Federal Register, Volume 74, Number 46, March 11, 2009, Pages 10455-10672 Page: 10,491
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Federal Register/Vol. 74, No. 46/Wednesday, March 11, 2009/Rules and Regulations
appropriate in lieu of the proposed
individual tolerances on berry
commodities. The reason for this change
is explained in Unit IV.C.
III. Aggregate Risk Assessment and
Determination of Safety
Section 408(b)(2)(A)(i) of FFDCA
allows EPA to establish a tolerance (the
legal limit for a pesticide chemical
residue in or on a food) only if EPA
determines that the tolerance is "safe."
Section 408(b)(2)(A)(ii) of FFDCA
defines "safe" to mean that "there is a
reasonable certainty that no harm will
result from aggregate exposure to the
pesticide chemical residue, including
all anticipated dietary exposures and all
other exposures for which there is
reliable information." This includes
exposure through drinking water and in
residential settings, but does not include
occupational exposure. Section
408(b)(2)(C) of FFDCA requires EPA to
give special consideration to exposure
of infants and children to the pesticide
chemical residue in establishing a
tolerance and to "ensure that there is a
reasonable certainty that no harm will
result to infants and children from
aggregate exposure to the pesticide
chemical residue...."
Consistent with section 408(b)(2)(D)
of FFDCA, and the factors specified in
section 408(b)(2)(D) of FFDCA, EPA has
reviewed the available scientific data
and other relevant information in
support of this action. EPA has
sufficient data to assess the hazards of
and to make a determination on
aggregate exposure for the petitioned-for
tolerances for residues of chlorimuron-
ethyl on berry, low growing, except
strawberry, subgroup 13-07H at 0.02
ppm. EPA's assessment of exposures
and risks associated with establishing
tolerances follows.
A. Toxicological Profile
EPA has evaluated the available
toxicity data and considered its validity,
completeness, and reliability as well as
the relationship of the results of the
studies to human risk. EPA has also
considered available information
concerning the variability of the
sensitivities of major identifiable
subgroups of consumers, including
infants and children.
Chlorimuron-ethyl has low or
minimal acute toxicity via the oral,
dermal and inhalation routes of
exposure. It is mildly irritating to the
eye and non-irritating to the skin; it is
not a skin sensitizer.
In subchronic toxicity studies with
chlorimuron-ethyl, no adverse effects
were observed up to the limit dosetested in mice; decreased body weight
gain and liver pathology (margination of
hepatocyte cytoplasmic content in the
centrilobular areas) were observed in
rats (males only); and mild hemolytic
anemia, atrophy of the thymus and
prostate and increased liver weights
were seen in dogs. Chronic exposure of
dogs to chlorimuron-ethyl also led to
mild anemia (decreased erythrocyte
count, hematocrit, and hemoglobin
concentration), but atrophy of the
thymus and prostate were not seen. In
rats, treatment-related effects observed
were limited to decreased body weight
and body weight gain in both sexes after
long-term exposure. Prostatitis (males)
and fatty replacement in the pancreas
(both sexes) were also observed but
considered incidental occurrences; and
biliary hyperplasia/fibrosis seen in
females was attributed to aging. In mice,
there were no treatment-related effects
observed up to the highest dose tested
(216 milligrams/kilograms/day (mg/kg/
day)). There were no treatment-related
increases in tumors in rat and mouse
carcinogenicity studies after exposure to
chlorimuron-ethyl. Chlorimuron-ethyl is
classified as "Not Likely to be
Carcinogenic to Humans."
In the developmental toxicity studies,
decreases in maternal body weight gain
and delayed ossification in fetuses were
observed in rats at the same dose (150
mg/kg/day). In rabbits, decreases in
maternal body weight gain were seen at
300 mg/kg/day, while delayed
ossification was seen in fetuses at a
lower dose of 48 mg/kg/day, indicating
increased quantitative susceptibility. In
a guideline 2-generation reproduction
study in rats, decreased body weight
and histopathology in the cerebellum
(cellular changes in the internal
granular and external germinal layers)
were seen in pups at 177 mg/kg/day.
These effects were seen in the absence
of maternal toxicity, indicating potential
increased quantitative susceptibility of
the pups to chlorimuron-ethyl.
However, these effects were not
associated with any neurotoxicity or
neurobehavioral changes and not
observed in other reproduction studies
in rats. In a non-guideline reproduction
toxicity study (1-generation) in rats,
decreased body weight (females) and
liver histopathology (males) were seen
in parental animals at 173 mg/kg/day,
along with decreases in litter weights. In
another reproduction study (1-year
interim sacrifice) in rats, decreases in
maternal and pup body weights were
observed at 195 mg/kg/day.
There is no indication of
neurotoxicity in the toxicity database for
chlorimuron-ethyl. In a 2-generation
reproduction study in rats,histopathological alterations were seen
in the cerebellum (cellular changes in
the internal granular and external
germinal layers) of F2 pups at 177 mg/
kg/day; however, these findings were
not associated with any neurobehavioral
changes or any indications of
neurotoxicity. In addition, these
histopathological alterations were not
observed in two other reproduction
studies, and there was no evidence of
neurotoxicity observed in other rat
toxicity studies or toxicity studies in
other species (rabbits, mice, or dogs).
Hematological changes (indicative of
mild anemia) and atrophy of the thymus
were observed in dogs after subchronic
exposure. However, atrophy of the
thymus was not associated with any
histopathology and not seen after
chronic exposure. No other potential
immunotoxic effects were observed in
the toxicology database.
Specific information on the studies
received and the nature of the adverse
effects caused by chlorimuron-ethyl as
well as the no-observed-adverse-effect-
level (NOAEL) and the lowest-observed-
adverse-effect-level (LOAEL) from the
toxicity studies can be found at http://
www.regulations.gov in document
Chlorimuron-ethyl: Human Health Risk
Assessment for Proposed Uses on
Cranberry and Low-growing Berry
Subgroup 13-07H, except Strawberry,
PP# 6E7153, page 36 in docket ID
number EPA-HQ-OPP-2007-0301.
B. Toxicological Endpoints
For hazards that have a threshold
below which there is no appreciable
risk, a toxicological point of departure
(POD) is identified as the basis for
derivation of reference values for risk
assessment. The POD may be defined as
the NOAEL in the toxicology study
identified as appropriate for use in risk
assessment. However, if a NOAEL
cannot be determined, the LOAEL or a
Benchmark Dose (BMD) approach is
sometimes used for risk assessment.
Uncertainty/safety factors (UFs) are
used in conjunction with the POD to
take into account uncertainties inherent
in the extrapolation from laboratory
animal data to humans and in the
variations in sensitivity among members
of the human population as well as
other unknowns. Safety is assessed for
acute and chronic dietary risks by
comparing aggregate food and water
exposure to the pesticide to the acute
population adjusted dose (aPAD) and
chronic population adjusted dose
(cPAD). The aPAD and cPAD are
calculated by dividing the POD by all
applicable UFs. Aggregate short-term,
intermediate-term, and chronic-term
risks are evaluated by comparing food,water, and residential exposure to the
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United States. Office of the Federal Register. Federal Register, Volume 74, Number 46, March 11, 2009, Pages 10455-10672, periodical, March 11, 2009; Washington D.C.. (https://digital.library.unt.edu/ark:/67531/metadc132908/m1/45/: accessed March 29, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.