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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [P.V. Shah, 703-308-1846]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases 

where the outline element does not apply, please insert “NA-Remove” and maintain the 

outline. Please do not change the margins, font, or format in your pesticide petition. Simply 

replace the instructions that appear in green, i.e., “[insert company name],” with the 

information specific to your action

EPA has received a pesticide petition ([Insert Petition Number]) from [Drexel Chemical 

Company, (EPA Company Number 19713),] P.O. Box 13327 Memphis, TN 38113-0327 USA

proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 

U.S.C. 346a(d), to establish an exemption from the requirement of a tolerance for [tetraethylene 

glycol CAS RN 112-60-7 as an inert ingredient in non-food and food use pesticide formulations 

under to the following uses pursuant to Section 408(d)(1) of the Federal Food, Drug, and 

Cosmetic Act (FFDCA)] under 40 CFR §180.920 pre-harvest applications. EPA has determined 

that the petition contains data or information regarding the elements set forth in section 408 

(d)(2) of FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at 

this time or whether the data supports granting of the petition. Additional data may be needed 

before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [Not applicable/Not required for the establishment of a tolerance 

exemption for inert ingredients.]

2. Analytical method. [Not applicable/Not required for the establishment of a tolerance 

exemption for inert ingredients.]

3. Magnitude of residues. [There is no specific crop residue information available for 

tetraethylene glycol. This information is typically not available or required for the establishment 

of a tolerance exemption for pesticide inert ingredients.] 

B. Toxicological Profile

1. Acute toxicity. [Tetraethylene glycol was tested in five (5) acute toxicity studies. The 

testing results indicate that the product exhibits low acute toxicity by oral, dermal and inhalation 

exposure routes. The product is minimally irritating to the eyes and is mildly irritation to the 

skin. There were no sensitization data for tetraethylene glycol, however, by bridging to a 

structurally similar linear alkyl glycol, triethylene glycol, which is not a sensitizer, tetraethylene 

glycol should not be considered a sensitizer. Based on these acute toxicity data, tetraethylene 

glycol is considered EPA Toxicity Category III/IV.
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2. Genotoxicity. [Tetraethylene glycol has a complete and extensive battery of in vitro and in 

vivo genotoxicity data. The weight-of-the-evidence indicates that tetraethylene glycol is not a 

genotoxin. Tetraethylene glycol was negative in an in vitro Ames Bacterial Reverse Mutation 

Assay with and without S9 activation and in a CHO/HGPRT Chinese hamster ovary cell assay 

with and without S9 activation. Tetraethylene glycol did not induce chromosome aberration in 

an in vivo rat bone marrow assay, and was also negative for genotoxicity in an in vivo rat 

dominant lethal assay. Equivocal results were observed in the Sister Chromatid Exchange Assay 

in Chinese Hamster Ovary Cells with and without S9 activation and in the Mouse Micronucleus 

Assay Although an in vitro Chromosomal Aberrations Chinese Hamster Ovary Assay 

demonstrated no statistically significant increase in incidence of chromosome aberrations with 

and without S9 activation, it was concluded that a higher response observed in the 10-hour 

sampling may be indicative of a DNA-dependent clastogen. However, the more definitive 

results of an in vivo Rat Bone Marrow Chromosome Aberration Test indicated no clastogenic 

results because there were no dose-related increases in relative numbers of chromosome 

aberrations compared to the controls values.The frequency of any observed simple chromatid

breaks and fragments within the range of spontaneous incidence.]

3. Reproductive and developmental toxicity. [There are no available studies to derive a NOAEL 

for reproductive and or developmental toxicity. Thus, bridging to triethylene glycol reproductive 

and developmental studies, to address these data has been proposed on the basis of the structural 

similarities of triethylene glycol and tetraethylene glycol. Additionally, these compounds have 

similar trends in their physicochemical properties, have consistent acute and subchronic repeat 

dose toxicology, and common oxidative metabolic pathways. The reviewed and cited triethylene 

glycol studies include a mouse developmental toxicity, a rat developmental toxicity study and a 

mouse reproductive toxicity study. Of those, the mouse developmental toxicity study was 

chosen as the most conservative endpoint and point of departure to conduct the I-DEEM dietary 

risk assessment. 

a. Mouse Developmental Toxicity Study of Triethylene Glycol Administered by Gavage (Union 

Carbide)

The purpose of this study was to evaluate the potential of triethylene glycol to cause 

developmental toxicity in the mouse. Undiluted triethylene glycol (CAS RN 112-27-6; 99.9% 

pure) was administered daily to female CD-1 mice (n=30/group) at 0, 0.5, 5, or 10 mL/kg/day. 

