UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

August 26, 20 15 

MEMORANDUM 

SUBJECT: PC Code: 842203 Tetraethylene Glycol; Human Health Risk Assessment 

and Ecological Effects Assessment to Support Proposed Exemption from 

the Requirement of a Tolerance When Used as Inert Ingredients in 

Pesticide Formulations. 

All PC Code: 842203 DP Barcode: N/A 

Decision No.: N/A Regulatory Action: Inert 

Tolerance Exemption; 40 

CFR 180.920. 

Petition No: IN-10753 All CAS Reg. No: 112-

60-7 

Inert Tracking No: N/A 

FROM: 

Through: 

TO: 

Lisa Austin, Ph.D., Toxicologist ~ l. _L_ 

Chemistry, lnerts and Toxicology Assessment ) Registration Division (7505P~ 

Kerry Leifer, Team Leader 

Chemistry, Jnctts and Toxicol g e sme 

Registration Division (7505P) 

PV Shah. Ph.D., Branch Chief 

Chemistry, Inerts and Toxicology Assessment Branch (CTTAB) 

Registration Division (7505P) 
EXECUTIVE SUMMARY 

EPA received a petition (IN-I 0753) from Exponent, Inc., on behalf of Drexel Chemical 

Company requesting the establishment of an exemption from the requirement of a tolerance for 

residues of tetraethylene glycol (CAS Reg. No. 11 2-60-7) as an inert ingredient solvent limited 

to 35% in pesticide products on all pre-harvest food commodities under 40 CFR part 180.920. 

Tetraethylene glycol is approved as an inert ingredient for non-food usc. It is also approved for 

use as a humectant in cosmetics and as an indirect food additive for food contact applications 

under 21 CFR 176.2 I 0. EPA published the notice of fi ling (NO F) for this petition in the Federal 

Register on May 20, 2015 (80 FR 28925). No comments were received in response to this 

notice. 

Acute, subchronic and mutagenicity studies were available on tetracthylene glycol. 

Tetraethylene glycol is a member of the ethylene glycols category of chemicals. All members of 

this group possess two terminal hydroxy groups and diffe r from each other only in the number of 

oxyethylene units. Because of this it is appropriate to classify ethylene glycol) and the higher 

glycols as a single group. Ethylene glycol and the higher glycols (di-. tri-, tetra-. and 

pentaethylene glycol) arc closely related in structure and have physicochemical properties which 

differ in a regular and expected way as a result of increasing molecular weight and consistent 

functionality of a relative ly less stable hydroxy moiety on each end of the molecule. Therefore, 

the hazard profi le and dose response are also expected to change consistently, with decreasing 

potential for adverse effect with increasing molecular weight (OECD SIDS SIAM 18, 2004). 

Based on this, toxicity data on triethylene glycol was used as surrogate data to bridge 

developmental, reproduction toxicity and metabolism data for tetraethylcnc glycol. 

The acute oral and dermal toxicity oftetraethylene glycol is low. The oral and dermal LDsos 

were > 20,000 mg/kg in the rat and rabbit. Acute inhalation toxicity in rats is also low; the LC50 

> 2.5 Llmin. Tetraethylene glycol is mildly irritating to the eyes and to the skin in rabbits. It is 

not a dermal sensitizer. 

Tetraethylene glycol did not cause toxicity at doses up to 2000 mg/kg/day in a subclu·onic 

oral toxicity study in rats. 

In developmental and reproduction toxicity studies based on triethylene glycol, it is not 

expected to be a developmental/reproduction toxicant. Neither maternal. developmental nor 

reproduction toxicity was observed up to 3300 mglkg/day (greater than three times the limit 

dose). 

Available mutagenic ity studies included the Ames test, mammalian gene mutation, sister 

chromosomal exchange, chromosome aberrations, the dominant lethal test, and mouse 

micronucleus assays. Tctraethylene glycol was negative for inducing mutations and aberrations 

in all of the studies except the sister chromosome exchange assay. However, based on the 

weight of evidence tetraethylene glycol is not expected to be mutagenic. 

Carcinogenicity studies were not available. However, based on the lack of systemic toxicity 

and the lack of mutagenicity tetraethylene glycol is not expected to be carcinogenic. 

2 
Neurotoxicity and immunotoxicity studies were not available for review. However, evidence 

of neurotoxicity and immunotoxicity was not observed in the submitted studies. 

