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SUPPLEMENTAL PETITION REQUESTING A PERMANENT EXEMPTION FROM 

THE REQUIREMENT OF A TOLERANCE FOR RESIDUES OF JOINT INERTS TASK 

FORCE CLUSTER SUPPORT TEAM 5: “ALKYLPHENOL ETHOXYLATES” IN OR 

ON RAW AGRICULTURAL COMMODITIES AND FOOD PRODUCTS

SUBMITTED BY

JOINT INERTS TASK FORCE

CLUSTER SUPPORT TEAM 5

ADDRESS

1156 15TH STREET, NW, SUITE 400

WASHINGTON, DC 20005

DATE

April 6, 2011
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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 determine 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, 

August 9, 2006, “Inert Ingredients; Revocation of Tolerance Exemptions with Insufficient Data 

for Reassessment”, that proposed revocation of specific exemptions from the requirement of a 

tolerance due to insufficient data. 

The following is a brief chronology of the Joint Inerts Task 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 Program (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 September 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 “Alkylphenol Ethoxylates” (APEs) under the Code 

of Federal Regulations (CFR) Title 40, Section 180.910 (inert ingredients used pre- and postharvest):

“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 

ingredients:
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− 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)ethanol, branched (CAS RN 9002-93-1) (MRID # 

47585801) indicated no adverse reproductive or developmental toxicity findings in the 

offspring. The NOAEL, for FQPA risk assessment purposes, was established at 150 mg/kg 

bw/day which was considered to be acceptable 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 identity, metabolism and safety 

assessment data that included drinking water exposure monitoring for the metabolite p-toctylphenol CAS RN 140-66-9. On May 15, 2009, CST 5 also provided additional dermal 

absorption and use 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 (HED)

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 are no human health risk considerations that would 

preclude the establishment of one-year time limited exemptions 

from the requirement of a tolerance as follows:
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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 population or to infants. The Agency also 

carefully considered the 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 requested 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 Oral 

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-
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tetramethylbutyl)phenyl]-ω-hydroxy- (CAS RN 9002-93-1) was concluded to be negative in the 

micronucleus test using male or female ICR mice.”

• The dose formulation analysis indicated that the mean concentrations for nominal 

concentrations of 22.5, 45, 90, and 100 mg/mL were 21.5, 39.7, 81.5 and 89.8 mg/mL, 

respectively. The percent 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 control 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 

female 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 test 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 

erythrocytes 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 control, 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 

published 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 of
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APE inert ingredients in pesticide formulations complies with the FQPA mandate of reasonable 

certainty 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 therefore confirming

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.