

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Elizabeth Fertich (703) 347-8560


Nichino America, Inc.

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Nichino America, Inc., 4550 Linden Hill Rd., Suite 501, Wilmington, Delaware, 19808, USA requesting, 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 by establishing a tolerance for residues of benzpyrimoxan, 5-(1,3-dioxan-2-yl)-4-[4-(trifluoromethyl)benzyloxy]pyrimidine in or on the raw agricultural commodity rice, grain at 0.9 parts per million (ppm).  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; 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.

A. Residue Chemistry

	1. Plant metabolism. The metabolic fate of benzpyrimoxan in rice is adequately understood. The metabolism of benzpyrimoxan was studied in rice grown under paddy conditions in a greenhouse using benzpyrimoxan radiolabeled in the phenyl ring ([phenyl-U-14C]benzpyrimoxan ) and the pyrimidinyl ring ([pyrimidinyl-4(6)-14C] benzpyrimoxan). Treatments were applied as a foliar spray at a target rate of 200 g ai/ha in each of 3 applications (total of 600 g ai/ha) for each radiolabel. Samples of foliage, panicle, rice grain, hulls, straw and roots were extracted and extracts analyzed to determine the nature of benzpyrimoxan residue. 

Relatively small amounts of radioactive residues were detected in grain (0.10 - 0.25 mg benzpyrimoxan eq./kg) and root (0.05 - 0.09 mg benzpyrimoxan eq./kg). This suggests that translocation of radioactivity is limited. Benzpyrimoxan was the most significant portion of the radioactivity (considering both labels), and was in panicle (81.7-84.7% TRR), foliage (68.8-70.2% TRR), hulled (unpolished or brown) rice (48.3-57.2% TRR), hulls (59.9-60.6% TRR), and straw (48.2-50.5% TRR). NNI-1501-2-OH (metabolite DH-04) was the only metabolite exceeding 10% TRR. In samples treated with [phenyl-(U)-14C]benzpyrimoxan, NNI-1501-2-OH accounted for 15.4% TRR in hulled rice. In samples treated with [pyrimidinyl-4(6)-14C]benzpyrimoxan, NNI-1501-2-OH exceed 10% TRR in foliage (10.9% TRR), hulled rice (17.3% TRR), and straw (11.9% TRR). The remainder of the residue consisted of several, minor products each present at levels <10% TRR.

	2. Analytical method. An adequate enforcement method is available for detection of residues for the proposed tolerance. The QuEChERS method is proposed as the enforcement method for benzpyrimoxan. This method was validated for the determination of benzpyrimoxan and NNI-1501-2-OH in rice grain at fortification levels of 0.010 mg/kg and 0.10 mg/kg. The LOQ for both benzpyrimoxan and NNI-1501-2-OH was 0.01 mg/kg. 

An LC-MS/MS analytical method was used in the residue studies. The method involves the extraction of benzpyrimoxan and NNI-1501-2-OH from crop matrices and LC MS/MS detection and was validated using unhulled rice, unpolished (brown) rice, and rice straw. The LOQ for both benzpyrimoxan and NNI-1501-2-OH in all matrices was 0.01 mg/kg.

	3. Magnitude of residues. Field trials were carried out in Japan from 2015 to 2017 in paddy rice to meet the Japanese country registration requirements as well as requirements for an import tolerance in the United States. Benzpyrimoxan was applied at 0.2 kg a.i./ha in each of three foliar applications. Samples of rice grain and straw were collected at 7, 14, and 21 days after the last application and were analyzed for benzpyrimoxan and NNI-1501-2-OH using an LC-MS/MS method with a limit of quantitation (LOQ) of 0.01 mg/kg for both analytes.


B. Toxicological Profile

	1. Acute toxicity. Benzpyrimoxan was found to have low (or practically non-toxic) acute toxicity following exposure via oral (gavage), dermal and inhalation routes of administration. Based on study results, benzpyrimoxan was considered to be a slight irritant to the skin, and to the eye, and to be a skin sensitizer.