Metabolism studies are not available on tetraethylene glycol. However, it is postulated that 

the metabolic pathway for tetraethylene glycol is similar to that of triethylene glycol in that it 

undergoes oxidation via alcohol dehydrogenases and aldehyde dehydrogenases to generate 

dicarboxylic acid metabolites. 

The available toxicity studies indicate that tetraethylene glycol has low toxicity. No effects 

were observed up to 2,000 mglkg/day following subchronic exposure. In the developmental and 

reproduction toxicity studies, effects were observed onl y at very high doses(> 3.300 mg/kg/day). 

Further, the only effect observed at 3,300 mg/kg/day was a minor decrement in bodyweight. 

Although, doses between 590 - 3300 mg/kg/day were not tested in the developmental and 

reproduction studies in mice, the Agency is reasonably certain that no harm wi ll occur to the 

general population or infants and children following the use of tetraethylenc glycol at any dose 

below the limit dose given the lack of effects being found and the fact that the only effect seen 

was a minor bodyweight decrease seen at 3.300 mg!kg/day. Since, no other effects were 

observed, the Agency concluded that there are no endpoints of concern for tctraethylene glycol 

and a qualitative risk assessment is appropriate. 

Tetraethylene glycol is used as an inert ingredient in pesticide products that could result in 

residential exposure. However, based on the lack of toxicity, a quantitative exposure assessment 

from " residential exposures" was not performed. 

Occupational exposure is not of concern since an endpoint was not identi fted. 

Tetraethylene glycol is not toxic to aquatic organisms. Based on EPISuite modeling, 

tetraethylene glycol is not expected to persist or bioaccumulate. 

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/ guidancc/j ustice/eo 12898. pdf. 

Taking into consideration all available information on tetraethylene glycol (CAS Reg. 'o. 

11 2-60-7), 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 tetraethylene glycol. 

Therefore, the establishment of an exemption from tolerance under 40 CFR 180.920 for residues 

oftetraethylene glycol when used as an inert ingredient limited to 35% in the end-product 

pesticide formulations in pre-harvest food commodities under 40 CFR 180.920 limited can be 

considered safe under section 408 of the FFDCA. 

1. BACKGROUND 

3 
On August 11 , 2014 Exponent, Inc. (1150 Connecticut Ave, Suite 1100 Washington, DC 

20036) on behalf of Drexel Chemical Company (P.O Box 13327 Memphis, TN 38 11 3) requested 

that EPA establish an exemption from the requirement of a tolerance for residues of tetraethylene 

glycol (CAS Reg. No. 11 2-60-7) as an inert ingredient limited to 35% in pesticide products on all 

pre-harvest food commodities under 40 CFR part 180.920. EPA published the Notice of Filing 

for this petition in the Federal Register on May 20, 2015 (80 FR 28925). No comments were 

received in response to the notice. 

Currently, tetraethylene glycol is approved as an inert ingredient for non-food use. It is also 

approved for use as a humectant in cosmetics and as an indirect food additive for food contact 

applications under 2 1 CFR 176.210. 

This document provides an assessment of the risk to human health and the environment for 

tetraethylene glycol when used as an inert ingredient in pesticide formulations applied to preharvest agricultural commodities. 

2. PHYSICAL AND CHEMICAL PROPERTIES 

Some of the physical and chemical properties oftetraethylene glycol are listed in table I. 

Table 1. Physical and Chemical Properties of Tetracthylene Glycol 

Parameter Value Source 

Structure ../"' .....__. ../"' .....__. 

Chemical Name Tetraethylcne Glycol 

CAS# 11 2-60-7 

Molecular Weight (g/mol) 194.23 EPISuiterM 

Ethanol. 2.2.-[ oxybis(2. 1- 4. 11 (ht!_Q://www.ega.gov/OQQtintr/exQosur Common Names ethanediyloxy)]bis- e/Qubs/egisuitedl.htrn) and 

Physical State liquid chem.sis.n lrn.n ih .gov/chem I Dplus. 

