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SUPPLEMENTAL PETITION

REQUESTING A PERMANENT EXEMPTION FROM THE

REQUIREMENT OF TOLERANCE FOR RESIDUES OF 

JOINT INERTS TASK FORCE, CLUSTER SUPPORT TEAM 9 

NONYLPHENOL ETHOXYLATE PHOSPHATE AND SULFATE 

DERIVATIVES IN OR ON RAW AGRICULTURAL COMMODITIES 

AND APPLIED TO ANIMALS

SUBMITTED BY

JOINT INERTS TASK FORCE

CLUSTER SUPPORT TEAM 9

ADDRESS

1156 15TH STREET, NW, SUITE 400

WASHINGTON, DC 20005

DATE

April 8, 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 9

(CST 9, EPA Company Number 84943) responses and data generation to comply with the 

August 9, 2006 revocation. 

• On August 30, 2007 the JITF CST 9 submitted a data development plan to the EPA, Office 

of Pesticides Program (OPP), Registration Division (RD), Inert Ingredient Assessment 

Branch (IIAB), proposing to test the representative Nonylphenol Ethoxylate (NPE)

phosphate (CAS RN 68412-53-3) and sulfate (CAS RN 9014-80-8) derivatives 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 November 12, 2008, CST 9 submitted a petition (PP 8E7478) to IIAB proposing to 

establish an exemption from the requirement of a tolerance to support the NPE phosphate and 

sulfate derivatives (NPEPSD) under the Code of Federal Regulations (CFR) Title 40, Section 

180.910 and Section 180.930

NPE Phosphate Derivatives (NPEPD) Supported by the JITF CST 9

α-(p-Nonylphenyl)-ω-hydroxypoly(oxyethylene) mixture of dihydrogen 

phosphate and mono hydrogen phosphate esters and the corresponding 

ammonium, calcium, magnesium, monoethanolamine, potassium, sodium, 

and zinc salts of the phosphate esters; the nonyl group is a propylene 

trimer isomer and the poly(oxyethylene) content averages 4-14 moles or 

30 moles

CAS RN Chemical Name

51811-79-1 Poly (oxy-1, 2-ethanediyl), α-(nonylphenyl)-ω-hydroxy-, 

phosphate
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CAS RN Chemical Name

59139-23-0 Ethanol, 2-amino-, compd. with α-(nonylphenyl)-ωhydroxypoly(oxy-1,2-ethanediyl) phosphate

67922-57-0

Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)-ω-hydroxy-, 

phosphate, magnesium salt Poly(oxy-1,2-ethanediyl), α-

(nonylphnyl)-ω-hydroxy-, phosphate, magnesium salt

68412-53-3 Poly(oxy-1,2-ethanediyl), α-(4-nonylphenyl)- ω-hydroxy-

, phosphate, sodium salt

68553-97-9 Poly(oxy-1,2-ethanediyl), α-(4-nonylphenyl)- ω-hydroxy-

, phosphate, sodium salt

68954-84-7 Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)- ω-hydroxy-, 

branched, phosphate, sodium salt

99821-14-4 Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)- ω-hydroxy-, 

phosphate, calcium salt

152143-22-1 Poly(oxy-1,2-ethanediyl), α-(4-nonylphenyl)- ω-hydroxy-

, branched, phosphates

51609-41-7 Poly(oxy-1,2-ethanediyl), α-(4-nonylphenyl)-ω-hydroxy-, 

phosphate

37340-60-6 Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)-ω-hydroxy-, 

phosphate, sodium salt

106151-63-7 Poly(oxy-1,2-ethanediyl), α-phosphono-ω-(4-

nonylphenoxy)-, dipotassium salt

68584-47-4 Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)-ω-hydroxy-, 

branched, phosphates, potassium salts

52503-15-8 Poly(oxy-1,2-ethanediyl), α-(nonylphenyl)-ω-hydroxy-, 

phosphate- , potassium salt

68458-49-1 Polyphosphoric acids, esters with polyethylene glycol 

nonylphenyl ether

NPE Sulfate Derivatives (NPESD) Supported by the JITF CST 9

α-(p-nonylphenol)- ω-hydroxypoly(oxyethylene) sulfate, ammonium, 

calcium, magnesium, potassium, sodium, and zinc salts the nonyl group is 

propylene trimer isomer and the poly(oxyethylene) content averages 4 

moles

CAS RN Chemical Name

9014-90-8 Poly (oxy-1, 2-ethanediyl), α-sulfo-ω- (nonylphenoxy), 

sodium salt

9051-57-4 Poly (oxy-1, 2-ethanediyl), α-sulfo-ω(nonylphenoxy), 

ammonium salt

9081-17-8 Poly (oxy-1, 2-ethanediyl), α-sulfo-ω- (nonylphenoxy), 

acid
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CAS RN Chemical Name

68649-55-8 Poly (oxy-1, 2-ethanediyl), α-sulfo-ω-(nonylphenoxy), 

branched, ammonium salt

68891-33-8 Poly (oxy-1, 2-ethanediyl), α-sulfo-ω-(nonylphenoxy), 

branched

• The OECD 422 study conducted on a representative NPE phosphate derivative (NPEPD), 

