U.S. Environmental Protection Agency 3 / 18 /2008 Supporting Documents for Risk

- Based Prioritization



### Supporting Documents for Initial Risk

- Based Prioritization of High Production Volume
Chemicals

Chemical/Category: CAS No. 111

- 96

- 6, (bis(2

- methoxyethyl)ether (D iglyme)

Contents:

• Page 2: Screening

- Level Risk Characterization
, 3 / 14 /2008

• Page 6 : Scr

eening

- Level Hazard Characterization
, 2/2 1 /2008

• Page 16 : Screening

- Level E xposure Characterization
, 3 /14 /2008U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 2 QUALITATIVE SCREENING

- LEVEL RISK CHARACTERIZATION FOR Diglyme (CAS No. 111

- 96

- 6)

1. Background

The High Production Volume (HPV) Challenge Pr ogram 1 is a voluntary initiative aimed at developing and making publicly available screening

- level health and environmental effects information on chemicals manufactured in or imported into the United States (U.S.) in quantities greater than one million po unds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to “SIDS” (Screening Information Data Set 1

, 2 ) endpoints that are screening

- level indicators of potential hazards (toxicity) for humans or the environment and
environmental fate.

The Environmental Protection Agency’s Office of Pollution Prevention and Toxics (OPPT) is evaluating th e data submitted in the HPV Challenge Program on approximately 1,400 sponsored chemicals. Data submitted to the Organisation for Economic Co

- operation and Development (OECD) HPV Programme are also being evaluated. OPPT developed a screening

- level hazard characterization that consists of an objective evaluation, conducted according to established EPA guidance 2

, 3 , of the quality and completeness of the data set provided and is based primarily on hazard data provi ded by sponsors. The characterization does not draw conclusions regarding the completeness of all data generated with respect to a specific chemical or mixture. The OECD SIDS documents (SIDS Initial Assessment Profile; SIAP and SIDS Initial Assessment Re port; SIAR) provide similar information. Under both the HPV Challenge and OECD HPV Programs, chemicals that have similar chemical structures, properties and biological activities may be grouped together and their data shared across the resulting category. Evaluation of chemical category formation and data extrapolation(s) among category members is performed in

accord with established U.S. EPA 1 and OECD 4 guidance.

In 2006 and 2007, EPA received data on uses of and reasonably likely exposures to chemicals on the Toxic Substances Control Act (TSCA) Inventory of existing chemicals, submitted in accordance with the requirements of the Inventory Update Reporting (IUR) rule 5 . Inf ormation is collected every five years under IUR , promulgated under the authority of section 8(a) of TSCA. The most recent reports pertain to chemicals manufactured in (including imported into ) the U.S. during calendar year 2005 in quantities of 25,000 pounds or more at a single site. Information is reported on the identity of the che mical manufactured or imported and the quantity, physical form, and number of persons reasonably likely to be exposed during manufacture of the chemical. For chemicals manufactured or imported in quantities of 300,000 pounds or more at a single site durin g calendar year 2005, additional information was reported on the industrial processing and uses of the chemical, the number of industrial processing sites and of employees reasonably likely to be exposed to the chemical at these sites, the consumer and

com mercial uses of the chemical and an indication whether the chemical is used in products intended for use by children under 14 years of age.

For the se qualitative screening

- level risk characterization documents, EPA has reviewed the IUR data to evaluate

ex posure potential. In addition, exposure information that may have become available through prior Agency actions has been considered, as appropriate. The resulting exposure information has been combined with the screening

level hazard characterizations to develop this qualitative screening

- level risk characterization 6

, 7

. These screening

level risk characterizations are technical documents intended to support subsequent decisions and actions by OPPT. Accordingly, the document is not written with the goal of informing the general public. T he purpose of the

1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm

. 2 U.S. EPA. HPV Challenge Program

–Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm

. 3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm

. 4 OECD . Guidance Document on the D evelopment and Use of Chemical Categories; http://www.oecd.org/document/7/0,2340,en_2649_34379_1947463_1_1_1_1,00.html

. 5 U.S. EPA

–Basic IUR Information: http://www.epa.gov/opptintr/iur/pubs/guidance/basic

- information.htm

6 U.S. EPA Guidelines for Exposure Assessment; http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=15263

7 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm

.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 3 qualitative screening level risk ch aracterizations is two

- fold: to support initial risk

- based decisions to prioritize
chemicals and inform risk management options and to identify data need s for i ndividu al chemicals or chemical categories

.

2. Physical

- Chemical Properties and Environmental Fate

This report was prepared using the best available data from a number of sources , but draws no conclusions regarding whether additional relevant data may exist

. Dig lyme is a liquid at room temperature. It is miscible with water, has high vapor pressure, and is not significantly volatile from water. It is highly mobile in soil, does not bioaccumulate (is rated B1), and does not hydrolyze under environmental pHs. In the atmosphere, it is expected to photodegrade within one day. Based on experimental data for diglyme and analogs, biodegradation of diglyme is expected to be slow and the substance is judged to be moderately persistent (P2).

3. Hazard Characterization

Aq uatic Organism Toxicity. T he evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants indicate s the potential acute hazard of diglyme t o aquatic organisms is low

.

