EPA Registration Division contact: Andrew Ertman; 703-308-9367

Interregional Research Project Number 4

PP No. 2E7993 

EPA has received pesticide petition (2E7993) from Interregional Research Project 

Number 4 (IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 increasing the tolerance for residues of 

ethephon in or on the raw agricultural commodity tomato from 2.0 ppm to 3.5 ppm. The 

increased tolerance is required to accommodate tomatoes of less than one inch in 

diameter grown in the greenhouse. 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 qualitative nature of the residue in plants is adequately understood based on tomato, 

cantaloupe, apple, fig, pineapple, tobacco, grape, walnut, filbert, cherry, tangerine, and 

lemon metabolism data. Ethephon degrades to ethylene, phosphate, and chloride. Data 

indicate that proximal and distal translocation of ethephon to fruits may occur following 

application to leaves. The residue of concern in plants is ethephon per se.

The residue of concern in milk and ruminant tissues is ethephon per se. The qualitative 

nature of the residue in ruminants is adequately understood based on goat metabolism 

data. In ruminant tissues and milk, ethephon is incorporated into natural products 

(glutathione conjugates, protein, glycogen, triglycerides) and expired as 14CO2 and 14Cethylene. No residues of ethephon were detected in the goat metabolism study; however, 

residues of ethephon were detected in ruminant tissues and milk in a ruminant feeding 

study which was conducted at exaggerated rates. The residue of concern in eggs and 

poultry tissues is ethephon per se. The qualitative nature of the residue in poultry is 

adequately understood based on poultry metabolism data. Ethephon per se was detected 

in liver, muscle, and kidney. The metabolic pathway for ethephon in poultry proceeds via 

initial cleavage of chlorine and formation of 2-hydroxyethyl phosphonic acid followed by 

formation of intermediates that are incorporated into the amino acid and fatty acid 

biosynthetic pathways.] 

2. Analytical method. Adequate methods for purposes of enforcement of ethephon 

tolerances in plant commodities, ruminant tissues and milk are available. 

The FDA Pestdata (PAM Vol. I Appendix, 8/93) indicates that ethephon is not recovered 

through any of the Multiresidue Protocols. 
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 3. Magnitude of residues. To provide residue chemistry data to support the 

establishment of a tolerance for ethephon in or on tomato (large- and small-fruited 

varieties), three greenhouse trials were conducted for this study, one in Colorado (EPA 

Region 9); one in Florida (Region 3); and one in Texas (Region 6). The OPPTS 

guidelines do not provide guidance for the number and geographical distribution for a 

greenhouse residue study on any commodity. Three greenhouse trials, located in 

Colorado, Florida, and Texas, using different non-soil growing media are considered to 

be representative and adequate. At each trial, one foliar application of Ethrel at a rate of 

approximately 1.25 lb ai/A each was applied. No adjuvant was added to the spray 

mixtures. The application was timed so that commercially mature tomatoes could be 

collected approximately 24 hours and 48 hours after the application. Large-fruited 

varieties were collected at the Colorado and Florida trials, while a small-fruited variety 

was collected at the Texas trial. 

Sample analysis for residues of ethephon showed that residues in greenhouse 

tomato following a total application of approximately 1.25 lb ai/A were highest in the 

small-fruited variety, with maximum residues of 2.0 ppm for both the 24- and the 48-hour 

pre-harvest intervals (PHIs). For large-fruited varieties, residues ranged from 0.32 to 0.88 

ppm for the 24-hour PHI and from 0.56 to 1.1 ppm for the 48-hour PHI. 

B. Toxicological Profile

1. Acute toxicity. Ethephon has low acute toxicity in experimental animals by the 

oral (Category III), dermal (Category III) and inhalation routes (Category IV). The acute 

oral LD50 is 3030 milligrams/ kilograms/ body weight (mg/kg bw) for both male and 

female rats. The acute dermal LD50 was 1560 mg/kg bw in rats. The 4-hour inhalation 

LC50 was 4.53 mg/L for male and female rats. Ethephon is a severe irritant to the eyes 

(Category I), is corrosive to the skin (Category I), but is not a dermal sensitizer.

2. Genotoxicty. Based on the results of numerous studies there is no concern for 

mutagenicity for ethephon. 