Melting Point (

0C) 82.91 

Boiling Point (0C) 3 15.80 

Vapor Pressure (mrn Hg @ 26 

OC) 4.65£-05 

Partition Coefficient ( o~ Kow) -2.02 

Water Solubility (mg/L at 25°C) I.Ox I 06:Miscible 

Henry's Law Constant (atrn 5.50E-19 

rn3

/rnol at 25 °C) 

3. Hazard Assessment 

4 
Acute, subchronic and mutagenicity studies were available on tetraethylene glycol. 

Tetraethylene glycol is a member of the ethylene glycols category of chemicals. All members of 

this group possess two terminal hydroxy groups and differ from each other only in the number of 

oxyethylene Lmits. Because of this it is appropriate to classify EG and the higher glycols (up to 

and including n=5) as a single group. Ethylene glycol and the higher glycols (di-, tri-, tetra-, and 

pentaethylene glycol) arc closely related in structure and have physicochemical properties which 

differ in a regular and expected way as a result of increasing molecular weight and consistent 

functionality of a relatively less stable hydroxy moiety on each end of the molecule. Therefore. 

the hazard profile and dose response are also expected to change consistently, with decreasing 

potential for adverse effect with increasing molecular weight (OECD SIDS SIAM 18, 2004). 

Based on this, toxicity data on triethylene glycol was used as surrogate data to bridge 

developmental, reproduction toxicity and metabolism data for tetraethylene glycol. 

Acute Toxicity Studies 

Acute, repeat dose and mutagenicity toxicity data were reproduced from ClR Expert Panel 

Safety Assessment oftetraethylene glycol and PEG-4 (polyethylene glycol). (2006), National 

Library of Medicine llazardous Substance Database, International Unifom1 Chemical 

Information Database (IUCLID) Dataset 2000 and Schladt et.al. (1998). 

Table 2. Acute Toxicity Profile of Tetraethylene Glycol 

Study Type Results 

Acute Oral - Rat LD50 = 32.7-34 glkg (32,700-34,000 mglkg) 

Acute Dermal - Rabbit >20 glkg (20,000 mglkg) 

Acute Inhalation - Rat No signs of toxicity at 2.5 1/min for 8 hours 

Dermal Irritation-Rabbit Mild irritation 

Eye Irritation-Rabbit Minimal irritation 

Sensitization-Guinea Pig Not sensitizing 

Repeated Dose Studies: 

33-day Oral Toxicity-Rat: 

In a 33 Day oral toxicity study, Wistar rats were administered via gavage 0, 220, 660 and 

2000 mglkg/day of tetraethylene glycol (CAS No. I 12-60-7). The NOAEL was 2000 

mg/kg/day, the highest dose tested (CIR Expert Panel Safety Assessment ofTEG and PEG-4. 

2006. 

5 
Developmental/Reproduction Toxicity Studies 

Triethylene glycol (CAS Reg. No. 112-27-6) was administered daily to virgin female 

Sprague Dawley rats (n=25/group) at 0, 1, 5 or I 0 mL/kg/day via gavage on gestational days 

(GDs) 6-15. Control rat 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, are equivalent to 

0; 1 ,I 26; 5,630 and 11 ,260 mg/kg/day, respectively. The dosing period covers the period of 

organogenesis, but is slightly less than what is recommended in the US EPA testing guidelines. 

Dams were observed daily for mortality, any clinical signs of toxicity and weighed on GD 0, 6, 

9, 12, 15, 18 and 21. Food and water consumption were measured over three-day intervals from 

GD 0 to GO 21. On GO 2 1, the dams were sacrificed by carbon dioxide asphyxiation and 

examined macroscopically for any gross lesions. The liver, kidneys and uterus were weighed 

and the lddneys fixed for subsequent histopathologic examination. The numbers of corpora 

1utea, implantations, resorptions, live and dead fetuses were counted. Uteri from females that 

presented as non-gravid were stained with I 0% ammonium sulfide to detect the presence of early 

resorptions. All live fetuses were sexed, weighed and examined for external and visceral 

anomalies. One half of the fetuses were decapitated and their heads fixed for examination using 

the Wilson's sectioning. All fetuses were then eviscerated, fixed and processed for examination 

of skeletal anomalies. 

One female at 5 ml/kg/day died on GD II ; the cause of her death could not be determined. 

No other deaths or abortions were noted. One dam in the control group delivered early on GO 

20; data from this animal were not included in the calculation of pregnancy outcome data. 

Clinical signs of toxicity, including urine stains, audible respirations, periocular encrustation. and 

perioral wetness, were noted in a few dams at I 0 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 statisticall y increased at 5 and 10 mllkg/day during the dosing period. At 

the end of the study, corrected terminal body weights were reduced and relative kidney we ights 

were increased at the high dose of I 0 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. 

