Page 2 of 15

The polyglycerol esters of fatty acids represent a large group of closely related compounds with complex compositions. “However, the individual components are found as normal constituents of the human diet, i.e. glycerol, glycerol mono-, di- and tri-fatty acid esters and individual fatty acids, with the exceptions of the artificially pr oduced polymers of glycerol, polymers of certain fatty acids and the actual separate esters be tween these polymers. These latter compounds represent the toxicologically important constitu ents.” (WHO, 1974) Hydrolysis by enzymes or gastric juices to form esters and carbon dioxide is the main pathway for metabolic degradation for polyglycerol esters of fatty acids.

Acute toxicity studies conducted with polyglycerol es ters of fatty acids in rats and rabbits shows no adverse effects at doses up to 29 g/kg body weight. Repeated dose testing in rats over 5 days did not result in any deaths at doses up to 10 g/kg body weight.

In a short-term study, rats were maintained on 9% polyglycerol ester (equivalent to 4500 mg/kg/day) and 1% ground-nut oil for 17 weeks. No systemic toxicity was observed in the study. There were also no adverse effects noted in a study where rats were maintained on a diet of 10% polyglycerol ester (equivalent to 5000 mg/kg/ day) for 90 days. In a third study, rats were fed a diet containing 15% polyglyc erol ester (equivalent to 7500 mg/kg/day) of fatty acids for

five weeks. No adverse effect s were reported during this study.

In a long-term study, mice were fed a diet of ei ther 5% polyglycerol es ter (equivalent to 2500 mg/kg/day) or ground-nut oil for 80 weeks. A ll animals survived th e study and no adverse effects were reported on body we ight, food consumption or pe ripheral blood picture. Microscopic examination of all major organs show ed nothing remarkable. Similar results were exhibited in a study with rats fed the same diet for two year s. In a third study, mice were maintained on a diet of 1% pol yglycerol ester (equivalent to 500 mg/kg/day) for 15.5 months.

There were no adverse eff ects noted in this study.

In a reproductive study, rats were fed a diet containing 1.5% polygl ycerol ester (equivalent to 750 mg/kg/day) for three genera tions. There were no significa nt effects of fertility or reproductive performance during the first year. There were also no consistent, compound-related abnormalities noted after gross and histological examination of the third generation.

No carcinogenicity studies are available on trig lycerol diisostearate, however, there was no systemic toxicity observed in mice and rats at doses up to 2500 mg/kg/ day for 80 weeks and 2 years, respectively.

No neurotoxicity studies are ava ilable in the database; however, there was no systemic toxicity in mice and rats at doses up to 2500 mg/kg/day during prolonged exposure.

No mutagenicity studies are ava ilable, however, polyglycerol este rs of fatty acids are normal constituents in the diet. Therefore, th ere is no concern for mutagenic effects.

The toxicity database is sufficien t for polyglycerol esters of fatty acids and potential exposure is adequately characterized given the low toxicity of the chemical. In terms of hazard, there arePage 3 of 15

low concerns and no residual uncertainties rega rding prenatal and/or postnatal toxicity. Polyglycerol esters of fatty acids have low s ubchronic and chronic toxi city. No reproductive effects were noted in a study for three generations. No neurotoxic ity studies are available, but there were no signs of neurological effects observe d in the database at high doses. Therefore, the Agency concluded that the developmenta l neurotoxicity study is not required. No immunotoxicity study is available, however, no systemic toxicity was observed in mice and rats at high doses. Based on this information, there is no concern at this time for increased sensitivity to infants and children to triglycerol diisostearate when used as an inert ingredient in pesticide formulations applied to animals and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additio nal safety factor is no t needed to protect the safety of infants and children.

Residues of concern are not anticipated from dietary exposure (food and drinking water) or for residential exposure from the use of triglycerol d iisostearate for the proposed use pattern as an inert ingredient (emulsifier) in pesticide formulations applied to animals. A quantitative dietary risk or residential risk assessment was not perf ormed since no endpoint of concern was identified

in the database.

Based on the proposed use pattern as an inert ingred ient in pesticide produc ts applied to animals,

there is little likelihood of adve rse effects on the environment or exposure to non-target birds, aquatic organisms or insects.

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 . No human studies were used in this

assessment.

