Page 2 of 36 corneas

. An eye irritation test with New Zealand white rabbits indicate s it to be moderately irritating. Two skin sensitization tests with Hartley guinea pigs show it is not a sensitizer to the guinea pig.

A 28

- day repeat dose oral toxicity stud y was conducted with Wistar rats . In this study, rats were treated via gavage with D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- N

- C 8

- 10 deriv ative s at doses up to 500 mg/kg/day

. At the 500 mg/kg/day dose, mortality was observed as well as t oxicity reflected as microscopic findings in the GI tract, trachea, lung, spleen and bone marrow

. The NOAEL was 250 mg/kg/day

. In a reproduction/developmental toxicity screening test , rats were dosed for 54 days with D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- N

- C 8

- 10 deriv ative s at doses up to 312.5 mg/kg/day

. Neither parental, developmental nor reproduction toxicity was observed at 312.5 mg/kg/day, the highest dose tested.

A gene reverse mutation study with Salmonella, an in vitro mammalian cell gene mutation study with Chinese hamster V 79 cells, a mammal ian micronucleus mutagenicity test of micronuclei in polychromatic erythrocytes in the mouse bone marrow, a mammalian micronucleus test with murine peripheral blood cells, a mutagenesis assay using L5178Y TK+/

- mouse lymphoma cells, an in vivo rat bone marrow cytogenicity study all were negative for mutagenic and clastogenic effects.

There were no neurotoxicity data per se however there were no indications of neurotoxic effects in the functional observation battery in the 28

- day oral toxicity study in the rat

. In addition, t he DEREK predictive modeling system did not identify any alerts for potential neurotoxicity.

There were no data regarding immunotoxicity. However evidence of potential immunotoxicity was observed in the 28 day oral toxicity st ud y in the rat. In this study, atrophy is seen in the spleen and bone marrow at 500 mg/kg/day. These effects will be protected since the established chronic reference dose (cR f D) is 1. 04 mg/kg/day.

There were no study data presented specifically addre ssing metabolism. Modeling data using the DEREK (Nexus) and METEOR modeling systems indicate 80 % absorption via the gastrointestinal system and less than 1 % via dermal absorption. The major route of excretion is via the urine.

The toxicological endpoint selected for use in chronic dietary risk assessment is taken from reproduction/developmental toxicity screening study in the rat. In this study, no effects are observed up to 312.5 mg/kg/day. The standard uncertainty factors (100x) are applied f or intra

- and interspecies variation and an additional uncertainty factor (3X) is applied to account for extrapolation from subchronic to chronic exposures. The Agency considers an uncertainty factor of 3X protective as no toxicity was observed up to 312. 5 mg/kg/day in an OECD 422 Guideline study. Dermal and inhalation absorption are assumed to be 100 %. For all short

- and intermediate

- term residential and occupational risk assessments, the toxicological endpoint selected for use is the assessment is taken from reproduction/developmental toxicity screening study in the rat. In this study, no effects are observed up to 312.5 mg/kg/day. The level of concern is for margins of exposure (MOEs) of 3 00 or less.Page 3 of 36 The general public is expected to be exposed via the oral route via dietary residues from treated crops and from ingestion of drinking water that may contain D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s . The Agency has assessed dietary exposure with the Dietary Exposure Evaluation Model DEEM

– FCIDTM, Version 3.16

. EPA used food consumption information from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What we eat in America, (NHANES/WWEIA). For D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s , aggregate risk include dietary exposure from food and drinking water. Exposures to children 1

- 2 years (the most highly exposed population subgroup from dietary sources) include food and water exposures. Dietary exposure estimates for food and drinking water are below the Agency’s level of concern (<100% cPAD) for the U.S. population and all population s ubgroups. The total dietary exposure for food and drinking water is 14.6 % of the cPAD for the U.S. population and 54.4 % of the cPAD for children 1

- 2 yrs. old, the most highly exposed population subgroup.

The Agency assessed aggregate exposures to D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s by considering potential dietary exposures, as discussed above, as well as potential residential applicator an d post

- application exposures via the oral, dermal and inhalation routes of exposure to both adults and children. The Agency’s level of concern is for Margins of Exposure < 300. The estimated screening level aggregate MOEs (assuming 100 % absorption via th e dermal and inhalation routes) are > 3 00 and do not exceed the Agency’s level of concern. Screening level occupational exposures resulted in Margins of Exposure (MOE) greater than 3 00 and thus do not exceed the Agency’s level of concern.

D

- Glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s exhibits low levels of toxicity to fish, Daphnia , algae and aquatic microorganisms. Study data indicate it is readily biodegradable within 28 days. The physical nature of the substance and the low vapor pr essure indicate minimal concern for volatility. It is essentially insoluble in water It is therefore not expected to bioaccumulate or be persistent in soil or water.

Based upon the factors and discussion presented above, an exemption from the requirement of a tolerance for D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s as an inert ingredient (surfactant) in pesticide formu la tions applied to growing crops and raw agr icultural commodities at a maximum concentration of 40% by weigh t can be established

.

II. BACKGROUND

On 23 December 2014, Keller & Heckman (1001 G Street, N.W., Suite 500 West, Washington, DC 20001) on behalf of the Clarian t Corporation (4000 Monroe Road, Charlotte, NC 28205) submitted a request to the U.S. EPA for the establishment of an exemption from the requirement of a tolerance for D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s (CAS Reg. No. 1591782

- 62

- 5) when used as an inert ingredient in pesticide formulations applied growing crops and raw agricultural commodities after harvest. . D

- Glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s is also referred to as C 8

- 10 acyl N

- methylglucanamide or C 8

- 10 acyl NMGA in portions of this document.Page 4 of 36 The submission relies, to a large degree, upon “read

- across” data regarding a structurally similar chemical analogue. 1

- Deoxy

- 1

- (methyl(C 12 - C 14

- (even)

- alkanoyl)amino )

- D

- glucitol ( CAS Reg. No. 287735

- 50

- 6 ) is identified as an analogue to address data gaps for the D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s The molecular structural difference is distinguished by only 2 to 4 CH 2 units in the alkyl chain. The Agency believes that based on the similarities in structural, functional and metabolic behavior of the target and source molecules, it is reasonable and scientifically justified to accept the “read

- across” approach as the source of effects on mammalian systems and on env ironmental fate and effects. 1

- Deoxy

- 1

- (methyl(C 12 - C 14

- (even)

- alkanoyl)amino)

- D

glucitol D

- Glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s is also referred to as C 12

- 14 acyl N

- methylglucanamide or C 12

- 14 acyl NMGA in portions of this documen t

III. PHYSICAL/CHEMICAL PROPERTIES

Table 1.0

Property C 8

- 10 acyl NMGA C 12

- 14 acyl NMGA State Solid Solid Molecular Weight 334.1 386.2 Melting Point 59

- 64 °C 77

- 113°C Boiling Point No boiling point under atmospheric conditions No boiling point under atmospheric conditions Relative Density D 4 R = 1.16 @ 20.6°C D 4 20 = 1.14 @ 19.9

- 20.5° C Vapor Pressure 1.1 x 10

- 8 hPa @ 25°C = ~ 8.25 x 10

- 9 mm Hg 1.4 Pa @ 25°C

Solubility in Water Not applicable: test substance Is surface active substance C 12 68 mg/L @ 20° C (24 hr) C 14 95 mg/L @ 60

- 70°C 30 minutes Octanol/Water Coefficient Calculated log P OW 1.43 @ pH 9.36 Solubility in n

- Octanol 47 g/L @ 20°C 28 g/L @ 20°C

Taken from pp 44

- 47/125 MRID 49537200 (Volume 2)

IV. HAZARD CHARACTERIZATION

1

- Deoxy

- 1

- (methyl(C 12 - C 14

- (even)

- alkanoyl)amino)

- D

- glucitol

Acute Oral Toxicity

In an acute oral toxicity study by Leoni (2013 ; MRID 49537203 ) the oral LD 50 for Wistar Crl: WI(Han) rats was determined to be 500 mg/kg for C 8

- 10 following a single oral dose

. Acute Dermal Toxicity

The acute dermal toxicity of C 8

- 10 was studied by Allingham (2013; MRID 49537206). Five male and five female Wistar Crl: WI(aHan) rats were administered a single dermal dose of 2000 mg/kg appliedPage 5 of 36 to 10% of the body surface area. The dermal LD 50 for a single dermal dose of C 8

- 10 was determined to be > 2000 mg/kg.

Acute Inhalation Toxicity

Acute inhalation toxicity was evaluated by van Huygevoort (2014; MRID 49537208) using a single four hour, nose only exposure to three male and three female Wistar rats. The test was conducted according to OECD test guideline 436. The mean actual vapor co ncentration was 22.2 ± 1.4 mg/L of the test substance C 8 - C 10 . The Mass Median Aerodynamic Diameter of vapor particles was 2.0 μ m. Animals were observed on days 1, 2, 4, 8, and 15. There was no mortality and no clinical signs were seen. Body weight loss and reduced body weight gain was noted for the females between Days 4 and 15 which were considered as signs of toxicity. The inhalat ion LC 50 , - 4

- hr value of a 1 % water solution of C 8 - C 10 in Wistar rats was established to exceed 20 mg/L. According to th e OECD Guideline 436 test guideline and considering the effects on body weights of females, the LC 50, 4

- hr
cut

- off value was considered to be 50 mg/L.

In another study by van Huygevoort (2011; MRID49537209), the acute inhalation toxicity was evaluated in Wistar rats. Three male and three female rats were exposed for four hours to a concentration of 5 mg/L. The mean actual concentration was 5.1 ± 0.13 mg/L. Exposures were nose

only to restrained animals. Animals were observed on days 1, 2, 3, 4, 8 and 1 5. At the 5 mg/L dose two males and one female died within 3 days post

- treatment. No further mortality was observed. At the 5 mg/L dose, animals showed slow breathing and one animal was restless during the exposure. After exposure, lethargy, hunched po sture, abnormal gait, labored respiration, rales, chromodacryorrhea and/or ptosis was noted for the animals between Days 1 and or 9. One female showed hunched posture till Day 14.

After noting the results/observations from the 5 mg/L exposure group, a se cond group of rats was exposed in a similar fashion to 1 mg/L of C 8 - C 10 for four hours. At 1 mg/L no clinical signs were noted during exposure. After exposure, hunched posture was seen in all animals between Days 1 and 4. One male showed labored respiration and ptosis between Days 1 and/or 2. Overall body weight gain in m ales and females was within the historical range expected for rats of that strain and age thus not considered toxic effects. The inhalat ion LC 50, 4hr value in Wistar rats was established to be within 1

– 5 mg/L. According to the OECD Guideline 436 the LC 50, 4hr cut

- off value was considered to be 5 mg/L.

