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**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 re place the instructions that appear in**  **green , i.e., “**  **[ insert company**  **name ]**  **,” with the information specific to your action.**

**TEMPLATE:**
**Eastman Chemical C ompany** **, Inc. [**  **IN -**  **10841 ]**  EPA has received a pesticide petition **( IN**  **- 10841**  **)** from **Eastman C hemical**  **Company , Inc.**  **, 200 S outh 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 P art 180. to establish an exemption from the requirement of a tolerance for

**N -**  **butyl -**  **3 -**  **Hydroxybutyrate (CAS R**  **eg. N**  **o. 53605**  **- 94** **- 0)**  **and Isopropy**  **l -**  **3 -**  **Hydroxybutyrate (C** **AS R**  **eg. N**  **o. 54074** **- 94** **- 1)**  **when used as an inert solvent**2 **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 th e 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 d a ta at this time or whether the data supports granting of the petition. Additio nal 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**  **( IP**  **HB )**  **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 ne urotoxicity. The Estrogen Receptor**  **Transactivation Screen showed no evidence of estrogenic agonism or antagonism was noted.** 3

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

1. Acute toxicity.
**Endpoint NBHB**  **IPHB Toxicity**  **Category OPPTS 870.1100**  **Acute Oral LD**  **50 > 5000 mg/kg of** 

**body weight in female rats (no lethality**  **observed) LD**  **50 > 5000 mg/kg of body**  **weight in female rats (no**  **lethality observed) IV** 

**OPPTS 870.1200 Acute Dermal**  **Not available LD**  **50 > 5000 mg/kg of body**  **weight in male and female rats (no lethality observed)**  **IV**

**OPPTS 870.1300 Acute Inhalation**  **Not available LC**  **50 > 5.11 mg/L in male**  **and female rats (4 hr, nose only)**  **rats (no lethality o**  **bserved) 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.4

**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 combin**  **ed 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 NO** **A EL for reproducti**  **ve 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 pre** **ferred test for repeat -**  **dose toxicity is the “ C**  **ombined 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 Sec tions 2 and 3 of this document.** 

6. Animal metabolism. **Both IPHB and NBH B**  **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**5

**IPH B**  **in vitro in rat plasma and liver S9 fraction was studied. In summary, IPHB went**  **from 70 μ**  **M to below LOD within 30 minutes with ONLY slight increases in beta**   ** hydroxybutyrate (BHB, CAS** **R eg.**  **N o.**  **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.**

**T he hydrolysis product BHB is of low concern since it is an endogenous metabolite**  **in humans and is considered GRAS. Regarding the other two hydrolysis product**  **s , 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 . **No t 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 Exposure6

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 assess es**  **potent i**  **a l dietary exposures to inert ingredient used in agricultural**  **pesticide formulations u**  **s ing 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 ingredie nt 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**  **assume s**  **that the inert is prese**  **nt at a concentration of 5 0% in all the pesticide**  **formulations. As a**  **n added cons**  **ervative measure, residues of 10 0 ppb in water**  **drinking water were also assumed .**  **Using these assumptions the chronic dietary e xposure 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 Observ able Adverse Effects Level (NOAEL)**  **of 1000 mg/kg/** **day was selected for IPHB and N**  **BH B**  **. 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.**7

**B ased on the I**  **- DEEM screening level calculated, the**  **chronic dietary ex posures 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 con tact**  **s anitizin**  **g s olutions using several worst**  **- case Food and Drug Administration (FDA)**  **assumptions . Using these assumptions the**  **daily dietary dose was estimated to be**  **0.0 029 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 N**  **OAEL of 1000 mg/ kg/** **day was selected for IPHB**  **and N BH**  **B .**  **An uncertainty factor of 100 was applied using the same logic as specified**  **above. Based on the FDA assumptions, t**  **he chronic dietary e xposures are estimated to be**  **0.029 of the %cPAD for adult male, 0. 033**  **of the %cPAD for adult fe**  **male, and 0.0 133**  **of the %cPAD for**  **children.**
**Total When the dietary exposures**  **from the a**  **gricultural uses and the food contact surface**  **s anitizing**  **s olutions 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. **T he total dietary exposures are below the**  **cPAD and therefore, are below E PA** **’ s**  **established level of concern for all U.S. subpopulations**  **.**
ii. Drinking water.8

**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 w as 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 Effects9

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

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 rel**  **iable 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 quantit**  **at ive**  **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. Therefo re, the FQPA Safety Factor**  **was reduced to 1x.** 

F. International Tolerances
**There are no know n**  **international tolerances for either IPHB or NBHB.**