Document ID: EPA-HQ-OPP-2011-0587-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-08-29T04:00Z

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.

TEMPLATE:

[Loveland Products, Inc.]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [Loveland Products, Inc.], [3005 Rocky Mountain Ave., 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 establish an exemption from the requirement of a tolerance for

	[2-hydroxy-4-methoxybenzophenone (common name) (HMB), (CAS nomenclature: methanone, (2-hydroxy-4-methoxyphenyl)phenyl-; CAS No. 131-57-7) when used as an inert ingredient as a UV-stabilizer at no more than 25% in pesticide formulations under 40 CFR §180.920 (pre-harvest uses)].  This petition proposes to establish exemptions from the requirement of a tolerance for residues of 2-hydroxy-4-methoxybenzophenone (HMB) in or on [all] raw agricultural commodities.  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.  [NA-Remove based on the fact that this information
Is generally not required for the establishment of a tolerance exemption.]

	2. Analytical method. [The petition proposes to establish exemptions from the requirement of a tolerance and no analytical method is generally required for establishment of a tolerance exemption.]

	3. Magnitude of residues. [NA-Remove based on the fact that this information
Is generally not required for the establishment of a tolerance exemption.]

B. Toxicological Profile
[HMB is a member of the 2-hydroxybenzophenone class of chemicals.  Many members of this class are used as UV-stabilizers in medicine, food packaging, and the cosmetics industry as a sunscreen and color fastener.  The proposed use of HMB is to act as a light stabilizer in end use products to prevent photodegradation of the active ingredient in pesticide formulations.  HMB is cleared as an antioxidant under 21 CFR § 177 (Indirect Food Additives:  Polymers) Subpart B (Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces) and § 177.1010 (Acrylic and modified acrylic plastics, semi-rigid and rigid).  It is approved for use in pesticide formulations which are applied to non-food crops such as turf and ornamentals.  The amount of HMB in pesticide formulations will be no more than 25%.
In addition to data on 2-hydroxy-4-methoxybenzophenone (HMB), toxicity data are also summarized herein for a surrogate chemical, 2-hydroxy-4-n-octyloxybenzophenone (OH-OBP; CAS No. 1843-05-6).  OH-OBP is structurally similar to HMB, the only difference is the methoxy substituent on HMB is substituted with an n-octyloxy group in OH-OBP.  Data generated for 2-hydroxy-n-octyloxybenzophenone (OH-OBP) should be considered as surrogate data for HMB where data for HMB is limited.  Metabolism studies indicate that 2-hydroxybenzophenones are rapidly excreted in feces and urine of rats and the metabolites have been identified as glucuronides.]
	1. Acute toxicity.  [The acute oral toxicity of HMB is low with reported oral LC50s ranging from >6000 mg/kg to >12,800 mg/kg in the rat.  The surrogate compound, OH-OBP, also has low acute oral toxicity with LC50s of >10,000 and >12,000 mg/kg in the rat.  The acute dermal toxicity of HMB is very low with a reported dermal LD50 value of >16,000 mg/kg in the rabbit.  No acute inhalation toxicity studies were located for HMB or OH-OBP.  In several studies, HMB was shown not to be an eye irritant when administered to rabbits and an irritant to rabbit skin.  No skin irritation studies were found for OH-OBP, but it was not an eye irritant in rabbits.  HMB was tested for dermal sensitization in two guinea pig studies and in the mouse local lymph node assay and was not a dermal sensitizer.  OH-OBP was shown to be a dermal sensitizer in guinea pigs.]

	2. Genotoxicty. [HMB produced mixed results in the Ames Salmonella assay.  In one assay it was weakly positive in two tester strains (TA97 and TA100) and in the second assay it was negative.  In in vitro assays in Chinese hamster ovary cells, HMB was positive for inducing SCE and chromosomal aberrations.  However, in three in vivo assays, it was negative:  mouse micronucleus assay, chromosomal aberration assay in rat bone marrow and in the Drosophila SMART assay.  OH-OBP was negative in the Ames Salmonella assay and for chromosomal aberrations in an in vitro human lymphocyte assay.]

	3. Reproductive and developmental toxicity. [HMB has been tested for reproductive toxicity in rats and mice and for developmental toxicity in rats.  The NOAEL for reproductive toxicity in the mouse continuous breeding study conducted by the National Toxicology Program (NTP) was 1.8 g/kg/day and the LOAEL was 4 g/kg/day.  In a study conducted by industry at Argus Laboratories to address the effects on male reproductive toxicity observed in the NTP subchronic dermal studies in B6C3F1 mice, no effects on male fertility were observed and the NOAEL in the study was >400 mg/kg/day. The NOAEL for maternal and developmental toxicity was 200 mg/kg/day in the rat teratology study.  The surrogate compound, OH-OBP, was tested for reproductive toxicity in rats:  feeding OH-OBP to rats from weaning through reproductive age for four successive generations at a level of 6000 ppm (~532.9 mg/kg/day in males and 614.3 mg/kg/day) did not produce lesions in parents or anomalies in offspring which could be attributed to treatment.  Overall, neither HMB nor OH-OBP when administered to rats or mice resulted in reproductive and/or developmental toxicity in the absence of parental and/or maternal toxicity.]

