


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

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[Rosen's Inc.]

[Insert petition number]

	EPA has received a pesticide petition ([IN-xxx]) from Rosen's Inc., 700 SW 291 Hwy, Suite 204, Liberty, MO 64068 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.920 to establish an exemption from the requirement of a tolerance in or on all raw agricultural commodities for the inert ingredient potassium polyaspartate (CAS Reg. No. 64723-18-8) when used as a complexing agent at no more than 10% 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.  Plant metabolism data are not required for the establishment of a tolerance exemption.

	2. Analytical method. An analytical method is not required when proposing an exemption form the requirement of a tolerance.

	3. Magnitude of residues. Magnitude of the residue studies are not required for the establishment of a tolerance exemption.

B. Toxicological Profile

	1. Acute toxicity.  The acute oral toxicity of sodium polyaspartate as an ~ 40% aqueous solution was tested in two acute oral toxicity studies.  In both studies the acute oral LD50 was greater than 5000 mg/kg (Toxicity Category IV).  In one of the studies, the LD50 was based on the weight of the dry material administered and the other on the amount of the solution administered.  Aspartic acid was also tested in an acute oral toxicity study at 2000 mg/kg which caused no mortality (Toxicity Category III).  

In an acute dermal toxicity study on aspartic acid, the acute dermal LD50 was greater than 5000 mg/kg (Toxicity Category IV).  

The acute inhalation LC50 of the 40% aqueous solution of sodium polyaspartate was greater than 5.1 mg/L (Toxicity Category IV).  This same aqueous solution of sodium polyaspartate was neither a dermal irritant nor an eye irritant (Toxicity Category IV).  

Aspartic acid was not a dermal irritant (Toxicity Category IV) and was slightly irritating to the eye (Toxicity Category III).  In addition, aspartic acid was not a dermal sensitizer in the guinea pig maximization test.  

Overall, the sodium salt of polyaspartate and aspartic acid exhibit low acute toxicity via inhalation, dermal and oral routes.  Sodium polyaspartate (40% aqueous solution) is not a dermal or eye irritant.  Aspartic acid is not a dermal irritant, is a slight eye irritant and is not a dermal sensitizer.  Reading across the database, potassium polyaspartate can be considered to have low acute oral, dermal and inhalation toxicity, and is not likely to be dermal or eye irritant or a dermal sensitizer based on results of studies conducted on sodium polyaspartate and L-aspartic acid.

	2. Genotoxicity. Potassium polyaspartate was tested in an Ames Salmonella assay for its ability to induce gene mutations and in an in vitro micronucleus assay in human lymphocytes.  The results of both studies were negative.  In addition, L-aspartic acid and N-acetyl-L-aspartic acid were negative in the Ames Salmonella assay up to the limit dose of 5000 ug/plate and in an in vivo mouse micronucleus assay up to the limit dose of 2000 mg/kg.  The rationale for inclusion of L-aspartic acid is as follows.  In a simulated gastric digestion study of potassium polyaspartate using porcine pepsin and pancreatin, less than 4% of was broken down to aspartic acid.  The majority of the material remained as polyaspartate following the in vitro simulated gastric digestion.  Based on the results of an in vitro study using Caco-2 cell absorption model, it was concluded that negligible absorption of polyaspartate would occur in vivo; however, in vivo absorption studies have not been conducted.  As noted in a Joint FAO/WHO Expert Committee on Food Additives (JECFA) document, should polyaspartate be orally absorbed microbial fermentation in the human colon could occur and there could be resulting exposure to L- and D-aspartic acid.  Consequently studies, on L-aspartic acid are summarized and L-aspartic acid is being used as a possible surrogate for potassium polyaspartate.  Studies on N-acetyl-L-aspartic acid are summarized since it is metabolized in vivo to L-aspartic acid making it a surrogate for potassium polyaspartate as well.  Based on the results of these studies, it can be concluded that based on a weight of the evidence evaluation that potassium polyaspartate has no genotoxic potential.

