IR-4. Pesticide Petition. PP 6E7151. Proposal to establish a tolerance for residues of the herbicide flumioxazin in or on food commodities:

Practical analytical methods for detecting and measuring levels of flumioxazin have been developed and validated in/on all appropriate agricultural commodities and respective processing fractions. The LOQ of flumioxazin in the methods is 0.02 ppm which will allow monitoring of food with residues at the levels proposed for the tolerances.

-- Strawberry at 0.07 ppm

-- Fruit, pome, group 11 at 0.02 ppm

This group includes 10 commodities.
apple • apple, dried pomace • apple, juice • apple, wet pomace • crabapple • fruit, pome • loquat • mayhaw • pear • pear, oriental • quince

-- Fruit, stone, group 12 at 0.02 ppm

This group includes 14 commodities.
apricot • cherry, sweet • cherry, tart • fruit, stone • fruit, stone, except plum, prune, dried • nectarine • peach • plum • plum, chickasaw • plum, damson • plum, japanese • plum, prune • plum, prune, dried • plum, prune, fresh

Valent. Pesticide tolerance. FINAL RULE.

Requests to Voluntarily Cancel Certain Pesticide Registrations.

IR-4. Notice of Filing a Pesticide Petition to Establish a Tolerance in or on STRAWBERRY at 0.10 ppm. PP (Pesticide Petition) 4E6845.

The toxicological profile for flumioxazin which supports this petition for tolerances was published in the Federal Register on March 31, 2004.

-- Note from FAN: Dried fruits will have higher levels of pesticide compared to fresh fruits. One would expect the residues on dried fruits to be several times more because of the water lost in drying. Dried fruit weighs at least 2X less and maybe as much as 6X or more times less than the fresh fruit.

-- The toxicological profile for flumioxazin which supports this petition for tolerances was published in the Federal Register of April 18, 2001 (66 FR 19870) (FRL-6778-5).

-- Note new language from EPA on Cumulative Effects

Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' Available information in this context
include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments.
Although, the Agency has some information in its files that may turn
out to be helpful in eventually determining whether a pesticide shares
a common mechanism of toxicity with any other substances, EPA does not
at this time have the methodologies to resolve the complex scientific
issues concerning common mechanism of toxicity in a meaningful way for
most registered pesticides.

-- Note EPA's retention of a Safety Factor

The FQPA safety factor (as required by the Food Quality Protection Act
of August 3, 1996) has been retained at 10x in assessing the risk posed
by flumioxazin. The reasons for retaining the 10x safety factor are as
follows. First, there is evidence of increased susceptibility of rat
fetuses to in utero exposure to flumioxazin by the oral and dermal
route in the prenatal developmental toxicity studies in rats. In
addition, there is evidence of increased susceptibility of young
animals exposed to flumioxazin in the 2-generation reproduction
toxicity study in rats. Finally, there is concern for the severity of
the effects observed in fetuses and young animals when compared to
those observed in the maternal and parental animals.

Three Pesticide Emergency Exemptions.
• Louisiana
--- Crisis: On May 7, 2004, for the use of flumioxazin on sweet potatoes to control annual broadleaf weeds. This program ended on July 15, 2004. Contact: (Libby Pemberton)
--- Specific: EPA authorized the use of flumioxazin on sweet potatoes to control annual broadleaf weeds; May 13, 2004 to July 31, 2004. Contact: (Libby Pemberton)
• Mississippi - EPA authorized the use of flumioxazin on sweet potatoes to control annual broadleaf weeds; May 13, 2004 to July 31, 2004. Contact: (Libby Pemberton)

-- EPA determined that the special 10X SF to protect infants and children should be removed. The FQPA factor is removed because developmental toxicity and offspring toxicity NOAELs/LOAELs are well characterized; there is a well-defined dose-response curve for the cardiovascular effects and the
endpoints of concern are used for overall risk assessments are
appropriate for the route of exposure and population subgroups.

IR-4; Valent. Pesticide tolerance petition.

1. PP 3E6777 proposes tolerances for peppermint, tops; peppermint,
oil; spearmint, tops; and spearmint, oil at 0.04 ppm.
2. PP 3E6788 proposes tolerances for onion, dry bulb; garlic, bulb;
and shallot, bulb at 0.02 ppm.
3. PP 3E6779 proposes tolerances for vegetable, tuberous and corm
subgroup 1C at 0.02 ppm.

[This group includes: arracacha; arrowroot; artichoke, chinese; artichoke, jerusalem; canna, edible; cassava; chayote root; chufa; dasheen; ginger; leren; potato; potato culls; potato granules flakes; potato peel, wet; potato processed potato waste; potato, specialty; sweet potato; tanier; turmeric; yam bean; yam, true.]

