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**Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for Tetraacetylethylenediamine** 

**(TAED) and its metabolite**  **Diacetylethylenediamine (DAED) Docket ID Number:**  **EPA -**  **HQ -**  **OPP -**  **201 3**  **- 0277** 

**Date: August 29**  **, 2014** Section 408(c)(2)(A)(i) of FFDCA allows the EPA 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 throu gh 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 certaint y that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue....” Additionall y, FFDCA section 408(b)(2)(D) requires that the EPA consider “available informat ion 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 analy ses to determine the risks from aggregate exposure to pesticide residues. F irst, 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 October 25, 2013 , (7 8 FR 63941 ) , the 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 3F8148 ) by Technology

Sciences Group, Inc., on behalf of Agri - Neo, Inc., 3485 Ashby Saint - Laurent (Quebec), H4R 2K3, Canada . The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of Tetraacet yl eth yl enediamine (TAED) and its metabolite Diacet yl eth yl enediamine (DAED). The notice referenced a summary of the petition prepared by the petitioner, Technology

Sciences Group, Inc., (on behalf of Agri - Neo, Inc. ) , which is available in D ocket ID Number EPA - HQ - OPP - 201 3 - 0277 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 Tetraacet yl eth yl enediamine (TAED) and its metabolite Diacet yl eth yl enediamine (DAED) , 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**  **Tetraacetylethylenediamine (TAED) and its metabolite**  **Diacetylethylenediamine (DAED).** Tetraacet yl eth yl enedi amine, commonly abbreviated TAED (CAS No. 10543 - 57 - 4), is a federally registered antimicrobial active ingredient used most often as a bleaching activator. As a pesticide, TAED is present2 in combination with two other biochemical active ingredients (potas sium silicate, and sodium percarbonate) in an end use product intended for the early season control of bacterial and fungal pathogens on turf grass, golf courses, greenhouses and in nursery or in field - grown rice and strawberries. As an antimicrobial act ive ingredient, TAED is often present with sodium percarbonate for the sole purpose of generating perox yacetic acid (PAA) and hydrogen peroxide. For pesticidal uses, the end use product is in granular form. The product must be tank mixed with water. As a result of the tank mixing, part of the TAED molecule generates PAA and the remaining part of the TAED molecule metabolizes into diacet yl eth yl enediamine (DAED). The potassium silicate, also a part of the tank mixing, remains unchanged in the mixture and enhances s ys temic acquired resistance (SAR) to bacterial and fungal pathogens in the treated plants. Based on the above chemical reactions, it can be concluded that TAED has no direct pesticidal activity . Additionally , upon completion of the chemical r eaction, the substances which are exhibiting the pesticidal activity are PAA, h ydrogen peroxide and potassium silicate. DAED, although present on the commodities at the time of application, exhibits no pesticidal activity and is considered to be a metabol ite of TAED. All of the biochemical active ingredients in this product that are present either at the start or formed upon tank - mixing, are exempt from the requirement of tolerance as follows:

 Potassium silicate : All food commodities when applied at rat es not exceeding 1% b y weight in aqueous solutions (40 CFR 180.1268)  Sodium percarbonate : exempted under as h ydrogen peroxide, since it is converted to h ydrogen peroxide immediately

when in contact with water and it is the hydrogen peroxide that is the res idue of concern.  Hydrogen peroxide is exempt from the requirement of a tolerance in or on all food commodities when applied at < 1% per application (40 CFR 180.1197)  Perox yacetic Acid : In or on all food commodities (40 CFR 180.1196(c)) Currently , there are registered antimicrobial uses for TAED/DAED as a commercial laundry sanitizer and hard surface disinfectant used in medical settings only . Therefore, the uses of TAED/DAED as a pesticide, as described above, are considered as a new use/first food use. TAED is not classified as a biochemical active ingredient because it is not a naturally occurring substance, does not have a nontoxic mode of action, nor a history of exposure to humans and the environment demonstrating minimal toxicity . However, since T AED generates PAA, a biochemical active ingredient, data and other information submitted in support of the registration of a new use/first food use for TAED as a fungicide/bactericide under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodentic ide Act (FIFRA) has been reviewed by the Biopesticides and Pollution Prevention Division (BPPD) , and it has been determined that the current data requirements (40 CFR part 158.2010 through 158.2070) for registration of a new use/first food use for a pestic ide have been satisfied. **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 Tetraacetylethylenediamine (TAED) and its metabolite Diacet yl eth yl enediamine (DAED) in or on rice and strawberries have been fulfilled with data or information submitted by the petitioner or data waiver requests that have been granted b y the EPA.3 As desc ribed in the overview section of this document, certain chemical reactions between the a.i.s, sodium percarbonate and TAED occur, when in the presence of water in the tank mix. As a result of the chemical reaction, TAED generates PAA and DAED, a metabolite of TAED. Due to the potential that residues of TAED’s metabolite , DAED, could be present on food commodities, all TGAI Tier I human health data requirements were required including information on the toxicity on the metabolit e. In formation from **a** recent kinetic study has shown that TAED is converted >99% to DAED (HERA, 2002). In support of this application and petition for the requirement of a tolerance exemption, the majority of the available toxicity studies submitted were conduc ted on TAED with a few studies tested on DAED. However, g iven that almost all of TAED is converted to DAED, and the recognized structural - similarity of TAED and DAED, EPA has assumed that both chemicals have similar toxicity ; and therefore, TAED toxicity data will be used for DAED . The following is a summary of EPA’s review of the toxicity profile of th is biochemical: 1. Acute Toxicity (OCSPP Guideline Nos. 870.1100, 870.1200, 870.1300, 870.2400, 870.2500, and 870.2600; Master Record Identification (MRID) Nos. 48653202, 48653203, 48653204, 48653205, 48653206, 48653207, 45299702 , 49043703, 45712902, 46204801 , 45712903, & HERA 2002 , ): The petitioner submitted data on the proposed End Use Product (EP), Ato Cide Granular (EPA File Sy mbol No. 88306 - G) , in ord er to fulfill the biochemical pesticide date requirements for Acute Toxicity . The acute oral median lethal dose (LD 50 ) in rats was equal to 1,750 milligrams per kilogram (mg/kg) body weight in rats. There were no observed toxicological effects on the EP in the acute oral study submitted by

the petitioner. The EP is further classified as Toxicity Category I II for acute oral toxicity . The acute dermal LD 50 in rats was greater than 5,050 mg/kg bodywei ght in rabbits. The EP is further classified as Toxicity Category IV for acute dermal toxicity . The acute inhalation median lethal concentration (LC 50 ) was greater than 2.26 milligrams per liter (mg/L) in rats and showed no significant inhalation toxicity . The EP is classified as Toxicity Category IV for acute inhalation toxicity . A primary

eye irritation study

on rabbits indicates that EP caused eye iritis, corneal opacit y , a conjunctivae (redness and chemosis) in rabbit eyes. Redness and chemos is was observed in all three animals after 1 hour and lasted until day

