Page 2 of 19

also used as an ingredient in personal car e products such as shampoos, conditioners, and

moisturizers.

DBS is not expected to pose a hazard when used for its proposed use pattern. A skin sensitization study on guinea pigs determined that DBS is not a sensitizer. A primary dermal irritation study in rats de termined that DBS is not irritating. The combined LD 50 of DBS in an acute oral toxicity study in mi ce was 12,800 mg/kg/day. The dermal LD 50 in mice (males only) was 6400 mg/kg/day.

In a 90-day subchronic oral toxi city study in mice and rats, th e NOAEL was determined to be 3200 mg/kg/day for mice and 2000 mg/ kg/day for rats. No treatment-related clinical signs of toxicity were noted during the 90-day test peri od at the highest dose tested. In a 90-day subchronic oral toxicity study in dogs the NOAEL was determined to be 92.1 mg/kg/day for males and 91.5 mg/kg/day for females. No eviden ce of systemic toxicity was observed at doses as high as 2500 ppm (92.1 and 91.5 mg/kg/day in males and females, respectively). In a 13- week oral toxicity study in rats there were no si gnificant treatment-relate d effects noted and the NOAEL was determined to be 20,000 ppm (1261.3 for males and 1479.2 mg/kg/day for females).

In a mammalian cell gene mutation assay at th e TK locus, mouse lymphoma L5178Y cells

cultured in vitro were exposed to Millad 3905. The study concluded that Millad 3905 was negative in the in vitro mammalian cells in cu lture gene mutation assay in mouse lymphoma L5178Y cells, both with and without S9-m ix under the conditions of testing.

In a mouse bone marrow micronucleus assay mice were treated orally by gavage with Millad 3905. There were no signs of toxicity during th e study and the test substance is considered negative in the mouse bone marrow micronucleus test.

In a reverse gene mutation assay in bacteria of S. typhimurium were exposed to Millad 3905. It was negative for mutagenicity in both the pr esence and absence of metabolic activation.

Based on the results from these studies, EPA conc luded that DBS is not likely to be genotoxic. No carcinogenicity studies are available on DBS. Based on the lack of any systemic toxicity at high doses in rats and mice in a 90-day study and the lack of mutagenicity, EPA concluded that DBS is not likely to be carcinogenic. It is also likely that DBS will be metabolized into sorbitol and benzaldehyde in the body. Sorbitol is a na tural constituent and is considered noncarcinogenic and benzaldehyde has been shown to be non-carcinogenic in rats at doses up to 400 mg/kg/day. (Bishop, 1990)

No neurotoxicity studies are av ailable on DBS; however, ther e were no clinical signs of neurotoxicity were observed in the database.

Residues of concern are not anticipated for di etary exposure (food and drinking water) or for residential exposure from the use of DBS for the proposed use pattern as an inert ingredient in pesticide products. EPA expects aggregate exposur e to DBS to pose no appreciable dietary riskPage 3 of 19

given that the data on DBS shows a lack of any systemic toxicity at doses of up 3200 mg/kg/day. There was also a lack of any apparent developmental effects in the database.

The toxicity database is sufficient for DBS and potential exposure is adequately characterized given the low toxicity of the chemical. In terms of hazard, there are low concerns and no residual uncertainties regarding pren atal and/or postnatal toxicity. DBS has low subchronic toxicity. Although no developmental or reproductiv e studies, per se, were identified, subchronic 90-day studies in dogs, rats and mice have not dem onstrated any systemic toxicity or effects on the reproductive organs. No acute or subchronic neurotoxicity studies ar e available, but there were no signs of neurological e ffects observed in the database at high doses. Therefore, the Agency concluded that the developmental ne urotoxicity study is not required. No immunotoxicity study is available, however, no systemic toxicity was observed in mice, rats and dogs at high doses. In addition, no hazard has been identified following exposure to DBS. Based on this information, there is no concern at th is time for increased se nsitivity to infants and children to DBS when used as an inert ingredient in pesticide formulati ons and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safety of infants and children.

The values for melting point and boiling point of DBS are high. These two factors, along with the vapor pressure indicate that DBS exists primarily as a soli d. The low vapor pressure and Henry’s Law Constant estimates indicate that DBS is unlikely to volatilize from dry surfaces or

moist surfaces or moist soils or sediments. The Koc values for DBS indicate that sorption to soils and sediments may occur and is not likel y to enter groundwater. DBS also has low bioconcentration potential and is considered to be nonvolatile.

The ecotoxicity of DBS was estimated using Ecological Structure Ac tivity Relationships (ECOSAR). The results indicate that the ecotoxi city of DBS ranges from practically nontoxic to slightly toxic.

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations”, http://www.eh.doe.gove/oepa/ guidance/justice/eo12898.pdf . This assessment does not rely in part on data from studies in which adult hum an subjects were inten tionally exposed to a pesticide.

