Makhteshim -Ag an of North America, Inc.

PP 0F7708 EPA has received a pesticide petition (PP # to be assigned) from Makhteshim
-Ag an of N orth America, Inc., 4515 Falls of N euse Road, Raleigh, NC 27609, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.598 by establishing a tolerance for residues of novaluron (N
- [[[3
-chloro
-4
- [1,1,2
-trifluoro
-2
- trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]
-2,6
-difluorobenzamide) in or on all food commodities (other than those already covered by a higher tolerance as a result of u se on growing crops) in food handling establishments where food products are held, processed or prepared at 0.01 parts per million (ppm). Makhteshim
-Ag an of

N orth America, Inc. , is the manufacturer and basic registrant of n ovaluron. Makhteshim
-Ag an of

N orth America, Inc., prepared and summarized the following information in support of the subject pesticide petition for novaluron. EPA has determined that the petition contains data or information regarding the elements set fo rth 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. A.Residue Chemistry 1

. Plant and Livestock Metabolism The qualitative nature of the residue of novaluron in plants is adequately understood based on acceptable plant metabolism studies reflecting its uses on apples, cabbage, cotton, and potatoes. These plant metabolism studies have demonstrated that novaluron does not metabolize and is non -systemic (does not translocate within the plant). The results observed in the plant and livestock metabolism studies show similar metabolic pathways. The residue of concern, which should be regulated, is the parent compound, novaluron, only. 2. Analytical Method An adequate analytical enforcement method, gas chromatography/electron capture detector (GC/ECD) and a high performance l iq uid chromatography/ultraviolet method (HPLC/UV) fo r enforcing tolerances of novaluron residues in or on different matrices are available, as published in the Federal Register of January 27, 2010 (Volume 75, Number 17; FRL
-8807
-2). Concerning this petiti on a validation method was conducted determining residue concentrations of n ovaluron in/on butter, meat, milk, bread, lettuce and typical dinner plates serving as representative commodities in a simulated food
- handling establishment to which novaluron was applied. The LOQ in butter, processed meat (turkey), milk, bread and lettuce was established as 0.01 mg/kg (0.01 ppm), the lowest fortification concentration tested where recoveries were acceptable (70 to 120% with RSD < 20%).3. Magnitude of Residues

In a Food Handling Establishment, novaluron was applied to the room as a typical space spray treatment, simulating a routine pest control treatment in the form of afine mist (fog) at an exaggerated rate (3x of the maximum label rate or 38.75 mg ai/m 2). Samp les of common food matrices (butter, turkey lunchmeat, milk, sliced bread and lettuce) and bare vitreous china plates were placed into the treated room to measure direct deposition, re-deposition and decline (or concentration) of

residues over a 12
- hour sa mpling period. Covered and non -covered samples were collected 4, 8 and 12 hours after application, frozen, and sent to the analytical laboratory for analysis. The results of

the proposed use of novaluron in food handling establishments demonstrate minimal residues on covered food items. Novaluron residues did not increase or decrease during the sampling period covered by the study (12 hours). Novaluron residues on uncovered foods at exaggerated rates (3x) ranged up to 10 ppm, whereas residues on covered food were non detectable (<0.01 ppm), with the exception of one bread sample at a residue concentration of 0.01 ppm. Therefore, covered food matrices and surfaces had approximately 1000X less novaluron than uncovered food matrices and surfaces. There was no significant re-deposition of novaluron residues following the initial test substance application In conclusion, at the maximum, nominal application rate (1x), novaluron residues are anticipated to be less than 0.01 ppm on food that has been covered or rem oved during treatment. Therefore, the proposed tolerance for the use of novaluron in food handling establishments should be set at 0.01 ppm. B. Toxicological Profile 1. Acute Toxicity In an acute oral toxicity study in rats, novaluron had an LD50 >5,000 mg/kg. A dermal toxicity study in rats resulted in an LD50 greater than 2,000 mg/kg. The LC50 for acute inhalation in rats was greater than 5.15 mg/l. In rabbits, novaluron is not a skin irritant, but it is a mild eye irritant. Novaluron is not a sensitizer in guinea pigs. 2. Genotoxicity The mutagenic potential of Novaluron was investigated in several in vivo and in vitro studies. Results in two Ames assays, an in vivo mouse micronucleus assay, an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro cell mutation assay, and an in vitro human lymphocyte clastogenicity test were negative. Novaluron is therefore considered to have no potential to induce mutagenicity. 3. Reproductive and Developmental Toxicity i. A two generation rat reproduction study was conducted with dose levels of 1,000, 4,000, and 12,000 ppm (74.2, 297.5, 894.9 mg/kg/day, and 84, 336.7, 1,009.8 mg/kg/day for males and females, respectively). Maternal and offspring toxicity was evidenced by increasedabsolute and relative splee n weights, whereas reproductive toxicity was observed only in males