	3. Reproductive and developmental toxicity. Developmental/reproductive toxicity studies were not available on potassium polyaspartate; however, reproduction and fertility effects studies were available on L-aspartic acid and N-acetyl-L-aspartic acid.  

L-Aspartic acid is being used as a surrogate for potassium polyaspartate based on the following rationale.  In a simulated gastric digestion study of potassium polyaspartate using porcine pepsin and pancreatin, less than 4% of potassium polyaspartate was broken down to aspartic acid.  The majority of the material remained as polyaspartate following the in vitro simulated gastric digestion.  Based on the results of an in vitro study using Caco-2 cell absorption model, it was concluded that negligible absorption of polyaspartate would occur in vivo; however, in vivo absorption studies have not been conducted.  As noted in a Joint FAO/WHO Expert Committee on Food Additives (JECFA) document, should polyaspartate be orally absorbed, microbial fermentation in the human colon could occur and there would be exposure to L- and D-aspartic acid.  Consequently, studies on L-aspartic acid are also summarize herein and L-aspartic acid is being used as a surrogate for potassium polyaspartate.  Studies on N-acetyl-L-aspartic acid are summarized since it is metabolized in vivo to L-aspartic acid making it a surrogate for potassium polyaspartate as well.

The L-Aspartic acid study was conducted according to OECD guideline 416 with additional response variables.  Male and female Sprague-Dawley rats (25/sex/group) were administered L-aspartic acid in the diet at target levels of 0 and 500 mg/kg bw/day over two generations.  The rats were exposed to the diets for 10 weeks prior to mating.  The day of parturition was defined as day 1 of lactation.  To avoid potential biases in pup viabilities and body weight gains, F1 and F2 generations litters were not culled during the lactation period.  Both generations were weaned on postnatal day (PND) 22 through 25.  Pups were assigned to one of 4 subsets (1 pup/sex/litter/subset, when possible).  Clinical observations and body weight and food consumption were conducted according to OECD guideline 416.  Ophthalmological examinations were performed for all rats assigned to F1 generation Subset 3 between PNDs 22-27 and PNDs 74-82 and F2 generation Subset 7 between PNDs 22-28 and PND 80.  Estrous cyclicity was evaluated for P and F1 generation dams before the scheduled cohabitation period.  Male and female rats from F1 generation Subset 3 and F2 generation Subsets 7 and 8 were observed for the age at which sexual maturation began, age of preputial separation (PS) and vaginal patency (VP), respectively.  Body weight was recorded on the day of sexual maturation was observed.  Behavioral and developmental assessment of F1 (Subset 3) and F2 (Subset 7) rats was conducted at various times depending on the variable.  Motor activity assessment was conducted at weaning on days 22 and 61 postpartum.  The same rats tested on day 22 were tested again on day 61.  The same rats were also tested for passive avoidance beginning on days 23 to 25 and water maze performance beginning on days 59 to 63 postpartum.  Following sacrifice, the following organs were weighed:  brain, pituitary gland, liver, kidney, ovaries and uterus with cervix, epididymides testes, prostate and seminal vesicles with coagulating gland.  Histopathology was conducted on P generation rats and rats from the progeny randomly selected from subsets assigned to this evaluation (F1 generation Subsets 2 and 4; F2 generation Subsets 6 and 8).  With the exception of salivary glands, tissues only from the control group and the 500 mg N-acetyl-L-aspartic acid/kg bw/day were examined.  The salivary glands from all exposure groups from rats in Subset 3 (F1 generation) and Subset 7 (F2 generation) were evaluated.  The following other tissues were examined:  pituitary gland, gross lesions, ovaries, oviducts, mammary gland vagina, uterus, cervix, testes, epididymides seminal vesicles, coagulating land and prostate.  Neurohistopathology was conducted on randomly selected rats (10/sex/group for F1 generation Subsets 1 and 3 and F2 generation Subsets 5 and 7).  Tissues from the control and high dose N-acetyl-L-aspartic acid groups were examined as well as those from the aspartic acid comparative control group.