3. Reproductive and developmental toxicity. The reproductive database for 

ethephon is considered adequate. Reproductive effects occurred at doses causing parental 

toxicity. There were no indications of increased susceptibility for the young. In a 2-

generation reproduction study, rats were administered dietary levels of 0, 300, 3000 and 

30,000 ppm. The No Observed Effect Level (NOAEL) for parental and offspring toxicity 

was 300 ppm (24 mg.kg/day). 

Two developmental toxicity studies were conducted in rats with ethephon using dose 

levels of 0, 125, 200, 250, 500, 600, or 1800 mg/kg bw. The NOAELs for maternal and 

developmental toxicity were established at 500 mg/kg bw. Additionally, two 

developmental toxicity studies were conducted with rabbits, one with pure ethephon and 

one with approximately 72% ethephon representing technical material. The pure 
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ethephon gave a maternal and developmental NOAEL of 50 mg/kg bw while the 

technical material gave a maternal and developmental NOAEL of 300 mg/kg bw. 

4. Subchronic toxicity. A ninety-day feeding study was conducted in rats at levels 

of 0, 50, 100, and 200 mg.kg bw/day. The NOAEL was established at 100 mg/kg/day. 

 5. Chronic toxicity. A 2- year chronic toxicity study was conducted in the dog at 

dose levels of 0, 30, 300, and 3000 ppm in the diet (equivalent to 0, 0.75, 7.5 and 75 

mg/kg/day). The NOAEL for this study was 1500 ppm. 

Four carcinogenicity studies (two in the rat and two in the mouse) were conducted with 

the technical material (70-75% ethephon) at dose levels of 0 to 50,000 ppm (0 to 7750 

mg/kg/day). The NOAEL in the mouse was 1000 ppm (156 mg/kg/day) and the NOAEL 

in the rat was 3000 ppm (131-150 mg/kg/day). Ethephon was found not to be oncogenic 

in rat or mouse. 

Reported human studies showed that humans may be more susceptible to the clinical 

toxicity of ethephon than experimental animals. In a human clinical study five men and 

five women were given oral doses of 124 mg of ethephon (approximately 1.8 mg/kg/day) 

by capsule daily for 28 consecutive days. The LOAEL was established at 1.8 mg/kg/day. 

 6. Animal metabolism. In the rat oral and iv doses were rapidly absorbed and 

excreted in the urine accounting for 48-71% of the administered dose (AD). The iv 

dosing indicated that biliary excretion is minimal since less than 2% of the AD was 

recovered in the feces. Exhaled 14CO2 was <1%, 14C-ethylene was 10 to 20% of the AD. 

Less than 7% of the AD was excreted in the feces. Residual radioactivity in tissues was 

less than 0.1% of the AD. Total recovered radioactivity was 84-90%. There were no 

significant differences in the pharmacokinetics between the sexes. Multiple dosing did 

not significantly alter the excretion pattern. Ethephon was not extensively metabolized. 

Ethephon as disodium salt accounted for 90% of the recovered radioactivity in the urine 

and feces with less than 5% as monosodium salt and other unidentified metabolites. 

 7. Metabolite toxicology. Available data indicate that there are no metabolites of 

ethephon that are of toxicological concern. Therefore, no additional toxicity studies were 

needed for metabolites. 

 8. Endocrine disruption. In the available toxicity studies on ethephon, there was 

no estrogen or androgen, mediated toxicity. When additional appropriate screening and/or 

testing protocols being considered under the Agency’s EDSP have been developed, 

ethephon may be subjected to further screening and/or testing to better characterize 

effects related to endocrine disruption. 

C. Aggregate Exposure

 1. Dietary Exposure. There are no residential uses for ethephon; therefore 

aggregate exposure consists of dietary (food and drinking water) exposures. The acute 

and chronic reference dose (RfD) and population adjusted dose (PAD) was 0.06 mg/kg 
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bw/day based on a 28-day repeat dose oral human study which had a LOAEL of 1.8 

mg/kg/day. Application of an uncertainty factor of 30X resulted in the RfDs/PADs of 

0.06 mg/kg/day. The 30X uncertainty factor is based upon the 10X for intraspecies 

variability and a 3X for use of a LOAEL instead of a NOAEL. The typically used 

interspecies uncertainty factor (10X) was eliminated since the endpoint was based on a 

human study 

i.Food. A dietary assessment was conducted using the above hazard and exposure 

information. All current and proposed uses of ethephon are included in the assessment. 