Control mice were administered deionized water at a volume of 10 mL/kg/day. These doses, 

which were selected based on the results of a dose range-finding study and are equivalent to 0, 

563, 5,630, and 11,260 mg/kg/day, respectively. 

No maternal deaths or abortions were observed. Hypoactivity was observed in two dams at 10 

mL/kg/day; one of these animals also displayed audible, rapid respirations. Triethylene glycol 

treatment was not associated with significant alterations in food consumption; however, water 

consumption was slightly increased during the dosing period at 5 and 10 mL/kg/day. Maternal 

body weight gain was also slightly, albeit not statistically, reduced during the dosing period at 

these doses. The large amount of variability in these data, however, should be noted. Gravid 

uterine weights, corrected terminal body weights, and relative liver weights were unaffected by 

triethylene glycol treatment. Although relative kidney weights were statistically increased at 10 

mL/kg/day, this change was not associated with any histopathologic alterations.
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For pregnancy outcome data the numbers of corpora lutea, implantations, and resorptions were 

similar across treatment groups. Live/dead fetuses per litter and sex ratios were also unaffected 

by treatment. Fetal body weights, however, were statistically lower in the 5 and 10 mL/kg/day 

dose groups. Malformations rates were similar across treatment groups. Although skeletal 

malformations were slightly higher at 10 mL/kg/day, some of the reported findings (e.g., missing 

lumbar arches or centrum) are more likely indications of reduced bone ossification, which was 

reported at both 5 and 10 mL/kg/day; this finding correlates with the reduced fetal weights and 

indicates possible developmental delay.

Based on the above data, the study investigators reported the following no observed adverse 

effect levels (NOAELs). The developmental NO(A)EL was observed in the presence of maternal 

toxicity. 

 Maternal toxicity: 5 mL/kg/day (5,630 mg/kg/day) – based primarily on clinical signs 

and increased relative kidney weights;

 Developmental toxicity: 0.5 mL/kg/day (563 mg/kg/day) – based on reduced fetal 

weights and reduced bone ossification at ≥5 mL/kg/day. 

Although maternal food consumption, water consumption and body weight gains were not 

significantly different from control values at 5 and 10 mL/kg/day, these data were highly 

variable and suggest an effect of treatment on these parameters at these doses. Further, the 

observed fetal effects are indications of developmental delay, which is a transient and reversible 

finding. The doses administered in this study are significantly above the generally accepted 

limit dose of 1,000 mg/kg/day. 

b. Rat Developmental Toxicity Study of Triethylene Glycol Administered by Gavage (Union 

Carbide)

The purpose of this study was to evaluate the potential of triethylene glycol to cause 

developmental toxicity in the rat. The methods used in this study are the same as those described 

above for the developmental toxicity study in mice. Triethylene glycol (CAS RN 112-27-6; 

99.9% pure) was administered daily to female Sprague Dawley rats (n=25/group) at 0, 1, 5, or 10 

mL/kg/day. Control rats were administered deionized water at a volume of 10 mL/kg/day. The 

dosing volumes administered were based on each animal’s most recent body weight 

measurement. These doses, which were selected based on the results of a dose range-finding 

study, are equivalent to 0, 1,126, 5,630, and 11,260 mg/kg/day, respectively. 