Taking into consideration all available information on triglycerol diisostearate, 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 triglycerol diisostearate. Theref ore, the establishment of an exemption from tolerance under 40 CFR 180.930 for residues of trig lycerol diisostearate when used as an inert ingredient (emulsifier) in pesticide formulations applied animals can be

considered safe under section 408 of the FFDCA.

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.

Valent Biosciences Corporation submitted a peti tion dated May 9, 2008 proposing to establish an exemption from the requirement of a toleran ce under 40 CFR 180.930 (Inert ingredients appliedPage 4 of 15

to animals) without limitation for triglycerol di isostearate. The propos ed use of triglycerol diisostearate is as an inert ingredient (emulsif ier) in pesticide formula tions. EPA published the Notice of Filing for this petition in the Fe deral Register of May 6, 2009 (74 FR 20947, FRL8412-7). No comments were received in response to this notice.

This document provides an asse ssment of triglycerol diisostearate for the requested tolerance exemption, and is based on information and data submitted by the petitioner, information found in the public literature and a 2004 US EPA Tolera nce Reassessment Docume nt for Glycerol and Glycerol Esters of Fatty Acids. (Smegal, 2004)

The Agency has determined that triglycerol diisostearate is represented by the group of chemicals known as polyglycerol esters of fatty aci ds. The manufacturing process for triglycerol

diisostearate involves oleic acid that is formed from a vegetable source, namely tall oil fatty acids. Under 21 CFR 172.854, “polyglycerol esters of fatty acids, up to and including the decaglycerol esters, may be safely used in f ood in accordance with the following prescribed conditions: (a) They are prepared from corn oil, co ttonseed oil, lard , palm oil from fruit, peanut oil, safflower oil, sesame oil, soybean oil, and tallow and the fatty acids derived from these substances (hydrogenated and nonhydrogenated) meeting the requi rements of 172.860(b) and/or oleic acid derived from tall oil fatty acids meetin g the requirements of 172.862.” Where specific information on triglycerol diisostearate is not av ailable, information on polyglycerol esters of fatty acids is used to assess toxicity.

II. Use Information

A. Pesticide Uses 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is approved for use as an inert ingredient in nonfood use pesticid e products. (EPA, 2009)

Polyglycerol esters of fatty acids conformi ng to 21 CFR 172.854 are approved for use as inert ingredients used pre- and post-ha rvest under 40 CFR 180.910 (eCFR, 2009)

B. Other Uses Polyglycerol esters of fatty acids are a pproved under 21 CFR 172.854 as multi-purpose direct food additives. (US FDA) They are used as em ulsifiers in food, in amounts not greater than required to produce the intended physi cal or technical effects. Pol yglycerol esters of a mixture of stearic, oleic, and coconut fatty acids are used as a cloud inhibitor in vegetable and salad oils (EPA, 2004). They are also widely used in person al care products such as lipstick, lip gloss, sunscreen, makeup, skin cream and cleanser. (EWG, 2009)Page 5 of 15

III. Physical and Chemical Properties

Table 1. Physical and Chemical Properties

Parameter Value References Systemic Name 1,2,3-Propanetriol homopolymer,

diisooctadecanoate

Molecular Formula C18-H36-O2

CAS # 63705-03-3 Synonyms 1,2,3-Propanetriol homopolymer, isostearic acid ester (1:2),

i sostearic acid, 1,2,3- propanetriol ester (2:1), homopolymer; Isostearic acid, 1,2,3- propanetriol ester (2:1), homopolymer ChemIDplus Lite

Common Names Triglycerol Diisostearate; Triglycerine Diisostearate; Glycerin fatty acid esters Chemical Group Polyglycerol esters of fatty

acids Physical State Liquid Appearance Amber viscous liquid with fatty odor

Flash Point 455 oF Specific Gravity 0.90 Solubility Insoluble in water; soluble in organic solvents and oils As cited in PP#8E7354, Valent Biosciences, 2008

IV. 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 children. The Agency has determined that triglycerol diisos tearate is represented by the group of ch emicals known as polyglycerol esters of fatty acids. Where specific information on triglyce rol diisostearate is not available, information on polyglycerol esters of fatty acids is used to assess toxicity. The natu re of the toxic effects caused by polyglycerol esters of fatt y acids are discussed in this unit.Page 6 of 15

“The Joint FAO/WHO Expert Committee on food additives (1974) has evaluated the polyglycerol esters of fatty acids and assi gned an acceptable daily intake (ADI) of 0.25 mg/kg/day (calculated as total polyglycerol ester of palmitic acid). This value is based on a noadverse effect level (NOAEL) for rats of 2500 mg/kg/day (50,000 ppm or 5%) in the diet.” (EPA. 2004) However, it is unclear from the FAO/WHO document what uncertainty factors were applied to the NOAEL. Based on the documen tation, it appears that th is database does not require an additional uncertainty factor and therefore the ADI value may have been due to typographical error (25 mg/ kg, rather than .25 mg/kg).