Human Health Toxicity. The acute toxicity of d igly me to rats via the oral and inhalation routes of exposure is low. The target organs for toxicity following repeated exposure to d iglyme via inhalation were testes (decreased sperm

p roduction) and bone marrow (atrophy ). Other major effects were anemia (re duction in red blood cell count, hemoglobin, hematocrit and platelet count) and lymphoid tissue atrophy of the spleen and thymus (in male and female rats). Diglyme also affected pregnancy frequency and developing conceptuses (post

- implantation loss, fetal growth, viability morphological development). A reproductive toxicity test was not submitted to address the reproductive toxicity endpoint , but data submitted from another, different test (dominant

- lethal test in male rats) indicates diglyme has the pote ntial to cause reproductive toxicity. Submitted in vitro gene mutation and in vivo chromosomal aberration tests indicated negative results.

The potential health hazard of diglyme is high based on repeated

- dose toxicity to blood and blood

- forming organs

a nd developmental toxicity at relatively low doses in animal studies. Available data also indicate diglyme has the potential to cause reproductive toxicity.

4. Exposure Characterization

This exposure characterization was completed using available 2006 Invent ory Update Rule (IUR) submissions. Data and information that are claimed Confidential Business Information (CBI) by the submitter were reviewed and considered by EPA in preparing this assessment but are not disclosed in this summary.

In addition, the f

ollowing sources were reviewed to identify exposure and use information: the HPV Challenge Submissions, OECD SIDS Data , the Toxics Release Inventory (TRI) , OSHA PEL documentation

, various d atabase s and public sources

.

Diglyme was manufactured and/or impo rted in the United States in amounts ranging from 1,000,000 to 10,000,000 pounds in 2005

. The HPV submission indicates that the chemical is used primarily as a specialty solvent in a wide variety of applications (as a reaction solvent for Grignard

- reactio ns, reduction

- reactions, alkylation

- reactions, and

organo

- metallic reactions). Other applications include use in the coating industry and photolithography for the manufacture of semiconductor chips. Specific examples of uses from non

- CBI information incl ude uses in sealants and adhesives, automotive care products, and paints and coatings.

Exposure to Workers The National Occupational Exposure Survey (NOES), which was conducted between 1981 and 1983, estimated a total of 207 workers potentially exposed t o this chemical. Based on IUR reporting, the maximum total number of workers likely to be exposed to this chemical during manufacturing and industrial processing and use is between 100 and 999. There may be additional potentially exposed workers that are not included in this estimate since not all production volume has been accounted, and there is at least one use that contains a "Not Readily Obtainable" (NRO)U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 4 response among the submissions. This chemical has a vapor pressure of 2.96 torr at 25°C . OPPT has established 0.001 torr as a value above which worker exposures to vapors should be estimated for chemical assessments. Therefore, this chemical’s vapor pressure could result in worker exposure to vapors if workers were near diglyme liquid. This chemic al does not have an OSHA Permissi ble Exposure Limit

.

The IUR

- based ranking for worker exposure is high.

Exposure to General Population and the Environment

The chemical is not on the Toxics Release Inventory

. Based on use information, EPA assumes for t he purpose of this risk prioritization that there is potential for exposures to the general population and the environment. The IUR

based ranking for the general population and the environment is high due to the assumption that there will be
exposure to t his chemical.

Exposure to Commercial Workers and Consumers

N on

- CBI IUR information indicates exposure to diglyme by commercial workers or consumers through adhesives and sealants, automotive care products, and paints and coatings. Based on its vapor pres sure as cited above, there
could be significant exposures to vapors if commercial workers or consumers are near products containing this

chemical

. The IUR

- based ranking for commercial workers and consume rs is high due to the assumption that diglyme is use

d in commercial worker/consumer products.

Exposure to Children There is the possibility of exposure to children from products containing diglyme. The submitter(s) indicated that the product use information for children was not readily obtainable. Thu s, the IUR

- based ranking for children ’s exposure to diglyme is medium due to the assumption that it may be in products intended for use by children.

5. Risk Characterization

The statements and rationale provided below are intended solely for the purpose of this screening

- level and qualitative risk characterization and will be used for prioritizing substances for future work in the U.S. HPV Challenge Program

.

5.1. Risk Statement and Rationale

Potential Risk to Aquatic Organisms from Environmental Releases ( LOW CONCERN): EPA assumes there is potential for exposure to aquatic organisms from environmental releases. Although diglyme is considered moderately persistent in the environment, it has a low acute aquatic toxicity hazard, which suggests a low

concern for p otential risk to aquatic organisms from environmental releases

.

Potential Risk to the General Population from Environmental Releases ( MEDIUM CONCERN): EPA assumes
there is potential for exposure to the general population from environmental releases. D i glyme is considered to be moderately persistent in the environment. The high concern for hazard to human health (at relatively low doses in animal studies) combined with potential exposures suggests a medium concern for potential risk to the general popul ation from environmental releases.

Potential Risk to Workers ( HIGH CONCERN): Available IUR data indicate that workers may be exposed to diglyme. The high concern for hazard to human health (at relatively low doses in animal studies) combined

with the likely exposures that occur in occupational settings suggests a high concern for potential risk to
workers.