Taking into consideration all available inform ation on DBS, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to DBS. Therefore, th e establishment of an ex emption from tolerance

under 40 CFR 180.920 for residues of DBS when used as an inert ingred ient in pesticide formulations applied pre-harvest can be c onsidered safe under section 408 of the FFDCA.Page 4 of 19

I. Background

Inert ingredients are those ingr edients that are added to end use products that are not active ingredients. The terms "active ingredient" and "inert ingredie nt" are defined under the Federal Insecticide, Fungicide, and Roden ticide Act (FIFRA). An active in gredient is one that prevents, destroys, repels or mitigates a pest, or is a plant regulator, defoliant, desiccant or nitrogen

stabilizer. The statute defines th e term "inert ingredient" as an ingredient that is not active.

Dow Agrosciences submitted a petition dated Ju ne 11, 2009 proposing to establish an exemption from the requirement of a tolerance unde r 40 CFR §180.920 (pre-harvest only) limited to herbicides only with a 3% formulation cap for:

Dibenzylidene sorbitol (CAS Reg. No. 32647-67-9)

The proposed use of DBS is as an inert ingredie nt in pesticide formula tions (herbicide only) applied to growing crops under 40 CFR §180.920 with a limit of 3% in pesticide formulations. EPA published a Notice of Filing for this petition in the Federal Register of September 4, 2009 (71 FR 45848, FRL-8434-4). The Agency did not re ceive any substantive comments in response

to this notice.

This document provides an assessment of DBS for the requested tolerance exemption and is based on information and data submitted by the petitioner and information found in the public

literature.

II. Use Information

DBS is an organic molecule capable of inducing gelation in a variety of organic solvents and polymers at low concentrations. (Wilder, et. al.) Its purpose in formula tion is as a clarifying agent or nucleating agent. (Milliken) DBS ha s reported uses in antiperspirant and deodorant products. (EWG) According to th e US Department of Health and Human Services, Household Products Database, DBS is used as an ingredie nt in personal care products such as shampoos, conditioners, and moisturizers.

DBS is also approved for use as a Food Additive under 21 CFR 178.3295, for use only as a clarifying agent for olefin polymers complyi ng with 177.1520 (c) 1.1, 3.1, and 3.2 of this chapter under conditions of use C, D, E, F, and G, descri bed in table 2 of 176.170 (c ) of this chapter at a level not exceeding 0.25 percen t by weight of the polymer. (http://www.accessdata.fda.gov/scripts/cd rh/cfdocs/cfCFR/CFRSearch.cfm?fr=178.3295)Page 5 of 19

III. Structural Information

Table 1: Structural Inform ation for Dibenzylidene Sorb itol (CAS Reg. No. 32647-67-9)

Structure: Chemblink

SMILES

Code: OC(CO)C1C2C(OC(C3=CC=CC=C3)O1)COC(C4=CC=CC=C4)O2 As cited in

PP#9E7581Page 6 of 19

IV. Physical and Chemical Properties Table 2. Physical and Chemical Properties of DBS

Parameter Value References

Systemic Name: D-Glucitol, bis-O- (phenylmethylene)- Common Name: Dibenzylidene sorbitol

Molecular Formula: C20-H22-O6

CAS # 32647-67-9 Synonyms: Bis-O-(phenylmethylene)-D-glucitol; D-Sorbitol, diO-benzylidene-; Dibenzalsorbitol; Dibenzylidene-D-sorbitol ChemIDplus Lite

Appearance White to off-white powder Boiling Point 548.7 oC at 760 mmHg

Flash Point 285.6 oC LookChem

Molecular Weight 358.39 Density 1.272 Melting Point 224-228 oC ChemBlink

Log K
ow 1.98 (+/-) 0.35) MRID 47777901 Reactivity The product is stable at

ambient conditions. Hazardous polymerization

will not occur. Milliken, 2009

Water Solubility Reported as Nil (6) estimated as 6 mg/L (Table 3) As cited in PP#9E7581

Vapor Pressure 6.31E-013 ((mm Hg, 25 oC) Modified Grain Method) Henry’s Law Constant 4.959E-014 atm-m3/mole (via VP/WSol estimate)

K
oc 3.226-13.44 L/kg

OH Reaction Rate 98.7E-12 cm3/molecule-sec (half-life=1.3 hours) BCF 5.22 L/kg Level III Fugacity Model/Mass Amount (%) Air 5.28e-006

Water 32.6

Soil 67.3

Sediment 0.0831 EPISUITE estimates (*)

* Estimated from EPISUITE version 4 base d on Log Low=1.98, Melting point=220, water solubility of 6 mg/L and SMILES codePage 7 of 19

V. Hazard Assessment

Consistent with section 408(b)(2 )(D) of FFDCA, EPA has reviewed the available scientific data and other relevant information in support of this action and considered its validity, completeness and reliability and the relationship of this inform ation to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and chil dren. The nature of the toxic effects caused by DBS are discussed in this unit.

