Document ID: EPA-HQ-OPP-2014-0418-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-05T04:00Z

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

EPA Registration Division contact: [P. V. 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.

[Loveland Products, Inc.]

[IN-10704]

	EPA has received a pesticide petition (IN-10704) from Loveland Products, Inc., 3005 Rocky Mountain Avenue, Loveland, CO 80538 proposing, 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 amend the exemption from the requirement of a tolerance for

	[Phenol, 2-(2H-Benzotriazol-2-yl)-6-dodecyl-4-methyl- (CAS No. 23328-53-2)] as an inert ingredient (UV stabilizer) not to exceed 10% w/w in pesticide formulations under 40 CFR §180.920 (pre-harvest uses).  The petition proposes to amend the exemption from the requirement of a tolerance for residues of Phenol, 2-(2H-Benzotriazol-2-yl)-6-dodecyl-4-methyl- in or on [all] raw agricultural commodities. CAS Reg. No. 23328-53-2 is approved as an inert ingredient (UV stabilizer) for use at no more than 0.6% in insecticide formulations applied to adzuki beans, canola, chickpeas, cotton, faba beans, field peas, lentils, linola, linseed, lucerne, lupins, mung beans, navy beans, pigeon peas, safflower, sunflower, and vetch (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

	1. Plant metabolism. [Not applicable. Remove based on the fact that this information is not required for the establishment of a tolerance exemption.]

	2. Analytical method. [Not applicable.  The petition proposes to amend the exemption from the requirement of a tolerance and no analytical method is required for establishing or amending a tolerance exemption.]

	3. Magnitude of residues. [Not applicable.  Remove based on the fact that this information is not required for the establishment of a tolerance exemption.]

B. Toxicological Profile
[In addition to data on phenol, 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methyl- (CAS Reg. No. 23328-53-2; Tinuvin(R) 571), toxicity data are available on five surrogates:  drometrizole (Tinuvin(R) P), octrizole (UV 329), Tinuvin(R) 328, Tinuvin(R) 234, and 2-(2'-hydroxy-3,5;-di-tert-butylphenyl benzotriazole (HDBB; UV-320).  The five surrogates have an identical molecular base, a benzotriazole moiety plus a mono- or di-substituted phenol.  Therefore, data on these five surrogates is used to the support the toxicity database for CAS Reg. No. 23328-53-2. 

EPA previously considered data for CAS Reg. No. 23328-53-2 and structurally-related surrogate chemicals (Petition Nos. 8E7362 and 8E7363) and the data considered in those petitions, publicly available data not considered in previous risk assessments, and new data for CAS Reg. No. 23328-53-2 are summarized below.  .  Based on discussions with the Agency and on EPA's previous risk assessment that retained the 10X FQPA safety factor due to an incomplete database (lack of a reproduction study), Loveland Products Inc. conducted an extended one-generation rat reproduction study with CAS 23328-53-2.  That report is submitted with this petition.  These data in addition to other available data not considered previously should allow the Agency to remove the 10X FQPA safety factor.]

	1. Acute toxicity.  [Acute toxicity studies on CAS Reg. No. 23328-53-2 are not available; however, studies are available on drometrizole, octrizole, Tinuvin 328 and Tinuvin 234.  The acute oral toxicity of drometrizole, octrizole, Tinuvin 328 and Tinuvin 234 is low with LD50s ranging from <1000 mg/kg (octrizole) to >10000 mg/kg (drometrizole).  The acute dermal LD50 of Tinuvin 234 is >2000 mg/kg.  The acute inhalation LC50 of drometrizole is >1420 mg/m[3] or 1.42 mg/L. Drometrizole is minimally irritating to the rabbit eye and was not irritating to rabbit skin.  Drometrizole was tested in a maximization test in guinea pigs (positive), a human patch test (negative) and a LLNA assay (negative).]