In Vitro Skin Irritation

An in vitro skin irritation study (Lehmeir, 2013; MRID 49537210) was conducted using the human skin model test with C 8

- 10 . The test was conducted according to OECD Guideline te st 404 (OPPTS Guideline 870.2500) which uses the Draize scoring method. The test was conducted with the reconstituted three

- dimensional human skin model, EPISKIN

- SM TM (SkinEthic). The skin model consists of normal, adult human

- derived epidermal keratinoc yts (NHEK) which have been cultured to form a multilayered, highly differentiated model of the human epidermis. The NHEK are cultured on chemically modified, collagen

- coated cell culture inserts. A highly differentiated and stratified epidermis model is obtained after 13

- day culture period comprising the main basal, supra basal, spinous and granular layers and a functional stratum corneum.Page 6 of 36 In this study, C 8

- 10 was applied topically to the EPISKIN SM TM tissue for 15 minutes followed by a 42 hour post

- incu bation period and immediate determination of cytotoxic effects via MTT reduction assay (MTT = 3

- (4,5

- dimethylthiazol

- 2

- yl)

- 2,5

- diphenyltetrazolium bromide). Irritant potential of the test item was predicted from the relative mean tissue viability obtained compared to the corresponding negative control tissues concurrently treated with PBS. The test item showed no irritant effects. The mean relative tissue viability was > 50 % (100.2%) after 15 minute treatment and 42 hour post

incubation. The controls c onfirmed the viability of the study. The mean Optical Density (OD) 550 of the six blank values was < 0.1. The mean absolute OD 550 of the three negative control tissues was ≥ 0.6 and ≤ 1.5. The mean relative tissue viability (% negative control) of the po sitive control was ≤ 40% (28.5 %). Under the conditions of this study, the test material showed no irritant effects and was classified as non

- irritating.

An in vitro eye irritation study (Schmitz, 2013; MRID 49537212) was conducted using C 8

- 10 using the b ovine corneal opacity and permeability (BCOP) method. The bovine corneas were obtained from animals freshly sacrificed at the abattoir. Three corneas were used for the test item, three were used as positive controls (treated with imidazole 20 % in physio logical saline, 0.9 % NaCl, and three were used as negative controls treated with physiological saline, 0.9 % NaCl. The BCOP assay is considered valid if the in vitro irritation score obtained with the positive control falls within the two standard deviat ions of the current historical mean. The mean in vitro irritation score was calculated to be 130.97 therefore the test item is considered to be a severe irritant to the eye.

Skin Sensitization

A skin sensitization study was conducted by van Huygevoort (2013; MRID 49537214) using 10 female Dunkin Hartley albino guinea pigs. The test article is identified as C 8

- 10 . The study followed the Magnusson and Kligman protocol. The study was based on findings from a preliminary study. The ten animals were intr adermally injected with a 0.5 % concentration and epidermally exposed to a 5 % concentration. Five control animals were similarly treated but with vehicle (water) only. Two weeks after the epidermal application all animals were challenged with a 5 % test substance concentration and the vehicle. No skin reactions were evident after the challenge exposure in the experimental and control animals. There was no evidence that C 8 had caused skin hypersensitivity in the guinea pig since no responses were obser ved in the experimental animals in response to a 5 % test substance concentration in the challenge phase.

28

- Day Repeat Dose Oral Toxicity

In a 28

- day oral toxicity study (Stiller, 2014: MRID 49537217 )

, C8/10 was administered by gavage to four groups of 5 male and 5 female Crl: WI(Han) rats/group at 0, 100, 250, and 500 mg/kg/day for 28 consecutive days. Two additional groups of 5 male and 5 female rats were administered the test material at 0 and 500 mg/kg/day for 28 days and kept for a 14

- day recovery p eriod prior to necropsy.

During the study 1/10 males and 3/10 females were sacrificed in extremis at the high dose and one female at the high dose was found dead. The first was a male sacrificed on Day 12 and the last death was a female on Day 22. Numerou s treatment

- related findings were observed that predominantly were associated with direct

- acting irritating effects of the test material. Immediately after administration,Page 7 of 36 moving the nose through cage bedding was observed at all three dose levels in a dose dependent manner. Piloerection was observed at the high dose in some females and one male animal on single or occasional days of the treatment period. Piloerection was also observed at the high dose during the first week of the recovery period. Respirator y sounds were heard at all three doses in a dose

- dependent manner, but not during the recovery period. No statistically significant or biologically relevant findings were observed in the clinical chemistry results, functional observational battery, or urin alysis data. There was no statistically significant effect on body weight or weight gain at any dose, although female body weight at the high dose was 6.7% lower and weight gain was 27% lower at the end of the treatment period. Statistically significant in creases (p≤0.001) in neutrophils (20.2% vs. 10.0% in controls) and lymphocytes (75.7% vs. 87.2% in controls) were observed in females at the high dose at the end of the treatment period, but no microscopic correlate was observed. Somewhat increased
uterus weight was observed at all three doses at the end of the treatment period (49%, 38% and 58% higher at 100, 250 and 500 mg/kg bw/day, respectively) that was related to fluid distension of the uterus/cervix, but no microscopic correlate was observed. Females in the recovery group (N = 2) did not appear to have substantially higher uterine weight. Gaseous distension of the gastrointestinal (GI) tract was observed in one male and four females sacrificed in extremis at the high dose. At scheduled sacrifice, gase ous distension of the GI tract was observed in one male at the mid

- dose, one female at the low dose, and two females at the high dose. This finding was related to direct irritating effects to the GI tract observed microscopically. Minimal to moderate granu lomatous inflammation in the lungs was observed in animals at the high dose that did not survive the treatment period. The high dose female found dead also showed minimal alveolar edema and congestion, and marked epithelial necrosis of the trachea along wi th slight bronchiolar necrosis. Minimal basophilic foreign material and bronchiolar hyperplasia was observed in the lung of one male at the high dose, and acute alveolar/interstitial inflammation and bronchiolar hyperplasia was observed in one female at th e high dose. One high dose female at terminal sacrifice had moderate amounts of basophilic foreign material located in bronchioles and alveoli. Respiratory tract lesions were attributed to direct

- acting irritation effects of the test material following asp iration of gavage doses. Lung lesions were not observed in animals that survived to the end of the recovery period. All premature deaths showed slight to moderate lymphoid atrophy in the spleen and minimal bone marrow atrophy and/or myeloid hypercellularit y. The LOAEL for C 8/10 was 500 mg/kg/day in both sexes of Wistar rats based on mortality, microscopic findings in the GI tract, trachea, lung, spleen, and bone marrow . The NOAEL was 250 mg/kg/day in both sexes.

Reproduction/Developmental Toxicity in the Rat

In a reproduction/developmental toxicity screening study ( Allingham, 2014; MRID 49537220), study, D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8 - C 10 acyl derivs; was administered to 10 Wistar rats/sex/dose by gavage in water at dose levels of 0, 50, 125, or 312.5 mg/kg/day for at least 14 days prior to mating, during mating, after mating (males), throughout gestation, and through lactation day (LD) 4. The total treatment period was 54 days. Males were sacrificed on study day 29 and females and offspring were sacrificed on lactation day 4. Evaluated parameters included clinical observations, parental body weight, parental food consumption, parental organ weights, parental gross necropsy observations, parental histopathology, l itter size, offspring sex and weight, and offspring gross examination.Page 8 of 36 There were no treatment

- related effects on mortality, body weight, body weight gain, food consumption, gross or histopathological findings. Transient clinical signs attributable t o local effects of the test substance (salivation, moving bedding, piloerection, and abnormal breathing) were observed in males and females of the high

- dose group. Treatment

- related, but non

- dose

- related, increased uterus+cervix weights were noted at all dose levels (absolute w eight s: +14

- 20%; relative

- to

body w eight s : +13

- 24%; not significant ). However these increases were not considered adverse due to the absence of correlated alterations in histopathology

. Therefore, the parental systemic LOAEL is not identified, and the parental systemic NOAEL is 312.5 mg/kg/day.

Aside from increased uterus+cervix weights, there were no treatment

- related effects on the evaluated reproductive parameters, including mating, conception, fertility, precoital interval, gestation length, corpora lutea, implantation sites, pre

- or post

- implantation loss, or pregnancy outcomes, or gross/microscopic pathology of the male and female reproductive tracts. Therefore, the reproductive LOAEL is not identified, and the reproducti ve NOAEL is 312.5 mg/kg/day.

There were no treatment

- related effects on gestation survival, numbers of litters, litter size and weight, sex ratio, live born or born dead, viability indices, or macroscopic findings. Therefore, the developmental LOAEL is n ot identified, and the developmental NOAEL is 312.5 mg/kg/day.

Reverse Mutation Assay

In 2012, Schreib ( MRID 49537223) conducted a gene reverse mutation study to evaluate C 8 - C 10 for its ability to induce gene mutations in Salmonella typhimurium test strains TA 98, TA 100, TA 1535, TA 1537 and TA 102. In two different experiments several concentrations of the test substance were used. The concentrations including the controls were tested in triplicate. The dosing concentrations were 3.16, 10.0 , 31.6, 100, 316, 1000, 2500 and 5000 μ g/plate. No precipitation of the test item was observed in any tester strain used in experiment I and experiment II, with and without metabolic activation. Toxic effects from the test item were noted in most teste r strains used in experiments I and II.

In experiments I and II, toxic effects from the test item were observed at concentrations of 1000
μ g/plate and higher (without metabolic activation) and at concentrations of 2500 μ g/plate and higher (with metaboli c activation), depending upon the particular test strain.

No biologically relevant increases in revertant colony numbers of any of the five test strains were observed following treatment with the test substance at any concentration level, not in the pre sence or absence of metabolic activation in experiments I and II.

Under the conditions of this study, the test substance did not cause gene mutations by base pair changes or frame shifts in the genome of the test strains used. Therefore, the test subst ance is considered to be non

- mutagenic in this bacterial mutation assay.

In Vitro Mammalian Cell Gene Mutation

An in vitro mammalian cell gene mutation test was conducted by Wallner (2013, MRID 49537224) using Chinese hamster V79 cells exposed to the tes t substance C 8 - C 10 . The test was designed to assessPage 9 of 36 the potential for the test substance to induce mutations at the hypoxanthine

- guanine

- phosphoribosyl

transferase (HPRT) locus of V79 Chinese hamster cells. Two tests were conducted with and without metab olic activation. The test concentrations were: Test I: without metabolic activation

– 0.5, 0.75, 1.00, 1.50, 1.60, 1.90, 1.95 and 2.05 mM and with metabolic activation

– 0.25, 0.5, 1.0, 2.0, 2.5, 2.7, 2.8, 2.9, 3.0 and 3.1 mM. Test II without metabolic activation the concentrations were 0.010, 0.025, 0.05, 0.10, 0.25, 0.50, 1.00, 1.50, 1.75 and 2 mM. a nd with metabolic activation the concentrations were 0.20, 0.40, 0.80, 1.5, 2.10, 2.35, 2.60 and 2.95 mM. No precipitation of the test item was noted in the experiments.