The nominal dose of 500 mg/kg bw/day corresponded to an actual average dose of 462.9 mg/kg bw/day in males and 629.8 mg/kg bw/day in females. Compared to the control group, no effects were observed in the L-aspartic acid group on mortality, clinical signs, body weight, food consumption, behavioral assessment, reproductive parameters, sexual maturation, estrous cycling, neurohistopathological evaluations, gross necropsy or histopathology of selected tissues/organs.  In the P generation, lower mean absolute pituitary weights and lower mean pituitary weight relative to terminal body weight were observed in male rats.  The effects on pituitary weights were not considered to be treatment related because the differences were not dose related and because the individual data values were within the range of the historical control values.  In addition, there was no histopathology of the pituitary. The NOAEL was considered to be >462.9 mg/kg bw/day in males and >629.8 mg/kg bw/day in females.

This N-acetyl-L-aspartic acid study was conducted according to OECD guideline 416 with additional response variables.  Male and female Sprague-Dawley rats (25/sex/group) were administered N-acetyl-L-aspartic acid in the diet at target levels of 0, 100, 250 and 500 mg/kg bw/day over two generations.  The rats were exposed to the diets for 10 weeks prior to mating.  The day of parturition was defined as day 1 of lactation.  To avoid potential biases in pup viabilities and body weight gains, F1 and F2 generations litters were not culled during the lactation period.  Both generations were weaned on postnatal day (PND) 22 through 25.  Pups were assigned to one of 4 subsets (1 pup/sex/litter/subset, when possible).  Clinical observations and body weight and food consumption were conducted according to OECD guideline 416.  Ophthalmological examinations were performed for all rats assigned to F1 generation Subset 3 between PNDs 22-27 and PNDs 74-82 and F2 generation Subset 7 between PNDs 22-28 and PND 80.  Estrous cyclicity was evaluated for P and F1 generation dams before the scheduled cohabitation period.  Male and female rats from F1 generation Subset 3 and F2 generation Subsets 7 and 8 were observed for the age at which sexual maturation began, age of preputial separation (PS) and vaginal patency (VP), respectively.  Body weight was recorded on the day of sexual maturation was observed.  Behavioral and developmental assessment of F1 (Subset 3) and F2 (Subset 7) rats was conducted at various times depending on the variable.  Motor activity assessment was conducted at weaning on days 22 and 61 postpartum.  The same rats tested on day 22 were tested again on day 61.  The same rats were also tested for passive avoidance beginning on days 23 to 25 and water maze performance beginning on days 59 to 63 postpartum.  Following sacrifice, the following organs were weighed:  brain, pituitary gland, liver, kidney, ovaries and uterus with cervix, epididymides testes, prostate and seminal vesicles with coagulating gland.  Histopathology was conducted on P generation rats and rats from the progeny randomly selected from subsets assigned to this evaluation (F1 generation Subsets 2 and 4; F2 generation Subsets 6 and 8).  With the exception of salivary glands, tissues only from the control group and the 500 mg N-acetyl-L-aspartic acid/kg bw/day were examined.  The salivary glands from all exposure groups from rats in Subset 3 (F1 generation) and Subset 7 (F2 generation) were evaluated.  The following other tissues were examined:  pituitary gland, gross lesions, ovaries, oviducts, mammary gland vagina, uterus, cervix, testes, epididymides seminal vesicles, coagulating land and prostate.  Neurohistopathology was conducted on randomly selected rats (10/sex/group for F1 generation Subsets 1 and 3 and F2 generation Subsets 5 and 7).  Tissues from the control and high dose N-acetyl-L-aspartic acid groups were examined as well as those from the aspartic acid comparative control group.