Potential Risk to Commercial Workers and Consumers from Known Uses ( HIGH CONCERN): Available IUR
data indicate that commercial workers and consume rs may be exposed to diglyme. The high concern for hazard to human health (at relatively low doses in animal studies) combined with the possible exposures that occur in both commercial worker and consumer use settings suggests a high concern for potential risk to both groups.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 5 Potential Risk to Children (HIGH CONCERN): Available IUR data indicate that children may be exposed to diglyme. The high concern for hazard to human health is important in the case of children’s health because
animal studies ind icate this chemical is toxic to developing organisms at relatively low doses in animal studies. Therefore, the high hazard concerns combined with possible exposures suggest a high concern for potential risk

to children.

5.2. Uncertainties

Diglyme may hav e minor uses that were not reported in IUR.

5.3. Data Needs

No data needs have been identified at this time.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 6 SCREENING

- LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS

SPONSORED CHEMICAL

D iglyme (CAS No. 111

- 96

- 6) [ 9 th 

### CI Nam

e: bis (2

- Methoxyethyl ) E ther ]

August 2007

Revised: February 2008

Prepared by

High Production Volume Chemicals Branch
Risk Assessment Division

and Exposure Assessment Branch Economics, Exposure and Technology Division

Office of Pollution Preve ntion and Toxics Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460

- 0001U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 7 SCREENING

- LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS

The High Production Volume (HPV) Challenge Program 8 is a voluntary initi ative aimed at developing and making publicly available screening

- level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge P rogram, producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do

not exist

, and m

aking both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to “SIDS” (Screening Information Data Set 1

, 9 ) endpoints that

a re screening

- level indicators of potential hazards (toxicity) for humans or the environment.

The Environmental Protection Agency’s Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approxim ately 1,400 sponsored chemicals. OPPT is using a hazard

based screening process to prioritize review of the submissions. The hazard

- based screening process consists of two
tiers describ ed below briefly and in more detail on the Hazard Characterization we bsite 10

.

Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established criteria to “bin” chemicals/categories for OPPT review. This is an automated process performed on the data as submitted by the spons or. It does not include evaluation of the quality or completeness of the data.

In Tier 2, a screening

- level hazard characterization is developed by EPA that consists of an objective evaluation of the quality and completeness of the data set provided in t he Challenge Program submissions. The evaluation is performe d according to established EPA guidance 2

, 11 and is based primarily on hazard data provided by sponsors

. EPA may also include additional or updated haz ard information of which EPA, sponsors or other parties have
become aware . The hazard characterization may also identify data gaps that will become the basis for a subsequent data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical stru ctures, properties and biological activities may be grouped together and their data shared across the resulting category. This approach often significantly reduces the need for conducting tests for all endpoints fo r all category members. As part of Tier 2, evaluation of chemical category rationale and composition and data extrapolation(s ) among category members is performed in accord with established EPA 2 and OECD 12 guidance

.

The screening

- level hazard characterizations that emerge from Tier 2 are important contributors to OPPT’s existing chemicals review process. These hazard characterizations are technical documents intended to support subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously no t readily available to the public. The public, including sponsors, may offer comments on the hazard characterization documents

.

The screening

- level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a ch emical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of and exposure s to high

- volume TSCA existing chemicals, submitted in accordance with the requirements of the Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the screening

- level hazard characterizations to develop screening

- level risk charact erizations 4

, 13 . The screening

- level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts

are currently underway to consider how best to utilize these screening

- level risk characterization s as p art of a risk

based decision

- making process on HPV chemicals which applie s the results of the successful U.S. High Production Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.

8 U.S. EPA. High Production Volume (HPV) C hallenge Program; http://www.epa.gov/chemrtk/index.htm

. 9 U.S. EPA. HPV Challenge Program

–Information Sources; http://www.epa.gov/c hemrtk/pubs/general/guidocs.htm

. 10 U.S. EPA. HPV Chemicals Hazard Characterization website ( http://www.epa.gov/hpvis/abouthc.html ).

11 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/nc ea/raf/rafguid.cfm

. 12 OECD. Guidance on the Development and Use of Chemical Categories ; http://www.oecd.org/dataoecd/60/47/1947509.pdf

. 13 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm

.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 8 SCREENING

- LEVEL HAZARD CHARACTERIZATION

Diglyme (CAS No. 111

- 96

- 6)

Introduction

The sponsor, Ferro Corporation , submitted a Test Plan and Robust Summaries to EPA for d iglyme (CAS No.
111

- 96

- 6 ; 9 th CI name: bis(2

- m ethoxyethyl) ether) dated 31 December 2003. EPA posted the sub missio n on the
ChemRTK HPV Challenge Website on March 4, 2004 ( http://www.epa.gov/chemrtk/pubs/summaries/diglyme/c15023tc.htm ). EPA comments were posted on 1 6 May 2005. Publ ic comments were also received and posted to the website . The sponsor did not submit updated/revised documents.

This screening

- level hazard characterization is based primarily on the review of the test plan and robust summaries of studies submitted by th e sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor’s responses to comments and revisions made to the submission

. Su mmary tables of SIDS endpoints are provided herein and the structure of the chemical is provided in the appendix. The screening

- level hazard characterization for environmental and human health toxicity is based largely on SIDS endpoints and is described a ccording to established EPA or OECD effect level definitions and hazard assessment practices.