at 297.5 mg/kg/day (LOAEL) based on decreased epididymal sperm counts and increased age at preputial separation in the F1 generation. The no observed adverse effect level (NOAEL) in males was 1,000 ppm (74.2 mg/kg/day) and in females it was $12,000 ppm (1,009.8 mg/kg/day).
ii. Teratology studies were conducted in the rat and rabbit. No treatment
- related mortalities were observed in either study. No effect on survival, development or growth of fetuses was noted in either species in either study. No maternal or developmental toxicity was observed up to and including the limit dose of 1 ,000 mg/kg/day (NOAEL). These two studies demonstrate that novaluron was not teratogenic in either rats or ra bbits. 4. Subchronic Toxicity Rats, mice and dogs all show the same toxicologic response. Generally, novaluron induces small increases in methemoglobin; red cells are sequestered; and, compensatory hematopoiesis occurs. The severity of these changes is well within the physiological capacity of the animals and is judged not adverse. Rats treated topically with novaluron in a 28
-day study at 0, 75, 400 and 1,000 mg/kg/day did not show signs of systemic toxicity. Small treatment
- related increases in methemoglobin were seen in both sexes at 1,000 mg/kg/day and in fe males at 400 mg/kg/day. The highest methemoglobin value seen in females was 1.28% compared with 0.86% in controls. Organ weights, macroscopic and microscopic examination of organs and tissues did n ot reveal any treatment
- related changes. Two 13
-week rat studies were conducted. In one study, doses were administered at 50, 100, 200, 400 ppm (3.52, 6.93, 13.83, 27.77 mg/kg/day and 4.38, 8.64, 17.54 and 34.39 mg/kg/day for males and females, respective ly). The LOAELs from the combined results were 27.77 mg/kg/day in males based on increased occurrence of extramedullary hematopoiesis and hemosiderosis in spleen; and 8.64 mg/kg/day in fe males based on reduction in hemoglobin, hematocrit and RBC count; in creased occurrence of extramedullary hematopoiesis and hemosiderosis in spleen and liver. The NOAEL was determined to be 4.38 mg/kg/day. A 13
-week mouse study was conducted with dose levels of 30, 100, 1,000, 10,000 ppm (4.2, 12.8, 135.9, 1,391.9 and 4.7, 15.2, 135.6, 1,493.1 mg/kg/day, for males and females, respectively). The NOAEL was determined to be 100 ppm (12.8 and 15.2 mg/kg/day, male and females, respectively). The LOAEL was 1,000 ppm (135.9 and 135.6 mg/kg/day, males and females, respectively) based on increased body weight gain, low erythrocyte counts, and secondary splenic changes. There were no clinical treatment
- related signs noted. Two 13
-week dog studies were conducted. One study resulted in an NOAEL of 100 mg/kg/day and a LOAEL of

300 mg/kg/day based on low erythrocyte counts and secondary splenic and liver changes. No clinical treatment
- related signs were noted. Another study, was conducted using only one dose level of 10 mg/kg/day. There were no clinical or histopathological treatment
rel ated signs and the NOEL was determined to be 10 mg/kg/day. 5. Chronic Toxicityi. Chronic toxicity and oncogenicity was evaluated in the rat, mouse and dog. The rat chronic