Actual consumed doses across generations were 0, 92.8, 231.8 and 471.2 mg/kg bw/day in males and 0, 119.5, 306.5 and 632.8 mg/kg bw/day in females for the 0, 100, 250 and 500 mg/kg bw/day groups, respectively.  Compared to the control group, no effects were observed in the N-acetyl-L-aspartic acid groups on mortality, clinical signs, body weight, food consumption, behavioral assessment, reproductive parameters, sexual maturation, estrous cycling, neurohistopathological evaluations or gross necropsy.  In the P generation, lower mean absolute pituitary weights and lower mean pituitary weight relative to terminal body weight were observed in male rats in the 100 and 500 mg/kg bw/day groups.  The effects on pituitary weights were not considered to be treatment related because the differences were not dose related and because the individual data values were within the range of the historical control values.  In addition, there was no histopathology of the pituitary observed in these test groups.  An increase in the incidence of minimal acinar cell hypertrophy of the submandibular salivary gland was observed in high dose males of subsets 3 and 7 and in high dose females of subset 3.  The study authors concluded that this observation is not an adverse effect since salivary gland hypertrophy is commonly observed in laboratory animals in response to different physical and chemical stimuli, is considered to be an adaptive physiological mechanism and there were no microscopic findings of inflammation, degeneration, necrosis or hyperplasia in the salivary gland indicative of cytotoxicity.   The NOAEL for N-acetyl-L-aspartic acid in this study was considered to be 500 mg/kg bw/day or 471.2 mg/kg bw/day in males and 632.8 mg/kg bw/day in females.


	4. Subchronic toxicity. Potassium polyaspartate (A-5D K SD; 94%) was administered to Wistar rats by gavage in a 14-day range-finding study at dose levels of 0 (analytical grade water), 60, 125, 250, 500 or 1000 mg/kg bw/day to determine dose levels for a subsequent 90-day repeated dose oral toxicity study.  No mortality occurred during the study nor did any treatment-related clinical signs.  Body weights and food consumption were comparable across dose groups.  Eosinophilic count was statistically decreased in 500 mg/kg bw/day males and 125 mg/kg bw/day females.  This finding was not considered to be treatment related because there was no dose response.  In males, AST was statistically decreased at 125 mg/kg bw/day and at 1000 mg/kg bw/day, glucose was statistically decreased at 250 mg/kg bw/day and urea nitrogen and urea were statistically increased at 500 mg/kg bw/day.  In females, albumin was statistically increased at 125 and 1000 mg/kg bw/day and total cholesterol was statistically increased at 125 and 500 mg/kg bw/day.  The clinical chemistry findings in males and females were not considered to be treatment related because of a lack of dose response for all parameters which were statistically impacted.  Absolute kidney weights were statistically increased in females at 500 and 1000 mg/kg bw/day without a dose response.  In males, relative kidney weight was statistically increased at 60, 250, 500 and 1000 mg/kg bw/day and in females at 500 and 1000 mg/kg bw/day.  There were no findings upon gross necropsy.  Based on the results of this study, dose levels of 0, 250, 500 and 1000 mg/kg bw/day were selected for the 90-day study gavage study.  

The 90-day study was conducted according to OECD guideline 408.  Male and female Wistar rats (10/sex/group) were administered the test material by gavage at doses of 0 (analytical grade water), 250, 500 and 1000 mg/kg bw/day for 90 days.  Additional groups of 5 rats/sex/group received the vehicle or 1000 mg/kg bw/day of the test material were observed for an additional 28 days following the 90-day dosing period.  Dose levels were selected based on the results of a 14-day dose range finding study, the results of which are summarized above.  Rats were checked for mortality twice per day and examined for clinical signs once daily.  They were subjected to a detailed clinical examination before initiation of treatment and weekly thereafter.  Ophthalmoscopic examinations were conducted prior to treatment and study termination on the control and high dose rats.  During the 13th week of dosing, all animals were examined for assessment of sensory reactivity, grip strength and motor activity.  Body weights were recorded before initiation of treatment and weekly thereafter and at necropsy.  Food consumption was recorded weekly.  On study day 90 and at termination of the recovery period, the stage of estrous cycle of all females was determined from vaginal smears.  Hematology (hemoglobin, packed cell volume, red cell count, white cell count, MCV, MC, MCHC, neutrophils, lymphocytes, eosinophils, monocytes, basophils and platelet count), coagulation parameters (prothrombin time and activated partial thromboplastin time), clinical chemistry (total protein, albumin, globulin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, glucose, urea nitrogen, urea, creatinine, total bilirubin, calcium, phosphorous, total cholesterol, triglycerides, triiodothyronine, thyroxine, TSH, sodium and potassium) and urine (color, appearance, specific gravity, pH, protein, glucose, ketone, bilirubin, urobilinogen, nitrite, blood, leucocytes, epithelial cells, casts, crystals and volume) parameters were evaluated at study termination.  At the end of the treatment period or recovery period, rats were sacrificed and subjected to a complete necropsy.  The following organs were weighed:  kidneys, liver, adrenals, testes, epididymides, uterus, thymus, spleen, brain, ovaries and heart.  A complete set of organs/tissues were examined microscopically for all animals from the control and high dose group.  

