Document ID: EPA-HQ-OPP-2015-0719-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-11-23T05:00Z

EPA ANTIMICROBIALS 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:

Eastman Chemical Company, Inc.

[IN-10841]

	EPA has received a pesticide petition (IN-10841) from Eastman Chemical Company, Inc., 200 South Wilcox Drive, Kingsport, TN  37660-5280 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend the existing exemptions from the requirements of a tolerance in 40 CFR Part 180. 
		to establish an exemption from the requirement of a tolerance for
      N-butyl-3-Hydroxybutyrate (CAS Reg. No. 53605-94-0) and Isopropyl-3-Hydroxybutyrate (CAS Reg. No. 54074-94-1) when used as an inert solvent applied to pre- and post-harvest crops under 40 CFR 180.910, applied to animals under 40 CFR 180.930, and food-contact surface sanitizing solutions under 40 CFR 180.940(a) in pesticide formulations.
EPA has determined that the petition contains data and 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/Not required for the establishment of a tolerance exemption for inert ingredients.

	2. Analytical method. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients.

	3. Magnitude of residues. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients.

B. Toxicological Profile

The studies performed on Isopropyl-3-Hydroxybutyrate (IPHB) and N-butyl-3-Hydroxybutyrate (NBHB) did not identify any potential concerns for the following end-points: carcinogenicity, acute mammalian toxicity, reproductive and developmental toxicity, repeated-dose toxicity, and neurotoxicity.  The Estrogen Receptor Transactivation Screen showed no evidence of estrogenic agonism or antagonism was noted.

To further support these statements, it should be highlighted that NBHB passed the US EPA Safer Choice Criteria for Solvents.  While Eastman did not request this same designation for IPHB, it should be noted that this NBHB application relied heavily on IBHB information to address some of the toxicity data requirements.

	1. Acute toxicity.  

                                   Endpoint
                                     NBHB
                                     IPHB
                               Toxicity Category
OPPTS 870.1100 
Acute Oral 
LD50 > 5000 mg/kg of body weight in female rats (no lethality observed)
LD50 > 5000 mg/kg of body weight in female rats (no lethality observed)
                                      IV
OPPTS 870.1200 
Acute Dermal 
Not available
LD50 > 5000 mg/kg of body weight in male and female rats (no lethality observed)
                                      IV
OPPTS 870.1300 
Acute Inhalation 
Not available
LC50 > 5.11 mg/L in male and female rats (4 hr, nose only) rats (no lethality observed)
                                      IV
OPPTS 870.2400 
Eye Irritation
Moderately irritating; cleared by Day 7
Not available
                                      III
OPPTS 870.2500 
Skin Irritation
Slightly irritating
Not a skin irritant
MRID 49642107
                                      IV
OPPTS 870.2600 
Dermal Sensitization
Not a sensitizer
Not a sensitizer
                                Not applicable

	2. Genotoxicty. 
Neither material displayed mutagenic activity in the following assays: reverse mutation assay; in vitro mammalian chromosome aberration test; and the in vitro mammalian cell gene mutation assay.

      3. Reproductive and developmental toxicity. 
Under the conditions of this combined 28-day repeat dose toxicity study with the reproductive/developmental toxicity screening study on IPHB, a dosage of 1000 mg/kg/day was considered to be the NOAEL for reproductive toxicity when administered orally by gavage to Crl:CD(SD) rats.

	4. Subchronic toxicity. 
Under conditions of this combined 28-day repeat dose toxicity study with the reproductive/developmental toxicity screening study on IPHB, the NOAEL for systemic toxicity was considered to be 1000 mg/kg/day.

	5. Chronic toxicity. 
No chronic toxicity data for IPHB and NBHB are available.  Based on the Federal Register Notice (August 9, 2006, Volume 71, Number 153, pages 45415-45424), the Agency states that the preferred test for repeat-dose toxicity is the "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD Test Guideline 422)."  Therefore, an OECD study has been submitted and the results are summarized under Sections 2 and 3 of this document.

	6. Animal metabolism. 
Both IPHB and NBHB have a low water solubility and therefore, it is unlikely that either material will be absorbed by the body and become systemically bioavailable.  

Furthermore, both compounds are expected to hydrolyze quickly and completely in vivo, and the resulting hydrolysis products are very close in structure or are the same, depending on the specific hydrolysis product.  The extent and rate of hydrolysis of IPHB in vitro in rat plasma and liver S9 fraction was studied. In summary, IPHB went from 70 μM to below LOD within 30 minutes with ONLY slight increases in beta-hydroxybutyrate (BHB, CAS Reg. No. 6168-83-8/625-72-9) levels, so while BHB is formed it appears it is only present at very low levels and/or it is rapidly removed from circulation.

No studies were identified on the metabolism of NBHB. However, based on structural similarity with IPHB, it is expected to be hydrolyzed rapidly in vivo as well.

The hydrolysis product BHB is of low concern since it is an endogenous metabolite in humans and is considered GRAS.  

Regarding the other two hydrolysis products, n-butanol is a linear molecule with an even number of carbon atoms. It is expected to undergo beta oxidation leading to the generation of acetyl-CoA that is directly available to be used in the Tricarboxylic (TCA) cycle to produce energy. Isopropanol is a branched molecule with an odd number of carbon atoms. Its beta oxidation leads to the metabolite of propionyl-CoA, which has to be changed to succinyl-CoA to enter the TCA cycle.  Both n-Butanol and Isopropyl alcohol have existing exemptions from the requirements in place.

