Federal Register, Volume 74, Number 41, March 4, 2009, Pages 9343-9564 Page: 9,360
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Federal Register/Vol. 74, No. 41/Wednesday, March 4, 2009/Rules and Regulations
assessment of exposures and risks
associated with establishing these
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.
Famoxadone has low acute toxicity by
the oral, dermal and inhalation routes of
exposure. It is a moderate eye and skin
irritant but is not a dermal sensitizer. In
subchronic and chronic feeding studies
in rats, mice, dogs and cynomolgus
monkeys, famoxadone generally caused
decreased body weights and body
weight gains, often accompanied by
decreased food consumption and food
efficiency. A mild regenerative
hemolytic anemia was also regularly
observed in these animals as evidenced
by decreased erythrocyte counts,
hemoglobin and/or hematocrit,
increased reticulocytes, and other
related changes in hematologic
parameters. Famoxadone also induced a
mild hepatotoxicity in treated animals
characterized by elevated levels of
clinical chemistry enzymes indicative of
liver damage (increased alkaline
phosphatase, alanine aminotransferase,
aspartate aminotransferase, and/or
sorbitol dehydrogenase) and by
histopathological lesions in the liver
(single cell or focal necrosis,
hepatocellular degeneration, diffuse
fatty change, foci of eosinophilic
cellular alteration, apoptosis and
increased mitotic figures). Both the
anemia and the hepatotoxicity were
mild and did not significantly
compromise the overall health status of
the treated animals. In repeated dose
studies the anemia, which occurred
early in the studies, often appeared to be
fully compensated for in the latter stages
of the studies. Although the
hepatotoxicity persisted throughout the
duration of the studies, it was mild or
moderate in intensity and not severe or
life-threatening.
Additional treatment-related effects
were observed in dogs that were not
observed in other species. In a 13-week
feeding study, clinical signs of
neurotoxicity (myotonic twitches) were
observed in male and female dogs at the
highest dose tested throughout the
duration of the study. These twitches
were not observed, however, at lower
doses in the same study or in a 1-yearfeeding study in dogs. Also, in both
male and female dogs, famoxadone
induced treatment-related cataracts in
the lens of the eye in the 13-week
feeding study and in the 1-year feeding
study. The eye effects were observed at
dose levels below those at which any
other effects were observed in any other
species and served as the basis for many
of the risk assessments in humans.
There was no indication of increased
quantitative or qualitative susceptibility
of fetuses or offspring to famoxadone
exposure in the developmental toxicity
studies in rats and rabbits or the 2-
generation reproduction toxicity study
in rats. In a developmental toxicity
study in rats, no developmental toxicity
was observed in the fetuses at the
highest dose tested. Transient decreases
in body weight gain and food
consumption were noted in the dams in
this study. In a developmental toxicity
study in rabbits, an increased incidence
of abortions was observed. The does
which aborted had markedly decreased
body weight, body weight gain and food
consumption. There was also an
equivocal increase in percent
postimplantation loss and mean number
of resorptions per doe in this study. In
the reproduction toxicity study in rats,
offspring toxicity (decreased body
weights for Fl and F2 pups throughout
lactation) was noted at a dose that also
resulted in parental toxicity (decreased
body weight, body weight gain, and
food consumption; and hepatotoxicity).
No reproductive toxicity was observed
in this study at the highest dose tested.
In an acute neurotoxicity study in
rats, there was equivocal evidence of a
possible slight neurotoxic effect at the
limit dose. In this study, an increased
incidence of palpebral (eyelid) closure
was observed, but only in males and
only on day one. Other than this
equivocal evidence and the clinical
observations in the 13-week feeding
study in dogs of myotonic twitching in
the high dose male and female animals,
there was no evidence of treatment-
related neurotoxicity in the toxicity
studies on famoxadone, including a
subchronic neurotoxicity study in rats.
In 28-day immunotoxicity studies in
rats and mice, there was no evidence of
immunotoxicity following exposure to
famoxadone.
In carcinogenicity studies in male and
female rats and mice, famoxadone did
not demonstrate any biologically
significant evidence of carcinogenic
potential. Famoxadone is classified as
"not likely to be carcinogenic to
humans."
Specific information on the studies
received and the nature of the adverse
effects caused by famoxadone as well asthe no-observed-adverse-effect-level and
the lowest-observed-adverse-effect-level
from the toxicity studies can be found
at http://www.regulations.gov in the
document Famoxadone. Human Health
Risk Assessment for the Proposed Food
Use of Famoxadone on Bulb Vegetables,
Crop Group 3; Leafy Greens, Subgroup
4A; Leaf Petioles, Subgroup 4B; and
Cilantro at page 54 in docket ID number
EPA-HQ-OPP-2007-1192.
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 highest dose at which no adverse
effects are observed (the NOAEL) in the
toxicology study identified as
appropriate for use in risk assessment.
However, if a NOAEL cannot be
determined, the lowest dose at which
adverse effects of concern are identified
(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 POD to ensure that the
margin of exposure (MOE) called for by
the product of all applicable UFs is not
exceeded. This latter value is referred to
as the Level of Concern (LOC).
For non-threshold risks, the Agency
assumes that any amount of exposure
will lead to some degree of risk. Thus,
the Agency estimates risk in terms of the
probability of an occurrence of the
adverse effect greater than that expected
in a lifetime. For more information on
the general principles EPA uses in risk
characterization and a complete
description of the risk assessment
process, see http://www.epa.gov/
pesticides/factsheets/riskassess.htn.
A summary of the toxicological
endpoints for famoxadone used for
human risk assessment can be found at
http://www.regulations.gov in the
document Famoxadone. Human HealthRisk Assessment for the Proposed Food
9360
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United States. Office of the Federal Register. Federal Register, Volume 74, Number 41, March 4, 2009, Pages 9343-9564, periodical, March 4, 2009; Washington D.C.. (https://digital.library.unt.edu/ark:/67531/metadc132903/m1/25/: accessed March 18, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.