Document ID: EPA-HQ-OPP-2021-0274-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2021-06-08T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[ADAMA Makhteshim, Ltd. c/o Makhteshim Agan of North America d/b/a ADAMA
3120 Highwoods Blvd., Suite 100
Raleigh, NC 27604]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [ADAMA Makhteshim, Ltd. c/o Makhteshim Agan of North America d/b/a ADAMA], [3120 Highwoods Blvd., Suite 100, Raleigh, NC 27604] 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

	2. to establish an exemption from the requirement of a tolerance for 

	[acetophenone, CAS No. 98-86-2) under 40 CFR 180.920 when used as an inert ingredient as a solvent/co-solvent) in pesticide formulation, without any limitation. As an inert ingredient, acetophenone is exempt from the requirement for a tolerance when used as an attractant in pesticide formulations when used on growing crops only under 40 CFR 180.920. This petition is for expansion of use of acetophenone as solvent/cosolvent in pesticide formulation under 40 CFR 180-920 (Inert ingredients used pre-harvest; exemptions from the requirement of a tolerance).
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.parts per million (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. NA-Remove based on fact this information is not required for the establishment of a tolerance exemption. No specific plant metabolism data is available, nor is it required for the establishment of a tolerance exemption.

	2. Analytical method. [NA- Analytical methods for crop commodities are not required for the establishment of a tolerance exemption.]

	3. Magnitude of residues. [No specific residue data is available, nor is it required for the establishment of a tolerance exemption. Default inert residue data were used for dietary assessment.]

B. Toxicological Profile

	1. Acute toxicity.  [Acetophenone is relatively of low acute toxicity via oral and dermal routes of exposure. Acute oral LD50 is 815-3200 mg/kg (rat) and dermal LD50 is 20,000 mg/kg (Guinea pigs). It is a mild skin irritant and severely irritating to the eye's of rabbits. It is not a skin sensitizer.]

	2. Genotoxicty. [Available mutagenicity studies such as reverse mutation assays, mouse lymphoma assay, chromosomal aberration test and in vivo micronucleus assay. No studies are available. Acetophenone is not a genotoxic agent based on available data.]

	3. Reproductive and developmental toxicity. [In a repeat dose toxicity test combined with a reproduction/developmental screening test conducted following OECD Guideline No. 422, mean forelimb grip strength and motor activity were decreased in the high dose males. Predose and post dose salivation was noted in both the 225 and 750 mg/kg/day groups. The intensity of salivation, duration of salivation and number of animals affected were not reported. The salivation may be due to gavage dosing and/or irritating property of acetophenone. There were no parental deaths in the reproduction study; however, the live birth index, pup survival during the lactation phase and mean pup body weights were decreased in the high dose group. Hence, the 225 mg/kg/day dose level was considered a NOAEL for reproductive effects. The NOAEL for systemic, reproductive and off spring toxicity was 225 mg/kg bw/day based on clinical and neurobehavioral findings, decreased in live birth index, and decreased in pup body weights seen at the LOAEL of 750 mg/kg bw/day.
      In a developmental toxicity study in rats, the maternal and developmental toxicity NOAEL was 300 mg/kg was based on increased clinical signs and decreased in uterus weights in maternal animals, and on a slight body weight reduction and skeletal findings (bilateral pelvic girdle caudal shift) in fetuses (low concern, at the limit of historical control level and with no other adverse effects) as cited in ECHA]

	4. Subchronic toxicity. [In a 30-day repeat dose toxicity study in rats, no treatment-related toxicity was observed at doses up to 102 mg/kg/day; the highest dose tested. Similarly in another repeat dose study in rats fed acetophenone in diets at dose up to 10,000 ppm (equivalent to 423 mg/kg/day), no treatment related toxicity was observed.