Biologically relevant growth inhibition was observed i n experiment I and II with and without metabolic activation. In experiment I without metabolic activation the relative growth was 11.8 % for the highest concentration (2.05 mM) evaluated. The highest biologically relevant concentration evaluated with met abolic activation was 3.1 mM with a relative growth of 12.7%. In experiment II without metabolic activation the relative growth was 15.9 % for the highest concentration (2 mM) evaluated. The highest concentration evaluated with metabolic activation was 2 .95 mM with a relative growth of 10.0 %.

In both experiments no biologically relevant increase of mutants was found after treatment with the test item with or without metabolic activation. No dose

- response relationship was observed. 7,12

- dimethylbenz( a)anthracene (DMBA) and ethylmethanesulfonate (EMS) were used as positive controls and showed distinct and biologically relevant effects in mutation frequency. Under the conditions of these two tests, the test substance is considered to be non

- mutagenic i n the HPRT locus of V79 Chinese hamster cells.

Mammalian Micronucleus Mutagenicity Test

A mammalian micronucleus test of murine peripheral blood cells with C 8 - C 10 was conducted by Wessels (2013, MRID 49537225) to investigate the potential of the test substance to induce micronuclei in polychromatic erythrocytes (PCE) in the bone marrow of the mouse. After a dose range finding study, the following doses were select ed, 2000 mg/kg/day the maximum tolerated dose (MTD), 1,000 mg/kg/day and 400 mg/kg/day . The animals treated with 400 and 1000 mg/kg/day showed no signs of systemic toxicity. The animals treated with 2000 mg/kg/day showed mild to moderate signs of sys temic toxicity such as reduction of spontaneous activity, catalepsis, constricted abdomen, piloerection and half eyelid closure. For all dose groups, including positive and negative controls, 10000 polychromatic erythrocytes per animal were scored for inc idence of micronucleated immature erythrocytes. The negative controls (44hr and 68 hr) were within the range of the laboratory control data. The mean values noted for the dose groups which were treated with the test substance (44 hr and 68 hr) were withi n the negative control data range.

No biologically relevant increase of micronuclei was fond after treatment with the test substance in any of the dose groups evaluated. The nonparametric Mann

- Whitney Test was performed to verity the results. No statis tically significant increases/decreases (p<0.05) of cells with micronuclei were noted in the dose groups of the test item evaluated.

Cyclophosphamide (40 mg/kg/day ) was administered i.p. as a positive control which induced a significant increase in micron ucleus frequency. This demonstrates the validity of this assay. Based onPage 10 of 36 the evidence obtained under the conditions of this study, the test substance did not induce structural and/or numerical chromosomal damage in the immature erythrocytes of the mouse. The test substance is not mutagenic.

Neurotoxicity

– There were no data presented regarding neurotoxicity per se. However, there were no indications of neurotoxic effects in the negative findings in the functional observation battery (FOB) in the repe at

- dose toxicity studies. The predictive modeling system DEREK Nexus (v 3.0) did not identify C 8

- 10 glucamide as being potentially neurotoxic. The C 8

- 10 molecule lacks the phosphate or carbamate functionality which is typically expected to induce neuroto xic effects.

Immunotoxicity

– A weight of evidence approach suggests the lack of concern regarding the potential for C 8

- 10 to induce immunotoxicological effects. The glucamides in general do not induce delayed

type hypersensitivity responses which is demonstrated by the absence of sensitization potential in the guinea pig maximization tests. The data presented regarding standard toxicology endpoints (i.e. hematology organ weigh ts macroscopic and microscopic pathology of immune organs) suggest minimal concern for Immunotoxicity from exposure to C 8

- 10

.

M etabolism

– There were no metabolism study data presented. The submission notes that a combined analysis using “METEOR” for the prediction of metabolic fate and subsequent evaluation through DEREK (Nexus) for structural alerts, metabolites of toxicological significance are not believed to be expected. The submission states that C 8

- 10 is expected to undergo enzymatic hydrolysis of the amide linkage catalyzed by fatty acid amide hydrolase. The resulting metabolites are meglumine, an amino sugar (normally derived from sorbitol) and fatty acids. Meglumine would be expected to be rapidly excreted in the urine and the fatty acids are metabolized via the general β

- oxidation pathway to generate acetyl

- CoA. The projected metabolism was evaluated using accepted in silico programs. In addition, data are available regarding absorption, distribution, metabolism and elimination (ADME) of

a s urrogate Glucamide (C 12 ). These data indicate oral absorption of over 80% and dermal absorption of less than 1 % of the administered dose. The major route of excretion is via the urine.

Surrogate

Acute Oral Toxicity

Holalagoudar (2014 ; MRID 49537204 ) reported the LD 50 of 5000 mg/kg for Wistar Crl: WI(Han) rats from a single oral dose.

Decker (1991 ; MRID 49537205 ) reported “the acute oral toxicity” of E

- 4086.01 was reported to be “greater than 2000” mg/kg. It was not reported as an LD 50

.

A cute Dermal Toxicity

The acute dermal toxicity in the rabbit was evaluated by Baldrick and McRae (1991 ; MRID 49537207 ). The hair was removed from the dorso

- lumbar region of five male and five female New Zealand White rabbits equivalent to 10% of the body surface area. A single dose of 2 g/kg C 12 - C 14 was applied and then covered with gauze and backed by a non

- irritating dressing which was boundPage 11 of 36 around the body trunk. At the end of 24 hours, the dressing was removed and the treated area washed with warm water and blotted dry with absorbant paper. The animals were observed from 2 to 12 days. There were no signs of systemic reaction to the treatment. There was well defined erythema in all ten animals following removal of the dressings. After days 14 and 15 the skins showed minimal irritation and appeared normal at termination. The acute lethal dermal dose to rabbits was determined to be > 2 g/kg bw (not stated as LD 50 ).

Primary Skin Irritation

A primary skin irritation study on three New Zealand White rabbits (one female, two male) was conducted by Decker et al., (1991 ; MRID 49537211 ). The test was conducted according to OECD Test Guideline number 404 adopted 12 May 1981. A single dose of 0.5 g/animal was applied for four hours unde r a 100 cm 2 occlusive patch where the hair had previously been removed with clippers. The test substance was 98 % pure C 10 - C 16 . After four hours the patch was removed and the skin was flushed with luke

- warm tap

- water. Observations were conducted a 1, 24 , 48, 72 hours and 7 and 14 days after removal of the patch. Local signs (mean values from 1 hour to 14 days) consisted of grade 0.78 erythema and grade 0.39 edema. They were reversible within 14 days. No corrosive effect occurred on the treated skin of any animal. Under the conditions of this experiment, C 10 - C 16 was found to cause a primary irritation score of 1.5 when applied to intact rabbit skin. Thus, the test article is classified as not being an irritant to rabbit skin.

Eye Irritation

An eye i rritation study (Liggett and McRae, 1991 ; MRID 49537213 ) was conducted using three New Zealand White rabbits. The test substance was C 10

- 16. One eye of each of two rabbits received 6.3 mg directly onto the corneal surface, the other eye of each rabbit re mained untreated. A third rabbit received a single dose of 4.6 mg placed onto the cornea of one eye. Treated eyes were examined 1, 2, 3, 4, 7, 14, 21, 28 and 35 days after treatment. Scoring was according to the Draize method of appraisal. Corneal opac ities were present in two animals the day following instillation. An opacity was still evident in one animal 35 days after treatment. It resolved 14 days after treatment in the other animal. Vascularisation of the corneal epithelium was recorded in one animal 14, 21, 28 and 35 days after instillation. Iridial inflammation was seen at Day 3 in one animal and for the first four days in a second animal. Transient mild conjunctival inflammation only was observed in the remaining animal. All conjunctival r eactions had resolved 7, 14 or 35 days after treatment. The study authors concluded that under the conditions of the study, C 10

- 16 is moderately irritating to the rabbit eye.

Skin Sensitization

A nother skin sensitization study was conducted by Ullman et al. (1991 ; MRID 49537215 ) using the modified Beuhler method. Ten male and female albino guinea pigs (GOHI, SPF

- quality = Himalayan spotted) were tested, five male and female guinea pigs were untreated a nd served as controls. The test substance was identified as C 10 - C 16 with a physical state of being a white gel of 45 % purity for the test substance. Hair was closely clipped from the dorsal aspect of the animals. Approximately 3 ml of 10% test material was applied with a spatula and then quickly covered with a cloth patch which was in turn covered with a rubber dental dam and the animals were restrained for 6 hours. After the exposure the dams and patches were removed and the skin flushed with lukewarm tap

- water and padded dry.Page 12 of 36 Responses were graded at 12 hours and 24 hours post

- treatment. According to the European Economic Community classification system in Guideline B3/457 16 SEPT 1983, the test article is considered not to be a sensitizer to this g uinea pig strain.

Bouds (1999 ; MRID 49537216 ) conducted a dermal sensitization study with Hartley

- derived guinea pigs and followed the same basic protocol as outlined above

. The potential for dermal sensitization from exposure to the test article C 10 - C 16 was evaluated using ten male and 10 female guinea pigs. The test animals received intradermal injections of 5 % w/v of the test substance in distilled water along with injections of Freund’s Complete Adjuvant (FCA) and the test substance in FCA. One wee k later, the test animals received a topical application of 25 % w/v test substance C 10 - C 16 in distilled water. Challenge and re

- challenge control animals received similar intradermal and topical treatments except distilled water was used in place of the test substance. Following a two

- week rest period, a challenge was performed whereby the nineteen test and ten previously untreated (naïve) challenge control guinea pigs were topically treated with 5 % w/v test substance in distilled water. One female (an imal number 7838/F) was found dead on study day 16. The cause of death was not considered a result of test
treatment. Challenge responses in the test animals were compared with those of the challenge control animals. Following a seven

- day rest period, a re

- challenge was performed whereby the nineteen test animals and ten previously untreated (naïve) re

- challenge control animals were topically treated with 1 % w/v test substance in distilled water. Re

- challenge responses in the test animals were compare d with those of the re

- challenge control animals. Based on the results of this study, the test substance produced a 10 % (2/19) sensitization rate at re

- challenge versus a clean control thus was classified as a

non

- sensitizer in guinea pigs (according to European Union labeling regulations (Annex VI of the Council Directive 67/548/EEC).

In a 28

- day oral toxicity study (Schulze, 1991; MRID 49537218) D

- Glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C8

- 10 acyl derivs was administered by gavage to five groups of 10 male and 10 female Crl:CDF F344 rats/group at 0, 10, 100 (mid

- 1), 500 (mid

- 2), and 1000 mg/kg/day for 28 consecutive days.

