1

FILE NAME: DFB

- A357 citrus 201 2 NOF



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Petition number 2F8015

Summary of Petitions

EPA has received a pesticide petition ( [ 2F8015 ] ) from [ Chemtura Corporation ]

, [ 199 Benson Road, Middlebury, CT ] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 34 6a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of diflubenzuron, [N

- [[(4

- chloro phenyl)amino]

- carbonyl]

- 2,6

- difluorobenzamide (DFB) and its metabol ites 4

- chlorophenylurea (CPU) and 4

- chloroaniline (PCA) in or on the raw agricultural commodities [ Fruit, citrus, Group 10

- 10 , at 3.0 ppm, and the processed commodity C itrus oil at 3 2 pp m. ] EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports gr anting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolis m

. The nature of the residue in plants is adequately understood.2

In plants, the m eta bolism of diflubenzuron was investigated in soybeans, citrus, mushroom, and rice. The main component of residues in rice was CPU; levels of PCA were negligible to non

- detectable. The main component of the residues in soybeans and oranges was the parent d iflubenzuron. A considerable portion of the residues were bound. Diflubenzuron showed very limited absorption and translocation in plants with most of the residues remaining on the surface. The Agency has concluded that the residues of concern are difluben zuron and its metabolites CPU and PCA.

2. Analytical method. A practical analytical method for detecting and quantifying levels of diflubenzuron in or on food with a limit of detection that allows monitoring of the residue at or above the level set in t he tolerance was used to determine residues in citrus RAC and processed commodities.

Residues of the individual analytes are detectable and quantifiable using three separate analytical methods. Residues of diflubenzuron (DFB) were quantitated by LC

- MS/M S, and residues of the metabolites 4

- chlorophenylurea (CPU) and 4

- chloroaniline (PCA) were derivatized with HFBA and quantitated by GC/MS.

Residues of diflubenzuron were repeatedly extracted with methylene chloride in the presence of anhydrous sodium su lfate and the extracts combined. The volume was adjusted to measurable volume and a 50% aliquot was removed for further clean

- up. The extract was roto

- evaporated to dryness and reconstituted in acetonitrile. The resultant solvent mixture was partitioned wi th hexane by shaking for ~1 minute and the acetonitrile layer was collected in a concentration flask. After concentration, the residue was dissolved with 2 mL acetonitrile and 8 mL water. Using a preconditioned C18

- SPE cartridge, the reconstituted acetonit rile extract was passed through the cartridge for clean

- up followed by additional clean

- up using a Si SPE cartridge. The solvent was evaporated and the residue was reconstituted in acetonitrile and water. An appropriate volume was transferred to a gas chro matography (GC) vial for analysis. The DFB method for citrus juice was slightly different in that no second filtration was required. The DFB method for orange oil involved repeated partition of the oil with acetonitrile and hexane. The combined acetonitril e extracts were analyzed without further cleanup. The samples were analyzed by LC

- MS/MS. The limit of quantitation was 0.05 ppm in citrus matrices, except for orange oil with an LOQ of 1.0 ppm.

CPU was repeatedly extracted with ethyl acetate in the presen ce of anhydrous sodium sulfate and the extracts combined. The volume was adjusted to measurable volume and a 50% aliquot was removed for further clean

- up. The extract was roto

- evaporated to dryness and reconstituted in acetone and petroleum ether. Using a preconditio ned Si SPE cartridge, the reconstituted organic extract was passed through the cartridge for clean

- up with gradient elution. The solvent was evaporated and the residue was reconstituted in hexane. The CPU residue method for oil involved a partit ion of the oil between hexane and acetonitrile:water. The combined acetonitrile:water phases were concentrated and were3

cleaned up by means of a C18

- SPE cartridge followed by a Si

- SPE cartridge. The CPU was derivatized with HFBA and submitted for analysis by GC/MS. The limit of quantitation was 0.01 ppm in citrus.

