

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

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

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.


BYK Additives Inc.

[IN-10780]

	EPA has received a pesticide petition (IN-10780) from BYK Additives Inc., 1600 W. Hill Street, Louisville, KY 40210 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 Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite (CAS #1588523-05-0) when used as an inert suspending or structuring agent applied to growing crops under 40 CFR 180.920 in pesticide formulations. The inert substance will be used as part of an inert mixture intended for use in pesticides. 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.

	2. Analytical method. NA remove

	3. Magnitude of residues. NA remove

B. Toxicological Profile

	1. Acute toxicity.  Acute oral and inhalation studies have been conducted in animals with many of the organoclay materials and give consistent results that classify these materials as Toxicity Category IV for these two endpoints. Oral LD50 values exceed 5000 mg/kg bw and inhalation LD50 values were consistently greater than 2 mg/L.   An acute dermal toxicity study was conducted on stearalkonium bentonite; this substance was classified as Toxicity Category III for acute dermal toxicity based on the LD50 of >2000 mg/kg bw. Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite is not expected to be irritating to the skin, based on results in other organoclays.  Minimal eye irritation may occur in humans as a result of the physical nature of the clay particles, although moderate irritation has been reported in animals exposed to organoclays via the eye. Sensitization reactions were not observed in two structurally similar treated clays when tested in guinea pigs and humans.



	2. Genotoxicty. Treated clays similar to quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite have been studied in a variety of bacterial and mammalian cell genotoxicity studies as well as in vivo genotoxicity studies. All of the genotoxicity studies on treated clays have been negative. These include an in vivo micronucleus assay and a modified mammalian bone marrow chromosome aberration assay.  

	3. Reproductive and developmental toxicity. A one-generation reproductive toxicity study was carried out on the structurally similar substance, Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, salts with hectorite (CAS #121888-67-3) using OECD guideline 415. Female and male Sprague Dawley rats (24 sex/group) were dosed with 0, 50, 225, and 1000 mg/kg bw during mating and through post natal day 21. The following endpoints were assessed: morbidity/mortality, clinical signs, body weight, food consumption, mating, gestation, number of live/dead offspring, litter body weight, litter clinical signs; food conversion ratio; mating performance and fertility; pre-coital interval; fertility indices (mating index and pregnancy index); gestation length; gestation and parturition index; lactation data including live birth index, viability indices; sex ratio; and offspring physical development and reflexology. A difference in mean litter body weights was not considered to be toxicologically important and there were no effects on other developmental endpoints.  The study authors determined the NOAEL for systemic and reproductive/developmental effects to be the highest dose, 1000 mg/kg bw/day.
In a 28-day toxicity study of stearalkonium bentonite, there were no histopathological findings in any reproductive organ including testis, epididymis, ovary, prostate, or uterus.

	4. Subchronic toxicity. Three 28-day OECD test guideline 407 studies (or close variations) were identified for three structurally similar treated clays. Study authors considered the highest dose (1000 mg/kg bw/day) in each test to be the NOAEL. In the first study, rats receiving stearalkonium bentonite at 0, 100, 316, or 1000 mg/kg bw/day showed no test substance-related effects after 28 days of dosing. A parallel high dose plus recovery group showed some differences from controls, but these were not seen in the high dose/non-recovery rats and therefore were not considered test substance -related.  In the second study, a 1000 mg/kg/day dose of quaternary ammonium compounds, benzyl(hydrogenated tallow alkyl)dimethyl, chlorides, compounds with bentonite for 28 days resulted in no mortalities, clinical signs of toxicity, effects on body weight or food consumption, or statistically significant findings for hematology or clinical chemistry in Charles River/CD rats. Changes in organ weights of treated animals were not considered toxicologically relevant. In the third study, quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, salts with hectorite was dosed to Charles River/CD rats at 0 or 1000 mg/kg bw/day. There were no mortalities, clinical signs of toxicity, changes in body weight gains, food consumption or hematological parameters. There were some differences from controls in clinical chemistry parameters and adrenal weights (males). None of the effects were considered toxicologically relevant based on their appearance in only one sex and their small deviation from control values, which were often still within the historical range of normal values. The authors considered the NOAEL to be 1000 mg/kg bw/day.