The assessment results are reported at the 99.9th percentile since the assessment includes 

field trial, PDP (Pesticide Data Program), and percent crop treated data. Estimated acute 

dietary exposure was equal to 30% of the acute RfD for the U.S. Population and 89% of 

the acute RfD for infants, the most exposed population subgroup. These values include 

the potential exposure from ethephon residues in drinking water as well as in food. The 

estimated chronic exposure to ethephon residues in food and water was determined to be 

4% of the chronic PAD for ethephon for the U. S. Population and 17% of the chronic 

PAD for Children 1-2, the most exposed population subgroup. 

 ii. Drinking Water. US EPA’s Standard Operating Procedure (SOP) for Drinking 

Water Exposure and Risk Assessments was used to perform the drinking water 

assessment. This SOP uses a variety of tools to conduct drinking water assessment. 

These tools include water models such as SCI-GROW, FIRST, PRZMS/EXAMS, and 

monitoring data. If monitoring data are not available then the models are used to predict 

potential residues in surface and ground water and the highest is assumed to be the 

drinking water residue. In the case of ethephon, monitoring data do not exist, therefore 

PRZMS/EXAMS and SCI-GROW were used to estimate a water residue in the ethephon 

TRED. In the TRED the calculated drinking water residue levels were 5% or less of the 

acute reference dose and 1% or less of the chronic reference dose. These same levels 

were assumed for the current assessment. 

2. Non-dietary Exposure. Residential uses of ethephon are limited to outdoor 

ornamental plants and home garden vegetables. The USEPA residential exposure 

assessment as reported in the June 15, 2006 TRED indicated that only inhalation 

exposure was assessed since no endpoint appropriate for dermal risk assessment was 

identified in the ethephon toxicology database. Based on the EPA assessment, only 

short-term adult handler exposure is anticipated. The MOEs for this short-term inhalation 

exposure were 20,000 compared to the target MOE of 30 indicating no risks of concern. 

D. Cumulative Effects

 Based on the 2006 TRED document issued by the Environmental Protection 

Agency, the EPA does not have, at this time, available data to determine whether 

ethephon has a common mechanism of toxicity with other substances. Unlike other 

pesticides for which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 

ethephon and any other substances and, ethephon does not appear to produce a toxic 

metabolite produced by other substances which have tolerances in the U. S. For the 
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purposes of this tolerance reassessment action, therefore, EPA has not assumed that 

ethephon has a common mechanism of toxicity with other substances.

E. Safety Determination 

 1. US Population. Using the conservative exposure assumptions described above 

and based on the completeness of the toxicity data, it can be concluded that aggregate 

exposure to residues of ethephon present a reasonable certainty of no harm. Exposure 

from residues in crops and water utilizes 35% of the aPAD and 5% of the cPAD. 

Residential exposure for adults does not add to the dietary exposure. EPA generally has 

no concerns for exposures below 100% of the Population Adjusted Doses. 

 

 2. Infants and children. EPA has assessed the potential for additional sensitivity 

of infants and children to residues of ethephon based on the available reproductive and 

developmental toxicity studies in both the rat and rabbit. The EPA FQPA SFC concurred 

with the HIARC that no Special FQPA Safety Factor is necessary to protect the safety of 

infants and children in assessing ethephon exposure and risks. The committee concluded 

that no Special FQPA safety factor was needed because the toxicology database for 

ethephon contains acceptable guideline developmental and reproduction studies as well 

as acute and subchronic neurotoxicity studies. HIARC concluded that there is no 

quantitative or qualitative evidence of increased susceptibility following in utero or 

postnatal exposure in any of the developmental or reproductive studies. The RfDs and 

toxicity endpoints established are protective of pre/postnatal toxicity following acute and 

chronic exposures. 

Dietary and drinking water assessments include conservative assumptions or are based on 

conservative modeling estimates and postapplication residential exposure to children is 

not expected based on residential use patterns. Therefore, based on above conservative 

exposure assessments the total aggregate exposure to ethephon will utilize at most 94% 

of the acute RfD/PAD and 18% of the chronic RfD/PAD even for the most highly 

exposed population subgroup (all infants). 

F. International Tolerances

 

Several maximum residue limits (MRLs) for ethephon have been established by 

Codex. Both Codex and the U.S. regulate ethephon per se. The Codex MRLs, applicable 

U.S. tolerances, and recommendations for harmonizing U.S. tolerances with Codex 

MRLs were summarized by EPA in the Product and Residue Chemistry assessment used 

for the 2007 ethephon TRED.