UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

March 17, 2015

MEMORANDUM

SUBJECT: PC Codes 911028, 911029, 911030: Alkyl (C 8 -C 20 ) polyglucoside Esters (AGEs);

Human Health Risk Assessment and Ec ological Effects Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations.

All PC Code: 911028, 911029, 911030 DP Barcode: N/A

Decision No.: N/A Regulatory Action: Inert Tolerance Exemption; 40

CFR 180.910

Petition No: IN-10765 All CAS Nos: 1079993- 97-7, 1079993-92-2,

1079993-94-4
Inert Tracking No:

FROM:

Jennifer Zielinski Chemistry, Inerts and Toxicology Assessment Branch (CITAB) Registration Division (7050P)

Elizabeth Fertich

Invertebrate and Vertebrate Branch 1 Registration Division (7505P)

Lisa Austin, Ph.D., Toxicologist Chemistry, Inerts and Toxicology Assessment Branch (CITAB)

Registration Division (7505P)

THROUGH: Kerry Leifer, Team Leader Chemistry, Inerts and Toxicology Assessment Branch (CITAB) Registration Division (7505 P)Page 2 of 22 TO: Pv Shah, Ph.D., Branch Chief Chemistry, Inerts and Toxicology Assessment Branch (CITAB) Registration Division (7505P)

Executive Summary

On December 5, 2013, Lamberti USA Inc. submitted a petition (IN-10675) requesting an exemption from tolerance for residues for three s ubstances collectively referred to as alkyl (C8- C20) polyglucoside esters (AGEs) when used as inert ingredients (surfactants) in pesticide formulations applied pre- and post-harvest. The three AGEs are D-glucopyranose, oligomeric, 6-(dihydrogen citrates), C 8-20 branched and linear al kyl glycosides, sodium salts (CAS Reg. No. 1079993-97-7); D-glucopyranose, oligomer ic, 6-(hydrogen sulfosuccinates), C 8-20 branched and linear alkyl glycosides , sodium salts (CAS Reg. N o. 1079993-92-2); and D-glucopyranose, oligomeric, lactates, C 8-20 branched and linear alkyl gl ycosides (CAS Reg. No. 1079993-94-4)

For the human health risk assessment and ecologi cal effects assessment evaluation of the AGEs, since limited data are available on the AGEs, da ta on surrogate chemicals were considered, including other polyalkylglucoside ethers and polyalkylglucoside sulfosuccinates as well as metabolites lactic acid, citric acid and disodium sulfosuccinates. Lactic acid is exempted from tolerance under 40 CFR 180.910, 930 and 940 b,c. Citric acid is exempted from tolerance under

40 CFR 180.950e. Disodium sulfosuccinates ar e exempted from tolerance under 40 CFR

180.910 and 930.

AGEs have low acute toxicity via the oral route (oral LD 50 > 5,000 mg/kg). There is no available data regarding acute exposure via th e dermal, eye or inhalation routes.

In a combined repeated dose toxicity study with th e reproduction/developmental toxicity screening test in rats there were no observed adverse effects for parental systemic or reproductive/developmental e ffects at 1000 mg/kg/day.

A 2 year chronic oral study in rats treated with citric acid was available for review. Rats were

administered 5% or 3% citric acid (approx. 2,000 or 1,200 mg/kg/d) in the diet. There were no adverse effects observed at 2,000 mg /kg/day. Chronic studies were also available for the rabbit and dog. There were no adverse effects observe d in either study at doses up to 1500 and 1400 mg/kg/day, respectively.

Neurotoxicity studies with AGEs we re not available for review. However, neurotoxicity was not observed in the OECD 422 study at concentra tions as high as 1,000 mg/kg/day (limit dose).Page 3 of 22 Mutagenicity studies (Ames Test) were availabl e for review for the surrogate chemicals, dglucopyranose, oligomeric, 6-(dihydrogen 2-hydr oxy-1,2,3-propanetricarboxylat e), l-(coco alkyl) ethers, sodium salts (CAS No. 151911-51-2), d-glucopyranose, oligomeric, 6-(hydrogen 2- sulfobutanedioate), 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-53-4) or dglucopyranose, oligomers, monosulfosuccinate , coco alkyl glycosid es, sodium salts, dglucopyranose, oligomeric, 6-[hydrogen (2R ,3R)-2,3-dihydroxybutanedioat e), 1-( coco alkyl) ethers, sodium salts (CAS N o. 151911-52-3). The results of th ese studies were negative.

Studies on the metabolism of orally administered β -glucosides (metabolic cleavage of alkylglycosides) in mice show that rapid hydrolytic acetal cleavage takes place principally in the

stomach and intestine of the mice. The cl eavage products pass in to the fatty acid and carbohydrate metabolic pathways. That assumpti on is also confirmed by another study on alkylglycosides where the β -glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage products, sugars and long-chain alc ohols, entered the pathways of lipid and carbohydrate metabolism.

The absence of toxicity is s upported by studies in monographs and reports under World Health Organization (WHO), WHO Food Additives Seri es, and FAO Nutrition Meetings Reports on lactic acid and citric acid. Also, evidence of toxi city was not reported in peer reviewed studies in the Hazardous Substances Data Bank (HSDB).

There was no hazard attributable to a single exposu re seen in the toxicity database for AGEs. Therefore, AGEs are not expected to pose an acute risk.

There was no endpoint of concern identified in toxicity studies up to 1,000 mg/kg/day. In addition, metabolism studies on alkyl glycosides reported that the β -glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage products, sugars a nd long-chain alcohols, entered the pathways of lipid and carbohydrate metabolis m. Based on the low acute toxicity, the body’s ability to rapidly metabolize the inert ingredient into expected metabolites that are normal constituents of the body, exempted as inert ingred ients, and the lack of an endpoint of concern for repeat dose studies at the limit dose (1,000 mg/kg/day) a qualitative risk assessment was

conducted.

