EPA REGISTRATION 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 prep aring 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 replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action

[Joint Inerts Task Force, Cluster Support Team 14]

[Insert Petition Number]

EPA has received a pesticide petition ([Insert Petition Number]) from [Joint Inerts Task Force, Cluster Support Team 14, EPA Company Number 84946], [c/o CropLife America, 1156 15 th Street, N.W., Suite 400, Washington, DC 20005] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosm etic Act (FFDCA), 21 U.S.C. 346a(d), to

amend [the current 40 CFR 180.920 tolerance exemptio n for the Sodium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid (SS NA) inert ingredients to include the exemption from the requirement of a tolerance for Sodi um and Potassium salts of N-alkyl (C 8 – C 18 )- β

iminodipropionic acid under 40 CFR §180.940 uses, including:

Sodium and potassium salts of N-alkyl (C 8 – C 18 )- β -iminodipropionic acid where the C 8 – C 18 is linear and may be saturated and/or unsatur ated provided that the concentration of

the inert is limited to no more than 30% by weight in pesticide formulations.

Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid

CAS RN Chemical Name

110676-19-2 β -alanine, N-(2-carboxyethyl)-N-oc tadecyl-, dipotassium salt

3655-00-3 β -alanine, N-(2-carboxyethyl)- N-dodecyl-disodium salt

61791-56-8 β -alanine, N-(2-carboxyethyl)-N- tallow alkyl derivs-,disodium

salts

14960-06-6 β -alanine, N-(2-carboxyethyl)-N- dodecyl-, monosodium salts

26256-79-1 β -alanine, N-(2-carboxyethyl)- N-dodecyl-,disodium salt

90170-43-7 β -alanine, N-(2-carboxyethyl)-N- coco alkyl derivs-,disodium

salts

91696-17-2 β -alanine, N-(2-carboxyethyl)-N- (C 8 -C 18 and C 18 unsat’d alkyl) derivs, disodium salt

97862-48-1 β -alanine, N-(2-carboxyethyl)-N- (C 14 -C 18 and C 18 unsat’d alkyl) derivs, disodium salt

]EPA has determined that the petition contains da ta or information regarding the elements set forth in section 408 (d)(2) of FFDCA; however, EP A 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. [Not Applicable]

2. Analytical method. [Not Applicable]

3. Magnitude of residues. [There is no specific crop res idue information available for

Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid, and this information is typically not available nor re quired for the establishment of a tolerance exemption for inert ingredients.]

B. Toxicological Profile

1. Acute toxicity. [ The Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β

iminodipropionic Acid inerts have low acut e oral (EPA Category III or IV) and dermal toxicity (EPA Category III), but are potentially corrosive to the skin, and mild to moderate eye irritants. The acute oral LD 50 of CAS RN 3655-00-3 was found to be greater than 2,000 mg/kg while LD 50 values CAS RN 3546-96-1 are reported to be greater than 5,000 mg/kg in rats, 8,000 mg/kg in rabbits, and 17,800 mg /kg in mice. The acute dermal LD 50 for CAS RN 3546-96-1 was greater than 6,800 mg/kg in ra bbits. CAS RN 3546-96-1 showed irritating properties up to corrosive effe cts to the rabbit skin in in vivo studies. An in vitro study carried out with CAS RN 3655-00-3, demonstrated the potential to be co rrosive to the skin after a contact period of 24 hours. In vivo studies carried out with mixtures containing CAS RN 3546-96-1 showed moderate to mildly irri tating properties to the rabbit eye, and practically nonirritating effects with rins ing. CAS RN 3655-00-3 was considered to possess a weak potential to cause delayed contact hypers ensitivity when tested in a guinea pig skin

maximization test. ]

2. Genotoxicity. [ No mutagenicity data were found in the public domain. IARC, NTP and OSHA do not list CAS RN 3655-00-3, or any other Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid, as a carci nogen. Additionally, DEREK SAR modeling did not identify any structural al erts for genotoxicity or carcinogenicity.]

3. Reproductive and developmental toxicity. [ CAS RN 3655-00-3, β -alanine, N-(2- carboxyethyl)-N-dodecyl-disodium salt

, was tested in an OECD 422 Combined Repeat Dose Toxicity Study with the Reproduction/D evelopmental Toxicity Screening Test. The NOEL (No Observed Effect Level) for reproduction and developmental toxicity was established as 600 mg/kg/day, the highest dose tested. A reproductive/developmental LOAEL was not observed.]

4. Subchronic toxicity. [Based on the Federal Register Notice (August 9, 2006 Volume 71, Number 153, pages 45415-45424), the Agency stat ed that the preferred test for repeat-dose toxicity is the “Combined Repe ated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screenin g Test (OECD Test Guideline 422).” CAS RN 3655-00-3, β -alanine, N-(2-carboxyethyl)-N-dodecyl-disodium salt, was tested in the OECD 422 Combined Repeat Dose Toxicity St udy with a Reproduction /Developmental Toxicity Screening Test in rats.