The numbers of corpora lutea, implantations, and resorptions were similar across treatment 

groups. Live/dead fetuses per litter and sex ratios were a lso unaffected by treatment. Fetal body 

weights, however, were statistically lower in the I 0 ml/kg/day dose group. Malformations rates 

were 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. These findings likely represent varying degrees of the same alteration, and although 

classified in the study report as malformations, would be more appropriately called skeletal 

variations using current c lassification standards. Reduced bone ossification was also noted at l 0 

ml/kg/day. The skeletal findings correlate with the reduced fetal weights observed at this dose 

and likely represent indications of developmental delay. 

6 
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. The maternal LOAEL (lowest observed adverse effect level) was 5 ml/kg/day (5,630 

mg/kg/day) based on reduced food consumption, body weights and body weights gains, and 

increased water consumption. The maternal NOAEL was 1 mllkg/day (I, 126 mg/kg/day). The 

developmental LOAEL was 5 ml/kg/day (5,630 mglkg/day). The developmental NOAEL was I 

ml/kg/day (1,126 mg/kg/day) (Neeper-Bradley. 1991). 

Mouse: 

Undiluted triethylene glycol (CAS Reg. No. 11 2-27-6) was administered daily to virgin 

female CD-1 mice (n=30/group) at 0, 0.5, 5 or 10 mL/kg/day on gestational days (GDs) 6-15. 

Control mice were administered deionized water at a volume of I 0 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, 563, 5630 and II260 mg/kg/day, respectively. The dosing period covers the 

period of organogenesis. but is slightly less than what is recommended in the US EPA testing 

guidelines. Dams were observed daily for mortality. any clinical signs of toxicity and weighed 

on GD 0, 6, 9, I2, 15 and 18. Food and water consumption were measured over three-day 

intervals from GD 0 to G D 18. On GD I8, the dams were sacrificed by carbon dioxide 

asphyxiation and examined macroscopically for any gross lesions. The liver, kidneys and uterus 

were weighed and the kidneys fixed for subsequent histopathologic examination. The numbers 

of corpora lutea, implantations, resorptions, live and dead fetuses were counted. Uteri from 

females that presented as non-gravid were stained with 10% ammonium sulfide to detect the 

presence of early resorptions. All live fetuses were sexed, weighed and examined for external 

and visceral anomalies. One halfofthe fetuses were decapitated and their heads fixed for 

examination using the Wilson's sectioning. All fetuses were then eviscerated, fixed and 

processed for examination of skeletal anomalies. 

No maternal deaths or abortions were observed. One dam in the 10 ml/kg/day (11,260 

mg/kg/day) delivered earl y on GD 18; data from this animal were not included in the calculation 

of pregnancy outcome data. Hypoactivity was observed in two dams at I 0 ml/kg/day ( Il ,260 

mg/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 closing period at 5 and I 0 ml/kg/day (5,630 and 

11 ,260 mglkg/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 re lative kidney weights were 

statistically increased at I 0 mllkg/day (11 ,260 mg/kg/day), this change was not associated with 

any histopathologic alterations. 

The numbers of corpora lutea, implantations. and resorptions were similar across treatment 

groups. Live/dead fetuses per litter and sex rations were also unaffected by treatment. Fetal 

body weights, however, were statistically lower in the 5 and I 0 mllkg/day (5,630 and 11 ,260 

mg/kg/day) dose groups by 6 and 9%, respectively. Malformation rates were similar across 

7 
treatment groups. Although skeletal malformations were slightly higher at I 0 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 (5,630 and 11 ,260 

mg/kg/day); this finding correlates with the reduced fetal weights and indicates possible 

developmental delay. 

The maternal LOAEL was not established. The maternal NOAEL was I 0 ml/kg/day (I I ,260 

mg/kg/day, the highest dose tested). The developmental LOAEL was 5 ml/kg/day (5,630 

mg/kg/day) based on reduced fetal weights and reduced bone ossification. The developmental 

NOAEL was 0.5 mVkg/day (563 mglkg/day) (Neeper-Bradley, 1990). 