10 (redness) and day

17 (chemosis). Iritis was observed in one animal after 24 hours and lasted until day

10. Corneal opacity

was observed in three animals after 24 hours and lasted in one animal through 21 day s when experiment was terminated. T he EP is classified as severel y irritating to the eye; therefore is classified as Toxicity Category Ifor primary

eye irritation. A skin irritation study

on rabbits indicates that the EP is caused slight to severe ery thema through day

14 and very slight to slight edema at 24 hours through day 10 in rabbits. The substance was scored moderatel y irritating; however, based on the presence of necrosis in one animal, the EP is classified as corrosive. The EP is classified as Toxicity Categ ory I . for primary

dermal irritation. Data indicate s very

faint to faint ery

thema in 17 of 20 test animals after challenge treatment. The EP is considered a dermal sensitizer **.** Due to this likely

potential of residues of TAED/DAED being present on food commodities, the petitioner also submitted data on the TAED, and its metabolite DAED.4 The acute oral median lethal dose (LD 50 ) in rats was equal to 7,940 milligrams per kilogram ( mg/kg) body weight in rats. There were no observed toxicological effects on TAED in the acute oral study submitted by

the petitioner. TAED is further classified as Toxicity Category IV for acute oral toxicity . T he HERA (2002) document indicates that a subm itted acute oral toxicity study on DAED is defined as non - toxic by

the study authors. LD 50 > 2,000 mg/kg body weight in rats (highest dose tested) . The acute dermal LD 50 in rats was greater than 2,000 mg/kg bodywei ght in rabbits (highest dose tested) . TAED and its metabolite DAED is further cla ssified as Toxicity Category III for acute dermal toxicity . The acute inhalation median lethal concentration (LC 50 ) was greater than 2.08 milligrams per liter (mg/L) in rats and showed no significant inhalation toxicity . TAED and its metabolite is classified as Toxicity Category IV for acute inhalation toxicity . A primary

eye irritation study

on rabbits indicates that caused produced mi nimal ocular irritation in 2 of 6 animals. Effects at 24 hours consisted of minimal palpebral redness. All irritation had ameliorated at 72 hours. TAED is classified as minimally irritating to the eye . Two skin irritation studies were performed for TAED on rabbits . The first study , the test substance produced minimal cutaneous irritation in 3 of 6 animals. Effects at the 24 hours consisted of barel y perceptible ery

thema, with one site showing minimal edema. All irritation had disappeared at 72 hours. Th e second study , no dermal irritation was noted at any time during the study . Based on the results of the two studies, TAED is classified as minimally irritating to non - irritating to the skin . TAED and its metabolite DAED is classified as Toxicity Category IV . for primary dermal irritation. Data indicates that TAED and its metabolite are not dermal sensitizer s **.** 2. Subchronic Toxicity, Developmental Toxicity, and Mutagenicity Testing (Tier I) (OCSPP Guideline Nos. 870.3100, 870.3250, 870.3465; 870.3700, 870.5100, 870.5300, 870.5375; MRID Nos. 45299704, 45274306, 49043703, 45547201, 45547202 &HERA, 2002 ): A 90 - day oral toxicity

study was conducted on TAED. TAED was administered to Sprague Dawley rats orally at dosages of 25, 500, and 1,000 mg/kg/day . A group of 10 animals/sex received the test vehicle, 1% carbox ym eth yl cellulose. No mortality was observed in any

dose group and no treatment - related clinical signs were noted. Dose - related decreases in body weights were noted with 10, 15, and 25% in the low, mid, and high - dose groups in males and 10 and 15% in the mid - and high - dose groups in females. Food consumption wa s decreased in these groups with statistical significances in the high - dose males. In the clinical pathology

there were significant increases in red blood cells, total protein, albumin, and cholesterol, and decreases in hemoglobin, hematocrit, MCV, MCH, glucose, creatinine, AST, chloride, and trigl ycerides mostly in the mid - dose or high - dose males and/or females; however, the study authors felt that these increases/decreases were not clinically significant. The liver was considered to be the target organ ba sed on changes in organ weight, gross necrops y, and microscopic pathology . The livers were enlarged in the high - dose males and females and accompanied by an increase in absolute and relative organ weights in the high - dose males and the mid - and high - dose f emales. There was centrilobular cy tomegal y in the mid and high - dose males and females and a mild degeneration of the seminiferous tubules in the high - dose males. Based on body weight changes there would not be a NOEL in males, but a NOEL of 25 mg/kg/day in females. Based on microscopic changes in the liver, the NOAEL would be 25 mg/kg/day in males and females.5 Another 90 - day

oral toxicity

study was performed on Sprague - Dawley rats at daily

dose levels of 0, 90, 250, and 800 mg/kg/day

and summarized in the HERA document on TAED ( Ref 1 and 3 ). No mortality occurred in an y dose group and salivation observed in the high - dose group was the onl y clinical finding. Total body

weight gain was decreased in male and female rats in high - dose groups. Slightly decreased hematocrit values in all male dose groups and increased leukocy tes in female high - dose group were observed were observed. Increased protein values in males and females of the high - dose group and increased cholesterol values in female high - dose group were also observed. Relative liver and testes weights were significantly increased in male rats of the 250 mg/kg/day dose group. Absolute and relative liver weights of males and females and relative adrenal and testes weights in males were statistically signifi cantl y increased in the 800 mg/kg/day dose group. Histopathological examination revealed centrilobular h ypertrophy of hepatocytes in all high - dose group animals. This effect reversed completely with the 28 day

