.  Prepared by: The forty-first
meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

Kirby, P.E., Pizzarello, R.F., Lawlor, T.E., et al., (1983).  Evaluation
of di-(2-ethylhexyl) phthalate and its major metabolites in the Ames
test and L5278Y mouse lymphoma mutagenicity assay.  Environ. Mutagen. 5:
657-663.

Lington, A.W., and Bevan, C., 1994.  Alcohols.  In Patty’s Industrial
Hygiene and Toxicology, 4th Edition.  John Wiley & Sons, Inc.

Litton Bionetics, Inc. 1982a.  Mutagenicity evaluation of 2-ethylhexanol
(2-ethylhexanol) in the Ames Salmonella/microsome plate test.  Final
report; LBI project no. 20988; July 1982.

Litton Bionetics Inc. 1982b. Mutagenicity evaluation of 2-ethylhexanol
in the in vitro transformation of BALB/3T3 cells assay.  Final report;
LBI project no. 20992. Sept. 1982.

Litton Bionetics Inc. 1982c. Mutagenicity evaluation of 2-ethylhexanol
(2-ethylhexanol) in the mouse micronucleus test.  Final report; LBI
project no 20996; September 1982.

Nelson, B.K., Brightwell, W.S., Khan, A., et al., (1988).  Teratological
evaluation of 1-pentanol, 1-hexanol and 2-ethyl-1-hexanol administered
by inhalation to rats.  Teratology 37(5): 480.

NTP. 1989.  U.S. Department of Health and Human Services.  National
Toxicology Program.  In Vitro Cytogenetics- Chromosome Aberrations.
Study ID: 463951.  Study date: 03/30/1989.

NTP. 1991.  U.S. Department of Health and Human Services.  National
Toxicology Program.  Developmental Toxicity of 2 Ethylhexanol (CAS No.
104-76-7) in CD-1 Swiss Mice.  NTP Study: TER 90029.  Report Date: March
15, 1991.  NTIS #PB91-185900.

OECD SIDS.  1995.  SIDS Initial Assessment Profile.  SIAM 13.  February
13-15, 1995.  2-Ethylhexanol.   HYPERLINK
"http://cs3-hq.oecd.org/scripts/hpv/"
http://cs3-hq.oecd.org/scripts/hpv/

Phillips, BJ., James, T.E.B., Gangolli, S.D., 1982.  Genotoxicity
studies of di(2-ethylhexyl)phthalate and its metabolites in CHO cells.
Mut. Res. 102, 297-304.

Price, C.J., Tyl, R.W., Marr, M.C., et al., 1991.  Developmental
toxicity evaluation of DEHP metabolites in Swiss mice.  Teratology 43(5)
457.

Putnam, D.L., Moore, W.A., Schechtman, L.M., Hodgson, J.R., 1983.
Cytogenic evaluation of di-(2-ethylhexyl)phthalate and its major
metabolites in Fischer 344 rats.  Environ. Mutagen. 5: 227-231.

Ritter, E.J., Scott, W.J. Jr. Randall, J.L., Ritter, J.M., 1987.
Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol,
2-ethylhexanoic acid and valproic acid, and potentiation by caffeine.
Teratology.  35(1):41-6.

Seed, J., 1992.  Mutagenic activity of phthalate esters in bacterial
liquid suspension assays.  Environ Health Perspect. 45:111-4.

Tomita, I., Nakamura, Y., Aoki, N., Inui, N., 1982.
Mutagenic/carcinogenic potential of DEHP and MEHP.  Environ. Health
Perspect. 45; 119-125.

Tyl, R.W., Fisher, L.C., Kubena, M.F., et al., 1992.  The developmental
toxicity of 2-ethylhexanol applied dermally to pregnant Fischer 344
rats.  Fundam. Appl. Toxicol. 19(2): 176-85.

U.S.EPA. 2002.  Memo from Sid Abel, Environmental Fate and Effects
Division to Kathryn Boyle.  “Tolerance Review of Compounds Known as
Aliphatic Alcohols of the C to C18 Category as Inert Ingredients in
Terrestrial and/or Aquatic Agricultural and Non-Agricultural Uses.  May
3, 2002.

U.S.EPA 2004.  Estimation Program Interface Suite (EPI Suite v3.12)
Screen Level Tools.  Exposure Assessment Tools and Models.  United
States Environmental Protection Agency.  Office of Prevention,
Pesticides & Toxic Substances.  Office of Pollution Prevention and
Toxics.

U.S. EPA.  2006a.  Office of Prevention, Pesticides & Toxic Substances.
Chemical Information Collection and Data Development (Testing).  Results
of Section 4 Chemical Testing.  2-Ethylhexanol (EH) Test Results.

U.S. EPA. 2006b.  Memo from Kathleen Martin. Inert Ingredient Assessment
Branch to Pauline Wagner.  “Reassessment of the Three Exemptions from
the Requirement of a Tolerance for 2-Ethyl-1-hexanol (CAS#104-76-7).
March 30, 2006.

Zeiger, E., Haworth, S., Mortelmans, K., Speck, W., 1985. Mutegenicity
testing of di (2-ethylhexyl)phthalate and related chemicals in
Salmonella.  Environ. Mutagen. 7: 212-232.