Summary of Acute Toxicology Study Results  -  Benzpyrimoxan:
Type of study
Species
Result
Oral route
Rat
LD50 > 2000 mg/kg bw
Dermal route
Rat
LD50 > 2000 mg/kg bw
Inhalation
Rat
LC50 > 3.9 mg/L
Primary skin irritation
Rabbit
Slight irritant
Eye irritation
Rabbit
Slight irritant
Skin sensitization
Guinea pig
Skin sensitizer

An acute neurotoxicity study was conducted in rats with benzpyrimoxan administered once by oral gavage at doses of 0, 500, 1000, and 2000 mg/kg. Neurotoxicity was not observed at any dose level; therefore, the NOAEL for acute neurotoxicity is 2000 mg/kg.

	2. Genotoxicity. Benzpyrimoxan has been evaluated in a comprehensive battery of in vitro and in vivo genotoxicity assays for mutagenicity and clastogenicity. The assays were conducted in compliance with OPPTS, OECD or Japan MAFF guidelines and all were considered to be valid assays based on sensitivity to known positive control substances. The results of these studies indicate that benzpyrimoxan does not have genotoxic potential in these assays. Additionally, the metabolite NNI-1501-2-OH was assayed in a bacterial reverse mutation test and a human lymphocyte micronucleus assay and results did not indicate genotoxicity.

	3. Reproductive and developmental toxicity. Guideline pre-natal developmental oral (gavage) toxicity studies in rats and rabbits and a dietary 2-generation reproductive toxicity study have been conducted with benzpyrimoxan. 

Benzpyrimoxan was administered at doses of 0, 10, 50, or 250 mg/kg/day in the rat developmental study. Oral administration of NNI-1501 to maternal rats at a dose of 250 mg/kg bw/day suppressed body weight, body weight gain, and food consumption of maternal rats, while no adverse effects were observed on their fetuses. No increases were seen in the incidences of variant or anomalous fetuses at any dose level examined. Therefore, it was concluded that the NOAELs of NNI-1501 for maternal rats and for their fetuses are 50 mg/kg bw/day and 250 mg/kg bw/day, respectively, and that NNI-1501 is not teratogenic at dose levels up to 250 mg/kg bw/day.

In the rabbit developmental study, benzpyrimoxan was administered at doses of 0, 3, 10, or 30 mg/kg bw/day. In the 3 and 10 mg/kg groups, no adverse effects related to the test article administration were found on maternal rabbits and their fetuses in any parameter examined. Oral administration of NNI-1501 to maternal rabbits at a dose of 30 mg/kg bw/day suppressed body weight, body weight gain, and food consumption of maternal rabbits. This dose also resulted in abortion and low gravid uterine weight. 
It was concluded that the NOAELs of NNI-1501 for both maternal rabbits and their fetuses were 10 mg/kg bw/day, and that NNI-1501 is not teratogenic at dose levels up to 30 mg/kg bw/day.

In the 2-generation reproductive toxicity study, benzpyrimoxan was administered at 0, 60, 300, or 2000 ppm over two successive generations to rats. Based on results of the 2-generation study in rats, it was concluded that the parental NOAEL for benzpyrimoxan for reproductive and general toxicity was 300 ppm (15.5 mg/kg bw/day (males) and 23.6 mg/kg bw/day (females), and the dose level of 2000 ppm was the toxic level for general toxicity in parental rats. As for rat pups, the dose level of 300 ppm was the NOAEL (15.5 mg/kg bw/day (males) and 23.6 mg/kg bw/day (females).

	4. Subchronic toxicity. 28-day dietary dose range finding studies were conducted in the rat and mouse to establish appropriate dose levels for use in the 90-day studies. 90-day dietary studies were conducted in the rat, mouse and dog. Data was obtained for the selection of dose levels for the subsequent carcinogenicity studies.

In the 90 day mice toxicity study benzpyrimoxan was administered to males at 0, 400, 2000 and 4000 ppm, and to females at 0, 400, 2000 and 6000 ppm in the diet. Effects on kidney and liver were observed at the 2000 ppm dose level, but there were no toxicologically significant findings at 400 ppm in males or females. Therefore, the 400 ppm dietary dose level was the NOAEL (equivalent to 56.4 mg/kg bw/day in males and 66.1 mg/kg bw /day in females). 

