Document ID: EPA-HQ-OPP-2013-0265-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-07-19T04:00Z

EPA ANTIMICROBIALS DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  
EPA ANTIMICROBIALS DIVISION CONTACT: VELMA NOBLE, 703-308-6233
EPA INERT INGREDIENTS ASSESSMENT BRANCH CONTACT: P.V. SHAH, 703-308-6341

The informative summary, which may be published in accordance with Section 2, is provided separately in both hard and electronic copy in the current Notice of Filing template format.

The Environmental Protection Agency (EPA) has received a pesticide petition from The Clorox Company ("Clorox"), 1221 Broadway Oakland, CA 94612-1888 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 180.940 to establish an exemption from the requirement of a tolerance for Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids when used as fragrances in formulations used on food-contact surfaces when applied/used in indoor residential settings at a maximum rate of 0.025%.  EPA has determined that the petition contains data and information regarding the elements set forth in section 408 (d)(2) of the FFDCA; 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.

The low-molecular weight saturated aliphatic primary alcohols, aldehydes and acids are ubiquitous in nature and these compounds have been found in the vast majority of all fruits and vegetables and their associated fats and oils, animal tissue and fats and beverages.  These compounds collectively have use as conventional, biochemical and antimicrobial pesticides in addition to being used as both flavoring and fragrance agents.  In most cases, exposures from natural sources exceed those from use as a flavor compound or a fragrance component.  Some group members (such as propionic acid) are endogenous and normal products of mammalian metabolism and all are readily and rapidly metabolized to innocuous products that are either excreted or incorporated into biomolecules.  The Congener group members all pose low toxicity to mammals, are readily biodegradable, and have a safe history of use.  Both the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Flavor Extract Manufacturers' Association (FEMA) have evaluated every member of the Congener group for use as a flavor compound.  All Congener group members are listed in the regulations at either 21 CFR 172, 21 CFR 182 or 21 CFR 184 governing Food Additives Permitted for Direct Addition to Food for Human Consumption, Generally Recognized as Safe (GRAS) or Direct Food Substances Affirmed as GRAS, respectively.  Every Congener group member is on the EPA Fragrance Ingredient List (a list of inert fragrance ingredients approved for non-food use).  At least one Congener group member (valeric acid) has been "reassessed" as an inert ingredient.  

A. Plant metabolism. Because Clorox is petitioning for an exemption from the requirement of a tolerance, plant metabolism data are not needed.

Analytical method. Because Clorox is petitioning for an exemption from the requirement of a tolerance, an enforcement analytical method is not needed.

Magnitude of residues. Because Clorox is petitioning for an exemption from the requirement of a tolerance, residue data are not needed; however, estimates of residue magnitude from use of indoor food contact sanitizing solutions are presented herein. Assuming a maximal concentration of 0.025% in a food-contact sanitizing solution, a summary of these residues is as follows:

                                Child Resident
                                Adult Resident
Dermal exposure/non-dietary
0.68 ug/kg BW/day 
(see RES-2)
Dermal exposure/non-dietary (during application)
0.33 ug/kg BW/day
(see RES-1)
Incidental ingestion/non-dietary
1.4 ug/kg BW/day
(see RES-3)

Oral ingestion/dietary
1 ug/kg BW/day
(see RES-4)
Oral ingestion/dietary
0.36 ug/kg BW/day
(see RES-4)
TOTAL
3.1 ug/kg BW/day
TOTAL
                              0.69 ug/kg BW/day

B.   Toxicological profile:

Linear aliphatic acyclic alcohols, aldehydes and carboxylic acids are absorbed through the gastrointestinal tract and rapidly metabolized.  Following absorption, alcohols are oxidized to their corresponding aldehyde, and aldehydes are oxidized to corresponding carboxylic acids via enzyme pathways with a high capacity (i.e. fatty acid and tricarboxylic acid cycles, which are a fundamental mechanism of cell biochemistry).  Fatty acids are endogenous and essential dietary components.  Short- and medium-chain fatty acids are converted rapidly to carbon dioxide and water in the mitochondria of liver and other tissues.  Fatty acids taken up by tissues can be stored chiefly as triglycerides in adipose tissue or oxidized for energy via the above pathways.  Some aliphatic acids undergo beta-oxidation to yield products that are then further metabolized by the fatty acid cycle.  In general, the fatty acid pathway converts aliphatic alcohols and aldehydes to acetyl Coenzyme A units, which then enter the tricarboxylic acid cycle (i.e. citric acid cycle, or most commonly "Krebs cycle").  The Krebs cycle is a series of reactions through which aerobic organisms make energy from carbohydrates, fats and proteins. 