During the study, 4/10 females were sacrificed in extremis at the high dose and five males and three females in the high dose group s were found dead (most during Week 1). The first death was a female on Day 3 and the last death was a male on Day 30. Only two high dose females survived to terminal sacrifice, therefore minimizing the effectiveness of statistical analysis. Several treatm ent

- related clinical findings were observed, primarily associated with direct irritating effects of the test material. Salivation after dosing was observed beginning on Day 1 in all animals at the mid

- 2 and high doses. Wheezing and/or dyspnea were observed sporadically in the mid

- 2 and high dose groups beginning on Day 1. Statistically significant differences (relative to control values) in mean clinical pathology parameters were generally limited to the mid

- 2 and high dose groups and were considered to be secondary to decreased food consumption and body weight. ALT levels were increased (p≤0.05) at the mid

- 2 (37.0% in males, 29.7% in females) and high (119.6% in males, 146.0% in females) dose levels. Alkaline phosphatase was increased in females at the mid

- 2 (16.4%) and high doses (24.3%). No microscopic correlates were observed for these findings. No statistically significant differences were noted in urinalysis parameters in either sex. Average body weight was statistically significantly decreased in the mid

- 2 (9.2%

- 13% in males; 9.8

- 11% in females) and high dose (20.3

- 27.4% in males; 11.5

- 13.5% in females) groups in a dose

- dependent manner beginning at Week 1. Average body weight gains were also decreased (p≤0.05) in the mid

- 2 (32.9% in males; 31% in females) and high

-Page 13 of 36 dose (84% in males; 55% in females) groups. Hematological c hanges included a decrease (p≤0.05) in lymphocytes in males at the high dose (57%) which correlated with microsco pic changes in the thymus. At the mid

- 2 dose, lymphoid depletion was observed in 1/10 males and 3/10 females. One high dose female exhibited moderate anemia accompanied by an erythrocytic regenerative response, and lymphocytosis with a minimal left shift in neutrophils. The other high dose female exhibited mild lymphopenia. These findings were consistent with the presence of inflammatory lesions and focal hemorrhaging in the stomach in the mid

- 2 and high dose groups. Absolute stomach weights were increased (p≤0.05) in both sexes at the mid

- 2 (24.8% in males; 29.1% in females) and high (30.7% in males; 43.0% in females) doses, as were relative (to body weight) stomach weights (38.4% in males and 38.6% in females at the mid

- 2 dose; 74.8% in males and 59.9% in females at the high dose) and relative (to brain weight) stomach weights (25.1% in males and 12.5% in females at the mid

- 2 dose; 36.0% in males and 24.7% in females at the high dose). Decreases (p≤0.05) in absolute thymus weights (26.3

- 38.9% in males; 44. 2

- 47.4% in females) and relative (to brain weight) thymus weights (29.2

- 50.6% in males; 36.3

- 44.2% in females) were observed at the mid

- 2 and high doses, and thymus to body weight was decreased (p≤0.05) in mid

- 2 and high dose females (36.7

- 41.8%). The prim ary treatment

- related gross lesions were found in the stomach and were consistent with direct

- acting irritant effects of the test material. Thickened and/or rough mucosa in the nonglandular region of the stomach was observed in three female and six male an imals in the high dose group and seven male and four female animals in the mid

- 2 dose group. A dark area in the nonglandular region of the stomach was observed in three animals (one low dose female, one mid

- 2 and one high dose male). The nonglandular stoma ch of all animals in the mid

- 2 and high dose groups demonstrated acanthosis, and parakeratosis was also observed at the mid

- 2 (9/10 males, 3/9 females) and high (10/10 males, 8/10 females) doses. Varying incidences of acute inflammation, ballooning degener ation of surface epithelium, erosion, ulceration, and focal hemorrhage were noted at the two highest doses. Additionally, an increased number of goblet cells and/or mucus on the mucosal surface of the glandular region of the stomach was observed in seven m id

- 2 and four high dose males and in three mid

- 2 females. Microscopic changes in the thymus included necrosis at the high dose (2/9 males, 5/10 females) and lymphoid depletion at the mid

- 2 (1/10 males, 3/9 females) and high (7/10 males, 5/10 females) doses . All animals examined (except two high

- dose females found dead or moribund) demonstrated peribronchial/perivascular lymphoid infiltration with or without alveolar macrophages. Two males and three females at the high dose and one mid

- 2 female exhibited nec rosis of tracheal epithelium with acute inflammation. Focal hemorrhage was present in the lungs of three of the affected rats. Respiratory effects were attributed to inadvertent aspiration or instillation of the test material into the trachea.

The LOAEL f or C 10 - C 16 in Fischer 344 rats was 500 mg/kg/day in both sexes based on gross and microscopic findings in the stomach and thymus. The NOAEL was 100 mg/kg/day in both sexes.

13

- Week Oral Toxicity Study

In a 13

- week oral toxicity study, ( Isaacs
, 1994; MRI D 49537219 )

, C 12 - C 14 was administered by gavage to five groups of 10 male and 10 female HanIbm: WIST (SPF) rats/group at 0, 10, 50, 200, and 500 mg/kg/day for 13 weeks (main group). An additional ten male and ten female rats per dose level

were administered the test material and kept for a 28

- day recovery period prior to sacrifice and necropsy (recovery group). Histopathology was conducted on tissues from rats in the control and highPage 14 of 36 dose groups as part of the original study (1991). A follow

- up p athology study (1994) was conducted to examine respiratory tract tissues. This examination was more comprehensive than the original pathology study, since respiratory tissues from the control and all four treatment groups were included.

Dose

- related incre ases in the incidence and severity of respiratory clinical signs (rales, dyspnea, and labored respiration) were observed. Rales were most prominent with incidences of 2/10, 3/10, and 17/20 at 50, 100, and 500 mg/kg / day, respectively in males, and 0/10, 5/1 0, and 11/20, in females. Rales were observed at the high dose beginning Week 4 in both sexes and dyspnea was observed early as Week 2. Ruffled fur was a common finding among all animals at the high dose beginning Week 4. These clinical signs at the high d ose persisted only into the first week of the recovery period. There were eight unscheduled (premature) mortalities during the study. These included 4/20 males and 2/20 females at the high dose between Days 27 and 91 (of these, intubation error was the cau se of death for one male and one female, leaving four unexplained mortalities). In addition, one male at the low dose and one male at the mid

- high dose died of intubation errors.

Body weight was statistically less in males at the mid

- high (beginning Week 9) and high dose (beginning Week 2). At the end of the treatment period, body weight in males was 7% lower at the mid

- high dose and 12% lower at the high dose and the respective weight gains were

- 14% and

- 26%. At the end of the 4

- week recovery period, bod y weight in males at both of these doses was 6% to 7% lower, but the differences were not statistically significant. Food consumption was statistically lower at the high dose in males for Week 2 (

- 17%), and was statistically lower by 9% to 15% during weeks 5

- 10. In females, food consumption was significantly lower by 13% at the high dose for Week 2, but closely tracked with controls thereafter. During the recovery period food consumption was similar to controls in both sexes at all dose levels.

Relative (to body weight) food consumption was statistically lower at the high dose during the first week of treatment in males (

- 11%) and females (

- 16%). Both sexes at the high dose were generally similar to controls thereafter. Slight, but statistically significant, increases in hematocrit and RBCs in both sexes at the high dose indicated some shift in fluid balance (not biologically significant). No
treatment

- related findings were observed in the clinical chemistry results or in ophthalmology examination s. The overnight mean urinary output in the main group was 43% higher in males and 63% higher in females at the high dose (p≤0.01).

Several organ weight parameters at the high dose (main group, but not the recovery group) were observed that reflect treat ment

- related stress and adaptation by the animals. For example, the adrenal:body weight ratio was elevated in main group males by 22% relative to controls; the absolute and relative liver weight in females was higher by about 30%. No histological correlate s were observed in these organs. No treatment

- related macroscopic findings were observed in animals that survived to terminal sacrifice. In main group males, a total of 7/10 animals (including all four decedents) at the high dose and 1/10 at the mid

- high d ose were observed with lesions in the nasal cavity. The lesions were generally widespread, but large areas of affected epithelia (respiratory, transitional, and olfactory) were unaltered, an observation that led to the conclusion that test material entered the nasal cavity during dosing and caused direct adverse effects (as opposed to those effects being caused by systemic toxicity). The types of lesions included acute inflammation, epithelial degeneration/regeneration, and focal squamous metaplasia. Typica lly, these lesions at the high dose were slight to moderate, except for epithelial degeneration which was moderate to severe. The onePage 15 of 36 lesion observed at the mid

- high dose in males (focal fused turbinates) was minimal. In females, a total of 6/10 animals (i ncluding both decedents) at the high dose and 3/10 at the mid

- high dose were observed with similar types of lesions in the nasal cavity as males and with similar dose

- dependent severity (test material concentrations increased with dose as the dosing volume was held constant). The incidence and severity of nasal cavity lesions in the recovery groups of both sexes were somewhat lower, although 3/10 males were affected at the mid

- high dose, while only one was affected from the main group. Bedding material was observed in the nasal cavity of one control male from the recovery group and in one high dose female from the main group, showing that the nasal lesions were not caused by inhalation of bedding material. No treatment

- related findings in the nasal cavity we re seen in either sex at the low and mid

- low dose levels. No findings were observed in the larynx or trachea of the control and high dose animals, and none was observed in the decedents. The lungs of animals that survived to terminal sacrifice were general ly unremarkable. In the original pathology report, no
treatment

- related lesions were observed in organs other than those of the respiratory tract.

The LOAEL for C 12 - C 14 was 500 mg/kg/day in both sexes of Wistar rats based on mortality, body weight effects, and the clinical observation of ruffled fur . The NOAEL was 200 mg/kg/day in both sexes.

Prenatal Developmental Toxicity

In a developmental toxicity study (Saylor, 1991; MRID 49537221 ), C 10

- 16 was administered to 25 female Crl:CD VAF/Plus ® rats/ dose by gavage in deionized water at dose levels of 0, 15, 150, or 363 mg/kg/day (constant dosing volume of 10 mL/kg) on days 6 through 15 of gestation. On gestation day (GD) 20, the females were sacrificed and the fetuses removed by cesarean section. Th e evaluated parameters included clinical signs, mortality, body weight, body weight gain, embryo

- fetal death, and fetal body weight. All fetuses were examined for external malformations and variations; half of all fetuses were examined for visceral malfor mations and variations, and the remaining half were examined for skeletal malformations and variations.

No mortalities occurred during the study. Increased salivation was observed post

- dosing in all females of the high

- dose group on one or more occasio ns (starting on GD 6). Material around the mouth and/or nose and decreased activity were observed post

- dosing in 4/25 and 2/25, respectively, of the females of the high

- dose group. Post

- dosing salivation was also seen in 5 mid

- dose females, on 1

- 2 occasi ons each. There were no observations of post

- dosing salivation in control or low

- dose animals. Although mean absolute body weights were similar among the groups, females of the high

- dose group did not gain weight during the first three days of the treatm ent period (0 g vs. +5 g for controls (p<0.05). Body weight gain in the high

- dose group over the duration of the treatment period was decreased by 32%, compared with controls (p<0.01). The adjusted (for gravid uterus) GD 0

- 20 body weight gain for females in the high

- dose group was decreased by 11%, compared with controls (n.s.). Although treatment

- related effects (post

- dose salivation and decreased body weight gain) were observed, there was no indication that the effects were adverse. Therefore, the mat ernal LOAEL is not established. The maternal NOAEL is 363 mg/kg/day.

