UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460

OFFICE OF CHE M ICAL 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 Prop osed Exemption from th e Requirement of a To lerance When Used as Inert Ingredients in P est icide Formulations.

All PC Code: 842203 DP Barcode: N/ A D e cis ion No.: N/A Regulatory Action: Inert Tolerance Exemption; 40 CFR 180.9 20. Petition No: IN-10753 All CAS Reg. No: 112- 60-7 

### Inert Tracking No: N/A

FROM:

Through:

TO: 

### Lisa Austin, Ph.D. , Toxicol ogis t



# ~ l

. _L_ Chemistry, ln erts and Toxicology



# Assessment

**)** Registration Division

**(7505P~** Kerry Leifer , Team Leader Chemistry , Jn c t ts and Toxicol g e sme R eg istrati on Division (7505 P) PV Shah. Ph.D. , Branch Chief C hemi stry, In erts and Toxicology Assessment Branch (C T TAB) Reg istration Divi s ion (7505P)

### EXECU TIVE SU MMARY EPA received a petition ( IN-I 0753) from Expone nt , Inc., on beha lf of Drexe l Chemical Co mpany req uesti ng th e estab li s hme nt of a n exemp tion fro m the req uire m en t of a tole rance for residues of tetr aethy lene glyco l (CAS Reg. No. 11 2-60-7) as an inert ingredient so lvent l imi ted to 35% in pesticide products on a ll pre - harvest food commodities under 40 CFR part 180

. 920. Tetraethylene glycol is approved as an inert ingredient for non- food usc. It i s also approved for use as a humectant i n cosmetics and as an indi rect food additive for food contact applications under 21 CFR 1 76.2 I 0. EPA published t he notice of fi li ng (N O F ) fo r this petit ion in the Federal Register on May 20 , 2015 (80 FR 28925). No comments were received in response to this notice. Ac ute, subchron ic and m utagen ic i ty stud ies we re ava il ab le o n te tr act hy le ne glyco l. Tetraethy l ene g lycol is a me m ber of th e ethyle ne g lyco ls ca tego ry of che m ica ls . All m embers of th is group possess two termina l hydroxy groups and d i ffe r fro m each other only in the number of oxyethylene units. Because of this it is approp r iate to classify ethylene g lycol) and the higher glycols as a single group. Ethylene glycol and the h igher glycols (di-. tri- , tetra-. and pe ntaethylene glyco l) 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 functiona li ty of a relative ly less stable hydroxy mo i ety on each end of the molecule. Therefore , the hazard p rofi l e and dose r esponse are a lso expected to c h ange consis tent ly, wi th decreasing pote n ti al for adve rse effec t w ith in c r eas i ng mo lecular weigh t ( O EC D S ID S S IAM 1 8, 2004). B ased o n this, tox i c ity da ta on trie th y lene g lyco l was used as s u rrogate data to bridge deve lopmental , reproduction tox i c ity and metabolism data for tetraethylcnc glycol. The acute oral and derma l toxicity oftetraethylene glycol is low. The oral and dermal LD so s we re > 20,000 mg/kg in the rat and rabbit. Acute inhalation toxicity in rats is also low; the LC 5 0 > 2.5 Llmi n. Tetraethylene g l ycol is m i ldly irritating to the eyes and to the skin in rabbits

. It is not a dermal sensitizer. T etraeth ylene g lyco l d id not ca u se tox ic ity at doses up to 2000 mg/ kg/ day in a subclu·onic o r

al tox ic ity st u dy in rats.

In developmental and reproduction toxicity studies based on triethylene glycol, it is not expected to be a developmenta l / reproduction toxicant. Neither maternal. developmental nor reproduct ion toxicity was observed up to 3300 mglk g/ day (greater than three times the limit dose). Avai lab le mutagen ic ity stud ies i ncluded the Ames test, mammalian gene mutati on , s i ster c h ro m oso m al exchan ge , c hro m oso m e aberrat io n s, the do min ant l ethal test, and m o u se mic ronucle u s assays. Tctraethy lene glyco l was negative for i nducing mutat ions and aberrations in all of the studies except the s i ster chromosome exchange assay. However , based on the weight of evidence tetraethylene glyco l is not expected to be mutagenic. Carc inogenicity studies were not availab le. However , based on the lack of systemic toxicity and the lack of mutagenicity tetraethylene glycol is not expected to be carcinogenic.

2Neurotoxicity and immunotoxicity studies were not available for review. However, evidence of neurotoxicity and immunotoxicity was not observed in the submitted s tudi es. Metabolism studies are not available on t etraethy le n e glyco l. How eve r , it i s postulated that the metabolic pathw ay for tetraethy lene glyco l i s s imilar to that of triethylene g l yco l in that it undergoes oxid a tion via a lco hol dehydro ge na ses and aldehyde dehydrogenases to gene r ate dicarboxylic acid metabolites. The available toxicity s tudie s indicate that tetraethy le ne glycol h as low toxic i ty. No effects we re observed up to 2 , 000 mglkg/day following subch ronic exposure. In the developmental and reproduction toxicity stud i es, effects were observed o nl y at ve r y high doses( > 3.300 m g/kg/ day). Furthe r , the only effec t observed at 3,300 m g/kg/day was a minor decrement in bodyweight. Although, doses between 590

