   Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for 1-Octanol

                    Docket ID Number: EPA-HQ-OPP-2014-0353
                             Date: March 13, 2015
                                       
Section 408(c)(2)(A)(i) of FFDCA allows the U.S. Environmental Protection Agency (EPA or the Agency) to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if the EPA determines that the exemption is "safe." Section 408(c)(2)(A)(ii) of FFDCA defines "safe" to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." This includes exposure through drinking water and in residential settings but does not include occupational exposure. Pursuant to FFDCA section 408(c)(2)(B), in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must take into account the factors set forth in FFDCA section 408(b)(2)(C), which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance exemption, and to "ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue...." Additionally, FFDCA section 408(b)(2)(D) requires that the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."
The EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, the EPA determines the toxicity of pesticides. Second, the EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings.
I.  Summary of Petitioned-for Tolerance Exemption
In the Federal Register of August 1, 2014 (79 FR 44729) (FRL-9911-67), EPA issued a notice pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 3F8195) by D-I-1-4, Inc., a division of 1,4-Group, Inc. (the Petitioner), P.O. Box 860, Meridian, ID 83360. The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of 1-octanol, applied post-harvest to stored potatoes and other sprouting root and tuber crops. The notice referenced a summary of the petition prepared by the Petitioner, which is available in Docket ID Number EPA-HQ-OPP-2014-0353 via http://www.regulations.gov.
II. Toxicological Profile
Consistent with section 408(b)(2)(D) of FFDCA, the EPA reviewed the available scientific data and other relevant information on 1-octanol, and considered its validity, completeness, and reliability, as well as the relationship of this information to human risk. The EPA also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.
A.  Overview of 1-Octanol	

1-Octanol, or octyl alcohol, is a linear saturated aliphatic alcohol containing eight carbons. It is classified as a biochemical pesticide and functions as a plant growth regulator (PGR) by inhibiting sprout growth on stored potatoes and other sprouting root and tuber crops when applied after harvesting.  

There is a significant history of human dietary exposure to 1-octanol. 1-Octanol occurs naturally in the essential oils of green tea, grapefruit, California orange, bitter orange, Turkish rose and Bulgarian rose. 1-Octanol has also been identified as a component of fried bacon, roasted filberts, raw and roasted earth almonds, mutton, chicken, pork, raw beef, frankfurters, nectarines, apple juice, common guava, Gruyere cheese and in foods processed from cassava root. The amount of 1-octanol has been quantified in some foods: fermented soybean curds were found to contain 164.8 to 337.1 micrograms per kilogram (ug/kg) of 1-octanol, and duck meat and duck fat were found to contain 1-octanol as a volatile component at 8.88 parts per billion (ppb) and 12.69 ppb, respectively (Ref 1). 1-Octanol is approved by the FDA for use as a direct food additive under 21 CFR § 172.230 in microcapsules for flavoring substances and under 21 CFR § 172.515 as a synthetic flavoring substance and adjuvant.  

EPA has already determined under the FFDCA that there is a reasonable certainty that no harm will result from aggregate exposures to 1-octanol, when 1-octanol is used as an inert ingredient (specifically as a solvent or co-solvent) in pesticide products applied to food.  40 CFR § 180.910.  In addition, 1-octanol has been registered for use as an active ingredient to control tobacco sucker and as an inert ingredient for nonfood and fragrance uses (Ref`2).

Based on the data submitted in support of this petition (summarized in Unit II. B., below) and the comprehensive risk assessment conducted by the Agency (Ref. 1, below), EPA concludes that there is a reasonable certainty of no harm from aggregate exposures to 1-octanol, including the consumption of food treated with this active ingredient in accordance with label directions and good agricultural practices. EPA has made this determination because available toxicology data indicate that the active ingredient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure.

B.  Biochemical Pesticide Toxicology Data Requirements

All applicable mammalian toxicology data requirements supporting the request for an exemption from the requirement of a tolerance for residues of 1-octanol when used post-harvest to root and tuber crops have been fulfilled with data submitted by the petitioner. The following is a summary of EPA's review of the toxicity profile of this biochemical:
  
Acute Toxicity: Acute toxicity studies on 1-octanol (99% pure), confirm a low toxicity profile. The acute toxicity data show virtual nontoxicity for all routes of exposure, with the exception of eye irritation (MRID 48964402; Ref. 1, and references therein). 

