Page 1 of 6 SUPPLEMENTAL PETITION REQUESTING A PERMANENT EXEMPTION FROM THE REQUIREMENT OF A TOLERANCE FOR RESID UES OF JOINT INERTS TASK

FORCE CLUSTER SUPPORT TEAM 5: “ALKYLPHENOL ETHOXYL ATES” IN OR ON RAW AGRICULT URAL COMMODITIES AND FOOD PRODUCTS

SUBMITTED BY JOINT INERTS TASK FO RCE CLUSTER SUPPORT TEAM 5
ADDRESS 1156 15 TH STREET, NW , SUITE 400 WASHINGTON, DC 20005
DATE April 6 , 2011Page 2 of 6 Background As mandated by the Food Quality Protection Act (FQPA) of 1996, EPA conducted a reassessment of tolerances and exemptions from the requirement of tolerances for inert ingredients used in pesticide products to deter mine if they met Federal Food, Drug, and Cosmetic Act’s (FFDCA) revised standard of safety. As a result of that reassessment, the Agency published a Final Rule in the Federal Register (FR) Notice Volume 71, No. 153, p. 45422, Aug ust 9, 2006 , “ Inert Ingred ients; Revocation of Tolerance Exemptions with Insufficient Data for Reassessment”, that propos ed revocation of specific exemptions from the requirement of a tolerance due to insufficient data. The f ollowing is a brief chronology of the Joint Inerts Ta sk Force (JITF) Cluster Support Team 5 ( CST 5 , EPA Company Number 84941) responses and data generation to comply with the August 9, 2006 revocation.

**•** On August 29, 2007 the JITF CST 5 submitted a data development plan to the EPA , Office of Pesticides Prog ram (OPP), Registration Division (RD), Inert Ingredient Assessment Branch (IIAB), proposing to test Poly (oxy

- 1, 2

- ethanediyl), α - [4

- (1,1,3,3

- tetramethylbutyl) phenyl]

- ω - hydroxy ( CAS RN 9002

- 93

- 1) using the OECD 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity in Rats Screening Test. The data development plan was accepted by the Agency on S eptember 19, 2007

.

**•** On October 31, 2008 ( PP 8E7466 ) , CST 5 submitted a petition to IIAB proposing to establish an exemption from the requirement of a tolerance to support pre

- and post

- harvest uses of a group of inerts known collectively as the “ Alkylphen ol Ethoxylates ” ( APEs ) under the Code of Federal Regulations (CFR) Title 40, Section 180.910 (inert ingredients used pre

- and post

harvest) :

“ α - [p

- (1,1 ,3,3

- tetramethylbutyl)phenyl]

- ω - hydroxypoly (oxyethylene) produced by the condensation of 1 mole of p - (l,1,3,3

- tetramethylbutyl)phenol with a range of 1

- 14 or 30

- 70 moles of ethylene oxide: if a blend of products is used, the average range number of moles of ethylene oxide reacted to produce any product that is a component of the blend shall be in the range of 1

- 14 or 30

- 70 ”

**•** The October 31, 2008 petition requested support for the following two inert ingredient s:Page 3 of 6 **−** CAS RN 9036

- 19

- 5: Poly (oxy

- 1, 2

- ethanediyl), α - [(1,1,3,3

- tetramethylbutyl)phenyl]

- ω - hydroxy

-

**−** CAS RN 9002

- 93

- 1 : Poly (oxy

- 1, 2

- ethanediyl), α - [4

- (1,1,3,3

- tetramethylbutyl) phenyl]

- ω - hydroxy

-

**•** The OECD 422 study conducted on the approved representative parent compound octylphenoxy poly(ethyleneoxy)et hanol, branched ( CAS RN 9002

- 93

- 1 ) (MRID # 47585801) indicated no adverse reproductive or developmental toxicity findings in the offspring. T he NOAEL , for FQPA risk assessment purposes, was established at 150 mg/kg bw/day which was considered to be accepta ble according to the criteria specified in the EPA Inerts

- Dietary Exposure Evaluation Exposure Model (I

- DEEM)

.

