Federal Register, Volume 75, Number 226, November 24, 2010, Pages 71519-72652 Page: 71,554
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71554 Federal Register/Vol. 75, No. 226/Wednesday, November 24, 2010/Rules and Regulations
products containing NTHE as an inert
ingredient. In this assessment,
representative scenarios, based on end-
use product application methods and
labeled application rates, were selected.
The Agency did not identify any
products intended for use on pets or
home cleaning products that contain
NTHE. For each of the use scenarios, the
Agency assessed residential handler
(applicator) inhalation exposure for
outdoor scenarios with high exposure
potential (i.e., exposure scenarios with
high end unit exposure values) to serve
as a screening assessment for all
potential residential pesticides
containing. Similarly, residential post
application oral exposure assessments
were also performed utilizing high end
outdoor exposure scenarios. Further
details of this residential exposure and
risk analysis can be found at http://
www.regulations.gov in the
memorandum entitled "JITF Inert
Ingredients. Residential and
Occupational Exposure Assessment
Algorithms and Assumptions Appendix
for the Human Health Risk Assessments
to Support Proposed Exemption from
the Requirement of a Tolerance When
Used as Inert Ingredients in Pesticide
Formulations" (D364751, 5/7/09, Lloyd/
LaMay) in docket ID number EPA-HQ-
OPP-2008-0710.
4. 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 NTHE to share a
common mechanism of toxicity with
any other substances, and NTHE does
not appear to produce a toxic metabolite
produced by other substances. For the
purposes of this tolerance action,
therefore, EPA has assumed that NTHE
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 Web site at
http://www.epa.gov/pesticides/
cumulative.
D. Safety Factor for Infants and
Children
1. In general. Section 408(b)(2)(C) of
FFDCA provides that EPA shall apply
an additional tenfold (10X) margin of
safety for infants and children in thecase of threshold effects to account for
prenatal and postnatal toxicity and the
completeness of the database on toxicity
and exposure unless EPA determines
based on reliable data that a different
margin of safety will be safe for infants
and children. This additional margin of
safety is commonly referred to as the
FQPA Safety Factor (SF). In applying
this provision, EPA either retains the
default value of 10X, or uses a different
additional safety factor when reliable
data available to EPA support the choice
of a different factor.
2. Prenatal and postnatal sensitivity.
The existing toxicology database for
NTHE consists of one OPPTS
Harmonized Guideline 870.3650
combined repeated dose toxicity study
with the reproduction/developmental
screening study in rats, and several
studies in the scientific literature on
acute oral toxicity and mutagenicity.
In the case of NTHE, there was no
increased susceptibility to the offspring
of rats following pre- and post-natal
(PND 0-4) exposure in the OPPTS
Harmonized Guideline 870.3650 study
(gavage dosing of males for 28 days,
females for 46 days). There were no
offspring effects at any dose level up to
the limit dose (1,000 mg/kg/day) where
maternal/paternal toxicity was
manifested as microscopic lesions in the
brain at 1,000 mg/kg/day. Although the
parental NOAEL selected as the point of
departure for the chronic dietary,
incidental oral, and inhalation risk
assessments is protective of the adult
animal, the particular findings in the
parental animals lead to uncertainties
for the offspring. There is a concern for
neurodevelopment since this is not
addressed in the OPPTS Harmonized
Guideline 870.3650 screening study.
3. Conclusion. Despite the fact that no
quantitative or qualitative increased
susceptibility to offspring was seen in
the OPPTS Harmonized Guideline
870.3650 combined repeated dose
toxicity study and the conservative
exposure assessment, EPA has
determined that the FQPA SF cannot be
reduced because of the neurotoxic
effects seen in the OPPTS Harmonized
Guideline 870.3650 reproductive/
developmental study and the absence of
standard neurotoxicity and
developmental studies. EPA considered
the following factors in determining that
a 10X FQPA SF should be retained:
In the OPPTS Harmonized Guideline
870.3650 study in rats there is some evidence
of neurotoxicity in the adult animals in the
OPPTS Harmonized Guideline 870.3650
reproductive/developmental study, which
occurred only at the highest dose tested of
1,000 mg/kg/day. The vacuoles in thechoroid plexus epithelial cells of the lateral
ventricles of the brain were of different size,and some of the epithelial cells were signet-
ring shaped. None of the other dose groups
(100 and 300 mg/kg/day) showed a similar
change. These results indicate a potential
concern for effects on neurodevelopment at
high doses following repeat exposure. Given
that neither neurotoxicity nor standard
developmental toxicity studies are available
on NTHE, retention of the FQPA Safety
Factor is appropriate.
E. Aggregate Risks and Determination of
Safety
Determination of safety section. EPA
determines whether acute and chronic
dietary pesticide exposures are safe by
comparing aggregate exposure estimates
to the acute PAD (aPAD) and chronic
PAD (cPAD). For linear cancer risks,
EPA calculates the lifetime probability
of acquiring cancer given the estimated
aggregate exposure. Short-,
intermediate-, and chronic-term risks
are evaluated by comparing the
estimated aggregate food, water, and
residential exposure to the appropriate
PODs to ensure that an adequate MOE
exists.
1. Acute risk. An acute aggregate risk
assessment takes into account acute
exposure estimates from dietary
consumption of food and drinking
water. No adverse effect resulting from
a single oral exposure was identified
and no acute dietary endpoint was
selected. Therefore, NTHE is not
expected to pose an acute risk.
2. Chronic risk. Using the exposure
assumptions described in this unit for
chronic exposure, EPA has concluded
that chronic exposure to NTHE from
food and water will utilize 84% of the
cPAD for children 1-2 years old, the
population group receiving the greatest
exposure. Based on the explanation in
this unit, regarding residential use
patterns, chronic residential exposure to
residues of NTHE is not expected.
3. 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).
NTHE is currently used as an inert
ingredient in pesticide products that are
registered for uses that could result in
short-term residential exposure, and the
Agency has determined that it is
appropriate to aggregate chronic
exposure through food and water with
short-term residential exposures to
NTHE.
Using the exposure assumptions
described in this unit for short-term
exposures, EPA has concluded the
combined short-term food, water, and
residential exposures result in aggregate
MOEs of 4,800 and 5,000 for adult malesand females, respectively. Adult
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United States. Office of the Federal Register. Federal Register, Volume 75, Number 226, November 24, 2010, Pages 71519-72652, periodical, November 24, 2010; Washington D.C.. (https://digital.library.unt.edu/ark:/67531/metadc52807/m1/44/?rotate=270: accessed April 18, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.