# i

**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 re place the instructions that appear in**  **green , i.e., “**  **[ insert**  **company name ]**  **,” with the information specific to your action. TEMPLATE:**  **[ Bayer HealthCare LLC, Animal Health Division**  **] [**  **I N**  **- 10884**  **]** EPA has received a pesticide petition **( IN**  **- 10884**  **)** from **Technology Sciences Group Inc.**  **(1150 18 th**  **Street, N.W. Suite 1000, Washington, D.C. 20036) on behalf of**  **Bayer HealthCare ,**  **LLC , Animal Health Division**  **, (** **P.O Box 390 Shawnee Mission, KS 66201**  **)** 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 **iron oxide yellow (CAS #**  **20344 -**  **49 -**  **4 )**  **]** in or on the raw agricultural commodity **[ honey**  **] .**  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**  **.]** 2. Analytical method. **[ NA** **- Remove**  **.]** 3. Magnitude of residues. **[ NA** **- Remove**  **.]** B. Toxicological Profile 1. Acute toxicity. **Iron oxides are an inorganic source of iron, and iron is an essential element required by all forms of life. Iron is a critical component of the**  **heme proteins: hemoglobin, myoglobin and cytochromes, as well as iron -**  **sulfur enzymes, iron st**  **orage and transport proteins, and other iron -**  **containing or iron -** 2

**activated enzymes. Data from laboratory animal studies i**  **n dogs and cats indicated that**  **high levels of iron oxide in the diet (up to 10 g/kg) did not cause adverse effects.** 2. Genotoxicty. **Iron oxide yellow is**  **an inorganic the essential element,**  **iron that is**  **required by all forms of life. It is not necessary to evaluate the potential**  **genotoxicity of this simple source of the essential element, given the natural occurrence of iron oxides in**  **food.** 3. Reproductive and developmental toxicity. **N o adverse effects on reproduction**  **were reported in rats that consumed more than 50 mg/kg/day iron oxide for 8 -**  **generations .**  4. Subchronic toxicity. **The National Academy of Sciences (NAS)**  **Institute of Medicine published a detailed report that included derivation of a Tolerable Upper**  **Intake Level (UL) for iron of 40 mg/day for children (2 to 13 years of age), and a UL of 45 mg/day for adolescents and adults (14 years of age and older). The**  **US Food and Drug Administration**  **(FDA) accepted these ULs as the highest levels of iron that**  **pose no risk of an adverse effect when the nutrient is consumed over long periods of time.**  5. Chronic toxicity. **The NAS**  **- derived**  **Tolerable Upper Intake Level s**  **( UL**  **s )**  **for iron of 40 mg/day for children (2 to 13 years of age), and 45 mg/day for adolescents**  **and adults (14 years of age and older) are suitable for chronic exposure assessment**  **. The US**  **FDA accepts these ULs as the highest levels of iron that pose no risk**  **of an adverse effect when the nutrient is consumed over long periods of time**  **, and this indicates the ULs are suitable for evaluation of chronic exposure.**  6. Animal metabolism. **Elemental iron is the key metabolite of iron oxide in the body.**  **A key biolo gical function of iron is transfer of oxygen from the environment**  **to the tissues. Oxygen binds to the iron -**  **containing porphyrin ring of hemoglobin where it is transported within the erythrocytes to the tissues, and it may be**  **transferred to myoglobin which facilitates oxygen diffusion through the muscle**  **tissues. Iron is also an important component of cytochrome heme proteins that are active in the mitochondrial respiratory systems**  **.** 7. Metabolite toxicology

. **The iron oxide**  **metabolite of interest is elemental iron, which is an essential element.**  8. Endocrine disruption

. **Toxicity related to endocrine disruption was not observed in the**  **iron oxide yellow database.**  C. Aggregate Exposure 1. Dietary exposure. **The estimated chronic dietary exposure to iron oxide**  **yellow was determined using the Dietary Exposure Evaluation Model**  **(DEEM) software with the Food Commodity Intake Database**  **. The assessment assumes**  **that: 1)**  **the inert ingredient is used on only honey from**  **bee hives, 2)**  **100% of hives are**3

**treated with the inert , and**  **3) 100% of the inert is transferred to the honey. The**  **maximum exposure was 0.0 % of the Population Adjusted dose.**  i. Food. **The food commodities included in the assessment were honey, and honey,**  **baby food.** ii. Drinking water

. **No drinking water exposure from the use of iron oxide**  **yellow in honey bee hives to control varroa mites is expected**  **.** 2. Non

- dietary exposure

. **The only non**  **- dietary**  **exposure to iron oxide yellow**  **from use of the bee hive str ips**  **possible would be dermal exposure to workers that**  **apply the strips to the hives if they do not wear gloves**  **.** D. Cumulative Effects **I ron oxide yellow**  **has been used for many years in food, drugs and cosmetics**  **. The additional exposure to 0.0**  **% of the Population Adjusted D**  **ose of iron oxide**  **is not expected to increase the current exposures significantly.**  E. Safety Determination 1. U.S. population. **The low toxicity of iron oxide yellow**  **and the lack of**  **potential exposure from the proposed use suggest th**  **at the total aggregate exposures to iron**  **will be well below the acceptable exposure. Thus, a safety finding for iron**  **oxide yellow can be concluded for aggregate exposures from dietary and non**  **** **dietary uses.** 2. Infants and children

. **The low toxicity of iron oxide**  **and the lack of potential**  **dietary exposure suggest that the total aggregate exposures for infants and children**  **will be well below the acceptable exposure. Thus, a safety finding for**  **iron oxide yellow**  **can be concluded for infant and child exposu**  **res from dietary uses**  **.** F. International Tolerances **There are no international tolerances for iron oxide yellow. Codex general standards for food additives (GSFA) for iron oxides have been developed for more**  **than a dozen foods, including breakfast cerea ls (75 mg/kg), chewing gum (10,000**  **mg/kg), and jams, jellies and marmalades (200 mg/kg) to name a few .**  **]**