Regarding maternal data, one female at 5 mL/kg/day died on GD 11; the cause of her death could 

not be determined. No other deaths or abortions were noted. Clinical signs of toxicity, including 

urine stains, audible respirations, periocular encrustation, and perioral wetness, were noted in a 

few dams at 10 mL/kg/day. During the dosing period, food consumption was statistically 

reduced at 10 mL/kg/day; this finding was associated with a statistically significant reduction in 

body weight gains during the same period. Water consumption was also statistically increased at 

5 and 10 mL/kg/day during the dosing period. At the end of the study, corrected terminal body 
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weights were reduced and relative kidney weights were increased at the high dose of 10 

mL/kg/day; this latter finding, however, was not associated with any histopathologic alterations. 

Gravid uterine weights and relative liver weights were unaffected by treatment.

Pregnancy outcome data indicate that the numbers of corpora lutea, implantations, and 

resorptions were similar across treatment groups. Live/dead fetuses per litter and sex ratios were 

also unaffected by treatment. Fetal body weights, however, were statistically lower in the 10 

mL/kg/day dose group. Malformation rates were statistically similar across treatment groups. 

However, the incidences of rudimentary rib #13 and bone island (rather than rib) on thoracic arch 

#13 was reported to be slightly increased at 10 mL/kg/day. Reduced bone ossification was also 

noted at 10 mL/kg/day. The skeletal findings correlate with the reduced fetal weights observed 

at this dose and likely represent indications of developmental delay.

Based on the above data, the study investigators reported the following no observed adverse 

effect levels (NOAELs). The developmental NOAEL was observed in the presence of maternal 

toxicity. 

 Maternal toxicity: 1 mL/kg/day (1,126 mg/kg/day) – based primarily on reduced food 

consumption, body weights and body weight gains, and increased water consumption at 

≥5 mL/kg/day1;

 Developmental toxicity: 5 mL/kg/day (5,630 mg/kg/day) – based on reduced fetal 

weights, skeletal anomalies and reduced bone ossification at ≥5 mL/kg/day. 

As in the mouse developmental toxicity study, the observed fetal effects are indications of 

developmental delay, which is a transient and reversible finding. Further, this study suffers from 

the same major guideline deviation as the mouse study. That is, the doses administered in this 

study are significantly above the current generally accepted limit dose of 1,000 mg/kg/day. As 

such, the findings observed at the high dose of 11,260 mg/kg/day may be of questionable 

relevance to assessing the potential developmental toxicity of triethylene glycol.

c. Mouse Reproductive and Fertility Study with Triethylene Glycol Administered in the 

Drinking Water (NTP)

The objective of this study was to evaluate the potential of triethylene glycol to cause 

reproductive toxicity in the mouse. This study also provides useful information to supplement the 

Union Carbide data, but there are deviations and gaps from current study guideline 

specifications. Triethylene glycol (CAS RN 112-27-6; <99% pure) was administered daily in the 

drinking water at concentrations of 0, 0.3, 1.5, and 3% to male and female CD-1 mice 

(n=20/sex/group). The final concentrations administered equate to daily doses of 0, 590, 3,300, 

and 6,780 mg/kg/day, respectively. 

 
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Triethylene glycol in the drinking water at concentrations ≤3% was reported to have no effect on 

physical appearance, body weight gain, or water consumption of P animals. Two females in the 

control group, one male and one female in the mid-dose group, and two females in the high dose 

group died during the course of the study; none of these deaths were considered to be treatment 

related. Triethylene glycol at drinking water concentrations of ≤3% did not affect fertility, the 

number of litters produced by each breeding pair, the mean number of live pups per litter, the 

proportion of pups born live or the sex ratio of the pups (Table 10). However, drinking water 

concentrations of 1.5% and 3% were associated with reduced live pup weights. These findings 

are similar to those reported in the mouse developmental toxicity study for fetal weights.

Fertility and reproduction were also assessed in animals in the control and high dose groups of 

the F1 generation. The triethylene glycol treatment was not associated with effects on fertility, 

the mean number of live pups per litter, the proportion of pups born live, or the sex ratio of the 

pups. Unlike for the F1 pups, however, triethylene glycol had no effect on live F2 pup weights. 

Treatment also had no effect on the absolute weights of reproductive organs in adult F1 males 

and females or on F1 sperm parameters; liver weights, however, were statistically increased for 

males only.