- 3300 mg/ kg/ day were not tested in the developmental and r epro duction studies in m ice, the Age nc y is reaso n ably certain that n o harm wi ll occur to the general population or infants and children following the use of tetraethylenc g l ycol at any dose below the limit dose g iven 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 Age n cy conclu d ed that there are no endpo int s of concern for tctraethylene glycol and a qualitative risk assessment is appropriate. Tetraethylene g lycol i s u sed as an inert in gred ien t in pesticide product s th a t could result in res idential exposure. How eve r, based on the lack of toxicity , a quantitat ive expos ure assessment f rom " residential expos ures" was not performed. Occupational exposure is not of concern since an endpoin t was not identi fted. Tetraethylene glycol is not toxic to aqua ti c organ i sms. Based on EP I Suite modeling , tetraethylene glycol i s not expected to persist or bioaccumulate. Potential areas of env ironmental justice concerns , to the extent possible, we re considered in thi s human health ri s k assessment, in acco rd ance w ith U.S

. Executive Order 1 289 8 , "Federal Actions to Address E nvironmental Justice in Min ori t y Population s and Low-Income Populations," http: // www.eh .d oe. gov/ oepa/ guidancc / j ustice/ eo 12898.pdf. Taking into considerati on all available information on tetraethylene glycol ( CAS Reg. ' o. 11 2-60 -7 ), EPA concludes that there i s a reasonable certainty that no harm will result to the ge n eral population or to infants and children from aggregate exposure to tetraethylene glycol. T h erefore, the establishment of an exemption from to lerance under 40 CF R 180.920 for residues oftetrae thylen e g lyc o l when used as an inert in gred ien t limit ed to 35% in the e nd-product pesticide formulation s in pre-harvest food commodities under 40 CFR 1 80.920 limited can be considered safe und e r sectio n 408 of the FFDCA.



### 1. 

### BACKGRO UN D

3On August 11 , 2014 Expo nent , In c . (1150 Co nnecticut Ave, Suite 1100 Wa s hin g ton , D C 20036) on be half of Dr exe l C he mical Company ( P.O Box 1 3327 Memphis , TN 38 11 3) reque s ted that E P A es tablish an exemption from the requireme nt of a to le rance for re s idues of tetraethylene glycol (CAS Reg. No. 11 2

- 60-7) as an inert ingredie nt limited to 35% in pe s ti c id e prod ucts on all pre-har ves t food comm odities under 40 CF R part 180.9 20. E PA publis hed the Notice of Filing for this pe titi on in th e Federal Register o n Ma y 20, 2015 (80 F R 2 8925). No comments we re rec e i ved in r es pons e to th e no tice. C urrentl y, tetraeth y len e g lyco l i s approv e d as an inert in g redi e nt for non-f oo d u se . It is also approved for u se as a hum ec tant in cosmet ics a nd as an indir ec t food additive for food co n tact applications under 2 1 CF R 176.210

. Thi s docu ment provid es an ass essment of th e ri s k to hum a n health and the e nv ironment for tetraethy le n e g lyco l w h e n u se d as an ine rt in gred ient in pe s ticide formulation s app li ed to preharve st ag ri c ultural comm o diti es. 2. PHYSICAL AND CHEMICAL PROPERTIES So m e of the ph ys ica l a nd chemical p ro p e rti es oftetrae thy le ne g lycol a r e li ste d in tabl e I.
Tab l e 1. Physical and Chemica l Properties of Tetracthy l ene Glycol Pa rameter Val u e Source

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

C hem ical Na me T etrae th y lcn e Glycol C A S# 11 2-60-7 Mol ec ular Wei g ht (g/ mo l) 1 94.23 EPI S uiterM E

th anol. 2.2.-[oxyb i s(2. 1- 4. 11 (ht!_Q: //www.ega.gov / OQQtintr / exQosur Common Names ethaned iyloxy)]bis

- e/Qubs/egisuitedl.htrn) and

Ph ysica l State liquid chem.sis. nlrn.n ih .gov /chem IDp lus. Melting Poin t ( 0 C) 82.91 Boilin g Point ( 0 C) 3 1 5.80 Vap or Press ure ( mrn H g @ 26 4.65£- 0 5 O C) Partiti on Coefficient (

**o~** K ow) -2.02 Water Solubi lity (mg/L at 25 ° C) I.Ox I0 6 :Miscible H

enry's Law Con stant (atrn 5.50E-19 rn 3/rnol at 25 °C)

3. Hazard Assessment

4Acute , subchronic and mutagenicity studies were available on tetraethylene glycol. Tetraethylene g lycol is a member of the ethylene glycols category of chemicals. All members of this group possess two terminal hydroxy groups and differ from each othe r only in the number of oxyethylene Lm its. Because of this it is app ropriate to classify EG and th e higher glycols ( up to and inc lud ing n=5) as a s in g le group . Ethylene g lyco l and the higher g lyco ls (d i- , tri-, tetra

- , and pentaethylene g lyco l) arc closely related in structure and have physicochemical properties wh i ch differ in a regular and expected way as a result of increasing molecular weight and consistent functionality of a relatively less stab le hydroxy moiety on each end of the molecule. Therefore. the hazard profile and dose response are also expec t ed to change consistently , with decreasing potential for adverse effect with increasing molecular weight (OECD S IDS SIAM 18, 2004). Based on this , toxicity data on triethylene glycol was used as surrogate data to b rid ge developmental, reproduc ti o n toxicity and metabolism data for tetraethy lene glyco l. 