toxicity and oncogenicity was conducted with dose levels of 25, 700, 20,000 ppm ( 1.1, 30.6, 884.2 and 1.4, 39.5, 1,113.5 mg/kg/day for males and fe males, respectively). The LOAEL in male and fe male rats was 30.6 and 39.5 mg/kg/day, respectively, based on evidence of erythrocyte damage and turnover resulting in a regenerative anemia in both sexes. The corresponding NOAEL was 25 ppm (1.1 and 1.4 mg/kg/day fo r male and fe male rats, respectively). There was no evidence of carcinogenicity in this study. A mouse chronic toxicity study was conducted with dose levels of 30, 450, 7,000 ppm (3.6, 53.4, 800.0 and 4.3, 63.3, 913.4 mg/kg/day for males and females, respectively). The LOAEL in male and female mice was 53.4 and 63.3 mg/kg/day, respectively, based on erythrocyte turnover due to hemoglobin oxidation and resulting in a compensated anemia. The corresponding NOAEL was 30 ppm (3.6 and 4.3 mg/kg/day for male and fe male mice, respectively). There was also no evidence of carcinogenicity in this study. Chronic toxicity was investigated in dogs using dose levels of 10, 100, 1,000 mg/kg/day. The NOAEL of 100 mg/kg/day was based on methemoglobin. ii. The chronic reference dose (cRfD) of 0.011 mg/kg/day has been established on the basis of the chronic carcinogenicity study in rats. An uncertainty factor (UF) of 1 00 was applied to the NOAEL of 1.1 mg/kg/day for male rats deriving to the cRfD. iii. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July 1999), novaluron is classified as not likely to be carcinogenic to humans due to results of o ncogenicity studies that show no evidence of carcinogenicity in rats and mice. 6. Animal Metabolism Metabolism studies in rats and goats were conducted with the parent material labeled in both the difluorophenyl and chlorophenyl moieties. Rats absorb little novaluron when it is administered orally. More than 90% of the dietary administered [chlorophenyl 14C(U)] novaluron is recovered in the feces. W hen the diflurophenyl ring of the molecule is labeled, the recovered 14C activity in the feces is lower but still above 75%. The difference i s thought to reflect intestinal metabolism by microbial flora and the higher absorption of the diflurophenyl metabolites.
The parent molecule as we ll as its degradates are absorbed from the gastrointestinal tract. All parent material is metabolized either upon initial entry into the systemic circulation or, if sequestered to the fat, upon its depuration back to the systemic circulation. There is no intact novaluron found in the urine. Novaluron=s high octanol
-water partition coefficient is responsible for its preferential movement to fat. The half
- life i n fat calculated from the rat metabolism study is approximately 55 hours. Two groups of

m etabolites are formed after oral administration of novaluron. One group is typified by the aniline metabolite 3
-chloro-4
- (1,1,2
-trifluoro
-2
-trifluoromethoxyethoxy) aniline, referred to as 3
-TFA. The other group of m etabolites is typified by 2,6
-difluorobenzoic acid is from the diflurophenyl moiety of the molecule. Nearly all the metabolites are formed at a level of 1% or less of the applied dose. They are rapidly excreted.The metabolism in goats and hens mimics that seen in rats.

7

. Metabolite Toxicology Makhteshim
-Ag an of

N orth America Inc., has determined that there are no metabolites of toxicological concern and th erefore, no metabolites need to be included in the tolerance expression and require regulation. For drinking water assessment the soil degradates, chlorophenyl urea and chloroaniline will be included besides the parent, novaluron. 8. Endocrine Disruption No special studies investigating potential estrogenic or other endocrine effects of novaluron have been conducted. However, inspection of in
- life data from toxicology studies does not indicate that novaluron is an endocrine disruptor. Specifically, endocrine organ we ights (e.g., thyroid, testes, ovaries, pituitary fro m the two
-generation study) were not adversely affected by novaluron. Milestones of sexual development were not affected by novaluron; and, reproduction was not adversely affected. Based on th ese observations, there is no evidence to suggest that novaluron has an adverse effect on the endocrine system. C. Aggregate Exposure 1. Dietary