The determination of PCA residues in citrus matrices utilizes an internal standard method. Samples of matrix to be analyzed are fortified with an internal standard. Residues of PCA and the inter nal standard are subjected to acid and base hydrolysis. The extraction was repeated two more times and the extracts were combined. The pH of the combined extracts was adjusted to pH>12 and the sample was repeatedly partitioned with hexane. The combined org anic phases were partitioned with a small volume of aqueous acid. The aqueous acid phase was basified to pH >12 and was repeatedly partitioned with a small volume of hexan e. The resultant extract was passed through a Florisil SPE cleanup prior to derivatiz ation with HFBA. All citrus matrices were conducted by the same method, with the exception that filtration was not required for orange juice or oil. The PCA present was determined by GC/MS analysis. The limit of quantitation was 0.005 ppm (5.0 ppb) in citr us.

The methods were successfully validated on orange fruit, orange juice, orange dried pulp, and orange citrus oil prior to or concurrently with sample analysis.

3. Magnitude of residues A complete crop residue program has been completed for diflubenz uron and its metabolites in the major citrus growing areas of the US

. Raw agricultural commodities, treated according to the proposed label, were sampled. The analytical data demonstrated that residues in crops are not expected to exceed the proposed tole rance levels.

A total of 23 citrus fruit trials (12 orange, 6 grapefruit, and 5 lemon) were conducted in EPA Regions 3, 6, and 10 during the 2008 and 2009 growing seasons. Twelve orange trials were conducted in U.S. EPA Regions 3 (FL, 8 trials), 6 (TX , 1 trial), and 10 (CA, 3 trials). Six grapefruit trials were conducted in U.S. EPA Regions 3 (FL, 3 trials), 6 (TX, 1 trial), and 10 (CA, 2 trials). Five lemon trials were conducted in Regions 3 (FL, 1 trial) and 10 (CA, 4 trials). One decline orange t rial was conducted in EPA Region 3, one decline lemon trial and one decline grapefruit trial were conducted in EPA Region 10. A further 5 trials (3 orange and 2 grapefruit) were also conducted using ultra low volume (ULV) equipment. Additionally, data on orange processed commodities were provided from one site in EPA Region 10. The number and geographic locations of field trials are adequate to support a revised U.S. tolerance for residues of diflubenzuron (DFB) and its 4

- chlorophenylurea (CPU) and 4

- chl oroaniline (PCA) metabolites in the citrus fruits crop group, based on the proposed field use conditions.

Chemtura Corporation is proposing diflubnzuron tolerances for Fruit, Citrus, Group 10

- 10 at 3 .0 ppm , and Citrus oil at 32 ppm.4

B. Toxicological Pr ofile

1. Acute toxicity

. Studies for diflubenzuron technical indicate the acute oral toxicity in rats and mice is >4,640 mg/kg, and the acute dermal toxicity in rats is >10,000 mg/kg. The acute inhalation LC 50 in rats is >35 mg/l (6 hours). Diflubenzuro n technical is not an eye or skin irritant to rabbits, and is not a dermal sensitizer in guinea pigs.

2. Genotoxicity

. Diflubenzuron did not show any mutagenic activity in point mutation assays employing S. typhimurium, S. cerevisiae, or L5178Y Mouse Ly mphoma cells. Diflubenzuron did not induce chromosomal aberrations in Chinese Hamster Ovary cells and did not induce unscheduled DNA synthesis in human WI

- 38 cells. Diflubenzuron was also negative in Mouse Micronucleus and Mouse Dominant Lethal
assays an d it did not induce cell transformation in Balb/3T3 cells.

3. Reproductive and developmental toxicity

. In a rat developmental toxicity study, diflubenzuron was administered by oral gavage to pregnant female rats at dosage levels of 0, 1, 2 and 4 mg/kg/da y. No treatment related effects were seen. A subsequent study was conducted in pregnant Sprague Dawley rats at a dose of 0 and 1,000 mg/kg/day. No maternal toxicity was observed. The incidence of fetuses with skeletal abnormalities was slightly increased in the treated group, but was within historical background range. The NOEL for maternal and developmental toxicity in rats was greater than 1,000 mg/kg/day.