	2. Genotoxicty. [Genotoxicity studies are not available on CAS Reg. No. 23328-53-2; however, studies are available on drometrizole, octrizole, Tinuvin 328 and Tinuvin 234.  Drometrizole was tested in a dominant lethal assay in mice, a somatic mutation assay in Chinese hamsters (in vivo), a chromosomal aberration assay in Chinese hamsters (in vivo), in two Ames Salmonella assays and a UDS assay in primary rat hepatocytes.  Drometrizole was negative in all of the assays except for the UDS assay.  Octrizole was tested in an Ames Salmonella assay in which it was negative.  Tinuvin 328 was tested in two Ames Salmonella assays and was negative in both assays.  Tinuvin 234 was tested in a nucleus anomaly assay (in vivo), a sister chromatid exchange assay (in vivo), an Ames Salmonella assay and an UDS assay in primary rat hepatocytes.  The results of all assays were negative.  A weight of the evidence on the results of the genotoxicity studies conducted on phenol benzotriazole would indicate that they have no genotoxic potential.]

	3. Reproductive and developmental toxicity. [An extended one-generation rat reproduction study is available on CAS Reg. No. 23328-53-2 and a combined repeated dose toxicity reproduction/developmental toxicity screening test is available on drometrizole.  In the CAS Reg. No. 23328-53-2 study, the NOAEL for parental and reproductive toxicity was 10,000 ppm (500 mg/kg/d).  The NOEL for offspring toxicity was considered to be 2500 ppm based on effects on body temperature in PND 4 pups and on TSH levels in PND 22 female pups and the NOAEL was considered to be 5,000 ppm (250 mg/kg/d) based on the decreased body weight and body weight gain observed in pups at 10000 ppm from PND 4 to 21.  After weaning, body weights were comparable to control body weights.  In the drometrizole study, the reproductive/developmental toxicity NOAEL was the highest dose tested, 300 mg/kg/day.  The NOEL in males was considered to be <30 mg/kg/day based on increased relative liver weights observed in all dose groups and 30 mg/kg/day based on effects on liver and kidney weights and kidney histopathology.  The NOAEL was concluded to be 300 mg/kg/day for males and 30 mg/kg/day in females based on kidney lesions.  

Developmental toxicity studies are not available on CAS 23328-53-2; however, studies are available on drometrizole (mouse and rat) and Tinuvin 234 (rat).  In the rat and mouse studies on drometrizole, the NOAEL for maternal and developmental toxicity was considered to 1000 mg/kg/day, the limit dose for studies of this type.  For the Tinuvin 234 study, the maternal NOAEL was considered to be 3000 mg/kg/day and the developmental NOAEL was considered to be 300 mg/kg/day based on the findings at 1000 mg/kg/day.]

	4. Subchronic toxicity. [Subchronic toxicity studies are not available on CAS Reg. No. 23328-53-2; however, 28-day and/or 90-day rat studies are available on drometrizole, octrizole, Tinuvin 328, Tinuvin 234 and HDBB and 90-day dog studies are available on drometrizole and Tinuvin 328.  The liver and kidney were the primary target organs in these studies.  The NOAEL in a 90-day dietary rata study on drometrizole was considered to be the low dose (0.2% in diet) based on the effects on body weights, hematology parameters and kidney histopathology observed at the mid and high dose.  The NOAEL in a 30-day dietary rat study on octrizole was considered to be 5.658 mg/kg/day, the highest dose tested.  Based on the results from a 90-day dietary rat study on Tinuvin 238, the NOAEL was considered to be < 100 ppm and the NOAEL was considered to be 100 ppm (approximately 20 mg/kg/day) based on increased liver weights and microscopic findings in the liver.  In a 90-day dietary rat study on Tinuvin 234, the NOAEL was considered to be 50 ppm or approximately 2.5 mg/kg/day, based upon findings in the liver (increased liver weights and microscopic findings) at 300 ppm (approximately 15 mg/kg/day).  Seventeen-day, 28-day and 90-day gavage studies on HDBB were conducted in rats.  The 17-day study was conducted using PND 4 to PND 21 rat pups.  The NOAEL was 2.5 mg/kg/day in male and female pups based on liver pathology observed at 12.5 mg/kg/day.  The 28-day and 90-day studies were conducted in adult rats.  The NOAEL in the 28-day study was determined to be <0.5 mg/kg/day in males and 2.5 mg/kg/day in females based on the increased A/G ratio observed in males at all dose levels and effects on liver weights and liver histopathology in in females observed at 12.5 mg/kg/day.  The NOAEL in the 90-day study was 0.1 mg/kg/day in males and 2.5 mg/kg/day in females based on hematology and clinical chemistry findings, increased liver weights and liver pathology observed in males at 0.5 mg/kg/day and in females at 12.5 mg/kg/day.  In the 90-day non-rodent drometrizole, the NOAEL was considered to be 1000 ppm or 31.75 mg/kg/day in males and 34.6 mg/kg/day in females based on increased levels of alanine aminotransferase at 3000 ppm and above.  For Tinuvin 328 90-dog study, the NOAEL was considered to be 30 mg/kg/day based on body weight effects and histopathology (primarily in the liver) observed at 60 mg/kg/day.]