Summary

- Conclusion

Diglyme is a liquid at room temperature. It is miscible with water, has high vapor pressure, and is not significantly

volatile from water. I

t is highly mobile in soil, does not bioaccumulate (is rated B1), and does not hydrolyze under environmental pHs. In the atmosphere, it is expected to photodegrade within one day . Based on experimental data for diglyme and analogs, biodegradation of digl yme is expected to be slow and the substance is judged to be moderately persistent (P2).

T he evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants indicate s the potential acute hazard of diglyme t o aquatic organ isms is low

.

The acute toxicity of d iglyme to rats via oral and inhalation routes is low. The target organs for toxicity following repeated exposure to d iglyme via inhalation were testes (decreased sperm production) and bone marrow (hypoplasia). Other m

ajor effects were anemia (reduction in red blood cell count, hemoglobin, hematocrit and platelet count) and lymphoid tissue atrophy of the spleen and thymus (in male and female rats). A reproductive toxicity test was not submitted to address the reproduct ive toxicity endpoint , but data submitted from a dominant

lethal test indicates diglyme has the potential to cause reproductive toxicity in male rats. Diglyme affected pregnancy frequency and developing conceptuses (post

- implantation loss, fetal growth, v iability morphological development). Diglyme did not induce gene mutation in vitro or chromosomal aberration s in vivo.

The potential health hazard of diglyme is high based on repeated

- dose (blood and blood

- forming organs) and developmental toxicity

. Available data (dominant

- lethal test) indicate that diglyme has the potential to cause reproductive toxicity.

No data gaps were identified under the HPV Challenge Program.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 9 1. Physical

- Chemical Properties and Environmental Fate

This report was pr

epared using the best availabl e data from a number of sources, including information from the HPV test plan and robust summaries (Ferro, 2003), the Hazardous Substance Data Bank (HSDB, 2007) and estimations using EPI Suite TM (U.S. EPA, 2007).

Basic physic al

- chemical and environmental fa te properties of diglyme are listed in Tables 1a and 1b , respectively

.

Physical

- Chemical Properties Characterization Diglyme is highly soluble in water and has a high vapor pressure.

Table 1a . Physical

- C hemical P roperti es of D iglyme

Structure 

### O O O 

### C H 3 

### C H 3

Property Value/ Descriptor Reference

CAS Registry No. 111

- 96

- 6

IUPAC name 1

- methoxy

- 2

- (2

- methoxyethoxy)ethane

Molecular w eight 134.17 HSDB (2007) Physical s tate Colorless liquid HSDB (2007)

Meltin g p oint

- 68° C (m) Ferro Corporation ( 200 3 ) Boiling p oint 162° C at 760 mm Hg (m) Ferro Corporation ( 200 3 ) Vapor p ressure 2.96 mm Hg at 25°C (m)

3.49 hPa at 25°C HSDB (2007) Ferro Corporation ( 200 3 )

Water s olubility Miscible >1000 g/L at 25°C (m) HSDB (2007) Ferro Corporation ( 200 3 ) Density 0.9451 g/cm 3 at 20°C Ferro Corporation ( 200 3 ) Log K ow - 0.36 at 25° C (m) Ferro Corporation ( 200 3 ) (m) denotes measured property.

Environmental Fate Characterization Diglyme is not significantly volatile from wat er or moist soil surfaces. However, based on the high vapor pressure, the potential for volatilization from dry soil exists. In the atmosphere, diglyme will exist solely in the vapor phase, where it will be rapidly degraded by reaction with photochemical ly produced hydroxyl radicals. Diglyme is expected to be highly mobile in soil. It is not expected to undergo hydrolysis or direct photolysis in the environment due to a lack of functional groups that are susceptible to these processes. In water, diglym e is not expected to adsorb to sediment or particulate matter. Biodegradation may be a removal mechanism for diglyme in aerobic soil and water based on data on compounds with similar structures, but data from OECD ready and inherent biodegradation

tests s uggest that it will be relatively slow. Diglyme in soil has the potential to reach ground water resources due to its high mobility and relatively slow expected rate of degradation. Persistence and bioaccumulation are qualitatively characterized according to the criteria set forth in the PMN program (FR, 1999). As summarized in Table 2, available data are consistent with moderate persistence (i.e. rating of P2). Diglyme is not significantly bioaccumulative (i.e. it is rated B1).U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 10 Table 1 b . Environment

al F ate P roperties of D iglyme Property Value/ Descriptor Reference Photodegradation Half

- life = 7.33 hours (calculated)

Half

- life = 1 day (calculated) Ferro Corporation ( 200 3 ) HSDB (2007)

Aerobic d egradation Not Readily Biodegradable
The submitted data a were considered inadequate by EPA (U.S. EPA, 2005); however another study b was identified by EPA and was used to assess this endpoint Ferro Corporation ( 200 3 )

Hydrolysis Half

- life = >1 year (calculated) Ferro Corporation ( 200 3 )

Bioaccumulation Not signi ficant Estimated log BCF = 0.5 (calculated; EPI Suite 3.20) HSDB (2007) U.S. EPA (2007) Henry’s Law Constant 5.2x10 - 7 atm

- m

3 /mole (calculated) HSDB (2007) Direct photolysis Not significant HSDB (2007)

K oc 15 mL/g (estimated) HSDB (2007) Fugacity Air: 0 .505%
Water: 60.4%
Soil: 38.9%
Sediment: 0.113% Ferro Corporation ( 200 3 )

Bioaccumulation rating B1 (low) Persistence rating P2 (moderate)

a No biodegradation observed in a closed

- bottle test over a 5

- day incubation period and 31

- 42% biodegradation
obs erved after 28 days in OECD Test Guideline 302B

. b 0

- 2% biodegradation after 28 days in OECD Test Guideline 310C; not readily biodegradable ( http://www.safe.nite.go.jp/english/kizon/KIZON_start_hazkizon.html )

.