Diflubenzuron was also administered by oral gavage to pregnant New Zealand White rabbits at dosag e levels of 0, 1, 2 and 4 mg/kg/day. No treatment related effects were seen. A subsequent study was conducted in pregnant rabbits at a dose of 0 and 1,000 mg/kg/day. No maternal or developmental toxicity was seen. The NOEL for maternal and developmental to xicity in rabbits was greater than 1,000 mg/kg/day.

In a rat reproduction study, diflubenzuron was fed to two generations of male and female rats at dietary concentrations of 0, 10, 20, 40, and 160 ppm. No effects were seen on parental body weight gain an d there were no reproductive effects. In a subsequent study, diflubenzuron was fed to two generations of male and female rats at dietary concentrations of 500, 5,000 and 50,000 ppm. Systemic adult toxicity was seen at all dosage levels. No effects were s een on reproductive parameters, however, litter and mean pup weights of F1 offspring were reduced at 50,000. The NOEL for reproductive toxicity in rats was 50,000 ppm (2.5 g/kg/day), and for pre

- weaning development it was 5,000 ppm (250 mg/kg/day).

4. Subchronic toxicity. [To assess subchronic toxicity, a four

- week inhalation study and a three

- week dermal study were conducted. In the inhalation study rats were exposed nose only to 10, 30 or 100 mg/m 3 for 6 hours per day, 5 days per week for 4 weeks. T reatment related findings were a slight reduction in erythrocytes, hemoglobin and hematocrit in male and female rats at a concentration of 100 mg/m 3 and an increase in total5

bilirubin in high dose female rats. There was no effect on methemoglobin concent ration at any dose level. The NOEL for subchronic inhalation toxicity was 30 mg/m 3

.
In the dermal toxicity study, diflubenzuron was applied to the backs of male and female CD rats for three weeks at dose levels of 20, 500 and 1,000 mg/kg/day. Hematology evaluation showed reductions in red blood cell (RBC), hemoglobin (Hgb) and hematocrit values at 500 and 1,000 mg/kg/day. An increased incidence of polychromasia, hypochromasia and anisocytosis was seen at 500 and 1,000 mg/kg/day. An increase in methemog lobin and sulfhemoglobin values was seen at 1,000 mg/kg/day. The NOEL for systemic toxicity was 20 mg/kg/day. Also, a dermal absorption factor of 0.5% for systemic absorption, was derived from a study where rats were dosed with either 0.005 or 0.05 mg/cm 2 of [ 14 C] diflubenzuron technical. This value can be used for converting dermal exposure to oral equivalents.

5. Chronic toxicity. Diflubenzuron was given by capsule to male and female Beagle dogs for one year at dose levels of 0, 2, 10, 50 and 250 mg/kg /day. Body weight gain was slightly reduced in females at 250 mg/kg/day. Absolute liver and spleen weights were increased in males given 50 and 250 mg/kg/day. A reduction in hemoglobin and mean corpuscular hemoglobin concentration, with an elevation in reticulocyte count, was seen at 50 and 250 mg/kg/day. Methemoglobin and sulfhemoglobin values were increased at doses of 10 mg/kg/day and greater. Histopathological findings were limited to pigmented macrophages and Kupffer cells in the liver at doses of 50 and 250 mg/kg/day. The NOEL for chronic toxicity in dogs was 2 mg/kg/day.