### Ac u te Toxicity Studi es 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 ll azardous Substance Database , International U nifom1 Chemical Information Database (IUCLID) Dataset 2000 and Schladt et.al. (1998). 

### Tabl e 2 . Ac ute Toxicity Profile of Tetraethy l ene G lyco l
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 s igns of toxicity at 2

. 5 1/min for 8 hours Dermal Irritation-R abb it Mild irritation

Eye Irritation- R abbit Minimal irrit ation Sensitization-Guinea Pig Not sensitizing



### R e pe ated Do se S tudi es :

33 -day Oral Tox icity-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

### Dev e lopm e ntal/Reproduction Toxicity Studi es

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 gestat ional days (GDs) 6-15. Co ntrol rat were adm ini stered de io nized water at a vo lume of 10 ml / kg/day

. Th ese doses, wh ich were selected based on the res ult s of a do se range-finding study , are eq ui va lent to 0; 1

### ,I 26; 5 , 630 and 11 , 260 mg/kg/day , respectively. The dosing period covers the period of organogenesis , but is sl ig htl y less than what is recommended in the US EPA te s tin g guide lin e s . Dam s were observed da il y for mortality , any clinica l signs of toxicity and weighed on GD 0 , 6 , 9 , 12 , 15 , 18 and 21. Food a nd water consumption were measured over three-day int ervals from GD 0 to GO 2 1. On GO 2 1 , the dams we re sac rificed by carbon dioxide asp hyxia tion and examined macroscopica ll y for any gross lesions. T he liver , kidneys and ut erus were we ig hed and the lddneys fixed for subsequen t hi stopatholog ic exam in ation. The numbers of corpora 1utea, im p lantatio n s , resorptions , live and dead fetuses were counted. Ute ri from fema le s th at presented as non-gravid were stained with I 0% ammonium su lfid e to detect th e presence of early resorptions. All live fetuses were sexed , weighed a nd exami n ed for external a nd visceral anomali es. One half of the f etu ses we re decap itated and their heads fixed for exa mination u si ng the W il so n' s sect ioning. A ll fetuses were then ev i scerated , fixed and proc essed for exam in ation of skeletal anoma lies. One female at 5 ml/k g/ day died on GD II ; the cause of her death could not be determined. N o other deaths or abortions were noted

. One dam in the control g roup deliv ered early on GO 20; data from this an i mal were not includ ed in the ca lculation of pregnancy ou tcome data. C li nical s igns of toxic ity , in c luding urine stains , audib l e r esp ir at ions , periocul ar e ncrustation

. and perioral we tn ess, wer e noted in a few dams at I 0 ml/kg/day. During the dos i ng p eriod , food consumption was statistically reduce d at 10 m l /k g/ day; this finding was associated with a statistically s ignificant reductio n in body weight ga in s durin g the same period. Water consumption was also stati st i ca ll y increa sed at 5 and 10 mllkg/ day during th e dosing period. At the end of th e stu d y, corrected term in a l bod y weights we re red uced and relat ive kidney we ig ht s were increased at the hi g h dose of I 0 ml/k g/day; this latter finding, however , was not associated with any histopathologic alterations. Gravid uterine weights and relative li ve r we ig ht s were unaffected b y treatment. Th e numbers of corpo r a lutea , implantations , and resorptions were similar ac ro ss treatment g ro ups. L ive/dead fetu ses per litter and sex r a ti os were a lso unaffected by treatment. Fe tal body weight s , howev er, were stat ist ica ll y lower in th e I 0 ml/k g/day dose group. Malformations rate s were s imil ar across treatment groups. However. the incid e nces of rudimentary rib # 13 and bon e island (rat her than rib ) on thoracic arch # 13 was reported to b e slightly increased at 1 0 ml/kg/ day. Th ese findings likely represent vary in g degrees of th e same alteration , and although clas sified in th e study report as malformati o n s , wou ld be more appropriate ly ca lled s keletal variations u s in g current c lassificat ion standards. Reduced bon e ossificat ion was a l so noted at l 0 ml/k g/da y. The skeletal findings corr elate with the reduced feta l weights obse r ved at this dose and lik ely represent indi cat ions of developmental delay.

6Based on the above data, the study in vestigators reported the following no observed adverse effect levels (NOAELs). The developmental NOAEL was observed in th e 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 in creased water consumption. The maternal NOAEL was 1 mllkg/day (I, 126 m g/kg/day). Th e developmental LOAEL was 5 ml/kg/day (5 , 630 m glkg/day). The developmental NOAEL was I ml/kg/day (1,126 mg/kg/day) (Neeper -Bradle y. 1991). 