	4. Subchronic toxicity. [In a 90-day rat feeding study with HMB, the NOEL was 6250 ppm or approximately 312.5 mg/kg/day based on effects on platelet counts and kidney histopathology observed at 12,500 ppm (~625 mg/kg/day).  In a 90-day mouse feeding study with HMB a NOAEL was not established based on effects on sperm abnormalities observed at all dosage levels (NOAEL <468.75 mg/kg/day).  

Two 90-day rat feeding studies have been conducted with OH-OBP.  In the first study, a NOAEL was established at 1.8% in the diet or approximately 900 mg/kg/day which was the highest dose tested.  In the second study, the NOAEL was >75 mg/kg/day.  In a 120-day feeding study in the dog, the NOAEL was >0.6% OH-OBP in the diet or approximately 150 mg/kg/day.  

Several subchronic dermal toxicity studies are available on HMB.  In a 90-day dermal study in the rat, the NOEL was 25.0 mg/kg/day and the NOAEL is 200 mg/kg/day based on a questionable finding in platelet counts in female rats at >50 mg/kg/day.  In a mouse 90-day dermal study on HMB, a NOAEL was not established in males based on a statistically significant decrease in sperm density observed at all dosage levels tested (NOAEL <22.8 mg/kg/day).  An additional study was conducted to address the lack of a NOAEL in this study.  The study was designed to specifically address the effects of HMB on sperm parameters.  In the study, male B6C3F1 mice were dermally administered HMB.  HMB did not affect body weight gain and treatment did not result in any clinical signs of toxicity or dermal irritation.  There were no treatment-related effects on organ weights during the 90-day study or at the end of the recovery period.  In addition, there were no effects on any of the sperm parameters examined or on testicular histology.  The systemic NOEL in this study was >400 mg/kg/day.]

	5. Chronic toxicity. [There are no chronic toxicity studies on HMB or the surrogate compound, OH-OBP.  There are no developmental neurotoxicity data for HMB or OH-OBP.  However, none of the developmental or reproduction studies conducted with HMB or OH-OBP showed any evidence of neurotoxicity.]

	6. Animal metabolism. [HMB administered orally or applied dermally to male rats is rapidly absorbed, metabolized and excreted.  Three metabolites were identified in plasma, tissues, urine and/or feces and included 2,4-dihydroxybenzophenone (DHB), 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) and 2,3,4-trihydroxy-benzophenone (THB).  DHB was formed by o-demethylation and subsequently converted into THB and DHMB, which was formed by the aromatic hydroxylation of HMB.  Urine was the major route of excretion after oral administration and feces were the major route of excretion after dermal administration.  The liver contained the highest level of HMB and its metabolites followed by kidney from either route of administration.  ]

	7. Metabolite toxicology. [A rat metabolite of HMB, 2,2'-dihydroxy-4-methoxybenzophone (DHMB), was positive in the Ames Salmonella assay (strain TA1537) in the presence of rat and hamster S-9, but not without metabolic activation.]

	8. Endocrine disruption. [From the results of the assays conducted on HMB to determine its effects on hormonal systems, it can be concluded that it appears to have very weak (if any) estrogenic activity.  HMB has been demonstrated to have both positive and negative results in the uterotrophic assay.  It has also been shown to have both positive and negative effects on MCF-7 (estrogen-sensitive human breast cancer cells).  HMB did not bind to the ERα receptor.  When positive estrogenic effects were seen, they were observed at dosages very much lower than effects observed with 17β-estradiol.  HMB has also been shown to affect the binding of E2 to the estrogen receptor and to induce the production of vitellogenin in rainbow trout and Japanese medaka.  

Three metabolites of HMB were tested for estrogenic activity in one study and were shown to have some activity in the assays used.  DHB and THB competed with 17β-estradiol binding to the recombinant human estrogen receptor α in a concentration-dependent manner.  The IC50 for diethylstilbestrol was approximately 1 x 10-8M compared to 5 x 10-5 and 5 x 10-4 M for DHMB and THB, respectively.  DHB caused a concentration-dependent proliferation of MCF-7 cells from 10-8 to 10-5 M.  DHMB and THB also caused a slight increase in proliferation of MCF-7 cells at concentrations of 10-7 and 10-6 M.  17β-estradiol was effective in this assay at a concentration of 10-9 M.]