Diflubenzuron was fed to male and female Sprague Dawley rats for two years at dose levels of 0, 156, 625, 2,500 and 10,000 ppm. Methemoglobin values were elevated in female rat s at all dose levels and in male rats at the two highest dose levels. Sulfhemoglobin was elevated in females, only, at dose levels of 2,500 and 10,000 ppm. Mean corpuscular volume (MCV) and reticulocyte counts were increased in high dose females. Spleen and liver weights were elevated at the two highest doses. Histopathological examination demonstrated an increase in hemosiderosis of the liver and spleen, bone marrow and erythroid hyperplasia and areas of cellular alteration in the liver. In another stu dy diflubenzuron was administered to male and female CD rats for two years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated methemoglobin levels were seen in high dose males and females. No additional effects, including carcinogenic findings, were ob served. The NOEL for chronic toxicity in rats was 40 ppm (2 mg/kg/day).

A ninety

- one week oncogenicity study in CFLP mice was conducted at doses of 0, 16, 80, 400, 2,000 and 10,000 ppm. There was no increase in tumor incidence as a result of diflu benzuron administration. Target organ effects included: increased methemoglobin and sulfhemoglobin values, Heinz bodies, increased liver and spleen weight, hepatocyte enlargement and vacuolation, extramedullary hemopoiesis in the liver and spleen, sideroc ytosis in the spleen and pigmented Kupffer cells. A NOEL for these effects was 166

ppm (2 mg/kg/day).

Diflubenzuron was fed to male and female Sprague Dawley rats for two years at dose levels of 0, 156, 625, 2,500 and 10,000 ppm. Methemoglobin values w ere elevated in female rats at all dose levels and in male rats at the two highest dose levels. Blood sulfhemoglobin was elevated in females, only, at dose levels of 2,500 and 10,000 ppm. MCV and reticulocyte counts were increased in high dose females. S pleen and liver weights were elevated at the two highest doses. Histopathological examination demonstrated an increase in hemosiderosis of the liver and spleen, bone marrow and erythroid hyperplasia and areas of cellular alteration in the liver. There was no increase in tumor formation. In another study diflubenzuron was administered to male and female CD rats for two years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated methemoglobin levels were seen in high dose males and females. No additional e ffects, including carcinogenic findings, were observed.

Immunotoxicity. Diflubenzuron was fed to mice at concentrations of 0, 80, 400, 2,000 and 10,000 ppm for 28 days. There was no observed effect of diflubenzuron, at any dose tested, on the anti

- SRBC IgM response. The immunotoxicity NOAEL for this study was the highest dose tested dose concentration of 10,000 ppm.

6. Animal metabolism

. The qualitative nature of the residues in livestock is adequately understood based on data from ruminant and poult ry metabolism studies. The Agency has concluded that the residues of concern are diflubenzuron and its metabolites CPU and PCA.

DFB in rats at a single dose of 100 mg/kg and 5 mg/kg single and multiple oral doses depicted limited absorption from the gastr ointestinal tract. No major difference was observed between the single and multiple doses. In single dose treatments, after 7 days, 20% and 3% of the applied dose 5 and 100 mg/kg, respectively were excreted in urine, while 79% and 98% of the applied do se 5 and 100 mg/kg, respectively, were eliminated in the feces. Very little bioaccumulation in the tissues was observed. In the feces, only unchanged parent compound was detected. Several metabolites were observed in the urine which are, among others, 2

- 6

- difluorobenzoic acid (DFBA), 2,6

- diflurophippuric acid, 2

- 6

- difluorobenzamide (DFBAM), and 2

- hydroxydiflubenzuron (2

- HDFB). An unresolved peak that was characterized as p

- chloroaniline (PCA) and/or
p - chlorophenylurea (CPU) was found. This latter pea k accounted for about 2% of the administered dose (5 mg/kg). To resolve if PCA and CPU are indeed metabolites of DFB, rats were administered a single oral dose, 100 mg/kg of 14C DFB. The major metabolites identified in rat urine were 4

- chloroaniline

- 2

- su lfate, accounting for almost 50% of the total radioactive residue (TRR) in the urine and N

- (4

- chlorophenyl)oxamic acid which accounted for about 15% of the (TRR). Neither CPU, PCA nor their N

- hydroxylderivatives were found in rat urine at a limit of de tection of 23 parts per billion (ppb). As in the previous study, DFB was the only residue found in the feces.7

7. Metabolite toxicology. NCI/NTP conducted chronic feeding and gavage studies with p

- chloroaniline (PCA), a minor potential metabolite of diflu benzuron, in Fischer 344 rats and B6C3F1 mice.