recovery period. Centrilobular hy

pertrophy was also noted in some of the male and female rats in the 90 and 250 mg/kg/day groups; however, the effect was borderline not considered a clear substance related effect since it was also noted in some of the control animals. Adverse effects were clearl y note d in the 800 mg/kg/day dose group and changes in organ weights were present in the 250 mg/kg/day dose group; therefore, the NOAEL is 90 mg/kg/day and the LOAEL is 250 mg/kg/day . The HERA document also makes mention of a 13 - week rat feeding study on DAED with a NOEL of 5,700 mg/kg/day

reported in a handbook of environmental chemistry ; however, no reference was given in the handbook so the study

could not be validated (Ref. 1). A 90 - day dermal toxicity

study was performed on Sprague - Dawley rats at daily

dose levels of 0, 20, 200, and 2,000 mg/kg/day

and submitted (Ref. 3) . The daily doses were delivered by

dermal application once a day for six hours. One control male, two 200 mg/kg/day females, and one 2,000 mg/kg/day female did not survive to termination of the study ; however, these deaths were attributed to the wrapping procedure and not result of the TAED since no clinical signs were noted prior to death that would have suggest ed an effect from the test substance. No treatment related effects were noted at the 0, 20, or 200 mg/kg/day in clinical observations, body weight and food consumption data, ophthalmologic findings, clinical pathology findings, gross necrops y findings, and organ weight data. The onl y effect found was minimal centrilobular hy pertrophy (cy tomegal y) in 8/10 males and 4/10 females at the 2,000 mg/kg/day dose. This effect was not found in the lower dosed rats that died in the study or had gross lesions associate d with the liver. The NOEL is determined to be of equal to or greater than 200 mg/kg/day . Based on the minimal effects seen at the high dose group, the NOEL is likely to be much closer to 2,000 mg/kg/day than 200 mg/kg/day . A 13 - week inhalation toxicity s tudy was performed on three groups of 12 male Wistar rats at daily dose levels of 12.2, 60.3, and 99.7 mg/m 3 and summarized in the HERA document on TAED ( Ref 1 and 3) . Male rats were exposed in whole body inhalation chambers to TAED for six hours a day , fi ve day s a week, for 13 weeks. Male rats were used as they were more sensitive than females in the acute inhalation study . Following exposure, six rats were killed and examined by whole body

necropsy . The remaining six rats of each dose group were maintaine d without further treatment for 13 weeks to investigate the reversibility of treatment - related effects. There was no mortality in any dose group. There were statisticall y significant increases in absolute and relative liver and kidney weights; however, all organ weights returned to normal values following the recovery period except for a small increase in liver weight for the high - dose group. There was a statisticall y significant reduction in hemoglobin and an increase in platelet numbers in the high - dose g roup and an increase in the number of monocy tes in the high and mid - dose groups; however, these values returned to normal following the recovery period. Glucose levels and aspirate transaminase activity were reduced in all dose groups. Increased CA +2 , serum total protein, and albumin and reduced alanine transaminase activity were found in the high and mid - dose groups and increases in total cholesterol6 and pseudocholinesterase activity and reduced alkaline phosphatase activity in the high - dose group; however , these values returned to normal following the recovery period. Following necrops y, one rat in the high - dose group had a slight enlargement of the liver, but no other abnormal features were noted in any of the other rats. Microscopic examination showed no treatment - related effects in the lungs. There was a sy stemic response as reported by significant increases in kidney weights in the high and mid - dose groups and in liver weights in all dose groups. Hy pertrophy of centrilobular hepatocy tes was considered t o be due to induction of hepatic microsomal drug metabolizing enz ym es based on further ultrastructural studies that demonstrated proliferation of smooth endoplasmatic reticulum in these hepatocy tes. Eosinophilic droplets in the tubular epithelial cells in kidney s were also noted, usually referred to as hyaline droplets composed principally

of the normal male rat urinary protein α 2 μ - globulin. Due to the fact that in another study where female and male rats were fed TAED and male rats developed this same kidney issue and female rats did not, the kidney

findings in this study

are specific to the male rat and not relevant to humans. Examination of recovery

rats showed that these effects were reversible and returned to normal. The NOAEL for s ystemic effects c annot be determined from this study as the whole body

of the animal was exposed to TAED dust and the oral ingestion of unquantifiable amounts of TAED would have occurred due to normal grooming practices. Under the condition of the study , the NOAELin rat lungs, respiratory tract or nasal mucosa is 99.7 mg/m 3

. A developmental toxicity study was performed on pregnant Sprague - Dawley rats during day s 6 through 15 of pregnancy

at dail y dose levels of 0, 40, 200, and 1,000 mg/kg/day and submitted (Ref. 3) . On day 20, the pregnant females were caesarean - sectioned and subjected to post - mortem examination. No clinical signs, behavioral changes, death or abortion were noted in any dose group. A dose - related lower mean body weight gain and mean daily food consumption was observed in the 200 and 1,000 mg/kg/day dose groups. No embryotoxic effects were found. In the 40 and 200 mg/kg/day dose groups, there were statistically lower mean fetal weight and higher percentage of skeletal variants, these values were well within the range of historical control values; therefore, these effects were considered not toxicologically significant. However, mean fetal weight and placental weight were lower and skeletal variants were higher in the 1,000 mg/kg/day

dose group. The maternal t oxicity NOELwas determined to be 40 mg/kg/day . The developmental toxicity