	5. Neurotoxicity:  [No neurotoxicity studies were available on CAS Reg. No. 23328-53-2 or its surrogates; however, no indications of neurotoxicity were observed in any of the repeated dose studies summarized above.  In addition, some FOB parameters and motor activity was evaluated in the extended one-generation rat reproduction study with CAS Reg. No. 23328-53-2 and no effects were observed up to a dose of 10000 ppm (~500 mg/kg/day).  Body temperature was reduced in PND 4 pups, but not PND 0 pups in the absence of any other indications of neurotoxicity.  Since the effect occurred in conjunction with other toxicity in the pups (reduced body weight and body weight gain), it was attributed to general toxicity.]

      6.  Chronic toxicity. [A chronic toxicity study is not available on CAS Reg. No. 23328-53-2; however, a study (gavage) is available on HDBB in rats.  In this study, the NOAEL was 0.1 mg/kg/day in males and 2.5 mg/kg/day in females based on hematology and clinical chemistry findings, increased liver weights and liver pathology observed in males at 0.5 mg/kg/day and of hematology findings, increased liver weights and liver pathology in females at 12.5 mg/kg/day.  The study authors concluded from the results of a second study that castration reduced but did not abolish the gender differences in susceptibility of male and female rats to the effects of HDBB.  A carcinogenicity study on CAS Reg. No. 23328-53-2 is not available; however, a study in mice is available on drometrizole.  The NOAEL in this study was greater than 64 mg/kg/day in male mice and 62 mg/kg/day in female mice.  Drometrizole was not carcinogenic to mice under the conditions of this study.

	7. Animal metabolism. [A metabolism study is not available on CAS Reg. No. 23328-53-2; however, a study in male rats is available on drometrizole.  Drometrizole was mainly excreted in the urine and was completely eliminated by 168 hours after administration.  Residual radioactivity was found in the liver, blood, kidney and aorta.]

	8. Metabolite toxicology. [No studies are available on the toxicity of CAS 23328-53-2 or its surrogates.]

	9. Endocrine disruption. [No studies on the potential endocrine disruption potential of CAS Reg. No. 23328-53-2 have been conducted.  However, estrogen receptor competitive binding assays are available on drometrizole, Tinuvin 328 and HDBB and yeast two-hybrid estrogen assays (which tested for agonist and antagonist activity) have been conducted on drometrizole, Tinuvin 328, Tinuvin 234 and HDBB.  The results of these assays indicate that these compounds have no estrogen agonist or antagonist activity.]

C. Aggregate Exposure

	1. Dietary exposure. [Concentrations of CAS Reg. No. will be 10% in pesticide formulations applied to growing crops.  As a result, humans may be exposed to very low residue levels through the diet from food and water.  The lowest NOAEL of 250 mg/kg/day (extended one-generation rat reproduction study) is selected for risk characterization of chronic dietary exposures to CAS Reg. No 23328-53-2.  Although the NOAEL in this study was lower in pups than adults, the pup body weight effects were observed only during lactation when dietary intake for offspring is the highest; therefore, an additional FQPA safety factor is not considered necessary.  Assuming standard 100X uncertainty factors for inter- and intra-species variability and an FQPA safety factor of 1X, the reference dose for chronic dietary exposures of CAS Reg. No. 23328-53-2, cRfD, is 2.5 mg/kg/day.]

	i. Food. [Using I-DEEM, the estimated chronic dietary exposure estimates for a generic inert ingredient that is assumed to constitute up to 50% of a formulated pesticide product are presented Table 1.  Chronic dietary exposures based on default residues on all foods range from 0.142 mg/kg/day for Youth 13-19 years old to 0.621 mg/kg/day for children aged 1-2 years old.  CAS Reg. No. 23328-53-2 is proposed to be used at no more than 10% in pesticide formulations so the dietary exposures are lower ranging from 0.0288 mg/kg/day for Youth 13-19 years old to 0.125 mg/kg/day for children aged 1-2 years old.]