Based on these findings, the NOELs for reproductive and developmental effects are concluded to 

be the following. The developmental NO(A)EL was observed in the presence of maternal 

toxicity. 

 Reproductive toxicity

o F1 generation: 3% (6,780 mg/kg/day) – the highest dose tested;

o F2 generation: 3% (6,780 mg/kg/day) – the highest dose tested.

 Developmental toxicity

o F1 generation: 0.3% (590 mg/kg/day) – based on reduced F1 pup weights at 

≤1.5%;

o F2 generation: 3% (6,780 mg/kg/day) – the highest dose tested.]

4. Subchronic toxicity. [The evaluation of systemic toxicity and derivation of a repeat 

dose, subchronic NOAEL was determined for tetraethylene glycol from a 33-day rat study in 

which the test material was administered via gavage at doses of 220,660 and 2,000 mg/kg/day. 

The NOAEL was determined to be 2,000 mg/kg/day.]

5. Chronic toxicity [No chronic toxicity data are available for tetraethylene glycol.

However, based on the available rat subchronic repeated dose gavage testing in which the 

highest dose tested, 2000 mg/kg bw/day, produced no treatment-related effects, the potential for 

chronic toxicity is low.] 

6. Animal metabolism. [There are no published mammalian metabolism data for 

tetraethylene glycol that are comparable to other linear alkyl glycol publically available data. 

The available literature supports that for linear alkyl glycols with three or more oxyethylene 

groups, they may be excreted unchanged in the urine or undergo oxidative metabolism of the end 

primary hydroxy groups sequentially by alcohol dehydrogenase and aldehyde dehydrogenase 
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enzymes to generate mono and di-carboxylic acid metabolites (which would also be excreted in 

the urine). Ether cleavage to generate ethylene glycol or diethylene glycol is not the favored 

pathway for linear alkyl glycols with three or more oxyethylene groups.]

7. Metabolite toxicology. [Toxicology studies confirm that tetraethylene glycol does not 

generate metabolites that are toxic to the kidney such as oxalic acid. The lack of observed kidney 

toxicity in the subchronic and other repeat dose studies confirms that ether cleavage to generate 

ethylene glycol (a kidney toxin due to the generation of oxalic acid) is not a favored pathway for 

tetraethylene glycol]

8. Endocrine disruption. [Tetraethylene glycol does not belong to a class of chemicals 

designated or potentially designated as endocrine disruptors. Although at some future date EPA 

may screen tetraethylene glycol for potential endocrine effects in the EDSP assays, the current 

repeat dose database of mammalian toxicology studies, including reproductive and 

developmental toxicity testing, does not indicate potential adverse endocrine effects.]

C. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs EPA to consider available 

information concerning exposures from the pesticide residue in food and all other nonoccupational 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). It is unlikely that humans (adults and children) would be exposed to tetraethylene glycol

via potential residues on foods and in drinking water. 

Dietary exposure. [The dietary (food plus drinking water) exposures for tetraethylene glycol are 

expressed as a percentage of the proposed chronic population adjusted dose (cPAD) for the 

general US population and children 1-2 years old, the subpopulation with the highest potential 

exposures. 

The proposed and most conservative chronic NOAEL (563 mg/kg/day) for tetraethylene glycol 

was bridged from the triethylene glycol mouse developmental toxicity study. Based on I-DEEM 

screening level calculations, and taking into account the 35% cap in pesticide formulations, 

chronic dietary exposures are estimated to be 0.133 mg/kg.day (2.4% of the cPAD) for the 

general U.S. population and 0.278 mg/kg/day (8.8% of the cPAD) for children 1-2 years old. 

These data demonstrate that the I-DEEM screening-level chronic dietary (food and drinking 

water) exposures are well below the cPAD and are, therefore, below EPA’s established level of 

concern for all U.S. subpopulations up to and including a cap of 35% of tetraethylene glycol in 

food-use pesticide formulations.]
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Study

Proposed Chronic 

Systemic NOAEL1

(mg/kg bw/day)

cPAD2

(mg/kg bw/day)

Percent cPAD

(Including 35% formulation cap)

Children 1-2 

years of age

U.S. General 

Population

Mouse 

Developmental 

Toxicity3

563 5.63 8.8% 2.4%

1 NOAEL – No observed adverse effect level

2

cPAD – Chronic population adjusted dose, defined as: chronic NOAEL / (safety factor  FQPA factor).