There were no treatment

- related effects on developmental parameters. The developmental LOAEL is not established. The developmental NOAEL is 363 mg/kg/day.Page 16 of 36 The developmental toxicity study is classified Unacceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (OCSPP 870.3700; OECD 414) in rats. Based on the absence of maternal systemic toxicity and/or developmental ef fects, it is not clear that dose selection was appropriate. The OCSPP 870.3700 requirement is that the highest dose level should be chosen with the aim of causing toxic effects without inducing death or severe suffering, or the highest dose should be set at 1000 mg/kg/day. In this study, the highest dose was less than the limit dose and did not result in maternal systemic toxicity. The study may be ungraded if the results of the range

- finding study are reviewed and the dose selection for this study found to be appropriate.

Reproduction Toxicity

York (2000 ; MRID 49537222 ) conducted a study designed to provide information concerning the effects of the test substance C 10 - C 16 on the male and female reproductive systems in Crl:CD ® (SD)IGS BR VAF/Plus ® rats. Evaluations included gonadal function, estrous cycles, mating behavior, conception, parturition, lactation, weaning and the growth and development offspring. The study also provides information regarding neonatal morbidity, mortality and prelimina ry data on potential developmental toxicity.

One hundred male and female rats were randomly assigned to four dosage groups (Groups I through IV), 25 rats per sex per dose group. The test substance and the veh icle (processed deionized water ), was administ ered orally, via gavage, one time daily beginning 70 days before sacrifice at doses of 0 (vehicle), 15, 150 and 350 mg/kg/day respectively.

All P generation rats were observed for viability at least twice each day of the study. The rats were also exami ned for clinical observation of effects of the test substance, abortions, premature deliveries and deaths daily before and approximately one hour after administration. Body weights were recorded daily during dosage period and at sacrifice. Feed consumpti on values for male rats were recorded weekly until cohabitation and weekly during the post

- cohabitation period. Feed consumption values for female rats were recorded weekly until cohabitation, on gestation day (DG) 0, 6, 10, 15, 18, 20 and 25 (if necessar y) and on lactation day (DL) 1, 4, 7, 10 and 14. Because pups begin to consume maternal feed on or about DL 14, feed consumption values were not tabulated after DL 14.

No P (parental) generation male rats died as a result of treatment with C 10 - C 16 . Clinical observation considered test substance

- related in male rats in the 150 and 350 mg/kg/day dose groups included excess salivation, rales, chromorhinorrea, a red or dried red perioral substance and chromodacryorrhea in the 350 mg/kg/day only. Redu ced body weight gains in the 350 mg/kg/day dose group were considered related to the test substance. Absolute and relative feed consumption values were unaffected by dosages as high as 350 mg/kg/day . Totals of 24 (96.0 %), 25 (100 %), 21 (100 %) and 25 ( 100 %) male rats mated. Dosages of the test substance as hig h as 350 mg/kg/day did not affect the fertility index, mating index, precoital index or the number of male rats that mated in the first or second week of cohabitation.

All necropsy observation s were considered unrelated to the test substance. Terminal body weights were significantly reduced in the 350 mg/kg/day dose group. No biologically significant differences occurred among the four dose groups for weights of epididymides, left cauda epidi dymis and testes,Page 17 of 36 seminal vesicles, pituitary and brain or the ratios of these organ weights to the terminal body weights or brain weights. No statistically significant or biologically significant differences occurred in the number or the percentage of mo tile sperm, the number of nonmotile sperm and the sum of the motile and non

- motile sperm.

No parental generation female rats died as a result of treatment with the test article. Clinical observations considered test article related during the precohabita tion, gestation and lactation periods included excess salivation and rales in the 150 and 350 mg/kg/day dosage groups. Average body weights, body weight gains and absolute and relative feed consumption values during the precohabitation period were compara ble among the four dose groups. Maternal body weight gains and absolute feed consumption values were significantly reduced in the 350 mg/kg/day dose group for the entire gestation period. Although absolute maternal body weights were reduced or significantly reduced in the 350 mg/kg/day dose group on each day of the lactation period, maternal body weight gains were increased over the vehicle cont rol group value for the entire lactation period. Absolute and relative feed consumption values during the lactation period were comparable among the four dose
groups.
Doses as high as 350 mg/kg/day did not affect estrous cycling or natural delivery and litter parameters. All female rats were mated. Pregnancy occurred in 23 (92 %), 23 (92 %), 21 (100 %) and 22 (88 %) female rats in the four respective dose groups. Terminal body weights were unaffected by doses as high as 350 mg/kg/day . The weights of the pituitary, brain, left and right ovary and uterus and the ratios of these organ weighs to the terminal body weight or absolute brain weight of parental generation female rats were comparable among the four dose groups and did not differ significantly. Natural delivery and litter parameters were unaffected by doses of the test material as high as 350 mg/kg/day

. All clinical and necropsy observations in the F 1 generation pups were considered unrelated to the test substance. There were no test substa nce

- related microscopic changes observed in the brain, pituitary or reproductive tissues of male or female rats in the 350 mg/kg/day dose group.

Based upon the data and findings in this study, the no observable adverse effect level (NOAEL) for the
test substance is 15 mg/kg/day . The 150 and 350 mg/kg/day dose groups caused adverse clinical observation and the 350 mg/kg/day dose group caused reduced body weight gains and slight reductions in feed consumption values. The reproductive and developmental NO AEL is greater than 350 mg/kg/day . No adverse effects on fertility or development occurred at the highest dose tested (350 mg/kg/day ).

Mutagenesis Assay

Bigger and Clarke (1991 , MRID 49537226 ) conducted a L5178Y TK+/

- mouse lymphoma mutagenesis assay with the test article C10

- C 16 in the presence and absence of Aroclor induced rat liver S9. The non

- activated cultures selected for cloning in the initial assay were treated with doses of 2.3 to 36 μ g/ ml and exhibited Total Growths from 16% to 93%. The S9 activated cultures selected for cloning in the initial assay were treated with doses of 2.3 to 50 μ g/ml which produced from 18% to 107% Total Growths.Page 18 of 36 In the confirmatory assay, the non

- activated cultures selected for cloning were treated with doses of 2.3 to 32 μ g/ml and exhibited Total Growths from 10% to 106%. The S9 activated cultures selected for cloning in the confirmatory assay were treated with doses of 13 to 45 μ g/ml which produced from 12 to 109% Total Gr owths.

None of the non

- activated cultures that were cloned exhibited a mutant frequency which was at least twice the mean mutant frequency of the solvent controls. A dose

- dependent response was not noted in the treated cultures. None of the S9 activat ed cultures that were cloned exhibited a mutant frequency which was at least twice the mean mutant frequency of the solvent controls. A dose

- dependent response was not noted in the treated cultures. Therefore under the conditions of this study the test

m aterial was negative in both the presence and absence of exogenous metabolic activation.

Cytogenicity

An in vivo rat bone marrow cytogenicity study was conducted by Putman and Young (1991 , MRID 49537227 ). Male and female Sprague

- Dawley rats were treat ed with the test article C 10 - C 16 administered by a single oral gavage dose in 20 ml/kg of vehicle (water) . Males received doses of 180, 600 or 1800 mg/kg and females received a single dose of 210, 700 or 2100 mg/kg/day . Bone marrow cells arrested in metaphase and collected 8 and 12 hours after treatment, were examined microscopically for structural chromosome aberrations. No statistically significant increase in percentage of aberrant cells were observed in the test a rticle treated groups, regardless of sex or one marrow harvest time. Under the conditions of this study the test article did not induce chromosomal aberrations in bone marrow cells of male or female rats.

V. TOXICITY ENDPOINT SELECTION

The toxicolo gical endpoint selected for use in risk assessment is taken from the

r eproduction/developmental toxicity screening study in the rat. In this study, no toxicological effects

are observed up to 312.5 mg/kg/day. The lowest NOAEL (250 mg/kg/day) in the database is observed in a 28 day oral toxicity study in the rat. The LOAEL i s 500 mg/kg/day based on mortality, microscopic findings in the GI tract, trachea, lung, spleen and bone marrow

. Since similar effects are not observed in the reproduction/developmental toxicity screening study in which treatment occurred for 54 days, it was concluded that the lower NOAEL (250 mg/kg/day) is simply due to dose spread

. Therefore, the higher N OAEL (312.5 mg/kg/day) i s selected for risk assessment. The standard uncertainty factors (100x) are applied for intra

- and interspecies variation and an additional uncertainty factor (3X) i s applied to account for extrapolation from subchronic to chronic e xposures. Dermal and inhalation absorption are assumed to be 100 %.

VI. Special Consideration for Infants and Children (FQPA Safety Factor)

Section 408 (b)(2)(c) of the FFDCA provides that EPA shall apply an additional margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA det ermines that a different margin of safety will be safe for infants and children. EPAPage 19 of 36 concludes that the 10X FQPA safety factor should be retained for D

- glucitol for the following

reasons:

The database is considered adequate for FQPA assessment. The fol lowing acceptable

s tudies are available:

A Reproduction/Developmental study in rats A Prenatal Developmental Toxicity study in the rat A Reproduction Study in the rat

i. Fetal susceptibility was not observed in the reproduction/developmental toxicity sc reening test in the rat. Neither parental, developmental, nor reproduction toxicity were observed at doses up to 312 .5 mg/kg/day. No susceptibility was seen in the developmental toxicity study in rats at doses up to 300 mg/kg/day; the highest dose tested.

ii. There were no data specific to neurotoxicity. However there were no indications of neurotoxic effects in the functional observation battery tests in the 28 day oral toxicity study in the rat.

iii. Immunotoxicity studies were not available for revie w. However evidence of potential immunotoxicity was observed in the 28 day oral toxicity stud y in the rat. In this study, atrophy is seen in the spleen and bone marrow at 500 mg/kg/day. These effects will be protected since the established chronic refer ence dose (cRFD) is 1.04 mg/kg/day.

iv

. The dietary food exposure assessment utilizes proposed tolerance level or higher residues and 100% crop treated (CT) information for all commodities. In addition, a conservative drinking water concentration val ue of 100 parts per billion (ppb) was used to assess the contribution to drinking water. By using these screening

- level assessments, chronic exposures/risks will not be underestimated.

As part of its qua ntitative assessment of exposure via pesticide us e and via exposure through food and
water , the Agency re duced the FQPA safety factors for assessing risk to infants and children to 3 X. The toxicological database for D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s is considered adequate

.