NOELwas determined to be 200 mg/kg/day . A bacterial reverse mutation assay (Ames test) with five strains of Salmonella typhimurium with and without metabolic activation at dose co ncentrations of 10, 100, 1,000, and 10,000 μg/plate was performed and submitted (Ref 3) . The results of the test indicated that TAED exerted no bactericidal/static properties and all strains were non - mutagenic. In another bacterial reverse mutation assay a s summarized in the HERA document on TAED, DAED was evaluated in the presence of four strains of S. typhimurium and one strain of E. coli with and without S9 metabolic activation ( Ref. 1 and 3) . Prior to the main study , a range finding assay

was performed with one strain of S. typhimurium without metabolic activation to determine cy totoxicity . DAED assayed at concentrations from 0.1 to 10,000 μg/plate in triplicates and found not to be cy totoxic and not mutagenic. In the main assay study , DAED was tested at 5,000 μg/plate. A statistically significant increase in the number of colonies was not observed with DAED; therefore, DAED was determined to be non - mutagenic. Two in vitro mammalian chromosome aberration tests conducted in human ly mphocy tes we re performe d and submitted (Ref. 3) . Four treatment conditions were used, 4 hours of exposure to TAED in the presence of S9 metabolic activation with cell harvest at 16 and 40 hours later, and 20 and 44 hour continuous exposures in the absence of metabolic activation . In experiment one, 20 - hour harvest cultures were exposed to eight concentrations of TAED, 17.81, 35.63, 71.25, 142.5, 285, 570, 1,140, and 2,280 μg/ml. The three highest dose concentrations, 570, 1,140, and 2,280 μg/ml were selected for chromosomal anal y sis. The test substance did not induce any significant increases in the frequency of cells with aberrations either with or7 without S9 metabolic activation. The test substance also did not induce any significant increase in the numbers of pol yploid cells at any of the dose levels. In experiment two, three dose concentrations, 570, 1,140, and 2,280 μg/ml were harvested at 20 - hours and observed for chromosomal analy sis similar to experiment one; however, the highest dose concentration, 2,280 μg/ml, was also harvested at 44 hours and observed for chromosomal anal ys is. The 44 hour mitotic index data indicated a toxic effect at the maximum dose level tested of 2,280 μg/ml (~35% reduction in mean mitotic index) with and without S9 metabolic activation, although the re was some inter - culture variation. Statistical analysis indicated that only a single significant increase in aberrant cell frequency in TAED treated cultures (at 570 μg/ml with S9 mix, 20 hour harvest, experiment two, p = 0.03); however, there was no suc h statistical increase in experiment one and the results were not reproducible. The test material did not induce a significant increase in the numbers of poly ploid cells at an y dose level in experiment two. Based on the results of the two experiments, the test substance, TAED, did not induce biologically or reproducible statisticall y significant increases in the frequency of cells with chromosome aberrations with or without S9 metabolic activation and is considered to be non - clastogenic to human ly mphocy tes in vitro . Inanother in vitro mammalian chromosome aberration test as summarized in the HERA document on TAED, TAED was evaluated in V79 cells of the Chinese hamster (Ref. 1 and 3) . The V79 cells were exposed to TAED for four hours with and without S9 met abolic activation and harvested at 7, 18, and 28 hours and evaluated for chromosome aberrations. The TAED concentrations tested were 500 μg/ml in cultures harvested at 7 and 28 - hours and 20, 200, and 500 μg/ml in cultures harvested after 18 - hours. The mito tic index was only slightly reduced in the 500 μg/ml concentration at the 7 hour harvest with and without S9 activation. There was no relevant increase in cells with structural aberrations. Based on these results, TAED was determined to be non - clastogenic in V79 cells of the Chinese hamster in vitro . One in vivo m ammalian micronucleus test was conducted in mice and submitted (Ref. 3 - 5). The test substance, TAED, was given to ten mice (five males and five females) at the dose concentrations of 312.5, 625, and 1,250 mg/kg bw. The control and 1,250 mg/kg dose group were sacrificed at 24, 48, and 72 hours after dosing. The 312.5 mg/kg, 625 mg/kg, and positive control dose groups were sacrificed at 24 hours after dosing. Bone marrow was extracted from the femur s and smear preparations were made and stained. There were no statistically significant increases in the frequency of micronucleated pol ychromatic erythrocy tes in the treatment groups compared to the control groups. No significant change in the polychromat ic/normochromatic ery throcy tes (PCE/NCE) ratio was observed (compared to the positive test control) after dosing with the test material, but the presence of clinical observations and premature deaths (three animals dosed at 1,250 mg/kg) indicated that sy st emic absorption had occurred. Based on the test results, TAED was considered to be non - genotoxic. In another in vivo m ammalian micronucleus test in mice as summarized in the HERA document (Ref.1) on TAED, TAED was tested at dose levels of 250, 1,250, and 2 ,500 mg/kg bw administered twice, separated b y an interval of 24 hours ( Ref. 1 and 3) . The animals were sacrificed at 30 hours after the first test substance application and bone marrow smears were prepared. No premature deaths occurred and the mean micron ucleated cell count of TAED was comparable to the negative control at all dose levels. No significant change to the PCE/NCE ration was observed, but the presence of clinical observations indicates that the sy stemic absorption had occurred. Based on the tes t results, TAED was considered to be non - genotoxic. Toxicity endpoints and points of departure (PODs) for residential and occupational exposure scenarios to TAED are summarized below. Description of studies used as the basis for the selected endpoints are as follow: Acute Dietary

Endpoint: An acute endpoint was not selected based on the absence of an appropriate endpoint attributable to a single dose.8 Chronic Dietary

Endpoint: The chronic dietary endpoint was derived from the rat 90 day oral study , where the NOAEL was 90 mg/kg/day . The LOAEL is 250 mg/kg/day based on significant increase in relative liver and testes weights in male rats . This study is also protective of the maternal and developmental effects observed in the developmental toxicity study (MRID 45299704). Short (1 - 30 day s) Term incidental Oral Endpoint: The short - term incidental oral endpoint was derived from the 90 day

study in rats, where the NOAEL was 90 mg/kg/day . The LOAEL is 250 mg/kg/day based on significant increase in relative liver and testes weights in male rats . This study is appropriate for the duration of exposure as well as it is protective for the population of concern (young children). This s tudy is also protective of the maternal and developmental effects observed in the developmental toxicity study (MRID 45299704). Short (1 - 30 day s) Term Dermal Endpoint: A dermal endpoint was not selected based on the absence of an appropriate endpoint from the available dermal study . An affect was not observed at the limit dose of 2000 mg/kg/day . Short (1 - 30 day s) Term Inhalation Endpoint: An inhalation endpoint was not selected based on the absence of an appropriate endpoint from the available inhalati on study . An effect was not observed the highest dose tested (99.7 mg/m 3 ). R esidue study