In repeated dose toxicity studies, doses were given as percent in diet. The percent values were converted to mg/kg/day using standard defa ult values for older rats, assuming 0.40 g body weight and 20 g of food consumed per day.

A. Metabolism The polyglycerol esters of fatty acids represent a large group of closely related compounds with complex compositions. “However, the individual components are found as normal constituents of the human diet, i.e. glycerol, glycerol mono-, di- and tri-fatty acid esters and individual fatty acids, with the exceptions of the artificially pr oduced polymers of glycerol, polymers of certain fatty acids and the actual separate esters be tween these polymers. These latter compounds represent the toxicologically important constituents.” (WHO, 1974)

In vitro experiments on lipase digestion of polygl ycerol esters showed that the esters were digested at a slower rate than th at of olive oil. It also show ed that the ester did not affect digestion of olive oil (WHO, 1974).

In one study, 16 male and female rats were fe d a diet containing 1% ground-nut oil and 9% polyglycerol ester (equivalent to 4500 mg/kg/day) or a control dose of 10% ground-nut oil for 6 and 12 weeks. In this study digestibility or calor ic utilization were used to determine metabolic conversion. Based on growth rate , polyglycerol ester and ground-nut oil were almost equivalent when used as an energy source. In a second st udy, rats were fed a re stricted diet of 18 calories/day for 17 days. There were no adverse effects noted following realimentation with 9% polyglycerol ester and 1% ground-nu t oil. In a third study, rats were fed 9% polyglycerol ester for 54 days. These rats were compared with gr oups fed 1% or 10% grou nd-nut oil. There was no difference between the groups in terms of compos ition of carcass fat, liver fat, liver free fatty acids, liver phosphorus, and liver vitamin A levels. (WHO, 1974)

“Hydrolysis of the tri- and polygl ycerol esters in vitro with fr esh pancreatic juice plus bile

showed that 89 to 98% of oleate esters we re hydrolyzed. Eicosanoate compounds were hydrolyzed at a much slower rate than the oleate esters.” (WHO, 1974)

A study in rats tested the metabolic fate of polyglycerol esters us ing C14 labeled (oleic acid and eicosanoic acid), tri- and polyglycerol esters. Approxima tely 40% of the C14 labeled polyglycerol was absorbed and more than 90% of the triglycerol was absorbed. Hydrolysis occurred primarily prior to abso rption. “66 to 70% of the radio activity from the oleic acid and 55% from the eicosanoic-labeled compounds appeared as respiratory CO2 during the test periodPage 7 of 15

(51 hours); most of the remaining activity bei ng incorporated into the carcass. Rats fed polyglycerol esters labeled with C14 in the tri- or polyglycerol moiety excreted the unchanged polymerized glycerol, primarily in the urine with less than 7% of the C14 label appearing in respiratory CO2 and the carcass.” (WHO, 1974)

“Weanling rats were fed each day a restricted 5 gram basic diet supplemented with either 0, 0.5 or 1 gram lard or 1 gram polyglycerol ester ofvarious molecular weights prepared from cottonseed or peanut oil. After th ree weeks, the rats were placed on unrestricted diets containing polyglycerol or lard of 8% for a period of 8 weeks. Weight gain of rats fed the polyglycerol ester was the same as those fed lard. Autopsy and hi stopathological examinati on of the liver, kidneys and ileum showed no compound-related effects. No appreciable residues of polyglycerol esters were detected in the epid idemal fat.” (WHO, 1974)

