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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 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 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 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. 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 HPLC column, derivatized with heptaflouro-p-tolylhydrazine 

(HFTH), cleaned up, then analyzed 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/MSD system. The samples are 

extracted with water, derivatized, cleaned-up, then analyzed for endothall (as endothall 

acid) by HPLC. An alternative enforcement method is listed as Method I in the Pesticide 

Analytical manual (PAM, Volume II) for the determination of endothall in plant 

commodities. The commodities are extracted, derivatized, and analyzed with a GC with 

a nitrogen-specific detector. 
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3. Magnitude of residues. In controlled field trials, endothall (0.4 lb ae (where ae 

is endothall acid equivalents)/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 harvested 91-152 days 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 

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 (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 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 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 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 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 

dermally to 0, 30, 100, and 300 mg/kg/day for 21 days. The lowest observed adverse 
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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 

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 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 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.

6. Animal metabolism. Following a single oral administration of 14C-endothall to 

males 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 
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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 endocrinerelated 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 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 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. 

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.

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 
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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.