Acute toxicity.  Linear aliphatic alcohols, aldehydes and carboxylic acids exhibit low acute toxicity.  Available oral or gavage studies in rodents (mainly rats) indicate LD50 values ranging from 720 to in excess of 20,000 mg/kg BW.  This is expected given the rapid and complete metabolism the Congener group members undergo in vivo.  
Genotoxicity.  Available in vitro and in vivo genotoxicity studies for the saturated aliphatic acyclic linear primary alcohols, aldehydes, and carboxylic acids generally exhibited consistent negative results in the Ames assay, the unscheduled DNA synthesis test, and in vitro or in vivo mouse micronucleus test.  However, genotoxic activity has been reported for some low molecular weight alcohols, carboxylic acids and aldehydes, including in the sister chromatid exchange (SCE) assay, the chromosomal aberration test and the forward mutation assays with mouse lymphoma and Chinese hamster lung cells. The positive results from the in vitro genotoxicity assays for aliphatic aldehydes is likely due to reactivity of the aldehyde functional group. 
Reproductive and developmental toxicity.  There is no evidence to conclude that oral ingestion of the Congener group as fragrance ingredients would be associated with reproductive or developmental toxicity, particularly in the light of low acute and chronic toxicity, rapid metabolism and low and infrequent exposure.  
Subchronic and chronic toxicity.  The alcohols and aldehydes display slightly greater relative toxicity than the acids (which overall is quite low for the entire Congener group), and this is to expected as these classes must be metabolized to acids prior to complete degradation to water and carbon dioxide.  As seen with the acute toxicity data, the repeat-dose toxicity for the Congener group members is fairly consistent when route of exposure, species differences, etc. are taken into account.
   
   The toxicity data for the aldehydes are largely derived from either Komsta et al. (1988) or Trubek (1958), which were all done on murine species where no effect was found at the highest dose for several chemicals and the resultant no-observed effect levels (NOELs) range from > 112 to > 166 mg/kg BW/day.  In one instance (acetaldehyde), a NOEL and a low-observed effect level (LOEL) of 125 and 625, respectively, were reported based on rat forestomach irritation. Given that there is no analogous structure in humans, others have adjusted no-effect levels based on rat forestomach irritation for human equivalency.  For nonanoic acid, a NOEL of 150 mg/kg BW/day based on forestomach irritation was adjusted to a human NOEL of 1,000.  (See description below.)  Furthermore, the High Production Volume Challenge submission for the C7-C9 aldehydes speculated that the NOEL for all the aldehydes in the category should likely be in excess of 300.

   The toxicity data for the alcohols demonstrate similar toxic potential in dog and rabbit in addition to rodents that are of the same magnitude as the aldehydes.  Available gavage studies indicate that this route of exposure results in lower NOELs (greater toxicity to experimental animal), although two of the three available gavage studies did not find effects at the highest dose (ranging from > 50 to > 180).  Available dietary studies cover rat, dog and rabbit and range from 695 to 1,000.