 PAGE

 PAGE   2


[Federal Register Volume 80, Number 147 (Friday, July 31, 2015)]
[Rules and Regulations]
[Page 45606]
[FR Doc No: 2015-18845]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket No. USCG-2011-1126]

Security Zones; Seattle's Seafair Fleet Week Moving Vessels,
Puget Sound, WA

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

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

SUMMARY: The Coast Guard will enforce Seattle's Seafair Fleet Week
Moving Vessels Security Zones from 12:00 p.m. on July 28, 2015 through
6:00 p.m. on August 3, 2015. These security zones are necessary to help
ensure the security of the vessels from sabotage or other subversive
acts during Seafair Fleet Week Parade of Ships. The Designated
participating vessels are: The HMCS BRANDON (MM 710), the HMCS
WHITEHORSE (MM 705), HMCS VANCOUVER (FFH 331), and the USCGC MIDGETT
(WHEC 726). During the enforcement period, no person or vessel may
enter or remain in the security zones without the permission of the
Captain of the Port, Puget Sound or their Designated Representative.
The COTP has granted general permission for vessels to enter the outer
400 yards of the security zones as long as those vessels within the
outer 400 yards of the security zones operate at the minimum speed
necessary to maintain course unless required to maintain speed by the
navigation rules.

DATES: The regulations in 33 CFR 165.1333 will be enforced without
actual notice from July 31, 2015 through 6 p.m. on August 3, 2015,
unless canceled sooner by the Captain of the Port, Puget Sound or their
Designated Representative. These regulations will be enforced with
actual notice from noon on July 28, 2015 until July 31, 2015.

FOR FURTHER INFORMATION CONTACT: If you have questions on this notice,
call or email LTJG Johnny Zeng, Sector Puget Sound Waterways
Management, Coast Guard; telephone<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The Coast Guard will enforce the security
zones for Seattle's Seafair Fleet Week Moving Vessels in 33 CFR
165.1333 from 12:00 p.m. on July 28, 2015 through 6:00 p.m. on August
3, 2015.
    In accordance with the general regulations in 33 CFR part 165,
subpart D, no person or vessel may enter or remain in the security
zones without the permission of the Captain of the Port (COTP), Puget
Sound or their Designated Representative. For the purposes of this
rule, the following areas are security zones: All navigable waters
within 500 yards of the HMCS BRANDON (MM 710), the HMCS WHITEHORSE (MM
705), HMCS VANCOUVER (FFH 331), and the USCGC MIDGETT (WHEC 726) while
each such vessel is in the Sector Puget Sound COTP Zone.
    The COTP has granted general permission for vessels to enter the
outer 400 yards of the security zones as long as those vessels within
the outer 400 yards of the security zones operate at the minimum speed
necessary to maintain course unless required to maintain speed by the
navigation rules. The COTP may be assisted by other federal, state or
local agencies with the enforcement of the security zones.
    All vessel operators who desire to enter the inner 100 yards of the
security zones or transit the outer 400 yards at greater than minimum
speed necessary to maintain course must obtain permission from the COTP
or a Designated Representative by contacting the on-scene Coast Guard
patrol craft on VHF 13 or Ch 16. Requests must include the reason why
movement within this area is necessary. Vessel operators granted
permission to enter the security zones will be escorted by the on-scene
Coast Guard patrol craft until they are outside of the security zones.
    This notice is issued under authority of 33 CFR 165.1333 and 5
U.S.C 552(a). In addition to this notice, the Coast Guard will provide
the maritime community with advanced notification of the security zones
via the Local Notice to Mariners and marine information broadcasts on
the day of the event.

    Dated: July 17, 2015.
T.A. Griffitts,
Captain, U.S. Coast Guard, Acting Captain of the Port, Puget Sound.
[FR Doc. 2015-18845 Filed 7-30-15; 8:45 am]
 BILLING CODE 9110-04-P


[Federal Register Volume 78, Number 74 (Wednesday, April 17, 2013)]
[Rules and Regulations]
[Pages 22777-22778]
[FR Doc No: 2013-09033]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 100

[Docket No. USCG-2013-0161]

Special Local Regulations; Recurring Marine Events in the Seventh
Coast Guard District; St. Croix, U.S.V.I.

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

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

SUMMARY: The Coast Guard will enforce the special local regulation for
the Ironman St. Croix 70.3 Triathlon from 5 a.m. until 10 a.m. on May
5, 2013. This action is necessary to ensure safety of life on navigable
waters of the United States during the Ironman St. Croix 70.3
Triathlon. During the enforcement period, the special local regulation
will consist of a race area, which will exclude the presence of any and
all non race participants and non safety vessels. Non-participants and
non safety vessels will be prohibited from entering, transiting
through, anchoring in, or remaining within the area unless authorized
by the Captain of the Port San Juan or a designated representative.

DATES: This regulation will be enforced from 5 a.m. until 10 a.m. on
May 5, 2013.

FOR FURTHER INFORMATION CONTACT: If you have questions on this rule,
call or email CWO Anthony Cassisa, Sector San Juan Prevention
Department, Coast Guard; telephone<PHONE_NUMBER>, email
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The Coast Guard will enforce the special
local regulation pertaining to a Half Ironman Triathlon on the first
Sunday in May for the annual Ironman St. Croix 70.3 Triathlon, located
in 33 CFR 100.701 Table 1 from 5 a.m. until 10 a.m. on May 5, 2013. The
2013 event is sponsored by Project St. Croix, Inc.

    Under the provisions of 33 CFR 100.701, a vessel may not enter the
regulated area, unless it receives permission from the COTP. Vessels
may safely transit outside the regulated area, but may not anchor,
block, loiter in, or impede the race participants or official patrol
vessels. The Coast Guard may be assisted by other Federal, State, or
local law enforcement agencies in enforcing this regulation.
    This notice is issued under authority of 33 CFR 100.701 and 5
U.S.C. 552 (a). The Coast Guard will provide notice of the regulated
areas by Local Notice to Mariners, Broadcast Notice to Mariners, and
on-scene designated representatives.

    Dated: April 5, 2013.
D.M. Flaherty,
Captain, U.S. Coast Guard, Acting Captain of the Port, San Juan.
[FR Doc. 2013-09033 Filed 4-16-13; 8:45 am]
BILLING CODE 9110-04-P