Some of the toxicological studi es available in the database were conducted with Millad 3905 and

Millad 3988. These are tradenam e for the inert ingredient DBS and contains a minimum of 96%

DBS.

Table 3: Acute Toxicity Profile for DBS

Study Type Test Organism/

Strain Results Toxicity Category MRID

Skin

Sensitization Guinea Pig (White Hartley) Not a sensitizer N/A 47777902

Primary

Dermal

Irritation Rat (Wistar) Not irritating IV 47777903

Acute Oral Toxicity Mouse (dd-system) Oral LD 50 Males= >12,800 mg/kg/day Females= >12,800 mg/kg/day Combined= >12,800 mg/kg/day IV 47777904

Acute Dermal Toxicity Mouse (dd-system) LD 50 Males= >6400 mg/kg/day

Females not tested

Combined not available N/A 47777904

A. Skin Sensitization In a dermal sensitization study (MRID 47777902) with Dibenzylidene-Sorbitol (purity not reported , Batch No. not reported), five Hartle y guinea pigs were tested with 0.1% water suspension of Dibenzylidene-Sorbitol (conta ining 1% gum Arabic) using intracutaneous injection. One control animal was treated with water solution of 1% gum arabic.

The animals (sex not reported) were induced and challenged with intracutaneous injections. The test solution was 0.1% water susp ension of dibenzylidene-sorbitol (containing 1% gum Arabic). For the induction, the back of the five test anim als was treated with 0.05 mL of the test solution for the first time, and henceforth, each 0.1 mL fo r three times a week, “and repeated 10 times.” Two weeks after the induction, th e back of the animals was chal lenged with 0.05 mL of the testPage 8 of 19

solution. After 24 hours, the treated site was checked for reactions as compared with the site just

after the treatment. One animal was induced and challenged with the control liquid (1% gum Arabic in water) using the same procedure as the test animals.

“No specific differences” were noted at the treated site after the induction and challenge. The test and control animals had an erythema with a diameter of 1±0.5 cm. There were some cases

of hair loss at the treated sites with a diameter of approximately 0.5 cm. No specific differences”

were noted at the treated site after the induction and challenge. Dibenzylidene-sorbitol was not a sensitizer. The study author stated that the test material does not dissolve or uniformly disperse in physiological salt solution, thus , the test material was injected as a gum arabic suspension.

The test solution was not isotonic and it was consid ered the appearance of erythema was due to the stimulation caused by the discrepancy of osmotic pressure. No positive control study was available to validate the current study.

B. Primary Dermal Irritation In a primary dermal irritation study (MRID 47777903), eight Wistar rats (sex not reported) were dermally exposed to 0.08 to 0.12 g of dibenzylid ene-sorbitol (purity not reported , Batch No. not reported) preparation applied to th e shaved back of the rats. Th e test material preparation was prepared as follows: Fifty mL of propyleneglycol was added to 1.5 g of dibenzylidene-sorbitol and heated to 150oC. After dissolving, the mi xture was cooled down to about 60oC and poured into a tube to solidify at room temperature before use. It was not stated whether the treated site

was covered. The sites were checked for existe nce of erythema, edema, incrustation and other symptoms 24 hour and 72 hours after treatment. Occasional observation was made immediately

after treatment until 7 hours afte r treatment. No erythema or ot her abnormalities were noted on any animal during the study. Hair growth was nor mal. In this study, di benzylidene-sorbitol was not irritating to the skin a nd is in Toxicity Category IV. This study is classified as Acceptable/non-guideline.

C. Acute Oral Toxicity In an acute oral toxicity study (MRID 47777904), groups of dd-syst em mice (10/group/sex) were given a single oral dose of water suspension (c ontaining 10% gum Arabic) of DibenzylideneSorbitol (Purity not reported, ba tch No. not reported) at 0%, 8% , 10%, or 32% (w/v) (equivalent to 0; 3200; 6400; or 12,800 mg/kg, resp ectively) and observed for 7 days.

All animals survived the study. No abnormal clini cal signs were noted from any male animal. The food intake was decreased for all females, in cluding the controls, on th e first day of dosing. The average body weight of the males dosed at 12,800 mg/kg decreased ( 1.2 g) on day one with gradual recovery, but the mice di d not regain their initial body we ight. The average body weight of the males dosed at 6400 mg/kg decreased ( 0.7 g) on day 1 with recovery by day 3 and the mice gained weight thereafter. The control ma les and the males dosed at 3200 mg/kg showed no difference in body weight gains. A slight decreas e in body weight was seen in the females dosed at 6400 and 12800 mg/kg with gradually recovery. No necropsy was reported. The Oral LD 50 for males, females and combined was greater than 12,800 mg/kg body weight. DBS is in EPA Toxicity Category IV. This acute oral toxicity study is classified as Acceptable/Non-guideline.Page 9 of 19

D. Acute Dermal Toxicity In an acute dermal toxicity study (MRID 47777904), groups of dd- system male mice (10/group) were subcutaneously injected at doses of 0, 1600, 3200, or 6400 mg/kg body weight with water suspension (containing 10% gum Arabic) of Dibe nzylidene-Sorbitol (Purity not reported, batch No. not reported) of 0%, 3.2%, 6.4%, or 12.8% (w/v) and observed for 7 days.