   The best coverage of the three groups is found among the acids, with all but one study (rabbit) done in the rat and as a result, the data set is remarkably consistent.  Again, exposure via gavage results in lower NOELs (ranging from 1,000 to 1,750 in three studies) than the dietary studies (ranging from 1,000 to 10,000 in nine studies).  One study (acetic acid) was via unspecified oral route and did not observe effects at the only reported dose (> 350 mg/kg BW/day).
Carcinogenicity.  Overall, the Congener group poses low concern for carcinogenicity given several observations.  First, the Congener group displays consistent negative findings in the Ames test, unscheduled DNA synthesis and both in vivo and in vitro mouse micronucleus tests. Second, the aliphatic aldehydes (for which there are several positive findings) are rapidly oxidized to acids that are metabolized via the citric acid cycle.  Third, some members of the Congener group are endogenous and products of normal metabolism.   Finally, exposures are infrequent and of low magnitude.
Endocrine effects.  A review of information from public sources, including the World Health Organization, the Agency of Toxic Substances and Disease Registry, and the Environmental Protection Agency indicate that potential endocrine effects from exposure to members of the Congener group have not been studied. To the best of our knowledge, nothing in the available literature suggests that Congener group members are "endocrine disruptors" or mimic intrinsic hormonal activity.  

C. Aggregate Exposure

The exposure assessment consisted of two parts, a dietary and a non-dietary assessment.  The dietary assessment included exposure to group constituents in food based on their use as flavoring additives and as naturally occurring substances.  The dietary assessment also included potential oral exposure to group constituents when used as fragrances in antimicrobial pesticides because it was assumed end-use products would be used on both food and non-food contact surfaces, therefore, an estimate of the potential exposure to a fragrance ingredient in antimicrobial residue that could migrate to food was included.

The non-dietary assessment included potential exposures to group constituents when end-use products are used on either food or non-food contact surfaces.  Based on review of the residential exposure assessments in recent Re-registration Eligibility Decision (RED) documents by EPA, it was concluded that dermal exposure to an adult resident applying a cleaning product to a surface, and a child exposed to this same surface post-application via dermal contact and incidental ingestion (i.e., hand-to-mouth contact), constitute the applicable scenarios and exposure routes with the greatest potential exposure.  

Dietary and non-dietary exposures, as presented previously, were aggregated for short-term durations (i.e., 1-30 days) for all exposures, using available NOELs from sub-chronic oral toxicity studies (a repeat exposure study of at least 21 days).  This approach is consistent with the EPA Office of Pesticide Programs (OPP) principles for aggregate risk assessment as well as JECFA's Procedure for Evaluating Flavor Ingredients.  Oral NOELs were used to assess potential risk from dermal absorption by conservatively assuming 100% dermal absorption and the same potential health effect whether exposed via the oral or dermal route. Health risk was estimated using margin of exposure (MOE) as the hazard metric.  Use of an MOE is particularly appropriate for chemicals whose underlying mechanism of toxicity involves a threshold process, where a NOEL is identified for a chemical, such as those identified for group constituents. 

1. Dietary exposure - food.
      i.  Acute.  There are no acute dietary exposure concerns as the acute toxicity of the Congener group members is quite low and there is an extensive history of safe ingestion given virtually all the Congener group members are found naturally in foods and/or beverages.  An acute dietary risk assessment is not required, as further evidenced by waiving dietary assessment requirements for all EPA pesticide actions taken on Congener group members to date (i.e. propionic acid, aliphatic alcohols, octanoic acid, nonanoic acid, and decanoic acid all were not considered dietary risks).
      ii.  Chronic indirect.  Using a worst-case scenario, the exposure resulting from the use of Congener group members at the maximal concentration of 0.025% in a food-contact sanitizing solution would be 3.1 ug/kg BW/day for a 15-kg person (child) and 0.69 ug/kg BW/day for a 60-kg person (adult)  (0.59 ug/kg BW/day for a 70-kg adult).  This is generally well below levels found in naturally occurring sources in the diet.
      iii.  Chronic direct.  A typical adult ingests from < 1 to 39,700 ug/day of Congener group members via diet, all from naturally occurring sources in food and/or beverages.  See Table 6 for daily per capita intakes of individual Congener group members and refer to Section 6 for a description of methodology.  Exposure to Congener group members in specific food items, such as the ingestion of acetic acid through foods containing vinegar or propionic acid through foods containing the preservative calcium propionate, can exceed daily intakes via uses of flavors or fragrances, yet have demonstrated a history of safe ingestion. 
2.	Drinking water exposure
      i.  Acute. There are no acute dietary exposure concerns via drinking water as the acute
      toxicity of the Congener group members is quite low and there is an extensive history of safe 
      ingestion given virtually all the Congener group members are found naturally in 
      foods and/or beverages.  A drinking water assessment is not required, as further evidenced by 
      waiving dietary assessment requirements for all EPA pesticide actions taken on Congener 
      group members to date (i.e. propionic acid, aliphatic alcohols, octanoic acid, nonanoic 
      acid, and decanoic acid all were not considered risks via this pathway).
      ii.  Chronic.  There are no chronic dietary exposure concerns via drinking water as the acute 
      toxicity of the Congener group members is quite low and there is an extensive history of safe 
      ingestion given virtually all the Congener group members are found naturally in 
      foods and/or beverages.  A drinking water assessment is not required, as further evidenced by 
      waiving dietary assessment requirements for all EPA pesticide actions taken on Congener  
      group members to date (i.e. propionic acid, aliphatic alcohols, octanoic acid, 
      nonanoic acid, and decanoic acid all were not considered risks via this pathway).
3.	Nondietary exposure.  Non-dietary exposure to an adult during application of a food contact sanitizing solution was estimated to be 0.33 ug/kg BW/day.  Total non-dietary exposure to a child was determined from post-application contact with treated surfaces as well as incidental ingestion following hand-to-mouth contact.  The former exposure was estimated to be 0.68 ug/kg BW/day and the latter 1.4 ug/kg BW/day, for a total non-dietary exposure estimate of 2.08 ug/kg BW/day for a child resident.