PCA was administered in the diet to Fischer 344/N rats at dietary concentrations of 250 and 500 ppm for 78 weeks, followed by a 24 week observation period. A slight body weight depression was seen in high d ose females rats, compared to controls. Survival was reduced in high dose males compared to controls. In male rats there was a slight increase in uncommon fibromas or fibrosarcomas of the spleen, which was not statistically significant. Non

- neoplastic p roliferative and chronic inflammatory lesions were found in spleens of treated rats. It was concluded that, under the conditions of the assay, sufficient evidence was not found to establish the carcinogenicity of PCA for Fischer 344/N rats.

PCA was admin istered 5 days/week by oral gavage, as a hydrochloride salt in water, to male and female F344/N rats at doses of 0, 2, 6 or 18 mg/kg/day. Mean body weights of dosed rats were generally within 5% of those of controls throughout the study. High dose animal s generally showed mild hemolytic anemia and dose

- related methemoglobinemia. Non

- neoplastic lesions seen were bone marrow hyperplasia, hepatic hemosiderosis and splenic fibrosis, suggesting treatment related effects on the hematopoietic system. Adrenal

m edullary hyperplasia was observed in high dose female rats. The incidence of uncommon sarcomas of the spleen was significantly increased in high dose male rats. A marginal increase in pheochromocytomas of the adrenal gland was seen in high dose male and female rats. It was concluded that, under the conditions of this 2 year gavage study, there was clear evidence of carcinogenic activity of PCA hydrochloride for male Fischer 344/N rats and equivocal evidence of carcinogenic activity of PCA hydrochloride f or female Fischer 344/N rats.

PCA was administered in the diet to B6C3F6 mice at dietary concentrations of 2500 and 5000 ppm for 78 weeks followed by a 13

- week observation period. A body weight depression was seen in treated mice of both sexes, compared to controls. An increased incidence of hemangiomas and hemangiosarcomas in spleen, kidney, liver and other sites was seen in treated mice of both sexes; however this increase was not statistically significant compared to controls. Non

- neoplastic prolife rative and chronic inflammatory lesions were found in spleens of treated mice. The evidence was considered insufficient to conclusively relate the hemangiomatous tumors in mice to compound administration. It was concluded that, under the conditions of th e assay, sufficient evidence was not found to establish the carcinogenicity of PCA for B6C3F1 mice.

PCA hydrochloride was administered 5 days/week by oral gavage to male and female B6C3F1 mice at doses of 0, 3, 10, or 30 mg/kg/day. Mean body weights of h igh dose male and female mice were generally within 5% of those of controls throughout the study. The incidence of hepatocellular adenomas or carcinomas (combined) was8

increased in a non

- dose

- dependent manner in treated male mice. Metastasis of carcinoma to the lung was seen in the high dose group. An increased incidence of hemangiosarcomas of the liver or spleen was seen in high dose male mice. It was concluded that, under the conditions of this 2

- year gavage study, there was some evidence of carcinogeni c activity of PCA hydrochloride for male B6C3F1 mice and no evidence of carcinogenic activity of PCA hydrochloride for female B6C3F1 mice.

In addition to PCA, 4

- chlorophenylurea (CPU) is also a potential minor metabolite of diflubenzuron. By associati on with Monuron, the EPA had assumed that CPU has oncogenic potential with the same carcinogenic potency (q1*) as Monuron.9

9. Endocrine disruption. The standard battery of required studies has been completed and evaluated to determine potential estrog enic or endocrine effects of diflubenzuron. These studies include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following repeated or long

- term exposure. These studies are generally considered to be sufficient to detect any endocrine effects. No such effects were noted in any of the studies with diflubenzuron.

