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 tolera nce for residues of ethephon in or on the raw agricultural comm odity tomato from 2.0 ppm to 3.5 ppm. The increased tolerance is required to accomm odate 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 fort h 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 plan ts is adequately unders tood based on tomato, cantaloupe, apple, fig, pineapple, tobacco, grap e, walnut, filbert, cherry, tangerine, and lemon metabolism data. Ethephon degrades to ethylene, phosphate, and chloride. Data indicate that proximal and distal transloca tion 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 ru minants 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 14 CO 2 and 14 Cethylene. No residues of ethephon were det ected 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 rate s. 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 forma tion 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, rumina nt tissues and milk are available.

The FDA Pestdata (PAM Vol. I Appendix, 8/93) indicates that ethe phon is not recovered through any of the Multiresidue Protocols.2

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 gree nhouse trials were conducted for th is study, one in Colorado (EPA Region 9); one in Florida (Region 3); a nd 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 medi a are considered to be representative and adequate. At each trial, one foliar applica tion of Ethrel at a rate of approximately 1.25 lb ai/A each was applie d. 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 hour s after the application. Large-fruited

varieties were collected at th e 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 applic ation 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) a nd inhalation routes (Category IV). The acute

oral LD 50 is 3030 milligrams/ kilograms/ body wei ght (mg/kg bw) for both male and

female rats. The acute dermal LD 50 was 1560 mg/kg bw in rats. The 4-hour inhalation

LC 50 was 4.53 mg/L for male and female rats. Ethephon is a severe ir ritant 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 numer ous 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 in creased susceptibility for the young. In a 2- generation reproduction study, rats were admi nistered 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 establishe d at 500 mg/kg bw. Additionally, two developmental toxicity studi es were conducted with rabbi ts, one with pure ethephon and one with approximately 72% ethephon re presenting technical material. The pure3

ethephon gave a maternal and developm ental NOAEL of 50 mg/kg bw while the technical material gave a maternal an d 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 NOAE L 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 th e 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 ra t 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 wa s 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 animal s. In a human clinical study five men and five women were given oral doses of 124 mg of ethephon (a pproximately 1.8 mg/kg/day) by capsule daily for 28 consecutive days. Th e 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 14 CO2 was <1%, 14 C-ethylene was 10 to 20% of the AD.

Less than 7% of the AD was excreted in the feces. Residual radioac tivity 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 ex cretion pattern. Ethephon was not extensively metabolized. Ethephon as disodium salt accounted for 90% of the recovered radioa ctivity in the urine

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

7. Metabolite toxicology . Available data indicate th at there are no metabolites of ethephon that are of toxicologi cal concern. Therefore, no addi tional toxicity studies were

needed for metabolites.

8. Endocrine disruption . In the available toxicity studies on ethephon, there was no estrogen or androgen, mediated toxicity. Wh en additional appropria te screening and/or testing protocols being considered under the Agency’s EDSP have been developed, ethephon may be subjected to further screeni ng and/or testing to better characterize effects related to endocrine disruption.

C. Aggregate Exposure

1. Dietary Exposure . There are no residential us es for ethephon; therefore aggregate exposure consists of dietary (f ood and drinking water) exposures. The acute and chronic reference dose (RfD) and popul ation adjusted dose (PAD) was 0.06 mg/kg4

bw/day based on a 28-day repeat dose or al human study which had a LOAEL of 1.8 mg/kg/day. Application of an uncertainty f actor 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 99.9 th 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 acu te RfD for the U.S. Population and 89% of the acute RfD for infants, the most expos ed population subgroup. Th ese values include the potential exposure from ethephon residues in drinking water as well as in food. The estimated chronic exposure to ethephon residue s 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 Operati ng Procedure (SOP) for Drinking Water Exposure and Risk Assessments was used to perform the drinking water assessment. This SOP uses a variety of t ools 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 th e 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 ethe phon, monitoring data do not exist, therefore

PRZMS/EXAMS and SCI-GROW were used to estimate a wate r residue in the ethephon TRED. In the TRED the calculated drinking wa ter 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 ap propriate for dermal risk assessment was identified in the ethephon toxicology da tabase. Based on the EPA assessment, only short-term adult handler exposur e is anticipated. The MOEs fo r this short-term inhalation exposure were 20,000 compared to the target MOE of 30 indi cating no risks of concern.

D. Cumulative Effects

Based on the 2006 TRED document issu ed 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 cu mulative 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, ethe phon does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the5

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 exposur e 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 r easonable 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 exposur e. 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 th e 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 F actor is necessary to protect the safety of infants and children in assessing ethephon expos ure and risks. The committee concluded that no Special FQPA safety factor was n eeded because the toxicology database for ethephon contains acceptable guideline deve lopmental and reproduction studies as well as acute and subchronic neurotoxicity st udies. HIARC concluded that there is no quantitative or qualita tive evidence of increased susceptibility following in utero or postnatal exposure in any of the developmen tal or reproductive st udies. The RfDs and toxicity endpoints established are protective of pre/postnatal toxicity following acute and chronic exposures.

Dietary and drinking water asse ssments include conservative assumptions or are based on conservative modeling estimates and postapplic ation residential exposure to children is not expected based on residential use pattern s. Therefore, based on above conservative exposure assessments the total aggregate expos ure to ethephon will utilize at most 94%

of the acute RfD/PAD and 18% of the ch ronic 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 Produc t and Residue Chemistry assessment used for the 2007 ethephon TRED.