B. Acute Toxicity Acute toxicity data in rats and rabbits shows no adverse effects at doses up to 29 g/kg body weight (bw) of polyglycerol esters of fatty acids. Repeated do se testing in rats over 5 days did not result in any deaths at doses up to 10g/kg bw. There were also no adverse effects noted when rats were treated with a single in traperitoneal (i.p.) dose of up to 7g/kg. In the same test, a single i.p. dose of 10g/kg caused some peritoneal reaction, but no deaths. (WHO, 1974)

C. Subchronic Toxicity In a short-term study, 13 rats were maintained on 9% polyglycerol es ter (equivalent to 4500 mg/kg/day) and 1% ground nut oil for 17 weeks and showed no effects on kidney function. Rats maintained on the same diet for 22 weeks showed no difference in weights of liver, kidney, adrenal, spleen and testes, as compared to th e controls maintained on 10% ground nut oil. No compound related effects were noted after auto psy and histological ex amination. (WHO, 1974)

In another study, rats were fed up to 10% polyglycerol ester (deca-glycerol decaoleate)(equivalent to 5000 mg/kg/ day) for 90 days. “There were no adverse effects on survival, growth, organ weights, body wei ght ratios and hematologic para meters.” (WHO, 1974) Urinary nitrogen values for female rats were elevated at weeks three and nine. There were no compound related effects noted upon autopsy and microscopic evaluation. (WHO, 1974)

In a third study, rats were fed a diet contai ning 15% polyglycerol este r (equivalent to 7500 mg/kg/day) of fatty acids for five weeks. No adverse effects were reported during this study. (WHO, 1974)

D. Chronic Toxicity In a long-term study, groups of 25 male and fe male mice were fed a diet of either 5% polyglycerol ester (equivalent to 2500 mg/kg/day) or ground-nut o il for 80 weeks. There were no adverse effects reported on body weight, food cons umption or peripheral blood picture. All animals survived the study. “The levels of fr ee fatty acids, unsaponifiable material, fatty acid composition of carcass fat and organ weights were th e same in test and control groups, except for the liver and kidney weights of female mice, wh ich were significantly higher. Microscopic examination of all major organs showed nothing remarkable. (WHO, 1974)Page 8 of 15

In another long-term study, groups of 28 male and female rats we re fed a diet containing 5% polyglycerol ester (equivalent to 2500 mg/kg/day) or ground-nut o il for two years. As in the aforementioned study in mice, there were no adverse effects reporte d on body weight, food consumption or peripheral blood pi cture and all the animals survive d. “The carcass fat contained no polyglycerol and the levels of free fatty acid, unsaponifiable re sidue and fatty acid composition of carcass fat were no different from controls. Organ weights, tumor incidence and

tumor distribution were similar in control and te st groups. Complete histological examination of major organs showed nothing remarkable.” (WHO, 1974)

In a third study, mice were maintained on a diet containing 1% polyglycerol (equivalent to 500 mg/kg/day) ester emulsifier fo r a period of 15.5 months. There were no adverse effects noted on growth rate or longevity of test and control animals. There was also no evidence of carcinogenic activity. (WHO, 1974)

E. Developmental Toxicity In a reproductive study, 22 rats were fed a diet containing 1.5% pol yglycerol ester (equivalent to 750 mg/kg/day) for three genera tions. There were no significa nt effects of fertility or reproductive performance during the first year. There were also no consistent, compound-related abnormalities noted after gross and histological examination of the third generation. (WHO, 1974)

F. Carcinogenicity No carcinogenicity studies are available on trig lycerol diisostearate, however, there was no systemic toxicity observed in mice and rats at doses up to 2500 mg/kg/ day for 80 weeks and 2 years, respectively.

G. Neurotoxicity No neurotoxicity studies are ava ilable in the database; however, there was no systemic toxicity in mice and rats at doses up to 2500 mg/kg/day during prolonged exposure.

H. Mutagenicity No mutagenicity studies are ava ilable, however, polyglycerol este rs of fatty acids are normal constituents in the diet. Therefore, th ere is no concern for mutagenic effects.