All animals survived the study. “The change of the lie of hair for the worse was seen in 1-4 animals of both the test groups and control gr oup, however, it was almost recovered after 7 days.” No other abnormalitie s were noted in the study. The food intake of the test group animals was decreased (30-40%) as compared to the control group, and was noted on the first day of treatment with recovery within 3-4 days in the low and medium dose group and later in the high dose group. Body weight gain was norma l for all groups. No necropsy was reported.

The Oral LD 50 for males was greater than 6400 mg/kg body weight. Females were not tested. EPA Toxicity Category cannot be assigned for Di benzylidene-Sorbitol, since the females were

not tested. This acute oral toxicity study is classified as Unacceptable/Non-guideline.

E. Subchronic Oral Toxicity in Rats and Mice In a 90-day oral toxicity st udy (MRID 47777905), dibenzylidene sorb itol (purity not reported , Batch No. not reported) was admi nistered to groups of 10 male and 10 female ICR mice and SD

rats/sex/dose in the diet at concentrations of 0.0, 0.5, 1.0, or 2.0% (equivalent to a theoretical concentration of 0, 800, 1600, and 3200 mg/kg bw/day for mice and 0, 500, 1000, and 2000 mg/kg bw/day for rats).

No treatment-related clini cal signs of toxicity or toxicologically releva nt effects on body weight, food and water intake, urinalysis, hematology or clinical chemistry were noted. The absolute and relative liver weights of tr eated male and female mice and rats were increased, but the

increases were unrelated to dose. No microsc opic treatment-related effects were noted in the

liver. The absolute but not th e relative-to-body weight of kidne y from female mice in the lowdose and high-dose groups was stat istically increased, but the increa ses were unrelated to dose. In this study, no significant treat ment-related effects were noted dur ing 90-days of treatment with the test material. Based on the results, th e NOAEL for male and female mice was 3200 mg/kg bw/day and 2000 mg/kg bw/day for male and female rats.

F. Subchronic Oral Toxicity in Dogs In a 90-day oral t oxicity study (MRID 47777910 ), Millad 3905 (assumed to be 100% a.i., Batch

# X3005) was administered to six beagle dogs/sex/g roup in the diet at dose levels of 0, 500, 1000 or 2500 ppm (equivalent to 0, 17.2, 36.2 and 92.1 mg/kg bw/day for males and 0, 17.6, 36.5 and 91.5 mg/kg bw/day for females).

No deaths or clinical signs of toxicity were observed. No treatment-related effects on body weight, body weight gain, food consumption, clinical pathology (hematology and clinical chemistry) or post-mortem examination were observed. The animals could have tolerated a higher dose.Page 10 of 19

No evidence of systemic toxicity was obs erved at doses as high as 2500 ppm (92.1 and 91.5 mg/kg/day in males and females, respectivel y) when Millad 3905 was administered in the diet of beagle dogs for 90 days. Since no tr eatment-related effects were found, the NOAEL for beagle dogs was 92.1 mg/kg bw/day for males a nd 91.5 mg/kg bw/day for females (highest dose tested). A LOAEL wa s not identified.

G. 90-Day Oral Toxicity in Rats In a 13-week oral toxicity study (MRID 47777909), Millad 3988 (97.3% a.i.; Batch No. 9236- 23) was administered to ten Sprague Dawley rats/sex/dose in the diet at dietary con centrations of 0, 2000, 6500, or 20,000 ppm (equivalent to 0, 12 3.1, 406.5, or 1261.3 mg/kg bw/day for males and 0, 146.9, 478.5, or 1479.2 mg/kg bw/day for female s) for 13 weeks. An additional group of

five animals/sex/dose was treate d at dietary concentrations of 0 or 20,000 ppm for 13 weeks, followed by a 4-week recovery period.

There were no significant treatme nt-related effects on mortality, clinical signs, body weight or body weight gain, food consumption, food effi ciency, ophthalmology, hematology, clinical chemistry, organ weight, or gr oss or microscopic pathology. The LOAEL for Millad 3988 in Sprague Dawley rats is not id entified, and the NOAEL is greater than or equal to 20,000 ppm (1261.3 for males and 1479.2 mg/kg/day for females).

H. In Vitro Mammalian Cells in Culture Gene Mutation In a mammalian cell gene mutation assay at the TK locus (MRID 47777906), mouse lymphoma

L5178Y cells cultured in vitro were exposed to Millad 3905 (unreported % a.i., lot # U2097) dissolved in dimethyl sulfoxide at co ncentrations of 0, 200, 400, 600, 800, 900, or 1000 μ g/mL in the absence and presence of mammalian metabo lic activation (S9-mix with S9 fraction from

livers of Aroclor 1254 induced male rats) for 4 hours.