C. Aggregate Exposure

	1. Dietary exposure. [The lowest NOAEL of 150 mg/kg/day (120-day feeding study in the dog on OH-OPB) is selected for risk characterization of chronic dietary exposures to HMB.  Assuming standard 10X uncertainty factors for inter- and intra-species variability and an FQPA safety factor of 1X, the reference dose for chronic dietary exposures of HMB, cRfD, is 1.5 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 0.086 mg/kg/day for adults 50+ years old to 0.421 mg/kg/day for children aged 1-2 years old.  HMB is proposed to be used at no more than 25% in pesticide formulations so the dietary risks are expected to be even lower than with this I-DEEM assessment.]

	ii. Drinking water. [Chronic dietary exposures based on default residues on all foods and drinking water at 100 ppb range from 0.088 mg/kg/day for adults 50+ years old to 0.425 mg/kg/day for children aged 1-2 years old.  The chronic dietary (food + water) exposures are expressed as a percentage of the reference dose (1.5 mg/kg/day) in Table 1.  HMB is proposed to be used at no more than 25% in pesticide formulations so the dietary risks are expected to be even lower than with this I-DEEM assessment.

                  Table 1. Chronic Dietary Exposure  -  HMB (I-DEEM)
                                       
Population Subgroup 
Chronic Dietary Exposure (mg/kg/d) 
% RfD (1.5 mg/kg/d) 
                                   Food Only
                                   Food Only
                       Food + Drinking Water at 100 ppb
                       Food + Drinking Water at 100 ppb
U.S. Population 
                                     0.120
                                     0.122
                                      8%
All infants (<1 year) 
                                     0.245
                                     0.252
                                      17%
Children 1-2 yrs 
                                     0.421
                                     0.425
                                      28%
Children 3-5 yrs 
                                     0.310
                                     0.313
                                      21%
Children 6-12 yrs 
                                     0.174
                                     0.176
                                      12%
Youth 13-19 yrs 
                                     0.100
                                     0.101
                                      7%
Adults 20-49 yrs 
                                     0.087
                                     0.089
                                      6%
Adults 50+ yrs 
                                     0.086
                                     0.088
                                      6%
Females 13-49 yrs 
                                     0.087
                                     0.089
                                      6%
]

	2. Non-dietary exposure. [HMB is used as a UV-stabilizer at levels not more than 6% in sunscreen products (21 CFR § 352.10).  HMB is approved for use in pesticide formulations which are applied to non-food crops such as turf and ornamentals.]

D. Cumulative Effects

	[EPA has not made a common mechanism finding for HMB. It is therefore appropriate to consider only the potential risks of HMB in the exposure assessment.]

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 HMB included in 40 CFR § 180.920 pre-harvest use pesticide formulations.]

	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.  
Developmental studies have been conducted on HMB and OH-OBP.  Overall, neither HMB nor OH-OBP when administered to rats or mice resulted in reproductive and/or developmental toxicity in the absence of parental and/or maternal toxicity.  The NOAEL for maternal and developmental toxicity was 200 mg/kg/day was observed in a rat teratology study on HMB.  The endpoint selected for the Rfd (150 mg/kg/day from the 120-day feeding study in the dog with OH-OPB) is protective for maternal and developmental toxicity effects, for which a NOAEL of 200 mg/kg/day was observed in a rat teratology study on HMB.  
The chronic Population Adjusted Dose, cPAD, is the same as the Chronic Reference Dose (cRfD) cited above; cPAD = cRfD = 1.5 mg/kg/day.
An additional 10X safety factor is not required:
   * A scientifically sound mammalian toxicology database, which includes acute, repeated-dose oral toxicity, reproductive, and developmental toxicity study data, found no adverse effects to sensitive populations. 
   * There was also no consistent evidence of effects on the nervous system in the acute, repeated-dose oral toxicity or reproduction study.
   * From the results of the assays conducted on HMB to determine its effects on hormonal systems, it can be concluded that it appears to have very weak (if any) estrogenic activity.  HMB has been demonstrated to have both positive and negative results in the uterotrophic assay.  It has also been shown to have both positive and negative effects on MCF-7 (estrogen-sensitive human breast cancer cells).  HMB did not bind to the ERα receptor.  When positive estrogenic effects were seen, they were observed at dosages very much lower than effects observed with 17β-estradiol.  HMB has also been shown to affect the binding of E2 to the estrogen receptor and to induce the production of vitellogenin in rainbow trout and Japanese medaka.]

F. International Tolerances

	[There are no known CODEX or international tolerances or tolerance exemptions established for HMB.]