Dietary exposure to AGEs can occur from eatin g food treated with pesticide formulations containing this inert ingredient. Non-dietary exposure from the proposed use as inert ingredients (surfactants) in pestic ide formulations applied pre- and post-harvest under 40 CFR 180.910 is not expected; however non-dietary exposure may occur fr om other approved uses of this chemical. Occupational exposure is also possible. However, the available data indi cate that there are no adverse toxicological effects which occur at e xposures less than 1,000 mg/ kg bw/day, therefore a quantitative risk assessm ent is not conducted.

AGEs are readily biodegradable, therefore it is not e xpected to persist in the environment. Also, potential to bioaccumulate is e xpected to be low/very low.

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal ActionsPage 4 of 22 to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

Taking into consideration all available informati on on AGEs, EPA has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to AGE when used as an inert ingredie nt in pesticide formulat ions applied during preand post-harvest when considering dietary e xposure and all other nono ccupational sources of pesticide exposure for which there is reliable in formation. Therefore, th e establishment of an exemption from tolerance under 40 CFR 180.910 for residues of AGEs (CAS Reg.Nos. 1079993-97-7, 1079993-92-2, 1079993-94-4) when used as inert ingredients in pre- and postharvest applications in pesticide formulations, can be considered assessed as safe under section 408(q) of the FFDCA.

I. Background

On December 5, 2013, Lamberti USA Inc. submitted a petition (IN-10675) requesting an exemption from tolerance for residues of AGEs when used as inert ingredients (surfactants) in pesticide formulations applied pre- and post-harv est. EPA published the Notice of Filing for this petition in the Federal Register on October 15, 2014 (79 FR 61844). One comment was received in response to this notice. The comment recei ved was from a private citizen who opposed any pesticide product that leaves a residue above 0.00. The Agency understands the commenter's concerns and recognizes that some individuals believe that no re sidue of pesticides should be allowed. However, under the existing legal fr amework provided by FFDCA section 408, EPA is authorized to establish pesticide tolerances or exemptions where persons seeking such tolerances or exemptions have demonstrated that the pesticide meets the safety standard imposed by the

statute.

The AGE category consists of the following chemicals:

D-glucopyranose, oligomeric, 6-(dihydrogen citrates), C 8-20 branched and linear alkyl glycosides, sodium salts---CAS Reg. No. 1079993- 97-7. This chemical will be referred to as AGE (C 8 -C 20 ) citrate.

D-glucopyranose, oligomeric, 6 -(hydrogen sulfosuccinates), C 8-20 branched and linear alkyl glycosides, sodium salts —CAS Re g. No. 1079993-92-2. This chemical will be referred to as AGE (C 8 -C 20 ) sulfosuccinate.

D-glucopyranose, oligomeric, lactates, C 8-20 branched and linear alkyl glycosides —CAS Reg. No. 1079993-94-4. This chemical will be referred to as AGE (C 8 -C 20 ) lactate.

For the evaluation of the AGEs, other chemical s were considered in the toxicological and ecotoxicological assessment. These chemicals include other carboxylic esters obtained with specific fatty alcohols (coconut) and the main de gradation products forming and environmental or metabolic degradation pathways (alkylpolyg lucosides and carboxylic acids) The list of

chemicals used in this evaluation are:Page 5 of 22  D-glucopyranose, oligomeric, 6-(dihydr ogen 2-hydroxy-1,2,3-propa netricarboxylate), 1-(coco alky) ethers, sodium salts (CAS No. 151911-51-2)

 D-glucopyranose, oligomeric, 6-(hydroge n 2-sulfobutanedioate), 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-53-4)

 D-glucopyranose, oligomeric, 6-[hydroge n (2R, 3R)-2,3-dih ydroxybutanedioate], 1- (coco alkyl) ethers, sodium salts (CAS No. 151911-52-3).

 (C9-11)alkyl polyslycosides solfosuccinate sodium salts (CAS No. 122857-41-0)

 Lactic acid

 Citric acid

 Disodium sulfosuccinate and other sulfosuccinates

Surogate chemicals d-glucopyranose, oligomeric, 6-(dihydrogen 2-hydroxy-1,2,3- propanetricarboxylate), 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-51-2), dglucopyranose, oligomeric, 6-(hydro gen 2-sulfobutanedioate), 1-(coc o alkyl) ethers, sodium salts (CAS No. 151911-53-4) and d-glucopyranos e, oligomeric, 6-[hydrogen (2R,3R)-2,3- dihydroxybutanedioate], 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-52-3) are considered acceptable in read across approach becasue their carbon chain lengths are in the range C 8 -C 20 and they are the same sulfosu ccinate or carboxylate esters.

Surrogate chemical (C9-11) al kyl polyglycosides solfosuccina te sodium salts (CAS No. 1228577-41-0) is considered accepta ble in the read across appr oach becasue the chemical physical properties of the alkyl polyglucoside Esters are very similar for the different chain lengths in the range C8-C20, the Alkyl polyglucos ide is the first degradation product in the biodegradation pathway of the Al kyl polyGlucoside Esters, and th e toxicity data of the Alkyl polyGlucoside are very similar for the different chain lengths in the range C8-C20. It should be noted that the Alkyl polyglucoside Sulfosuccinate appears more critical for health effects in comparison with other Alkyl polyglucoside Esters.

This document provides an assessm ent of the risk to human hea lth and the environment for the AGEs when used as inert ingredients (surfactants) in pesticide formulations applied to pre- and post-harvest agricultural commodities.

II. Use Information

The AGEs are used is a wide variety of cosmetics, lubricants and other ap plications applied to skin, hair, nails and mucous membranes. App lication of these products includes multiple daily uses with daily or occasional use extending over many years. The proposed use for the AGEs is as inert ingredients (surfactants) in pesticide formulations applied to pre- and post-harvest agricultural commodities.

III. Physical and Chemical Properties

The structures of each of the AGEs is provided in Table 1.