Millad 3905 was tested up to concentrations limited by so lubility. Concentrations higher than 1000 μg/mL were not tested because of the insolubl e nature of the test material. The abstract

stated that the test material formed a white gelatinous precipitate in media at and above 250 μg/mL. At the highest concentration tested, there was moderately high cytotoxicity, with approximately 30% relative growth both with and without S9-mix. The positive controls did induce the appropriate response. There was no evidence of induced mutant colonies over background.

The study concluded that Millad 3905 was negative in the in vitro mammalian cells in culture gene mutation assay in mouse lymphoma L5178Y cells, both with and without S9-mix under the conditions of testing.

I. In Vivo Mammalian Cytogeneti cs – Erythrocyte Micronucleus

In a mouse bone marrow micronucleus assay (MRID 47777907), five CD-1 (ICR) mice/sex/dose were treated orally by gavage with Millad 3905 (unreported % a. i., lot # U2097) at doses of 0,1250, 2500, or 5000 mg/kg bw. Bone marrow cells were harvested at 24, 48, and 72 hours posttreatment. The vehicle was 10% gum ar abic. Animals received a single dose.Page 11 of 19

There were no signs of toxicity during the st udy. One thousand polychromatic erythrocytes (PCEs) were examined for micronuclei in all anim als at all harvest times. Millad 3905 was tested at an adequate dose based on exceeding the limit dose for the assay by 2.5 fold. The positive control induced the appropriate response. There was not a signi ficant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.

The study concluded that Millad 3905 did not in duce a significant incr ease in micronuclei in bone marrow PCEs under the conditions of the study a nd that this test articl e is thus considered negative in the mouse bone marrow micronucleus te st. Furthermore, the test substance gave no indication of general toxicity.

J. Salmonella/Escherichis/Mammalian Activation Gene Mutation Assay In a reverse gene mutation assay in bacteria (MRID 47777908), strains TA98, TA100, TA1535, TA1537, and TA1538 of S. typhimurium were exposed to Millad 3905 (unreported % a.i., lot # U2097), dissolved in DMSO at concentra tions of 100, 333, 667, 1000, 3330, or 5000 μg/plate in the presence and absence of mammalian metabo lic activation in the plate incorporation procedure using triplicate plating. The S9 frac tion was obtained from Aroclor 1254-induced male Sprague-Dawley rat liver.

Millad 3905 was tested up to the limit concentration for the assay. Neither the mutagenesis assay nor the preliminary cytotoxicity assay, whic h was conducted only on strain TA100, showed any evidence of cytotoxicity. In both in stances there was moderate precip itation of the test article at the two highest concentra tions tested and slight precipitation at the two concentrations tested below them. The positive contro ls induced the appropriate re sponses in the corresponding

strains. There was no evidence of indu ced mutant colonies over background.

K. Carcinogencity There are no carcinogenicity st udies available on DBS. Based on the lack of any systemic toxicity at high doses in mice and rats in a 90-day study and the lack of mutagenicity, EPA concluded that DBS is not likely to be carcinoge nic. It is also likely that DBS will be metabolized to sorbitol and benzaldehyde in th e body. Sorbitol is a natural constituent and is considered to be non-carcinogenic. Benzaldehy de has been shown to be non-carcinogenic in F344/N rats at doses up to 400 mg /kg/day. In an NTP bioassay, “there was some evidence of carcinogenic activity of benzaldehyd e for male and female B6C3F 1 mice, as indicated by increased incidences of squamous cell papillom as and hyperplasia of the forestomach.” (Bishop, 1990) Based on the above information, EPA concl uded DBS is not likely to be carcinogenic.

L. Neurotoxicity No neurotoxicity studies are av ailable on DBS, however, ther e were no clinical signs of neurotoxicity were observed in the database.Page 12 of 19

Table 4: Toxicology Profile for DBS Guideline No./Study Type Test Organism/

Strain Doses Results MRID

OPPTS 870.3100

Subchronic Oral Toxicity Rats – JCL-SD

Mice – JCL-ICR 0.0, 0.5, 1.0, or 2.0% (equivalent to a theoretical concentration of 0, 800, 1600, and 3200 mg/kg bw/day for mice and 0, 500, 1000, and 2000 mg/kg bw/day for rats) Rats

NOAEL=2000 mg/kg/day

Mice

NOAEL=3200 mg/kg/day 47777905

OPPTS 870.3905

Subchronic Oral Toxicity Dogs – Beagles 0, 500, 1000 or 2500 ppm (equivalent to 0, 17.2, 36.2 and 92.1 mg/kg bw/day for males and 0, 17.6, 36.5 and 91.5 mg/kg bw/day for females) NOAEL/Males= 92.1 mg/kg/day