1.	The acute oral median lethal dose (LD50) in rats was greater than 5,000 milligrams per kilogram (mg/kg) bodyweight in one study and equal to 4,135 mg/kg bodyweight in a second study. The LD50 in mouse was 1,800 mg/kg bodyweight. 1-Octanol is classified as Toxicity Category III for acute oral toxicity. 

2.	The acute dermal LD50 in rabbit was greater than 5,000 mg/kg body weight. 1-Octanol is classified as Toxicity Category IV for acute dermal toxicity.

 3.	The acute inhalation median lethal concentration (LC50) in rats was greater than 6.4 milligrams per liter (mg/L) after 1-hour exposure (no deaths occurred) and greater than 5.6 mg/L after 4-hour exposure (3 rats dying within two days of exposure). 1-Octanol is classified as Toxicity Category IV for acute inhalation toxicity. 
 
4.	For primary eye irritation, EPA has classified 1-octanol as irritating because the available data indicate that 1-octanol is "irritating" or "an irritant," but information regarding the degree of severity is unavailable. Because specific data on the eye irritation severity of 1-octanol is unavailable and data on similar substances indicate varying levels of irritation from moderate to severe, a toxicity category II classification is appropriate at this time.    
 
 5.	A skin irritation study on rabbits indicates that 1-octanol is slightly irritating. 1-Octanol is classified as Toxicity Category IV for primary skin irritation. 
 6.	Data indicate that 1-octanol is not a dermal sensitizer.
 
Mutagenicity: Information on 1-octanol mutagenicity testing is contained in MRID 49458902. In an Ames assay, five strains of Salmonella typhimurium were exposed to 2,000 nanoliters per plate (nl/plate) of 1-octanol with or without metabolic activation; 1-octanol was not considered mutagenic in the assay. In a mouse lymphoma assay (L5178Y TK+/-), cells were exposed to 100 micrograms per milliliter (ug/ml) 1-octanol with or without metabolic activation; again, 1-octanol was not considered mutagenic in the assay. 

Subchronic Toxicity: 

1. 90-day oral data requirement is required to be addressed for uses of a pesticide on foods. In MRID 48964402, data were cited from the open scientific literature to satisfy the data requirement. The study has been reviewed and cited by the World Health Organization's (WHO) International Programme on Chemical Safety in its assessment of 1-octanol as a food additive. The study is also cited in the National Library of Medicine's (NLM) Hazardous Substances Database (HSDB) for 1-octanol. Mice were administered the chemical via gavage at a dose of 179 mg/kg body weight for 30 days. No adverse effects were reported. 
   
2. The 90-day dermal data requirement is conditionally required to support uses involving purposeful application to the human skin or uses that would result in prolonged dermal exposure and if data from a 90-day oral study are not required or the active ingredient is known or expected to be metabolized differently by the dermal route of exposure than by the oral route and the metabolite is of toxicological concern. The Agency has waived this data requirement at this time. Purposeful application and prolonged exposure to the human skin is not anticipated based on the use pattern of the proposed product; 1-octanol is intended to be applied inside crop storage facilities through ventilation systems from outside of the facility. Per label instructions, buildings are sealed until fully ventilated and early reentry requirements include the use of appropriate PPE which includes coveralls over long-sleeved shirt, long pants, shoes plus socks, chemical resistant gloves, face-sealing goggles and a respirator. During use of the pesticide, applicators and handlers are required to wear appropriate PPE (long-sleeved shirt, long pants, shoes, socks, gloves and protective eyewear. These PPE requirements mitigate the potential for repeated dermal exposure. Additionally, prolonged dermal exposure is also not anticipated as 1-octanol is a volatile chemical that is expected to degrade rapidly once introduced into the environment. The chemical has an estimated half-life of 3.5 minutes and is not likely to remain on skin if exposure occurs (Ref. 1).
   
3. 90-day inhalation data requirement is conditionally required if there is a likelihood of significant levels of repeated inhalation exposure to the pesticide as a gas, vapor or aerosol. The Agency has waived this data requirement at this time. Significant inhalation exposure is not anticipated based on the use pattern: 1-octanol is intended to be applied inside crop storage facilities through ventilation systems from outside of the facility. Per label instructions, buildings are sealed until fully ventilated and early reentry requirements include the use of a respirator. Additionally, prolonged inhalation exposure is also not anticipated as 1-octanol is a volatile chemical that is expected to degrade rapidly once introduced into the environment (Ref. 1). 

