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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: [**  **Kathryn Montague (703) 305 -**  **1243 ]**  **TEMPLATE: United Phosphorus, Inc.**  **[Insert petition number]** EPA has received a pesticide petition **( [insert**  **petition number] )**  from United Phosphorus, Inc., 630 Freedom Business Center, Suite 402, King of Prussia, Pennsylvania 19406 proposing, pursuant to section 408(d) of the Federal Fo od, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of the herbicide Endothall, mono (N,N - dimethylalkylamine) salt of endothall, and the dipotassium salt of endothall in or on apples at 0.05 ppm under 40 CFR Part 180.293 and apple pomace at 0.15 ppm under 40 CFR Part 180.293. 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 d ata 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 metabolism of endothall wa s examined in three crop ty pes: alfalfa, cotton, and sugarbeet. A ll three studies were conducted using C - 2 and C 3 - ( 14 C) endothall and showed the same pattern of metabolic breakdown. The parent compound endothall accounted for the majority of the total radioactive residue (85 - 110%). 2. Analytical method. The samples were analyzed using GC/ECD with a DB - 1701 column. In summary , the endothall residues in apples were extracted with acidified acetonitrile, purified on an HPL C column, derivatized with h eptaflouro - p - tolylhydrazine (HFTH), cleaned up, then anal yz ed using GC/ECD. The validated LOQ is 0.01 ppm . Additionally , an adequate method for purposes of enforcement of the proposed endothall tolerances is available. The method uses an HPLC/MS D system . The samples are extracted with water, derivatized, cleaned - up, then anal yz ed for endothall (as endothall acid) b y HP LC. An alternative enforcement method is listed as Method I in the Pesticide Analy tical manual (PAM, Volume II) for the determination of endothall in plant commodities. The commodities are extracted, derivatized, and anal yz ed with a GC with a nitrogen - specific detector.2 3. Magnitude of residues. Incontrolled field trials, endothall (0.4 lb ae (where ae is endothall acid equivalent s) /gal SC/L ; dipotassium salt) was applied twice to apple trees at about 0.30 lb ae/A/application, for a total of about 0.60 lb ae/A/season. This is 1.3X the proposed maximum label rate. Residues ranged from <0.01 - 0.023 ppm in or on 26 apple samples harv ested 91 - 152 day s posttreatment. Based on processing studies, residues concentrated in wet apple pomace, with a factor of 2.8 X. B. Toxicological Profile 1. Acute toxicity. Endothall acid and the dipotassium salt of endothall are moderatel y toxic by

oral ingestion and inhalation (Toxicity Category I I), slightl y toxic by dermal exposure (Toxicity Category III) and severely

irritating to the eye. The diamine salt of endothall is moderately toxic by oral, dermal, and inhalation routes of exposure (To xicity Category II) and is severel y irritating to the eyes and skin. 2. Genotoxicty. A full battery o f genetic toxicology

s tudies were conducted for endothall. Endothall was not mutagenic. 3. Reproductive and developmental toxicity. Ina teratology and postnatal behavioral study, pregnant Sprague Dawley rats were dosed via oral gavage on gestation day s 6 through 15 with endothall doses of 0, 10, 20, or 30 milligram/kilogram (mg/kg) /day . The maternal no observed adverse effect level (NOAEL) w as 20 mg/kg/day due to mortality seen at 30 mg/kg/day . The developmental NOAEL was 30mg/kg/day . In a subsequent developmental toxicity study , pregnant Sprague Dawley rats were orally dosed with 0, 6.25, 12.5, or 25.0 mg/kg/day from gestation day