NOAEL/Females =91.5 mg/kg/day 47777910

OPPTS 870.3100 90-Day Oral Toxicity Rats – Sprague Dawley 0, 2000, 6500, or 20,000 ppm (equivalent to 0, 123.1, 406.5, or 1261.3 mg/kg bw/day for males and 0, 146.9, 478.5, or 1479.2 mg/kg bw/day for females) Males=1261.3 mg/kg/day

Females=1479.2 mg/kg/day 47777909

OPPTS 870.5300

In Vitro Mammalian

Cells in Culture Gene Mutation Assay Mouse Lymphoma

L5178Y Cells 0, 200, 400, 600, 800, 900 or 1000 μg/ml Negative with

and without S9

Activation 47777906

OPPTS 870.5395

In Vivo Mammalian Cytogenetics – Erythrocyte Micronucleus Assay Mice – CD-1 (ICR) 0, 1250, 2500 or 5000 mg/kg/day Negative 47777907

OPPTS 870.5100

Salmonella/Escherichi

a/

Mammalian

Activation Gene Mutation Assay TA98, TA100, TA1535, TA1537,

and TA1538

strains of S. typhimurium 100, 333, 667, 1000, 3330, or 5000 μg/plate No evidence of

induced mutant

colonies over background 47777908Page 13 of 19

VI. FQPA Safety Factor Considerations Section 408 of the FFDCA provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to a ccount for prenatal and postnatal toxicity and the comp leteness of the database on to xicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as th e FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X or uses a different additional safety factor when reliable data to EPA supports the choice of a different factor.

The toxicity database is sufficient for DBS and potential exposure is adequately characterized given the low toxicity of the chemical. In terms of hazard, there are low concerns and no residual uncertainties regarding pren atal and/or postnatal toxicity. DBS has low subchronic toxicity. Although no developmental or reproductiv e studies, per se, were identified, subchronic 90-day studies in dogs, rats and mice have not dem onstrated any systemic toxicity or effects on the reproductive organs. No acute or subchronic neurotoxicity studies ar e available, but there were no signs of neurological e ffects observed in the database at high doses. Therefore, the Agency concluded that the developmental ne urotoxicity study is not required. No immunotoxicity study is available, however, no systemic toxicity was observed in mice, rats and dogs at high doses. In addition, no hazard has been identified following exposure to DBS. Based on this information, there is no concern at th is time for increased se nsitivity to infants and children to DBS when used as an inert ingredient in pesticide formulati ons and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safety of infants and children.

Endocrine Disruption EPA is required under the Federal Food, Drug a nd Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to determ ine whether certain substances (including all pesticide active and other ingredient s) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrin e effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone sy stems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommenda tion that the Program include evaluations of potential effects in wildlife. For pesticide chem icals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluati ons. As the science de velops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate scre ening and/or testing protocol s being considered under the Agency’s EDSP have been developed, DBS may be subjected to further sc reening and/or testing

to better characterize effects related to endocrine disruption.Page 14 of 19

VII. Exposure Assessment The proposed use of DBS is as an inert ingredie nt in pesticide formulations. For the general population, the primary route of exposure to DBS from its use as an inert ingredient in pesticide products would most likely be through consum ption of food to whic h pesticide products containing it have been applied and possibly thro ugh drinking water (from runoff). Dermal and inhalation exposures are also possi ble from residential use of pesticide products containing DBS. A quantitative dietary risk or re sidential risk assessment were not performed since no endpoint of

concern was identified in the database.

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

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

In addition to pesticide use, DBS has reporte d uses in personal care products, such as antiperspirants, shampoos, conditioners, and moisturizers.

For DBS, a qualitative assessment for all path ways of human exposure (food, drinking water, and residential) is appropriate gi ve the lack of human health c oncerns associated with exposure to DBS when used as an inert ingred ient in pesticide formulations.

B. Cumulative Exposure Section 408(b)(2)(D)(v) of FFFDC A requires that, when consid ering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s re sidues and “other substances that have a common mechanism of toxicity.”

Unlike other pesticide ingredients for which EP A has followed as cumulative risk approach

based on a common mechanism of to xicity, EPA has not made a co mmon mechanism of toxicity finding as to DBS and any other substances and, DBS does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

EPA has not assumed that DBS has a common mechan ism of toxicity with other substances. For information regarding EPA’s efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chem icals, see the policy statements released by EPA’s Office of Pesticide Program s concerning common mechanism determinations and procedures for cumulating effects from s ubstances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

VII. Environmental FatePage 15 of 19

The values for melting point and boiling point of DBS are high. These two factors, along with the vapor pressure indicate that DBS exists primarily as a soli d. The low vapor pressure and Henry’s Law Constant estimates indicate that DBS is unlikely to volatilize from dry surfaces or

moist surfaces or moist soils or sediments. The Koc values for DBS indicate that sorption to soils and sediments may occur and is not likel y to enter groundwater. DBS also has low bioconcentration potential and is considered to be nonvolatile.