V. 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.Page 9 of 15

The Agency has determined that triglycerol diisostearate is represented by the group of chemicals known as polyglycerol esters of fatty acids. Where specific in formation on triglycerol diisostearate is not available, information on polyg lycerol esters of fatty acids is used to assess toxicity. The toxicity database is sufficient for polyglycerol este rs of fatty acids and potential exposure is adequately characterized given the low toxicity of the chemical. In terms of hazard,

there are low concerns and no residual uncertaintie s regarding prenatal and/ or postnatal toxicity. Polyglycerol esters of fatty acids have low subchronic and chronic toxicity. There was no systemic toxicity in mice and rats at very high doses for 80 weeks and two years respectively. In a reproductive study with rats, there were no si gnificant effects on fertility or reproductive performance for three generations. There were also no consistent, compound-related abnormalities noted after gross and histological examination of the third generation. No neurotoxicity studies are available, but there were no signs of neurological effects observed in the database at high doses. Therefore, th e Agency concluded that the developmental neurotoxicity study is not required. No immunotoxi city study is availabl e, however, no systemic toxicity was observed in mice and rats at high doses. In addition, no hazard has been identified following exposure to triglycerol di isostearate. Based on this info rmation, there is no concern at this time for increased sensitivity to infants and children to triglycerol diisostearate when used as an inert ingredient in pesticide formulations app lied to animals 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 th e safety of infants and children.

VI. 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 endocrine 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, triglycero l diisostearate may be subjected to further screening and/or testing to better character ize effects related to endocrine disruption.

VII. Exposure Assessment The proposed use of triglycerol diis ostearate is as an inert ingred ient in pesticide formulations applied to animals. For the general population, the primary route of exposure to the subjectPage 10 of 15

chemical from this use as an inert ingredient in pesticide products applied to animals used for food would most likely be through consumption of food to which pesticid e products containing it have been applied and possibly through drinking wa ter (from runoff). A qua ntitative dietary risk

or residential risk assessment wa s 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, triglycerol diisos tearate has reported uses in personal care products, such as lipstick, lip gloss, sunscr een, makeup, skin cream and cleanser.

For triglycerol diisostearate, a qualitative assessment for all pathways of human exposure (food, drinking water, and residential) is appropriate give the lack of hu man health concerns associated with exposure to triglycerol di isostearate when used as an inert ingredient 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 triglycerol diisostearate and any other substances and, triglycerol diisostearate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assume d that triglycerol diis ostearate has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to

determine which chemicals have a common mech anism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechan ism determinations and procedures for cumulating effects from substances found to ha ve a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

VIII. Environmental Fate and Ecological Effects Specific information regarding the environmental fa te and ecological effects is not available for triglycerol diisostearate. According to US EP A Memorandum, Glycerol a nd Glycerol Esters of Fatty Acids: Antimicrobial Division Scie nce Assessment Document for Tolerance Reassessment; Smegal, 2004:Page 11 of 15

“For the glycerol fatty acid esters, micr obial degradation is the major route of transformation in the environment. Adsorp tion onto soil and sedime nt particulates is strong and, therefore, there is limited potential to reach surface water by dissolved runoff and/or leach to ground water. Volatilization from soils and wa ter is not likely to be a transport process in the environment. Alt hough the potential to bi oaccumulate is high, bioavailability is offset by the tendency to adsorb strongly to soil and sediment particulates, and to be biodegraded by micr oorganisms and be metabolized in animals. However, concentration at the water-air interface is likely to be higher than in the water column, which results in lowering the surf ace tension of the aqueous system. The lowering of the surface tension and the hydropho bic layer at the water-air interface has the potential to alter the physical and chemical characteristics of the aquatic environment. As a group, these compounds show the following trends with increasing chain length: decreasing water solubility, decreasing potenti al for volatilization, greater likelihood to partition and bind to soil and or sediment (EPA 2002, EFED memo).”

“Glycerol Fatty Acid Esters: EPA (2003) recent ly reviewed the C8, C10 and C12 straight chain fatty acid monoesters of glycerol: gl ycerol monocaprylate, glycerol monocaprate and glycerol monolaurate, and registered these compounds as new pesticidal active ingredients acting against bact eria, viruses, fungi and lipid-coated yeasts. The Agency concluded that these compounds are non-toxic on an acute basis (except for eye irritation) and are rapidly metabolized in vertebrate systems to polyols and free fatty acids. Breakdown products are indistinguishable fr om the natural background of these same compounds in living systems. (EPA, 2003)”

Based on the proposed use pattern as an inert ingred ient in pesticide produc ts applied to animals,

there is little likelihood of adve rse effects on the environment or exposure to non-target birds, aquatic organisms or insects.

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 . No human studies were used in this

assessment.

