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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: P.V. Shah; 703-308-1846.

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

Solvay USA Inc.

IN-11014

	EPA has received a pesticide petition (IN-11014) from Solvay USA Inc.,
c/o SciReg, Inc., 12733 Director’s Loop, Woodbridge, VA 22192
requesting, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.920 to
establish an exemption from the requirement of a tolerance for acetic
acid, 2-ethylhexyl ester (CAS Reg. No. 103-09-3) when used as a
solvent/cosolvent in pesticide formulations up to 50% (by weight). EPA
has determined that the petition contains data or information regarding
the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.

 

A. Residue Chemistry

	1. Plant metabolism.

	2. Analytical method. NA

	3. Magnitude of residues. NA.

B. Toxicological Profile

	1. Acute toxicity.  According to the results of acute toxicity studies
conducted with the oxo-alkyl acetates, these substances are considered
minimally toxic or of low order acute toxicity. The oxo-alkyl acetates
were non-toxic via the oral and dermal routes of exposure when evaluated
in rats and rabbits, respectively. Slight to minimal dermal irritation
and slight to moderate eye irritation were noted in rabbits.

	2. Genotoxicty. In two gene mutation studies, Salmonella/microsome
plate incorporation assays with strains TA98, TA100, TA1535, TA1537, and
TA1538 were exposed to Exxate 800 (i.e., oxo-octyl acetate) or Exxate
1300 (i.e., oxo-tridecyl acetate). Exxate 800 was applied at
concentrations of 50, 100, 200, 400, and 600 μg/plate in the initial
assay and at concentrations of 25, 50, 100, 200, and 400 μg/plate in a
repeat assay. Exxate 1300 was applied at concentrations of 625, 1,250,
2,500, 5,000, and 10,000 μg/plate in the initial assay and repeated,
due to beading, at lower concentrations of 156, 312.5, 625, 1,250, and
2,500 μg/plate. All assays were conducted with and without exogenous
metabolic activation. Positive and negative controls responded in a
manner consistent with previous laboratory assays. Exxate 800 was
cytotoxic to all strains of Salmonella exposed to ≥ 200 μg plate; no
cytotoxicity was caused by Exxate 1300. There was no evidence from
either study of induced mutant colonies over background at any dose,
with or without exogenous metabolic activation, up to the maximum
concentrations tested.

In two micronucleus studies, mice were each administered a single dose
of Exxate 800 (i.e., oxo-octyl acetate) or Exxate 1300 (i.e.,
oxo-tridecyl acetate) by oral gavage. Exxate 800 was administered at
doses of 625, 1,250, and 2,500 mg/kg body weight. Exxate 1300 was
administered at doses of 450, 900, and 1,800 mg/kg body weight.
Cytotoxicity was observed in both studies at the 48-hour sampling time.
Neither Exxate 800 nor Exxate 1300 significantly increased the frequency
of micronucleated polychromatic erythrocytes in mouse bone marrow at any
dose or sampling time

Based on the four mutagenicity studies, there was no evidence that the
oxo-alkyl acetates produce mutagenic effects. In addition, the oxo-alkyl
acetates are not structurally related to any known carcinogen.

	3. Reproductive and developmental toxicity. Three developmental
toxicity studies were conducted with the oxo-alkyl acetates. 

In the first study, pregnant Sprague-Dawley rats were dosed with an
oxo-octyl acetate mixture at dose levels of 100, 500, and 1,000
mg/kg/day. The results of the study indicated that oxo-octyl acetate is
not a selective developmental toxicant. The maternal systemic toxicity
NOEL was determined to be 100 mg/kg/day and the developmental toxicity
NOEL was 500 mg/kg/day. 

In the second study, pregnant Sprague-Dawley rats were dosed with an
oxo-tridecyl acetate mixture at dose levels of 500, 1,000, and 2,500
mg/kg/day. Based on the results, oxo-tridecyl acetate is not regarded as
a selective developmental toxicant. Both the maternal and developmental
toxicity NOEL were determined to be 500 mg/kg/day.