On the basis of the OECD 422 results, the CAS RN 3655-00-3 maternal and paternal parental systemic NOAEL was established at 43mg/kg/day due to the death of one female rat after blood sanpling. Parental LOAEL= 160 mg/kg/day based on decreased body weight gain in males and females during the pre-mating period and an increased incidence of microscopic lesions in the ki dney’s of males and acanthosis of the glandular and nonglandular stomachs of females.]

5. Chronic toxicity. [Based on the Federal Regi ster Notice (August 9, 2006, Volume 71, Number 153, pages 45415-45424), the Agency stat ed that the preferred test for repeat dose toxicity is the “Combined Repe ated Dose Toxicity Study with the Reproduction/Developmental Toxicity S creening Test (OECD Test Guideline 422).” Therefore, the results of OECD 422 study were submitted and the results are summarized under the Reproductive and Developmental Toxicity section of this document.]

6. Animal metabolism. [There are no published metaboli sm studies for Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid surfactants and the mammalian metabolism pathway is based on analogy to well-described pathways for tertiary amines and fatty acids. Overall it is anticipated that the various metabolites are not systemically toxic and would be rapidly conjugated and excreted. The Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid surfactants (mono and disodium propionates) may be conjugated and excreted directly. The mono and di-potassium salts would also be biologically equivalent to the mono and di-sodium salts. Alternatively, the tertiary amine dipropionate may be oxidi zed in the liver by monoamine oxidases to generate the intact tertiary amine dipropionate N-oxide wh ich may either be conjugated and excreted or metabolically cleaved to a di propionate oxime type metabolite that is conjugated and excreted. The linear fatty acid is metabolized via successive beta-oxidation cycles to release acetic acid and ev entually carbon dioxide and water.]

7. Metabolite toxicology

. [ Based on the proposed Sodium and Potassium Salts of NAlkyl (C 8 – C 18 )- β -iminodipropionic Acid animal meta bolic pathway, no metabolites of toxicological concern are expected and there is no concern that the postulated animal metabolites would have toxicity gr eater than the parent compounds.]

8. Endocrine disruption. [ T he Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β

iminodipropionic Acid surfactants do not belong to a class of chemicals known or suspected of having adverse effects on estrogen receptors or the endocrine system and have been evaluated in acute, repeat dose oral toxi city, developmental and reproductive studies capable of detecting effects on endocrine-media ted events. Additionally, the results of these studies did not provide any indica tion of a treatment-related effect on estrogen receptors or the endocrine system.]C. Aggregate Exposure

1. Dietary exposure. [ EPA assesses potential dietary exposures to inert ingredients used in agricultural pesticide formulations using a screening-level model referred to as “I-DEEM,” in which the “I” st ands for inerts and “DEEM” is the dietary exposure evaluation model that is used by EPA to assess dietary exposures to active ingredients in pesticide products. EPA’s Inert Ingredients Assessment Branch and residue

chemists in the Health Effects Division of the Office of Pestic ide Programs jointly developed I-DEEM.

The dietary (food plus drinki ng water) exposures for Sodi um and Potassium Salts of NAlkyl (C 8 – C 18 )- β -iminodipropionic Acid surfactants a re expressed as a percentage of the proposed chronic population adjusted dose (cPAD) for the general US population and children 1-2 years old, the subpopulation wi th the highest potential exposures.

The dietary exposure assessment for Sodi um and Potassium Salts of N-Alkyl (C 8 – C 18 )- β

iminodipropionic Acid utilizes the EPA’s dietary screening-level model I-DEEM with appropriate adjustments to reflect the use lim itations proposed in this petition, i.e.,

concentration is limited to no more than 30% by weight in pesticide formulations.

Based on I-DEEM screening level calculations, with adjustment for use limitations, the chronic dietary exposures for SSNA surfacta nts are estimated to be 0.115748 mg/kg/day (27% of the proposed cPAD) and 0.375655 mg /kg/day (87% of the proposed cPAD) for children 1-2 years old.

These estimates demonstrate that the I-DEEM screening-level chronic dietary (food and drinking water) exposures are below the cPAD for the general U.S. population and all U.S. sub-populations when the proposed formulation concentration limits a re accounted for.

On the basis of the OECD 422 repeat dose to xicity study and comparison of I-DEEM exposures to the proposed cPAD, the JITF CS T 14 asserts that there is sufficient basis for EPA to expand a tolerance exemption for the Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic acid inert ingredie nts from 40 CFR 180.920 to include 40 CFR Part §180.940 uses.Chronic Dietary Safety Assessment, % cPAD

Study Chronic Systemic

NOEL 1

mg/kg bw/day cPAD 2
mg/kg bw/day Percent

cPAD

Children 1-2 years

of age Percent

cPAD

U.S. Gen Population

Oral (Gavage) Combined Repeated Dose Toxicity Study with a Reproduction/Developmental Toxicity Screening Test of β

alanine, N-(2-carboxyethyl)- N-dodecyl-disodium salt (CAS RN 3655-00-3) 43 0.43 87% 27%

Note:

1 NOEL – No observed effect level

2 cPAD – Chronic population adjusted dose, de fined as: chronic NOAEL / (safety factors × FQPA factor)

i. Food. [The available data demonstrate that the I-DEEM screening level chronic dietary (food and drinking water) exposures are at or below 100% of the cPAD, and have

been concluded not to be of concern due to the exceptionally conservative nature of the IDEEM assessment.]

ii. Drinking water. [Drinking water is included in the I-DEEM exposure assessment. Exposure to Sodium and Pota ssium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid inert ingredients from drinking wat er is expected to be negligible.]