6 through 15. The NOAEL for maternal toxicity was 12.5 mg/kg/day. The developmental NOAELwas 25.0 mg/kg/day . A developmental toxicity study was conducted in female CD - 1 mice. Groups of pregnant mice were orally dosed with 0,5,20, or 40 mg/kg/day on day s 6 through 16 of gestation. The NOAEL for maternal toxicity was 5mg/kg/day

based on mortality

seen at 20 mg/kg/day . The developmental NOAEL was 20 mg/kg/day . Developmental changes seen at 40 mg/kg/day

were related to the severe maternal toxicity at that dose . A developmental toxicity

study was conducted in New Zealand white rabbits by oral exposure. Preliminary

studies indicated that the rabbit was extremely sensitive to endothall. Groups of pregnant rabbits were dosed with 0, 0.3, 1.0, or 3.0 mg/kg/day on gestation day s 6 through 19. The fetal and maternal toxicity NOAE Ls were 1.0 mg/kg/day . A 2 - generation reproduction study was conducted in rats. In this study, groups of rats received dietary doses of 0, 30, 150 and 900 ppm (0, 1.9, 9.5, or 58.9 mg/kg/ day

for male and 0, 1.9 - 3.4, 9.6 - 18.5, or 59.0 - 106.5 mg/kg/day for female F0 animals; 0, 2.1, 10.9, or 77.1 for male and 0,1.8 - 3.1, 9.5 - 17.3, or 63.5 - 107.7 for female F1 animals). The NOAEL for parental effects was 30 ppm based on dose related body weight effects. The NOAELfor reproductive toxicity was 900 ppm. 4. Subchronic toxicity. Male and female Sprague Dawley rats were exposed dermally to 0, 30, 100, and 300 mg/kg/day for 21 day s. The lowest observed adverse3

effect level (LOAEL) was 30 mg/kg/day based on decreased body weight gain and dermal irritation. A NOAELwas not established. Male and female Sprague Dawley rats were exposed to oral concentrations of 0, 150, 600, or 1,800 ppm (0, 10, 39, or 118 mg/kg/day

for males; 0,12,51,or 153 mg/kg/day for females respectively) for 13 weeks. The LOAEL was 1,800 ppm based on decreases in body weight gain and food intake. The NOAEL was 600 ppm. Male and female Beagle dogs were exposed to oral concentrations of 0, 100, 400, or 1,000 ppm (0, 3.2, 11. 7, or 27.5 mg/kg/day for males and 0, 3.2, 13.0, or 28.9 mg/kg/day for females respectively) for 13 weeks. The LOAEL was 1,000 ppm based on decreases in body weight gain and food intake. The NOAEL was 400 ppm. 5. Chronic toxicity. **[** In a combined chronic toxicity and oncogenicity study , male and female Sprague Dawley rats were fed endothall dietary c oncentrations of 0, 150, 300, 900, and 1,800 ppm for 104 weeks. N o evidence of carcinogenicity was seen in this study . The NOAEL was 150 ppm. The incid ence of acanthosis and hy perkeratosis of the stomach was slightl y higher than control for the 150 ppm males. This finding was not considered an adverse effect since the incidence of this finding in the 300 ppm males was similar to control. B eagle dogs were fed diets containing 0, 100, 300, or 800 ppm disodium endothall (equivalent to 0, 2 , 6 , or 16 mg/kg/day endothall) for 24 months. N o clinical sign of toxicity

w ere seen at any dose level. The 100 ppm dietary c oncentration (2 mg/kg/day) was the NOAEL. In a 52 - week oral toxicity study , groups of 4 male and 4 female Beagle dogs were fed diets containing 0, 150, 450, or 1,350/1,000 ppm (0, 5.7, 17.1, and 35.8 mg/kg/day for males; 0, 6.4, 18.8 and 36 mg/kg/day for females). The 1,350 ppm dietary level had to be 1,000 ppm after 6 weeks of treatment due to marked reductions in body weight, food consumption, and subsequent sacrifice of 5 animals from this group. Minimal to very mild gastric epithelial effects were seen in some of the dogs receiving 150 ppm. This effect was considered as a low grade reaction to chronic epithelial irritation and 150 ppm is considered a NOAEL. I N an 18 - month oncogenicity s tudy , Swiss Albino mice were fed in the diet at concentrations of 0, 50, 100, and 300 ppm (0, 8.1, 16.7, an d 50 mg/kg/day