Exposure Tolerances have been established (40 CFR 180.598) for the residues of n ovaluron, in or on the following raw agricultural commodities: Apple, wet pomace at 8.0; Brassica, head and stem, subgroup 5A at 0.5 ppm; cattle, fat at 11 ppm; cattle, fat at 11 ppm; cattle, kidney at 1.0 ppm; cattle, liver at 1.0 ppm; cattle, meat at 0.60 ppm; cattle, meat byproducts, except liver and kidney at 0.60 ppm; cotton, gin byproducts at 30 ppm; cotton, undelinted seed at 0.60 ppm; egg at 0.05 ppm; fruit, pome, group 11 at 2.0 ppm; goat, fat at 11 ppm; goat, kidney at 1.0 ppm; goat, liver at 1.0 ppm; goat, meat at 0.60 ppm; goat, meat byproducts except liver and kidney at 0.60 ppm; hog, fat at 0.05 ppm; hog, meat at 0.01 ppm; hog, meat byproducts at 0.01 ppm; horse, fat at 11 ppm; horse, kidney at 1.0 ppm; horse, liver at 1.0 ppm; horse, meat at 0.60 ppm; horse, meat byprod ucts, except liver and kidney at 0.60 ppm; milk at 1.0 ppm; milk, fat at 20 ppm; poultry, fat at 0.40 ppm; poultry, meat at 0.03 ppm; poultry, meat byproducts at 0.04 ppm; sheep, fat at 11 ppm; sheep, kidney at 1.0 ppm; sheep, liver at 1.0 ppm; sheep, meat at 0.60 ppm; sheep, meat byproducts, except liver and kidney at 0.60 ppm, sugarcane, cane at 0.50 ppm; vegetables, tuberous and corn, subgroup 1C at 0.05 ppm; vegetable, fruiting, group 8 at 1.1 parts per million (ppm); vegetable, cucurbit, group 9 at 0 .25 ppm; berry, low growing, subgroup 13
-07G at 0.50 ppm; cocona at 1.1 ppm; eggplant, African at 1.1 ppm; eggplant, pea at 1.1 ppm; eggplant, scarlet at 1.1 ppm; goji berry at 1.1 ppm; huckleberry, garden at 1.1 ppm; martynia at 1.1 ppm; naranjilla at 1.1 ppm; okra at 1.1 ppm; roselle at 1.1 ppm; sunberry at 1.1 ppm; tomato, bush at 1.1 ppm; tomato, currant at 1.1 ppm; tomato, tree at 1.1 ppm; bean, snap, succulent at 0.60 ppm; bean, dry at 0.20 ppm; and Swiss chard at 12 ppm. In addition to the existing tolerances, this Notice of Filing includes exposure assessments for potential residues of novaluron in or on all food commodities in food handling establishments (FHE), where food products are held, processed or prepared, as well as the pending tolerance of novaluron in or on grain sorghum (PP# 9F7547), which is presently being reviewed by theAgency. The assessment is based on average residues from field trials (except cottonseed, for

wh ich tolerances were used), DEEM default processing factors and percent crop treated assumptions from previous assessments for pending and registered crops. Although lowbush blueberries are included in Crop Subgroup 13
-07G, the anticipated residue for strawberries (representative crop for Subgroup 13
-07G) is 0.14 ppm, whereas that for highbush blueberries is 1.97 ppm. Therefore, EPA has approved the tolerance for low
-growing berries with lowbush blueberries excluded. For the proposed FHE use, an estimated residue of 0.005 ppm 

### (1⁄2 LOQ) was assumed only for each food without a tolerance representing EPA’s approach for including FHE tolerances in chronic dietary assessments.i. Food