on rice or strawberries were not submitted ; therefore, the Agency calculated residues using the known environmental fate information for TAED and DAED and the revis ed application rates from label, intervals, and timing for rice and strawberries as inputs in the Agency’s Terrestrial Residue Exposure (T - REX) model. The Agency used a default foliar dissipation half - life value of 35 day s in calculating estimated residues in its T - REX model Version 1.5.2. Tank mixture data (the proposed EP, Ato Cide Granular, mixed with water) submitted by the applicant under MRID 49043702 showed that at the time of application, TAED from the proposed EP had reacted with hydrogen peroxide (h ydrogen peroxide was formed from the reaction of sodium percarbonate from the proposed EP with the water in the mixing tank) to form perox ya cetic acid (PAA) and its metabolite DAED. The amount of DAED formed from the reaction of TAED and h ydrogen peroxid e in the tank mixture was approximately 50% of the initial amount of TAED in the proposed EP. Based on the application use rates and intervals, the amount of potential DAED is 2.23 ppm on rice and 8.79 ppm on strawberries. The Agency also calculated residu es in drinking water sources from use of the pesticide using the screening model, FQPA Index Reservoir Screening Tool (FIRST). The FIRST model calculated surface water estimated drinking water concentrations (EDWCs) of 74 ppb. Based on the residues estim ated in the T - REX model from the application rates and intervals on the proposed EP label, the percent of the chronic Population Adjusted Dose (%cPAD) calculated in the Dietary Exposure Evaluation Model - Food Commodity Intake Database ( DEEM - FCIDTM ) Version 3 .16 analy sis for dietary exposure is the highest in the population subgroups, Non - nursing infants and Children (age 1 - 2), at 9.2%. The Agency ’s Level of Concern (LOC) for %cPAD is 100; therefore, the calculated %cPAD for DAED is well below the Agency ’s LOC for the quantitative chronic dietary risk assessment. In addition, any possible quantifiable dietary exposure is expected to be mitigated even further due to the use of the pesticide product containing TAED/DAED as an effective control of earl y s eason fun gus and bacterial diseases that will be applied well before an y food commodity is harvested .9 **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). The Agency

aggregated e xposure of potential short (1 - 30 day s) term residential post - application incidental oral exposure and chronic dietary exposure for the population subgroup, children (age 1 to < 2). The quantitative exposures via the diet and residential uses (post - applicat ion incidental oral) for this pesticidal use. The aggregate MOE for the population subgroup, children (age 1 to < 2), is 7400 MOEs greater than 1000 do not exceed the Agency ’s LOC; therefore, aggregate risks for this new pesticidal use of TAED/DAED are n ot considered to be of concern. Based on the results of the aggregate risk assessment, unreasonable adverse effects are not anticipated when the pesticide product is used according to label instructions. EPA recognizes that there are additional uses for T AED/DAED Antimicro bial Division. The two current federally registered end - use products are for use in institutional and commercial laundry sanitization (EPA Reg. No. 16930 - 5) and part of a two - part sy stem to create an end use hard surface disinfectant solution in medical/dental/veterinary facilities (EPA Reg. No. 1043 - 125). These two products have a similar perh ydrol ys is reaction that yields PAA and hydrogen peroxide, along with the metabolite , DAED. The current dietary

and residential risk assessment for this new pesticidal use is highl y conservative and protective of an y potential exposure to these additional antimicrobial uses because the aggregate MOE of 7400 is well above the Agency ’s LOC of 1000. For additional information on these antimicrobial uses, refer to the preliminary

work plan for TAED (docket ID number EPA - HQ - OPP - 2013 - 0608; www.regulations.gov ), which is currentl y undergoing registration review. In consideration of the above information, the Agency h as determined the risk from aggregate exposure (via oral, dermal, and inhalation exposures) is negligible; there is reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to TAED and its m etabolite , DAED. Food Exposure : In the absence of residue data on rice or strawberries; the Agency calculated residues using the known environmental fate information for TAED and DAED and the revised application rates, intervals, and timing for rice and strawberries as inputs in the Agen cy ’s T - REX model Version 1.5.2. In the absence of chemical - specific half - life data, the Agency

used the Environmental Fate and Effects Division’s (EFED’s) default foliar dissipation half - life of 35 day s in calculating estimated residues in its T - REX model. The Agency

used EFED’s default foliar dissipation half - life value of 35 day s, which represents the upper bound of the half

- lives reported in Willis and McDowell (1987). For more information on the use of this default foliar dissipation half - life value of 35 day s in T - REX modeling, refer to the T - REX User’s Guide located at the following website: http://www.epa.gov/oppefed1/models/terrestrial/trex/t_rex_user_guide.htm . Tank mixture data (the proposed EP, Ato Cide Granular, mixed with water) submitted by the applicant under MRID 49043702 showed that at the time of application, TAED ( from the proposed EP ) had reacted with hydrogen peroxide (hydrogen peroxide was formed fro m the reaction of sodium percarbonate from the proposed EP with the water in the mixing tank) to form PAA and the metabolite of TAED, DAED. The amount of DAED formed from the reaction of TAED and h ydrogen peroxide in the tank mixture was approximately 50% of the initial amount of TAED in the proposed EP. Based on the application use rates and intervals, the amount of10 potential DAED is 2.23 ppm on rice and 8.79 ppm on strawberries. The T - REX Version 1.5.2 inputs to determine the potential residues were as fo llows: 1) EFED’s default foliar dissipation half - life of 35 day s, 2) application rate (from label) of 0.3 lbs a.i./acre (DAED), 3) application interval (from label) of 7 days, and 4) max number of applications (from label) of 2 for rice and 3 for strawberries. The application rate of 0.3 lbs a.i./acre of DAED was calculated b y multiplying the application rate of 3 lbs product/acre by 10% DAED. The T - REX upper bound Kenaga worksheet values for rice and strawberries (represented by the dietary - based estimated environmental concentrations [EECs] “fruits/pods/seeds”) were 8.42 ppm and 11.83 ppm, respectivel y; however, these residue values do not take into consideration any pre - harvest intervals (PHIs). The T - REX Version 1.5.2 model worksheets do provide residue values for each day up to 370 day s after first application based on first - order decay rates (see T - REX User’s Guide for details on residue calculations http://www.epa.gov/oppefed1/models/terrestrial/trex/t_rex_user_guide.htm#Section3_1 ); therefore, based on the proposed product PHI s of 60 day s for rice and 15 day s for strawberries, the amount of potential DAED is 2.23 ppm for rice and 8.79 ppm for strawb erries. Timing of Application in Rice and Strawberries For rice, the product would be applied at least 60 day s prior to harvest; therefore, very little DAED residue would be expected at the time of harvest due to the following facts: 1) the rice kernel i s not fully formed at application 60 day s before harvest and 2) DAED is readil y biodegradable (HERA, 2002). To further expand on the timing of application in rice and the potential for residues, additional information was submitted in MRID 49266701, pages 4 - 6. The information explained outlined rice production. Specifically , that there are four major milestones in a growing season of U.S. rice: 1) planting, 2) panicle initiation, 3) heading, and 4) harvest. From planting to harvest, the ty pical U.S. rice gr owing season is 130 day s. At the panicle initiation, which is approximately at the half

