Aminoethoxyvinylglycine Hydrochloride Case #: 6070

129104 Human Health Assessment

— Registration Review

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 August 8, 2011 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION **MEMORANDUM SUBJECT**  : Product Chemistry Scoping Document for the Registration Review of Aminoethoxy

vinylgly c ine Hy drochloride. **Registration Review Case #: 6070**  **PC Code :**  **129104 CAS Num**  **bers: 55720**  **- 26**  **- 8**  **Chem ical Class:**  **Biochem ical**  **FROM:** Jacob Moore, Chemist /s/ 07/27 /2011

Biochemical Pesticides Branch Biopesticides & Poll ution Prevention Divisi on (7511P ) **TO :**  John Fournier, Regulatory Action L eader Biochemical Pesticides Branch Biopesticides & Poll ution Prevention Division (7511P ) **ACTION REQUESTED** A preliminary

assessment of available information on product chemistry data associated with the biopesticide aminoethoxy vinylgly cine hy drochloride in support of the development of a Registration Review Work Plan.Aminoethoxyvinylglycine Hydrochloride Case #: 6070

129104 **Introduction** The EPA has made the determination that there is adequate information available on aminoethoxy

vinylgly cine hy drochloride, commonly known as AVG, and does not foresee the need to require additional data from products currently registered that contain AVG as the active ingredient . AVG is a plant growth regulator used on apples, pears, and ornamentals. Inapples, it may delay fruit maturity , leading to benefits such as a reduction in pre - harvest fruit drop and improved fruit quality . In pears, AVG may help maintain fruit firmness. For specific ornamentals (miniature carnations, hibiscus, and rooted geranium cuttings and seedlings), AVG may reduce problems, such as flower senescence and flower bud abscission, that occur during shipping. AVG products have been registered with the EPA since 1997 . Currently there are 11 active registrations containing AVG, including two technical grade active ingredient registrations, six end - use or manufacturing - use products, and three experimental use permits . The technical registration contain 86% active ingredient by weight with the balance consisting of impurities. The Agency

exempts AVG from the requirement of a tolerance under the following conditions under 40 CFR §180.502. The tolerances for residues was established by the Agency

on May 7, 1997 in 62 FR 24838 and further amended up to February 18, 2004, the current version , and can be read in 69 FR 7606. The biochemical human health assessment data requirements of technical grade AVG have been satisfied and are summarized in Table 2. While no further toxicity data are necessary for the products currently

registered, future product s must adequately address all of the biochemical pesticides human health assessment data requirements .Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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3 **Table 1. Product Identity and Composition for AVG Common Name**  Aminoethoxy vinylgly cine Hy drochloride (AVG) **Chemical Name, IUPAC** (3E) - 2 - amino - 4 - (2 - aminoethoxy ) - 3 - butenoic acid hy drochloride **Molecular Weight** 196.6 g/mol **PC Code** 129104 **CAS Registry Number** 55720 - 26 - 8 **Empirical Formula** C 6 H 1 3 N 2 O 3 Cl **Registration Review Case Number** 6070 **Chemical Structure**Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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4 **Human Health Assessment** The Agency

has conducted a review of the available human health assessment data and information. These data are summarized below and in Table 2. **I. Toxicology**  **Acute and Short -**  **term Toxicity:** The Agency

has reviewed all toxicity studies for AVG and has determined th at the toxicological database is sufficient. The toxicological database for AVG is currently comprised of published and unpublished studies submitted to the Agency or obtained from published literature. AVG is considered Toxicity Category I V for Acute Ora l, Primary Ey e Irritation, and Primary Dermal Irritation. I t is considered Toxicity Category I II for Acute Dermal and Acute In halation. AVG is not a dermal sensitizer. **Genotoxicity :**  AVG was tested in a gene mutation assay (Ames), a ly

mphoma assay

(mouse) and a micronucleus assay . No mutagenic activity was observed. **Reproductive and Developmental Toxicity:** Ina rat reproduction study , AVG exposure decreased viability of F 1 pups and retarded growth in F 1 and F 2 pups (NOAEL=2.5 mg/kg - day ; LOAEL=4 mg/kg - day ). Higher doses (NOAEL=4 mg/kg - day ; LOAEL=8 mg/kg - day ) decreased testicular weight, changed sperm morphology

and increased the incidence of testicular histopathology . Parental sy stem effects in the same study

were induced at 2.5 mg/kg - day and 4 mg/kg - day . A developmental study

in rats revealed decreased body weight gain, food consumption, defecation and red perinasal material in dams (NOAEL=1.77 mg/kg - day ; LOAEL=8.06 mg/kg - day

). A rabbit developmental study reported decreased body

weight gains and food consu mption in dams (NOAEL=0.4 mg/kg - day ; LOAEL=0.7 mg/kg - day ) and developmental malformations in fetuses (NOAEL=0.2 mg/kg - day ; LOAEL=0.4 mg/kg - day ). **Subchronic Toxicity:** Subchronic studies were performed on mice, rats and dogs and were deemed acceptable by th e Agency . Instudies conducted on mice, rats, and dogs, AVG primarily induced liver pathologies such as increased weight, hepatocellular vacuolation, fat accumulation, inflammatory

cell infiltration, hy

pertrophy , and reduced ALT and AST activity at L OAELs that ranged from 1.2 to 9.4 mg/kg - day . Body weight, weight gain, and food consumption were also affected at similar concentrations.Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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5 **Chronic Toxicity/Cancer:** A one y ear chronic rat toxicity study reported increased testicular atrophy in males, chronic rena l nephropathy

in females and decreased food consumption and body weight gain in both sexes at L OAEL of 7.0 mg/kg - day . A NOAEL was recorded at 0.7 mg/kg - day in males and females. The Agency