### Mo use: Undiluted triethylene g l yco l (CAS Re g . 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. Co ntrol mice were admin istered deioni ze d water at a volume of I 0 ml/kg/ day. The dosing volumes administered were based on each anima l 's most recent body weight measurement. These doses, wh ich were se lected based on the resu lt s of a dose ran ge-find in g s tud y , 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 recommend ed in the US EPA testing guide lines. Dams were observed daily for mortality. any clinical signs of toxicity and we igh ed on GD 0 , 6, 9 , I2 , 1 5 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 exa mined macroscopically for any gross lesions. The liver , kidneys and uterus were weig hed and the kidneys fixed for subsequent histopathologic examination. The numbers of co rpora lutea , implantation s , resorption s, liv e and dead fetuses were counted. Uteri from females that presented as non-gravid were stained with 10% ammonium s ulfid e 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 section in g. A ll fetuses were then evisce rated , fixed and processed for exami n at ion of skeletal anomalies.

No maternal death s or abortions were observed. One dam in the 10 ml / kg/ day (11,260 m g/kg/ day) d e livered ea rl y on GD 18 ; data from thi s animal were not includ ed in the calculation of pregnancy outcome data. Hypoactivity was observed in two dams at I 0 ml / kg/day ( Il , 260 m g/ 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 sligh tl y increased during the closing period at 5 and I 0 ml/k g/ day (5 , 630 and 11 , 260 mglkg/day). Maternal body weight gain was also slightly , albeit not s tatistically, reduced during the dosing peri od at these doses. The large amo unt of variability in these data; however, s hould be noted. G ravid uterine weights , corrected terminal body weights , and relative liver weights were unaffected by triethylene glycol treatment. Althou gh r e lat ive kidney weights were stat i s tically 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 , implant at ions. and resorptions were s imilar across treatment groups. Live/dead fetuses per litter and sex rations were also unaff ected by treatment. Fetal body weig ht s , however, were statist ically lower in the 5 and I 0 mllk g/ day (5 , 630 and 11 , 260 m g/kg/day) dose g roup s by 6 and 9%, respectively. Malformation rates were sim ilar across 7treatment groups. A lth ough skeletal malformations were slightly higher at I 0 ml /kg/day, some of the reported findings (e.g. , missing lumb ar arch es or centrum) are more likely indications of reduced bone ossification , which was repo rted a t both 5 and 10 ml/kg/ day (5 , 630 and 11 ,260 m g/kg/day); this findin g correlates with the redu ced fetal weights and indicat es possible developmental delay. The maternal LO AE L was not established. The maternal NOAEL was I 0 ml/ kg/day (I I , 260 mg/kg/day, the highest dose tested). The developmental L O AEL was 5 ml/k g/ day (5,630 mg/kg/day) based o n reduced fetal weights and reduced bone ossification. The developmental NOAEL was 0.5 mVk g/ day ( 563 mglkg/day) (Neeper-Brad l ey, 1 990). 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 f e male CD-I mice (n = 2 0/ sex/ g roup ) beginnin g 7 days prior to mating a nd throu g hout the 14-week continuous bre ed in g period a nd a 21-day segregat ion period following cohabitation. T he drinking water concentrations adm ini ste red in this study were based on results of a dose ran ge-finding study

. The final concentrat ions admin istered equate to daily doses of 0 , 590 ; 3 , 300 and 6 , 780 mg/kg/day. re s pectively. Parental (P) mice were observed for mort al ity , clinical signs of toxicity and weighed at the beginning of study weeks I , 2 , 3, 5 , 9 , 1 3 and 18. Food and water co n sumption were monitored once per month. All FI pups delivered during the cohabitation period were counted , sexed , weighed and examined for exte rn a l abno rmalities on p ostn a ta l day (PND) 0 ; dead o r cannibali zed pups were also noted

. Res ulting offspring were also weighed on PND 4 , 7 , 14 and 2 1 a nd the percent s urvi val calculated. Dams were weighed after eac h litter was delivered and th e number of da ys to litter was calculated for each breeding pair. Because no effect on r ep roductive performance was observed during this portion of the study , offsprin g from th e control and high dose groups we re randomly selec ted afte r weani ng to assess ferti li ty a nd reproductive performance ofF I offsp rin g ( n =20 / se x/g roup , 2/ sex/ litter from 10 litters of each d ose group). At approximately 74 days of age , these animal s were cohabitated with non-sibling for 7 days, then separated for delivery of any resulting offsprin g . Data rega rdin g mating and fertility were then tabulated as in th e previous portion of the s tudy. Additionally , se lect Fl adult male and female organ weights were collected and spe rm analyses conducted. Triethylene glycol in th e drinking water at co ncentrat ion s 

### :S 3% was reported to ha ve no effect on physical appearance , body weight gain , or water consumption of P animals. Two females in the contro l group , one male and o n e female in the mid-dose gro up , and two females in the high dose group died durin g the course of the s tud y ; none of these deat h s were considered to be treatment related. Triethylene glycol at drinking water concentration s 

### :S 3 % did not affect fertility, the numb e r of litters produced by each breeding pair, the mean numb e r of li ve pups per lit

te r , the proportion of pups born live or the sex r atio of the pups. Howev er , drinking water co nce ntrations of 1.5 an d 3% were associated with r e duc e d live pup weights (4%)

. These findings are si milar to those reported in the m ouse developmental tox ici t y study for feta l weights

. Fertility and reproduction we re also assessed in animals in the con trol and high dose group s of the F1 generation. Again , triethylene glyco l treatment was not associated w ith effects o n fertility , the m ean number of li ve pups per litter , th e proportion of pups born live , or the sex ratio