	7. Metabolite toxicology. 
Not required

	8. Endocrine disruption. 
Neither IPHB nor NBHB belong to a class of chemical known or suspected of having adverse effects on the estrogen receptor or endocrine system. To support this statement, an estrogen receptor transactivity screen was performed on both IPHB and NBHB and neither shows any evidence of estrogenic agonism or antagonism.

C. Aggregate Exposure

	1. Dietary exposure. 
Dietary exposures from the use of either IPHB or NBHB is expected to be minimal.

While no specific food use residue information is available for either IPHB or NBHB, estimates were calculated based on standard EPA guidance/modeling that assumes worst case scenarios.

Dietary Risk Assessment

Agricultural uses
EPA assesses potential dietary exposures to inert ingredient used in agricultural pesticide formulations using a screening-level model referred to as "I-DEEM." The model, as developed by the EPA, uses crop-specific residue data (i.e., maximum tolerances) for 57 active ingredient as surrogates for potential inert ingredient residue levels.  I-DEEM estimates that inert ingredient are used on all crops, and that 100% of all crops are assumed to be "treated" with the inert ingredient(s).  I-DEEM also assumes that the inert is present at a concentration of 50% in all the pesticide formulations.  As an added conservative measure, residues of 100 ppb in water drinking water were also assumed.  

Using these assumptions the chronic dietary exposure is estimated to be 0.190 mg/kg/day for the general U.S. population and 10.692 mg/kg/day for children 1-2 years (i.e., the  most highly exposed subpopulation).

From the 28-day oral toxicity study, a No Observable Adverse Effects Level (NOAEL) of 1000 mg/kg/day was selected for IPHB and NBHB.  An uncertainty factor of 100 (10 for intraspecies variability and 10 interspecies extrapolation) was then applied to the NOAEL.  Thus, the chronic reference dose (cRfD) was calculated to be 10 mg/kg/day.

Based on the I-DEEM screening level calculated, the chronic dietary exposures are estimated to be 1.9% of the cPAD for the general population and 6.9% of the cPAD for children 1-2 years.

Food Contact Surface Sanitizing Solutions
EPA assesses potential dietary exposures to inert ingredient used in food contact sanitizing solutions using several worst-case Food and Drug Administration (FDA) assumptions.  Using these assumptions the daily dietary dose was estimated to be 0.0029 mg/kg/day for an adult male, 0.0033 mg/kg/day for an adult female, and 0.0133 mg/kg/day for children.

From the 28-day oral toxicity study, a NOAEL of 1000 mg/kg/day was selected for IPHB and NBHB.  An uncertainty factor of 100 was applied using the same logic as specified above.

Based on the FDA assumptions, the chronic dietary exposures are estimated to be 0.029 of the %cPAD for adult male, 0.033 of the %cPAD for adult female, and 0.0133 of the %cPAD for children.

Total
When the dietary exposures from the agricultural uses and the food contact surface sanitizing solutions are summed, the chronic aggregate exposure are estimated to be 1.53 of the %cPAD for adults and  7.03 of the %cPAD for children.

	i. Food. 
The total dietary exposures are below the cPAD and therefore, are below EPA's established level of concern for all U.S. subpopulations. 

	ii. Drinking water. 
Drinking water is included the I-DEEM exposure assessment and based on anticipated concentrations expected to be negligible.

	2. Non-dietary exposure. 
Occupational Uses
A screening level assessment was conducted to determine potential exposure (i.e., dermal and inhalation) as a result of occupational activities.  Since no label information was available, several worst-case EPA assumptions were made.

From the 28-day oral toxicity study, a NOAEL of 1000 mg/kg/day was selected.  An uncertainty factor of 100 was applied using the same logic as specified in the dietary exposure section.

When the dermal and inhalation exposures were summed, the worst case exposure (single layer with no glove) was calculated to be 7.54 mg/kg bw/day.  The associated Margin of Error (MOE) was calculated to be 132.  

These estimates show that the occupational exposures are not expected to exceed the Agency's level of concern.

Non-occupational uses
No non-occupational exposures were calculated.  It is assumed that all non-occupational exposures will be of smaller magnitude than these worst-case occupational exposures calculated above. Thus, the calculated values overestimate the non-occupational exposures. 

D. Cumulative Effects

It has not been determined that either IPHB or NBHB have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. 
Based on the conservative exposure estimates used to support this petition, there is reasonable certainty that no harm will result to the U.S. population from the aggregate exposures to IPHB and NBHB.

	2. Infants and children. 
The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database.  Where an adequate and reliable data base is available and there is a lack of evidence of increased susceptibility, the FQPA safety factor may be reduced or removed.

The toxicity database is complete. There is no evidence of increased qualitative or quantitative susceptibility in the young, and the endpoint selected for risk assessment purposes is protective of any potential neurological effects.  No immunotoxicological effects were observed in the available database and exposure estimates are unlike to underestimate risk.  Therefore, the FQPA Safety Factor was reduced to 1x. 

F. International Tolerances

There are no known international tolerances for either IPHB or NBHB.