2. Environmental Effects

– Aquatic Toxicity

Acute Toxicity to Fish

Golden orfe (

Leuciscus idus

) were exposed to diglyme at nominal concentration of 2000 mg/L under st atic conditions for 96 hours. No mortality was observed and no visible changes were evident at necropsy.
96

- h LC

50 > 2000 mg/L

Acute Toxicity to Aquatic Invertebrate

Daphnia magna were exposed to diglyme at nominal concentrations of 100 or 1000 mg/L u nder static conditions for
48 hours. There were no adverse effects observed at either concentration.
48

- h EC 50 > 1000 mg/L

Toxicity to Aquatic Plants

Green algae ( Scenedesmus subcapitatus ) were exposed to diglyme at nominal concentration of 1000 mg/L f or 72 hours. No other details were provided in the robust summary.
72

- h E C 50 (growth) > 1000 mg/L

Conclusion: T he evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants
indicate s the potential acute hazard of d iglyme t o aquatic organisms is low

.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 11 3. Human Health Effects

Acute Oral Toxicity

(1) Male CD

- 1 rats were administered diglyme in water via gavageat 1500

– 23,000 mg/kg

- bw and observed for 14 days. Clinical signs were restlessness unrest, disturbed se nse of balance, prone position and reduced respiration rate. At high doses, there was red discharge of a red secretion from the eyes. An Approximate Lethal Dose (ALD) of for
d iglyme was calculated as 7500 mg/kg

- bw.

LD 50 = 7500 mg/kg

- bw

Acute Inhalation Toxicity

Wistar rats (male and female) were expose d (nose only) to a saturated vapor of diglyme at greater than 11,000 mg/m 3 (11

– 14 mg/L) for 7 hours and observed 14 days aft er which they were sacrificed and subjected to a gross necropsy. Clinical sign s were restlessness, narrowing of palpebral fissures, and irregular breathing. No mortality

was seen. LC 50 > 11

– 14 mg/ L

Repeated

-

D ose Toxicity

(1) Groups of 20 male and 10 female rats (Crl:CD1BR) were exposed ( nose only ) to d iglyme vapor at 0 (control

), 110, 370 or 1100 ppm (approx imately 0.6, 2.0 or 6.0 mg/L/day), 6 hours / day, 5 days / week for 2 weeks. Five rats/sex/group were sacrificed after the tenth exposure and after a 2

- week recovery period. The remaining five male rats/group each were sacrific ed after 6

- and 12

- week recovery periods. Overall, male rats were more sensitive than females. In males, the primary target organs were thymus and reproductive organs (testes, epididymes, seminal vesicles and prostate). Stage specific germ cell damage o ccurred at all concentrations and the effects were both

concentration

- and time

- dependent. Other treatment

- related effects noted in males at every test concentration were decreased leukocyte counts at the end of the exposure period and statistically signi ficantly (p < 0.05) lower mean body weights throughout the treatment period. At 1100 ppm, there was anemia (decreased red blood cell count, hemoglobin, hematocrit, and platelet count) and hematopoietic tissue atrophy (minimal to severe bone marrow hypopl asia and lymphoid tissue, atrophy of the spleen and thymus (in male and female rats) and reduced absolute and relative weights of male reproductive organs (concentration response is unclear because data and statistical analyses are not provided for relativ e organ weights). Evidence of hematopoietic effects in males was not seen after 42 days of recovery. The LOAEL in males was 110 ppm based on testicular atrophy, germ cell damage, reduced leukocyte count, and lower mean body weight. Data evaluation sugge sted a LOAEL for females of 1100 ppm based on anemia (decreased red blood cell count, hemoglobin, hematocrit, and platelet count), reduced leukocyte count, increased relative liver weight, and atrophy of hematopoietic tissues (minimal to severe bone marrow hypoplasia and lymphoid tissue atrophy of the spleen and thymus); the NOAEL was 370 ppm. NOAELs/LOAELs in this study

were as follows: LOAEL (male)

~ 0.60 mg/L /day ( based on testicular effects ) NOAEL (male) = Not established LOAEL (female) ~ 6.0 mg/L/da y ( based on hemolytic effects ) NOAEL (female) ~ 2 mg/L/day

The data summarized were from the only repeated

- dose toxicity study provided by the sponsor . EPA considered the
14

- day study adequate to address the endpoint for the purposes of the HPV Challenge Program because the effects on male reproductive organs were seen at the lowest concentration tested. The study was conducted according to GLP and the summary pr ovided thorough details. A 28

- day study ( the minimum requirement to address the endpoint) wo uld be expected to show similar, possibly exacerbated, effects. A 90

- day study would strengthen the assessment by establishing NOAELs /LOAELs to properly assess systemic toxicity and characterize the hazards of diglyme.