8of the pup s. Unlike the 

### F1 pup s, howeve r, tri ethylene glycol had no effect on li ve F2 pup weights. T r eatment al so h a d no ef fect on th e a b so lute weights o f rep roducti ve o rga n s in adult F I m ales and fe mal es or on F 1 spe rm parameters: li ve r weights. however, were s tat ist icall y increased for males o nl y. B ased o n the findings , th e parental and rep rod uction LOAELs were not es tabl is hed. The parental and re production N OAELs were 3% (6 , 780 mg/kg/ da y) , the highe s t dose tes ted. Th e offsprin g LOAE L was 1 .5% (3 , 300 m g/k g / d ay) base d on r ed uce d F l pup weigh t s. The offspring NOAEL was 0.3% (590 mg/kg/day) ( Re e l and Lamb IV. 1984 )

. Chronic / Carcinogenicity Carcinogenicity stud ies were not availabl e . However, b ase d on the lack of sys temic toxicity and the lack o f mutagenicity t e tra ethyl e ne g l yco l is not expected to be carcinogen ic. Mutagenicity


### In V itro : An Ames test was conducted inS. 

### typhimurium TA 98 , TA 100 , TA 1 535 m , TA 1537 and TA 1 538 a t 112.6 mg/p la t e of tetraethylene g lyco l (CAS No. 11 2-60-7) with and without metabolic activation. There was n o increased in cidenc e of revertant colo ni es. A mammalian gene mutation assay was co ndu c ted in C hin ese Ham ste r Ovary ce ll s with 24- 50 mg/ml of t etraethylen e g lyco l (CAS No. 11 2-6 0-7) with and without me tabo lic ac ti vati on. A n incr eased in ci de nce of chromosomal aberrat io n s was not observed. A sis t er chromosome exchange assay was conducted in C hin ese Ham ster Ovary cells w ith 24 -50 m g/ ml of tetraethylene g lyco l (CAS No. 11 2

- 60-7) w ith and w ith ou t metabolic act ivat ion. The results were equivocal. 

### In Vivo: In an 

### in vivo dominant lethal test in the rat , tetraethylene glycol (CAS No. 112-60-7) was admin is te r ed at 0 , 5000 , 25000, o r 50000 ppm in drinkin g water. No significant dominant-lethal effects were observed

. A chromosomal aberrat io n s assay was co nducte d in Sp r ag ue- Dawle y rats. Rats we re o ra ll y administered 0

. 1250. 2500 o r 5000 mg/kg of t e tr aeth y lene glycol ( CAS No. I 12

- 60

- 7). Tetraethylene glycol was not clastogenic in th i s assay. A mic r o nucleu s assay was co nducted in mi ce (strain no t reported). A si ng le d ose of2500. 4000 or 50 00 mg/ kg was admin istered intrap e ritoneall y. Blo o d sampl es were take n at 30, 48 and 72 hour s post-dosi ng and m ic ronucleate d p o lyc hromatic erythr ocytes (MN- PCE) we re co unt ed. Incr eased incidence of MN- PCE was observed at the low and high doses only.

9

### Meta boli s m-Rat Metabolism stud ies are not avai lable on tetraethyl e ne glycol. However , based on metaboli sm data on ethylene glycol , diethylene glycol and tri e th y lene g lycol, it is postu lated that the metabolic pathway for te tra ethylene glycol is sim i lar to triethylene g l yco l in that it undergoes ox idation via alcohol dehydrogenases and aldehyde dehydrogenases to generate dicarboxylic ac id metabolites.



### Ta bl e 3. T o x icolo gy Pr o fil e for Tetrac th y l c o c G l yc o l
S tu dy T y p e Do s es R es u l ts
33 Day Oral Toxicity 0. 220, 660 and 2000 NOAEL 

### = 2000 mg/k g/ day. Study-Wistar rat mglkg/ day LOAEL was not established. D

eve lopmental Toxicity - 0, I , 5 and I0 ml/kg/day (0. Mate rnal NOAEL 

### = I rn llk g/

day ( 1126 mglk g/day). Sprague-Dawley rat

- I 1 26, 5630. and I 1 260 gavage mg/ k

g/

day) Mat e rn al LOAEL 

### = 5 ml /kg/day (5630 mg/k g/ day) based on reduced maternal food consumption, body weights and body weight gai ns and increa sed water consumption. Developmental NOAEL = 5 ml/k g/

day (5630 mg/kg/day). Deve lopmental LOAEL = I0 ml /k g/day ( 11 260 m gf

kg/ da y) based on skeletal anomalies. reduced fetal weights and bone ossification. Developmental Toxicity- 0. 0.5, 5 and I0 mllk g/ da y Maternal NOAEL 

### = 10 ml/kg/day ( 11260 mglkgf day ). CD- I mouse -gavage (0.563,5630.a nd 11260 Maternal LOAEL was not established. mglk g/ day) Developmental NOAEL 

### = 0.5 ml/ k g/

day (563 mg/kg/day). Deve l opmental LOAEL 

### = 5 mllk g! day (5630 mg/kg/day) ba se d on r ed uced fetal weights and bone ossification. 14-week Continuo us 0. 0.3. 1.5 , 3.0% Maternal NOAEL = 3.0% (67 80 rn glkg/ day). Breeding and 21 days Separation Toxicity Study- (0