The toxicological profile for flumioxazin which supports thesepetitions for tolerances was previously published in the Federal
Register of April 18, 2001

• Infants and children-- Safety factor for infants and children.The FQPA safety factor has been retained at 10X in assessing the risk posed by flumioxazin. The reasons for retaining the 10X safety factorare as follows. First, there is evidence of increased susceptibility of rat fetuses to in utero exposure to flumioxazin by the oral and dermal route in the prenatal developmental toxicity studies in rats. In addition, there is evidence of increased susceptibility of young
animals exposed to flumioxazin in the 2-generation reproduction toxicity study in rats. Finally, there is concern for the severity of the effects observed in fetuses and young animals when compared to those observed in the maternal and parental animals.
Since the additional 10X safety factor has been retained to account for the apparent increased susceptibility from prenatal or postnatal exposures to flumioxazin, it would be appropriate to apply the extra 10X safety factor to only selected subpopulations, e.g. infants and children <6 years old and females >13 years old. For these assessments, however, the 10X safety factor has been applied to all population subgroups for all exposure durations (acute and chronic), thus making these assessments additionally conservative.

Pesticide tolerance for Emergency Exemption. This regulation establishes a time-limited tolerance for residues of flumioxazin in or on sweet potato, roots at 0.02 ppm in connection with a crisis exemption declared by the State of Louisiana. This regulation establishes a maximum permissible level for residues of flumioxazin in this food commodity. The tolerance will expire and is revoked on June 30, 2006.
-- parent flumioxazin and the metabolites 482-HA and APF are the residues of concern in drinking water.
-- Acute Dietary. NOAEL = 3.0. Cardiac effects (interventricular septal defects) were seen in the oral developmental and supplemental prenatal studies in rats.
-- Chronic Dietary. NOAEL = 2. Kidney effects were seen in males and anemia was seen in females in the 2-year toxicity study in rats.
-- FQPA Safety Factor. A 10x Safety factor was retained because
(1) there was evidence of increased susceptibility of fetuses exposed to flumioxazin by both the oral and dermal route in the prenatal developmental toxicity studies in rats,
(2) there was evidence of increased susceptibility of young animals exposed to flumioxazin in the 2-generation reproduction toxicity in rats, and
(3) there is concern for the severity of the effects in fetuses and young animals when compared to the maternal or parental animals.

EPA denied 2 Emergency Exemption requests for the use of flumioxazin:
-- Louisiana: Denial: On July 18, 2002, EPA denied the use of flumioxazin on cotton to control weeds. This request was denied because it did not meet the criteria of an urgent, non-routine situation based on the availability of registered alternatives.
-- Mississippi: Denial: On July 18, 2002 EPA denied the use of flumioxazin on cotton to control weeds. This request was denied because it did not meet the criteria of an urgent, non-routine situation based on the availability of registered alternatives.

• Requests for Pesticide Emergency Exemptions.
• Louisiana: On August 3, 2001, EPA denied the use of flumioxazin on sugarcane to control red morning glory species. This request was denied based on the fact that it was not demonstrated that an urgent and non-routine situation exists due to the presence of red morning glory species. Additionally, the economic data were not sufficient to demonstrate that significant economic losses could be expected.
• Louisiana: On August 9, 2001, EPA denied the use of flumioxazin on cotton to control pigweed and other weeds. This request was denied based on the fact that it was not demonstrated that an urgent and non-routine situation exists due to the presence of pigweed and other weeds in cotton.
• Mississippi: On August 9, 2001, EPA denied the use of flumioxazin on cotton to control pigweed and other weeds. This request was denied based on the fact that it was not demonstrated that an urgent and non-routine situation exists due to the presence of pigweed and other weeds in cotton.

VALENT - Pesticide Tolerances for residues in or on soybean seed and peanut nutmeat at 0.02 ppm. - FINAL RULE.

VALENT - Petition to Establish Tolerances; for residues in or on the raw agricultural commodities soybean seed and peanut nutmeat at 0.01 ppm, and on sugar cane at 0.2 ppm.

Children ... Developmental toxicity was observed by both oral and dermal routes in rats. Therefore, reliable data support use of the standard 100-fold uncertainty factor and an additional uncertainty factor of 10X for flumioxazin to be further protective of infants and children.

Developmental toxicity studies. Flumioxazin shows developmental toxicity in the absence of maternal toxicity in rats. Mechanistic studies demonstrate that the effect is specifically related to the inhibition of heme synthesis, that the effect shows considerable species specificity, and that the rat is a conservative surrogate species for the potential for developmental toxicity in man. No developmental toxicity was observed in rabbits. Developmental toxicity to the pups was seen in the rat reproduction study at doses that were not toxic to the parental animals.

