EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kathryn Montague (703)

- 305

- 1243

United Phosphorus, Inc.

PP4F8293

EPA h as received a pesticide petition ( PP4F8293 ) from United Phosphorus, Inc., 630 Freedom Business Center, Suite 402, King of Prussia, PA 19406, request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to a mend 40 CFR part 180 by establishing a tolerance for residues of the aquatic herbicide Endothall, mono (N,N

- dimethylalkylamine) salt of endothall, and the dipotassium salt of endothall in cattle, sheep, goat, and hog meat at 0.05 ppm; cattle, sheep, goat, and ho g fat at 0.05 ppm; cattle, sheep, goat, and hog liver at 0.05 ppm; cattle, sheep

, goat, and hog kidney at 0.06 ppm; milk at 0.01 ppm; poultry meat, liver, fat

, and meat byproducts at 0.05 ppm; egg at 0.05 ppm. EPA has determined that the petition cont ains 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 metabolism of endothall was examined in three crop types: alfalfa, cotton, and sugarbeet. All three studies were conducted using C

- 2 and C

3

- ( 14 C) endothall and s howed the same pattern of metabolic breakdown. The parent compound endothall accounted for the majority of the total radioactive residue (85

- 110%).

2. Analytical method. An adequate method for purposes of enforcement of the proposed endothall toleran ces is available. The method us es an HPLC/MS/MS system. The meat, milk, poultry, and egg samples are extracted twice with water, derivatized with heptafluoro p

- tolylhydrazine (HFTH), cleaned

- up, then analyzed as the endothall

HFTH derivative by HPLC/MS/M S. The method also hydrolyzes any monomethyl esters back to the parent compound, so that both endothall and its monomethyl ester are analyzed as a common moiety.

3. Magnitude of residues. The magnitude of the residues in livestock have been
determined in poultry and cow feeding studies at 1X, 3X, and 10X the expected dietary concentrations. In the poultry feeding study, at the 1X feeding level the residues in eggs and tissues were below the limit of quantitation (LOQ) of 0.05 ppm in all samples. In t he2

dairy cow feeding study, at the 1X level the residues in milk were all less than the LOQ of 0.01 ppm. Tissue sample residues were all less than the LOQ of 0.05 ppm with the exception of one of three kidney samples with a residue slightly above the LOQ.

B. Toxicological Profile

1. Acute toxicity. Endothall acid and the dipotassium salt of endothall are moderately toxic by oral ingestion and inhalation (Toxicity Category II), slightly toxic by dermal exposure (Toxicity Category III) and severely irr itating to the eye. The diamine salt of endothall is moderately toxic by oral, dermal, and inhalation routes of exposure (Toxicity Category II) and is severely irritating to the eyes and skin.

2. Genotoxicty. A full battery of genetic toxicology stu dies were conducted for endothall. Endothall was not mutagenic.

3. Reproductive and developmental toxicity. In a teratology and postnatal behavioral study, pregnant Sprague Dawley rats were dosed via oral gavage on gestation days 6 through 15 with en dothall doses of 0, 10, 20, or 30 milligram/kilogram /day (mg/kg/day ) . The maternal no observed adverse effect level (NOAEL) was 20 mg/kg/day due to mortality seen at 30 mg/kg/day. The developmental

NOAEL was 30 mg/kg/day. In a subsequent developmental t oxicity 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 NOAEL was 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 days 6 through 16 of gestation. The NOAEL for maternal toxicity was 5 mg/kg/day based on mortality seen at 20 mg/kg/day. The developmen tal 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 t hat 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 days 6 through 19. The fetal and maternal toxicity NOAELs were 1.0 mg/kg/day. A 2

- generation reproduction study wa s 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 NOAEL for reproductive toxicity was 900 ppm.

4. Subchronic toxicity. Male and female Sprague Dawley rats wer e exposed3

dermally to 0, 30, 100, and 300 mg/kg/day for 21 days. The lowest observed adverse effect level (LOAEL) was 30 mg/kg/day based on decreased body weight gain and dermal irritation. A NOAEL was not established. Male and female Sprague Dawley rat s 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. T he 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 concentrations of 0, 150,

300 , 900, and 1,800 ppm for 104 weeks. No evidence of carcinogenicity was seen in this study. The NOAEL was 150 ppm. The incidence of acanthosis and hyperkeratosis of the stomach was slightly 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. Beagle 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 month s. No clinical sign of toxicity were seen at any dose level. The 100 ppm dietary concentration (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 reduced to 1,000 ppm after 6 weeks of treatment due to marked reductions in body weight, food consumption, and subsequent s acrifice 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 study, Swiss Albino mice were fed in the diet at concentrations of 0, 50, 100 , and 300 ppm (0, 8.1, 16.7, and 50 mg/kg/day for males; 0, 10.8, 22.4, and 68 mg/kg/day for females ) for 92 weeks. The systemic NOAEL was 100 ppm ba sed 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 male and 50
female Swiss Albino mice were fed the disodium salt of endothall at dieta ry concentrations of 0, 750, and 1,500 ppm (0, 122, and 258 mg/kg/day for males; 0, 152, and 319 mg/kg/day for females). Toxicity results for the 1,500 ppm dietary level clearly show that the maximum tolerance dose (MTD) was exceeded. At 750 ppm, compoun d

related effect consisted of decreased body weight gain, rectal prolapse and an increase in the incidence and severity of mucosal hyperplasia of the glandular stomach. Endothall was not considered carcinogenic in this study.4

6. Animal metabolism. Follo wing a single oral administration of 14C

- endothall to male and female rats, the majority of the radioactivity was excreted within 24 hours. The majority of the radioactivity was found in the feces. Chromatographic analysis of extracts of urine, feces, ce cum, and large intestine of both male and female rats gave a single radioactive component corresponding to unchanged endothall. The nature of the residue in goat and poultry studies has been determined in metabolism studies. The residues of concern are p arent 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. Further, histopathologic evaluation of hormone sensitive tissues from chronically exposed rats, mice, and dogs did not reveal any changes suggestive of an
endocrine

- related effect.

C. Aggregate Exposure

1. Dietary exposure. EPA conducted a ch ronic, aggregate dietary exposure for food and water using the dietary model DEEM

- FCIDTM Version 2.03.

i. Food. The residue data for the food exposure was based on 18 field trials and 9 associated processing studies conducted by IR

- 4. The exposures ass umed that the maximum labeled rate of endothall was applied to irrigation canals. The average residues from the field trials were used for all crops. The exposure assessment assumed that all livestock consumed both water and feeds containing maximum endo thall residues. Therefore, the exposure estimate is very conservative.

ii. Drinking water

. Drinking water exposure to endothall may be expected. However, this exposure is not considered to be significant due to the seasonal intermittent use of the pr oduct 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 chem ical.5

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 level 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 children 1

- 2 years old, with 85% cPAD. This level is below EPA’s level of concern.

F. International Tolerances

No intern ational tolerances have been established for endothall.