Table 1. Structures of AGEsPage 6 of 22 Chemical Name Structure D-glucopyranose, oligomeric, 6- (dihydrogen 2- hydroxy-1,2,3- propanetricarboxylate), 1-(C8-C20 linear and branched alkyl) ethers,

sodium salts—CAS Reg. No. 1079993-97-7

D-glucopyranose, oligomeric, 6- (hydrogen sulfobutanedioate), 1- (C8-C20 linear and branched alkyl) ethers,

sodium salts—CAS Reg. No. 1079993-92-2Page 7 of 22 D-glucopyranose, oligomeric, propanoic acid, 2-hydroxy-, 1- (C8-C20 linear and branched alkyl) ethers—CAS Reg. No.

1079993-94-4.

Source: Laberti Group Read across rationa le for Alkyl polyBlucoside Esters (AGE) group

Some of the physical and chemical characte ristics of the AGEs ar e found in Table 2.

Table 2. Physical and Ch emical Properties of AGEs

Parameter Value

1079993-97-7 AGE (C 8 -C 20 ) citrate 1079993-92-2 AGE (C 8 -C 2 0 ) sulfosuc c ina t e 1079993-94-4 AGE (C 8 - C 20 ) lactate

Appearance at 20 ° C and

101.3 kPa Yellowish liquid (aqueous

solu t ion) Yellowish liquid (aqueous

so l ution) Yellowish l iquid (aqueous solution)

Molecular Weight 670.59-839.92 660.61-828.94 562.58-694.91

Melting Point ("C) - 2°C (wa t er solutio n ) 1

349.84°C (substance) * - 2°C (wa t er solutio n ) 2 349.84°C (subs t ance) * - 2°C (wa t er solutio n ) 3 349.84°C (substance) *

Boiling Point (0C) ~ 100 ° C (water s olut i on) >600°C (substance) * 98°C @101

. 3 kPa (water solution) 1 >600°C (su b stan ce ) * ~100° C (water solution) >600° C (substance) *

Log Kow -0.93 - 4 .96 * log Pow at 20°C <-2.8 2

- 1

. 41- 4.48 * 0.08- 5.98 *

Water Solubility (mg/L at 25 ° C) 395 mg/g at 25°C 1

1E+06 (C 8 ) - 23297(C 20 ) * 686 mg/g at 25 ° C 2 1E+06 (C 8 ) -1468.8 (C 20 ) * 498 mg/g at 25 ° C 3

1E + 06 (C 8 ) - 5612.2 (C 2 0 ) *
Vapor Pressure

(Pa at 2 5· C ) 3

. 89E-2 2- 3.19E -27 (substance) * 0.34 kPa at 20°C 2

3 .22E-22 - 2.63E3 .2E-16 - 3 .7 2 E

- 21 (substance)*Page 8 of 22 27(substance)*

Soil Adsorption Coefficient (Kow method) Koc: 0

. 02457

- 44.5 L /kg * Koc : 0.01333 - 24 .1 5 L/kg * Koc : 0

. 523 - 959.3 L/kg *

S tability in Water 2 .6 3 6(p H 8)

- 26. 3 6 3 (pH 7 )

D a ys* 218.566 (pH8)- 5.984 (p H7 )

D ays * 3

. 2 96 (pH8)- 32

. 960 (pH7) Days *

Source: As cited in Lamberti USA Inc. Petition #IN-10675

1 read across data on AGE Coco Citrate

2 read across data on AGE Coco Sulfosuccinate

3 read across data on AGE Coco Tartrate

* data calculated using EPIWIN (v. 4. 00) for the range C8-C20 of alkyl parPage 9 of 22 IV. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data (Repro duced from AGEs_Assessment Lamberti)

Acute Toxicity

For AGE (C8-C20) citrate, a single study on a si milar chemical (D-Gluc opyranose, oligomeric,6- dihydrogen 2 hydroxy-1,2,3-propanetri carboxylate), 1-(coco alkyl) et hers, sodium salt (CAS No. 151911-51-2) was available. According to this study, a single dose of 5,000 mg/kg was given to 5 Wistar Rats of each sex as an aqueous solution vi a gavage. No deaths occurred within 24 hours.. Two males and two females had slight piloereciton and mucosa enteritis in small intestine lesions

was seen in two males at terminal necropsy. As such, the Oral LD 50 was >5,000 mg/kg. (MRID 48179203)

For AGE(C8-C20) sulfosuccinate, a single st udy on a similar chemical (D-Glucopyranose, oligomeric, 6-(hydrogen, 2-sulfobutanedioate), 1- (coco alkyl) ethers, sodium salts (CAS No. 151911-53-4) was available. According to this study, a single dose of 5,000 mg/kg was given to 5 Wistar Rats of each sex as an aqueous solution vi a gavage.. No deaths occurred within 24 hours..

Four males and two females had s light piloereciton and mucosa ente ritis was seen in two males.

The acute oral LD 50 in rats was >5,000 mg/kg. (MRID 48179202)

In addition, a single study on a similar chemical (D-Glucopyranose, olig omeric, 6-[hydrogen, 2R, 3R)-2,3-dihydroxybutanedioate], 1-(c oco alkyl) ethers, sodium sa lts (CAS No. 151911-52-3) was available. According to this study, a single dos e of 5,000 mg/kg was given to 5 Wistar Rats of each sex as an aqueous solution via gavage. No deaths occurred within 24 hours.. All treated animals had pilorection and slight diarrhea. Mucosa enteritis in small intestine lesions were seen in the surviving animals at terminal necropsy. The acute oral LD 50 in rats was >5,000 mg/kg. (MRID 48179204)

No specific acute dermal or in halation studies are available.