f or males; 0, 10.8, 22.4, and 68 mg/kg/day f or females ) for 92 weeks. The sy stemic NOAEL was 100 ppm based on decreased mean body weight in 300 ppm males. No evidence of carcinogenicity was seen in this study . In a second 18 - month dietary oncogenicity study , groups of 50 males and 50 females Swiss Albino mice were fed the disodium salt of endothall at dietary concentrations of 0, 750, and 1,500 ppm (0, 122, and 258 mg/kg/day f or males; 0, 152, and 319 mg/kg/day

f or females). T oxicity

r esu lts for the 1,500 ppm dietary l evel clearl y show that the maximum tolerance dose (MTD) was exceeded. At 750 ppm, compound related effect consisted of decreased body w eight gain, rectal prolapse and an increase in the incidence and severity o f mucosal hy

perplasia of the glandular stomach. Endothall was not considered carcinogenic in this study . 6. Animal metabolism. Following a single oral administration of 14C - endothall to males and female rats, the majority of the radioactivity w as excreted within 24 hours. The majority of the radioactivity w as found in the feces. C hromatographic anal ys is of extracts of urine, feces, cecum, and large intestine of both male and female rats gave a single radioactive component corresponding to unchanged endothall. The nature of the4

residue in goat and poultry s tudies has been determined in metabolism studies. The residues of concern are parent endothall and its monomethyl ester. 7. Metabolite toxicology . NA/REMOVE 8. Endocrine disruption . Evaluation of the results from 2 - generation reproduction studies does not demonstrate any effects suggestive of disruption of hormonal stasis in the rat. F urther, histopathologic evaluation of hormone sensitive tissues from chronically exposed rats, mice, and dogs did n ot reveal any c hanges suggestive of an endocrine related effect. C. Aggregate Exposure 1. Dietary exposure. EPA conducted a chronic, aggregate dietary exposure for food and water using the dietary model DEEM - FCIDTM, Version 2.03. i. Food. Th e food exposure was based on residue results from 18 field trials on numerous crops and 9 associated processing studies conducted by IR - 4. The exposures assumed that the maximum labeled rate of endothall was applied to irrigation canals. The average resid

ues from the field trials were used for all crops. The exposure assessment assumed that all livestock consumed both water and feeds containing maximum endothall residues. ii. Drinking water. Drinking water exposure to endothall may be expected. Ho wever this exposure is not considered to be significant due to the seasonal intermittent use of the product for aquatic weed control, its low mobility in surface waters and rapid degradation. 2. Non
- dietary exposure . NA/REMOVE D. Cumulative Effects United Phosphorus has reviewed chemical structure data to determine if any other pesticide products are chemically similar to endothall and produce gastrointestinal changes specific to endothall. Endothall appears to be chemically and toxicologically dissimilar to existing chemical substances. Therefore, cumulative risk should not be an issue for this chemical. E. Safety Determination 1. U.S. population. The chronic RfD is 0.007 mg/kg/day, with a chronic population adjusted dose (cPAD) also of 0.007 mg/kg/day based on the 2 - generation reproduction study in rats. The 2 - generation rat reproduction study has a LOAEL of 2 mg/kg/day

(UF total = 300). The cPAD for the general U.S. population is 33%. This level5

is below EPA’s level of concern. An acute endpoint was not identified for endothall, therefore an acute dietary risk assessment is not appropriate. Endothall is not likely to be carcinogenic in humans.

2. Infants and children . The % CPAD for the most sensitive subgroup is chil dren 1 - 2 years old, with 85% cPAD. This level is below EPA’s level of concern. F. International Tolerances No international tolerances have been established for endothall.