- way point of the growing season (60 - 70 day s), most fungicides and bactericides, including this proposed EP, are spray ed by aerial application onto the rice crop since i t is at this time that many rice pathogens attack the plant and induce disease. The rice diseases in the U.S. that the EP is intended to control are the bacterial panicle blight and the fungal pathogens sheath blight, blast, smut, stem rot, and narrow brown leaf spot. The EP is intended to control all of these diseases preventivel y so the diseases cannot establish on the rice crop as this is when the EP is most effective. The EP is not intended to be applied on the crop once the disease is already present and established as it is not intended to be a cure - all. In addition, the EP contains the a.i., potassium silicate, a known Sy stemic Acquired Resistance (SAR) inducer, which stimulates crop plant immunity to disease. Appl yi ng this EP earl y in the growing sea son induces SAR and further protects the plant against any surviving bacteria or fungi that may

remain on the plant or in the field. The EP will be applied no later than 60 - 70 day s after planting during the panicle initiation stage, which is at least 60 days prior to harvest. The edible portion of the plant, the rice kernels, have not yet been formed. At the heading stage, which is 100 days after planting and 30 - 40 day s after application of the EP, the fertilized flowers have turned into the rice grains or kernels. These rice grains or kernels ripen over the next 30 day s and are harvested around day 130. Based on the provided information that the EP is applied around day s 60 - 70 (panicle initiation stage), the edible rice grain or kernel forming around day 10 0 (heading stage), and the rice grain or kernel harvested at day 130, the applicant expects that it is highly unlikel y that any DAED residue would be present on the edible portion of the rice crop. The Agency agrees that it is highly

unlikel y that DAED res idue would remain on the edible portion of the rice crop at the time of harvest, which is approximately 60 - 70 day s after application of the EP based on the preceding information; however, a quantitative risk assessment was co nducted for this use on rice to assess potential risks (if any) from dietary exposure. For strawberries, data was submitted on the timing of the application in strawberries and the potential for residues under the cover letter dated 10/15/2013 (value proposition information section) an d in MRID11 49266701, pages 7 - 8. The data indicated that the growing season for strawberries after transplant is ty picall y 90 - 120 day s in Florida and California and the EP would be applied within the first 30 - 45 day s of the growing season. The EP is applied in the earl y part of the growing season to control three major plant diseases, angular leaf spot, botry tis, and powdery

mildew. For angular leaf spot, caused by the bacterium, Xanthomonas fragariae , and powdery mildew, caused by

the fungus, Podosphaera aph anis , the plant diseases are generall y transmitted to the field by contaminated transplants; therefore, it is recommended to apply pesticides early

in the growing season to control the diseases before they are established in the strawberry

plant or contami nate other strawberry plants in the field. For grey mould, caused by

the fungus, Botrytis cinerea , the plant disease is from spores that lie dormant on dead strawberry leaves in the field and cover young flowers until fertilization and fruit set occur. At that stage the spores germinate and the fungus makes the fruit rot (MRID 49266701, page 7). Like with the other two main strawberry plant diseases, it is recommended to apply

fungicides earl y in the growing season to kill the grey mould spores before the d isease can get a foothold on the strawberry crop later in the season. As previously stated, the EP contains the a.i., potassium silicate, a known SAR inducer, which stimulates crop plant immunity to disease. Applying the EP earl y in the growing season allo ws the strawberry plant to trigger SAR and further protects the plant from fungal spores that remain on the plant or in the field. The first harvest of strawberries is at least 60 day s into the growing season and subsequent harvests occur weekl y after the first harvest. Based on the proposed labeling, the final application of the product would occur approximately 15 day s prior to the first harvest; therefore, potential residues of DAED would be expected to be less than the calculated residue of 8.79 ppm fro m the T - REX modeling and less in subsequent harvests since T - REX modeling does not take into consideration biodegradation of DAED and any loss of residues based on processing of the strawberry crop. (Ref 3) Drinking W

ater Exposure : To estimate drinking water exposure to DAED, EDWCs were generated by BPPD using the OPP’s standard suite of models. The generated EDWCs were used in DEEM - FCIDTM Version 3.16 to calculate the potential dietary exposure of DAED in drinking water sources. The screening model FQPA Index Reservoir Screening Tool (FIRST) was used to calculate surface water EDWCs. The FIRST model and its description are availabl e at the following EPA website: http://www.epa. gov/oppefed1/models/water/ .The following inputs were used to estimate surface water EDWCs in the FIRST screening model: 1) 0.26 lbs a.i. (DAED)/acre based on highest support use rate for turf and landscape applications on the proposed EP label, 2) maximum number of applications of 121 per ye ar and application interval of 3 day s for turf and landscape applications on the proposed EP label, 3) OPP’s EFED default percent cropped area (PCA) factor of 0.87 for turf uses, 4) Koc of 25 ml/g, 5) 35 day s for soil ae robic metabolic half - life (EFED default foliar dissipation half - life value used in T - REX modeling), 6) EFED default of 2 day s for non wetted - in pesticide, 7) EFED default for ground spray application of 6.4% for %drift and 99% for application efficiency , 8 ) no soil incorporation depth (0.0 inches), 9) water solubility of 2 g/l (converted to 2002 ppm), 10) 70 day s for aerobic aquatic metabolic half - life (EFED default of 2x the soil aerobic metabolic half - life if unknown), and 11) 365 day s for photoly sis half

- life. The inputs for Koc and water solubility were taken from the HERA document (2002) and the Agency ’s Registration Review Preliminary Work Plan (PW P) on TAED (EPA, 2014). For the photoly sis half