VI I

. EXPOSURE

Based upon information provided in the submission, human exposures are expected from several sources. The general public may be exposed via residues that may exist on treated crops. T he Agency has conducted a “screening level” assessment of hypothetical exposures and risks based on typical end

- use product information. The Agency’s level of concern is for Margins of Exposure < 3 00. The estimated screening level MOEs (assuming 100 % absorption via the dermal and inhalation routes) are

> 3 00 and do not exceed the Agency’s level of concern.

Finally, human exposure is expected to agricultural workers involved primarily in the preparation and delivery of pesticide applications in agricultural settings, in this case sprays as opposed to dusts or granules etc.Page 20 of 36 Dietary exposure

-

Because no a cute endpoint of concern was identified, a quantitative acute dietary exposure assessment is unnecessary. In conducting the chronic dietary exposure assessment using the Dietary Exposure Evaluation Model DEEM

– FCIDTM, Version 3.16, EPA used food consumptio n information from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What we eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. The Inert Ingredient Dietary Exposure Evaluation Model is a highly conservative model with the assumption that the residue level of the inert ingredient would be no higher than the highest tolerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation between the active and inert ingredient (if any) and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentration of the active ingredient. The model assumes 100 percent crop treated (PCT ) for all crops and that every food eaten by a person each day has tolerance

- level residues. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled ‘‘Alky l Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.’’ (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

– HQ

– OPP

– 2 008

– 0738.

The chronic analysis was based on a NOAEL of 312.5 mg/kg/day. The uncertainty factor of 3 00 (10x for intraspecies variability and 10x for inter species extrapolation and 3X for subchronic to chronic extrapolation ) was used for the chronic endpoints. One hundred percent crop treated was assumed, default processing factors and tolerance

- level residues for all foods and use limitations of not more than 0.5 0 % by weight in pesticide formulations. Drinking water (100 ppb) was incorporated direc tly into the dietary assessment. The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD). For the t otal U.S. population, the exposure for food and water utilized 14.6 % of the cPAD. The chr onic dietary risk estimate for the highest exposed population subgroup, children 1

- 2 years old

, is 54 .4 % of the cPAD. It is important to note that the Inert Ingredient Dietary Exposure Model assumes a default value of 100 ppb for the concentration of the inert in all sources of drinking water. Based on the physical and chemical properties of this chemical and the intended use pattern, exposure through drinking water is unlikely; therefore, these results are highly conservative in regards to the exposure t hrough drinking water.

The proposed use of this chemical as an inert ingredient in food

- use pesticide product formulations is 40%. Using the I nert Ingredient Dietary Exposure model to estimate the exposure to all subpopulations ( see the attachment ), it was determined that the exposure from the use of this inert ingredient at the proposed concentration (including exposure through drinking water) would result in acceptable exposure to all subpopulations.Page 21 of 36 Table 3 .0 Summary of Dietary (Food and Drinking Water) Exposure and Risk for CAS 1591782

- 62

- 5 Results Taken from I

- DEEM Model

Population Subgroup Acute Dietary
(95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population

No acute endpoint selected 0.151893 14.6

All Infants 0.316622 30.4

Children 1

- 2 years old 0.565597 54.4

Children 3

- 5 years old 0.389016 37.4

Children 6

- 12 years old 0.200810 19.3

Youth 13

- 19 years old 0.108143 10.4

Adults 20

- 49 years old 0.116210 11.2

Adults 5 5 + years old 0.122555 11.8

Females 13

- 50 years old 0.117539 11.3
The most highly exposed subgroup is bolded.
Residential Pesticide Handler Exposure.

Residential pesticide handler exposure is estimated using Standard Operating Procedure derived by the Science Advisory Council for Exposure (ExpoSAC), Health Effects Division/OPP. The algorithm used to estimate exposure is:

Unit Exposure * Application r ate * Units Treated ÷ Body weight

Factors used in residential exposure assessment: Assumed product density 9.0 lb gal. Assumed 5.0% of formulation = inert. RD reviewed a number of residential product labels

– solvents typically comprised 1.0

- 5.0 % of the product formulation. Assumed typical rate of application 3 fl oz formulation per gallon of finish spray 5 gallons spray per day applied to typical 1⁄2 acre lot from HED SOP Body weight 80 kg from HED SOP Dermal and inhalation absorption 100 % Unit Expos ures from Standard Operating Procedures for Residential Pesticide Exposure Assessment Health Effects Division/ OPP January 2012. Toxicological Endpoint NOAEL 312.5 mg/kg/day Margin of Exposure = NOAEL mg/kg/day ÷ Average Daily Dose mg/kg/day . Since t he same toxicological endpoint is used for dermal and inhalation exposure and was identified from the same study, the dermal and inhalation exposures are summed prior to dividing into the NOAEL. HED SOP.Page 22 of 36 9 lb/gallon formulation * 0. 05 (per cent inert) = 0.45 lb inert/gallon formulation 0.45 lb inert/gal formulation ÷ 128 fl oz /gal formulation = 0.0 035 lb inert/fl oz 3 fl oz/gallon finish spray * 0.0 035 lb inert/ fl oz = 0. 0105 lb inert per gallon finish spray For five gallons finish spray per day = 0. 0525 lb inert per day

Margin of Exposure = NOAEL/Average Daily Exposure (dermal and inhalation exposures are summed prior to division into the NOAEL).

Table 4.0 Estimated Residential Pesticide Handler (Outdoor Mixer/Loader/Applicator) Exposure and Ris k

Table 5.0 Estimated Residential Handler Indoor Exposures and Risks

For the mopping scenario , it was assumed that 1 gallon of diluted solution is used. R D assumes that cleaning products are assumed to have the same density as water (8.34 lbs/gallon). While typical product concentrate directions indicate that 1 oz concentrated product per 1 gall on of water should be used, R D followed the A ntimicrobials D ivision SOP and assumed a dilution factor of 2 oz concentrated product/128 oz (1 gallon) of water for the residential handler risk assessment to represent heavy

- duty cleaning formulations. Based on information from RD, the Agency assumed that the maximum percentage by weight of the inert ingredient in indoor products would be 5.0 %.

1 gallon formulated pesticide solution * (8.34 lb/gal) * (5.0%) * (2 fl oz/128 fl oz dilution factor) =0.0065 lb ine rt in formulated solution/ day
For wiping scenario

0.13 gallon formulated solution * (8.34 lb/gal) * (5.0%) * (2 fl oz/128 fl oz dilution factor) = 0.00085 lb inert in formulated solution/ day
For trigger pump spray Mixer/loader/ applicator Unit Exposure mg/lb handled Application Rate lb/gal Units Treated gal/day Body weight kg Average Daily Dose mg/kg/day Margin of Exposure Hose end

sprayer Dermal 13.4 Inhal. 0.022 0.0 105 lb/gal 5 gal/day
to treat 1⁄2 acre typical lot 80 kg Derm 0.0 0 88 Inhal 0 .000 0144 35, 450

Pump

- up hand

held sprayer Dermal 63 Inhal 0.018 Derm 0. 0 41 Inhal 0.0000 1 1 8 7,6 19

Backpack
sprayer Dermal 130 Inhal 0.14 Derm 0. 0 85 Inhal 0.000 092 3,67 2

Mixer/loader/ applicator Unit Exposure mg/lb handled Amount (lbs) Handled/day Body weight kg Average Daily Dose mg/kg/day Margin of Exposure Mopping Dermal 71.6 Inhal. 2.38 0.0 065 80 kg Derm 0. 0 058 Inhal 0. 00 0 1 9 54,000 1.6M Wiping Dermal 2870 Inhal 67.3 0. 0 0085 Derm 0.0304 Inhal 0. 0 0072 1 0,300 43,400 Trigger pump
spray Dermal 220 Inhal 2.4 0. 05 Derm 0.14 Inhal 0.0 015 2230 208,300Page 23 of 36 0.13 gallon formulated solution * (8.34 lb/gal) * (5.0%) = 0.00085 lb inert in formulated solution/ day

RESIDENTIAL and RECREATIONAL POST

- APPLICATION EXPOSURE

Table 6.0 Summary Recreational and Residential Post

- Application Exposures and Risks
Activity Exposure (Dose)
mg inert./kg/day MOE

Toddler short

- term oral hand to mouth from contacting treated turf 0.0 1 8 1 7,361

Toddler oral object to mouth (turfgrass) 0.0 011 284,000

Adult dermal post applic turf contact 0. 246 1,270

Child dermal post applic turf contact 0.17 1 ,838
Adult golfer post app turf contact 0.0274 11,405
Child golfer post app turf contact 0.0465 6,270
Toddler combined exposure 0.189 = hand to mouth + object to mouth + turf post

- application
exposure 1,653

MOE = NOAEL ÷ Dose. NOAEL = 110.0 mg inert/kg/day.

Adult and Adolescent Golfer Post

- Application Dermal Exposure may be estimated using the convention stated in Science Advisory Council for Exposure draft SOP regarding “Golfer Exposure Assessme nt For Adults and Children” (24 August 2000). The draft policy states that adult and adolescent golfer dermal post

- application exposure may be calculated as DE (t) (mg a.i./kg bw/day) = (TTR (t) (μg/cm2)) * TC (cm2/hr) * hr/day ÷ (CF (1000 μg/mg)) * BW (body weight (kg)) Where:

DE (t) = dermal exposure at time (t) attributable to golfing on previously treated turf (mg a.i./kg bw/day). TTR (t) = turf transferable residue at time t (μg/cm2) TC = Transfer Coefficient ( 500 cm2/hr) hr = exposure period (4 hours) CF = conversion factor to change μg to mg. BW = body weight (kg) (80 kg for adult; adjusted (multiplied) by a factor of 1.7 for child golfers)

and where TTRt = AR * F * (1

- D) t * CF2 * CF3Page 24 of 36 A R = application rate (lb inert/acre); 0. 105 lb ai/acre (taken from Table 4.0 above where 0. 0525 lb is applied to 1⁄2 acre) DA = Dermal absorption 100 % F = fraction of inert available on turf/grass (unitless); 5% D = fraction of residue that dissipates daily (unitless); 10 t = postapplication day on which exposure is being assessed; CF2 = weight unit conversion factor to convert the lbs ai in the application ra te to use for the DFR or GR value (4.54E+8 μg/lb) CF3 = area unit conversion factor to convert the surface area units (acre) in the application rate to cm 2 for the TTR or GR value (2.47E

- 8 acre/cm 2 )

Therefore, 0. 105 lb ai/A * 0.05 (%) * 4.54 8 μg/lb * 2.47

- 8 A/cm 2 = 0. 68 μg/cm2

DE = 0. 68 μg/cm2 * 500 cm2/hr * 4 hr/day * 0.001μg/mg ÷ 80 kg bw = 0. 0 17 mg inert/kg /day.