C. Aggre gate Exposure10

1. Dietary Exposure. An evaluation of chronic dietary exposure, including drinking water, has been performed for the U.S. population and various population subgroups including infants and children. One day single dose oral studies in rats and mice indicated there were no significant acute effects observed. As only marginal effects were noted , an acute exposure assessment is not needed for diflubenzuron.

i. Food

T he dietary exposure from diflubenzuron was estimated based on the tolerance residue values from the various currently labeled raw agricultural commodities (RAC’s), and the proposed citrus crop
group uses. Percent of crop treated was also factored into the estimate. Residues in meat, milk and egg products were obtained from extrapolation of metabolism study data to anticipated livestock dietary burdens.

A chronic dietary exposu re assessment was conducted on diflubenzuron using DEEM

- FCID TM Version 3.12 , which incorporates consumption data from NHANNES 2

- day food consumption data for 2003

- 2006

. Chemtura predicts that 28% of citrus crops will be treated at market maturity (~5 years following introduction of the new use pattern on citrus). Percent crop treated for mushrooms has declined considerably over the years from 31% (previous EPA’s assessments) to no more than 3.2% for a 5

- year average. A partially refined assessment in which the percent crop treated information for citrus w as incorporated, while the percent crop treated values for all other crops were maintained at 100%. With this refinement, the chronic dietary exposure to the US Populatio n (total) was estimated at 7.8% of the cPAD (0.001561 mg/kg/day). The most highly exposed subpopulation, children 1

- 2 years, has an estimated total exposure of 25.4 % of the cPAD. The total chronic dietary exposure associated with current and proposed uses of diflubenzuron on citrus has been demonstrated to be less than the cPAD (0.02 mg/kg/day) and are therefore not of concern. Using updated percent crop treated estimates on all crops would further refine the exposure estimate. Use of percent crop treated information for all crops and switch ing to average residues rather than tolerances would further refine the exposure downward.

Incremental cancer risk assessments were conducted for CPU and PCA with the proposed modified uses on citrus. When the 28% crop treated factor is included in the analysis for citrus, the incremental cancer risks are estimated to be 0.000042 mg/kg bw/day for CPU and 0.000007 mg/kg bw/day for PCA.

ii. Drinking water

. Diflubenzuron degrades in soil relatively quickly with an aerobic half

- life ranging from 3

- 7 days. Major degradates include difluorobenzoic acid (DFBA) and CPU. DFBA is further metabolized through decarboxylation and ring cleavage by soil microbes whereas CPU is slowly degraded to soil

- bound entities. Under anaerobic aquatic conditions, diflubenzuron ha s a half

- life of 34 days with the main degradates being DFBA and CPU. In surface water, diflubenzuron is degraded by microbes with a half

- life of 5

- 10 days.

Based on EPA’s SCI

- GRO and Tier II PRZM

- EXAM modeling, the average annual mean11

concentration of diflubenzuron in ground and surface water sources is not expected to exceed the level of concern. The DWLOC for chronic (cancer) exposure to diflubenzuron and CPU in surface/ drin king water was determined as 2.76 ppb for the U.S. population (total). The gr oundwater estimate from SCIGROW is 0.208 ppb. The estimated maximum concentrations of diflubenzuron and CPU in ground and surface water are less than the DWLOC’s as a contribution to chronic aggregate
exposure.

2. Non

- dietary exposure. Diflubenzuron is a restricted use pesticide based on its toxicity to aquatic invertebrates. This restricted use classification makes it unavailable for use by homeowners. Occupational uses of diflubenzuron may expose people in residential locations, parks, or forests treated with diflubenzuron. Based on very low residues detected in forestry dissipation studies, a low dermal absorption rate (0.5%), and extremely low dermal and inhalation toxicity, these uses are expected to result in insignificant risk, and are therefore not included in the aggregate risk assessment.