A summary of the acute toxicity da ta is presented in Table 2 below

Table 2. Summary of Acute Toxicity Data for AGEs

Parameter Toxicity Value Reference

Oral LD 50, rat (AGE(C8-C20) citrate Not Available

Oral LD 50, rat (AGE(C8-C20)

sulfosuccinate Not Available

Oral LD 50, rat (AGE(C8-C20) lactate Not Available

Oral LD 50, rat (151911-51-2) LD50 >5000 mg/kg Biolab SGS 1993 (MRID 48179203)

Oral LD50, rat (151911-53-4) LD50 >5000 mg/kg Biolab SGS 1993a (MRID

48179202Page 10 of 22 Oral LD50, rat (1079993-94-4) LD50 >5000 mg/kg* Biolab SGS 1993 (MRID 48179204)

Dermal LD50 Not available

Inhalation LC50, rat Not available

Eye Irritation, rabbit Not available

Skin Irritation, rabbit Not available

Skin Sensitization-guinea pig (Modified Maguire method) Not available

Subchronic Toxicity

Sub-chronic or repeated dose toxicity data were not submitted for AGEs. However, information on a similar alkyl polyglucosides and organic acids (metabolites) show no significant toxicity.

Carboxylic acids (lactic and citr ate acid) have been studied for implication in use as food

additives. No evidence of subchronic toxici ty was reported in monographs and reports under World Health Organization (WHO) ac tivities. (MRIDs 47867231, 47867232, 47867233, 47867234, 47867235, 47867236, 47867237)

Also, in the National Library of Medicine, T oxicology Data Network (TOXNET), Hazardous Substances Data Bank (HSDB), evidence of toxicity for lactic and citric acid was not reported in peer reviewed studies.

Carcinogenicity (Reproduced from HSDB)

No direct carcinogenicity data is available for the AGEs; how ever, carcinogenicity data is

available for citric aci d. A Chronic Exposure or Carcinogenicity/ A 2-year chronic oral study in rats given 5% or 3% citric acid (approx. 2 or 1.2 g/kg/d, 2000 or 1,200 mg/kg/day) in feed found slightly decreased growth in the higher dos age group but no tissue abnormalities in the major organs. As such, the NOAEL was determined to be 1200 mg/kg/d. Similarly, NOAELs of 1500 mg/kg/d (rabbit) and of 1400 mg/kg/d (dog) have been determined [

The Agency further evaluated the carcinogenic potent ial of alkyl polyglucosid e (C8-C20) esters by conducting a knowledge base qualita tive structure activity relationship (SAR) database, DEREK Nexus Version 2.0, to determine if there were structur al alerts. No structural alerts were identified including carcinogenicity.

Reproduction/Developmental ToxicityPage 11 of 22 No Reproductive and Developmental toxicity data were submitted for AGES. However, alkyl polyglucoside and organic acids (meta bolites) were used as surrogates.

For AGE (C8-C20) sulfosuccinate, data on a surrogate chemical , (C9-11) alkyl polyglycosides solfosccinate sodium salts, was obtained in a combined repeated dose toxicity study with the reproduction/developmental toxi city screening test, (MRID 492751-03-C/CA).

, (C9-11) alkyl polyglycosides solfosccinate sodium salts (was administered to ten Wistar

rats/sex/dose in corn oil by gavage at dose levels 0, 40, 200, or 1000 mg/kg bw/day for at least 14 days prior to mating, throughout mating, and after mating, up to and including the day prior to sacrifice. Terminal sacrifices took place followi ng at least 28 days of treatment for males, on lactation day (LD) 4 for females that littered, an d on or after presumptive gestation day (GD) 26

for mated females that did not litter. Evaluate d parameters in the parental animals included functional observational battery (FOB), hemato logy, clinical chemistry, organ weights, and histopathology.

There were no biologically relevant treatment-related effects on parent al mortality, clinical signs, conducted neurological evaluati ons, body weight, body weight gain, food consumption, clinical pathology, reproductive performance, macroscopi c findings, and histopathology of organs and tissues of the reproductive tract. Treatment-related increased (20-27%) absolute and relative thymus weights in males of the high-dose group, decreased (22%) relative right ova ry weights in females of the high-dose group, and increased (20- 56%) absolute and relativ e thyroid weights in females of the mid- and high-dose groups were obse rved. [Note: thyroid we ights from males were not recorded.] However, because there were no correlated alterations in clinical chemistry parameters and/or histopathology, th e differences are not considered adverse. Therefore under the conditions of this study, the pa rental systemic LOAEL for (C9-11) alkyl polyglycosides

solfosccinate sodium salts in rats is not id entified, and the parental systemic NOAEL is 1000 mg/kg bw/day.

Under the conditions of this study, there were no evident treatment-related effects on numbers of corpora lutea per dam, reproductive indices, pr ecoital intervals, gest ation length, number of corpora lutea and implantation sites, postimplan tation losses, live litte r size, pup sex ratio, pup weight, or pup survival to PND 4. Theref ore under the conditions of this study, the reproductive/developmental LOAEL for (C9-11) alkyl polyglycosides solfosccinate sodium

salts in rats is not identified, and the reproduc tive/developmental NOAEL is 1000 mg/kg bw/day.

Neurotoxicity

Neurotoxicity studies with AGEs were not av ailable for review. However, evidence of neurotoxicity was not observed in submitted studie s at concentrations as high as 1,000 mg/kg/day (limit dose) of the test material. In add ition, in the OCED 422 st udy it was reported that functional observational battery (FOB) parame ters were not affect ed by treatment at 1,000 mg/kg/day; however, no actual data was provided in the study report.

MutagenicityPage 12 of 22 Data for the mutagenic potential of AGEs were provided from data on surrogate chemicals dglucopyranose, oligomeric, 6-(dihydrogen 2-hydr oxy-1,2,3-propanetricarboxyl ate), 1-(coco alky) ethers, sodium salts (CAS No. 151911-51-2) , D-glucopyranose, oligomeric, 6-hydrogen 2- sulfobutanedioate), 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-53-4), and dglucopyranose, oligomeric, 6-[hydrogen (2R, 3R)-2,3-dihydroxybutanedioate], 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-52-3).