has concluded that the AVG data are inadequate for an assessment o f human carcinogenic potential. A two y ear study conducted on rats produced non - cancer effects. This is based on guideline studies that the Agency no longer requires . **Metabolic Studies** Evidence suggests that AVG rapidly metabolizes into less toxic polar m etabolites inc luding ω - N - acetyl - aminoethoxy

vinylgly cine and ethoxy

vinylgly cine. These metabolites are then primarily excreted in urine. **II. Dietary Assessmen**  **t** The majority

of dietary exposures to residues of AVG occur through ingestion of apples, pears and stonefruit. A dietary exposure and risk assessment for AVG revealed no adverse effects to various populations. **III. Aggregate and Cumulative Exposure**  Inexamining aggregate exposure, the Agency has taken into account the available and reliable information concerning exp osures to AVG in food, drinking water and other non occupational pesticide activities. AVG is unlikely to contaminate drinking water. In food, EPA internal testing concluded that dietary risk was below the level of concern for both acute and chronic exposures. **IV. Occupational/Residential Exposure**  AVG has no product registrations for residential non - food uses and exposure from non occupational, non - dietary sources is negligible. Exposures from applications of AVG are below EPAs level of concern. **V. Toleran**  **ces** AVG has an established tolerance for residues. The information is presented below: **Commodity Parts Per Million**  Apple 0.08 Fruit, stone, group 12, except cherry 0.170 Pear 0.08 40 CFR §180.502Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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6 **VI. Conclusion**  The Agency

has reviewed the hazard and expo sure databases for AVG and anticipates that no additional toxicity

and exposure data will be needed for registration review. In addition, the EPA anticipates that no additional occupational and residential handler assessments will be needed to ensure that the AVG registration review case meets the safety standards established by FFDCA, as amended by

FQPA. However, registrants presenting new products to the Agency must continue to meet all biochemical pesticides human health assessment data requirements. S imple citation of this document may

or may not be adequate to address current and future data requirements. This document speaks to currently registered technical grade AVG only . **Table 2. Biochemical Pesticides Human Health Assessment**  **Data Requirements f or AVG**  **Guidelin e No.**  **Physical and Chemical**

**Properties Status**  **1 Value**  **MRID 870.1100**  Acute oral toxicity

— rat A LD 50 = 6480 mg/kg

— IV 42672203 **870.1200** Acute dermal toxicity A LD 50 >2000 mg/kg

— I II 42672204 **870.1300** Acute inhalation toxicity

— rat A LC 5 0 = 1.1 3 mg/L

— III 42672205 **870.2400** Primary

ey e irritation

— rabbit A Conjunctival redness, chemosis, and discharge at 1 hr post exposure, resolved by day 7, no significant iridal or corneal effects

— IV 42672206 **870.2500** Primary

dermal irritation A Very sligh t to well defined ery thema at 30 - 60 min PE and 24 hr after patch removal. No significant dermal irritation at 4 hr PE

— IV 42672207 **870.2600** Dermal sensitization A No dermal sensitivity 43556801 **870.3100** 90 - day

oral

— rat A NOAEL= 2.2 mg/kg - day LOAEL = 9.4 mg/kg - day 43183609 **870.3200** 21 - day

dermal

—

rat A NOAEL = 1000 mg/kg - day (limit dose). 43846506 **870.3465** 90 - day

inhalation

— rat N/A No likelihood of significant levels of

repeated inhalation exposure to TGAI as a gas, vapor, or aerosol. Does not apply to MPs/EPs. -- **870.3700** Prenatal developmental

— rat A Maternal : NOAEL= 1.77 mg/kg - day ; LOAEL =8.06 mg/kg - day Developmental : NOAEL= 1.77 mg/kg - day ;

LOAEL= 8.06 mg/kg - day 43206902Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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7 **870.5100** Bacterial reverse mutation

test A No mutagenic activity 42672209 **870.5375** In vitro mammalian cell

assay A No mutagenic activity 42672210 **870.5385** In vivo Mammalian

Cy togenetics A No mutagenic activity 42672211 **875.1100 875.1200**  **875.1300 875.1400**  **875.1500** Application/User Exposure N/ A Not required; the data used for the human health assessment indicate that the biochemical will not pose a potential hazard to the applicator/user. --

**870.3800** Reproduction and fertility

effects A Parental/sy stemic: NOAEL = 0.8 mg/kg - day (males) NOAEL = 2.5mg/kg - day (females) LOAEL = 2.5 mg/kg - day Reproductive: NOAEL = 4 mg/kg - day LOAEL = 8 mg/kg - day Offspring: NOAEL = 2.5 mg/kg - day LOAEL = 4 mg/kg - day 44946501

**870.4100** Chronic oral

— rodent and non - rodent A NOAEL = 0.7 mg/kg - day LOAEL = 7.0 mg/kg - day 45359605 **870.4200** Carcinogenicity

—two species

— rat and mouse preferred A NOAEL = 0.7 mg/kg - day 45698801 **870.5380** Mammalian spermatogonial

chromosome aberration test N/A No indication of potential chr omosomal aberration. -- 1. A=Acceptable. N/A=Not Applicable.Aminoethoxyvinylglycine Hydrochloride Case #: 6070

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8 **References** Carlson, K., Gardner, R. Memorandum to D. Greenway . 12/15/2005. Devisetty , B., Bade, T. Product I dentity , Manufacturing Process, VBC - 30102 (AVG HCLL iquid Formulation). Pr ivate Study by Valent Biosciences Corp Submitted to EPA. MRI D 477707 - 01. 2009. Merck Index, Online. 07/19/2011. PubChem. http://pubchem.ncbi.nlm.nih.gov/summary /summary .chi?cid=6434508. 07/25/2011.