Triethylene glycol (CAS Reg. No. 11 2-27-6) was administered in drinking water at 

concentrations of 0, 0.3, 1.5 or 3% to male and female CD-I mice (n=20/sex/group) beginning 7 

days prior to mating and throughout the 14-week continuous breeding period and a 21-day 

segregation period following cohabitation. The drinking water concentrations administered in 

this study were based on results of a dose range-finding study. The final concentrations 

administered equate to daily doses of 0, 590; 3,300 and 6, 780 mg/kg/day. respectively. Parental 

(P) mice were observed for mortality, clinical signs of toxicity and weighed at the beginning of 

study weeks I, 2, 3, 5, 9, 13 and 18. Food and water consumption were monitored once per 

month. All FI pups delivered during the cohabitation period were counted, sexed, weighed and 

examined for externa l abnormalities on postnatal day (PND) 0; dead or cannibalized pups were 

also noted. Resulting offspring were also weighed on PND 4, 7, 14 and 2 1 and the percent 

survival calculated. Dams were weighed after each litter was delivered and the number of days 

to litter was calculated for each breeding pair. Because no effect on reproductive performance 

was observed during this portion of the study, offspring from the control and high dose groups 

were randomly selected after weaning to assess ferti lity and reproductive performance ofF I 

offspring (n=20/sex/group, 2/sex/litter from 10 litters of each dose group). At approximately 74 

days of age, these animals were cohabitated with non-sibling for 7 days, then separated for 

delivery of any resulting offspring. Data regarding mating and fertility were then tabulated as in 

the previous portion of the study. Additionally, select Fl adult male and female organ weights 

were collected and sperm analyses conducted. 

Triethylene glycol in the drinking water at concentrations :S 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 :S 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. However, drinking water 

concentrations of 1.5 and 3% were associated with reduced live pup weights (4%). 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. Again, 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 

8 
of the pups. Unlike the F 1 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 F I 

males and females or on F1 sperm parameters: liver weights. however, were statistically 

increased for males only. 

Based on the findings, the parental and reproduction LOAELs were not established. The 

parental and reproduction NOAELs were 3% (6,780 mg/kg/day), the highest dose tested. The 

offspring LOAEL was 1.5% (3 ,300 mg/kg/day) based on reduced Fl pup weights. The 

offspring NOAEL was 0.3% (590 mg/kg/day) (Reel and Lamb IV. 1984). 

Chronic/Carcinogenicity 

Carcinogenicity studies were not available. However, based on the lack of systemic toxicity 

and the lack of mutagenicity tetraethylene glycol is not expected to be carcinogenic. 

Mutagenicity 

In Vitro: 

An Ames test was conducted inS. typhimurium TA 98, TA 100, TA 1535m, TA 1537 and 

TA 1538 at 112.6 mg/plate of tetraethylene glycol (CAS No. 11 2-60-7) with and without 

metabolic activation. There was no increased incidence of revertant colonies. 

A mammalian gene mutation assay was conducted in Chinese Hamster Ovary cells with 24-

50 mg/ml of tetraethylene glycol (CAS No. 11 2-60-7) with and without metabolic activation. An 

increased incidence of chromosomal aberrations was not observed. 

A sister chromosome exchange assay was conducted in Chinese Hamster Ovary cells with 

24-50 mg/ml of tetraethylene glycol (CAS No. 11 2-60-7) with and without metabolic activation. 

The results were equivocal. 

In Vivo: 

In an in vivo dominant lethal test in the rat, tetraethylene glycol (CAS No. 112-60-7) was 

administered at 0, 5000, 25000, or 50000 ppm in drinking water. No significant dominant-lethal 

effects were observed. 

A chromosomal aberrations assay was conducted in Sprague-Dawley rats. Rats were orally 

administered 0. 1250. 2500 or 5000 mg/kg of tetraethylene glycol (CAS No. I 12-60-7). 

Tetraethylene glycol was not clastogenic in this assay. 

A micronucleus assay was conducted in mice (strain not reported). A single dose of2500. 

4000 or 5000 mg/kg was administered intraperitoneall y. Blood samples were taken at 30, 48 and 

72 hours post-dosing and micronucleated polychromatic erythrocytes (MN-PCE) were counted. 

Increased incidence of MN-PCE was observed at the low and high doses only. 

9 
Metabolism-Rat 

Metabolism studies are not available on tetraethyl ene glycol. However, based on metabolism 

data on ethylene glycol, diethylene glycol and triethylene glycol, it is postulated that the 

metabolic pathway for tetraethylene glycol is similar to triethylene glycol in that it undergoes 

oxidation via alcohol dehydrogenases and aldehyde dehydrogenases to generate dicarboxylic 

acid metabolites. 

