Document ID: EPA-HQ-OPP-2013-0237-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-05T04:00Z

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

EPA Registration Division contact: William Cutchin, 703-305-7990

TEMPLATE:

Becker Underwood, Inc., 801 Dayton Avenue, Ames, IA. 50010

2E8096

	EPA has received a pesticide petition (2E8096) from Becker Underwood, Inc., 801 Dayton Avenue, Ames, IA. 50010 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 to establish an exemption from the requirement of a tolerance for ammonium persulfate (APS; CAS RN 7727-54-0) in or on food crops under 40 CFR 180.910 for pre- and post- harvest applications at 0.05% in pesticide formulations. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. Not applicable to this petition.

	2. Analytical method. Not applicable to this petition.

	3. Magnitude of residues. Not applicable to this petition.

B. Toxicological Profile

	1. Acute toxicity. Exposure to APS will occur mainly through the diet. Acute toxicity testing of ammonium persulfate was performed by FMC Corporation and reviewed by OECD (OECD SIDS 2005). The LD50 for oral exposure to ammonium persulfate in the rat was 495 mg/kg bw (FMC 1991b cited in OECD 2005) to 700 mg/kg bw in females rats (FMC 2001 cited in OECD SIDS 2005) and 742 mg/kg bw in males rats in the same study. In another acute study of ammonium persulfate toxicity, published prior to the OECD review, the acute oral LD50 of ammonium persulfate was reported to be 689 mg/kg bw in rats by an unspecified oral route (ACGIH 1986, cited by CIR 2001) and 820 mg/kg bw when administered by gavage (Smyth et al. 1969, cited by CIR 2001). LD50 values of 600 mg/kg bw and 495 mg/kg bw were also reported in males administered distilled water and females administered a tap water solution of 25% weight/volume (CTFA 1994, cited by CIR 2001). Other salts of persulfate including sodium and potassium had similar, albeit slightly higher, LD50 values.

	2. Genotoxicty. All mutagenicity and genotoxicity studies reviewed for APS were negative, including reverse mutation assays in bacteria with and without metabolic activation, and assessment of chromosomal aberrations in Chinese hamster fibroblast cells. Genotoxicity studies of other persulfate salts, sodium and potassium, were also negative.

	3. Reproductive and developmental toxicity. In the studies identified, APS treatment did not result in toxic effects to reproduction or fetal development. The reproductive and developmental toxicity of ammonium persulfate has been tested in rats (12/sex/group) (Weaver 2004, cited in OECD SIDS 2005). The original citation was not located in the OECD SIDS assessment report, however, references to FMC studies for dose selection and the inability to locate the study through publically available databases suggests that this may have been a proprietary study provided to OECD. Male rats were administered ammonium persulfate at levels of 0, 40, 100, or 250 mg/kg bw/day through the diet for two weeks prior to mating and for an additional 3 and a half weeks thereafter. Females were exposed following mating with treated males and through gestation until the fourth day of lactation. There were no effects observed on the male reproductive organs or spermatogenesis at any stages. Pregnancy rates were similar between treated and control groups, and there were no treatment-related effects on mortality, number of live pups or live pups surviving at 4 days. There were also no treatment-related clinical signs or necropsy findings in the pups. Pups from the high dose group had statistically significantly depressed body weights on day 0, however, by day 4, the body weight depression had resolved. This effect was not considered adverse because of its transient nature. The NOAEL for embryo/fetal viability was determined to be greater than or equal to the highest dose tested, 250 mg/kg bw/day, and the NOAEL for reproductive  performance in the FO generation was determined to be greater than or equal to the high dose as well, 250 mg/kg bw/day.

	4. Subchronic toxicity. The repeat dose toxicity of APS and other persulfate salts has been reviewed by the CIR (2001), OECD (OECD SIDS 2005), and NICNAS (2001). Studies of oral and in11alation exposures exist. In a study of the oral toxicity of APS, male CR-CD rats were fed a diet containing 0, 100, 300, or 600 ppm for 28 days. A LOAEL of 600 ppm was concluded for decreased adrenal weight to body weight ratio (CTFA 1994, cited in CIR 2001, and FMC 1979b, cited in OECD SIDS 2005 and NICNAS 2001). The NOAEL was 300 ppm APS, and this is approximately equal to a dose of 41 mg/kg bw/day. No deaths occurred during the dosing period and no gross lesions were observed upon necropsy. In an earlier study, six young dogs (weight, species and sex not specified) were fed a diet containing flour treated with ammonium persulfate at a level of 15 g/45 kg for 6 days per week for 3 months. The study revealed no signs of toxicity (Arnold 1949). Repeat dose oral toxicity studies of sodium and potassium persulfate were also reviewed. Similar to the acute studies of APS compared to the other persulfate salts, the NOAEL and LOAEL values for the other salts were slightly higher, although of similar magnitude. APS is irritating to the skin and in situations of repeated exposure contact dermatitis has been documented in the occupationally exposed, in particular in hairdressers (OECD SIDS 2005, NICNAS 2001, CIR 2001). Repeat dose animals studies support this and also indicate that APS has the potential to be sensitizing following repeated dermal contact. Case reports and clinical studies also indicate that inhalation sensitization is possible. No reports of sensitization following oral exposure were identified. It is unlikely that APS could function as a sensitizer by oral exposure routes.