In an Ames Test salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537 were exposed to concentrations up to 5000 ug/ plate of CAS No. 151911-51-2 (surrogate for CAS No. 1079993-97-7). Cytotoxicity was observed at 1500 and 5000 ug/plate. No increases in mutation frequency were reported at any concentration tested with or without metabolic activation (MRID 48179210)

In an Ames Test salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537 were exposed to concentrations up to 5000 ug/ plate of CAS No. 151911-53-4 (surrogate for CAS No. 1079993-92-2). Cytotoxicity was observed at 1500 ug/plate. No increases in mutation frequency were reported at any concentration tested with or without metabolic (MRID 48179211)

In a non-guideline Ames Test salmonella typhimurium strains TA98, TA100, TA1538, TA1535, and TA1537 were exposed to concentrations up to 1000000 ug/plate of CAS No. 151911-52-3 (surrogate for CAS No. 1079993-94-4). No Cyto toxicity was observed at 10 mg/plate (10000 ug/plate). No increases in mutati on frequency were reported at a ny concentration tested with or

without metabolic activation (Instituto de Richerche Biomediches, 1995). (MRID 49549601)

Metabolism

Studies on the metabolism of orally administered β -glucosides in mice show that rapid hydrolytic acetal cleavage takes place principally in the stomach and intestine of the mice. The cleavage products pass in to the fatty acid and carbohydrate metabolic pathways. That assumption is also confirmed by another st udy on alkylglycosides where the β -glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage p roducts, sugars a nd long-chain alcohols, entered the pathways of lipid and carbohydrate metabolism.

A summary of the toxicology data for th e AGEs is provided in Table 3 below.

Table 3 Toxicology Profile for AGEs

Guideline No./ Study Type Classification /Doses ResultsPage 13 of 22 Table 3 Toxicology Profile for AGEs

Guideline No./ Study Type Classification /Doses Results

Combined repeated dose toxicity study with the Reproduction/developmental Toxicity Screening test- Rat

((C9-11)alkyl polyglycosides

solfosuccinate sodium salts hexahydrate) 0, 40, 200, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day.

LOAEL was not established.

Reproduction NOAEL = 1000 mg/kg/day.

Reproduction LOAEL was not

established.

Chronic/Carcinogenicity Study-rat (citric acid) 0, 3 or 5%

(1,200 or 2,000 mg/kg/day) NOAEL = 2000 mg/kg/day.

LOAEL was not established.

Combined repeated dose toxicity study with the Reproduction/developmental Toxicity Screening test- Rat
(disodium succinate hexahydrate) 0, 300, 1000 mg/kg/day

Reproduction NOAEL = 1000 mg/kg/day.

Reproduction LOAEL was not

established.

In vitro endocrine screening test
(alkyl polyglucosides) Not estrogenic nor antiestrogenic.

Ames test

870.5100
(CAS Reg. No. 151911-51-2 Up to 5000 ug/mL in the absence and presence of

metabolic activation. No increase in revertant

colonies.

Ames test

870.5100
(CAS Reg. No. 151911-53-4 Up to 5000 ug/mL in the absence and presence of

metabolic activation. No increase in revertant

colonies.

Ames test

870.5100
(CAS Reg. No. 151911-52-3) Up to 1000000 ug/mL in the absence and presence of

metabolic activation. No increase in revertant

colonies.

D. Toxicity Endpoint Selection

There was no endpoint of concern identified in toxicity studies up to 1,000 mg/ kg/day. In addition, metabolism studies on alkylglyc osides reported that the β -glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage products, sugars and long-chain alcohols, entered the pathways of lipid and carbohydrate metabolism. Based on the low acute toxicit y, the body’s ability to rapidly metabolize the inert ingredient, the expected meta bolites being fatty acids and carbohydrates which are normal constituents of the body, and the lack of an endpoint of concern for repeat dose studies at the limit dose (1,000 mg/kg/day) a quali tative risk assessment was conducted.Page 14 of 22 B. Special Considerations for Infants and Children

Section 408 of the FFDCA provides that EPA sha ll apply an additional margin of safety for

infants and children in the case of threshold effect s to account for prenatal and post natal toxicity and the completeness of the database on toxic ity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. EPA concludes that the FQPA safety factor could be removed for AGEs for the following reasons:

i. The database is considered adequate for FQPA assessment. The following acceptable

studies are available:

Ames tests-870.5100 Combined repeated dose toxicity study w ith the Reproduction/developmental Toxicity Screening test

ii. Fetal susceptibility was not observed in the combined repeat ed dose toxicity study with the reproduction/developmental toxicity screening test in the rat. There were no toxic effects were observed in either study at the hi ghest doses tested, 1000 and 700 mg/kg/day, respectively.

iii. Signs of neurotoxicity were not observed in any of the submitted studies. No treatment related effect on FOB and motor activity para meters evaluated in the OCED 422 study at doses up to 1,000 mg/kg/day; however, all of the supporting data was not provided in the study report. EPA concluded th at the developmental neurot oxicity is not required.

iv. Signs of potential immunotoxicity were not observed in any of the submitted studies.

v. The dietary food exposure assessment utilizes proposed tolerance level or higher residues

and 100% CT information for all commoditie s. By using these screening-level assessments, chronic exposures/ri sks will not be underestimated.

Taking into consideration the available in formation, EPA concludes the additional 10X FQPA safety factor can be reduced to 1X.