Table 3. Toxicology Profile for Tetracthylcoc Glycol 

Study Type Doses Results 

33 Day Oral Toxicity 0. 220, 660 and 2000 NOAEL = 2000 mg/kg/day. Study-Wistar rat 

mglkg/day LOAEL was not established. 

Developmental Toxicity - 0, I, 5 and I 0 ml/kg/day (0. Maternal NOAEL = I rnllkg/day ( 1126 mglkg/day). Sprague-Dawley rat - I 126, 5630. and I 1260 

gavage mg/kg/day) Maternal LOAEL = 5 ml/kg/day (5630 mg/kg/day) based on 

reduced maternal food consumption, body weights and body 

weight gai ns and increased water consumption. 

Developmental NOAEL = 5 ml/kg/day (5630 mg/kg/day). 

Developmental LOAEL = I 0 ml/kg/day ( 11 260 mgfkg/day) 

based on skeletal anomalies. reduced fetal weights and bone 

ossification. 

Developmental Toxicity- 0. 0.5, 5 and I 0 mllkg/day Maternal NOAEL = 10 ml/kg/day (11260 mglkgfday). CD- I mouse -gavage (0.563,5630.and 11260 Maternal LOAEL was not established. mglkg/day) 

Developmental NOAEL = 0.5 ml/kg/day (563 mg/kg/day). 

Developmental LOAEL = 5 mllkg!day (5630 mg/kg/day) 

based on reduced fetal weights and bone ossification. 

14-week Continuous 0. 0.3. 1.5, 3.0% Maternal NOAEL = 3.0% (6780 rnglkg/day). Breeding and 21 days 

Separation Toxicity Study- (0. 590. 3300. and 6780 Maternal LOAEL was not established. 

CD-I mouse-Drinking mg/kg/day) 

water 

Reproduction NOAEL = 3.0% (6780 mg/kg/day). 

Reproduction LOAEL was not established. 

Offspring NOAEL = 0.3 % (590 mg/kg/day). 

Offspring LOAEL = 1.5 % (3300 mg/kg/day) based on 

reduced F I pup body weights. 

10 
Study Type Doses Results 

Ames Test 11 2.6 mg/plate Negative 

Chromosomal Aberrations- 24-50 mg/ml o increase in chromosomal aberrations. CHO cells 

Sister Chromosome 24-50 mg/ml Equivocal 

Exchange-CHO cells 

Dominant Lethal Test-rat 0.5000.25000.or50000 Negative 

ppm (equivalent to 500. 

2500 or 5000 mglkg) 

Micronucleus Assay- 2500, 4000 or 5000 mglkg Increased incidence of MN-PCE was observed at the low 

Mouse and high doses only. 

5. Toxicity Endpoint Selection 

The available toxicity studies indicate that tetraethylene glycol has low toxicity. o effects 

were observed up to 2,000 mglkg/day following subchronic exposure. In the developmental and 

reproduction toxicity studies, effects were observed only at very high doses(:::_ 3,300 

mglkg/day). Further. the onl y effect observed at 3,300 mg/kg/day was a minor decrement in 

bodyweight. Although, doses between 590 - 3300 mg/kg/day were not tested in the 

developmental and reproduction studies in mice, the Agency is reasonably certain that no harm 

will occur to the general population or infants and children following the usc oftetraethylene 

glycol at any dose below the limit dose given the lack of effects being found and the fact that the 

only effect seen was a minor bodyweight decrease seen at 3,300 mglkg/day. Since. no other 

effects were observed, the Agency concluded that there are no endpoints of concern for 

tetraethylene glycol and a qualitative risk assessment is appropriate. 

6. Special Considerations for Infants and Cbildren 

As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, 

and no additional safety factor is needed for assessing risk to infants and children. Based on the 

lack of toxicity of tetraethylene glycol in the available studies, EPA has concluded that there are 

no toxicological endpoints of concern for the U.S. population, including infants and children. 

11 
7. Exposure Assessment 

In evaluating dietary exposure to the tetraethylene glycol, EPA considered exposure under 

the petitioned for exemptions from the requirement of a tolerance. EPA assessed dietary 

exposures from tetraethylene glycol in food as fo llows: 

Dietary Exposure 

Dietary exposure can occur from eating foods containing residues of tetraethylene glycol. 

Because no hazard endpoint of concern was identified for the acute and chronic dietary 

assessment (food and drinking water), a quantitative dietary exposure risk assessment was not 

conducted. 