	5. Chronic toxicity. Oral and inhalation studies of the carcinogenic and promoting potential of APS do not exist; however, the carcinogenic and promoting potential of APS was tested in a dermal non-guideline study by Kurokawa et al. (1984). In this study APS applied to the skin of mice biweekly for 51 weeks following initiation with the carcinogen dimethylbenzanthracene (DMBA), did not result in enhanced tumor promotion above control levels. Additionally, APS did not display activity as a complete carcinogen when APS treatment alone was tested.

	6. Animal metabolism. Metabolism of APS proceeds through dissociation of the salt, following by buffering and detoxification of its metabolites sulfate anion and ammonium cation.

	7. Metabolite toxicology. As noted in the United Nations Environment Programme (UNEP) publication OECD SIDS (2005), metabolism of ammonium persulfate is unlikely to generate toxic metabolites. As noted below the ammonium cation should be physiologically buffered and would have negligible effect on the mammalian toxicity. The persulfate anion should also be converted in vivo extracellularly through the formation of hydrogen peroxide to oxygen and water without apparent mammalian toxicity. If formed, the hydrogen peroxide would be rapidly metabolized to oxygen and water. 

      Moreover, the formation of two equivalents of sulfate anion is also not relevant or likely to affect mammalian toxicity since sulfate anion is a naturally occurring component in many foods and also a human metabolite formed from in vivo sulfur oxidation. Sulfate is also highly water soluble, and is therefore eliminated in the urine unchanged. Sulfate anion is also an important conjugate in the Phase II conjugation/elimination of oxidized (OH) aromatic ring metabolites and for hydroxyl steroid hormones, such as estrogen, where it acts as a transport agent to target organ tissue receptors (OECD SIDS 2005).

	8. Endocrine disruption. Based on structure the structure of APS, APS exposure is not reasonably anticipated to result in endocrine disruption. It is a simple salt and does not belong to a family of endocrine disrupting chemicals, nor does it possess structural features that would suggest this potential. Furthermore, the lack of effects observed in reproductive and development repeat dose studies indicates that APS does not have the potential to act as an endocrine disruptor.

C. Aggregate Exposure

	1. Dietary exposure. The dietary exposures (food plus drinking water) for APS are expressed as a percentage of the proposed aPAD and cPAD for the general U.S. population and children 1-2 years old, the most highly exposure subpopulation. Based on I-DEEM screening level calculations with adjustment for the maximum concentration of APS in pesticide formulations of 0.05%, chronic dietary exposures are estimated to be 0.6% of the cPAD for the general U.S. population, 1.8% of the cPAD for all infants (<1 year old) and 0.9% of the cPAD for children 1-2 years old. Acute (95[th] percentile) dietary exposures are estimated to be 0.2% of the aPAD for the general U.S. population, 0.8% of the aPAD for all infants (<1 year old) and 0.4% of the aPAD for children 1-2 years old. These estimates demonstrate that the I-DEEM screening-level chronic and acute dietary exposure estimates (food plus drinking water) are below the cPAD and aPAD and are therefore below the level of concern for all U.S. subpopulations.

	i. Food. The available data demonstrate that the I-DEEM screening level chronic dietary (food and drinking water) are well below 100% of the cPAD, and are therefore below EPA's established level of concern for all populations. 

	ii. Drinking water. See above, "i. Food"

	2. Non-dietary exposure. APS occurs in many available non-food and food products, which humans may be exposed to on a daily basis without apparent harmful effects. As noted in the UNEP publication OECD SIDS (2005), metabolism of ammonium persulfate is unlikely to generate toxic metabolites. APS is already approved by EPA for non-food use, and based on the dietary risk assessment uses of APS in food use pesticide formulations would not result in undue exposure and risks to infant and or adult populations Furthermore, considering that the food uses are very low, there is ample room in the MOE to safely accommodate aggregate exposures.

D. Cumulative Effects

	Section 408(b )(2)(D)(9v) 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." Unlike pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not conducted a common mechanism of toxicity evaluation for APS. In addition, the OECD SIDS (2005) document for persulfates confirms that APS does not generate toxic metabolites. Thus, the Agency would assume that APS does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. A dietary exposure assessment using current EPA inert screening level methodology (I-DEEM) was conducted. Based on the conservative I-DEEM dietary exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population from the aggregate exposure to APS.

	2. Infants and children. The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safety factor may be reduced or removed. The susceptibility and uncertainty issues associated APS have been considered, and it is recommended that the FQPA safety factor be reduced to IX for the following reasons:

      :: The database is adequate and contains acute and repeat dose studies by different exposure routes and for related salts, as well as sensitization studies, a tumor promotion and carcinogenesis study, and a reproductive and developmental study.
      :: There was no evidence of reproductive or teratogenic effects for APS, indicating that women and developing children would not be particularly vulnerable to the effects of APS compared to other subpopulations.
      :: There was no evidence of effects on the nervous system in the acute, repeat dose or reproduction studies.
      :: There is no evidence of endocrine disruption in the reproductive and developmental studies.
      :: The quality of many of the studies was good and several were guideline studies or studies performed at organizations that commonly conduct studies according to GLP.

F. International Tolerances

	There are no known international tolerances for APS.