Acute Dietary Exposure. No toxicological endpoint attributable to a single exposure was identified in the available toxicology studies, including the rat and rabbit developmental studies. Therefore, the acute aggregate risk is negligible. Chronic Dietary Exposure. A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model (DEEM) software with the Food Commodity Inta keDatabase (DEEM
- FCID TM Version 2.16), which incorporates consumption data derived from the 1994
- 1998 USDA Continuing Surveys of Food Intake by Individuals (CSFII). The assessment included all uses (existing, pending and proposed), assuming provided percent crop treated estimates at market maturity. A dietary exposure assessment conducted with the assumption of 100% crop treated is quite conservative, even when average residues from field trials are assumed. In order to produce a more accurate estimate of exposures, a refined assessment using best estimates of the percent crop treated at market maturity for all registered, pending and proposed commodities has been conducted assuming the following percent crop treated estimates at market maturity: cucurbits (18%), fruiting vegetables (14%), low growing berries (12%), dry beans (16%), snap beans (12%), Swiss chard (15%), grain sorghum (1%), stone fruit (20%), bushberries (15%), leafy brassica vegetables (20%), turnip greens (15%), apples (30%), pears (50%), h ead and stem brassica (30%), tuberous and corm vegetables (18%), cotton (12%) and sugarcane (28%). These percent crop treated numbers provide a more refined estimate of potential chronic dietary exposures to novaluron. All eligible food items are assumed to have novaluron residues associated with the FHE use (i.e., 100% crop treated is assumed for all foods for which the FHE tolerance is applicable), representing a very conservative assessment.
Anticipated residues in animal tissues (i.e., meat and milk) were calculated using standard methodology based on recent guidance for calculating the maximum reasonably balanced diets (MRBD) consisting of multiple treated feed items. Average residues in animal feed items were used in all calculations, with the exception of cotton seed commodities (seed, meal, hulls), for wh ich the tolerance (0.6 ppm) was used. The chronic population adjusted dose (cPAD) for novaluron is 0.011 mg/kg/day, based upon the NOAEL of 1.1 mg/kg/day from the chronic carcinogenicity study in rats, and an UF of 100. The total chronic dietary exposures associated with all pending, registered and proposed uses of novaluron accounts for less than the cPAD (0.011 mg/kg/d), and therefore is of no concern. The most highly exposed subpopulation, child ren aged 1 to 2 years, has an estimated total novaluron exposure (0.001995 mg/kg/day), which corresponds to 18.1% of the cPAD. Theestimated novaluron exposure for the general U.S. population (0.000579 mg/kg/day)

corresponds to 5.3% of the cPAD. Residues associated with the proposed FHE use (i.e., 0.005 ppm at 100% treatment of all foods without tolerances) contribute insignificantly to the total exposure. Thus, exposures associated with the FHE use, in addition to all current pending and registered uses, are not of concern. c. Novaluron was classified as “not likely to be carcinogenic to humans.''. Therefore, a quantitative cancer risk assessment was not conducted. ii

. Drinking Water a. Acute Exposure. Since no acute dietary endpoint was determined, Makhteshim
-Ag an of North America, Inc., concludes there is reasonable certainty of no harm from acute drinking water exposure. b. Chronic Exposure. Novaluron residues in drinking water were included in the dietary exposure assessment. Since there are currently insufficient monitoring data to characterize novaluron residues in drinking water, modeling approaches were used to estimate chronic concentrations in surface and ground water. The residues of concern in drinking water are novaluron and its chloroph enyl urea and chloroaniline degradates. The Agency used screening level water exposure models in the dietary exposure analysis and risk assessment for novaluron and its degradates in drinking water, as reported in the January 27, 2010, Federal Register Notice (EPA

–HQ

–OPP

–2009

–0273; FRL

–8807

–2). The Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) was used for parent novaluron in surface water, and the First Index Reservoir Screening Tool (FIRST) for chlorophenyl urea and chloroanilin e degradates in surface water, the Screening Concentration in Ground Water (SCI GROW)model for novaluron, chlorophenyl urea and chloroaniline in ground water. The estimated drinking water concentrations (EDWCs) of novaluron, chlorophenyl urea, and chloroa niline for chronic exposures for non
-cancer assessments are 0.76 parts per billion (ppb), 0.89 ppb and 2.6 ppb, respectively, for surface water and for ground water 0.0056 ppb, 0.0045 ppb and 0.0090 ppb, respectively. The highest drinking water concentrations were estimated fo r surface water. Of the three EDWCvalues fo r surface water, the chronic EDWCfor the terminal metabolite, chloroaniline, is the highest (assuming 100% molar conversion fro m parent to aniline). Therefore, the drinking water concentration of 2.6 ppb was used as the worst case in this assessment. 2. Non -Dietary Exposure Novaluron is proposed to be used for the following residential non -dietary sites: Indoor and outdoor control of

roaches, and crickets for spot, crack and crevice treatments. Both short
-and intermediate
-term exposures are of i nterest because the period of residual control for novaluron may result in exposures over a prolonged period. Since the product will be applied only by professional applicators, residential handler exposures are not of concern. Residential post
application exposures to novaluron residues from crack and crevice applications were taken into consideration as the worst
-case scenario based on the EPA’s Standard Operating Procedures for Residential Exposure Assessments