- life input, the Agency

used 365 day s as data/information l isted in the HERA document (2002) and the Agency ’s PWP on TAED (2014) indicate that DAED appears to be stable in this setting. Chronic exposure of DAED in surface drinking water sources is represented by annual average concentration s estimated by the FIRST model. Upper - bound Tier I modeling predicts that the concentrations of DAED in surface drinking water sources are not likel y to exceed 74 ppb (or 0.074 ppm) for the chronic annual average concentrations. DEEM -FCIDTM Version 3.16 Results using Residues from TREX and FIRST Modeling Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose that EPA has concluded will result i n no unreasonable adverse health effects). This dose is12 referred to as the population adjusted dose (PAD). The PAD is equivalent to the point of departure (POD, NOAEL, LOAE L, e.g.) divided by the required uncertaint y or safet y factors. For non - cancer chron ic exposures, EPA is concerned when estimated dietary risk exceeds 100% of the PAD. References that discuss chronic risk assessments in more detail are available on the EPA/pesticides web site: “Available In formation on Assessing Exposure from Pesticides, A User’s Guide,” 21 - JUN - 2000, web link: http://www.epa.gov/fedrgstr/EPA - PEST/2000/July /Day - 12/6061.pdf; or see SOP 99.6 (20 - AUG - 1999). To evaluate chronic dietary exposure to residues o f DAED when used as a pesticide on food (rice and strawberry

crops) and drinking water sources, the Agency conducted a chronic dietary exposure assessment using the Dietary

Exposure Evaluation Model software with the Food Commodity Intake Database DEEM FCI DTM, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. The data are based on the reported consumption of more than 20,000 individuals over two non - consecutive survey day s. Foods “as consumed” (e.g., apple pie) are linked to EPA - defined food commodities (e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) u sing publicl y available recipe translation files developed jointly b y USDA/ARS and EPA. For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups. Based on anal ys is of the 2003 - 2008 WWEIA consumption data, which took into account dietary

patterns and survey r espondents, EPA concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 y ear old), children 1 - 2, childr en 3 - 5, children 6 - 12, youth 13 - 19, adults 20 - 49, females 13 - 49, and adults 50+ years old. For a chronic dietary

exposure assessment, an estimate of the residue level in each food or food - form (e.g., orange or orange juice) on the food commodity residue l ist is multiplied by the average dail y consumption estimate for that food/food form to produce a residue intake estimate. The resulting residue intake estimate for each food/food form is s ummed with the residue intake estimates for all other food/food form s on the commodity

residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/kg body weight/day

and as a percent of the chronic Population Adjusted Dose (cPAD). This procedure is performed for each population subgroup. The Agency used the following inputs for the DEEM - FCIDTM anal ys is: 1) calculated residue of 2.23 ppm for rice and 8.79 ppm for strawberries from the T - REX modeling, 2) 0.074 ppm for “water, direct, all sources” and “water, indirect, all sources” food categorie s for drinking water from the FIRST modeling, and 3) the chronic Reference Dose (cRfD) or chronic Population Adjusted Dose (cPAD) of 0.09 mg/kg bw/day . A PAD is an estimate (with consistent applications of generall y order - of

- magnitude uncertaint y factors) of a dail y dietary exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The uncertainty factor (UF) that is generally used is 1000, which represents 10X uncertainty factor for interspecies (extrapolation from animal data to humans), 10X uncertainty factor for intraspecies (variability

of humans), and the 1 0X FQPA safet y factor. The PAD is represented by the equation below: Point of Departure (e.g., NOAE L) PAD = ------------------------------------------

Uncertaint y Factors (e.g., 1000) The chronic PAD (cPAD) was calculated b y dividing the NOAEL of 90 mg/kg/day from the 90 - day oral toxicity study on TAED by

the uncertaint y factor of 1000, which result s in a cPAD of 0.09 mg/kg bw/day . DEEM - FCIDTM anal ys is calculates a percent of the cPAD (%cPAD) for each population subgroup by dividing the dietary

exposure (estimated in DEEM - FCIDTM) b y the cPAD and multiplying the result by 100%. EPA is concerned when die tary risk exceeds 100% of the cPAD. The %cPAD is represented by the equation below:13 Exposure %cPAD = ------------- * 100%

cPAD Based on the residues estimated in the T - REX and FIRST models from the application rates and intervals on the proposed EP label, the %cPAD is the highest in the population subgroups, Non - nursing infants and Children (age 1 - 2), at 9.2%. As stated above, for chronic dietary assessments, the Agency is concerned when dietary

risks exceeds 100% of the cPAD; therefore, the calcu lated %cPAD for DAED is well below the Agency ’s LOC. Based on the preceding information, if dietary exposure to humans occurs, the Agency has determined that there is reasonable certainty of no harm to humans when exposed to residues of DAED, the metabol ite of TAED, from pesticidal use from this particular pesticide product when label instructions are followed. ( Ref. 3 ) Other Non - occupational Exposure : The residential post - application exposure risk assessment was conducted using a POD of 90 mg/kg bw/day (the NOAEL from the 90 - day oral toxicity study) for the incidental oral route of exposure. The short (1 - 30 day s) term incidental oral endpoint selected f or DAED is appropriate for the duration of exposure as well as it is protective for the population of concern (young children). This endpoint is also protective of the maternal and developmental effects observed in the developmental toxicity

study (MRID 45 299704). BPPD used the POD inputs in the residential post application exposure calculation spreadsheet developed in the OPP’s HED (spreadsheets available at the following EPA website: http://www.epa.gov/pesticides/science/residential - exposure - sop.html ). The body weight of 11 kg (age 1 to < 2 years) was used for incidental oral exposure scenario since the endpoint selected was not developmental and/or fetal effects. The body weights of: 80 kg (adults), 57 kg (age 11 to < 16 years), and 32 kg (age 6 to < 11 y ears) were not used in this residential post - application exposure scenario since the onl y endpoint selected was for short (1 - 30 day s) term incidental oral exposure. The app lication rate used for the residential exposure was the maximum application rate on the turf and landscape sub label of 0.26 lbs a.i./acre. The application rate input was calculated by multiplying the maximum application rate for the turf and landscape use by 10%. The 10% represents the concentration of DAED that is applied to the turf and landscape based on the known chemical reaction of the EP with water in the tank mix and the results of the tank mix study which showed that at the time of application, DA ED is approximately