V. EXPOSURE ASSESSMENT

A. Dietary Exposure

Dietary exposure to AGEs can occur from eating food treated with AGEs or from drinking water. However, a quantitative assessment was not con ducted since an endpoint of concern for risk

assessment was not identified.

i. Acute exposure . No adverse effects attributable to a si ngle exposure of sim ilar chemicals to the AGEs were seen in the toxicity databases. Ther efore, acute dietary risk assessment for AGEs is not required.Page 15 of 22 ii. Chronic exposure. A chronic dietary exposure assessm ent was not conducted for the AGEs because no toxicological endpoint of concern was identified for chronic dietary exposure. The

available studies/literature contained no eviden ce of a chronic dietary endpoint of concern.

iii. Dietary exposure from drinking water: Dietary exposure from dr inking water to AGEs can occur by drinking water that has been contaminated by run-off from a pesticid e treated area. Since an endpoint for risk assessment was not identifie d, a quantitative dietary exposure assessment from drinking water for AGEs was not conducted.

iv. Cancer exposure. Based on the available toxicity data (carcinogenicity study in rats and mice) and lack of mutagenicity concerns, AGEs is not expected to be carcinogenic. Ther efore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

B. Residential (Non-dietary) Exposure

The term “residential exposure” is used in this document to refer to non-occupational, non-dietary exposure (e.g., textiles (clothi ng and diapers), carpets, swimming pools, and hard surface disinfection on walls, floors, tables ). AGEs have reported uses in personal care products, such as antiperspirants, shampoos, conditioners, and mo isturizers. 180.910. Residential exposure to AGEs is possible; however, since th ere are no toxicological effect s of concern occurring below 1,000 mg/kg bw/day, it is not necessa ry to conduct assessments of residential (non-occupational) exposures and risks. There are no dermal or inha lation toxicological endpoi nts of concern to the Agency therefore quantitative assess ments have not been conducted.

C. Occupational Exposure

In the case of AGEs the Agency has reviewed th e available toxicological information. The data

indicate that there are no adverse toxicological effects (endpoi nts of concern) identified in the available database, therefore a quantitative risk assessment is not necessary and is not conducted.

D. Aggregate Exposure

In examining aggregate exposure, the Federa l Food, Drug, and Cosmetic Act (FFDCA) section

408 directs EPA to consider available information concerning exposures from pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

In addition to pesticide use, the AGEs have re ported uses in persona l care products, such as antiperspirants, shampoos, condi tioners, and moisturizers.Page 16 of 22 For the AGEs, a qualitative assessment for all pa thways of human exposure (food, drinking water, and residential) is appropriate gi ve the lack of human health con cerns associated with exposure to AGEs when used as an inert ingredie nt in pesticide formulations.

E. Cumulative Exposure

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires th at, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available info rmation” concerning the cumulative effects of a particular pesticide's residues and “other substanc es that have a common mechanism of toxicity.”

EPA has not found the AGEs to share a comm on mechanism of toxicity with any other substances, and does not appear to produce a toxi c metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assume d that does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine

which chemicals have a common mechanism of toxici ty and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.

VII. Environmental Justice Statement

Potential areas of environmental justice concerns , to the extent possible, were considered in this human health risk assessment, in accord ance with U.S. Executive Order 12898, "Federal

Actions to Address Environmental Justice in Mino rity Populations and Lo w-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

VIII. Environmental Fate Considerations

No specific information regarding the environmenta l fate properties of the AGEs are available. However, there are several biodegradation studies available on the surrogate chemicals:

 D-glucopyranose, oligomeric, 6-(dihydr ogen 2-hydroxy-1,2,3-propane tricarboxylate), 1- (coco alky) ethers, sodium salts (CAS No. 151911-51-2),

 D-glucopyranose, oligomeric, 6-hydrogen 2-su lfobutanedioate), 1-(c oco alkyl) ethers, sodium salts (CAS No. 151911-53-4); and

 D-glucopyranose, oligomeric, 6-[hydrogen (2 R, 3R)-2,3-dihydroxybutanedioate], 1-(coco alkyl) ethers, sodium sa lts (CAS No. 151911-52-3).

The results of these tests all indicate that the surrogate chemicals are readily biodegradable. (MRIDs 48179218, 48179212, 48179215, 48179214, 48179219 and 48179213)

Alkylpolyglucosides were assessed in order to de fine aerobic and anaerobic biodegradability of APG, a series of standard labor atory tests, representi ng either discontinuous screening tests or continuous test systems with activated sludge. Evalua tion of the results of su m parameters analysis (DOC removal, TOC removal, COD and BOD) a llowed classification of alkylpolyglucosides as "readily biodegradable" according to OECD defi nitions. Ultimate biodegradation was proved by the coupled-units test (OECD 303A) giving a DOC removal of 89 % and even the anaerobic biodegradability testing (ECETOC screening test) indicated co mplete transformation into C02 andPage 17 of 22 CH4 amounting to 84 % theoretical gas production. The findings of these studies were confirmed in two other OECD studies. (S teber et al. (1995) and Garcia et al., 1997; Madsen et al., 1996.)

The EPI (Estimation Programs Interface) SuiteTM is a Windows ® -based suite of physical/chemical property and environmental fate estimation programs developed by the EPA’s Office of Pollution Prevention Toxics and Syracuse Research Corp oration (SRC). EPI SuiteTM estimates for AGE (C 20 ) citrate, AGE (C 20 ) lactate, AGE (C 20 ) sulfosuccinate, AGE (C 8 ) citrate, AGE (C 8 ) lactate, and AGE (C 8 ) sulfosuccinate all provide further ev idence that these chemicals are readily biodegradable. (MRIDs 47867225, 47867226, 47867227, 47867228, 47867229, and 47867230)

VII. Ecotoxicity

No specific ecotoxicity data are available for the AGEs, however there are several studies on surrogate chemicals D-glucopyranose, oligomeric, 6-(dihydrogen 2-hydroxy-1,2,3- propanetricarboxylate), 1-(coc o alky) ethers, sodium sa lts (CAS No. 151911-51-2); Dglucopyranose, oligomeric, 6-hydrogen 2-sulfobutane dioate), 1-(coco alkyl) ethers, sodium salts (CAS No. 151911-53-4); and D-glucopyranose, oligomeric, 6-[hydrogen (2R, 3R)-2,3- dihydroxybutanedioate], 1-(coco alky l) ethers, sodium salts (CAS No. 151911-52-3). The results

of these studies are outlined in Table 4.