VIII. Ecological Effects The ecotoxicity of DBS was estimated using Ecological Structure Ac tivity Relationships (ECOSAR). ECOSAR is a computerized predictive system that estimates th e aquatic toxicity of

industrial chemicals. The program estimates a chemical's acute (short-term) toxicity and chronic (long-term or delayed) toxicity to aquatic orga nisms such as fish, aquatic invertebrates, and aquatic plants by using Structur e Activity Relationships (SARs). ( http://www.epa.gov/oppt/newchems/tools/21ecosar.htm )

The estimated ecotoxicity values for DBS are lis ted in Table 5. The results indicate that the ecotoxicity of DBS ranges from prac tically nontoxic to slightly toxic

Table 5: ECOSAR Predicted Calculatio ns for DBS (CAS Reg. No. 32647-67-9) Organism Duration End Point Predicted mg/L (ppm)

Fish 96-hr LC50 959.312 * Fish 14-day LC50 960.414 * Daphnid 48-hr LC50 493.980 * Green Algae 96-hr EC50 179.562 Fish 30-day ChV 95.913 Daphnid ChV 51.955 Green Algae ChV 61.933 Fish (SW) 96-hr LC50 1397.457 * Mysid Shrimp 96-hr LC50 1482.969 * Fish (SW) ChV 98.148 Mysid Shrimp (SW) ChV 153.786

Earthworm 14-day LC50 721.581 *

* Asterisk designates: Chemical may not be soluble enough to measure this predicted effect

IX. Environmental Justice Statement

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.Page 16 of 19

X. Human Health Risk Characterization Dow Agrosciences submitted a petition (#9E7581) proposing to establish an exemption from the requirement of a tolerance under 40 CFR §180.920 (p re-harvest only) for residues of DBS when used as a pesticide inert ingredient, limited to herbicide use only with a 3% formulation cap.

Based upon review of the data supporting the petition, EPA has modified the requested exemption. No limitations are necessary because no hazard was identified.

DBS is an organic molecule capable of inducing gelation in a variety of organic solvents and polymers at low concentrations. (Wilder, et. al.) Its purpose in formula tion is as a clarifying agent or nucleating agent and has reported uses in antiperspirant and deodorant products. It is also used as an ingredient in personal car e products such as shampoos, conditioners, and

moisturizers.

DBS is not expected to pose a hazard when used for its proposed use pattern. A skin sensitization study on guinea pigs determined that DBS is not a sensitizer. A primary dermal irritation study in rats de termined that DBS is not irritating. The combined LD 50 of DBS in an acute oral toxicity study in mi ce was 12,800 mg/kg/day and the LD 50 (males only) in an acute dermal toxicity study on mi ce was 6400 mg/kg/day.

Three subchronic oral toxicity stud ies, showed no signs of systemic toxicity at high doses. In a 90-day oral toxicity study of DBS in mice and rats, the NOAEL for mice was 3200 mg/kg/day and 2000 mg/kg/day for rats. In a 13-week oral toxicity study of Millad 3988 in rats, the NOAEL was 1261.3 mg/kg/day for males and 1479.2 mg /kg/day for females. In a 90-day toxicity study of Millad 3905 in dogs, th e NOAEL was 92.1 mg/kg/day for males and 91.5 mg/kg/day for females (highest dose tested).

Based on the results of mutagenicity studies, DBS is not likely to be mutagenic. No neurotoxicity studies are available; however, no signs of neur otoxicity were observed in any of

the available studies.

The toxicity database is sufficient for DBS and potential exposure is adequately characterized given the low toxicity of the chemical. In terms of hazard, there are low concerns and no residual uncertainties regarding pren atal and/or postnatal toxicity. DBS has low subchronic toxicity. Although no developmental or reproductiv e studies, per se, were identified, subchronic 90-day studies in dogs, rats and mice have not dem onstrated any systemic toxicity or effects on the reproductive organs. No acute or subchronic neurotoxicity studies ar e available, but there were no signs of neurological e ffects observed in the database at high doses. Therefore, the Agency concluded that the developmental ne urotoxicity study is not required. No immunotoxicity study is available, however, no systemic toxicity was observed in mice, rats and dogs at high doses. In addition, no hazard has been identified following exposure to DBS. Based on this information, there is no concern at th is time for increased se nsitivity to infants and children to DBS when used as an inert ingredient in pesticide formulati ons and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safety of infants and children.Page 17 of 19

Residues of concern are not anti cipated for dietary (food and dri nking water) or for residential exposure from the use of DBS for the proposed use pattern as an inert in gredient in pesticide products. As discussed above, EPA expects aggr egate exposure to DBS to pose no appreciable dietary risk, given that the data on DBS show a lack of systemic toxi city at doses up to 3200 mg/kg/day.

Taking into consideration all available inform ation on DBS, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to DBS. Therefore, th e establishment of an ex emption from tolerance

under 40 CFR 180.920 for residues of DBS when used as an inert ingred ient in pesticide formulations applied pre-harvest can be c onsidered safe under section 408 of the FFDCA.

