Document ID: EPA-HQ-OPP-2017-0249-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-09-15T04:00Z

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

EPA Registration Division contact: PV Shah, (703) 308-1846

Attune Agriculture, LLC

[IN-11048]

	EPA has received a pesticide petition (IN-11048) from Technology Sciences Group (1150 18th Street, N.W., Suite 1000, Washington, DC 20035) on behalf of Attune Agriculture, LLC, 10552 Philadelphia Road, White Marsh, MD 21162 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 Konjac glucomannan (CAS No. 37220-17-0) when used in pesticide formulations applied to growing crops at a maximum use level of 1% under 40 CFR 180.920.  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 NA Remove.

	1. Plant metabolism.NA Remove

	2. Analytical method. NA Remove

	3. Magnitude of residues. NA Remove

B. Toxicological Profile

	1. Acute toxicity.   Acute oral toxicity studies have derived LD50 values of >2,800 mg/kg body weight (bw) glucomannan in male and female CD-1 mice; >5,000 mg/kg bw konjac flour in male and female Sprague-Dawley rats.  Konjac flour had an acute dermal LD50 of >2,000 mg/kg bw in male and female rabbits Unground konjac flour, at a maximum attainable concentration of 1.5 mg/m[3], was administered to rats in a four-hour acute inhalation study and produced no mortality or adverse clinical signs. An irritation study of konjac flour in rabbits indicated the substance was not irritating to the skin. Using the Draize method, konjac flour produced only minimal eye irritation in the form of conjunctivitis in rabbits after 24 hours, and no irritation after 48 and 72 hours. The application of mechanically ground konjac flour to the skin of guinea pigs according to the Buehler closed patch method did not produce skin sensitization reactions.

	2. Genotoxicity  Konjac gum or flour has been studied in an Ames test, mouse lymphoma assay, and in vivo mouse micronucleus test. All genotoxicity assays were negative. These results indicated that konjac glucomannan is not a genotoxic agent.  

	3. Reproductive and developmental toxicity.  British short-hair domestic cats were fed diets containing 2% konjac flour (6 cats) or a control diet with 2% carob gum (9 cats) or during gestation (JECFA 1993). Biochemical and hematological parameters were reported to be within normal ranges throughout the study. There was no significant difference in body weight gain or meaningful differences in reproductive outcomes between the two groups of cats. Based on the lack of bioavailability of this high molecular weight polysaccharide, konjac glucomannan is not expected to be toxic to the reproductive system or the developing fetus. 

Guar gum is a similar dietary polysaccharide that is a galactomannan with a mannose:galactose ratio of about 2:1. Osborne-Mendel rats were fed various levels of dietary guar gum for 13 weeks before mating, during mating and throughout gestation.  The dams fed 15% guar gum (~11,800 mg/kg bw/day) had slightly fewer corpora lutea and implantations than the controls but no effect was seen on implantation efficiency. No other compound-related effects on fertility or other reproductive parameters, on systemic toxicity, or on fetal development were noted at 15% or at the next lowest dose of 7.5% dietary guar gum. 

	4. Subchronic toxicity. Groups of male Sprague-Dawley rats fed 10% konjac flour for 28 days had reduced digestion and absorption of protein in the large intestine, which resulted in a decrease in body weight gain. There was no indication of toxicity resulting from the intake of konjac flour. Konjac meal containing about 80% glucomannan was fed to rats for 12 weeks at 2.5, 5, or 10% of the diet. Compared to the basal diet group, the konjac groups initially had livers with spreading fatty degeneration with focal necrosis and a non-specific inflammation reaction. This effect had disappeared by week 12 and livers were morphologically similar to those of control rats. 

After 18 months dietary exposure, rats consuming a 1% konjac flour diet (~500 mg/kg bw/day) showed no difference compared to controls in body weight gain, absolute or relative organ weights, or femur weights and no evidence of treatment-related pathological changes or effects on calcium and phosphorus metabolism. There were some inconsistent changes in the serum cholesterol and triglycerides levels, but these were not consistent across the sexes and/or over time. Minor observations were noted in the hepatocytes of treated rats. Overall, there was no evidence that 1% konjac flour in the diet was toxic to rats.

A GRAS mixture comprising 48-90% konjac flour was fed to Sprague-Dawley rats (10/sex/group) at 0, 1.25, 2.5, or 5.0% of the diet for 90 days. There was no effect on body weight, neuromotor behavior, or mean or relative organ weight, or histopathology. Changes in hematological and biochemical parameters were within laboratory historical control values and/or did not correlate with any histopathological changes, and were not considered adverse. High dose animals of both sexes had increased urinary volume, with a concomitant decrease in urinary specific gravity and protein concentration (females only). This may have been the result of increased drinking because of consumption of powdered food and was not considered toxicologically relevant. The NOAEL was 5% in the diet, equivalent to 3219 and 3799 mg/kg bw/day of the mixture in male and female Sprague Dawley rats, respectively, or 1545-2897 mg/kg bw/day konjac flour in males and 1824-3419 mg/kg bw/day konjac flour in females.