There were no treatment-related effects on any parameter examined in this study, except perhaps for a decrease in % neutrophils in high dose males.  However, this value (20.36%) was at the high end of the normal range for this parameter in Wistar rats 19-21 weeks of age (normal range = 1-29%) as was the control value (29.53).  Another reference gave a mean of 20.7% + 6.5 for male Wistar rats.  In addition, it occurred in the absence of any other findings that could result from a significance decrease in neutrophils and was considered marginal in light of the control value.  Therefore, the decrease was considered unrelated to treatment and not of toxicological significance.  The NOAEL in the study was considered to be 1000 mg/kg bw/day in male and female Wistar rats.

L-Aspartic acid was also tested in a 90-day study in rats.  Male and female Fisher 344 rats (10/sex/group) were administered the test material in the diet at concentrations of 0, 0.05, 1.25, 2.5 or 5.0% for 90 days.  These concentrations were equivalent to 0, 26.9, 696.6, 1416.6 and 2770.2 mg/kg/day in males and 0, 28.7, 715.2, 1470.4 and 2965.9 mg/kg bw/day in females, respectively.  Rats were checked for mortality and examined for clinical signs once daily.  Body weights and food consumption were recorded weekly.  Hematology (hemoglobin, red cell count, white cell count, MCV, MC, MCHC, differential leukocyte counts and platelet count), clinical chemistry (total protein, albumin, globulin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, glucose, blood urea nitrogen, uric acid, creatinine, total bilirubin, calcium, phosphorous, total cholesterol, triglycerides, sodium and potassium) and urine (urobilinogen, occult blood, bilirubin ketone, glucose, protein, pH and nitrous acid) parameters were evaluated at study termination.  At the end of the treatment period or recovery period, rats were sacrificed and subjected to a complete necropsy.  The following organs were weighed:  brain, thyroids with parathyroids, heart, spleen, liver, adrenals, kidneys, testes, ovaries and uterus.  A complete set of organs/tissues were examined microscopically.