(2) A very short description was pr esented in the test plan of a rat inhalation study using 0, 3.1, 9.9, 30, or 98 ppm concentrations (10 exposures followed by a 14

- day recovery period), that confirms the study described above

, although no robust summary for this study was provided. This s tudy established a NOAEL of 30 ppm and aU.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 12 LOAEL of 98 ppm (approximately 0.5 mg/L/day) for male rat reproductive effects , which is consistent with the study described above

.

Reproductive Toxicit

y

A reproductive toxicity test was not submitted to address the reproductive toxicity endpoint. Data submitted for the following test indicates diglyme has the potential to cause reproductive toxicity via male germ cell mutations.

In a dominant

- lethal test, adult male Sprague

- Dawley rats (10/dose) were exposed v ia inhalation to diglyme at 0, 250 or 1000 ppm (approximately 1.4 or 5.5 mg/L/day) for 7 hours/day for 5 days. After the exposure period , the rats were serially mated with untreated virgin females, two females per male. The females were sacrificed 17 day s after first being caged with exposed males and examined for evidence of pregnancy. Exposure of male rats to 1000 ppm
d iglyme was associated with a significant reduction in the pregnancy rate where only 50% of mated females showed evidence of implantatio ns. The pregnancy rate was further reduced in week s 5, 6 and 7 of mating to about 10% in

females that were mated with males ex posed to 1000 ppm d iglyme. Diglyme also affected male fertility and embryonic development.

Developmental Toxicity

Pregna nt CD

- 1 mice were administered d iglyme via gavage at 0 (water), 62.5, 125, 250 or 500 mg/kg

- bw/day daily during gestation days 6

- 15 and were sacrificed on day 17. Uterine contents were evaluated for the number of implantations, resorptions, late fetal deaths a nd live fetuses. Skeletal and external morphological abnormalities and
visceral examinations of fetuses were conducted. Maternal body, uterus and liver weights were significantly decreased at the two high doses. Doses of 125 mg/kg

- bw/day and above prod uced adverse effects on fetal growth, percent implantations, post implantation losses, fetal viability and fetal morphological develo pment. At the highest
dose , 94% of the fetuses were malformed compared to 0.35% of the fetuses in the control group.
LOAEL (maternal toxicity) = 250 mg/kg

- bw/day (based on decreases in body, uterus and liver weights) NOAEL ( maternal toxicity ) = 125 mg/kg

- bw/day LOAEL (developmental toxicity) = 125 mg/kg

- bw/day (based on adverse effects on fetal growth, fetal viability

and mor phological development and malformations) NOAEL (developmental toxicity) = 62.5 mg/kg

- bw/day

Genetic Toxicity

– Gene Mutation

In vitro Salmonella typhimurium strains TA98, TA 100 , TA 1535 and TA 1537 were exposed to diglyme at concentrations of 0, 100, 333, 1000, 3333 and 10,000 μ g/plate in the presence and absence of metabolic activation . No cytotoxicity was observed at any concentration. Positive controls were tested concurrently but their responses were not provided. Diglyme was non

- mutagenic in the pr esence and absence of metabolic activation in all four strains. Diglyme was not mutagenic in this assay.

Genetic Toxicity

– Chromosomal Aberrations

In vivo Sprague

- Dawley rats (10/sex/dose) were exposed to diglyme vapor at 0, 250 or 1000 ppm for 7 hours /day for 1 or 5 days. Animals exposed for one day only were sampled at 6, 24 and 48 hours after exposure and animals exposed for 5 days were sampled 6 hours after exposure. After the last exposure animals were injected with colchicine 2 hours prior to sa

crifice, at which time bone marrow was removed, fixed and stained for examination of metaphase (50 metaphases per rat were scored). Positive controls responded appropriately. The only significant increase in
abberations occurred in one low

- dose male expo sed for 1 day. A slight increase in total aberrations was also observed in males exposed to 250 ppm. The increase in aberrations was observed only in males and was not dose

related. The robust summary includes very brief summaries of other studies that support the non

- clastogenic findings of this study. Diglyme did not induce chromosomal aberrations in this assay.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 13 Conclusion: The acute toxicity of d iglyme to rats via oral and inhalation routes is low. The target organs for toxicity following r epeated exposure to d iglyme via inhalation were testes (decreased sperm production) and bone marrow (hypoplasia). Other major effects were anemia (reduction in red blood cell count, hemoglobin, hematocrit and platelet count) and lymphoid tissue atrophy of the spleen and thymus (in male and female rats). A reproductive toxicity test was not submitted to address the reproductive toxicity endpoint , but data submitted from a dominant

lethal test indicates diglyme has the potential to cause reproductive toxici ty in male rats. Diglyme affected pregnancy frequency and developing conceptuses (post

- implantation loss, fetal growth, viability morphological development). Diglyme did not induce gene mutation in vitro or chromosomal aberration s in vivo.

The potent ial health hazard of diglyme is high based on repeated

- dose (blood and blood

- forming organs) and developmental toxicity . Available data (dominant

- lethal test) indicate that diglyme has the potential to cause reproductive toxicity.