8. Residential Exposure (non-dietary exposure) 

The term "residential exposure" is used in this document to refer to non-occupational, nondietary exposure (e.g .. textiles (clothing and diapers), carpets, swimming pools, and hard surface 

disinfection on walls, floors, tables). Tetraethylene glycol is used as an inert ingredient in 

pesticide products that could result in short- and intermediate-term residential exposure. 

However, based on the lack of toxicity, a quantitative exposure assessment from residential 

exposures was not performed. 

9. Aggregate Risk 

Based on the lack of any endpoints of concern, 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 tetraethylene glycol residues. 

10. Occupational Exposure/Risk Pathway 

Occupational exposure was qualitatively assessed since an endpoint of concern was not 

identified. Occupational exposure is not of concern. 

11 . Cumulative Exposure: 

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

modify, or revoke a tolerance, the EPA consider "available infonnation" concerning the 

cumulative effects of a particular pesticide's residues and "other substances that have a common 

mechanism of toxicity." Unlike other pesticides for which EPA has followed a cumulative risk 

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

of toxicity finding as tetraethylene glycol and any other substances and, this material 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 tetraethylene glycol have 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 

12 
cumulative effects of such chemicals, see the policy statements released by EPA's Office of 

Pesticide Programs concerning common mechanism detenninations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA's website at 

http://www.epa.gov/pesticides/cumulative/. 

12. Ecotoxicity and Environmental Fate 

The following summaries were reproduced from the petitioner" s submission. 

SIAM 18 2004 has stated the following regarding the ecotoxicity of linear alkyl glycols with 

1-5 oxyethylene groups: 

"Toxicity to Daphnia (measured as LCSO in mg/L) is greater than 20,000 for all category 

members except tetraEG (tetraethylene glycol; LCSO = 7800in mg/L) indicating low toxicity, but 

the toxicity was not as uniform in fish. Toxicity evaluations in another invertebrate, brine 

shrimp (Artemia salina) were imprecise, but appear to be more consistent than the measured 

Daphnia toxicity values (no toxicity observed at the highest tested dose. 20 g/1 for EG [ethylene 

glycol], 10 g/1 for DEG [diethylene glycol], TEG [triethylene glycol], and tetraEG. Algal 

toxicity has been tested for EG, DEG, TEG and PentaEG [pentaethylene glycol] and no toxicity 

was found at concentrations less than or equal to I 00 mg/1. Based on the low toxicity of tested 

category members, it can reasonably be assumed that tetraEG likewise poses no appreciable 

hazard to algae. The QSAR predictions indicate that the category members should exhibit low 

toxicity, with trends of decreasing toxicity with increasing chain length and are supportive of the 

available experimental data." 

On the basis of comparable physicochemical EPISuite 4.11, it was concluded that triethylene 

glycol and tetraethylene glycol would have comparable biological and environmental 

physicochemical properties. Results were as follows: 

• Low Kow, would not bioaccumulate in mammalian lipophilic tissues or aquatic 

organisms (such as fish) 

• High water solubility 

• Not volatile 

• Readily decompose in the atmosphere 

• Would not bind to soil 

• Primary Fugacity: Comparable preference for soil (76%) and water (24%) 

compartments; \.4 life primary degradation: soil = 4-5 days and water= l day 

• Ultimate Fugacity: Comparable preference for soil (31 %) and water (69%) 

compartments; \.4 life ultimate degradation (mineralization): soil = 30 days and water 

= 1-2 days 

13. Environmental Justice 

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/eo I 2898.pdt). 

13 
As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP poli cy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup's food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consLm1ption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postappli cation are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 

14. Risk Characterization 

Acute, subchronic and mutagenicity studies were available on tetraethylene glycol. 

Tetraethylene glycol is a member of the ethylene glycols category of chemicals. All members of 

this group possess two terminal hydroxy groups and differ from each other only in the number of 

oxyethylene units. Because of this it is appropriate to classify EG and the higher glycols (up to 

and including n=S) as a single group. Ethylene glycol and the higher glycols (di-, tri-, tetra-, and 

pentaethylene glycol) are closely related in structure and have physicochemical properties which 

differ in a regular and expected way as a result of increasing molecular weight and consistent 

functionality of a relative ly less stable hydroxy moiety on each end of the molecule. Therefore, 

the hazard profile and dose response are also expected to change consistently, with decreasing 

potential for adverse effect with increasing molecul ar weight. Based on this, toxicity data on 

triethylene glycol was used as surrogate data to bridge developmental, reproduction toxicity and 

metabolism data for tetraethylene glycol. 