No mortality occurred during the study nor were there any treatment-related clinical signs of toxicity.  Body weights and food consumption were unaffected by treatment.  In male rats, RBC values of the 1.25% and 5.0% groups, and HCT for the 1.25% or greater groups were significantly increased compared to control values.  Values for MCH of the 0.05%, 1.25% and 5.0% groups, and MCHD of the 0.05% or greater groups were significantly decreased compared to controls.  In female, MCH and MCHC values of the 5.0% group were also significantly decreased.  Data were not resented in the literature references; however, the study authors stated that all values were within the normal range of the historical control values.  In males, total cholesterol was statistically significantly decreased in the 2.5% and 5.0% groups and triglycerides were statistically decreased at all dietary concentration.  In females, total cholesterol was statistically increased at the highest dietary concentration and triglycerides were statistically decreased at 1.25% and above, blood urea nitrogen was statistically decreased at the highest dietary concentration, uric acid and creatinine were statistically decreased at 1.25% and above, potassium was statistically decreased at 2.5% and 5.0% and chloride was statistically decreased at 5.0%.  The study authors state that most of these values were within the range of the historical control values, except for triglycerides.  The values for triglycerides of the 2.5% and lower in males were higher than the historical control values.  In male rats, incidences of positive bilirubin in the 5.0% group and ketone and protein in the 1.25% group and above were significantly higher than the control group.  In females, incidences of positive ketone in the 1.25% and 2.5% group and ketone in the 2.5% group and above were also significantly increased.  In male rats, relative kidney weights were statistically increased in the 5.0% group.  No treatment-related macroscopic changes were observed in males or females.  In males, the incidence of regenerative renal tubules with tubular dilation was statistically increased in the 2.5% and 5.0% groups, submandibular gland acinar cell hypertrophy was significantly increase in the 5.0% group and parotid gland acinar cell hypertrophy was statistically increased in the 2.5% and 5.0% groups.  The α 2u-globulin immunohistochemistry for the kidney sections demonstrated positive granular signals in animals of both sexes, which was more marked in males and in both the treated and control rats. The study authors go on to say that there were neither quantitative nor qualitative differences in the outcome for α2u-globulin between the control and treated rats.  The acinar cell atrophy of the salivary gland was a diffuse change affecting the whole gland with serous acinar cells featuring granular cytoplasm and pyknotic nuclei located in the basal area. In female rats as in male rats, submandibular gland acinar cell hypertrophy was significantly increased in the 5.0% group and parotid gland acinar cell hypertrophy was significantly increased in the 2.5% and 5.0% groups.  The study authors concluded that the NOAEL for aspartic acid in this study was 696.6 mg/kg bw/day in males and 715.2 mg/kg bw/day in females based on histopathology of the kidney and possibly of the salivary gland observed at higher doses.  It should be noted that the authors of the literature reference on the 2-generation rat reproduction study on L-aspartic acid and N-acetyl-L-aspartic acid concluded that the observation of acinar cell hypertrophy of the salivary is not an adverse effect since salivary gland hypertrophy is commonly observed in laboratory animals in response to different physical and chemical stimuli, is considered to be an adaptive physiological mechanism and there were no microscopic findings of inflammation, degeneration, necrosis or hyperplasia in the salivary gland indicative of cytotoxicity .  The study authors go on to say that although changes in urinalysis and serum biochemistry were observed in males at 1.25% and higher, histopathology of the kidney only showed toxic changes in male rats at 1.25% and above to justify their selection of the NOAEL in this study.

	5. Chronic toxicity. No carcinogenicity data are available for polyaspartic acid.  Polyaspartic acid is not listed by the US National Toxicology Program (NTP) or the International Agency for Research on Cancer (IARC), and it is not regulated as a carcinogen by the US Occupational Safety & Health Administration (OSHA).  Studies on carcinogenicity should not be required based on a weight of evidence approach and taking into account that:
      ::	minimal proteolytic digestion of PPA was observed in vitro, and an in vitro study found no evidence of absorption across a human intestinal cell monolayer;
      ::	potassium polyaspartate was not genotoxic;
      ::	there was no evidence from subchronic studies of lesions that could lead to neoplasia through non genotoxic mechanisms, and
      ::	there was no evidence of adverse effects on reproductive tissues or the oestrus cycle in the 90-day toxicity study.

	6. Animal metabolism. No animal metabolism data are available for potassium polyaspartate.  However, as noted in a Joint FAO/WHO Expert Committee on Food Additives (JECFA) document, should polyaspartate be orally absorbed microbial fermentation in the human colon could occur and there could be resulting exposure to L- and D-aspartic acid.  Consequently L-aspartic acid is used as a possible surrogate for potassium polyaspartate. [14]C-L- aspartic acid is metabolized in rats to expired [14]CO2; lesser amounts of [14]C are incorporated into protein and lipid and/or excreted in the urine.  Aspartate also participates in the urea cycle. Based on the n-octanol-water partition coefficient (Log P <0; Log P -1.16), PPA will not bioaccumulate.