D. Cumu lative Effects

The registrant has considered the potential for cumulative effects of diflubenzuron and other substances with a common mechanism of toxicity. The mammalian toxicity of diflubenzuron is wel l defined. Chemtura is not aware of any other pesticide product registered in the United States that could be metabolized to p

- chloroaniline. For this reason, consideration of potential cumulative effects of residues from pesticidal substances with a comm on mechanism of action as diflubenzuron is not appropriate. Thus, only the potential exposures to diflubenzuron were considered in the total exposure assessment.

E. Saf ety Determination

1. U.S. population. Based on the available toxicology and exposure d atabase for diflubenzuron, the registrant has determined that the total non

- occupational aggregate exposure from diflubenzuron would occur from food and drinking water routes. Based on the 0.02 mg/kg/day RfD (reference dose) derived from the dog chronic N OEL of 2 mg/kg/day and a 100

- fold safety factor, chronic dietary exposure to the U.S. population (total) is 7.8 % of the RfD. Aggregate exposure does not exceed 100% of the RfD when the potential theoretical residues in drinking water are included.

For PCA, the total non - occupational aggregate exposure would occu r from the dietary route. The risk from diflubenzuron

- derived PCA can be estimated using a linear extrapolation of the dose

- response from the rat chronic study conducted by the National Toxi cology Program in which rats were dosed via gavage with p

- chloroaniline [hydrochloride] for 24 mo nths. EPA has determined the Q * as 0.112 based on the combined incidence of liver adenomas and carcinom as in male mice. Using this Q *, the theoretical risk to the U.S. population (total) from dietary exposure to diflubenzuron

- derived PCA was estimated at 7.87 x 10 - 7

.

For CPU, total aggregate exposure could occur from food and drinking water. The EPA has determined that since CPU is structurally r elat ed to Monuron the most potent Q * of 1.52 x 10

- 2 (based12

on male rat liver neoplastic nodule a nd/or carcinoma combined tumor rates) from the NTP carcinogenesis data for Monuron should be used for assessing canc er risk from CPU. Using this Q * the theoret ical risk to the U.S. population (total) from dietary exposure to CPU was estimated at 6.41 x 10 - 7

. The aggregate cancer risk including drinking water does not exceed the level of concern.

2. Infants and children. The dietary exposure of diflubenz uron was calculated as 0.000835 and 0.001528 mg/kg/day respectively for nursing and non

- nursing infants. These values are 4.2% and 7 .6 % respectively of the RfD for diflubenzuron. The dietary exposure from diflubenzuron in children 1

- 6 and 7

- 12 years old was deter mined as 0.004332 mg/kg/day and 0.001972 mg/kg/day, res pectively. These values are 21.7 % and 9.9 % of the RfD, respectively. Aggregate exposure from food and drinking water does not exceed the level of concern.

As previously discussed, the NOE L’s for maternal and developmental toxicity in rats and rabbits were greater than 1,000 mg/kg/day, and the NOEL for reproductive toxicity was greater than 5,000 mg/kg/day. Therefore, based on the completeness and reliability of the toxicity data and the

c onservative exposure assessment, the registrant concludes that there is reasonable certainty that no harm will result in infants and children from aggregate exposure to residues of diflubenzuron and its conversion products conta ining the p - chloroaniline mo iety.

F. Inte rnational Tolerances

Codex MRL s have been established for diflubenzuron per se on many commodities including : citrus fruit ( 0.5 ppm ), mushrooms (0.3 ppm), pome fruits (5 ppm), rice (0.01 ppm), rice straw and fodder (dry; 0.7 ppm), edible of fal (mammalian) (0.1 ppm), eggs (0.05 ppm), poultry meat (0.05 ppm), milk (0.02 ppm). MRLs have been established for diflubenzuron in the EU for citrus (1.0 ppm), pome fruit ( 5 ppm), apricot (1 ppm), strawberry (2 ppm), grapes (1 ppm), and brassica vegetab les (1 ppm)

.