	5. Chronic toxicity. N/A Remove

	6. Animal metabolism. A guideline study of the treated clay quaternary ammonium compounds, benzylalkyl (C14-C22) dimethyl, salts with bentonite (CAS #71011-24-0) showed that only a negligible concentration of treated clays is absorbed by orally dosed rats. After 48 hours, 0.16% and 0.95% of the administered dose remained in the carcass of rats dosed with 5 and 500 mg/kg bw, respectively.
Deposition and kinetics of radiolabelled fused montmorillonite, a smectite group clay like saponite, after inhalation exposure have been studied in multiple species. Deposition of montmorillonite in the nasopharynx region increases with particle size in tests in rodents and dogs, while tracheobronchial deposition was low and independent of particle size. Pulmonary deposition decreased with increasing particle size and was much higher in dogs than in rodents. The elimination of particles took place by solubilization (dogs) and physical clearance (rodents). In humans, rapid initial clearance of 8% and 40% of aluminosilicate particles with aerodynamic diameters of 1.9 and 6.1 μm respectively, from the lung region occurred over the initial 6 days. Following this, 4% and 11% of the two particle sizes were removed at half-rate of 20 days, and the rest with half-rates of 330 and 420 days.


	7. Metabolite toxicology. N/A Remove

	8. Endocrine disruption. In the available toxicity studies on treated clays, there
was no evidence of endocrine disruptor effects.

C. Aggregate Exposure

	1. Dietary exposure. The estimated dietary exposure to quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite 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 inert ingredient is assumed to be in the formulation at a concentration of 50% for the default assessment, but this has been amended to account for the actual use level of Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl) dimethylammonium salts with saponite in the end use product. The estimated chronic exposure for the total US population is 0.0019 mg/kg/day about 0.019% of the chronic Population Adjusted Dose (cPAD). Children age 1 to 2 years old have the highest estimated exposure at 0.0069 mg/kg/day, about 0.069% of the cPAD. Both of these estimates give a margin of exposure that exceeds 1x10[5].

	i. Food. There are no other known dietary sources of quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite.

	ii. Drinking water. Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite exposure via drinking water from use as an inert ingredient is not expected to be significant. Based on the physical chemical characteristics of the treated clays, the substance is expected to settle out in water. Exposure via drinking water was estimated in the DEEM dietary exposure assessment assuming a concentration of 100 ppb.

	2. Non-dietary exposure. There are no known non-dietary sources of exposure to quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite.

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 quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite and other compounds. Quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite 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 quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite 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 quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite as an inert ingredient in pesticide products. A NOAEL of 1000 mg/kg/day obtained in three 28-day toxicity tests and the one-generation reproductive toxicity test was used as the point of departure for the chronic population adjusted dose (cPAD).  Intraspecies and interspecies uncertainty factors were combined for a total uncertainty factor of 100. The resulting cPAD is 10 mg/kg/day. For the total US population, the estimated chronic dietary exposure from food and drinking water for this treated clay, calculated as 0.49% of all agricultural formulations, is less than 0.1% of the cPAD. This estimated exposure to quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite 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 quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite as an inert ingredient in pesticide products. A one-generation reproductive toxicity study in rats demonstrated no reproductive effects or effects on developmental endpoints. A cPAD of 10 mg/kg/day is protective of infants and children. The cPAD was derived for quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite based on the NOAEL of 1000 mg/kg bw/day in the reproductive study as well as multiple subchronic studies. The estimated chronic dietary exposure from food and drinking water was highest (0.069% of cPAD) for children aged 1 to 2 years old. Estimated exposure of all infants to quaternary ammonium compounds, benzylbis(hydrogenated tallow alkyl)methyl, bis(hydrogenated tallow alkyl)dimethylammonium salts with saponite, was estimated to bes 0.039% of the cPAD. These estimated exposures are well below any level of potential concern.

F. International Tolerances

	N/A Remove



