FILE NAME: DFB-A357 citrus 2012 NOF 

 

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2F8015

Summary of Petitions

EPA has received a pesticide petition (2F8015) from [Chemtura Corporation], [199

Benson Road, Middlebury, CT 06749] proposing, pursuant to section 408(d) of the Federal 

Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.

Options (1)

1. by establishing a tolerance for residues of

[N-[[(4-chlorophenyl)amino]-carbonyl]-2,6-difluorobenzamide (DFB) and its metabolites 

4-chlorophenylurea (CPU) and 4-chloroaniline (PCA) in or on the raw agricultural commodities 

[orange, grapefruit, and lemon (citrus fruits crop group 10), at 1.3 ppm, and citrus oil 

processed commodity at 39 ppm.] 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 granting of the petition. Additional data may be needed before EPA rules on the 

petition.
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A. Residue Chemistry 

1. Plant metabolism. The nature of the residue in plants is adequately understood. 

In plants, the metabolism 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 diflubenzuron. 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 

diflubenzuron 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 the 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/MS, 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 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 acetonitrile. The resultant solvent 

mixture was partitioned with 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 acetonitrile 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 chromatography (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 acetonitrile 

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 presence 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 preconditioned Si SPE 
3

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 partition of the oil between hexane and 

acetonitrile:water. The combined acetonitrile:water phases were concentrated and were 

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 internal 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 organic 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 hexane. The resultant extract was passed through a Florisil SPE cleanup 

prior to derivatization 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 

citrus. 

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 

diflubenzuron 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 

tolerance 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 trial 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-chloroaniline (PCA) metabolites in the citrus 

fruits crop group, based on the proposed field use conditions. 
4

Chemtura Corporation is proposing a citrus crop group tolerance of 1.3 ppm, and a 

tolerance of 39 ppm on citrus oil processed commodity.

B. Toxicological Profile

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 LC50 in rats is >35 mg/l (6 hours). Diflubenzuron 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 Lymphoma 

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 and 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/day. 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 dosage 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 toxicity 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 and 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 seen 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 
5

and a three-week dermal study were conducted. In the inhalation study rats were exposed 

nose only to 10, 30 or 100 mg/m3for 6 hours per day, 5 days per week for 4 weeks. 

Treatment related findings were a slight reduction in erythrocytes, hemoglobin and 

hematocrit in male and female rats at a concentration of 100 mg/m3and an increase in total 

bilirubin in high dose female rats. There was no effect on methemoglobin concentration 

at any dose level. The NOEL for subchronic inhalation toxicity was 30 mg/m3. 

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 

methemoglobin 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/cm2of [

14C] 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 rats 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 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 effects, including carcinogenic findings, 

were observed. 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 
6

diflubenzuron 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, 

siderocytosis in the spleen and pigmented Kupffer cells. A NOEL for these effects was 16 

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 were 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. 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. 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 effects, 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 poultry 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 gastrointestinal 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 dose 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 peak 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-sulfate, accounting for almost 50% of the 
7

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 detection of 23 parts per 

billion (ppb). As in the previous study, DFB was the only residue found in the feces.

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

with p-chloroaniline (PCA), a minor potential metabolite of diflubenzuron, 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 dose 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 proliferative 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 administered 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 

animals 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 

medullary 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 for 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 proliferative 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 the assay, sufficient evidence was not found to 

establish the carcinogenicity of PCA for B6C3F1 mice.
8

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 high 

dose male and female mice were generally within 5% of those of controls throughout the 

study. The incidence of hepatocellular adenomas or carcinomas (combined) was 

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 carcinogenic 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 association 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 estrogenic 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. Aggregate Exposure
10

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

The dietary exposure from diflubenzuron was estimated based on the average 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 exposure assessment was conducted on diflubenzuron using DEEM-FCIDTM

Version 2.14, which incorporates consumption data fromUSDS’s CSFII, 1994-1996 and 1998. 

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 and 

mushroom was 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 Population (total) was 

estimated was 12.4% of the cPAD (0.00248 mg/kg/day). The most highly exposed subpopulation, 

children 1-2 years, has an estimated total exposure of 39.9% 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 switching 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 has 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 mean 
11

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/drinking water was determined as 2.76 ppb for the U.S. population (total). The groundwater 

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. Cumulative 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 well 

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 common mechanism of action as diflubenzuron is not 

appropriate. Thus, only the potential exposures to diflubenzuron were considered in the total exposure 

assessment.

E. Safety Determination

1. U.S. population. Based on the available toxicology and exposure database 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 NOEL of 2 mg/kg/day and a 100-fold safety factor, chronic dietary 

exposure to the U.S. population (total) is 12.4% 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 occur 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 Toxicology Program in which rats 

were dosed via gavage with p-chloroaniline [hydrochloride] for 24 months. EPA has determined the 

Q* as 0.112 based on the combined incidence of liver adenomas and carcinomas 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 related to Monuron the most potent Q* of 1.52 x 10-2 (based 
12

on male rat liver neoplastic nodule and/or carcinoma combined tumor rates) from the NTP 

carcinogenesis data for Monuron should be used for assessing cancer risk from CPU. Using this Q* 

the theoretical 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 diflubenzuron was calculated as 0.000986 and 

0.002911 mg/kg/day respectively for nursing and non-nursing infants. These values are 4.9% and 

14.6% respectively of the RfD for diflubenzuron. The dietary exposure from diflubenzuron in 

children 1-6 and 7-12 years old was determined as 0.006601 mg/kg/day and 0.003509 mg/kg/day, 

respectively. These values are 33.0% and 17.5% of the RfD, respectively. Aggregate exposure from 

food and drinking water does not exceed the level of concern. 

 As previously discussed, the NOEL’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 

conservative 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 containing the p-chloroaniline moiety.

F. International Tolerances

Codex MRLs 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 offal (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 vegetables (1 ppm).