Reproductive toxicity study. In the 2-generation reproduction study in the rat dietary levels of 0, 50, 100, 200 and 300 ppm established a systemic NOAEL of 200 ppm based on increased clinical signs (both sexes and generations); mortality, gross and histopathology
findings in the liver (F1 females); decreased body weight/ weight gain (F0 and F1 females during gestation, F1 males during premating) and decreased food consumption (F0 and F1 females during lactation). The reproductive NOAEL of 100 ppm was mainly based on developmental toxicity at 200 ppm. Observed at 200 ppm were a decreased number of
liveborn pups and reduced pup body weights. At 300 ppm the following effects were observed: decreased pup body weight (both generations); decreased number of live pups/litter and viability index (both generations); increased incidence of abnormalities of the reproductive organs (predominately atrophied or hypoplastic testes and/or epididymides in F1 males); decreased gestation index (F0 females); decreased mating and fertility indices (F1 males) and increased clinical signs (F1 pups).

Rats. In the definitive rat oral developmental toxicity study, pregnant rats were administered oral doses of 0, 1, 3, 10 or 30 mg/kg/ day of flumioxazin technical on days 6 through 15 of gestation. No maternal deaths were observed at any dosage and no treatment-related effects on clinical signs or food consumption were noted. A decrease in maternal body weight gain was found at 30 mg/kg/day. The number of live fetuses and fetal body weights were decreased in the 30 mg/kg/day group and the incidence of embryo mortality tended to be higher but was not statistically significant ... The incidence of fetuses with cardiovascular abnormalities, primarily VSD, was increased in the 30 mg/kg/day group. Other developmental effects observed at 30 mg/kg/day included an increase in the incidence of wavy ribs and curvature of the scapula, and a decrease in the number of ossified sacrococcygeal vertebral bodies. Based on these findings, a maternal NOAEL of 30 mg/kg/day and a developmental NOAEL of 3 mg/kg/day are proposed.

Mechanistic Studies. A series of scientific studies were conducted to examine the mechanism and species differences in the production of developmental toxicity by flumioxazin ... Specifically the studies demonstrate that: Flumioxazin interferes with normal heme biosynthesis resulting in sidroblastic anemia and porphyria in adult rats. \14\C-Flumioxazin administered to pregnant rats on day 12 of gestation crosses the placenta and reaches the rat fetus at maximum levels of radiocarbon (and flumioxazin), 4 hours later ... The critical period of sensitivity to the developmental effects of flumioxazin in rats is day 12 of gestation. This correlates with the peak period of protoporphyrin IX (PPIX) accumulation in maternal rat liver and the rat fetus. A histological examination of rat fetus indicated signs of fetal anemia within 6 hours after dosing, but no histological changes in the fetal rat heart were observed until 36 or 48 hour after treatment ...

Other observations in the pathogenesis of the developmental effects of flumioxazin in rat fetuses included: enlarged heart, edema, anemia (decreased red blood cell count and hemoglobin), delayed closure of the interventricular foramen, reduced serum protein and incomplete/delayed ossification of the ribs. The observation of enlarged heart, edema and anemia preceding the occurrence of fetal mortality suggest these effects may be instrumental in the cause of fetal deaths. The occurrence of an enlarged heart preceding the failure of interventricular foramen closure could be related to the pathogenesis rather than a direct toxic effect of flumioxazin on cardiac tissue.
A strong correlation exists between PPIX accumulation, an indicator of disrupted heme synthesis, and developmental toxicity. Evidence of this correlation exists on the basis of species differences between rats and rabbits; the critical period of sensitivity in the rat; and compound-specific differences with two chemicals structurally related to flumioxazin, one which produces developmental effects in rats and one which does not.

There are other pesticidal compounds that are structurally related to flumioxazin and have similar effects on animals ... Valent will submit information for EPA to consider concerning potential cumulative effects of flumioxazin consistent with the schedule established by EPA in the Federal Register (August 4, 1997) (62 FR 42020) (FRL-5734-4) and other subsequent EPA publications pursuant to the Food Quality Protection Act (FQPA)

• VALENT - Issuance of Experimental Use Permit:
• 59639-EUP-118; allows the use of 91.78 pounds (45.89 each year) of the herbicide on 480 acres of soybeans to evaluate the control of various broadleaf weeds. The program is authorized only in the States of Arkansas, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Michigan, Minnesota, Mississippi, Missouri, Nebraska, North Carolina, Ohio, Tennessee, and Virginia. The experimental use permit is effective from August 1, 1996 to August 1, 1998.