1

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 prepa ring 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 i n 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

pr oposing, 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 re garding 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 exempti on for inert ingredients. ]

3. Magnitude of residues. [ There is no specific crop residue information available for tetraethylene glycol . T his informat ion 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 mild ly 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 sensi tizer, tetraethylene glycol should not be considered a sensitizer

. Based on these acute toxicity data, tetraethylene glycol is considered EPA Toxicity Category III/IV.2

2. Genotoxicity

. [ Tetraethylene glycol has a complete and extensive battery of in vitr o 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 C hinese 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 result s 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 statisticall y 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, b ridging to triethylene glycol reproducti ve and developmental studies, to address these data has been proposed on the basis of the structural similarities of triethylene glycol and tetraethylene glycol

. A dditionally, these compounds have
similar t rends in their physicochemical properties, have c onsistent acute and subchronic repeat dose t oxicology , 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 th os e, 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, re spectively.

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 alterat ions 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 increas ed at 10 mL/kg/day, this change was not associated with any histopathologic alterations.3

For pregnancy outcome data the numbers of corpora lutea, implantations, and resorptions were similar across treatment groups. Live/dead fetuses per litter and sex ra tios 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 pos sible 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.

A lthough maternal food consumption, water consumption and body weight gains were not significantly different from contr ol 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 accepte d 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 evalu ate 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 ad ministered 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

measur ement. 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 duri ng the dosing period. At the end of the study, corrected terminal body4

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 bo ne 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 lik ely 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 tox icity: 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/day 1 ;

 Developmental toxicity: 5 mL/kg/day (5,630 mg/kg/day)

– based on reduced fetal weigh ts, 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 suffe rs 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 h igh 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 Adm inistered in the Drinking Water (NTP)

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

repro ductive toxicity in the mouse. T his study also provides useful information to supplement the Union Carbide data, but there are deviations and gaps from current study guideline specifications. Tr iethylene 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.5

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 a nd 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 fertil ity, 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 reduce d 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 F 1 generation. The t riethyl ene 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 F 1 pups, however, triethylene glycol had no effect on live F 2 pup we ights. Treatment also had no effect on the absolute weights of reproductive organs in adult F 1 males
and females or on F 1 sperm parameters; liver weights, however, were statistically increased for males only.

Based on these findings, the NOELs for reprod uctive 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 F 1 generation: 3% (6,780 mg/kg/day)

– the highest dose tested;

o F 2 generation: 3% (6,78 0 mg/kg/day)

– the highest dose tested.

 Developmental toxicity

o F 1 generation: 0.3% (590 mg/kg/day)

– based on reduced F 1 pup weights at
≤1.5%;

o F 2 generation: 3% (6,780 mg/kg/day)

– the highest dose tested. ]

4. Subchronic toxicity. [ The e valuation of s ystemic toxicity and derivation of a repeat dose, subchronic NO A EL was determined for tetraethylene glycol from a 33

- d ay r at study in
which the test material was admi nistered via gavage at doses of 2 2 0,6 6 0 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, b ase d on the available rat subchronic repeated dose gavage testing in which the highest dose tested, 2 000 mg/kg bw/day

, produc ed no treatment

- related effects , the potential for chronic toxicity is low. ]

6. Animal metabolism. [ There are no published mammali an 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 i n the urine or undergo oxidative metabolism of the end primary hydroxy groups sequentially by alcohol dehydrogenase and aldehyde dehydrogenase6

enzymes to generate mono and di

- carboxylic acid metabolites ( which would also be excreted in
the urine ) . Ether cl eavage 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 metaboli tes 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 t etraethylene g lycol for potential endocrine effects in the EDSP assays, the current repeat dose database of mammalian toxicology studies, includ ing reproductive and developmental toxicity testing, does not indicate potential adverse endocrine effect s .]

C. Aggregate Exp osure

In examining aggregate exposure, FFDCA section 408 directs EPA to consider available information concerning exposures from the 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). 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 t etraethylene 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 m ouse developmental toxicity study

. Based on I

- DEEM screening level calculations, an d taking into account the 35% cap in pesticide formulation s , 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 dem onstrate 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 .]7 Study Proposed Chronic

Systemic NOAEL 1 (mg/kg bw/day) cPAD 2

(mg/kg bw/day ) Percent cPAD

(Including 35% formulation cap)
Children 1

- 2 years of age U.S. General

Population

Mouse Developmental Toxicity 3 563 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 g lycol 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 exposure s

. [ N one]

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 evalua tion for tetraethylene glycol . Mo reover , 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

me thodology (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

. [ Th e 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 tet raethylene glycol has been perfor med.8

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 1 x 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,
subchron ic, 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 development al studies. In the 2005 Triethylene Glycol Reregistration Eligibility Decision, EPA did not express concerns that triethylene glycol poses undue risk to infants and children.

 EPISuite TM 4.1 1 environmental modeling results indicate it is unlikely that tet raethylene 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 sub population, 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 tetraeth y lene glycol .]