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 produced polymers of glycerol, polymers of certain 

fatty acids and the actual separate esters between these polymers. These latter compounds 

represent the toxicologically important constituents.” (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 esters 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% polyglycerol ester (equivalent to 7500 mg/kg/day) of fatty acids for 

five weeks. No adverse effects were reported during this study. 

In a long-term study, mice were fed a diet of either 5% polyglycerol ester (equivalent to 2500 

mg/kg/day) or ground-nut oil for 80 weeks. All animals survived the study and no adverse 

effects were reported on body weight, food consumption or peripheral blood picture. 

Microscopic examination of all major organs showed nothing remarkable. Similar results were 

exhibited in a study with rats fed the same diet for two years. In a third study, mice were 

maintained on a diet of 1% polyglycerol ester (equivalent to 500 mg/kg/day) for 15.5 months. 

There were no adverse effects noted in this study. 

In a reproductive study, rats were fed a diet containing 1.5% polyglycerol ester (equivalent to 

750 mg/kg/day) for three generations. There were no significant 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 triglycerol 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 available 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 available, however, polyglycerol esters of fatty acids are normal 

constituents in the diet. Therefore, there is no concern for mutagenic effects. 

The toxicity database is sufficient 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 
Page 3 of 15 

low concerns and no residual uncertainties regarding prenatal and/or postnatal toxicity.

Polyglycerol esters of fatty acids have low subchronic and chronic toxicity. No reproductive 

effects were noted in a study for three generations. No neurotoxicity studies are available, but 

there were no signs of neurological effects observed in the database at high doses. Therefore, 

the Agency concluded that the developmental 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 additional safety factor is not 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 diisostearate 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 performed since no endpoint of concern was identified 

in the database. 

Based on the proposed use pattern as an inert ingredient in pesticide products applied to animals, 

there is little likelihood of adverse effects on the environment or exposure to non-target birds, 

aquatic organisms or insects. 

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.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. Therefore, the establishment 

of an exemption from tolerance under 40 CFR 180.930 for residues of triglycerol 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 ingredients that are added to end use products that are not active 

ingredients. The terms "active ingredient" and "inert ingredient" are defined under the Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA). An active ingredient is one that prevents, 

destroys, repels or mitigates a pest, or is a plant regulator, defoliant, desiccant or nitrogen 

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

Valent Biosciences Corporation submitted a petition dated May 9, 2008 proposing to establish an 

exemption from the requirement of a tolerance under 40 CFR 180.930 (Inert ingredients applied 
Page 4 of 15 

to animals) without limitation for triglycerol diisostearate. The proposed use of triglycerol 

diisostearate is as an inert ingredient (emulsifier) in pesticide formulations. EPA published the 

Notice of Filing for this petition in the Federal Register of May 6, 2009 (74 FR 20947, FRL8412-7). No comments were received in response to this notice. 

This document provides an assessment 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 Tolerance Reassessment Document 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 acids. 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 food in accordance with the following prescribed 

conditions: (a) They are prepared from corn oil, cottonseed 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 requirements of 172.860(b) and/or 

oleic acid derived from tall oil fatty acids meeting the requirements of 172.862.” Where specific 

information on triglycerol diisostearate is not available, 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 pesticide products. (EPA, 2009)

Polyglycerol esters of fatty acids conforming to 21 CFR 172.854 are approved for use as inert 

ingredients used pre- and post-harvest under 40 CFR 180.910 (eCFR, 2009) 

B. Other Uses 

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, in amounts not greater than 

required to produce the intended physical or technical effects. Polyglycerol 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 personal 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), 

isostearic 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 information 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 diisostearate is represented by the group of chemicals known as polyglycerol esters of 

fatty acids. Where specific information on triglycerol diisostearate is not available, information 

on polyglycerol esters of fatty acids is used to assess toxicity. The nature of the toxic effects 

caused by polyglycerol esters of fatty 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 assigned 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 documentation, it appears that this 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 default 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 produced polymers of glycerol, polymers of certain 

fatty acids and the actual separate esters between these polymers. These latter compounds 

represent the toxicologically important constituents.” (WHO, 1974) 

In vitro experiments on lipase digestion of polyglycerol esters showed that the esters were 

digested at a slower rate than that of olive oil. It also showed that the ester did not affect 

digestion of olive oil (WHO, 1974). 

