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 has received a pesticide petition (PP4F8293) from United Phosphorus, Inc., 

630 Freedom Business Center, Suite 402, King of Prussia, PA 19406, 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

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 hog 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 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 metabolism of endothall was examined in three crop 

types: alfalfa, cotton, and sugarbeet. All three studies were conducted using C-2 and C3-(

14C) 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. An adequate method for purposes of enforcement of the 

proposed endothall tolerances is available. The method uses 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 endothallHFTH derivative by HPLC/MS/MS. 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 the 
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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 irritating 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 studies 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 endothall 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 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 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 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 days 6 through 19. The fetal and maternal toxicity NOAELs 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 NOAEL for reproductive toxicity was 900 ppm.

4. Subchronic toxicity. Male and female Sprague Dawley rats were exposed 
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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 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 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 months. 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 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. In 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 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 male and 50 

female 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 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, compoundrelated 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.
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6. Animal metabolism. Following 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, cecum, 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 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. 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 chronic, 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 assumed 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 endothall 

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 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.
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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 

(UFtotal = 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 international tolerances have been established for endothall.