In the third developmental toxicity study, oxo-octyl acetate was
administered by gavage to three groups of 22 pregnant Sprague-Dawley
rats/group on gestation days 6 through 15 at dose levels of 100, 500,
and 1,000 mg/kg/day. Decreased maternal body weight was noted at the 500
and 1,000 mg/kg/day dose levels. Vertebral malformations were noted in
four fetuses of four litters at the 1,000 mg/kg/day dose level.
Malformed ribs were noted in one control and in one 100 mg/kg/day fetus.
Based on these results, the maternal systemic toxicity NOEL was
determined to be 100 mg/kg/day and the maternal systemic toxicity LOEL
was 500 mg/kg/day based on decreased body weight. The developmental
toxicity NOEL was determined to be 500 mg/kg/day and the developmental
toxicity LOEL was 1,000 mg/kg/day based on increased incidence of
various types of vertebral malformations. 

Considering all three developmental toxicity studies conducted with
rats, the maternal systemic toxicity NOEL is 100 mg/kg/day and the
maternal systemic toxicity LOEL is 500 mg/kg based on decreased body
weight. The developmental toxicity NOEL is 500 mg/kg/day and the
developmental toxicity LOEL is 1,000 mg/kg based on increased incidence
of various types of vertebral malformations. The oxo-alkyl acetates are
not teratogenic.

	4. Subchronic toxicity. In two oral subchronic studies, four groups of
20 Sprague-Dawley rats/sex/group were dosed at 0, 100, 500, and 1,000
mg/kg/day with oxo-octyl acetate or oxo-tridecyl acetate for five days a
week for 13 weeks. 

For the oxo-octyl acetate study, clinical signs were unremarkable. Only
the body weights of the high-dose males and females were slightly lower
(not statistically significant) than the controls. This finding may be
due to the slightly lower food intake in the high-dose males. No
microscopic treatment-related findings were noted to be associated with
liver weight increases. The NOEL for oxo-octyl acetate was determined to
be 100 mg/kg/day and the LOEL was 500 mg/kg/day based on increased liver
weight in both sexes of rats. 

For the oxo-tridecyl acetate study, clinical signs were unremarkable and
no rats died during the study. The body weights of the high-dose males
and females were slightly lower (not statistically significant) than the
controls. Food intake differences among the groups were not evident. The
NOEL for oxo-tridecyl acetate was determined to be 100 mg/kg/day with a
LOEL of 500 mg/kg/day based on increased incidence of tubular
nephropathy in males and increased kidney and liver weight in both
sexes. 

Results of these two oral subchronic studies conducted with oxo-octyl
acetate and oxo-tridecyl acetate suggest that branched alkyl acetates in
this molecular weight range (C8-C13 alkyl acetates) are of a low order
of toxicity following subchronic administration at doses up to 1,000
mg/kg/body weight in rats.

No data exists on the inhalation hazard of the oxo-alkyl acetates or
acetic acid, 

2-ethylhexyl ester. Given that acetic acid, 2-ethylhexyl ester is
expected to have very low toxicity and limited irritation potential,
based on data on the oxo-alkyl acetates, it is projected that it would
demonstrate very low toxicity and irritation potential from an
inhalation route of exposure.

 

	5. Chronic toxicity. Based on the four mutagenicity studies, there was
no evidence that the oxo-alkyl acetates produce mutagenic effects. In
addition to the absence of any mutagenic or genotoxic effects, the
oxo-alkyl acetates are not structurally related to any known carcinogen,
and the two oral subchronic studies conducted with oxo-octyl acetate and
oxo-tridecyl acetate did not reveal any pre-carcinogenic or
proliferative lesions. Therefore, there is no indication that acetic
acid, 2-ethylhexyl ester would be carcinogenic.

	6. Animal metabolism. NA

	7. Metabolite toxicology. NA

	8. Endocrine disruption. NA

C. Aggregate Exposure

	1. Dietary exposure. It is anticipated that acetic acid, 2-ethylhexyl
ester will be used as a solvent/co-solvent in pesticide formulations at
a concentration no higher than 50%. Acetic acid, 2-ethylhexyl ester is
not expected to be persistent or bioaccumulable in the environment based
on a PBT evaluation of the oxo-alkyl acetates. Further, acetic acid,
2-ethylhexyl ester is expected to have a low toxicity profile as
demonstrated through acute, subchronic, developmental, and mutagenicity
testing of the oxo-alkyl acetates. Therefore, dietary exposure to acetic
acid, 2-ethylhexyl ester should not be of concern.