Developmental Toxicity: No adverse effects (maternal or developmental) were observed in a developmental toxicity study where pregnant rats were exposed to 100 mg/m[3] 1-octanol (the maximum achievable vapor) for seven hours per day on gestation days 1-19. No developmental toxicity occurred in a study were pregnant rats were dosed via gavage with a blend of 55% decanol and 40.7% octanol at 0, 125, 375 and 1,000 mg/kg/day on gestation days 6-16. Increased salivation was observed in dams at the highest dose. The Agency does not consider this to be an adverse effect because the effect occurs at a very high dose, much higher dose than the level at which humans are likely to be exposed, given the half-life of this substance and the classification of the pesticide: a plant growth regulator intended for use before long-term storage. The maternal no observed adverse effect level (NOAEL) = 375 mg/kg/day and the maternal lowest observed adverse effect level (LOAEL) = 1,000 mg/kg/day. 

III.  Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

Food Exposure: The proposed use patterns may results in dietary exposure to 1-octanol, however, dietary exposure as a result of the application of 1-octanol to post-harvest potatoes and other root tubers is expected to be insignificant.  Some dietary exposure is expected from the use of 1-octanol as an inert ingredient in pesticide formulations. Some dietary exposure to 1-octanol might occur through other nonpesticidal sources as a result of its natural presence in other foods or from its use as a food additive and flavoring substance. Should exposure occur, however, minimal to no risk is expected for the general population, including infants and children, due to the low toxicity of 1-octanol (Ref 1). 

Drinking Water Exposure:  No significant exposure via drinking water is expected from its use as an active ingredient in this pesticide as 1-octanol is applied indoors only.  

Other Non-occupational Exposure: Other non-occupational exposure to 1-octanol from pesticidal use may occur in tobacco products from its use on tobacco or in or on other food and non-food commodities, as a result of its use as a pesticide inert ingredient. However, minimal to no risk is expected for the general population, including infants and children, due to the low toxicity of this chemical.

IV.  Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."

The EPA has not found 1-octanol to share a common mechanism of toxicity with any other substances, and 1-octanol does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, the EPA has assumed that 1-octanol does not have a common mechanism of toxicity with other substances. Following from this, the EPA concludes that there are no cumulative effects associated with 1-octanol that need to be considered. For information regarding the EPA's efforts to determine chemicals that have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the EPA's website at http://www.epa.gov/pesticides/cumulative. 

V.  Determination of Safety for the United States Population, Infants and Children
	
FFDCA section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that the EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure, unless the EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the Food Quality Protection Act Safety Factor. In applying this provision, the EPA either retains the default value of 10X, or uses a different additional or no safety factor when reliable data are available to support a different additional or no safety factor. 

Because there are no threshold effects associated with this biochemical, an additional margin of safety for infants and children is not necessary.  

EPA has determined that there are no foreseeable dietary risks to the U.S. population, including infants and children, from the use of 1-octanol as a pesticide (plant growth regulator) on root and tuber vegetables when label instructions and good agricultural practices are followed. The available data and information indicate that the chemical is of low toxicity and not a developmental toxicant. Therefore, EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to the residues of 1-octanol when it is used as labeled and in accordance with good agricultural practices. Such exposure includes all anticipated dietary exposures and all other exposures for which there is reliable information. EPA has arrived at this conclusion because the data and information available on 1-octanol do not demonstrate significant toxic potential to mammals, including infants and children. 

VI.  Conclusions
EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of 1-octanol. Therefore, an exemption is established for residues of the biochemical pesticide 1-octanol when used on root and tuber vegetables in accordance with label directions and good agricultural practices.

VII.  References

1. EPA (2015a) Science Review in Support of the Registration of 1,4Zap Technical, Containing 99.0%               
   1-Octanol as its Active Ingredient. February 23, 2015.
   
2. EPA (2015a) Inert Use Information. Inert Finder. Pesticides. US EPA. U.S. Environmental Protection
      Agency. Available at: http://iaspub.epa.gov/apex/pesticides/f?p=101:1: (Accessed January 13, 2015).
