Document ID: EPA-HQ-OPP-2021-0659-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2021-10-21T04:00Z

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

 EPA Registration Division contact: Kerry Leifer, Branch Chief Inert Assessment Branch (IAB) 703-308-1846

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:

Morse Enterprises Limited, Inc. d/b/a KeyPlex

IN-11083

	EPA has received a pesticide petition (IN-11083) from Morse Enterprises Limited, Inc. d/b/a KeyPlex, PO Box 2515, Winter Park, FL 32790 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 180.920 in order to permit α-terpineol (CAS No. 98-55-5) as a solvent in pesticide formulations at rates of 5% of the formulation when applied pre-harvest to crops. 

(Options (pick one)

      1. by establishing a tolerance for residues of NA-Remove

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

	[NA-Remove] in or on the raw agricultural commodity [NA-Remove] at [NA-Remove] 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.

	2. Analytical method. [NA-Remove.]

	3. Magnitude of residues. [NA-Remove.]

B. Toxicological Profile

	1. Acute toxicity.  [The oral acute toxicity of α-terpineol in mice (LD50) has been reported as 2830 mg per kg. An oral gavage acute toxicity study with an α and β-terpineol mixture in rat yielded an LD50 of 4300 mg/kg. The dermal acute toxicity of α-terpineol in rabbits (LD50) has been reported as >3000 mg per kg. 

Exposure via injection is not expected with the use of α-terpineol as solvent in pesticide formulations however, in the public literature there are 2 acute toxicity studies where it is tested via injection.  In a mouse study α-terpineol was applied intramuscularly, the LD50 was noted to be 2000 mg/kg.  In a rat study α-terpineol was applied intraperitoneally in corn oil and the LD50 was noted to be 847 mg/kg. 

Given its use in cosmetics and toiletries, several evaluations of α-terpineol as a potential skin sensitizer or allergen have been conducted, both in animals and in human volunteers. In diagnostic patch tests with humans, a single subject among 1606 patients gave a positive reaction in one study, while 2 of 1200 patients gave positive reactions in another. In a human closed patch test for skin irritation, no subjects among 30 reported irritation, although it was irritating in similar trials with rabbits and mice, but not in Guinea pigs.]

	2. Genotoxicty. [A variety of genotoxicity studies have been conducted on α-terpineol. Most of the studies yielded negative results.  However, it was reported to give weakly positive results in an Ames study in 1 (TA102) out of 4 (TA97a, TA98, TA100, TA102) tested S. typhimurium strains.  In other studies, α-terpineol gave consistently negative results in Ames assays. In mammalian genotoxicity tests, α-terpineol was non-mutagenic when applied at doses up to 250 ng/ml (with S9) and 300 ng/ml (without S9).  Negative results were also obtained in another study in which α-terpineol was tested up to 460 nl/ml (with S9) and 380 nl/ml (without S9). "Based on the negative results obtained in gene mutation tests in mammalian cells, and in view of the sensibility of the TK+ /- system to mutagens specifically active toward the S. typhimurium strain TA102, the (European Food Safety Authority) Panel concluded that α-terpineol does not raise concern for genotoxicity".]

	3. Reproductive and developmental toxicity. [No data are available on the reproduction/developmental toxicity of α -terpineol specifically. However, a combined repeated dose and reproduction/developmental screening study on rats (OECD 422) is available on terpineol (CAS No. 8000-41-7).  Rats were dosed in groups at 60, 250, and 750 mg/kg/day.  The No Observed Adverse Effect Level (NOAEL) for males and unmated females was 250 mg/kg/day. The NOAEL for maternal toxicity was set at 250 mg/kg/day. The NOAEL for male and female offspring was determined to be >250 mg/kg/day. Terpineol and α-terpineol have similar acute toxicity and genotoxicity profiles.]

	4. Subchronic toxicity. [A 2-week dietary exposure to α-terpineol at a dose of 1000 mg/kg/day in rats resulted in decreased food intake and weight gain, and increased cholesterol and lipids, but no other adverse effects.]

	5. Chronic toxicity. [A 20-week chronic feeding study in rats indicates a No Observable Effect Level (NOEL) of > 500 mg/kg/day.]