2. Non-dietary exposure

. [The Sodium and Potassi um Salts of N-Alkyl (C 8 – C 18 )- β

iminodipropionic Acid surfactants are used as inert ingredients in agricultural and residential formulations as well as in non-pest icidal formulation uses such as, detergents, personal care products, industrial formulations , leather and textile fiber applications, and in emulsion polymerization.]

EPA has conducted screening-level short term and intermediate use residential (nonoccupational) exposure and risk assessmen ts Federal Register (July 29, 2009, Volume 74, Number 144, Pages 37584-37591) and has concluded that non-dietary exposure and risk are not a concern, (MOE not less than 100). EP A has determined that the combined shortterm aggregated food, water, and residential exposures result in aggregate MOEs of 160

for both adult males and females and 100 for children. EPA has also determined that the combined intermediate-term aggr egated food, water, and residential exposures result in aggregate MOEs of 430 and 450, for adult ma les and females, respectively and 110 for

children.EPA as concluded in its Determination of Safety in the Federal Register (July 29, 2009, Volume 74, Number 144, Pages 37584-37591):

“Based on these risk assessments, EPA conclu des that there is a reasonable certainty that no harm will result to the general po pulation, or to infants and children from aggregate exposure to residues of SSNAs. ”]

D. Cumulative Effects

[ EPA has not conducted a common mechanism e valuation or safety finding for the

Sodium and Potassium Salts of N-Alkyl (C 8 – C 18 )- β -iminodipropionic Acid surfactants. Additionally, as stated in the Federal Regi ster (July 29, 2009, Volume 74, Number 144 Page 37589):

“EPA has not found SSNAs to share a common mechanism of toxicity with any other substances, and SSNAs do not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has

assumed that SSNAs do not have a commo n mechanism of toxicity with other substances.”]

E. Safety Determination

1. U.S. population. [In its determination of safety (Federal Register, July 29, 2009, Volume 74, Number 144, Pages 37584-37591), EPA conc luded that “there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to residues of SSNAs.”]

2. Infants and children

. [The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infant s and children in case of threshold effects to account for prenatal and postnatal toxicity a nd an inadequate toxicity database. Where an adequate and reliable database is available a nd there is a lack of evidence for increased susceptibility, the FQPA safety factor may be reduced or removed. An evaluation of susceptibility and uncertainty issues has been published for the SSNA surfactants (Federal Register Notice, July 29, 2009, Volume 74, Number 144, Pages 37584 – 37591), and EPA has recommended that the FQPA safety factor be reduced from the default 10x to 1X based on the following

• “The toxicity database for SSNAs is considered adequate for assessing the risks to infants and children [...].

• No quantitative or qualitative increased susceptibility was demonstrated in the offspring in the OPPTS Harmonized Gu ideline 870.3650 combined repeated dose toxicity study with the reproduction/develop mental toxicity screening test in rats following in utero and post-natal exposure.

• While there is no chronic toxicity da ta, the Agency has concluded that an additional uncertainty factor is not needed for the use of a subchronic study for a chronic exposure assessment based on the minor nature of effects which were seenonly at the mid- and high-doses as well as the highly conservative nature of the exposure assessment. The conservative point of departure selected along with the standard uncertainty factor of 100X to account for inter- and intra-species variability is considered health protective.

• There are no neurotoxicity studies available fo r this series of nonionic surfactants. However a Functional Observation Battery (FOB) to evaluate neurotoxicity was performed in the Combined Repeated Dose/Developmental Screening study and only a minor decrease in temperature was ob served in males at the mid and high doses. The effect was likely due to norm al biological variation and; therefore, was

not considered treatment- related. Thus, there is no need for a developmental neurotoxicity study or additional UFs to acco unt for neurotoxicity.

• There are no residual uncertainties identified in the exposure databases. The food and drinking water assessment is not li kely to underestimate exposure to any subpopulation, including those comprised of infants and children. The food exposure assessments are considered to be highly conservative as they are based on the use of the highest tolerance leve l from the surrogate pesticides for every food and 100 PCT is assumed for all crops. EPA also made conservative (protective) assumptions in the ground a nd surface water modeling used to assess exposure to SSNAs in drinking water. EPA used similarly conservative assumptions to assess post-application exposure of children as well as incidental oral exposure of toddlers. These assessments will not underestimate the exposure and risks posed by SSNAs.”]

F. International Tolerances

[There are no known international toleran ces for Sodium and Potassium Salts of NAlkyl (C 8 – C 18 )- β -iminodipropionic Acid pesticide inert ingredients. ]