In one study, 16 male and female rats were fed 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 caloric 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 study, rats were fed a restricted diet of 18 

calories/day for 17 days. There were no adverse effects noted following realimentation with 9% 

polyglycerol ester and 1% ground-nut oil. In a third study, rats were fed 9% polyglycerol ester 

for 54 days. These rats were compared with groups fed 1% or 10% ground-nut oil. There was 

no difference between the groups in terms of composition of carcass fat, liver fat, liver free fatty 

acids, liver phosphorus, and liver vitamin A levels. (WHO, 1974) 

“Hydrolysis of the tri- and polyglycerol esters in vitro with fresh pancreatic juice plus bile 

showed that 89 to 98% of oleate esters were 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 using C14 labeled (oleic acid and 

eicosanoic acid), tri- and polyglycerol esters. Approximately 40% of the C14 labeled 

polyglycerol was absorbed and more than 90% of the triglycerol was absorbed. Hydrolysis 

occurred primarily prior to absorption. “66 to 70% of the radioactivity from the oleic acid and 

55% from the eicosanoic-labeled compounds appeared as respiratory CO2 during the test period 
Page 7 of 15 

(51 hours); most of the remaining activity being 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 of various molecular weights prepared from cottonseed or peanut oil. After three 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 histopathological examination of the liver, kidneys 

and ileum showed no compound-related effects. No appreciable residues of polyglycerol esters 

were detected in the epididemal 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 dose 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 intraperitoneal (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 ester (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 the controls maintained on 10% ground nut oil. No 

compound related effects were noted after autopsy and histological examination. (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 weight ratios and hematologic parameters.” (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 containing 15% polyglycerol ester (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 female mice were fed a diet of either 5% 

polyglycerol ester (equivalent to 2500 mg/kg/day) or ground-nut oil for 80 weeks. There were 

no adverse effects reported on body weight, food consumption or peripheral blood picture. All 

animals survived the study. “The levels of free fatty acids, unsaponifiable material, fatty acid 

composition of carcass fat and organ weights were the same in test and control groups, except for 

the liver and kidney weights of female mice, which 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 were fed a diet containing 5% 

polyglycerol ester (equivalent to 2500 mg/kg/day) or ground-nut oil for two years. As in the 

aforementioned study in mice, there were no adverse effects reported on body weight, food 

consumption or peripheral blood picture and all the animals survived. “The carcass fat contained 

no polyglycerol and the levels of free fatty acid, unsaponifiable residue and fatty acid 

composition of carcass fat were no different from controls. Organ weights, tumor incidence and 

tumor distribution were similar in control and test 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 for 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% polyglycerol ester (equivalent to 

750 mg/kg/day) for three generations. There were no significant 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 triglycerol 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 available 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 available, however, polyglycerol esters of fatty acids are normal 

constituents in the diet. Therefore, there 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 account for prenatal and 

postnatal toxicity and the completeness of the database on toxicity 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 the 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 information on triglycerol 

diisostearate is not available, information on polyglycerol esters of fatty acids is used to assess 

toxicity. The toxicity database is sufficient 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 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 significant 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, the Agency concluded that the developmental 

neurotoxicity study is not required. No immunotoxicity study is available, however, no systemic 

toxicity was observed in mice and rats at high doses. In addition, no hazard has been identified 

following exposure to triglycerol diisostearate. 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 additional safety 

factor is not needed to protect the safety of infants and children. 

VI. Endocrine Disruption 

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by 

FQPA, to develop a screening program to determine whether certain substances (including all 

pesticide active and other ingredients) “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 systems, in addition to the estrogen hormone 

system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of 

potential effects in wildlife. For pesticide chemicals, 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 evaluations. As the science develops and resources 

allow, screening of additional hormone systems may be added to the Endocrine Disruptor 

Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under the 

Agency’s EDSP have been developed, triglycerol diisostearate may be subjected to further 

screening and/or testing to better characterize effects related to endocrine disruption. 

VII. Exposure Assessment 

The proposed use of triglycerol diisostearate is as an inert ingredient in pesticide formulations 

applied to animals. For the general population, the primary route of exposure to the subject 
Page 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 pesticide products containing it 

have been applied and possibly through drinking water (from runoff). A quantitative dietary risk 

or residential risk assessment was not performed since no endpoint of concern was identified in 

the database. 

A. Aggregate Exposure 

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

408 directs EPA to consider available information concerning exposures from pesticide residue 

in food and all other non-occupational exposures, including drinking water from ground water or 

surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and 

other indoor uses). 

 

In addition to pesticide use, triglycerol diisostearate has reported uses in personal care products, 

such as lipstick, lip gloss, sunscreen, 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 human health concerns associated 

with exposure to triglycerol diisostearate when used as an inert ingredient in pesticide 

formulations. 

B. Cumulative Exposure 

Section 408(b)(2)(D)(v) of FFFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide’s residues and “other substances that have a common 

mechanism of toxicity.” 