3 Derived by bridging to the Neeper-Bradley, 1990 Developmental Toxicity Study for triethylene glycol

Administered by Gavage to CD-1 Mice. 

i. Food. [The available data demonstrate that the I-DEEM screening level chronic dietary 

(food and drinking water) exposures are well below 100% of the cPAD, and are therefore below 

EPA’s established level of concern for all U.S. subpopulations.]

ii. Drinking water. [Drinking water is included in the I-DEEM exposure assessment. 

Exposure to tetraethylene glycol from drinking water is expected to be negligible.]

2. Non-dietary exposures. [None]

D. Cumulative Effects

[Section 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency considers “available information” 

concerning the cumulative effects of a particular pesticide’s residues and “other substances 

that have a common mechanism of toxicity.” Unlike pesticides for which EPA has followed 

a cumulative risk approach based on a common mechanism of toxicity, EPA has not 

conducted a common mechanism evaluation for tetraethylene glycol. Moreover,

tetraethylene glycol does not produce a toxic metabolite(s) that may have a common 

mechanism of toxicity with other substances.]

E. Safety Determination

1. U.S. population. [A dietary exposure assessment using current EPA inert screening level 

methodology (I-DEEM) was conducted. Based on the conservative I-DEEM dietary exposure 

estimates, there is a reasonable certainty that no harm will result to the US population from the 

aggregate exposure to tetraethylene glycol.]

2. Infants and children. [The FFDCA Section 408 requires an additional tenfold margin of safety 

for the protection of infants and children in case of threshold effects to account for prenatal and 

postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database 

is available and there is a lack of evidence for increased susceptibility, the FQPA safety factor

may be reduced or removed. An evaluation of susceptibility and uncertainty issues associated 

with the proposed uses and tolerance exemptions for tetraethylene glycol has been performed. 
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Based on available information discussed thus far and below in Special Consideration for Infants 

and Children, Drexel requests reduction of the FQPA safety factor to 1x and that the additional 

tenfold safety factor for the protection of infants and children be removed.

 There is a robust database of acute, subchronic, and mutagenicity toxicology that supports 

the uses of tetraethylene glycol as an inert ingredient in food use pesticides at a maximum 

formulation concentration of 35%. Tetraethylene glycol does not pose undue acute, 

subchronic, and/or a cancer risk to humans including infants and children. 

 The tetraethylene glycol reproductive and developmental deficits have been justified and 

addressed by bridging to the extensive database of triethylene glycol reproductive and 

developmental studies. In the 2005 Triethylene Glycol Reregistration Eligibility Decision, 

EPA did not express concerns that triethylene glycol poses undue risk to infants and children. 

 EPISuiteTM 4.11 environmental modeling results indicate it is unlikely that tetraethylene 

glycol will persist or bioaccumulate to the extent that the compound would pose undue 

environmental risk or result in significant crop residues and dietary exposures to sensitive 

populations. 

 Tetraethylene glycol does not belong to a class of known endocrine disrupters. 

 I-DEEM modeling supports that there is no dietary risk for the use of tetraethylene glycol in 

foliar applications. Estimated dietary exposures to tetraethylene glycol for children 1-2 years 

of age, the most highly exposed subpopulation, are 8.8%, which is well below 100% of the 

cPAD.

 EPA has approved CAS RN 25322-68-3, a generic descriptor that may refer to various 

polyethylene oligomers and polymers (including PEG 200 which contains tetraethylene 

glycol), as a pesticide inert ingredient in non-food use formulations and also tolerance 

exemptions under 40 CFR §180.910 pre- and post-harvest and 40 CFR §180.930 animal 

uses.]

F. International Tolerances

[There are no known international tolerances for tetraethylene glycol.]