MOE for adult golfer is 312.5 mg a.i./kg bw/day ÷ 0. 0 17 mg inert/kg bw/day = 18,382

.

The adult dose level is adjusted by a factor of 1.7 to estimate child golfer exposure therefore 0. 0 17 mg inert./kg/day * 1.7 = 0.0 289 mg inert/kg/day.

MOE for child golfer is 312.5 mg inert/kg/day ÷ 0. 0 289 mg inert/day = 10,813

.

A MOE of 3 00 is adequate to protect golfers from dermal post

- application exposures to treated golf course turf. Inhalation exposure is believed to be negligible. The proposed use does not exceed the Agency’s level of concern.

Adult and child dermal post

- application exposure to treated residenti al turf is assessed using SOP (2.2) which indicates that

PDR = TTR * TC * ET * conversion factor μg to mg ÷ kg bw where:

Potential Dose Rate (PDR) Turf Transferable Residue (TTR) (0. 68 μg/cm2) TC = Transfer Coefficient (TC)(14,500 cm2/hr for adult and 5,200 cm2/hr for child) ET = exposure time (hours/day) (2) CF = 0.001 mg/μg Dermal absorption = 100 % Body weight = 80 kg for adult, 15 kg for toddler.

0. 68 μg/cm2 * 14,500 cm2/hr * 2 hr/day * 0.001 mg/μg ÷ 80 kg bw = 0. 246 mg inert/kg/day for adult.

MOE = NOAEL ÷ Dose and 312.5 mg a.i./kg bw/day ÷ 0. 246 mg a.i./kg bw/day = 1,270

0. 246 μg/cm2 * 5,200 cm2/hr * 2 hr/day * 0.001 mg/μg ÷ 15 kg bw = 0. 170 mg inert/kg/day for toddler

MOE = NOAEL ÷ Dose and 312.5 mg a.i./kg bw/day ÷ 0. 170 = 1,838

.Page 25 of 36 Children’s short

- term oral hand

- to

- mouth exposure =

TTRt * SA * EX * FQ * ET * CF1 where:

PDR t = potential dose rate on day “t” (mg/kg bw/day) TTRt = turf transferable residue on day “t” (μg/cm2 turf); 0.00056 μg/cm 2 SA = surface area of the hand (cm2/event; palmer surface area of 3 fingers = 20 cm2 EX = extraction factor from the hand by saliva = 50 % FQ = frequency of hand

- to

- mouth activity (events/hr); 20 events/hr ET = exposure time (hr/day); 2 hrs/da y CF1 = weight unit conversion factor to convert μg in the TTR value to mg for the daily exposure (0.001mg/μg).

0. 68 μg/cm2 * 20 cm2/event * 0.50 % extraction factor * 20 events/hr * 2 hr/day * 0.001 mg/μg ÷ 15 kg bw = 0.0 18 mg inert/kg/day.

MOE = NOAEL ÷ Dose 312.5 mg inert/kg/day ÷ 0. 0 18 mg inert/day = 17,361

. Children’s object

- to

- mouth (turfgrass) = Grt * IgR * CF1

PDR t = potential dose rate on day “t” (mg/kg bw/day) GRt = grass (and plant matter) residue on day “t”; 0.00056 μg/cm2 IgR = mouthing rate of grass (cm2/day); 25 cm2/day CF1 = weight unit conversion factor to convert μg units of residue on the grass to mg for the daily exposure (0.001mg/μg).

0. 68 μg/cm2 * 25 cm2/day * 0.001mg/μg ÷ 15 kg bw = 0.00 11 mg inert/kg/day

M OE = NOAEL ÷ Dose and 312.5 mg inert/kg/day ÷ 0.0 0 11 mg inert/kg/day = 284 ,000

.Page 26 of 36 VIII. AGGREGATE EXPOSURE

In estimating total dietary (food and drinking water) exposures to D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives as an inert ingredient in pesticide formulations applied to growing crops the Agency uses the Dietary Exposures Evaluation Model

– Food Commodity Intake Database ( DEEM

- FCID ) model for chronic dietary exposures which presented as Attachment One . The DEEM analysis was conducted using the NOAEL noted earlier, 312.5 mg/kg/day , with the appli cation of uncertainty factors ( 3 00X)

.

1. In evaluating dietary exposure to the D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives , EPA considered exposure s under the petitioned for exemptions from the requirement of a tolerance. EPA assess ed dietary exposures a s follows:

i. Acute exposure. No adverse effects attributable to a single exposure of D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives were seen in the toxicity databases. Therefore, an acute dietary risk assessment for D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives is not
necessary.

ii. D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives was not considered to be carcinogenic therefore cancer risk assessment was not conducted.

.

i ii. Chronic exposure. In conducting the chronic dietary exposure assessment, EPA used food consumption information from the U.S. Department of Agriculture’s (USDA’s) 2003

- 2008 National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). As to residue levels in food, no residue data were submitted for acetic acid. In the absence of specific residue data, EPA has developed an approa ch which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient. Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of high use insecticides, herbicides, and fu ngicides. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled ‘‘Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drink ing Water) Dietary Exposure and Risk Assessments for the Inerts,’’ (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

– HQ

– OPP

– 2008

– 0738.

In the dietary exposure assessment, the Agency assumed that the res idue level of the inert ingredient would be no higher than the highest tolerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentra tion of inert ingredient in the scenarios leading to these highest levels of tolerances would be no higher than the concentration of the active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an extremely

cons ervative assessment of dietary risk due to a series of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate exposure. The concentrations of active ingredient in agricultural products are generally at least 50 percent of the product and often can be much higher. Further,Page 27 of 36 pesticide products rarely have a single inert ingredient; rather there is generally a combination of d ifferent inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide product in relation to that of the active ingredient. In the case of D

glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivative s , EPA made a specific adjustment to the dietary exposure assessment to account for the use limitations of the amount of D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives

, acetic acid that may be in pesticide formulations (limited to no more th an 40 % final pesticide formulation) present at the max imum limitation rather than at equal quantities with the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the active ingredient with the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would be present at the level of the active ingredient in t he highest tolerance for every commodity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of all foods are treated with the inert ingredient at the rate and manner necessary to produce the highest residue legally possible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, then used this method ology to choose the highest possible residue that could be found on food and assumed that all food contained this residue. No consideration was given to potential degradation between harvest and consumption even though monitoring data shows that tolerance level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of th ese conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

iii. Cancer. D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl de rivatives is not expected to be carcinogenic therefore , a cancer dietary exposure assessment was not performed.

2. Dietary exposure from drinking water. For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for benzyl
acetate a conservative drinking water concentration value of 1 00 parts per billion (ppb) based on screening level modeling was used to assess the contribution to drinking water for chronic dietary risk assessments for D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl derivatives . These values were directly entered into the dietary exposure model. The DEEM model indicates the RfD (chronic population adjusted dose cPAD) is 1. 04 mg/kg/day

. Aggregate Exposure for an Adult

0.1 519 mg/kg/day the estimated dietary exposure to the “Total U.S. Population” (adult) is 7.3% of the cPAD 0.0 85 mg/kg/day = highest residential handler exposurePage 28 of 36 0. 246 mg/kg/day = post

- application dermal exposure to treated lawn/turf 0. 14 mg/kg/day = exposure from antimicrobial trigger pump spray 0. 0 17 mg/kg/day = adult golfer post

- applications exposure. 0. 6 39 mg/kg/day thus 312.5 mg/kg/day ÷ 0. 6 39 mg/kg/day = a Margin of Exposure 4 90

Aggregate Exposure to Child age 1

- 2

0. 5533 mg/kg/day the estimated dietary exposure to the most highly exposed subpopulation (toddlers 1

- 2 years) = 62.9% of the cPAD. 0. 170 mg/kg/day = post

- application dermal exposure to lawn/turf 0.0 18 mg/kg/day = hand to mouth exposure 0.00 11 mg/kg/day = object (turf grass) to mouth exposure 0.74 mg/kg/day thus 312.5 mg/kg/day ÷ 0.74 mg/kg/day = a Margin of Exposure 420

EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the probability of addi tional cancer cases given the estimated aggregate exposure. Short

- , intermediate

- , and chronic

- term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable UFs is not exceeded. A n aggregate risk assessment was conducted including exposures from food, water, residential handler and residential post

- application.

Occupational Exposure

For purposes of a “screening level” occupational exposure assessment, the Agency has selected a number of activities known to result in high levels of occupationally related exposure to agricultural workers performing various tasks. Estimates of occupatio nal exposure and risk are derived in the same manner described earlier. The rates of application are taken from Davis et al. (2009 , p 41,42/84 ) and adjusted for 40 % inert ingredient. Davis et al. assessed 30 % inert ingredient formulations.

Occupationa l Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”, Health Effects Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, March 2013 and are for a single layer of work clothing (l ong

sleeved shirt, long pants, shoes plus socks) and the use of protective gloves. Pilots in enclosed cockpits are considered to be using engineering exposure control mitigation via use of enclosed cockpits.

For occupational assessment the algorithm is : AR x Units x UE x AF ÷ BW where

AR = Application rate in lb inert/A Units = Acres treated/dayPage 29 of 36 UE = Unit Exposure in mg per pound inert handled : Unit Exposures are for workers wearing long

sleeved shirt, long pants and shoes plus socks and protective gloves (except for pilots)

. AF = Absorption Factor (1 0 0 % dermal; 100% inhalation) BW = body weight (80 kg average adult).

Table 6

. 0 Estimated Exposure and Risk for Occupation al Pesticide Handlers Exposure Scenario (Formulation/ Application/ Crop) Application Rate (lb inert/ A) Area Treated Daily (acres) Dermal Unit Exposure

(mg/lb inert) Inhalation Unit Exposure ( m g/ lb inert) Baseline Dermal Dose (mg/kg /day) Baseline Inhalation

Dose (mg/kg/ day) Baseline Dermal MOE Baseline I nhalation

MOE

Liquids/ Aerial Application/ High Acreage Crops (ST)

Mixer/loader 0.8 1200

0.0376 0.0002 19 0.45 0.0 026 694 120,000

Liquids/ Groundboom/ High Acreage Crops (ST)

Mixer/loader 0.8 200 0. 075 0.00 044 4,170 710,230

Liquid/ Aerial Applicat or / High Acreage Crops (ST ) 0.8 1200 Eng control only: 0.00 2 Eng control only: 0.0 000049 0.024 0.00006 13,000 5.2M

Groundboom/ High Acreage Crops (ST) applicator 0.8 200 0.0161 0. 00034 0.032 0.00068 9,800 459,560

Liquid/ Low Pressure Handwand/ Turf (ST) applicator 2.88 5 0.39 0.0039 0.0702 0.000702 4,450 445,000

Margins of Exposure (MOE) express the Agency’s Level of Concern (LOC). For this review, MOE < 100 exceed the Agency’s level of concern. MOEs are the ratio of toxicological endpoint (NOAEL) to estimated Dose, both expressed as mg inert/kg/day. MOE = NOAEL ( mg/kg/day )/Dose ( mg/kg/day ). The NOAEL is 312.5 mg/kg/day

. Since the estimated MOEs exceed 100, the proposed use patterns do not exceed the Agency’s level of concern.