	5. Chronic toxicity. No studies identified.  

	6. Animal metabolism. Konjac is a non-digestible polysaccharide with ß-glycosidic linkages, which cannot be hydrolyzed by salivary and pancreatic amylase. Dietary konjac, therefore, passes into the colon unchanged where it is fermented by colonic bacteria which enzymatically depolymerize glucomannan. Microbial enzymes with beta-mannanase and cellulase have been detected in human feces.  Fermentation of soluble, indigestible polysaccharides in the large intestine produces a variety of glucomanno-oligosaccharides. The ultimate depolymerization yields fatty acids, particularly short chain acids like acetate, propionate, butyrate and isovalerate. In the human and rat colon, short-chain fatty acids are rapidly and almost completely absorbed.  Short-chain fatty acids are metabolized efficiently in humans.

	7. Metabolite toxicology. N/A Remove

	8. Endocrine disruption. In the available toxicity studies on konjac glucomannan and related substances, there was no toxicologically significant evidence of endocrine disruptor effects. 

C. Aggregate Exposure

	1. Dietary exposure. The estimated dietary exposure to konjac glucomannan was determined using methods to estimate chronic dietary exposure for a generic inert ingredient.  This assessment considers drinking water and crop-specific residues from pre-harvest applications of agricultural insecticides, herbicides and fungicides, assuming the highest established tolerance level residue for each commodity.  The assessment assumes that the inert ingredient is used on all crops, and that 100% of all crops are treated with the inert.  The inert ingredient is assumed to be present in all commodities treated with 57 of the most significant active ingredients at the maximum tolerance level as identified by the U.S. EPA for the default assessment.  Chronic dietary exposure estimates were derived for the general US population and sub-groups of the population using the Dietary Exposure Evaluation Model, DEEM(TM).  The I-DEEM residue data set developed by EPA was used for the analysis. The estimated chronic exposure for the total US population is 0.189 mg/kg/day, 0.2% of the chronic Population Adjusted Dose (cPAD).  Children age 1 to 2 years old have the highest estimated exposure at 0.706 mg/kg/day, 0.7% of the cPAD.

	i. Food.  The use of konjac glucomannan as a food additive is estimated to be no more than 3 grams/day, or 43 mg/kg bw/day for a 70-kg person. The additional intake of 0.189 mg/kg bw/day from pesticide residues would increase overall consumption by about 0.4%. The total estimated dietary intake from all dietary sources is approximately 4.3% of the cPAD.

	ii. Drinking water. Konjac glucomannan exposure via drinking water from use as an inert ingredient is not expected to be significant. Based on the physical chemical characteristics of Konjac glucomannan, the compound is expected to partition primarily to the soil, and the comparatively small amounts that enter the water will readily biodegrade.  Exposure via the drinking water was estimated in the DEEM dietary exposure assessment assuming a concentration of 100 ppb.   

	2. Non-dietary exposure. Dermal exposure to consumers is common as a result of use of konjac glucomannan in pharmaceuticals and medical devices, including drug delivery systems, bio-adhesives, cellular therapy, and prosthetic implants, and in cosmetic products like leave-on hand and facial products.  

D. Cumulative Effects

	Section 408(b)(2)(D) (9v) of the 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."  EPA has not made a common mechanism of toxicity finding as to konjac glucomannan and other compounds.  Konjac glucomannan does not appear to produce toxic metabolites in common with other substances.  For the purpose of the tolerance exemption actions proposed, it is assumed that konjac glucomannan does not share a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. There is a reasonable certainty that no harm to humans will result from the use of konjac glucomannan as an inert ingredient in pesticide products.  In addition to its high molecular weight and inability to be absorbed by any route of exposure, short and long-term feeding studies in rodents have indicated an absence of toxicologically significant effects of konjac glucomannan. The main effects of dietary exposure to konjac gum (and other dietary gums) in animals and human studies include non-specific reductions in body weight and food consumption. In human feeding studies, the addition of dietary konjac did not result in toxicity. Furthermore, konjac glucomannan is not bioaccumulative or persistent, and the low use-level (<1% by weight) suggests negligible potential for exposure. 

For the purposes of deriving the chronic population adjusted dose (cPAD), the limit dose NOEL of 1000 mg/kg/day was used to represent a substance that is essentially nontoxic. Applying an intraspecies uncertainty factor of 10 gives a cPAD of 100 mg/kg/day.  For the total US population, the estimated chronic dietary exposure from food and drinking water for konjac glucomannan, calculated as 50% of all agricultural formulations, is 0.2 % of the cPAD.  This estimated exposure to konjac glucomannan is well below any level of potential concern.    

	2. Infants and children. There is a reasonable certainty that no harm to infants and children will result from the use of konjac glucomannan as an inert ingredient in pesticide products. A long history of use of konjac glucomannan as a dietary component indicates that there is essentially no toxicity associated with its consumption, no evidence of endocrine disruption, and no evidence of developmental toxicity or sensitivity in infants and children. Based on the cPAD of 100 mg/kg/day derived for konjac glucomannan, the estimated chronic dietary exposure from food and drinking water was highest (0.7% of cPAD) for children aged 1 to 2 years old. Estimated exposure of all infants to konjac glucomannan, assuming that konjac glucomannan makes up 50% of all agricultural formulations, is 0.4% of the cPAD.  These estimated exposures to konjac glucomannan are well below any level of potential concern.

F. International Tolerances

	N/A Remove