      In a 90-day toxicity study in rats, treatment related effects such as slight to moderate deceased in spontaneous activity, decreased in body weights, in males, and increased reticulocytes in both sexes associated with increased in cell volumes at the highest dose tested (500 mg/kg/day (gavage dosing). In males, hyaline inclusions in the kidneys increased in incidence and severity in all male dose groups. The hyaline inclusions corresponded with the presence of α2-microglobulin by immunohistochemistry. The increase of this protein was statistically significant in the male of the mid dose and the high dose compared to controls. It is not considered as an adverse response since it a typical issue in male rats and was considered as a non-adverse metabolic change as there were no further lesions in the kidneys. The NOAEL was 250 mg/kg/day based on increased reticulocytes counts, reduced activity and decreased in body weight development seen at 500 mg/kg/day.]

	5. Chronic toxicity. [No data are available. EPA (IRIS 1991) classified acetophenone as Group D- not classifiable as to human carcinogenicity.]

	6. Animal metabolism. [However, based on the plausible metabolic pathways, no metabolites of toxicological concern are expected.]

	7. Metabolite toxicology. [Acetophenone is rapidly absorbed from the gut, metabolized efficiently by the liver to benzoic acid or mandelic acid, and excreted primarily in the urine and, to a very small extent, in the feces. No metabolites of toxicological concern are expected.]

	8. Endocrine disruption. [Acetophenone does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. Available data for acetophenone do not show any alert for endocrine disruptor endpoints.]

C. Aggregate Exposure

	1. Dietary exposure. [The predominant route of potential human exposure to acetophenone associated with their proposed use is through the diet. A comprehensive dietary exposure assessment on acetophenone has been conducted and results support the proposed acetophenone tolerance exemptions. The basis of the dietary assessment builds on the screening-level dietary exposure model for inerts (l-DEEM) developed by the EPA with additional modifications that embody guidance provided by the Agency for dietary risk assessment for inert ingredient tolerance exemptions. The modeled dietary exposure is likely an over-estimation of dietary exposure because only negligible food residues are anticipated from pre-harvest uses of acetophenone. Dietary exposure is conservatively estimated to be 0.189 mg/kg bw/day for the general population and 0.706 mg/kg bw/day for the most highly exposed subpopulation of children aged 1-2 years old.]

	i. Food. [Acetophenone chronic dietary exposure assessment utilized the EPA's dietary screening-level model l-DEEM with appropriate adjustments to reflect the use without any limitations proposed in this petition.]

	ii. Drinking water. [EPA default value of 100 ppb in drinking water is included in the inert DEEM exposure assessment; exposure to acetophenone via drinking water is expected to be negligible.]

	2. Non-dietary exposure. [Thc predominant use of acetophenone is in pesticide products used for agricultural crop production, and to a significantly lesser extent in outdoor residential products. Acetophenone is unlikely to be used in indoor pesticide products and not believed to be widely used in consumer or personal care products. Therefore, non-dietary exposure to acetophenone is expected to be minimal.]

D. Cumulative Effects

	[EPA has not made a common mechanism of toxicity finding for acetophenone. It is therefore appropriate to consider only the potential risks associated with acetophenone.]

E. Safety Determination

	1. U.S. population. [A dietary exposure assessment using current EPA screening level methodology (l-DEEM) was conducted. Based on the highly conservative l-DEEM dietary exposure estimates, available information on the fate of acetophenone in soil and plants, and the low exposure associated with non-dietary uses of acetophenone, there is a reasonable certainty that no harm will result to the US population from the aggregate exposure to acetophenone as a result of its proposed use.]

	2. Infants and children. [A reliable toxicology database is available on acetophenone and includes acute toxicity, subchronic, mutagenicity, reproduction and developmental toxicity studies. The available data suggest no qualitative or quantitative evidence of increased susceptibility to infants and children. Therefore the dietary assessment conducted using EPA screening level methodology (1-DEEM) is below the EPA's level of concern, and there is a reasonable certainty of no harm to sensitive subpopulations, including infants and children, as a result of aggregate exposure to acetophenone.]

F. International Tolerances

	[There are no known international tolerances for acetophenone.]