. 590. 3300. and 6780 Maternal LOA EL was not established. CD -I mou se -Drin king mg/k g/ day) wa ter Reproduction NOAEL = 3.0% (6780 mg/k g/

day). R

ep r oduct ion LOAEL was not estab li shed. Offsprin g NOAEL = 0.3 % (590 m g/

k

g/

day). Offspring LOAEL 

### = 1.5 % (3300 m g/kg/day) based on reduc ed F I pup body weights.

10

### S tud y Type 

### Doses Res ults
Ames Test 11 2.6 mg/plate Negative

Chromosomal Aberrations- 24-50 mg/ ml o increase in chromosomal aberration s . C HO cell s

Sister Chromoso m e 24-50 mg/ ml Equivoca l Exchange-C H O ce ll s

Dominant Lethal Test-rat 0.5000.25000.or50000 Negative ppm ( equivalent to 500. 2500 or 5000 mglkg) Micronucleus Assay- 2500 , 4000 or 5000 mglkg Incre a s ed incidence of MN-PC E wa s observed at the low Mou se and high doses only.

5 . Tox i c i ty E nd p o i nt Se l ec ti o n The avail able toxicity stud ies i ndicate that t etraethylene glycol has low toxicity. o effects were observed up to 2 , 000 mglkg/day following subchronic exposure. In the developmental and reproductio n toxicity studies , effects were obse r ved only at very hig h doses( :::_ 3,300 mglkg/ day)

. Further. th e o nl y effect o b se r ved at 3,300 m g/kg/ d ay was a m i nor decre m e n t in bodywe i g h t. A lthoug h , doses b etwee n 590

- 3300 m g/kg/d ay were no t tes ted in th e deve lopmental and reprod uct io n s tudi es i n mi ce , th e Agency is reaso n ab ly cer tain that n o h arm w ill occur to the general popu lat io n or infants and ch il d r en following the usc oftetraethylene glycol at any dose be low the limit dose given the lack of effects bei n g found and the fact that the only effect seen was a minor bodyweight decrease seen at 3 , 300 mglkg/ day. Since

. no other effects we re observed , the Agency con cluded that the re are no endpoints of concern for tetraethy lene glyco l and a qualitative risk assessment is appropriate.

6 . S p ecia l Consi d e r a ti o n s fo r Inf a nts a nd C bildre n As part of its qualitative assessment , the Agency d id not use safety facto rs for assessi n g risk , and no add itiona l safety factor is needed for assessing risk to infants and child ren. B ased on the lack of tox i city of tetraeth y lene glyco l i n the available studies , E P A has concluded that there are no toxicological endpoints of concern for the U.S. population , including infants and children.

1 17 . Expo s ure Ass e ss ment I n evaluating dietary exposure to the tetraethylene glycol, EPA considered exposu r e under the peti ti o ned fo r exempt io n s f rom the req ui re ment of a tole rance . EPA assessed d i etary exposures from tetraethy lene g lyco l in food as fo ll ows: Di e tary Expo s ure Dietary exposure can occur from eating food s containing residues of te traeth y lene glycol. Because no hazard endpoint of concern was identified for the acute and chronic dietary assessment (food and drinki ng water), a quantitative dietary exposure risk assessment was not conducted. 8 . Residential Expo s ure (non-dietary expo s ure ) The term " residential exposure" is used i n thi s document to refer to non-occupational , nondietary exposure (e.g

.. tex tiles ( clothing and diapers), carpets , swimming pools , and hard surface disinfect ion on walls , floors , tables). Tetrae thy lene g lyco l is used as an inert ingredient in p es ticide products that could result in short- and intermediate-term residential exposure . However, based on the lack of tox i c ity , a quant i tat ive exposure assessment from residential exposures was not perfo rmed

. 9 . A g gregate Ri s k Based on the lack of any endpoints of concern, E PA concludes that there i s a reasonable certainty t h at no harm will result to the general p op ulation or to infants and children from aggregate exposure tetraethylene glycol residue s .
10. Occupational Expo s ure / Ri s k Pathwa y Occ upational exposu re was qualitatively assessed s ince an e ndpo int of conce rn was not identified

. Occupational exposure is not of concern.
11 . C umulative E xpo s ure : Sec tion 408(b)(2)( D )(v) of FFDCA requires that , when considering whether to establish , modify , or revoke a t ole r ance , the E P A co n side r "availab le i nfonnat ion" conce rn i ng t h e c um ul ative effects of a part icu la r pestici d e's res id ues an d "o th e r s ubs ta nces that h ave a co m mo n mechan is m of tox icity." Un li ke othe r pest ic ides for w hi ch E P A has followed a cumu lative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of tox icity finding as tetraethylene g lyco l and any other substances and , th i s material does not appear to produce a toxic metabolite produced by other substances. For the purposes of this to lerance action, therefore , EPA has not ass umed that tetraethy lene g lyco l ha ve a common mechanism of toxicity with other substances. For information regarding E PA 's efforts to determine which chemica ls have a common mechanism of toxicity and to eva luate the 1 2cumulative effects of such chemicals, see the policy statements released by E PA's Office of Pesticide Pro grams concerning common mechanism detenninations and procedures for cumulati ng effects from substances found to have a co mmon mechanism on EPA's website at http: // www . epa.gov/pesticides/ cumulative /

. 12. Eco toxicity and E nvironmenta l Fate The following summaries were reproduced from the petitioner" s submission. SIAM 18 2004 ha s stated th e following regarding the ecotoxicity of linear alkyl glycols with 1-5 oxyethylene groups: "Toxicity to 

### Daphnia (measured as LCSO in mg/ L) is g reater than 20,000 for all category members except tetraEG (tetraethylene g lyco l ; LCSO = 7800in mg/L) indi cating low toxicity , but the toxicity was not as uniform in fish. Toxicity evaluations in another invertebrate , brine shrimp 

### (Artemia salina) we re 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 glyco l], 10 g/ 1 for D EG [diethylene glycol] , TEG [triethylene glycol] , and t e traEG. 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 catego r y m embers, it can reasonably be assumed that tetraEG likewi se poses no apprec iable h aza rd to a l gae. The QSAR predictions indi cate that the category members s hould exhibit lo w toxicity , with trends of decreasing toxicity w ith increasing chai n length and are s upp orti ve of the available experimental data." On the basis of comparable physicochemica l EPISuite 4.11, it was concluded that triethylene glycol and tetraethylene g lycol would have comparable biological and environmental physicochemical properties. Results were as follows: • Low Kow , wou ld not bioaccumulate in mammalian lipophilic tissues or aquatic organ isms (s uch as fish) • Hi g h water sol ubility • Not vo l at il e • Read il y decompose in the atmosphere • Would not bind to soil • Prim ary Fugac ity: Comparable preference for soil (76%) and water (24%) compartment s; 

### \.4 life primary degradation: soil = 4

- 5 days and water= l day • U ltim ate Fugac it y: Comparab l e preference for soil (31 %) and water (69%) compartments ; 

### \.4 life ultimate degradation (mineralizati on): soil = 30 days and water = 1- 2 days 13 . Environmenta l Ju s tice Potential areas of environmental justice concerns , to the extent po ss ible. were considered in this human health risk assessment , in accordance with U.S. Executive Order 12898 , "Federal Actions to Address Environmental Justice in Minorit y Populations and Low-Income Populations ," http: //www.eh.doe.gov/ oepa/guidance / justice /eo I 2898.pdt).
13As a part of every pesticide risk assessment , OPP consi ders a l a r ge var i e ty of consumer s ub g roup s accord in g to we ll-e s tablished procedures. In line w ith OPP po li cy, H E D estimates ri sks to population s ub g roup s from pesticide exposu r es that are based on p atte rn s of that s ub gro up 's food and water co n su mption , and activities in and around th e h o m e that invol ve pesticide use in a residential settin g. Ex tensive data o n food consLm1ption patte rn s are compiled by the US D A under the Con tinuin g Survey of F ood In take by Indi v idu a ls (CS FII ) and are u sed in pesticide risk assessme nt s for a ll registered food u ses of a pesticide. Th ese data are analyzed and categorized by subgroups based on age , season of the year, ethnic group , and region of the country. Add iti o n a ll y, O PP is able to assess dietary exposu re to smaller , spec iali zed subg r oups and exposure assessments are performed w hen co nditi o n s o r circumstance s warrant. Whe never appropriate , non-di etary ex po s ures ba se d on hom e u se of pesticid e products and associated ri sks for adu lt applicato rs a nd fo r toddlers, youths , a nd adults entering or pla y in g o n tr ea ted areas postapp li cation are eva lu at e d. Further considerations are currently in d eve lop m e nt as OPP has com mitted resources and ex p e rti se to the development of speciali zed softwa r e an d models that conside r exposure t o bystande rs and farm workers as well as li festyle and traditional dietary patterns among spec i fic s ubgroups.



### 14. Ri s k C harac te riza t io n
Acute, subchronic a nd mut age nicity s tudi es we re avai lable on t e tr aet hyle ne g l yco l. Tetraethylene glycol i s a member of the ethy l e ne glyco ls ca tegory of c h emica l s. All members of this group po ssess two te rmin al hydroxy groups and diffe r from each othe r only in the number of oxyethyle ne units. B ecause of this it is appropriate t o class ify EG and the higher glyco ls ( up to and including n=S) a s a single group. E thylene g lycol and the higher glycols ( di- , tri

- , tetra

- , and pentaethy l ene glyco l) are c lose ly related in structure and have physicoch e mical properties which differ in a r eg ul ar an d expected way as a r es ult of in creas in g mol ecular we ig ht and consistent fu nctionality of a r e lati ve ly less s table h yd roxy m o iety on eac h e nd of the mo lec ul e. Therefore , th e h az ard profil e and d ose res pons e are also ex p ec t e d to change consistently , with d ec reas in g potential for adverse effec t w ith increasin g mo lec ul ar weight. Based on thi s, toxicity data on triethylene glycol was used as surrogate data to bridge developmental , reproduction toxicity and metabolism data for tetraethylene g l ycol. The acute oral , dermal and inhalation toxicity of tetraethylene g lyco l is low in rats and rabbits. Tetraethylene g l yco l is mildly irritating to the eyes and to the sk in in rabb i ts. It is not a dermal se nsi ti zer. Tetraethylene g lyco l did not cause tox icity at doses up to 2000 m g/kg/d ay in a s ubchroni c s tud y in rats. It i s not a deve lo pmental or r ep rod uc ti on tox icant. It is not expected to be carc in ogenic based on it s lack of syste mic toxicity a nd mu tage ni city. Ne ither is it neurotoxic nor immunotoxic. Metabo li sm studies are not a vai lable on tctracth y lene g l ycol. However , it is postu lated that the metabolic pathway for tetraethy lene g lyco l is s im ilar to th at oftriethylene glycol in that it