**•** In response to IIAB ’s request for additional information April 15, 2009, CST 5 provided supplemental information to the petition , chemical id entity, metabolism and safety assessment data that includ ed drinking water exposure monitoring for the metabolite p

- t
octylphenol CAS RN 140

- 66

- 9 . On May 15, 2009 , CST 5 also provided additional dermal absorption and us e information (MRID # 47752401).

**•** On July 14 2009 , EPA provided a draft risk assessment “ Alkylphenol Ethoxylates (APEs

– JITF CST 5 Inert Ingredients) Human Health Risk Assessment to Support the Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations ” (PC Code 800883, DP Barcode D366012) , which requested that the JITF CST 5 provide additional information on potential mammalian toxicology , mammalian and plant metabolism and environmental effects for the proposed metabolite , octylphenol

.

**•** In the “ Revised Human Health Risk Assessment to Support the Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations ” ( April 5, 2010, PC Code 800883 ; DP Barcode 371902 ) , OPP Health Effects Division (HE D) made the following regulatory stipulation :

“ Provided the amount of the APE inert is limited to no more than 7% by weight in final pesticide formulations for agricultural and outdoor residential products, and 3% for indoor residential products, there ar e no human health risk considerations that would preclude the establishment of one

- year time limited exemptions from the requirement of a tolerance as follows:Page 4 of 6 Under 40 CFR 180.910:

α - [p

- (1,1,3,3

- tetramethylbutyl)phenyl]

- ω - hydroxypoly (oxyethylene) produced by the condensation of 1 mole of p - (l,1,3,3

- tetramethylbutyl)phenol with a range of 1

- 14 or 30

- 70 moles of ethylene oxide: if a blend of products is used, the average range number of moles of ethylene oxide reacted to produce any product that is a component of the blend shall be in the range of 1

- 14

**•** On the basis of the risk assessment and the information submitted by CST 5 , EPA published the Final Rule (FR Notice Volume 75, No. 94 , pages 27443

- 27452, May 17, 2010) to establish a time

- limited exemption from the requirement of a tolerance for APEs when used as inert ingredients, not to exceed 7% in pesticide formulations applied to growing crops and raw agricultural commodities after harvest 40 CFR 180.910. This time

- limited exemption for the CST 5 compounds expires May 17, 2012

. EPA concluded that there is a “ reasonable certainty that no harm ” will result to the general popul ation or to infants. The A gency also carefully considered t he weight of the evidence with respect to carcinogenicity for both the parent compounds and the octylphenoxy degradate, and concluded that the cancer risks would be negligible. However, to resolve uncertainty in the mutagenicity database, the Agency reques ted confirmatory data and requested that CST 5 provide additional mutagenicity testing for Poly (oxy

- 1, 2

- ethanediyl), α - [4

- (1,1,3,3

- tetramethylbutyl) phenyl]

- ω - hydroxy ( CAS RN 9002

- 93

- 1

.

**•** In response to the May 17 , 2010 Federal Register Notice , CST 5 conducted an in vivo Mouse Bone Marrow Erythrocyte Micronucleus Test Following Oral Administration (OPPTS 870.5395; OECD 474) of the representative test compound, Poly(oxy

- 1,2

- ethanediyl),α

- [4

- (1,1,3,3

- tetramethylbutyl)phenyl]

- ω - hydroxy

- ( CAS RN 9002

- 93

- 1) (MRID # 48293301 )

. The data did not indicate mutagenic effects. In accordance to the deadline established by EPA, these data were submitted to the Agency on November 12, 2010

. Mouse Bone Marrow Erythrocyte Micronucleus Test (OCSPP 870.5395 ) Following Or al Administration of CAS RN 9002 - 93 - 1)(MRID # 48293301) Summary

Under the conditions of the assay described in the final report (MRID # 48293301) , “ a single oral administration of the test substance at doses up to and including 1800 mg/kg (males) and 2000 mg/kg (females) did not induce a significant increase in the incidence of micronucleated polychromatic erythrocytes in bone marrow. Therefore, Poly(oxy