Poly(oxy-1,2-ethanediyl), α-(4-nonylphenyl)- ω-hydroxy-, phosphate, sodium salt, CAS RN 

68412-53-3 (MRID # 47603701), indicated no adverse reproductive or developmental 

toxicity findings in the offspring. The NOAEL, for FQPA risk assessment purposes, was 

established at 396 mg/kg bw/day which was considered to be acceptable according to the 

criteria specified in the EPA Inerts - Dietary Exposure Evaluation Exposure Model (IDEEM). 

• The OECD 422 study conducted on representative NPE sulfate derivative (NPESD), Poly 

(oxy-1, 2-ethanediyl), α-sulfo-ω- (nonylphenoxy), sodium salt, CAS RN 9014-90-8 (MRID #

47603702), indicated no adverse reproductive or developmental toxicity findings in the 

offspring. The NOAEL, for FQPA risk assessment purposes, was established at 300 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). 

• On June 2, 2009, CST 9 provided supplemental information to the petition including 

chemical identity, metabolism and safety assessment data that included drinking water 

exposure monitoring (MRID # 47766401).

• On July 15, 2009, OPP Health Effects Division (HED) provided a draft risk assessment 

“Nonylphenol Ethoxylates and Their Phosphate and Sulfate (NPEs – JITF CST 9 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 911703, DP Barcode D366013), which requested additional toxicity studies, and 

residue chemistry data for both the parent compounds and nonylphenol metabolites. On 

August 7, 2009, EPA issued a FR Notice which delayed the effective date for the tolerance 

exemptions.

• In response to the Risk Assessment, CST 9 provided additional regulatory and technical 

information to support the establishment of NPEPD and NPESD tolerance exemptions. On 

August 14, 2009, CST 9 submitted copies of previously cited publically available data, and 
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copies of data and public literature that CST 9 identified as relevant to the uncertainties 

identified in the risk assessment. On August 19, 2009, CST 9 submitted a Position Paper 

regarding the FQPA safety factor.

• On the basis of the risk assessment and the information submitted by CST 9, EPA published 

the Final Rule (FR Notice Volume 75, No. 94, pages 27434-27443, May 17, 2010) to 

establish a time-limited exemption from the requirement of a tolerance for NPEPSDs 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) and applied to 

animals (40 CFR 180.930). This time-limited exemption for the NPEPSD inert ingredients 

supported by CST 9 will expire 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 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 9 provide additional mutagenicity testing.

• In response to the May 17, 2010 FR Notice, CST 9 conducted two in vivo Mouse Bone 

Marrow Erythrocyte Micronucleus Test (OCSPP 870.5395; OECD 474) Following Oral 

Administration of the representative NPEPD CAS RN 68412-53-3 (MRID # 47603701), and 

of the NPESD CAS RN 9014-90-8 (MRID # 47603702). In accordance with 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 the NPEPD, CAS RN 68412-53-3 (MRID # 47603701) Summary

Under the conditions of the assay described in the final report (MRID # 47603701), a single oral 

administration of the test substance at doses up to and including a dose of 2000 mg/kg did not 

induce a significant increase in the incidence of micronucleated polychromatic erythrocytes in 

bone marrow of male or female ICR mice. Therefore, Poly(oxy-1,2-ethanediyl),α-

(nonylphenyl)-ω-hydroxy-,branched,phosphates (CAS RN 68412-53-3), was concluded to be 

negative in the mouse micronucleus assay.
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• Dose formulation analysis indicated that all formulations were within the acceptance criteria 

(± 15% of the nominal concentration). Therefore, animals were exposed to the intended 

doses.

• No mortality was observed in any of the treatment groups. All mice in the control groups 

(vehicle or positive) and all female mice in the test substance treatment groups (500, 1000 

and 2000 mg/kg) and all male mice in 500 or 1000 mg/kg treatment groups appeared normal 

during the course of the study. Lethargy, piloerection and/or hunched position were observed 

in some of the male mice at 2000 mg/kg.

• In the bone marrow, dose dependent reductions in the ratio of polychromatic erythrocytes to 

total erythrocytes from 13% to 18% in male mice and from 3% to 8% in the female mice in 

the 24 hour test substance treatment groups were observed. Reductions of 10% and 1% were 

also seen in male and female groups at 48 hour post-dose, respectively, relative to the vehicle 

controls. These reductions suggest bioavailabilty of the test substance.