X. Human Health Risk Characterization Valent Biosciences Corporation submitted a peti tion dated May 9, 2008 proposing to establish an exemption from the requirement of a toleran ce under 40 CFR 180.930 (Inert ingredients applied to animals) without limitation for triglycerol di isostearate. The propos ed use of triglycerol diisostearate is as an inert ingredient (emulsif ier) in pesticide formulations applied to animals

under 40 CFR 180.930.Page 12 of 15

The Agency has determined that triglycerol diisostearate is represented by the group of chemicals known as polyglycerol esters of fatty acids. Where specific in formation on triglycerol diisostearate is not available, information on polygly cerol esters of fatty ac ids is used to make a determination of toxicity.

1,2,3-Propanetriol, homopolymer, diisooctadecanoate is approved for use as an inert ingredient in nonfood use pesticide products and polyglycerol esters of fatty acids conforming to 21 CFR 172.854 are approved for use as inert ingredient s used pre- and post-harvest under 40 CFR 180.910. Polyglycerol esters of fatty acids are approved under 21 CFR 172.854 as multi-purpose direct food additives. (US FDA) They are used as emulsifiers in food and as cloud inhibitors in vegetable and salad oils. They are also widely us ed in personal care pr oducts such as lipstick, lip-gloss, sunscreen, makeup, skin cream and cleanser.

Acute toxicity studies conducted with polyglycerol es ters of fatty acids in rats and rabbits show no adverse effects at doses up to 29 g/kg body weight. Repeated dose testing in rats over 5 days did not result in any deaths at doses up to 10g/kg bw.

In repeated dose toxicity studies, doses were given as percent in diet. The percent values were converted to g/kg/day using standard default values for older rats, assuming 0.40 g body weight and 20 g of food consumed per day.

In three short-term studies, rats were fed diet s consisting of 9% (equivalent to 4500 mg/kg/day), 10% (equivalent to 10 5000 mg/ kg/day) and 15% (equi valent to 7500 mg/kg/ day) polyglycerol ester for 17 weeks, 90 days and five weeks resp ectively. No adverse e ffects were noted during any of these studies.

In two long-term studies, mice were maintained on diets consisting of 5% polyglycerol ester (equivalent to 2500 mg/kg/day) for 80 weeks and two years respectively. In a third study, mice were fed 1% polyglycerol ester (equivalent to 500 mg/kg/day) for 15.5 months. No adverse effects were noted during any of these studies.

In a reproductive study, rats were fed a diet containing 1.5% polygl ycerol ester (equivalent to 750 mg/kg/day) for three genera tions. There were no significa nt effects on fertility or reproductive performance during the first year. There were also no consistent, compound-related abnormalities noted after gross and histological examination of the third generation.

No carcinogenicity studies are available on trig lycerol diisostearate, however, there was no systemic toxicity observed in mice and rats at doses up to 2500 mg/kg/ day for 80 weeks and 2 years, respectively.

No neurotoxicity studies are ava ilable in the database; however, there was no systemic toxicity in mice and rats at doses up to 2500 mg/kg/day during prolonged exposure.

The polyglycerol esters of fatty acids represent a large group of cl osely related compounds withPage 13 of 15

complex compositions. “However, the individual components are found as normal constituents of the human diet, i.e. glycerol, glycerol mono-, di- and tri-fatty acid esters and individual fatty acids, with the exceptions of the artificially pr oduced polymers of glycerol, polymers of certain fatty acids and the actual separate esters be tween these polymers. These latter compounds represent the toxicologically important constitu ents.” (WHO, 1974) Hydrolysis by enzymes or gastric juices to form esters and carbon dioxide is the main pathway for metabolic degradation for polyglycerol esters of fatty acids.

No mutagenicity studies are ava ilable, however, polyglycerol este rs of fatty acids are normal constituents in the diet. Therefore, th ere is no concern for mutagenic effects.