	i. Food. It is anticipated that acetic acid, 2-ethylhexyl ester will be
used as a solvent/co-solvent in pesticide formulations at a
concentration no higher than 50%. Acetic acid, 2-ethylhexyl ester is not
expected to be persistent or bioaccumulable in the environment based on
a PBT evaluation of the oxo-alkyl acetates. Further, acetic acid,
2-ethylhexyl ester is expected to have a low toxicity profile as
demonstrated through acute, subchronic, developmental, and mutagenicity
testing of the oxo-alkyl acetates. Therefore, dietary exposure to acetic
acid, 2-ethylhexyl ester should not be of concern.

	ii. Drinking water. It is anticipated that acetic acid, 2-ethylhexyl
ester will be used as a solvent/co-solvent in pesticide formulations at
a concentration no higher than 50%. Acetic acid, 2-ethylhexyl ester is
not expected to be persistent or bioaccumulable in the environment based
on a PBT evaluation of the oxo-alkyl acetates. Further, acetic acid,
2-ethylhexyl ester is expected to have a low toxicity profile as
demonstrated through acute, subchronic, developmental, and mutagenicity
testing of the oxo-alkyl acetates. 

Acetic acid, 2-ethylhexyl ester will not be applied directly to water.
Agricultural practices minimize spray drift and typical end-use product
labels prohibit direct application to water. Therefore, use of acetic
acid, 2-ethylhexyl ester as a solvent/co-solvent in pesticide
formulations does not pose a risk to drinking water.

	2. Non-dietary exposure. Acetic acid, 2-ethylhexyl ester is expected to
have a low toxicity profile as demonstrated through acute, subchronic,
developmental, and mutagenicity testing of the oxo-alkyl acetates.
Overall, acetic acid, 2-ethylhexyl ester is considered to be a low
toxicity substance with a reasonable certainty of no harm from dietary
exposure and all other nonoccupational sources of exposure.

D. Cumulative Effects

	Solvay has not found acetic acid, 2-ethylhexyl ester to share a common
mechanism of toxicity with any other substances, and acetic acid,
2-ethylhexyl ester does not appear to produce a toxic metabolite
produced by other substances.  

Resultant risks, separately and/or combined with other substances that
may have a common mechanism of toxicity, should be low for acetic acid,
2-ethylhexyl ester. Solvay does not expect any adverse cumulative
effects associated with the use of acetic acid, 

2-ethylhexyl ester.

In addition, EPA has not made a common mechanism of toxicity finding as
to the oxo-alkyl acetates and any other substances and the oxo-alkyl
acetates do not appear to produce toxic metabolites produced by other
substances. For the purposes of the tolerance reassessment, EPA has not
assumed the oxo-alkyl acetates have a common mechanism of toxicity with
other substances.

E. Safety Determination

	1. U.S. population. Acetic acid, 2-ethylhexyl ester is expected to have
a low toxicity profile as demonstrated through acute, subchronic,
developmental, and mutagenicity studies with the oxo-alkyl acetates
studies summarized above. 

When acetic acid, 2-ethylhexyl ester is used on raw agricultural
commodities in accordance with good agricultural practice, it is
expected to meet EPA’s reasonable certainty of no harm requirement.
Based on the expected low toxicity profile of acetic acid, 2-ethylhexyl
ester, there is no reason to believe that adverse effects on the U.S.
population will result from the use of this inert ingredient in
pesticide formulations.

	2. Infants and children. Acetic acid, 2-ethylhexyl ester is
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When acetic acid, 2-ethylhexyl ester is used on raw agricultural
commodities in accordance with good agricultural practice, it is
expected to meet EPA’s reasonable certainty of no harm requirement.
Based on the expected low toxicity profile of acetic acid, 2-ethylhexyl
ester, there is no reason to believe that adverse effects on the U.S.
population will result from the use of this inert ingredient in
pesticide formulations. In addition, there is no reason to believe that
infants and children will be disproportionately at risk to the use of
acetic acid, 2-ethylhexyl ester in pesticide formulations.

In addition, the Agency has reviewed three developmental toxicity
studies conducted with the oxo-alkyl acetates and concluded that the
maternal NOAEL is 100 mg/kg/day. The developmental NOAEL is 500
mg/kg/day. The oxo-alkyl acetates produce some evidence of developmental
toxicity at doses that are greater than the doses that produce maternal
toxicity, i.e., the mother is impacted before the developing fetus.
There is no concern for the oxo-alkyl acetates for increased sensitivity
to infants and children. A safety factor analysis has not been used to
assess the risk, and the additional tenfold safety factor for the
protection of infants and children is not needed.

F. International Tolerances

	NA

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