50% of the initial amount of TAED in the product. The Agency ’s LOC is 1000 for residential post - application incidental oral exposure. MOEs were greater than the Agency ’s LOC of 1000 for all residential post - application incidental oral exposure scenarios. The exposure scenario with the lowest MOE was hand to mouth for the population subgroup, children (age 1 to < 2), of 23000. Based on the results of the residential post - application incidental oral exposure risk assessment, unreasonable adverse effects for children (age 1 to < 2) to DAED are not anticipated when the pesticide product is used according to label instructions. (Ref 3 ) **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 Agency

consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity .”14 EPA has not found TAED nor its metabolite, DAED to share a common mechanism of toxicity with any other substances, and TAED nor its metabolite, DAED does not appear to produce a toxic metabolite produced b y other substances. For the purpos es of this tolerance action, therefore, EPA has assumed that TAED nor its metabolite, DAED does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of t oxicity and to evaluate the cumulative effects of such chemicals, see EPA’s website at http://www.epa.gov/pesticides/cumulative . **V. Determination of Safety for the United States Population, Infant**  **s 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, EPA shall assess the available information about consumption patterns among infants and chil dren, 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) provid es that 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 EPA determin es 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 appl yi ng this provision, EPA either retains the default value of 10X, or uses a different additional or no safet y. Based on the currentl y availabl e toxicity data, EPA has retained the FQPA Safety Factor (10X). T he available toxicology database for TAED indicate a potential increase susceptibility under FQPA . In the available developmental study , the maternal effects of dead fetuses and decrease food consumption were observed along with developmental effects of ↓ fetal weight and placental weight s. In addition, since a 2 generation reproductive study is not available, the severit y and extend of these toxicity effects cannot fully be examined. Therefore, to be protective of sensitive subpopulations, including infants and children, the 10X FQPA safet y factor was retained. Should additional toxicity informatio n on TAED become available to the Agency , retaining the FQPA safet y factor will be determined. **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 aggreg ate exposure to residues of Tetraacet yl ethylenediamine (TAED) and its metabolite Diacet yl eth yl enediamine (DAED ) . Therefore, an exemption is established for residues of the pesticide Tetraacetylethylenediamine (TAED) and its metabolite Diacet yl ethylenediami ne (DAED ) in or on rice and strawberries when used in accordance with label directions and good agricultural practices as a bactericide and a fungicide . **VII . References**  1. HERA. 2002. Human and Environmental Risk Assessment on ingredients of European household cleaning products. Targeted Risk Assessment of Tetraacetyl eth yl enediamine (TAED). December 2002 http://www.heraproject.com/files/2 - F - 04 - HERA%20TAED%20full%20web%20wd.pdf 2. Hill, E.F. 1993. Acute and subacute toxicology in evaluation of pesticide hazard to avian wildlife. In: Up and Down Procedure Peer Panel Report, July 25, 2000 Meeting, Appendix P - 3, National Toxicology

Program. P45 - P67. http://ntp.niehs.nih.gov/iccvam/docs/acutetox_docs/udpProc/udpfin01/append/AppP3.pdf15 3. U.S. EPA 2014. Memorandum from Colin G. Walsh to Menyon Adams. Science Review in Support of the Registration of Ato Cide (EPA File S ymbol No. 88306 - G), an End - Use Product (EP), Containing 42.50%, 19.99%, and 9.94% of Sodium Percarbonate, Tetraacetylethylenediamine (TAED), and Potassium Silicate as its Active Ingredient s (A.I.s) and Tolerance Exemption Petition Review in Support of TAED, and its Degradate, Diacet yl ethylenediamine (DAED) (First Food Use). U.S. Environmental Protection Agency Office of Pesticide Programs. August 26, 2014. 4. U.S. EPA 2014. Memorandum from Colin G. Walsh to Menyon Adams. Science Review in Support of the Registration of Ato Cide (EPA File S ymbol No. 88306 - G), an End - Use Product (EP), Containing 42.50%, 19.99%, and 9.94% of Sodium Percarbonate, Tetraacetylethyle nediamine (TAED), and Potassium Silicate as its Active Ingredient s (A.I.s) and Tolerance Exemption Petition Review in Support of TAED, and its Degradate, Diacet yl ethylenediamine (DAED) (First Food Use). U.S. Environmental Protection Agency Office of Pestic ide Programs. February 27, 2014. 5. U.S. EPA. 2012 a . Memorandum from Colin G. Walsh to Menyon Adams. Science Review in Support of the Registration of Ato Cide (EPA File Sy mbol No. 88306 - G), an End - Use Product (EP), Containing 42.50%, 19.99%, and 9.94% of Sodium Percarbonate, Tetraacetylethylenediamine (TAED), and Potassium Silicate as its Active Ingredient s (A.I.s). U.S. Environmental Protection Agency Office of Pesticide Programs. August 8 , 2012. 6. U.S. EPA. 2012 b . Memorandum f rom Colin G. Walsh to Menyon Adams. Science Review in Support of the Registration of Ato Cide (EPA File Sy mbol No. 88306 - G), an End - Use Product (EP), Containing 42.50%, 19.99%, and 9.94% of Sodium Percarbonate, Tetraacetylethylenediamine (TAED), and Potass ium Silicate as its Active Ingredient s (A.I.s). U.S. Environmental Protection Agency Office of Pesticide Programs. November 28 , 2012. 7. U.S. EPA. Dietary

Exposure Evaluation Model - Food Commodity Intake Database (DEEM FCID)/Calendex http://www.epa.gov/pesticides/science/deem/ 8. U.S. EPA. FIRST (FQPA Index Reservoir Screening Tool) http://www.epa.gov/oppefed1/models/water/ 9. U.S. EPA. SCI - GROW (Screening Concentration In Ground Water) http://www.epa.gov/oppefed1/models/water/ 10. U.S. EPA. Occupational Pesticide Post - application Exposure Data http://www.epa.gov/pesticides/science/post - app - exposure - data.html 11. U.S. EPA. Standard Operating Procedures (SOP) for Residential Pesticide Exposure Assessment http://www.epa.gov/pesticides/science/residential - exposure - sop.html