	ii. Drinking water. [Chronic dietary exposures based on default residues on all foods and drinking water at 100 ppb range from 0.144 mg/kg/day for Youth 13-19 years old to 0.624 mg/kg/day for children aged 1-2 years old (Table 1).  CAS Reg. No. 23328-53-2 is proposed to be used at no more than 10% in pesticide formulations so the chronic dietary (food + water) exposure ranges from 0.0303 mg/kg/day for Youth 13-19 years old to 0.128 mg/kg/day for children aged 1-2 years old.

Table 1. Chronic Dietary Exposure Using I-DEEM
Population Subgroup 
                           Chronic Dietary Exposure 
                              (50% Cap) (mg/kg/d)
                                    % cRfD 
                        (cRfD = 2.5 mg/kg/d) (50% Cap)
                                    % cRfD 
                             (cRfD = 2.5 mg/kg/d) 
                                   (10% Cap)
                                   Food Only
                                   Food Only
                       Food + Drinking Water at 100 ppb
                       Food + Drinking Water at 100 ppb
                       Food + Drinking Water at 100 ppb
U.S. Population 
                                    0.1894
                                    0.1915
                                     7.66
                                     1.62
All infants (<1 year) 
                                    0.3902
                                    0.3971
                                     15.88
                                     3.45
Children 1-2 yrs 
                                    0.6209
                                     0.624
                                     24.96
                                     5.12
Children 3-5 yrs 
                                     0.459
                                    0.4619
                                     18.48
                                     3.81
Children 6-12 yrs 
                                    0.2533
                                    0.2553
                                     10.21
                                     2.12
Youth 13-19 yrs 
                                    0.1426
                                    0.1441
                                     5.76
                                     1.21
Adults 20-49 yrs 
                                    0.1424
                                    0.1444
                                     5.78
                                     1.24
Adults 50+ yrs 
                                     0.15
                                    0.1521
                                     6.08
                                     1.30
Females 13-49 yrs 
                                    0.1434
                                    0.1454
                                     5.82
                                     1.24
]

	2. Non-dietary exposure. [There are no proposed uses for CAS Reg. No. 23328-53-2 that would result in residential exposures to the U.S. population.  Workers may experience dermal exposure during application of pesticide formulations if personal protective clothing is not worn.  Concentrations of CAS Reg. No. 23328-53-2 are less than 10% in the formulation and dermal exposure will be limited by the irritation potential of the formulation.  Thus, a safety finding for CAS Reg. No. 23328-53-2 can be concluded for non-dietary exposures.]

D. Cumulative Effects

	[It has not been determined that CAS Reg. No. 23328-53-2 has 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 US population from the aggregate exposure to CAS Reg. No. 23328-53-2 used at 10% w/w in pesticide formulations.  The chronic dietary exposure is estimated to be 0.1915 mg/kg/day (1.62% cPAD) for the general U.S. population.]

	2. Infants and children. [FFDCA section 408 provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the data base and exposure, unless EPA determines that a different margin of exposure (safety) will be safe for infants and children.  Based on the available information discussed herein, Loveland Products Inc. believes that the FQPA safety factor should be reduced to 1X for the reasons described below.  The cRfD is therefore equivalent to the chronic population adjusted dose (cPAD).

   * The use of CAS Reg. No. 23328-53-2 at 10% w/w in pesticide formulations resulted in I-DEEM estimated chronic dietary exposures to children 1-2 years of age, the potentially most exposed population, of 0.624 mg/kg/d (5.12% cPAD).
   * There is a scientifically sound mammalian toxicity database for CAS Reg. No. 23328-53-2 and structurally related surrogate compounds that includes acute, subchronic, developmental, reproductive, and genotoxicity data.  The data did not indicate developmental, reproductive, or neurological endpoints or genotoxic effects.
   * There was also no consistent evidence of effects on the nervous system in the acute, repeated-dose oral toxicity or reproduction studies.
   * CAS Reg. No. 23328-53-2 does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system.]

F. International Tolerances

	[There are no known CODEX or international tolerances or tolerance exemptions established for CAS Reg. No. 23328-53-2.]