	7. Metabolite toxicology. No data are available.

	8. Endocrine disruption. There is no information available that links PPA or its surrogates L-aspartic acid and N-acetyl-L-aspartic acid to direct effects on the endocrine system.  A 90-day sub-chronic toxicity study with PPA (OECD TG 408) was modified to include assessment of additional parameters described in the more recent OECD TG 407 guideline on repeated-dose 28-day oral toxicity study in rodents.  These additional parameters are intended to place more emphasis on endocrine-related endpoints, and include assessment of thyroid hormones, oestrus cycles, and histopathology of tissues that may indicate endocrine activity of test substances.  No toxicity was observed at the maximum dose level of 1000 mg/kg bw/day (no toxicological hazard identified) in the 90-day study performed with potassium polyaspartate in rats and a NOAEL of 1000 mg/kg bw/day was determined for potassium polyaspartate. There is no histopathological or behavioral evidence of an endocrine function in any toxicity evaluations of L-aspartic acid and N-acetyl-L-aspartic acid conducted in laboratory animals.  The L-aspartic acid and N-acetyl-L-aspartic acid one-generation reproduction toxicity studies conducted in rats included pre-mating, mating period, gestation, lactational and post-lactation dosing and no effects were observed on reproductive parameters up to doses >600 mg/kg bw/day.

C. Aggregate Exposure

	1. Dietary exposure. An inert dietary exposure evaluation based on the EPA I-DEEM model can be carried out.  I-DEEM uses a screening level dietary assessment of 57 of the most "significant" active ingredients as surrogates for inerts within the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02).  Exposure from food, animal commodities and drinking water would be included.  Rosen's Inc. has not carried out this dietary evaluation for PPA.  However, PPA will be applied at low rates (no more than 280 g per A per year).  For the general population, the estimated exposure through the diet is expected to be low.  Residues in drinking water are expected to be low due to biodegradation of PPA by soil microbes.

	2. Non-dietary exposure. No exposure to PPA is expected through residential application of pesticidal products containing PPA.  

Studies are not available to characterize the potential toxicity of PPA for the inhalation route of exposure.  Potential effects from inhalation exposure to PPA may be assessed based on the oral study data and assuming 100% absorption via inhalation.  PPA was not toxic in an acute oral toxicity study.

A dermal absorption rate of 100% may be assumed to estimate the potential exposure and risk from dermal exposure to PPA based on oral exposure studies.  This assumption will likely overestimate the potential risk from dermal exposure to PPA, although the dermal absorption is expected to be less than 100%.  No dermal toxicity was observed in the acute dermal toxicity study.

Some exposure to PPA from non-pesticidal uses may occur since PPA is approved as a stabilizer for use in red, rośe, and white wines to prevent tartrate crystal precipitation.  PPA is added to wine at typical levels of 100-200 mg/L (no more than 300 mg/L).  In addition, the sodium salt of polyaspartic acid is authorized for use in USA (Environmental Assessment LANXESS Deutschland GmbH, Food Contact Notification, 2007), (Environmental Assessment Food Contact Notification, NanoChem Solutions, 2013) and Australia (Summary Report "2-Butenedioic acid (2Z)-, ammonium salt, homopolymer, hydrolyzed, sodium salts" Reference No: NA/932) as a food contact substance, as a dispersant for fillers and an anti-scale additive in sugar processing; and as a water treatment agent used as a scale inhibitor in cooling tower and boiler water applications.

D. Cumulative Effects

	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.  Potassium polyaspartate does not appear to produce a toxic metabolite and Rosen's, Inc. has assumed that potassium polyaspartate does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. The proposed use of potassium polyaspartate is expected to be below the EPA's level of concern when evaluated against the chronic dietary toxicity cPAD value.  Rosen's, Inc. concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of potassium polyaspartate.

	2. Infants and children. Based on the data, Rosen's, Inc. concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of potassium polyaspartate. 

F. International Tolerances

	There are no known CODEX or international tolerances or tolerance exemptions established for potassium polyaspartate on food crops.  The European Food Safety Authority reviewed the safety data and the European Union approved the use of PPA at levels of 100 mg/L in wine.  The Australia New Zealand Food Standard Code has been revised to include PPA as a food additive (stabilizer) in wine at 100 mg/L.