The acute oral, dermal and inhalation toxicity of tetraethylene glycol is low in rats and 

rabbits. Tetraethylene glycol is mildly irritating to the eyes and to the skin in rabbits. It is not a 

dermal sensitizer. 

Tetraethylene glycol did not cause toxicity at doses up to 2000 mg/kg/day in a subchroni c 

study in rats. It is not a developmental or reproduction toxicant. It is not expected to be 

carcinogenic based on its lack of systemic toxicity and mutagenicity. Neither is it neurotoxic nor 

immunotoxic. 

Metabolism studies are not available on tctracthylene glycol. However, it is postulated that 

the metabolic pathway for tetraethylene glycol is similar to that oftriethylene glycol in that it 

14 
undergoes oxidation via alcohol dehydrogenases and aldehyde dehydrogenases to generate 

dicarboxylic acid metabolites. 

Since there is no indication of toxicity at the limit dose a toxicological endpoint of concern 

for risk assessment purposes was not identified. Therefore, a quantitative risk assessment for 

tetraethylene glycol is not necessary. 

Tetraethylene glycol is used as an inert ingredient in pesticide products that could result in 

residential exposure. However, based on the lack of toxicity, a quantitative exposure assessment 

from ··residential exposures"' was not performed. 

Occupational exposure is not of concern since an endpoint was not identi ti ed. 

Tetraethylene glycol is not toxic to aquatic organisms. Based on EPISuite modeling, 

tetraethylene glycol is not expected to persist or bioaccumulate. 

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/gu idance/justice/eo 12898. pdf. 

Taking into consideration all available information on tetraethylene glycol (CAS Reg. No. 

I 12-60-7), EPA concludes that there is a reasonable certainty that no harm wi 11 result to the 

general population or to infants and children from aggregate exposure to tetraethylene glycol. 

Therefore, the establishment of an exemption from tolerance under 40 CFR 180.920 for residues 

of tetraethylene glycol when used as an inert ingredient limited to 35% in the end-product 

pesticide formulations in pre-harvest food commodities under 40 CFR 180.920 limited can be 

considered safe under section 408 of the FFDCA. 

15 
REFERENCES 

EPISuiteTM 4.11 (http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm). 

Hazardous Substances Data Bank (HSDB) Database. U.S. National Library of Medicine (NLM). 

Tetraethylene Glycol CASRN 11 2-60-7. http://toxnet.nlm.nihgov. 

International Uniform Chemical Information Database (IUCLID) Dataset. 2000. Substance ID: 

112-60-7 (3, 6, 9-trioxaundecane-1, 11-diol). European Commission European Chemicals 

Bureau. 

Neeper-Bradley, T. L. ( 1990). Developmental Toxicity Study ofTriethylene Glycol 

Administered by Gavage to CD-1 ® Mice. Union Carbide Chemicals and Plastics Company inc. 

Danbury, CT 06817. Project Report 53-65 (unpublished). MRTD 49450003. 

Neeper-Bradley, T. L. (1991). Developmental Toxicity Study ofTriethylene Glycol 

Administered by Gavage to CD-1 ®(Sprague-Dawley). Union Carbide Chemicals and Plastics 

Company Inc. Danbury, CT 068 17. Project Report 53-65 (unpublished). MRID 49450003. 

OECD SIDS. SIDS Initial Assessment Profile-Ethylene glycol, Diethylene Glycol, Triethylene 

Glycol, Tetraethylene glycol, Pentaethylene Glycol (Ethylene Glycols Category). SIAM 18. 20-

23 April 2004. 

Reel, J., Lawton. A. and Lamb lV, J. 1984. Triethylene Glycol: Reproduction and Fertility 

Assessment in CD-I Mice When Administered in the Drinking Water. National Toxicology 

Program. 

Cosmetics Ingredients Review (CIR) Expert Pane l. 2006. Final Report on the safety assessment 

oftriethylene glycol and PEG-4, International Journal of Toxicology 25: 12 1- 138. 

Schladt. L., Ivens. l.. Karbe, E., Ruhl-Fehlert, C., Bombard, E., 1998. Subacute oral toxicity of 

tetraethylene glycol and ethylene glycol administered to Wistar rats. Exp. Tox. Pathol, 50:257-

265. 

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