Table 4: Ecotoxicity Test Resu lts for AGEs Surrogate Chemicals

Test Test

Material ( CAS No.) Species Duration Results MRID

Acute Toxicity

to Fish 151911-53-4 Oncorhynchus mykiss 96 hours LC50=15.0 mg/l 48179206

Acute Toxicity

to invertebrates 151911-51-2 Artemia salina 24 hours LC0=5 mg/l LC50= 19.7 mg/l 48179217

151911-53-4 Daphnia magna 48 hours EC50= 46.0 mg/l

NOEC= 35.2 mg/l 48179208

Artemia salina 24 hours LC50=14.4 mg/l 48179216

151911-52-3 Artemia salina 24 hours LC0= 1 mg/l LC50= 10.2 mg/l 48179217

Acute Toxicity

to Plants 151911-53-4 Selenastrum capricornutum 96 hours EC50=8.4 mg/l (biomass) EC50=16.9 mg/l (growth) NOEC= 6.5 mg/l 48179209

IX. Risk CharacterizationPage 18 of 22 AGEs have low acute toxicity via the oral route. There is no available regarding acute exposure via the dermal, eye or inhalation routes.

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was available for a surrogate chem ical in rats. There were no treatment related effects observed in parents or offspr ing at doses up to 1000 mg/kg/day.

Neurotoxicity studies with AGEs we re not available for review. However, neurotoxicity was not observed in the dietary studies at concentra tions as high as 1,000 mg/kg/day (limit dose).

Mutagenicity studies (Ames) for surrogate chemicals were availabl e for review. The results for these studies were negative.

Metabolism studies were not available. Ho wever, studies on the metabolism of orally

administered β -glucosides in mice show that rapid hydrolytic acetal cleavage takes place principally in the stomach and intestine of the mi ce. The cleavage products pass into the fatty acid and carbohydrate metabolic pathways. That as sumption is also confirmed by another study on alkylglycosides where the β -glycosidic bond was rapidly hydroly zed in intestine and liver. The cleavage products, sugars and l ong-chain alcohols, entered the pa thways of lipid and carbohydrate

metabolism.

Residues of concern are not anti cipated for dietary (food and dri nking water) or for residential exposure from the use of AGEs for the proposed use pattern as an inert ingredient in pesticide products. As discussed above, EPA expects aggregate exposure to the AGEs to pose no appreciable dietary risk, gi ven that the data on the AGEs show a l ack of systemic toxicity at doses up to 1000 mg/kg/day.

Taking into consideration all available informati on on AGEs, EPA has determined that there is a reasonable certainty that no harm to any populat ion subgroup will result from aggregate exposure to AGE when used as an inert ingredient in pesticide formulations applied during pre-and postharvest when considering dietary exposure and all other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption

from tolerance under 40 CFR 180.910 for re sidues of AGEs (CAS Reg.Nos. 1079993-97-7, 1079993-92-2, 1079993-94-4) when used as inert ingredie nts in pre- and post- harvest applications in pesticide formulations, can be considered assessed as safe unde r section 408(q) of the FFDCA.

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MRID 47867200 Lamberti USA, Inc. (2009) Submission of Product Chemistry and Toxicity Data in Support of the Amended Registration of Inert Ingredients. Transmittal of 18 Studies.

MRID 47867205 Curone, D. (2001) Freezing Point of (Inert Ingredient). Project Number: V0085, V0058, 08/02/2001. Unpublished study prepared by Cesalpinia Chemicals SpA. 3 p.

MRID 47867206 Curone, D. (2001) Freezing Point of (Inert Ingredient). Project Number: 08/02/2001, V0058. Unpublished study prepared by Cesalpinia Chemicals SpA. 3 p.

MRID 47867207 Curone, D. (2001) Freezing Point of (Inert Ingredient). Project Number: 08/02/2001, V0058. Unpublished study prepared by Cesalpinia Chemicals SpA. 3 p.

MRID 47867208 Curone, D. (2001) Water Solubility of (Inert Ingredient). Project Number: 08/11/2001. Unpublished study prepared by Cesalpinia Chemicals SpA. 5 p.

MRID 47867209 Curone, D. (2001) Water Solubility of (Inert Ingredient). Project Number: 08/11/2001. Unpublished study prepared by Ce salpinia Chemicals SpA. 5 p.

MRID 47867225 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti, S.p.A. 5 p.

MRID 47867226 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 47867227 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 47867228 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti S.p.A. 5 p.Page 20 of 22 MRID 47867229 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti, S.p.A. 5 p.

MRID 47867230 Leming, D. (2009) EPIWIN Calcul ation on (Inert Ingredient). Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 47867231 Leming, D. (1966) Toxicological Evaluation of Some Antimicrobials, Antioxidants, Emulsifiers, Stabilizers, Flou r-Treatment Agents, Acid s and Bases: 050. (Inert Ingredient). Published Study Prepared by Join t FAO/WHO Expert Committee on Food Additives; Dec 13-20, 1965, Rome & Oct 11-18, 1966, Geneva. 5 p.

MRID 47867235 Leming, D. (1973) Seventeenth Re port of the Joint FAO/WHO Expert Committee on Food Additives, Wld Hlth Org. T echn. Rep. Ser., 1974, No. 539; FAO Nutrition Meetings Report Series, 1974, No.53.: 293. (Inert Ingr edient). Published Study Prepared by Joint FAO/WHO Expert Committee on Food Additives; Jun-Jul 25-4, 1973, Geneva. 5 p.