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

based on a common mechanism of toxicity, EPA has not made a common 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 assumed that triglycerol diisostearate has a common 

mechanism of toxicity with other substances. For information regarding EPA’s efforts to 

determine which chemicals have a common mechanism 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 mechanism determinations and procedures for 

cumulating effects from substances found to have 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 fate and ecological effects is not available for 

triglycerol diisostearate. According to US EPA Memorandum, Glycerol and Glycerol Esters of 

Fatty Acids: Antimicrobial Division Science Assessment Document for Tolerance 

Reassessment; Smegal, 2004: 
Page 11 of 15 

“For the glycerol fatty acid esters, microbial degradation is the major route of 

transformation in the environment. Adsorption onto soil and sediment 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 water is not likely to be a 

transport process in the environment. Although the potential to bioaccumulate is high, 

bioavailability is offset by the tendency to adsorb strongly to soil and sediment 

particulates, and to be biodegraded by microorganisms 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 surface tension of the aqueous system. The 

lowering of the surface tension and the hydrophobic 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 potential for volatilization, greater likelihood to 

partition and bind to soil and or sediment (EPA 2002, EFED memo).” 

“Glycerol Fatty Acid Esters: EPA (2003) recently reviewed the C8, C10 and C12 straight 

chain fatty acid monoesters of glycerol: glycerol monocaprylate, glycerol monocaprate 

and glycerol monolaurate, and registered these compounds as new pesticidal active 

ingredients acting against bacteria, 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 from the natural background of these same 

compounds in living systems. (EPA, 2003)” 

Based on the proposed use pattern as an inert ingredient in pesticide products applied to animals, 

there is little likelihood of adverse effects on the environment or exposure to non-target birds, 

aquatic organisms or insects. 

IX. Environmental Justice Statement 

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. No human studies were used in this 

assessment. 

X. Human Health Risk Characterization 

Valent Biosciences Corporation submitted a petition dated May 9, 2008 proposing to establish an 

exemption from the requirement of a tolerance under 40 CFR 180.930 (Inert ingredients applied 

to animals) without limitation for triglycerol diisostearate. The proposed use of triglycerol 

diisostearate is as an inert ingredient (emulsifier) 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 information on triglycerol 

diisostearate is not available, information on polyglycerol esters of fatty acids 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 ingredients 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 used in personal care products such as lipstick, 

lip-gloss, sunscreen, makeup, skin cream and cleanser. 

Acute toxicity studies conducted with polyglycerol esters 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 diets consisting of 9% (equivalent to 4500 mg/kg/day), 

10% (equivalent to 10 5000 mg/kg/day) and 15% (equivalent to 7500 mg/kg/day) polyglycerol 

ester for 17 weeks, 90 days and five weeks respectively. No adverse effects 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% polyglycerol ester (equivalent to 

750 mg/kg/day) for three generations. There were no significant 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 triglycerol 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 available 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 closely related compounds with 
Page 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 produced polymers of glycerol, polymers of certain 

fatty acids and the actual separate esters between these polymers. These latter compounds 

represent the toxicologically important constituents.” (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 available, however, polyglycerol esters of fatty acids are normal 

constituents in the diet. Therefore, there is no concern for mutagenic effects. 

The toxicity database is sufficient 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 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 significant 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, the Agency concluded that the developmental 

neurotoxicity study is not required. No immunotoxicity study is available, however, no systemic 

toxicity was observed in mice and rats at high doses. In addition, no hazard has been identified 

following exposure to triglycerol diisostearate. 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 additional safety 

factor is not 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 diisostearate 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 performed 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. Therefore, the establishment 

of an exemption from tolerance under 40 CFR 180.930 for residues of triglycerol 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 Regulations (eCFR) (2009); 40 CFR 180.910; 

http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&sid=fb0c34cc98e15e41aca6e34af2ab0fbf&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.com/ingredient.php?ingred06=701926 (Search date 10/29/09) 

FAO/WHO (Food and Agriculture Organization of the United Nations/World Health 

Organization). Joint FAO/WHO Expert Committee on Food Additives; Geneva, June 25-July 4, 

1973. 17th Report of the Joint FAO/WHO Expert Committee on Food Additives, Wld. Hlth. Org. 

techn. Rep. Ser., 1974, No. 539; FAO Nutrition Meetings Report Series, 1974, No. 53. 

http://www.inchem.org/documents/jecfa/jecmono/v05je45.htm

Smegal, D. (2004) US EPA Memorandum: Glycerol and Glycerol Esters of Fatty Acids: 

Antimicrobial Division Science Assessment Document 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 the Registration of the Technical Grade Active 

Ingredient (TGAI) Product, VMX-42 Technology Propylene Glycol Monocaprylate (EPA File 

Symbol No. 10350-AN), Containing Two New Active Ingredients, 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 Monocarprylate (Chemical No. 082704); Propylene Glycol 

Monocaprate (Chemical No. 011289); and Propylene Glycol Monolaurate (Chemical No. 

011288); and Three Closely-Related Glycerol Monoesters [Glycerol Monocaprylate (Chemical 

No. 011292); Glycerol Monocaprate (Chemical No. 011297); and Glycerol Monlaurate 

(Chemical No. 011290)]. Memo from R. Jones 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 Classified 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, Special 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