In the rat 90-day toxicity study benzpyrimoxan was administered to both male and females at concentration levels of 0, 100, 300, 1000 and 3000 ppm in the diet (equivalent to 0, 6.26, 18.7, 64.2 and 194 mg/kg bw/day for males and 0, 7.41, 22.2, 78.1 and 227 mg/kg bw/day for females) for a period of more than 90 days (13 weeks). At the 1000 ppm dose level unusual crystals were observed in urine sediment in females and effects on the liver and kidney were detected in males and females. Therefore, the NOAEL was determined to be the 300 ppm dose level for both males and females (males, 18.7 mg/kg bw/day; females 22.2 mg/kg bw/day). 

A 90-day repeated dose oral toxicity study in dogs was conducted by dietary administration of benzpyrimoxan at dose concentrations of 0, 500, 2500, and 10000 ppm. Based on increased total cholesterol and phospholipid in the blood in both sexes at the 2500 ppm dose level, the NOAEL was determined to be 500 ppm (16.56 mg/kg bw/day for males and 15.89 mg/kg bw/day for females). 

	5. Chronic toxicity. Three guideline long-term toxicity studies have been performed with benzpyrimoxan, including a 1-year toxicity study in dogs, a 78-week carcinogenicity study in the mouse, and a combined chronic toxicity and carcinogenicity study in the rat. 

In the dog 1-year toxicity study, benzpyrimoxan was administered to male and female dogs in the diet at concentrations of 100, 500 and 2500 ppm. 

No toxicologically significant effects were seen in any animal at the 100 ppm dose concentration, however, the following changes related to treatment were noted at 500 and 2500 ppm:
Blood chemistry revealed an increase in ALP in females at 500 ppm and in both sexes at 2500 ppm, total cholesterol and phospholipid in both sexes at 500 and 2500 ppm, and in ALT and triglycerides in males at 2500 ppm.

In organ weight measurement, increased absolute and/or relative weights of the liver were noted in both sexes at 500 and 2500 ppm.

Gross pathological examination revealed dark discoloration of the liver in males at 500 ppm and in both sexes at 2500 ppm. In one male at 2500 ppm, enlarged liver was also observed. Histopathology revealed hypertrophy of the centrilobular hepatocytes in one male at 2500 ppm and pigmentation of the hepatocytes in both sexes at 500 and 2500 ppm. In the representative animals at 2500 ppm, the pigments of the hepatocytes showed positive reactions to the Schmorl method and Periodic acid-Schiff (PAS) reaction, and a weak positive reaction to the Hall method.

Based on the results described above, the NOAEL was estimated to be 100 ppm (equivalent to 2.92 mg/kg bw/day for males and 2.68 mg/kg bw/day for females) in this study.

In the 78-week carcinogenicity study in the mouse, benzpyrimoxan was administered to male and female mice orally through the diet at concentrations of 0, 80, 400, and 1500 (females) / 2000 ppm (males). 

It was concluded that the dietary administration of benzpyrimoxan to CD-1 mice for 78 weeks at concentrations up to 2000 ppm in males and up to 1500 ppm in females (equivalent to 194.9 and 162.9 mg/kg bw/day, respectively) produced no evidence that benzpyrimoxan was carcinogenic in mice. Observed hepatocyte hypertrophy was considered an adaptive response to treatment while the presence of crystals in the urinary system and calculi in the gall bladder were attributed to excreted benzpyrimoxan and as there was no associated inflammation, the finding was considered to be most likely non-adverse. The combination of reduced body weight gain and hyperplasia in the gall bladder for males given 2000 ppm was considered an adverse effect and, consequently, the NOAEL in males was set at 400 ppm (equivalent to 39.9 mg/kg bw/day). There were no findings of toxicological significance in females and, consequently, the NOAEL in females was 1500 ppm (equivalent to 162.9 mg/kg bw/day).

In the rat combined chronic toxicity and carcinogenicity study, benzpyrimoxan was administered to male and female rats orally through the diet at concentrations of 0, 60, 300, and 1500 ppm for a period of 52 weeks for the chronic toxicity group, and for a period of 104 weeks for the carcinogenicity group. 