4. Hazard Characteriza tion

Diglyme is a liquid at room temperature. It is miscible with water, has high vapor pressure, and is not significantly volatile from water. It is highly mobile in soil, does not bioaccumulate (is rated B1), and does not hydrolyze under
environmental pHs. In the atmosphere, it is expected to photodegrade within one day . Based on experimental data for diglyme and analogs, biodegradation of diglyme is expected to be slow and the substance is judged to be moderately persistent (P2).

T he evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants indicate s the potential acute hazard of diglyme t o aquatic organisms is low

.

The acute toxicity of d iglyme to rats via oral and inhalation routes is low. The target organs for toxicity following repeated exposure to d iglyme via inhalation were testes (decreased sperm production) and bone marrow (hypoplasia). Other major effects were anemia (reduction in red blood cell count, hemoglobin, hematocrit and platelet count) and l ymphoid tissue atrophy of the spleen and thymus (in male and female rats). A reproductive toxicity test was not submitted to address the reproductive toxicity endpoint , but data submitted from a dominant

lethal test indicates diglyme has the potential to cause reproductive toxicity in male rats. Diglyme affected pregnancy frequency and developing conceptuses (post

- implantation loss, fetal growth, viability morphological development). Diglyme did not induce gene mutation in vitro or chromosomal aberration s in vivo.

The potential health hazard of diglyme is high based on repeated

- dose (blood and blood

- forming organs) and developmental toxicity . Available data (dominant

- lethal test) indicate that diglyme has the potential to cause reproductive toxicity.

5. Data Gaps

No data gaps were identified under the HPV Challenge Program.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 14 APPENDIX

Summary Table of the Screening Information Data Set
as Submitted u nder the U.S. HPV Challenge Program

Endpoints SPONSORED CHEMICAL Diglyme ( 111

- 96

- 6 ) Summary of

Environmental Effects

–Aquatic Toxicity Data
Fish
96

- h LC 50 (mg/L) > 2000 Aquatic Invertebrates
48

- h EC 50 (mg/L) > 1000 Aquatic Plants
72

- h EC 50 (mg/L) (growth) > 1000 Summary of Human Health Data Acute Oral Toxicity

LD 50 (mg/kg

- bw) 7500

A cute Inhalation Toxicity
LC 50 (mg/L/6h/day) > 11

–14 Repeated

- Dose Toxicity NOAEL/LOAEL (mg/ L /day)
Inhalation LOAEL (male )

~ 0.60 (14

- d ) LOAEL (fe male)

~

6.0 (14

- d) )

Reproductive Toxicity NOAEL/LOAEL (mg/kg

- bw/day) A reproductive toxicity test was not submitted to address the reproductive toxicity endpoint. Data submitted from a dominant

lethal test indicate diglyme has the potential to cause reproductive

toxicity via male germ cell mutations. Developmental Toxicity NOAEL/LOAEL (mg/kg

- bw/day)
Mat ernal Toxicity

Developmental Toxicity LOAEL = 250
NOAEL = 125

LOAEL = 125
NOAEL = 62.5 Genetic Toxicity

–Gene Mutation
In vitro Negative Genetic Toxicity

–Chromosomal Aberrations
In vitro NegativeU.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 15 REFERENCES

Ferro Corporation. 2003. Diglyme. R obust Summaries & Test Plans. Submitted to U.S. EPA HPV Challenge Program. http://www.epa.gov/chemrtk/pubs/summaries/diglyme/c15023tc.htm

FR 1999, Category for Persistent, Bio accumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) Page 60194

- 60204

HSDB. 2007. Hazard Substances Data Base. As cited in HSDB record for Diglyme. Accessed August 28, 2007. http://toxnet.nlm.nih.gov/cgi

- bin/sis/htmlgen?HSDB

.

OECD. 2006. Revised Introduction to the Organization for Economic Cooperation and Development (OECD) Guidelines for Testing of Chemicals, Section 3 (adopted 23 March 200 6), paragraph 36. Available from Source
OECD at http://masetto.sourceoecd.org

.

USEPA. 2005. COMMENTS ON ROBUST S UMMARIES & TEST PLAN S: DIGLYME
http://www.epa.gov/chemrtk/pubs/summaries/diglyme/c15023tc.htm

US EPA. 2000. Interim Guidance for Using Ready and Inherent Biodegradability Tests to Derive Input Data for Multimedia Models and Wastewater Treatment Plants (WWT) Models (9/1 /2000). Part 2, Using Ready and Inherent Biodegradability Data to Derive Input Data for the EQC Model, Table 1. http://www.epa.gov/oppt/exposure/pubs/halflife.htm#eqc

.

USEPA. 2007. EP I SuiteTM (version 3.2) PC

- Computer software developed by the EPA Office of Pollution Prevention Toxics and Syracuse Research Corporation. http://www.epa.gov/opptintr/exposure/pubs/episu ite.htm

.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 16 

## Screening Level Exposure Characterization for HPV

Challenge Chemical

Bis (2

- Methoxyethyl) ether (Diglyme)

CAS #111

- 96

- 6

March 14 , 2008

Prepared by

Exposure Asses s ment Branch Chemical Engineering Branch Economics Expos ure and Technology Division
Office of Pollution Prevention and Toxics Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460

- 0001U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 17 

# Screening Level Exposure Characterization for HPV

Challenge Chemical

Bis (2

- Methoxyethyl) ethe r (Diglyme)

CAS #111

- 96

- 6

Non

- CBI Executive Summary

Diglyme [bis (2

- methoxyethyl) ether] is used as a reaction solvent for Grignard

- reactions,
reduction

- reactions, alkylation

- reactions, and organo

- metallic reactions in general. Other applications inclu

de in the coating industry and in photolithography for manufacture of semiconductor chips (Ferro, 2003)

.