### . At the maximum dilute application rate of 0.25% novaluron, short

-and intermediate

-term

### residential post

-application exposures resulted in acceptable Margins of Exposures (MOEs), and a

clear indication of reasonable certainty of no harm. Based on the crack and crevice treatment all of the route
-and product

- specific MOEs were greater than 100, and the aggregate MOEs were greater than 100 for all population subgroups. D. Cumulative Effects To Makhteshim
-Agan of North America’s Inc., kn owledg e, there are currently no available data or other reliable information indicating that any toxic effects produced by novaluron would be cumulative with those of other chemical compounds; thus only the potential risks of n ovaluron have been considered in th is assessment of its aggregate exposure. E. Safety

Determination 1. U.S. Population No acute aggregate risk assessment was conducted because there is no toxicological endpoint attributable to a single exposure. A chronic aggregate risk assessment was pe rformed based on potential exposure from food and drinking water, considering all existing and proposed uses. Short
-and intermediate
-term aggregate risk assessments were performed based on potential exposure from food and drinking water from existing uses, as well as the proposed spot, crack and crevice, and outdoor perimeter uses. No cancer aggregate risk assessment was conducted because novaluron has not been shown to be carcinogenic. The chronic dietary exposure, including drinking water, fo r the genera l U.S. population is 0.000579 mg/kg/day, or 5.3% of the cPAD. The chronic dietary exposures account for 3.5% to 18.1% of the cPAD (0.011 mg/kg/day) depending on the population subgroup. The calculation for the most sensitive population subgroup (children 1 to 2 years old) is 0.001995 mg/kg/day, utilizing 18.1% of the cPAD. In view of these assessments, Makhteshim
-Agan of North America Inc., concludes that there is reasonable certainty that no harm will result from the proposed uses of novaluron. Concerning the aggregate assessment from all potential sources of exposure (food, water, crack and crevice post
-application), it has been demonstrated that the aggregate MO Es associated with the existing and proposed uses of novaluron do not exceed the Ag ency’s leve l of concern. Based on these assessments, Makhteshim
-Ag an of N orth America Inc., concludes that novaluron does not pose a risk due to short
-and intermediate
-term aggregate exposure. 2. Infants and Children Section 408 of FFDCA provides that EPA may apply an additional safety factor for infants and children to account for prenatal and postnatal toxicity and the completeness of the database. The toxicology database for novaluron is complete including acceptable data from rat and rabbit developmental toxicity studies and a two generation rat reproduction study that have been used to assess the potential for increased sensitivity of infants and children. The data provided no quantitative or qualitative evidence of increased susceptibility of rats or rabbits to in utero and/or postnatal exposure to novaluron. In addition there is no concern for developmental neurotoxicity resulting from exposure to novaluron, and a developmental neurotoxicity study isnot required. Therefore, the Agency determined to reduce the FQPA Safety Factor to 1X

(Federal Register of June 2, 2004; 69 FR 31013; FRL
-7359
-2). Thus, the chronic population adjusted dose (cPAD) is considered 0.011 mg/kg/day. The DEEM analysis regarding the aggregate chronic exposure calculations utilizes less th an 18.1% of the cPAD for the most sensitive subgroup, children 1 to 2 years old. In addition, it is evident that short
-and intermediate
term aggregate residential exposures, based on the crack and crevice treatment as the worst case for post
-application exposures, result in MOEs greater than 100. Based on this information Makhteshim
-Ag an of North America Inc., concludes that there is reasonable certainty that no harm will result to infants and children fro m aggregate exposure to novaluron residues associated with existing agricultural uses, and the proposed new uses associated with the proposed spot, crack and crevice, and outdoor perimeters. F. International Residue Limits There are no Canadian, Mexican, or CODEX maximum residue limits (MRLs) established fo r novaluron in or on all food commodities in food or feed handling establishments, where food or feed products are held, processed or prepared. Therefore, international harmonization is not an issue at this time.