ReferencesPage 18 of 19

Bishop, J. (1990) NTP Technical Report on the Toxicology and Carcinogenesis Studies of Benzaldehyde (CAS No. 100-52- 7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). National Toxicology Program, PO Box 12233, Re search Triangle Park, NC 27709. NTP TR 378, NIH Publication No. 90-2833.

Cifone, M.A. (1994) Mutagenicity test on Mi llad 3905 in the L5178Y TK+/- mouse lymphoma forward mutation assay. Hazleton Washington, Inc., 9200 Leesburg Pike, Vienna, Virginia 22181. HWA Study No. 15899-0-431. September 1, 1994. MRID 47777906. Unpublished.

Chemblink: http://www.chemblink.com/products/32647-67-9.htm (Search date 9/8/09)

ChemIDplus Lite (Search date 9/8/09)

Hamauchi, C., S Fujita, H Isaka, and S Terashi. (Study date not reported) Subacute toxicity tests of dibenzylidene sorbitol in mice and rats . Faculty of Medicine, Kagoshima University, 1208-1, Usuki-cho, Kagoshima 890. Study No. 1208- 1DBS. Study date not reported, MRID 47777908. Unpublished.

Lawlor, T.E. (1994) Mutagenicity test on Mi llad 3905 in the Salmonella/mammalian-microsome reverse mutation assay (Ames test). Hazlet on Washington, Inc., 9200 L eesburg Pike, Vienna, Virginia 22181. HWA Study No. 15899-0-401. August 30, 1994. MRID 47777908. Unpublished.

LookChem: http://www.lookchem.com/cas-326/32647-67-9.html Search date 9/8/09

McIntyre, M.D. (1990) Millad 3905 – 13 week oral (dietary administration) toxicity study in the beagle dog. Hazelton France, L’Arbresle Ce dex, France. Study No. 837/001, February 28, 1990. MRID 47777910. Unpublished

Millken, Material Safety Data Sheet for Millithix* 925S, Material No. 3000004432, approval date April 21, 2009.

Millken, Material Safety Data Sheet for Mi llad 3905, Material No. 3000004354, approval date April 20, 2009.

Miyatake, T., S. Nakaya, K. Takazawa, a nd Y. Muramatsu (1971) Acute toxicity on dibenzylidene-sorbitol. Osaka Aerosol K ogyo KK., Development Division, Japan. Study ID Osaka-01-DBS, October 1971. MRID 47777904. Unpublished.

Miyatake, T., S. Nakaya, K. Takazawa, and Y. Muramatsu (1971) Local allergy test on dibenzylidene-sorbitol. Osaka Aerosol K ogyo KK., Development Division, Japan. Study ID Osaka-03-DBS, November 1971. MRID 47777902. Unpublished.Page 19 of 19

Miyatake, T., S. Nakaya, K. Takazawa, and Y. Muramatsu (1971) Skin stimulation test on dibenzylidene-sorbitol. Osaka Aerosol K ogyo KK., Development Division, Japan. Study ID Osaka-02-DBS, October 1971. MRID 47777903. Unpublished.

Murli, H. (1994) Mutagenicity test on Millad 3905 in vivo mouse micronucleus assay; Hazleton Washington, Inc., 9200 Leesburg Pike, Vie nna, Virginia 22181. HWA Study No. 15899-0-455. August 23, 1994. MRID 47777907. Unpublished.

Environmental Working Group’s Skin Deep Cosmetic Safety Database. http://www.cosmeticsdatabase.co m/ingredient.php?ingred06=701926 (Search date 9/29/09)

Wilder, E., Hall, C., & Khan, S. Abstract Sess ion S11-Poymer Gels and Solutions. Organogel Formation Due to the Self-Assembly of Dibenzylidene Sorbitol. http://flux.aps.org/meetings/Y R02/MAR02/baps/abs/S6510012.html (Search date 9/29/09)

US Department of Health and Human Services, Household Products Database. http://hpd.nlm.nih.gov/index.htm. Search date 9/29/09

US EPA. 2009. Ecological St ructure Activity Relationshi ps (ECOSAR) Class Program http://www.epa.gov/oppt/newchems/tools/21ecosar.htm

US EPA. 2009. Estimation Programs Interface Suite TM for Microsoft Windows, v 4.00. United States Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/oppt/expos ure/pubs/episuite.htm

US EPA Substance Registry Se rvices: (Search date 9/8/09) http://iaspub.epa.gov/sor_internet/reg istry/substreg/home/overview/home.do

US Food and Drug Administrati on: (Search date 9/8/09) http://www.accessdata.fda.gov/scripts/cd rh/cfdocs/cfCFR/CFRSearch.cfm?fr=178.3295

Vallet, L. (1993) Millad 3988 - 13 week oral (d ietary admixture) toxicity study in the rat followed by a 4 week treatment-free period. Ph armakon Europe, L’Arbresle Cedex, France. Laboratory project number 837/003, Decem ber 7, 1993. MRID 47777909. Unpublished.