	6. Animal metabolism. [α-Terpineol is metabolized to innocuous products.  It undergoes allylic oxidation of the exocyclic methyl group. This is further oxidised to a carboxylic acid group. Alternative or subsequent metabolism may occur by conjugation with glucuronic acid, followed by excretion in the urine. Metabolism of α-terpineol in rats in vivo has been well characterized, with carboxylic acid and glucuronide derivatives as the major metabolites in the urine.]

	7. Metabolite toxicology. [α-Terpineol is metabolized to innocuous products and therefore does not have metabolites of toxicological significance.]

	8. Endocrine disruption. [No data are available on the endocrine disruption of α-terpineol. However, based on lack of toxicity, its natural occurrence and history of human use and consumption, it is not expected to be an endocrine disruptor.]

C. Aggregate Exposure

	1. Dietary exposure. [α-Terpineol is currently used as a flavoring in foodstuffs and naturally occurring in various foods and beverages.  Therefore, the potential for aggregate exposure from dietary routes does exist for α-terpineol. While it is difficult to develop a precise estimate of total human exposure to α-terpineol, its low toxicity via oral and dermal routes of exposure and metabolism into innocuous compounds that are readily excreted, indicate that expected exposures are likely to be of low toxicological concern.  The addition of α-terpineol in biopesticide products at 5% of the formulation applied to food crops is not expected to significantly increase the dietary exposure potential of humans.]

	i. Food. [α-Terpineol when used as a solvent in pesticide formulations at 5% applied pre-harvest according to 40 CFR 180.920 will come into contact with food crops. α-Terpineol is also used as a flavoring in foods in addition to being found naturally in foods and beverages.  While it is difficult to develop a precise estimate of total amounts of α-terpineol in food, its low toxicity via oral and dermal routes of exposure and metabolism into innocuous compounds that are readily excreted, indicate that expected exposures are likely to be of low toxicological concern.]  

	ii. Drinking water. [α-Terpineol when used as a solvent in pesticide formulations at 5% applied pre-harvest according to 40 CFR 180.920 is not expected to come into contact directly with drinking water. α-Terpineol is soluble (2.87 g/L @ 23°C) and 100% biodegradable in water. Any potential exposure via drinking water is not expected to be of toxicological concern.]

	2. Non-dietary exposure. [α-Terpineol is currently found in a significant number of non-dietary products including pesticides (nonfood inert, fragrance uses), cosmetics, perfumes, toiletries, and cleaning products as a fragrance.  Therefore, the potential for aggregate exposure from non-dietary routes does exist for α-terpineol. While it is difficult to develop a precise estimate of total human exposure to α-terpineol, its low toxicity via oral and dermal routes of exposure, non-sensitizing potential, and metabolism into innocuous compounds that are readily excreted, indicate that expected exposures are likely to be of low toxicological concern.  The addition of α-terpineol in pesticide products at 5% of the formulation applied to food crops is not expected to significantly increase the non-dietary exposure potential of humans.]

D. Cumulative Effects

	[α-Terpineol has no known common mechanism of toxicity with any other toxic substances.]

E. Safety Determination

	1. U.S. population. [The safety of α-terpineol to humans has been previously evaluated based on its use in cosmetics, toiletries, household cleaning agents and as a flavoring in foods and beverages. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated α-terpineol and noted that it would not present safety concerns when used at current levels of intake as flavoring agents. A 2009 EFSA Flavouring Group Evaluation, further cited the JECFA determination. 

The Flavor and Extract Manufacturers Association (FEMA) Expert Panel determined that α-terpineol was GRAS (Generally Recognized as Safe) under conditions of intended use as flavor ingredients in 1965, several times thereafter, and in 2012. FEMA made this safety determination based on rapid absorption, metabolic conversion, and excretion in humans and animals; their low levels of use as flavors in food; the wide margins of safety between the conservative estimates of intake and the NOAEL or NOEL determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.

The Research Institute for Fragrance Materials (RIFM) Expert Panel concluded that cyclic terpene alcohols including α-terpineol, have no safety concerns when used as a fragrance. This determination is due to their low acute toxicity, no significant toxicity in repeat dose tests, non-mutagenic potential, classification as non-irritants, and non-sensitizers.]

	2. Infants and children. [The low toxicity and rapid metabolism of α-terpineol suggest there will not be a safety concern for infants and children.]

F. International Tolerances

	[No known tolerances exist for α-terpineol.]