Diglyme wa s manufactured and/or imported in the United States in calendar year 2005 (USEPA, 2006)

. This chemical has an aggregated volume produced an d/or imported in the range of one million to ten million pounds. Persons submitting Inventory Update Reporting (IUR)
information in 200 6 asserted that some of the information was confidential business information (CBI) and therefore cannot be disclosed

. Data and information that are CBI have been excluded from this summary.

Exposure was characterized using both public, non

- confidential sources and one or more IUR submissions available at the time the exposure characterization was written. If additional information warrants an update of the exposure characterization, the update will be posted on the
EPA website.

The chemical is not on the Toxics Release Inventory (USEPA, 2007a). A SIDS dossier has not been prepared for this chemical.

Exposure to Worker

s

This chemical has a vapor pressure of 2.96 torr at 25°C (USEPA, 2007b). OPPT has established 0.001 torr as a value above which worker exposures to vapors should be estimated for chemical assessments. Therefore, this chemical’s vapor pressure could res ult in worker exposure to vapors if workers were proximal to the liquid. This chemical does not have an OSHA Permissible Exposure Limit (NIOSH, 2007). The National Occupational Exposure Survey (NOES), which was conducted between 1981 and 1983, estimated a total of 207 workers potentially exposed to this chemical (NIOSH, 2007b). Based on IUR reporting, the maximum total number of workers likely to be exposed to this chemical during manufacturing and industrial processing and use is
between 100 and 999. T

here may be additional potentially exposed workers that are not included in this estimate since not all production volume has been accounted, and there is at least one useU.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 18 that contains a "Not Readily Obtainable" (NRO) response among the submissions. The IUR based ranking for worker exposure is high.

Differences between numbers of workers estimated by IUR submitters and by the NOES are attributable to many factors, including time, scope, and method of the estimates. For example,
NOES estimates are for all workplaces while IUR are for industrial workplaces only, and NOES used a survey and extrapolation method while IUR submitters simply provide their best estimates based on available information for the specific reporting year.

Exposure to General Populati on and the Environment

The chemical is not on the Toxics Release Inventory (USEPA, 2007a). Based on the totality of the information considered and expert judgment, it is assumed that potential environmental releases and subsequent exposures to the genera l population and the environment are likely.

EPA assumes

, for the purpose of this risk based prioritization, that the potential for exposures to the general population and the environment is high.

Diglyme is stable in water and not readily biodegradabl e; therefore diglyme is moderately persistent (P2). Diglyme is (B1) for bioaccumulation because its estimated BCF is 0.3 (USEPA, 2007b).

Exposure to Commercial Workers and Consumers

This chemical has a vapor pressure of 2.96 torr at 25°C (USEPA, 2007b). OPPT has established 0.001 torr as a value above which worker exposures to vapors should be estimated for chemical assessments. Therefore, this chemical’s vapor pressure could result in worker exposure to vapors if workers were proximal to the liquid. N on

- CBI IUR information indicates exposure to diglyme by commercial workers or consumers through adhesives and sealants, automotive care products, and paints and coatings. The IUR ranking for commercial workers and consumers is high due to
the likelihood t

hat there will be exposure to this chemical.

Exposure to Children

There is the possibility of exposure to children from products containing diglyme. The submitter(s) indicated that the product use information for children was not readily obtainable.
T he IUR ranking for children exposure is moderate that this chemical is used in products intended to be used by children, but there is uncertainty in the IUR data.U.S. Environmental Protection Agency 3 / 18/ 2008 Supporting Doc uments for Risk

- Based Prioritization



### 19 References

Ferro, 2003. Diglyme U.S. EPA HPV Challenge Program Submission. Ferro Corporat ion. 29 December 2003. http://www.epa.gov/chemrtk/pubs/summaries/diglyme/c15023tp.pdf

HSDB, 2007. Hazardous Substances Data Bank. Accessed December 2007, DIETHYLENE
GLYCOL DIMETHYL ETHER http://toxnet.nlm.nih.gov/cgi

bin/sis/search/f?.temp/~9aU4jq:1

NIOSH, 2007. OSHA PEL Project Documentation. Accessed August, 2007. http://www.cdc.gov/niosh/pel88/npelcas.html

NIOSH , 2007b. National Occupational Exposure Survey (NOES). Accessed December 2007. http://www.cdc.gov/noes/noes2/83728occ.html

USEPA, 2006. 2006 Partial Updating of TSCA Chemical Inventory.

USEPA , 2007a. Toxic Release Inventory. Accessed August, 2007. http://www.epa.gov/tri/

USEPA 2007b

. Physical/Chemical and Environmental Fate Characterization for High Production
Volume Chemicals Chemical Name: Diglyme