I X

. E NVIRONMENTAL FATE AND EFFECTS

The administrative volume of submission IN

- 10792 (Twaroski, Graham and Novak, 2014 ; MRID 49537200 (Volume 2) ) contains a “summary” of “available acute and chronic aquatic toxicity data for C 8

- 10 Glucamide....” Study citations and details were not provided.

Table 7.0

Test Type C 8

- 10 - Glucamide Acute fish ()OECD 203) LC 50 (96hr) > 100 mg/L LC 100 (96hr) > 100 mg/L Acute Daphnia (OECD 202) NOEC (48 hr) 100 mg/L LOEC (48 hr) > 100 mg/L Algae (OECD 201) ErC 50 (72 hr) > 100 mg/L NOEC r (72 hr) 100 mg/L Chronic fish (OECD 212) NOEC (9d) 200 mg/L LOEC (9d) > 200 mg/LPage 30 of 36 Chronic Daphnia (OECD 211) NOEC (21d) 50 mg/L LOEC (21d) 100 mg/L Aquatic microorganism (OECD 209) EC 50 (3hr) > 1000 mg/L NOEC (3h) 500 mg/L

A ready biodegradability modified Sturm test was conducted by Fiebig (2013) on C 8

- 10 acyl NMGA (CAS No. 85316

- 98

- 9 [C 8 ] and CAS No. 85261

- 20

- 7 [C 10 ] respectively). The test was conducted with a non

- adapted activated sludge over a test period of 28 days using the modified Sturm test. The test material was tested at a concentration of 19 mg/L with 2 replicates, corresponding to a carbon content (TOC) o f 10.7 mg C/L in the test vessel. The test vessels were incubated at low light condit i ons at 20

- 23 ° C. The biodegradation of the test material was followed by titrimetric analysis of the quantity of CO 2 produced by the respiration of the bacteria. The d egradation was stopped on day 28 by acidification of the test solutions. The last titration was made on day 29, after residual CO 2 had been purged from the test solutions over a period of 24 hr. The percentage of CO 2 production was calculated in relation to the theoretical CO 2 production (ThCO 2 ) of the test material. The biodegradation was calculated for each titration time. The test functional control was sodium benzoate and the percentage of functional control reached the pass level of 60 % within 8 d ays and a biodegradation of 100 % after 28 days.

In the toxicity control containing both test and reference material a biodegradation of 67 % was determined with 14 days and it came to 90 % after 28 days. The biodegradation of the test material was not inhibited by the test material in the toxicity control. Under the conditions of this study, the test material is readily biodegradable within 28 days.

Volatility

- As noted earlier, the vapor pressure of C 8

- 10 acyl NMGA is listed as being 1 .1 x 10

- 8 hPa @ 25°C = (~ 8.25 x 10

- 9 mm Hg). The physical state of most of the test substances were of “gel” nature i.e., nearly solid. These two characteristics indicate low levels of volatility thus negligible amounts are expected to enter the ambient air.

Solubility

– C 8

- 10 acyl NMGA is essentially insoluble in water as such there is minimal concern for persistence in water. The substance is a surface active substance. Results from a Critical Micelle Concentration study (ISO 4311) were 1.86 ± 0.23 g/L at pH 9.36 and 20 ° C based on the entire sample: 1.75 ± 0.22 g/L at pH 9.36 and 20 ° C based on active content (glucamides).

X. DETERMINATION OF SAFETY

For D

- g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s , aggregate risk include dietary exposure from food and water

. Exposures to toddlers (the most highly exposed population subgroup from dietary sources) include food and water exposures. Dietary exposure estimates for food and drinking water are below the Agency’s level of concer n (<100% cPAD) for the U.S. population and all population subgroups. The total dietary exposure for food and drinking water is 14.6 % of the cPAD for the U.S. population and 54.4 % of the cPAD for children 1

- 2 yrs old, the most highly exposed population su bgroup. Aggregate exposures to adults (MOE= 490 ) and children (MOE= 420 ) are below the levels of concern of MOE <300. he proposed use of D

-Page 31 of 36 g lucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s is not expected to induce unacceptable adverse effects in any population subgroup and thus is acceptable for use under 40 CFR §180.9 1 0.

X I

. ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as O PP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

XI I

. HUMAN STUDIES

This assessment does not rely on any studies in which human subjects were intentionally exposed to a pesticide.

XII I

. INTERNATIONAL LIMITS:

There are no international limits on CAS Reg. No. 1591782

- 62

- 5.

IV

. RISK CHARACTERIZATION

D

- glucitol, 1

- deoxy

- 1

- (me thylamino)

- , N

- C 8

- 10 acyl deriv ative s exhibits low levels of acute toxicity by the oral, dermal and inhalation routes of exposure. It is a severe eye irritant. There are multiple sub

- chronic oral feeding studies in the rat. There is a 13

- week oral toxicity study in the rat. There is a re productive/developmental toxicity study, a prenatal developmental study and a

one

- generation reproduction study in the rat. There are multiple genetic/mutagenicity studies in various organisms, all with negative effects. There were no specific studies on neurotoxicity, immunotoxicity or metabolism. However there were no signs of neurotoxicity in the functionalPage 32 of 36 observation battery (FOB) observations taken during the subchronic and longer term feeding studies. The DEREK (Nexus) and METEOR modeling systems indicate 80% absorption via the gastrointestinal system and less than 1.0 % via dermal absorption. The major route of excretion is via the urine. There were no data specific to carcinogenicity however the negative findings in the mutagenicity and clasto genicity studies indicate minimal levels of concern for carcinogenicity. In addition, no structural alerts were identified for the parent C 8

- 10 glucamide or potential metabolites using DEREK Nexus (v 3.0) and METEOR (V2.2.2) or the VEGA QSAR models.

The Agency performed screening level exposure/risk assessment for occupational and non

occupational subpopulations. The margins of exposure did not exceed the Agency’s level of concern. The Agency conducted an aggregate exposure assessment (residues from foo d + water + exposure from pesticide use) and Margins of Exposure do not exceed the Agency’s level of concern. There are no population subgroups including children with exposures exceeding levels of

concern.
Data regarding environmental fate and effects were considered includ ing acute and chronic toxicity to fish, daphnids, algae, aquatic micro

- organisms, modeled biodegradation, solubility in water and volatility. Based upon the proposed use pattern and the available information regarding environmental fate and effects, the Agency believes the proposed use would not pose adverse effects.

Having considered the data earlier discussed in detail, the Agency believes it is reasonable to approve the exemption from the requirement of a tolerance, under 40 C FR § 180.9 1 0 to exempt from the requirement of a tolerance for D

- glucitol, 1

- deoxy

- 1

- (methylamino)

- , N

- C 8

- 10 acyl deriv ative s (CAS Reg. No. 1591782

- 62

- 5) at a maximum concentration in formulations not to exceed 40 %

.Page 33 of 36 REFERENCES

Allingham, P. 2014. Reproduction/Developmental Toxicity Screening Test after Oral Administration in Wistar Rats with C 8

- 10 - Glucamide . Performing Lab. BSL Bioservice. Planegg, Germany. Unpublished study. MRID 49537220

Allingham, P. 2013. Acute Der mal Toxicity (Limit Test) with C8/10

- Glucamide AC93/13. Performing Lab. BSL Bioservice. Planegg, Germany. Unpublished study. MRID 49537206

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- 4194.01 . Performing Lab. Huntington Research Centre Lt., Cambridgeshire, England. Unpublished study. MRID 49537207.

Bigger, C.A. and J. J. Clarke. 1991. L5178Y TK+/

- Mouse Lymphoma Mutagenesis Assay with Confirmation Test Article SS 0001.01 . Performing L ab. Microbiological Associates, Inc. Rockville, MD. Unpublished study. MRID 49537226.

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Davis, D., B

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- 01

- 9. Unpublished MEMORANDUM June 8 to K. Leifer U.S. EPA.

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4194.01 in Rabbits. Performing Lab. RCC, Researc h & Consulting Com. AG. Itingen, Switzerland. Unpublis hed study. MRID 49537211.

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- 06

- 009. August 2006.

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- Week Oral Toxicity Study in Rats with E

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.
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Stiller, S. 28

- Day repeated dose oral toxicity study in Wistar rats with C8/10

- Glucamide AC93/13 including a 14

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.
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Wessels, A. 2013. Mammalian Micronucleus Test of Murine Peripheral Blood Cells with Glucamide 810 RM. Performing Lab. BSL Bioservice Scientific Laboratories GmbH. Planegg, Germany. Unpublished study. MRID 49537225.

York, R. 2000. Oral (Gavage) Reproduction Study of 10000506.01 in Rats. Performing Lab. Argus Research Laboratories, Inc. Horsham, PA. Unpublished study. MRID 4 9537222.Page 36 of 36 ATTACHMENT

US EPA Ver. 3.16, 03

- 08

- d
DEEM

- FCID Chronic analysis for INERTS

- D

- GLUCITOL40% 3X NHANES 2003

- 2008 2

- day Residue file name: C: \ Users \ mdow \ MARK \ InertsRA \ 2015 INERTS \ IN

- 10792 D

Glucitol \ Dglucitol40 3xINERTS_57ACTIVE_100PPBH2OREV.R08 Adjustment factor #2 used. Analysis Date 10

- 22

- 2015/12:53:36 Residue file dated: 10

- 22

- 2015/12:47:04 Reference dose (RfD, Chr onic) = 1.04 mg/kg bw/day COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

=============================================================================== Total exposure by population subgroup

--------------------------- ----------------------------------------------------

Total Exposure

----------------------------------- Population mg/kg Percent of

Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.151893 14.6% Hispanic 0.165810 15.9%
Non

- Hisp

- White 0.149071 14.3%
Non

- Hisp

- Black 0.141106 13.6%
Non

- Hisp

- Other 0.179167 17.2% Nursing Infants 0.198942 19.1%
Non

- Nursing Infants 0.369180 35.5% Female 13+ PREG 0.132585 12.7% Ch ildren 1

- 6 0.437875 42.1% Children 7

- 12 0.182277 17.5% Male 13

- 19 0.107298 10.3% Female 13

- 19/NP 0.109068 10.5% Male 20+ 0.113187 10.9% Female 20+/NP 0.122970 11.8% Seniors 55+ 0.122555 11 .8% All Infants 0.316622 30.4% Female 13

- 50 0.117539 11.3% Children 1

- 2 0.565597 54.4% Children 3

- 5 0.389016 37.4% Children 6

- 12 0.200810 19.3% Youth 13

- 19 0.108143 10.4% Adults 20

- 49 0.116210 11.2%