The toxicity database is sufficien t for polyglycerol esters of fatty acids 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 rega rding prenatal and/or postnatal toxicity. Polyglycerol esters of fatty acids have low subchronic and chronic toxicity. There was no systemic toxicity in mice and rats at very high doses for 80 weeks and two years respectively. In a reproductive study with rats, there were no si gnificant effects on fertility or reproductive performance in three generations. There were also no consistent, compound-related abnormalities noted after gross and histological examination of the third generation. No neurotoxicity studies are available, but there were no signs of neurological effects observed in the database at high doses. Therefore, th e Agency concluded that the developmental neurotoxicity study is not required. No immunotoxi city study is availabl e, however, no systemic toxicity was observed in mice and rats at high doses. In addition, no hazard has been identified following exposure to triglycerol di isostearate. Based on this info rmation, there is no concern at this time for increased sensitivity to infants and children to triglycerol diisostearate when used as an inert ingredient in pesticide formulations app lied to animals 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 th e safety of infants and children.

Residues of concern are not anticipated from dietary exposure (food and drinking water) or for residential exposure from the use of triglycerol d iisostearate for the proposed use pattern as an inert ingredient (emulsifier) in pesticide formulations applied to animals. A quantitative dietary risk or residential risk assessment was not perf ormed since no endpoint of concern was identified

in the database.

Taking into consideration all available information on triglycerol diisostearate, 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 triglycerol diisostearate. Theref ore, the establishment of an exemption from tolerance under 40 CFR 180.930 for residues of trig lycerol diisostearate when used as an inert ingredient (emulsifier) in pesticide formulations applied animals can be

considered safe under section 408 of the FFDCA.Page 14 of 15

References

ChemIDplus Lite: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp

Electronic Code of Federal Regul ations (eCFR) (2009); 40 CFR 180.910; http://ecfr.gpoaccess.go v/cgi/t/text/textidx?c=ecfr&sid=fb0c34cc98e15e41aca6e34af2 ab0fbf&rg=n=div8&view=text&node=40:23.0.1.

1.28.4.19.3&idno=40

Environmental Working Group’s (EWG) Skin Deep Cosmetic Safety Database. http://www.cosmeticsdatabase.co m/ingredient.php?ingred06=701926 (Search date 10/29/09)

FAO/WHO (Food and Agriculture Organizati on of the United Nations/World Health Organization). Joint FAO/WHO Expert Commit tee on Food Additives; Geneva, June 25-July 4,

1973. 17 th Report of the Joint FAO/WHO Expert Co mmittee on Food Additives, Wld. Hlth. Org. techn. Rep. Ser., 1974, No. 539; FAO Nutriti on Meetings Report Series, 1974, No. 53. http://www.inchem.org/documents/jecfa/jecmono/v05je45.htm

Smegal, D. (2004) US EPA Memorandum: Glycer ol and Glycerol Este rs of Fatty Acids:

Antimicrobial Division Science Assessment Docu ment for Tolerance Reassessment. May 12, 2004. Unpublished.

US EPA (2009) Inert Ingredients Permitted for Use in Nonfood Use Pesticide Products Last Updated January 27, 2009; http://www.epa.gov/opprd001/inerts/inert_nonfooduse.pdf

US EPA (2003) Science Review in Support of th e Registration of the Technical Grade Active Ingredient (TGAI) Product, VM X-42 Technology Propylene Glycol Monocaprylate (EPA File Symbol No. 10350-AN), Containi ng Two New Active Ingredient s, 68.12% Propylene Glycol Monocaprylate (Chemical No. 011289); and Science Review of Studies/Data/information to be used in Support of VMX Technology Chemicals, Consisting of Three Closely-Related Propylene Glycol Monoester [Propylene Glycol Monocar prylate (Chemical No. 082704); Propylene Glycol Monocaprate (Chemical No. 011289); and Propyl ene Glycol Monolaurate (Chemical No. 011288); and Three Closely-Related Glycerol M onoesters [Glycerol Monocaprylate (Chemical No. 011292); Glycerol Monocaprate (Chemical No. 011297); and Glycerol Monlaurate (Chemical No. 011290)]. Memo from R. Jone s to C. Frazer, Biopesticides and Pollution Prevention Division. April.

US EPA (2002) “Tolerance Review of Compounds Known as Fatty Acids, Fatty Acid Salts, and Fatty Acid Esters, and Fatty Acid Derivatives Classi fied as Inert Ingredients in Terrestrial and/or Aquatic Agricultural and Non-Agricultural Uses .” Memorandum from S.C. Termes/H. Craven,

Environmental Fate and Effects Division (EFED) to M. Perry, Sp ecial Review and Reregistration Division (SRRD). May 15, 2002.Page 15 of 15

US FDA 21CFR 172.854 http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm