Page 2 of 20 of a tolerance under 40 CFR § 180.920. A search of the internet revealed a DRAFT Interim REL (Reference Exposure Level) dated March 2010 (California Office of Environmental Health Hazard Assessment). No additional “new” information has been identified.

Non-pesticidal uses of 2-met hyl-2,4-pentandediol include use as a chemical intermediate, a selective solvent in petroleum refining, a componen t of hydraulic fluids, a solvent for inks, as an additive to cement, use in cosmetics and hair car e products, textile dye vehi cles, as a lubricant and fuel additive. The Food and Drug Administratio n (FDA) has approved of the use of hexylene glycol as an indirect food additive such as in adhe sives in contact with food ( www.cosmeticsinfo.org ).

Hexylene glycol is not acutely toxi c to rats via the oral route of exposure. An OECD-SIDS (2001) report indicates LD 50 ranges from 2 – 4.47 g/kg. A TSCA §8(e) submission indicates the oral

LD 50 in rats ranges from > 500 mg/kg to < 5000 mg/ kg. No deaths were reported at 500 mg/kg.

Acute dermal toxicity is low with dermal doses up to 2000 mg/kg that did not cause death (Gardner, 1996 cited in OECD).

Acute inhalation studies i ndicate hexylene glycol has low acute inhalation toxicity. Rats exposed to 0.31 mg/L hexylene glycol vapor for 1 hour survived and no LC 50 was determined (Biofax, 1970, cited in BIBRA).

Rabbits treated with 0.1mL undiluted hexylene glycol experienced conjunctival redness and slight corneal opacity (Gardner, 1996b, cited in OECD-SIDS). A TSCA §8(e) (1992) submission reported severe eye irritation when 0.1mL of hexylene glycol was administered to the conjunctival

sacs of rabbits.

Rabbits treated with 0.5mL of undiluted hexylene gl ycol showed slight, but reversible erythema

after 72 hours in a 4-hour semi-occlusive dermal irritation study (Parcel, 1995, cited in OECDSIDS).

A 1992 TSCA § 8(e) submission, a 24 hour covered application of 0.5 mL hexylene glycol to rabbit skin, produced slight to moderate erythema and severe erythema at 24 hours. At 72 hours, both the erythema and edema were sl ight to moderate in intensity.

Garner (1966d cited in OECD-SIDS) noted no positive sensitization responses in a guinea pig assay using undiluted hexylene glycol.

Ward (2005) reported a 90-day s ubchronic toxicity study with he xylene glycol administered by gavage to rats. Doses ranged from 50 – 450 mg /kg bw/day. A functiona l observational battery test gave no indication of neur otoxicity. The NOAEL in this st udy was 450 mg/kg/day, the highest

dose tested.

Hexylene glycol at ≥ 99 % was non-mutagenic in an Ames test with S. typhiumurium as well as E.

coli (Meyer et al, 1985 and Brooks et al., 1988 – cited in OECD-SIDS).Page 3 of 20 There was no reported evidence of cytotoxicity or clastogenicity when hexylene glycol was administered to a hamster ovary cell assay at 5000μg/mL.

Hexylene glycol has low potential for reprodu ctive or developmental toxicity (Ward, 2005; Fabreguettes, 199a; Clode, 1997 – cited in OECD-SID S). In a developmental toxicity study in rats, no fetal toxicity was observed at doses up to 300 mg/kg/day.

No carcinogenicity studies have been identified for hexylene glycol.

Based upon the available toxicological information th e Agency believes there is no concern, at this time, for increased sensitivity to infants and child ren to hexylene glycol when used as an inert ingredient in pesticide formulations. Thus, an additional safety factor to protect infants and

children is not needed.

No residue data were provided for hexylene glyc ol. In the absence of data, the Agency has developed an approach that uses surrogate in formation to derive upper bound exposure estimates for the subject inert ingredient. There was no hazar d attributable to a sing le exposure seen in the toxicity database for hexylene glycol. Theref ore, an acute dietary risk assessment was not

conducted.

A chronic dietary risk assessment was c onducted using the Dietary Exposure Evaluation Model software with the Food Commodity Inta ke Database (DEEM-FCI DTM, Version 2.03. The chronic analysis assumed 100% crop treated, de fault processing factors and tolerance-level

residues for all foods and use limitations of not more than 50% by weight in pesticide formulations. Drinking water (100 ppb) was incorporated directly into the dietary assessment. The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD). For the U.S. popul ation, the exposure for food and water utilized 3.8% of the cPAD. The chronic dietary risk es timate for the highest e xposed population subgroup, children 1-2 years old is 12.5% of the cPAD. RD has not identified any concerns for carcinogenicity relating to hexylen e glycol, therefore, a cancer di etary exposure assessment was not performed. An occupational exposure assessment was conducte d. In a hypothetical, hi gh-acreage (i.e., high volume) situation (1200 acres trea ted per day), a mixer/loader w ould have a Margin of Exposure (MOE) of approximately 8,000 provided protective gl oves were worn with a single layer of work clothing (long pants, long-sleeved shirt, shoes pl us socks). The estimated MOEs for various methods of commercial, agricultural applications ranged from 16,000 to 78,000.

Post-application exposure was not ev aluated quantitativly. In view of a very short environmental

half life and the restricted entry intervals associated with most pesticide products, post-application exposure is considered negligible.

Hexylene glycol is infinitely soluble in water. It has a low potential to sorb to soils. It is readily biodegradable. It is slig htly volatile. If released to the at mosphere, the calculated half-life is 9 hours due to photo-oxidation. OEHH A cites the OECD (2001) as believing hexylene glycol is unlikely to persist in the environment.Page 4 of 20 Taking into consideration all available inform ation on hexylene glycol, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure when considering dietary exposure (i ncluding crops, meats, and fish ) and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, it is recommended that the one exemption from the requi rement of a tolerance established for residues of hexylene glycol when used as a solvent in pesticide formula tions applied to pre- and post harvest under 40 CFR 180.910 and direct applic ation to animals under 40 CFR 180.930 can be

considered reassessed as safe unde r section 408(q) of the FFDCA.

INTRODUCTION

Under provisions in Section 408(d) of the Fe deral Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), the FBSciences, Inc., 153 N. Ma in Street, Suite 100, Collierville, TN 38017 has requested approval by the Envir onmental Protection Agency (EPA or the Agency) for the exemption from the requirements of a tolerance fo r residues of 2-methyl-2 , 4-pentanediol (CAS No. 107-41-5) when used as an in ert ingredient in pest icide formulations. The request is filed under petition number PP0E7693 and docket numb er EPA-HQ-OPP-2010-0330. The request is to amend 40 CFR § 180.910 and § 180.930 to include 2- methyl-2,4-pentanediol (hereafter hexylene glycol), without restrictions, as an inert ingred ient as a solvent in pe sticide formulations.

The Agency has previously assessed the human hea lth and environmental risks of hexylene glycol (Memorandum, 8 November 2005, R. Ward, “Reassessment of the One Exemption from the Requirement of a Tolerance for 2-Methyl-2,4-pent anediol (Hexylene glycol)”. The Agency’s assessment was in regards to the use of hexylene glycol applied to growing crops prior to crop emergence from the soil – exemption from the requirements of a tolerance under 40 CFR § 180-

920. A search of the internet revealed a DRAF T Interim REL (Reference Exposure Level) dated March 2010 (California Office of Environmental Health Hazard Assessment). With that exception, no new or additional risk assessments ha ve been identified. In support of its request, FBSciences relies principally upon the Agency’s 2005 assessment.

Non-pesticidal uses of hexylene glycol include us e as a chemical intermediate, a selective solvent in petroleum refining, a component of hydraulic fluids, a solvent for inks, as an additive to cement, use in cosmetics and hair care products, textile dye vehicles, as a lubricant and fuel additive. The Food and Drug Administration (FDA) has approved of the use of hexylene glycol as an indirect

food additive such as in adhe sives in contact with food ( www.cosmeticsinfo.org ).

In 2005, the Agency concluded: “Taking into account all available information on hexylene glycol, it has been determined that there is re asonable certainty that no harm to any population subgroup will result from aggregate exposure to this chemical when considering dietary exposure, and all other non-occupational sources of pes ticide exposure for which there is reliable

information.”Page 5 of 20 PHYSICAL/CHEMICAL PROPERTIES The physical-chemical properties described below are abstracted from NIH (2004).

Structure Common Names 2-methyl -2,4-pentanediol; diolane; 1,1,3-trimethyltrimethylene-diol; 2,4-dihydroxy-2-methylpentane; 4-methyl-2,4-pentanediol

CAS No. 107-41-5

Formula C 6 H 14 O 2 Physical state colorless liquid with mild, sweetish odor Molecular weight 118.175 Water solubility 1.00 x 10 6 mg/L at 25 ◦ - very water soluble Melting point -50 ◦ C Henry’s Law Constant 4.06 x 10 -7 atm-m 3 /mole @ 25 ◦ C Vapor Pressure 0.013 mm Hg @ 25 ◦ C

Octanol/Water Partition Coefficient Log P = 0.580

HAZARD ASSESSMENT

The majority of the remaining discussion in this document is taken directly and primarily from the Agency’s 2005 assessment (cited earlier). Excepti ons are noted. The Agency’s assessment was derived largely from an OECD-SIDS submission (2001), a BIBRA report (1991), a review by Cavender and Sowinski in Patty’s Toxicology (2 001), and a TSCA submission (1995). As the original assessment is available for review, for purposes of the document herein, the discussion is

abstracted.Page 6 of 20 Acute Toxicity

Acute Oral Toxicity - Based on information in the OECD -SIDS report (2001), hexylene glycol has low acute oral toxicity. Acute oral toxicity studies w ith the rat indicate the oral LD 50 ranges from 2 g/kg to 4.47 g/kg (Gardner 1996a and BIBRA , 1991 as cited in OECD-SIDS). According to Gardner, there were no deaths at 2 g/kg and no macroscopic le sions noted at necropsy in the majority of rats in the study.

A TSCA §8(e) submission (1992) indicates the acute oral LD 50 in rats is > 500 mg/kg but < 5000 mg/kg. No deaths were reported at 500 mg/kg but rats did exhib it increased salivation, retching, dyspnea and a decrease in activity and limb tone. At 5000 mg/kg, all rats died in the first day after exhibiting the same symptoms as the lower dose in addition to marked ataxia, prostration and alterations in placing, pinna and corneal reflexes.

Acute Dermal Toxicity - In a study by Gardner (1996 cited in OECD) hexylene glycol did not cause death in rats up to 2000 mg/kg with no macr oscopic lesions at necropsy. In a 1992 study (TSCA §8(e), there were no deaths in rabbits treated with 200 – 2000 mg /kg. Slight to moderate edema and erythema were seen at both doses in the first 24 hours. Thr oughout the 14-day dosing period, both doses induced varying degrees of necrosis, blanching and pus between skin layers. At the end, slight to moderate desquamation, leathery skin texture and fissuring were noted in all test subjects.

Acute Inhalation Toxicity – Some older studies suggest the hexylene glycol has low inhalation toxicity. Rats exposed to 0.31 mg/L hexyl ene glycol vapor for 1 hour survived, no LC 50 was determined (Biofax, 1970 cited in BIBRA). There were no deaths in rats exposed to saturated hexylene glycol vapor at a con centration of approximately 160 ppm (0.772 mg/L) (Union Carbide, 1949, Shell Chemical, 1958, Smyth and Carpenter, 1948 cited in Patty’s Toxicology). No LC 50 was determined.

Eye Irritation – Conjunctival redness and slight corneal opa city occurred in rabbits treated with 0.1mL undiluted hexylene glycol (Gardner, 1996b cited in OECD-SIDS). Symptoms resolved within 3-8 days. The TSCA §8(e) submission (1 992) reported severe eye irritation when 0.1mL of hexylene glycol was administered to the conjunctiv al sacs of rabbits. All rabbits had complete corneal opacity after 72 hours as well as purul ent discharge and marked extreme iridal and conjunctival irritation.

Skin Irritation – Rabbits treated with 0.5 mL of undilute d hexylene glycol showed slight, but reversible erythema after 72 hours in a 4-hours semi-occlusive dermal ir ritation study (Parcel, 1995 cited in OECD-SIDS). There was no ir ritation observed following a 24 hour covered application of 2000 mg/kg undiluted hexylene glyc ol (Gardner, 1996b cited in OECD-SIDS).

In the 1992 TSCA §8(e) submission, a 24 hour covere d application of 0.5 mL hexylene glycol to rabbit skin, produced slight to moderate erythema and severe edema at 24 hours. At 72 hours, both the erythema and edema were slig ht to moderate in intensity.Page 7 of 20 Skin sensitization – Gardner (1966d cited in OECD-SIDS) noted no positive sensitization responses in a guinea pig assay using undilute d hexylene glycol with topical induction and challenge applications. A challenge was al so conducted using a 50 % aqueous solution.

The summary table is taken from Ward , 2005. Sim ilar findings with regards to acute toxicity are

found in databases of the United Stat es National Librar y of Medicine ( www.chem2.sis.nlm.nih.gov ).

Subacute/Subchronic Toxicity

As noted and cited by Ward (2005), in a 90-day subchronic toxicity study, hexylene glycol was administered by oral gavage to rats at dose levels of 50, 150, or 450 mg/kg bw/day (Fabreguettes, 1999b, as cited in OECD-SIDS). A functional obse rvational battery test gave no indication of Summary of Acute Toxicity Data for Hexylene Glycol

Parameter Toxicity Value Toxicity Category Comments Reference

Oral LD 50 , Rat >2 but <5 g/kg bw III No deaths at 2 g/kg and no macroscopic lesions at this dose at necropsy. No other information given. Gardner, 1996a; BIBRA, 1991; Industrial Biotest, 1970; and German MAK Commission, 1997, as cited in

OECD-SIDS

Oral LD 50 , Rat > 0.5 but <5.0 g/kg bw III There were no deaths at 0.5 mg/kg, but all rats died at 5 g/kg dose level. TSCA 8(e) CP, 1992

Dermal LD 50 , Rat > 2 g/kg bw III/IV No deaths at this dose and no macroscopic lesions as this dose at necropsy. Gardner, 1996b, as

cited in OECD-SIDS

Dermal LD 50 , Rabbit > 2 g/kg bw III/IV Slight to moderate edema and erythema starting at 200 mg/kg, but no deaths. TSCA 8(e) CP, 1992

Inhalation LC 50 , Rat (1 hour) > 64 ppm, or

> 0.31 mg/L II/III Rats exposed to this concen tration survived. Bio-fax, 1970, as

cited in BIBRA

Inhalation LC 50 , Rat (8 hours) > 160 ppm, or

> 0.772 mg/L III/IV Rats exposed to saturated vapor survived. Union Carbide, 1949; Shell Chemical Co., 1958; and Smyth, and Carpenter, 1948; as cited in Patty’s Toxicology

Eye Irritation,

Rabbit 0.1 mL II The undiluted material caused irritation of conjunctiva and cornea that healed within 8 days. Gardener, 1996b, as

cited in OECD-SIDS

Eye Irritation,

Rabbit 0.1 mL II The chemical produced severe eye irritation and complete corneal opacity after 72 hours. TSCA 8(e) CP, 1992

Dermal Irritation,

Rat (24 hours) 2000 mg/kg bw IV Covered applicat ion of undiluted chemical for 24 hours produced no irritation. Gardener, 1996b, as

cited in OECD-SIDS

Dermal Irritation,

Rabbit (4 hours) 0.5 mL III Semi-occlusive e xposure to pure chemical produced slight to moderate erythema that was reversible, and no edema. Parcel, 1995, as cited

in OECD-SIDS

Dermal Irritation,

Rabbit (24 hours) 0.5 mL III Covered applicati on of the chemical produced slight to moderate edema and erythema at 72

hours. TSCA 8(e) CP, 1992Page 8 of 20 neurotoxicity. In both sexes, hype rplasia, hyperkeratosis , inflammatory cell infiltration and edema

of the mucosa and submucosa of the stomach we re observed starting at 150 mg/kg/day. These changes were indicative of a local irritative eff ect resulting from the or al gavage procedure. Hepatocellular hypertrophy with increased liver weight was observed at 450 mg/kg/ day in both sexes, and in males at 150 mg/kg/day. In the ab sence of degenerative or necrotic changes these findings were considered to be adaptive res ponses. At 150 and 450 mg/ kg/day, increased kidney weights and increased incidence of acidophilic globules in the t ubular epithelium in males were suggestive of male rat specific alpha-2-microglobulin nephropathy, which is not considered as an effect relevant to humans. Observed changes were either fully or partia lly reversible over the 4- week recovery period. There were no adverse e ffects on the reproductive organs. No effects were observed at 50 mg/kg/day. A NO AEL of 450 mg/kg/day was determined for systemic toxicity because the effects described were either produced by irritation from the oral gavage procedure, or were considered adaptive respons es. A range-finding 14-day study (Fabreguettes, 1999a, as cited in OECD-SIDS) gave similar results.

Ten rats and a rabbit exposed to an aeroso l of hexylene glycol at a concentration of 0.7 mg/L (about 145 ppm) for 7 hr/day for 9 days surv ived with mild upper respiratory irritation. No histopathological effects were reported (Union Carbide, 1976, as cited in OECD-SIDS). No

controls were used and no other details were given in the report.

Genotoxicity

Mammalian and nonmammalian in vitro toxicity studies were repo rted by Meyer et al, 1985 and Brooks et al, 1988 (cited in OECD -SIDS). Hexylene glycol at ≥ 99 % was non-mutagenic in an Ames assay in Salmonella typhimurium strains as well as with Escherichia coli . At concentrations up to 4000 μg/plate in the presen ce or absence of metabolic activ ation, there was no evidence of cytotoxicity at any dose level. There was no incr ease in reverse mutation rate with any of the

bacterial strains.

Mitotic gene conversion in Saccharomyces cerevisiae JD1 was measured in a liquid suspension assay at concentrations up to 5.0 mg hexylene glyco l/mL in the presence or ab sence of rat liver S9 fractions. There was no significant effect on cell vi ability and no increase in the rate of mitotic gene conversion according to Meyer et al, 1985 a nd Brooks et al, 1988 (cited in OECD-SIDS).

In a hamster ovary cell assay, cultures were treated with hexylene glycol at concentrations up to 5000μg/mL in the presence or abse nce of metabolic activ ation. There was no reported evidence of cytotoxicity at any dose level and no increase in the number of chromosome aberrations ( ibid ).

Reproductive/Developmental Toxicity

According to Ward (2005), no guideline reproduc tion studies were available for assessment, however, no adverse effects on reproductive organs (including testes, prostate, seminal vesicles, epididymis, ovaries, vagina, and uterus) were obs erved in the 90-day gava ge study in which rats were administered hexylene glycol at doses up to 450 mg/kg/day (Fabreguettes, 1999a, as cited in OECD-SIDS). Therefore, OECD SIDS conclude d that no additional studies are required under the SIDS program regarding fertility.Page 9 of 20 In a range finding developmental toxicity st udy, pregnant rats we re administered 30, 300, or 1000 mg/kg bw/day of hexylene glycol by gavage in 5 mL/kg of vehicle on gestation days (GD) 6-15 (Clode, 1997, as cited in OECD-SIDS). The NOAEL for maternal toxicity was 300 mg/kg/day based on a statistically significant re duction in group mean body weight gain and food consumption at 1000 mg/kg/day. There was a marg inal, non-statistically significant reduction in fetal body weight at 1000 mg/kg/day. Marginally higher incidences of fetal variations, some of which were statistically significant (occipitals in completely ossified, 21. 6%; extra thoracolumbar ribs, 18.7%; and hyoid arch not ossified, 18%), occurred at 1000 mg/kg/day. A delay in the normal ossification process was also observed in fetu ses, but this was considered by the authors to be related to reduced maternal body weight gain at this dose level. The NOAEL and LOAEL for maternal and fetal developmen tal toxicity were determined to be 300 and 1000 mg/kg/day, respectively.

In another developmental toxicity study, pregnant rats received 500, 1200, or 1600 mg/kg bw/day of hexylene glycol by gavage in 10 mL /kg of vehicle on GD 6- 17 (TSCA §8(e), 1995). At 1200 and 1600 mg/kg/day, dams had ataxia and re ductions in mean weight gain and food consumption. At the 1600 mg/kg/da y, pregnant rats had mean weight loss, and one female aborted prior to the end of the study. Mate rnal toxicity at these levels co rresponds to decreased fetal body weights and gravid uterine wei ghts. Additionally, at 1600 mg/kg/ day, there was one abortion and one whole litter resorption. However, the numbe r of fetal malformations, such as increased

incidence of skeletal variations (delayed ossification, extra ribs ), was not significantly different from controls. A maternal NOAEL of 500 mg/k g/day was determined by the Agency, and the same NOAEL was determined in the study for fetal toxicity. These result s support the results of Clode’s (1997) study described a bove and indicate that hexylene glycol has low potential for developmental toxicity.

Carcinogenicity – No carcinogenicity studies have been identified for hexylene glycol. There is no evidence that hexylene glycol is carcinogeni c. The Agency used a qualitative structure activity relationship (SAR) databa se, DEREK Version 11, to determin e if there were structural

alerts. No structural alerts were identified. In addition, it is negativ e for mutagenicity in mammalian and non-mammalian mutagenicity assays. Hexylene glycol is ra pidly metabolized and excreted as glucuronates. Based on the above me ntioned weight-of-evidence and low toxicity, 2- methyl-2,4-pentanediol is not ex pected to be carcinogenic.

Metabolism: Larsen (1958 cite d in OECD-SIDS 2001) reported th at male rats receiving 200 mg/day excreted 40% of the admini stered dose in the urin e, of this about 4% was in the form of free glycol. Diechmann & Dierker, (1946 cited in OECD-SIDS 2001), reported a substantial increase in the levels of glucuronates in the pl asma and urine of rats and rabbits fed hexylene glycol. Gessner et al, (1960 cite d in OECD-SIDS 2001) also reporte d excretion of glucuronate in

the urine of rabbits administered about 118 mg/kg by stomach tube. 67% of the dose was recovered from the urine in conjugated form. Th ey were unable to characterize the conjugate. These studies clearly indicate th at orally administered hexylen e glycol is rapidly absorbed, metabolized in the body and rapidly ex creted as glucuronide conjugates.Page 10 of 20 TOXICITY ENDPOINT SELECTION:

No acute endpoint of concern was identified in the avai lable toxicity studie s. The endpoint of concern for the chronic reference dose (cRfD) wa s identified from the developmental toxicity study in rats (main study). In this study, th e NOAEL (500 mg/kg/day) was based on increased

incidence of clinical si gns, reductions in mean body weight ga in and food consumption seen at the LOAEL of 1200 mg/kg/day and above. Th is NOAEL was supported by the 90-day gavage toxicity study in rats. There was a lower NOAEL ( 300 mg/kg/day) observed in the range finding study in rats based on a statistically significant re duction in group mean body weight gain and food consumption, and marginally higher incidences of fetal variations seen at the LOAEL of 1000 mg/kg/day. The differences between the NOAELs of the range finding study and the main developmental toxicity study in rats were cons idered due to artifact s of dose selection. An uncertainty factor 100X (10X for intraspecies vari ability and 10X interspeci es extrapolation) was applied to the NOAEL. No additional uncertainty f actor is necessary for use of the subchronic to chronic study because the effects were observe d at the limit dose of 1000 mg/kg/day and above. The FQPA factor for increased susceptibility of in fant and children was reduced to 1X. Therefore, the cRfD is equal to population adjusted dose (cPAD). This endpoi nt and the dose was also used for dermal and inhalation exposure assessment for all exposure scenarios. Inhalation and dermal absorption was assumed to be 100%. This appro ach would provide a highl y conservative estimate

of risk via the dermal and i nhalation routes of exposures.

CONSIDERATION FOR INFANTS AND CHILDREN (FQPA SAFETY FACTOR)

Section 408(b)(2)(c) of FFDCA provides that EPA sh all apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the comp leteness of the database on to xicity and exposure unless EPA

determines based on reliable data that a different margin of safety will be safe for infants and children. This additional marg in of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliab le data available to EPA support th e choice of a different factor.

The toxicity database for hexylene glycol is adequate for FQPA assessment and the potential exposure is adequately characterized gi ven the low toxicity of the chemical.

The Agency has previously held that hexylen e glycol has low subc hronic toxicity, with developmental NOAELs ranging from 300 to 500 mg/ kg/day. In addition, maternal toxicity corresponded with fetal toxicity in developmental studies, sugges ting that offspring do not have greater sensitivity to hexylene glycol than a dults. There were no guide line reproduction studies available on hexylene glycol, however, no adverse e ffects on reproductive orga ns (including testes, prostate, seminal vesicles, epididymis, ovaries, va gina, and uterus) were observed at doses up to 450 mg/kg/day in a 90-day toxicity study in rats . In addition, the reproduc tive indices were not affected in the two available developmental toxicity studies in rats. No evidence of neurobehavioral or neuropathology was seen in a 90-day toxicity study in rats. Therefore, a developmental toxicity study in rats is not necessary. No evidence of immunotoxicity was observed in the available database, therefore, an immunotoxicity study is not required. The dietary food exposure assessment utilizes highly cons ervative default assumptions and would not underestimate the dietary risk to all populations. For the purpose of the screening level dietary riskPage 11 of 20 assessment to support this request for an exemption from the requirement of a tolerance for hexylene glycol, a value of 100 ppb based on screen ing level modeling was used for the chronic dietary risk assessment. The value of 100 ppb is considered to be a high end, conservative assumption that is not likely to underestimate drinking water risks. Based on the reasoning presented above. EPA has de termined that an additional safety factor is not needed to protect the safety of infants and children.

EXPOSURE ASSESSMENT

Dietary Exposure

In evaluating dietary exposure to hexylene glycol , EPA considered exposu re under the petitioned for exemptions from the requirement of a tolera nce. EPA assessed dietary exposure from hexylene glycol in food as follows:

Residues of Concern

Sufficient data were provided on the chemical id entity of hexylene glycol, however, limited data

are available on the metabolism and environmenta l degradation of this compound. The Agency relied collectively on information provided on the re presentative chemical structures, the submitted physicochemical EPI SuiteTMdata, structure activ ity relationship information, as well as chemicals of similar size and functionality to determine the residues of concern for these inert ingredients. The residues of concern for ri sk assessment purposes are for the parent compound only.

Quantification of Dietary Risk

Acute No endpoint of concern attributed to a single dose was identified in the database. Therefore, acute dietary exposure assess ment was not required.

Chronic

In conducting the chronic dietary exposure asse ssment, EPA used food consumption information from the United States Department of Ag riculture (USDA) [19 94–1996 and 1998] Nationwide Continuing Surveys of Food Intake by Individuals (CSFII). As to residue levels in food, no residue data were submitted for hexylene glycol. In the absence of specific residue data, EPA has developed an approach, which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient. Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of high-use insecticides, herbicides, and fungicides. A complete descripti on of the general approach taken to assess inert ingr edient risks in

the absence of residue data is contained in the memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chroni c Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA-HQ-OPP-2008-0738.Page 12 of 20 In the dietary exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest to lerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) be tween the active and inert ingredient and that the concentration of inert ingred ient in the scenarios lead ing to these highest of tolerances would be no higher than the concentration of th e active ingredient.

The Agency believes the assumptions used to esti mate dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate exposure. The concentration of active ingredient in agricultural products is generally at least 50 percent of the product and often can be much higher. Further, pesticide products rarely have a single inert ingred ient; rather there is ge nerally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pes ticide product in relati on to that of the ac tive ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the active ingredient with the highest tole rance level. This assumption

overstates residue values becau se it would be highly unlikely, given the high number of inert ingredients, that a single inert ingr edient or class of ingredients woul d be present at the level of the active ingredient in the highe st tolerance for every commodi ty. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient at the highest tolerance level. In other words, EPA assumed 10 0 percent of all foods ar e treated with the inert ingredient at the rate and manner necessary to pr oduce the highest residue legally possible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, then used this methodology to choos e the highest possible

residue that could be found on food and assumed that all food contained this residue. No consideration was given to pot ential degradation between harv est and consumption even though monitoring data shows that tolera nce level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce. For details, see the Attachment: “DEEM-F-CID Chronic Analysis for Hexylene Glycol” (i.e., 2-methyl -2,4-pentandediol).

Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of these conserva tive assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

Cancer

Since the Agency has not identified any concerns for carcinogenicity relating to hexylene glycol a cancer dietary exposure assessment was not conducted.Page 13 of 20 Drinking Water Residue Profile

For the purpose of the screening level dietary risk assessment to suppor t this request for an exemption from the requirement of a tolerance fo r hexylene glycol, a conservative drinking water concentration value of 100 ppb, based on screen ing level modeling, was used to assess the contribution to drinking water fo r the chronic dietary risk assessments for parent compound. These values were directly entered in to the dietary exposure model.

NON- DIETARY EXPOSURE

.

Human exposure to hexylene glycol is expected as a result of commercial uses such as formulation of hydraulic fluids, selective solvent in petroleu m refining, solvent for inks, additive to cement, fuel additive and textile dye vehi cles. Regulation of these types of exposures are outside the aegis of the FIFRA and regulated by other agencies such as OSHA/NIOSH.

“Consumer” exposure to hexylene glycol can occur via use in cosmetics a nd personal care items. Negligible exposure may occur via its use in fo od packaging. According to OECD-SIDS (2001), consumer exposure to hexylene glycol is expected through its use in cosmetics, antifreezes and hydraulic fluids. It is the Agency’s opinion th at exposure from use of antifreezes and hydraulic fluids is indeed very limited with the vast majo rity of the general population never being exposed from these uses. Use of such materials is typica lly not even an annual occurrence. Most persons rely upon commercial auto servicing establishments to replenish or maintain appropriate levels of these fluids. The Agency believes these ar e not significant sources of exposure.

The Agency’s past position (Ward, 2005) was that dietary (food and drinking water) and residential (inhalation and dermal) exposures of concern are unlikely with hexylene glycol, because it is used in pesticide products that ar e applied infrequently and because the chemical readily biodegrades in the environmen t. IIAB concurs with that opinion.

However, it is possible that persons may experien ce exposure as a result of occupational activities such as agricultural or commercial pesticide handle rs (i.e., mixers, loaders, applicators). There are no compound or product specific data available to the Agency with which to assess exposure and risk to occupational pesticide handlers. Howe ver, a “screening level” assessment was conducted by the Agency based upon assumptions drawn from the Agency’s experience with registering and regulating pesticide products.

In this case, no product label information is availa ble thus certain factors regarding application and product density are assumed. The assumptions are by intent, designed to be “conservative” i.e., protective. The assessment methodology is that de veloped and utilized by the Health Effects Division’s Science Policy Couns el for Exposure (ExpoSAC).

For purposes of this screening a ssessment, the Agency assumes: The product density is 8.34 lb/gal The rate of applicati on is 4 fl oz product/A Hexylene glycol = 50 % of the product formulation.Page 14 of 20 Thus: 8.34 lb/gal ÷ 128 fl oz/gal = 0.065 lb/f l oz. And, 0.065 lb/fl oz * 0.5 (% hex.glyc) = 0.0326 lb hexylene glycol/fl oz.

And 4.0 fl oz/A * 0.0326 lb hex. glyc/fl oz = 0.13 lb hex.gly/A (a pplication rate).

See Table 2.0 for a summary of estimated exposur es and risks to occupa tional pesticide handlers applying a pesticide product containing 50 % he xylene glycol. The estimates assume 100 % absorption via the dermal and inhalation routes of exposure. Dermal and inhalation exposures are summed prior to use in calculating the Margins of Exposure. A 60 kg bw is used in calculating the average daily exposure. These are extremel y conservative (prot ective) assumptions.

For purposes of risk assessment, the No Observed Adverse Effect Level is 500 mg/kg bw. It is identified from the developmental toxicity st udy in rats (main study). In this study the NOAEL was 500 mg/kg/day based on increase d incidence of clinical signs, reductions in mean body weight gain and food consumption seen at the LOAEL of 1200 mg/kg/day and above. An uncertainty factor 100X (10X for intraspecies variability and 10X interspecies extrapolation) was applied to

the NOAEL.

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Versi on 1.1, August 1998. Dermal = Single Layer Work Clothing No Gloves ; Single Layer Work Clothing With Gloves ; Inhal. = Inhalation. Units = mg a.i. /pound of active ingredient handled. 2. Applic. Rate. = assumed

3. Units Treated are taken from “Standard Va lues for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised 25 September 2001; 4. Average Daily Dose = Unit Expos ure * Applic. Rate * Units Treated ÷ 60 kg Body Weight 5. MOE = Margin of Exposure = NOAEL ÷ ADE. Dermal and Inhalation exposures ar e summed prior to use in calculating MOE. NOAEL = 500 mg/kg bw/day. !00 % absorption via the dermal and inhalation routes of exposure. Table 2.0 Summary of Exposure & Risk to Occupational Handlers From Applying a Hypothetical Pesticide Product Containing 50 % Hexylene Glycol Unit Exposure 1
mg ai/lb handled Applic. Rate 2

lb ai/unit Units

Treated 3 Avg. Daily Exposure 4
mg ai/kg bw/day MOE 5

Mixer/Loader – Liquid - Open Pour

Dermal:

SLNoGlove 2.9

SLWithGlove 0.023

Inhal. 0.0012 0.13

lb ai/A 1200 A/day Dermal:

SLNoGlove 7.54

SLWithGlove 0.0598

Inhal. 0.00312 No Glove

66

With Glove

7946 Applicator – Ground-boom - Open-cab

Dermal:

SLNoGlove 0.014

SLWithGlove 0.014

Inhal. 0.00074 0.13

lb ai/A 200 A/day Dermal:

SLNoGlove 0.00606

SLWithGlove 0.00606

Inhal. 0.000321 No Glove 78,357With

Glove 78,357 Applicator - Air-blast - Open Cab

Dermal:

SLNoGlove 0.36

SLWithGlove 0.24

Inhal. 0.0045 0.13

lb ai/A 40 A/day Dermal:

SLNoGlove 0.0312

SLWithGlove 0.0208

Inhal. 0.00039 No Glove 15,827With

Glove 23,596 Aerial Applicator (Pilots not required to wear gloves)

Dermal:

SLNoGlove 0.005

Inhal. 0.000068 0.13

lb ai/A 1200 A/day Dermal:

SLNoGlove 0.013

Inhal. 0.000177 No Glove 37,945Page 15 of 20 A MOE of 100 is adequate to pr otect occupational pesticide handl ers from exposures to hexylene glycol. The estimated MOEs are all > 100 provide d that mixer/loaders us ing open pour loading wear protective gloves. Therefor e the proposed use as an inert ingredient does not exceed the Agency’s level of concern.

Post-application Exposure.

A post-application exposure asse ssment has not been conducted. In view of the very short

environmental half-life combined with the restricted entry interval on the vast majority of pesticide products leads IIAB to believe that post-applicat ion exposure is negligib le. It would not be expected to equal or exceed the exposures estim ated for occupational pesticide handlers therefore it is not expected to exceed the Agency’s level of concern.

Aggregate Exposures

In examining aggregate exposure, the FFDCA se ction 408 directs EPA to consider available information concerning exposures from the pe sticide residue in food and all other nonoccupational exposures, including drinki ng water, from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

For hexylene glycol, a qualitative assessment for all pathways of human exposure (food, drinking water, and residential) is appropr iate given the lack of human h ealth concerns associated with exposure to hexylene glycol as an inert i ngredient in pesticide formulations.

For the following reasons, a quantitative asse ssment of non-occupational exposures was not

conducted. 1). The toxicological endpoint chosen as a point of reference is highly conservative. The NOAEL of 500 mg/kg bw/day was identified from arat de velopmental toxicity stu dy in which the maternal effects were marginal i.e., reduced group mean body weight gain and food consumption at a dose of 1,200 mg/kg bw/day and above. A number of additional studi es indicate no toxicological effects up to doses of 450 mg/kg bw/day. 2). A quantitative exposure and risk assessmen t for residential uses was not conducted. An assessment of occupational exposures was conduc ted assuming high rates of application; 100 % dermal and inhalation absorption and high volumes of material applied per day. The lowest Margin of Exposure (8,000) was for a mixer/lo ader. MOEs for high exposure methods of commercial scale agricultural application range d from 16,000 – 78,000. The Agency believes it is not likely that residential expos ure(s) would exceed those asse ssed for occupationally exposed

individuals. 3). Dietary exposure (food and water) was assesse d assuming 100% level of tolerance residue, 100 % of the crop(s) were treated and an occurenc e of 50 % of the formulation being the inert ingredient. There was no hazard at tributable to a single exposure s een in the toxicity database for hexylene glycol. Therefore, the hexylene glycol is not expected to pose an acute risk. A chronic aggregate risk assessment takes into account exposu re estimates from chronic dietary consumption of food and drinking water. The ch ronic dietary exposure from food and water to hexylene glycolPage 16 of 20 is 3.8 % of the cPAD for the U.S. population and 12.5 % of the cPAD for children 1-2 yrs old, the most highly exposed population subgroup. The Agency has not identified any concerns for carcinogenicity relating to hexylene glycol

In view of the results from the screening le vel exposure assessments which were based upon highly conservative (i.e., protectiv e) assumptions, the Agency believes a quantitative assessment is not necessary. The Agency believes that any no n-occupational exposures that might occur would be of much smaller magnitude due to the expect ed small volumes of material that might be handled or contacted, and to the f act that residential products are ty pically diluted to a fraction of what was assumed and used in the occupational assessments. The Agency believes these factors are protective to persons who might experience non-o ccupational exposures.

CUMULATIVE EXPOSURE

Section 408(b)(2)(D)(v) of the FFDCA requires that, when cons idering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s re sidues and “other substances that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to hexylene glycol and any other substances, and this material does not appear to produce a toxic metabolite produced by other substances. For the pur poses of this tolerance action, therefore, EPA has not assumed that hexylene glycol has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to ev aluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pe sticide Programs concerning common mechanism determinations and procedures for cumulating e ffects from substances found to have a common

mechanism on EPA’s website at http://www.epa.gov/pest icides/cumulative

.

ENVIRONMENTAL FATE CHARACTERIZATION

Hexylene glycol can be released into the environment from various industrial sour ces, wastewater
effluents from wastewater treatment plants, and its use as an inert ingredient in pesticide products. Biological screening studies (Blok, 1985, as cite d in OECD-SIDS) have demonstrated that hexylene glycol readily biodegrades. It is infinitely water soluble, and has low potential to sorb to soil, so it is likely to leach from soil and distri bute primarily to water. Leaching to groundwater, although likely under certain conditi ons, will be reduced due to the compound’s biodegradability. Releases to surface water will undergo substan tial biological degradation prior to reaching drinking water intakes. As a result , concentrations in drinking water are likely to be below the low parts per billion. Hexylene glycol is slightly volatile (0.013 mm Hg @ 25oC). If re leased to the atmosphere, the chemical has a calculated half -life of 9 hours due to photo-oxidation (OECD-SIDS 2001).

Similar conclusions are presented in a Marc h 2010 draft Interim Reference Exposure Level document ( www.oehha.org.ca.gov ). The California Office of Environmental Health HazardPage 17 of 20 Assessment utilized the EPA’s EPIWIN/APO model to assess environmental effects from exposures to hexylene glycol. The estimated atmospheric photodegr adation (reaction with hydroxyl radicals) half-lif e of hexylene glycol is 9 hours, based on a 12 hours sunlight/day. Glycols have no hydrolysable groups and are generally not susceptibl e to hydrolysis in water under neutral conditions at ambient temperatures. The estimated Henry’s Law Constant of 2.94 x 10 -8

atm-m 3 /mole for hexylene glycol indicates it has limite d potential to partition fr om water to air. The environmental distribution of hexylene glyc ol, as predicted by Mack ay level I fugacity modeling, is 0.169% in air, 99.5% in water, 0.335 % in soil, and 0.0074% in sediment. Although there are insufficient experimental data to determine whether hexylene glycol is readily biodegradable, it is considered at least i nherently biodegradable . With a predicted bioconcentration factor of 3.162 and Log K OW of 0.58, hexylene glycol is not expected to bioaccumulate. Hexylene glycol is therefore unlik ely to persist in the en vironment (OEHHA cites OECD 2001).

Human Health Risk Characterization

IIAB agrees with the summary presented by Ward (2005). No additional information has been identified which would cause the Agency to modi fy its assessment of hexylene glycol. Hexylene glycol is low in acute oral and dermal toxicity, with LD 50 values in excess of 2000 mg/kg. It is irritating to the eye and skin, but is not a skin se nsitizer. It has low inha lation toxicity, with an

inhalation LC 50 (>160 ppm, or 0.772 mg/L) that is in exces s of the saturated vapor concentration. In addition, the vapor pressure is sufficiently low at normal temperat ures so that it does not present

an inhalation hazard. The chemical is also no t genotoxic in either mammalian or non-mammalian

cells in vitro . Developmental toxicity occurred at high doses in studies, with maternal and developmental NOAELs ranging fr om 300 to 500 mg/kg/day.

No residue data were provided for hexylene glyc ol. In the absence of data, the Agency has developed an approach that uses surrogate in formation to derive upper bound exposure estimates for the subject inert ingredient. There was no hazar d attributable to a sing le exposure seen in the toxicity database for hexylene glycol. Theref ore, an acute dietary risk assessment was not

conducted.

A chronic dietary risk assessment was c onducted using the Dietary Exposure Evaluation Model software with the Food Commodity Inta ke Database (DEEM-FCI DTM, Version 2.03. The chronic analysis assumed 100% crop treated, de fault processing factors and tolerance-level

residues for all foods and use limitations of not more than 50% by weight in pesticide formulations. Drinking water (100 ppb) was incorporated directly into the dietary assessment. The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD). For the U.S. popul ation, the exposure for food and water utilized 3.8% of the cPAD. The chronic dietary risk es timate for the highest e xposed population subgroup, children 1-2 years old is 12.5% of the cPAD. RD has not identified any concerns for carcinogenicity relating to hexylen e glycol, therefore, a cancer di etary exposure assessment was not performed.

Taking into consideration all available inform ation on hexylene glycol, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure whenPage 18 of 20 considering dietary exposure (i ncluding crops, meats, and fish ) and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, it is recommended that the one exemption from the requirement of a tolerance established for residues of hexylene glycol when used as a solvent in pesticide formulations applied to growing crops preand post-harvest 40 CFR 180.910 and for use on animals under 40 CFR 180.930 can be considered

reassessed as safe under sect ion 408(q) of the FFDCA.