• No statistically significant increase in the incidence of micronucleated polychromatic 

erythrocytes in test substance groups relative to the respective vehicle control substance 

groups was observed in male or female mice at 24 or 48 hours after dose administration (p > 

0.05, Kastenbaum-Bowman Tables).

• Cyclophosamide (CP), the positive control substance, induced a statistically significant 

increase in the incidence of micronucleated PCEs (p≤ 0.05, Kastenbaum-Bowman Tables) in 

both male and female mice relative to the respective vehicle control groups. The number of 

micronucleated PCEs in the vehicle control groups did not exceed the historical vehicle 

control range. Based upon these, all criteria for a valid test were met as specified in the 

protocol.

Mouse Bone Marrow Erythrocyte Micronucleus Test (OCSPP 870.5395) Following Oral 

Administration of the NPESD CAS RN 9014-90-8 (MRID # 47603702) 

Under the conditions of the assay described in the final report (MRID # 47603702), “a single 

oral administration of the test substance at doses up to and including a dose of 2000 mg/kg did 

not induce a significant increase in the incidence of micronucleated polychromatic erythrocytes 

in bone marrow of male or female ICR mice. Therefore, Poly (oxy-1, 2-ethanediyl), α-sulfo-ω-

(nonylphenoxy), sodium salt (CAS RN 9014-90-8) was concluded to be negative in the mouse 

micronucleus assay.”
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• The dose formulation analysis indicated that the mean concentrations for nominal 

concentrations of 25, 50, and 100 mg/mL were 24.7, 47.7, and 98.5 mg/mL, respectively. 

The percent recovery of the target concentrations were 98.8%, 95.4%, and 98.5%, 

respectively. These results were within the acceptance criteria (± 15% of the nominal 

concentration). Therefore, animals were exposed to the intended doses.

• No mortality was observed in any of the treatment groups. All mice in the control groups 

(vehicle or positive) and all mice in the 500 mg/kg treatment group appeared normal during 

the course of the study. Lethargy and/or piloerection were observed in some of the mice in 

1000 and 2000 mg/kg dose groups immediately after dose administration. However, these 

mice appeared normal during the remaining period of the study.

• No appreciable reductions in the ratio of polychromatic erythrocytes to total erythrocytes in 

the test substance groups relative to the respective vehicle control groups were observed in 

the bone marrow suggesting that the test substance did not inhibit erythropoiesis markedly.

• No statistically significant increase in the incidence of micronucleated polychromatic 

erythrocytes in test substance groups relative to the respective vehicle control substance 

groups was observed in male or female mice at 24 or 48 hours after dose administration (p > 

0.05, Kastenbaum-Bowman Tables).

• Cyclophosamide (CP), the positive control substance, induced a statistically significant 

increase in the incidence of micronucleated PCEs (p≤ 0.05, Kastenbaum -Bowman Tables) in 

both male and female mice relative to the respective vehicle control groups. The number of 

micronucleated PCEs in the vehicle control groups did not exceed the historical vehicle 

control range. Based upon these, all criteria for a valid test were met as specified in the 

protocol.

Summary Conclusion

To summarize, CST 9 believes it has duly fulfilled the testing requirements that were published 

in the FR Notices of August 9, 2006 and May 17, 2010, respectively. The results of testing, 

summarized below, provided definitive information for EPA to conclude that the use of NPEPSD

inert ingredients in pesticide formulations comply with the FQPA mandate of “reasonable 

certainty of no harm”.
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• 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 NPEPSD inert ingredients supported by CST 9. 

• CST 9 conducted two bone marrow assays (Harmonized Guideline 870.5395 — Mammalian 

erythrocyte micronucleus test) to address any uncertainty in the mutagenicity database. The 

results of these assays were negative and therefore confirm the Agency’s conclusion that 

cancer risks would be negligible.

Thus, based on the weight of evidence and body of data that has been submitted, and reviewed 

by EPA in support of the tolerance exemptions of NPEPSD inert ingredients, CST 9 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, and Section 180.930 for:

α-(p-Nonylphenyl)-ω-hydroxypoly(oxyethylene) mixture of 

dihydrogen phosphate and mono hydrogen phosphate esters and the 

corresponding ammonium, calcium, magnesium, monoethanolamine, 

potassium, sodium, and zinc salts of the phosphate esters; the nonyl 

group is a propylene trimer isomer and the poly(oxyethylene) 

content averages 4-14 moles or 30 moles not to exceed 7% in 

pesticide formulations.

α-(p-nonylphenol)- ω-hydroxypoly(oxyethylene) sulfate, 

ammonium, calcium, magnesium, potassium, sodium, and zinc salts 

the nonyl group is propylene trimer isomer and the 

poly(oxyethylene) content averages 4 moles (CAS RNs 9014-90-8, 

9051-57-4, 9081-17-8, 68649-55-8, 68891-33-8), not to exceed 7% 

in pesticide formulations.