14undergoes oxidation v ia alco hol dehydrogenases and a ld ehyde d ehydrogenases to generate dicarboxylic acid metabolites

. S ince there is no in d ication of toxicity at the limit do se a toxicolo g ic a l e ndpoint of concern fo r ri s k assessment purposes was not identifi e d. Th e r efo re, a quantitativ e ri sk assess ment for tetraethy le n e glyco l is not necessary. Tetraethylene glyco l is used as a n inert in g redient in pesticide products that could result in residential exposure. However, based o n the la c k of tox ic it y , a quant i tative exposure assessment from ··r es id e nti al exposures"' was not performed. Occupat io nal expos ure is not of concern s in ce a n e ndpoint was not id e nti ti ed. Tetraeth y lene g lyco l i s not toxic to aquatic organi s m s. Based on EP I S uit e m o deling , tetraethyle ne g l yco l is not expec t ed to persist o r bioaccumulate. Potential areas of environmental justice concerns , to the exte nt possible. were co n side red in thi s human health risk assessment , in acco rdan ce with U.S. Executive Order 12898 , "Federal Actions to Address En viro nm enta l Justice in Minority Popu lations and Low

- Income Pop ulati o n s," http: // www.eh.doe.gov/oepa/gu idance/justice /eo 12898. pdf. Taki n g into cons id e ration a ll available inform a ti o n on tetraethylene g lyco l (CAS Reg

. No

. I 12

- 6 0-7) , EPA concludes that there is a r easonab le certainty that no harm wi 11 r es ult to the gene ral popul ation o r to infants and chi ldre n from agg regate exposure to t e tr aet hyle ne glycol. Therefore , the establ i shment of a n exemption from tolerance under 40 CF R 1 80.920 for residues of tetraethylene g lyco l when used as an in ert ingredient limited to 35 % in the end-product pest icide fo rmu lations in pre-harvest food co mm odities under 40 CF R 180.920 l i mited can be considered safe under sec ti on 408 of the FF D CA.

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## REFERENC ES
EPISuiteTM 4.11 (http: //www.epa . gov/ opptintr /e xposure/ pubs/ep isuitedl.h tm ). Ha zardo us Substances Data Bank (HSDB ) Datab ase. U .S

. National L ibrary of Medicine (N LM ). Tetraethylene G l ycol CASRN 11 2-60-7 . http: //t oxnet.nlm .nih gov . International U ni fo rm Chemical Inf ormation D atabase (IUCLI D ) Dataset. 2000

. Substance ID: 112-60-7 (3, 6, 9 -tri oxaundecane- 1 , 11-diol). E uropean Com mi ssion E uropean Chem ical s B ureau. Neeper-Brad l ey, T. 

### L. ( 1990). Developme ntal To x icity Study ofTriethylene G lyco l Administered b y Gavage to C D-1 ® Mice. Union Carbid e C he mical s and Pl ast ic s Company in c. Danbury, CT 068 17

. Project Report 5 3 -6 5 ( unpu b li s he d). MRTD 49450003. Nee per-Bradley , 

### T. L. ( 1991). D eve lop me nt a l Toxic it y S tud y ofTrie th y len e Glycol Administe red by Gavage to CD-1 ® (Sp rague- Dawle y)

. U ni o n Carbide Chem icals and Plastics Company Inc. D a nbu ry, CT 068 17. Proj ect Report 53-65 ( unpubli shed). MRID 49450003

. OECD SIDS. S ID S Initi a l Assess ment Profil e-E th y le n e g l yco l, Di ethy le ne G lyco l, Trieth y len e G lyco l, Tetraethyl e ne g lyco l , Pentae thylen e Gl yco l (Ethy l ene Glycol s Catego r y). SIAM 18. 20- 23 Ap ril 2004. Reel , J., L awton
. A. and Lamb l V, J. 1984. Tr iethylene G lyco l : Reproduction and Fertility Assessment in CD-I M ice W hen Administered in the Dri nk in g Water. National Toxicology Program. Cos metic s Ingredients Review (C IR) Expert Pane l. 2006. Final R eport on th e safety assessment oftri et h y lene g lyco l and PEG-4 , International J ou rn a l o f Toxicology 25: 12 1- 1 38. Sc hl adt. 

### L., Ivens. 

### l.. Karbe, E., Ruhl-Fehl er t , C. , Bombard , E., 1998 . S ub ac ut e o ral toxicity of te traeth y lene g l yco l a nd ethy lene glyco l a dmini ste r ed to Wistar rat s. Exp. Tox. P atho l , 50:257

- 265.

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