Ecotoxicity and Ecologica l Risk Characterization

Hexylene glycol is classified as practically non-toxic, according to OPP's classification scheme, to aquatic organisms, with the LC 50 /EC 50 being in excess of 2,800 mg/L (NIH 2004). A toxicity test on frog tadpoles ( Rana catesbiana ) produced an LC 50 of 11,800 mg/L, which suggests low toxicity of this substance to this group of sensitive aquatic organisms. The chemical is also of low toxicity to algae, with a 72-hour EC 10 and EC 50 of >429 mg/L for the algae Slenastrum capricornutum

. Based on the log K

ow of 0.58, it has low potential to bioa ccumulate (BCF = 3.162, as calculated using the Syracuse Aopwin V1.85 model, OECD-S IDS 2001). Because of hexylene glycol’s low potential for bioaccumulation and low toxicity in te rrestrial and aquatic orga nisms, it is unlikely to be a risk concern to nontarget species at applic ation rates anticipated in pesticide formulations.

IIAB concurs with the assessmen t presented by Ward (2005).Page 19 of 20 ATTACHEMENT

DEEM FCID Chronic Anal ysis for Hexylene glycol

U.S. Environmental Protection Agency Ver. 2.00

DEEM-FCID Chronic analysis for HEXYLNE GLYCOL (1994-98 data) Residue file name: C:\Documents and Settings\adebesai\My Documents\hexylne glycol
500mg kg day.R98 Adjustment factor #2 NOT used. Analysis Date 04-14-2011/17:48:22 Residue file dated: 04-14-2011/16:35:47/8

Reference dose (RfD, Chronic) = 5 mg/kg bw/day

NOEL (Chronic) = 500 mg/kg bw/day

COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

=============================================================================== Total exposure by population subgroup

-------------------------------------------------------------------------------

Total Exposure

----------------------------------- Population mg/kg Margin of Percent
Subgroup body wt/day Exposure 1/ of RfD

-------------------------------------- ------------- ---------- --------- U.S. Population (total) 0.191509 2,611 3.8%

U.S. Population (spring season) 0.195512 2,557 3.9% U.S. Population (summer season) 0.193733 2,581 3.9% U.S. Population (autumn season) 0.188144 2,658 3.8% U.S. Population (winter season) 0.188739 2,649 3.8%

Northeast region 0.208249 2,401 4.2% Midwest region 0.190460 2,625 3.8% Southern region 0.171478 2,916 3.4% Western region 0.209414 2,388 4.2%

Hispanics 0.201698 2,479 4.0% Non-hispanic whites 0.187723 2,663 3.8% Non-hispanic blacks 0.185288 2,698 3.7% Non-hisp/non-white/non-black 0.246967 2,025 4.9%

All infants (< 1 year) 0.397082 1,259 7.9% Nursing infants 0.212711 2,351 4.3% Non-nursing infants 0.467077 1,070 9.3% Children 1-6 yrs 0.495834 1,008 9.9% Children 7-12 yrs 0.239839 2,085 4.8%

Females 13-19 (not preg or nursing) 0.138939 3,599 2.8% Females 20+ (not preg or nursing) 0.149292 3,349 3.0%
Females 13-50 yrs 0.154523 3,236 3.1% Females 13+ (preg/not nursing) 0.163842 3,052 3.3% Females 13+ (nursing) 0.192592 2,596 3.9%

Males 13-19 yrs 0.148194 3,374 3.0%
Males 20+ yrs 0.144142 3,469 2.9%
Seniors 55+ 0.152430 3,280 3.0%

Children 1-2 yrs 0.624005 801 12.5% Children 3-5 yrs 0.461958 1,082 9.2% Children 6-12 yrs 0.255310 1,958 5.1%
Youth 13-19 yrs 0.144122 3,469 2.9%
Adults 20-49 yrs 0.144401 3,463 2.9%
Adults 50+ yrs 0.152076 3,288 3.0%
Females 13-49 yrs 0.145389 3,439 2.9%

-------------------------------------------------------------------------------Page 20 of 20 REFERENCES

BIBRA. 1991. Toxicity Profile: Hexylene glycol . British Industrial Biological Research Association, Surrey, UK.

California Office of Environmental Health Ha zard Assessment. 2010. March 2010 draft Interim Reference Exposure Level document ( www.oehha.org.ca.gov ).

Cavender, F.L. and Sowinski, E.J. 2001. Glycols. Patty’s Toxicology, 5 th Edition. John Wiley and Sons, Inc., New York. Vol. 7, Ch.14, pp. 48-51.

Cosmetics Ingredient Review. 1985. Final report on the safety assessment of butylenes glycol, Hexylene glycol, ethoxydiglycol, and dipropylene glycol. J. Am . Coll. Toxicol. Vol. 4, No.5 pp. 223-248.

Cosmetics INFO.org. 2010. Hexylene Glyc ol. www.cosmeticsinfo.org/ingredient

NIH. 2004. ChemID Plus. U.S. National Library of Medicine. National Institutes of Health, Department of Health & Human Servi ces. Last modified: September 9, 2004. http://chem.sis.nlm.nih.gov/chemidplus/

Ibid. 2010. Update 30 March 2010.

OECD-SIDS. 2001. Organisation for Economic Cooperation and Development-Screening Information Data Set (SIDS Initial Assessment report and SIAR Publication; UNEP Publications). Hexylene glycol CAS N o. 107-41-5. OECD Integrated High Production Volume (HPV) Chemical Database. < http://cs3-hq.oecd.org/scripts/hpv/>

TSCA 8(e) CP No. 8EHQ-1092-12673. Microfiche No. OTS0572003. 1992. Initial Submission: Acute Toxicity Studies in Rats and Rabb its with DM 7664 with Cover Letter Dated 101292.

Elf Atochem North America Inc.

TSCA 8(e) No. 8EHQ-1195-13392. Microfic he No. OTS0572134-1. 1995. Support: Draft Summary of Results of Range-Finding Toxic ity Study with 2-Methyl-2,4-Pentanediol in Rats, with Cover Letter Dated 11/22/95.

Ward, R. Tracy. 2005. Reassessment of the One Exemption from the Requirement of a Tolerance for 2-Methyl-2,4-pentanediol (Hexylene glycol ). EPA/OPP Memorandum. November 8.

cc:M.Dow(IIAB) RDI: P. Shah; Toxicol Rev. P. Shah M.I.Dow:S7958:PY1:(703)305-5533:IIAB:7505P