MRID 47867236 Leming, D. (1973) Seventeenth Re port of the Joint FAO/WHO Expert Committee on Food Additives, Wld Hlth Org. T echn. Rep. Ser., 1974, No. 539; FAO Nutrition Meetings Report Series, 1974, No.53.: 298. (Inert Ingr edient). Published Study Prepared by Joint FAO/WHO Expert Committee on Food Additives; Jun-Jul 25-4, 1973, Geneva. 5 p.

MRID 48179200 Lamberti USA, Inc. (2010) Submis sion of Product Chemistry, Toxicity, Fate and Environmental Fate Data in Support of the Petition for Tolerance of (Inert Ingredient).

Transmittal of 19 Studies.

MRID 48179201 Costantini, G. (2001) Determina tion of Physical-Chemical Properties of (Inert Ingredient). Project Number: 01/2874. Unpub lished study prepared by Biolab S.p.A. 93 p.

MRID 48179202 Biffi, E. (1993) Acute Oral Toxicity in Rats (Inert I ngredient). Project Number: 93/06632; 93/409.A1. Unpublished stu dy prepared by Biolab SGS srl. 11 p.

MRID 48179203 Biffi, E. (1993) Acute Oral Toxicity in Rats (Inert I ngredient). Project Number: 93/06633. Unpublished study prep ared by Biolab SGS srl. 11 p.

MRID 48179204 Biffi, E. (1993) Acute Oral Toxicity in Rats (Inert I ngredient). Project Number: 93/06634; 93/409/C1. Unpublished stu dy prepared by Biolab SGS srl. 11 p.

MRID 48179205 Curone, D. (2001) Water Solubility of (Inert Ingredient ). Unpublished study prepared by Cesalpinia Chemicals SpA. 6 p.

MRID 48179206 Jenkins, C. (2000) (Inert Ingredie nt): Acute Toxicity to Rainbow Trout. Project Number: RTS/018, RTS/018/002978. Unpub lished study prepared by Huntingdon Life Sciences, Ltd. 64 p.Page 21 of 22 MRID 48179207 Todd, M. (2001) (Inert Ingredient), Validation of Anal ytical Methodology for the Determination in Aqueous Medi a. Project Number: RTS/021, RTS/021/003153. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 46 p.

MRID 48179208 Jenkins, C. (2000) (Inert Ingredie nt), Acute Toxicity to Daphnia magna. Project Number: RTS/017, RTS/017/002978. Unpub lished study prepared by Huntingdon Life Sciences, Ltd. 62 p.

MRID 48179209 Jenkins, C. (2000) (Inert Ingredient ), Algal Growth Inhi bition Assay. Project Number: RTS/019, RTS/019/002978. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 68 p.

MRID 48179210 Golzio, L. (1996) (Inert Ingred ient) Ames Test. Project Number: 950771. Unpublished study prepared by Istituto di Ricerch e Biomediche Antoine Marxer RBM S.p.A. 40 p.

MRID 48179211 Golzio, L. (1996) (Inert Ingred ient) Ames Test. Project Number: 950770. Unpublished study prepared by Istituto di Ricerch e Biomediche Antoine Marxer RBM S.p.A. 40 p.

MRID 48179212 Tonti, A. (1995) Zahn-Wellens Test of (Inert Ingredient). Project Number: 021/1995/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48179213 Tonti, A. (1995) Zahn-Wellens Test of (Inert Ingredient). Project Number: 021B/1995/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48179214 Tonti, A. (1995) Zahn-Wellens Test of (Inert Ingredient). Project Number: 021C/1995/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48179215 Tonti, A. (1997) Closed Bottle Test of (Inert Ingredient). Project Number: 061/1997/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48179216 Lezzeni, B. (2001) Acute Toxicity Test at 24 H Using Artemia salina (Inert Ingredient). Project Number: 001 /1998/BL. Unpublished study prep ared by Lamberti S.p.A. 4 p.

MRID 48179217 Lezzeni, B. (2001) Acute Toxicity Test at 24 H Using Artemia salina (Inert Ingredient). Project Number: 004 /1998/BL. Unpublished study prep ared by Lamberti S.p.A. 5 p.

MRID 48179218 Tonti, A. (2001) Closed Bottle Test of (Inert Ingredient). Project Number: 016A/1998/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48179219 Tonti, A. (1998) Closed Bottle Test of (Inert Ingredient). Project Number: 016B/1998/AT. Unpublished study prepared by Lamberti S.p.A. 5 p.

MRID 48368200 Lamberti-USA, Inc. (2011) Submission of Toxicity, Environmental Fate, Residue, and Exposure and Risk Data in Suppor t of the Petition for Tolerance of (Inert Ingredients) for Use on All Agricultur al Commodities. Transmittal of 1 Study.Page 22 of 22 MRID 48368201 D.H. Dawe & Associates, LLC (2011) Inert Ingredient Tolerance Exemption Petition: (Inert Ingredients): Revision and Consolidation Additional Information to Support Petition # 9E7621. Unpublished study prepared by Lamberti-USA, Inc. 630 p. 49275100 Kill Fleas Dead, LLC (2013) Submission of Exposure/Risk and Toxicity Data in Support of the Petition for Tolerance of a New F ood Use Inert Ingredient. Transmittal of 3 Studies.

MRID 49275101 Unknown (2013) Inert Assessm ents: Exposure Assessment: Revision October 2013, ppl-7 with Changes and Additions Highlighted in YELLOW. Unpublished study prepared by Lamberti S.p.A.. 7p.

MRID 49275102 Unknown (2013) Inert Assessments: Three Exemptions for the Requirement of a Tolerance: 29 October 2013, pp 1-27 with Ch anges and Additions Highlighted in YELLOW. Unpublished study prepared by Lamberti S.p.A. 27p.

MRID 49275103 Schleh, C. (2013) Combined Repeat ed Dose Oral Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats with Eucarol Age 91/S: Final Report. Project Number: 130340. Unpublished study prepared by BSL Bioservice Scientific Laboratories Gmbh. 383p.