- 1,2

- ethanediyl),α

- [4

- (1,1,3,3

-Page 5 of 6 tetramethylbutyl)phenyl]

- ω - hydroxy

- ( CAS RN 9002

- 93

- 1) was concluded to b e negative in the micronucleus test using male or female ICR mice. ”

**•** The dose formulation analysis indicated that the mean concentrations for nomin a l concentrations of 22.5, 45, 90, and 100 mg/mL were 21.5, 39.7, 81.5 and 89.8 mg/mL, respectively. The perc ent recovery of the target concentrations were 95.6%, 88.1%, 90.5% and 89.8%, respectively. These results were within the acceptance criteria (± 15% of the nominal concentration). Therefore, animals were exposed to the intended doses.

**•** All mice in the cont rol substance (vehicle or positive) groups and all mice in test substance groups at 450 or 900 mg/kg groups appeared normal during the study period. Piloerection and/or lethargy was observed in male mice at 1800 mg/kg while piloerection was observed in fem ale mice at 2000 mg/kg. Mortality was observed 1/5 male mice at 1800 mg/kg and 1/5 female mice at 2000 mg/kg, in the replacement group.

**•** In the bone marrow, no appreciable reductions in the ratio of polychromatic erythrocytes to total erythrocytes in the t est substance groups relative to the respective vehicle control groups was observed, suggesting that the test substance did not markedly inhibit erythropoiesis.

**•** No statistically significant increase in the incidence of micronucleated polychromatic erythro cytes in test substance groups relative to the respective vehicle control groups was observed in male or female mice at 24 or 48 hours after dose administration (p > 0.05, Kastenbaum

- Bowman Tables).

**•** Cyclophosamide ( CP, CAS RN 6055

- 19

- 2) the positive contr ol, induced a statistically significant increase in the incidence of micronucleated polychromatic erythrocyctes (PCEs) (p ≤ 0.05, Kastenbaum

- Bowman Tables) in both male and female mice. The number of micronucleated PCEs in the vehicle control groups did not exceed the historical vehicle control range. Based upon this, all criteria for a valid test were met as specified in the protocol. Summary Conclusion To summarize, the JITF CST 5 believes it has duly fulfilled the testing requirements that were publish ed in the Federal Register Notices of August 9, 2006 and May 17, 2010 , respectively

. The results of testing, provide definitive information to confirm EPA ’s conclusion that the use ofPage 6 of 6 APE inert ingredients in pesticide formulations complies with the FQPA m andate of reasonable certaint y of no harm

.

**•** EPA previously concluded that based on the weight of evidence there is no evidence of increased susceptibility, neurotoxicity, developmental toxicity, or reproductive toxicity for the APEs supported by the JITF CST 5

.

**•** CST 5 conducted a bone marrow assay (Harmonized Guideline 870.5395

— Mammalian erythrocyte micronucleus test) to address any uncertainty in the mutagenicity database . The results of this assay were negative indicating no mutagenic effect and there fore confirm ing the Agency’s conclusion that cancer risks would be negligible

. Thus, based on the weight of evidence and the body of data that has been submitted, and reviewed by EPA in support of the tolerance exemption for pre

- and post

- harvest uses of APEs, CST 5 requests that the Agency establish a permanent exemption for the requirement of a tolerance under the Code of Federal Regulations Title 40, Section 180.910 for :

α - [p

- (1,1 ,3,3

- tetramethylbutyl)phenyl]

- ω - hydroxypoly (oxyethylene) produced by the condensation of 1 mole of p - (l,1,3,3

- tetramethylbutyl)phenol with a range of 1

- 14 or 30

- 70 moles of ethylene oxide: if a blend of products is used, the average range number of moles of ethylene oxide reacted to produce any product that is a component of the blend shall be in the range of 1

- 14 or 30

- 70 not to exceed 7% in pesticide formulations

.