In this study, there was no increase in the incidence of neoplastic lesions in any treated groups of either sex. Besides, there were no increases of rare types of tumors, earlier onset of spontaneous neoplasms, or other signs indicating carcinogenicity. Therefore, it was concluded that benzpyrimoxan technical grade showed no carcinogenic effect. 

Benzpyrimoxan had effects on body weight, the liver, urinary system (kidney and/or urinary bladder) and several haematological parameters in both sexes treated at 1500 ppm in the carcinogenicity and/or chronic toxicity groups. Effects on food consumption and food efficiency in females at 1500 ppm in the carcinogenicity and chronic toxicity groups were also observed. The NOAEL was set at 300 ppm (equivalent to 11.7 mg/kg bw/day for males, and 14.7 mg/kg bw/day for females in the carcinogenicity group; equivalent to 13.9 mg/kg bw/day for males, and 17.5 mg/kg bw/day for females in the chronic toxicity group).

	6. Animal metabolism. Metabolism of benzpyrimoxan in rats was investigated as part of the absorption, metabolism, distribution, and excretion studies conducted with this compound. Benzpyrimoxan is rapidly absorbed from the gastrointestinal tract of rats. Radioactivity in organs and tissues declined rapidly with excretion into feces and urine. The major metabolites were formed by hydrolysis of the acetal moiety to form carboxylic acid or hydroxymethyl moiety, and hydroxylation and N-oxidation of pyrimidine ring. Various metabolites were produced with loss of pyrimidine or phenyl ring. There were no significant sex-related or dose-related difference in metabolic fate.

Metabolism of benzpyrimoxan was also investigated in studies conducted with lactating goats and laying hens. In both species, the majority of the administered radioactivity was excreted. The major metabolites were formed by hydrolysis of an acetal (R2C(OR')2) moiety of the test substance to form a hydroxymethyl (RCH2OH) moiety and its resulting carboxylic acid (RCOOH) moiety. Hydroxylation of the pyrimidine ring was also observed. 

Results of the metabolism studies showed that metabolism of benzpyrimoxan is similar in rodent (rat), ruminant (goat), and poultry (hen). Therefore, no significant species-related difference in the metabolic profiles of benzpyrimoxan is expected.

	7. Metabolite toxicology. Toxicity of the metabolite NNI-1501-2-OH was evaluated in a bacterial reverse mutation test, an in vitro human lymphocyte micronucleus assay, and in a 90-day oral toxicity study in rats. 

In the bacterial reverse mutation test, NNI-1501-2-OH was found to be negative for gene mutagenic activity. In the in vitro human lymphocyte micronucleus assay, NNI-1501-2-OH did not induce micronuclei in cultured human peripheral blood lymphocytes. 

Subchronic toxicity of NNI-1501-2-OH was evaluated in rats in a 90-day study. NNI-1501-2-OH was administered in feed at concentrations of 0, 100, 300, 1000 and 3000 ppm for a period of 92 days. The NOAEL was considered to be 100 ppm (equivalent to 6.36 mg/kg bw/day) in male rats, and 300 ppm for females (equivalent to 22.8 mg/kg bw/day).

	8. Endocrine disruption. Benzpyrimoxan does not belong to a class of chemicals known as suspected of having effects on the endocrine system. There is no evidence in other relevant toxicity studies (e.g. sub-chronic and chronic toxicity, developmental toxicity and multi-generation reproductive studies) which would suggest that benzpyrimoxan has any endocrine disruptive potential.


C. Aggregate Exposure

	1. Dietary exposure. Since the only proposed tolerance for benzpyrimoxan is on imported rice grain and there are no other existing or proposed U.S. registrations, the aggregate exposure and risk assessment was limited to dietary (food only) exposure and risk. Potential dietary exposure through drinking water or potential non-dietary exposures were not applicable. 

Acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02). The proposed definition of residue for risk assessment is the sum of benzpyrimoxan and NNI-1501-2-OH expressed as benzpyrimoxan. Both the acute and chronic dietary exposure evaluations were screening-level and assumed residue in rice grain at the proposed tolerance of 0.9 ppm together with the maximum residue level of NNI-1501-2-OH, expressed as benzpyrimoxan, and 100% crop treated. 

	i. Food. Acute Exposure. Acute dietary risk was evaluated for all population subgroups based on an aPAD of 0.1 mg/kg bw/day. An acute reference dose (aRfD) of 0.1 mg/kg bw/day was based on a developmental toxicity study in rabbits based on a NOAEL of 10 mg/kg-bw/day with an uncertainly factor of 100X for intra- and inter-species variations. Based on no additional FQPA Safety Factor (1X), the aPAD is proposed at 0.1 mg/kg bw/day.

Exposure was expressed as a percent of the aPAD. The screening-level evaluation indicated acute dietary exposure and risk was <= 4.7% of the aPAD for the general population and all population subgroups at the 95th percentile of the exposure distribution. Dietary exposure was 1.4% of the aPAD for the general population. The population subgroup with highest dietary exposure was non-nursing infants with exposure at 4.7% of the aPAD

Chronic Exposure. Chronic dietary risk was evaluated for all population subgroups based on a cPAD of 0.026 mg/kg bw/day. A chronic reference dose (cRfD) of 0.026 mg/kg bw/day was based on a chronic toxicity study in dogs with a NOAEL of 2.68 mg/kg-bw/day and an uncertainly factor of 100Xfor intra- and inter-species variations. Based on no additional FQPA Safety Factor (1X), the aPAD is 0.1 mg/kg bw/day.

Exposure was expressed as a percent of the cPAD. The screening-level evaluation indicated chronic dietary exposure and risk was <= 4.0% of the cPAD for the general population and all population subgroups. Dietary exposure was 1.1% of the cPAD for the general population. The population subgroup with highest dietary exposure was non-nursing infants with exposure at 4.0% of the cPAD.

	ii. Drinking water. Since this will be an import tolerance only, and there are no other existing or proposed U.S. registrations, no drinking water exposures are anticipated.

	2. Non-dietary exposure. Since this will be an import tolerance only, and there are no other existing or proposed U.S. registrations, no non-dietary exposures are anticipated.

D. Cumulative Effects

	It is not necessary at this time to consider cumulative effects because there is no indication that toxic effects of benzpyrimoxan have a common mechanism of toxicity with those of any other chemical compounds, and benzpyrimoxan does not appear to produce a toxic metabolite that is also produced from other substances.

E. Safety Determination

	1. U.S. population. Since the only proposed tolerance for benzpyrimoxan is on imported rice grain and there are no other existing or proposed U.S. registrations, the aggregate exposure and risk assessment was limited to dietary (food only) exposure. Both acute and chronic dietary exposures were evaluated based on highly conservative screening-level assessments. Based on these conservative exposure assumptions, the assessments indicated that acute exposure would occupy 1.4% of the aPAD for the total U.S. population, and that chronic exposure would occupy 1.1% of the cPAD for the total U.S. population. Therefore, these assessments indicate there is reasonable certainty that no harm to the U.S. population will result from the proposed tolerance for benzpyrimoxan.

	2. Infants and children. Based on the completeness and reliability of the toxicity data, the lack of indication of increased prenatal or postnatal sensitivity, and the conservative exposure assessments, it is proposed that infants and children would be adequately protected if the FQPA Safety Factor (FQPA SF) were reduced to 1X. Therefore, an FQPA SF of 1X is proposed. 

Both acute and chronic dietary exposures were evaluated based on highly conservative screening-level assessments. Among infants and children, the population subgroup with highest acute exposure was non-nursing infants with exposure at 4.7% of the aPAD. Non-nursing infants also had the highest chronic exposure with exposure at 4.0% of the cPAD. Therefore, these assessments indicate there is reasonable certainty that no harm to infants and children will result from the proposed tolerance for benzpyrimoxan.


F. International Tolerances

	Japan has established MRLs for benzpyrimoxan in/on rice grain and a number of animal commodities. There are currently no Codex MRLs; however, data and proposed MRLs for rice grain and animal commodities have been submitted for review. 