D. Cumulative Effects - No cumulative adverse effects are expected from long-term exposure to the members of the Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids Congener Group.  Despite the fact that the members share common mechanisms of toxicity with one another, cumulative effects are not anticipated due to the low mammalian toxicity and very low levels of exposure.  The common mechanisms of toxicity in this case (i.e. tricarboxylic acid cycle, or "Krebs cycle") are well-studied high-throughput pathways.

E. Safety Determination

A "worst case" exposure analysis was performed on the individual members of Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids to generate margin of exposure (MOE) values for both the US population (as estimated by an adult exposed dermally during the indoor application of a food contact sanitizing solution) and children (as estimated by indoor post-application dermal and incidental oral exposure to 3 year old).  This analysis estimated the MOE via inert ingredients used as flavor or fragrance components of a food-contact sanitizing solution as well as by considering those compounds that contain structural features that permit no strong initial presumptions of safety or may suggest toxicological effects (Munro et al., 2008).  The MOE calculation for an individual fragrance component is based on the combined or "aggregated" oral intake of the component from natural occurrence, use as a flavor compound and use as a fragrance in food-contact sanitizing solutions intended for use in indoor residential settings. Subchronic/chronic no effect levels (NOELs) were the primary toxicity metric used in the analysis and were obtained from mostly JECFA and supplemented by EPA, Organiziation for Economic Copperation and Development (OECD), etc.  Potential dietary exposures to residues on food were estimated using the IDREAM model and non-dietary exposures were estimated and aggregated to determine total exposure from use of Congener group members in a pesticide formulation.  Detailed methodology was previously submitted to the Agency and subsequently approved by EPA staff.  Given the exposure methodology is intended to be protective of a 3-year old child, the findings of this conservative, assessment is protective of both general US population as well as infants and children.

      1. U.S. population. This conservative screening-level risk analysis demonstrates acceptable (i.e. 100 or greater) margins of exposure (MOEs) for the U.S. population even when considering total aggregate intake from potential exposures from natural occurrence, use as a flavor compound and, most importantly, dietary and non-dietary routes of exposure during and following application of a food-contact sanitizing solution used indoors.

      2. Infants and children. The risk assessment used an exposure scenario protective of a three-year-old child resident exposed to Congener group members from both dietary and non-dietary sources, including post-application exposure to residue following indoor use as a food-contact surface sanitizer. This conservative screening-level risk analysis demonstrates acceptable (i.e. 100 or greater) margins of exposure (MOEs) for infants and children.

F. International Tolerances - No Codex Alimentarius maximum residue levels have been established for any of the Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids Congener Group members.