Ethyl Ether Toxicological Summary Minnesota Department of Health

Health Based Guidance for Water

ealth Risk Assessment Unit, Environmental Health Division

651-201-4899

Ethyl Ether - 1 of 5

Web Publication Date: June 2016

Expiration Date: June 2021

Toxicological Summary for: Ethyl Ether

CAS: 60-29-7

Synonyms: Anesthesia Ether, Diethyl Ether, Diethyl Oxide, Ethane, 1,1’-Oxybis-Ether,

Ether, Ethyl, Ethoxyane, Ethyl Oxide, 3-Oxapentane, 1,1’-Oxybisethane,

Solvent Ether

Acute Non-Cancer Risk Assessment Advice (nRAA

Acute

) = Not Derived (Insufficient Data)

Short-term Non-Cancer Risk Assessment Advice (nRAA

Short-term

) = Not Derived (Insufficient Data)

Subchronic Non-Cancer Risk Assessment Advice (nRAA

Subchronic

) = 1000 µg/L

(Reference Dose, mg/kg-d) x (Relative Source Contribution) x (Conversion Factor)

(Subchronic Intake Rate, L/kg-d)

= (0.42 mg/kg-d) x (0.2)

x (1000 µg/mg)

(0.070 L/kg-d)

= 1200 rounded to 1000 µg/L

Relative Source Contribution: MDH 2008, Section IV.E.1.

Intake Rate: MDH 2008, Section IV.E.1. and US EPA 2011, Exposure Factors Handbook, Tables 3-1 and 3-81

Reference Dose/Concentration: (500 x 0.25)/300 =0.42 mg/kg-d (Sprague Dawley

Rat)

ource of toxicity value: determined by MDH in 2015

oint of Departure (POD): 500 mg/kg-d (NOAEL, as cited by EPA IRIS 1993

and EPA NCEA 2009)

Human Equivalent Dose (MDH, 2011): 500 x 0.25 = 125 mg/kg-d

otal uncertainty factor (UF): 300

Uncertainty factor allocation: 3 for interspecies differences (for toxicodynamics),

10 for intraspecies variability, and 10 for database

uncertainty (due to lack of data in other species, no

oral 2-generation developmental or reproductive

studies, and no oral studies evaluating behavior

and endocrine effects)

Critical effect(s): Decreased body weight; anesthesia, increased

relative liver weight

Co-critical effect(s): None

Additivity endpoint(s): Hepatic (liver) system, Nervous system

Ethyl Ether - 2 of 5

Chronic Non-Cancer Risk Assessment Advice (nRAA

Chronic

) = 200 µg/L

(Reference Dose, mg/kg-d) x (Relative Source Contribution) x (Conversion Factor)

(Chronic Intake Rate, L/kg-d)

= (0.042 mg/kg-d) x (0.2)

x (1000 µg/mg)

(0.044 L/kg-d)

= 191 rounded to 200 µg/L

Relative Source Contribution: MDH 2008, Section IV.E.1.

Intake Rate: MDH 2008, Section IV.E.1. and US EPA 2011, Exposure Factors Handbook, Tables 3-1 and 3-81

Reference Dose/Concentration: (500 x 0.25)/3000 = 0.042 mg/kg-d (Sprague

Dawley Rat)

Source of toxicity value: determined by MDH in 2015

Point of Departure (POD): 500 mg/kg-d (NOAEL, as cited by EPA IRIS 1993

and EPA NCEA 2009, subchronic duration)

Human Equivalent Dose (MDH, 2011): 500 x 0.25 = 125 mg/kg-

Total uncertainty factor (UF): 3000

ncertainty factor allocation: 3 for interspecies differences (for toxicodynamics),

10 for intraspecies variability, 10 for database

uncertainty (due to lack of data in other species, no

oral 2-generation developmental or reproductive

studies, and no oral studies evaluating behavior

and endocrine effects), 10 for use of sub-chronic

study

Crit

ical effect(s): Decreased body weight, anesthesia, increased

relative liver weight

Co-critical effect(s): None

Additivity endpoint(s): Hepatic (liver) system, Nervous system

Cancer Health Based Value (cRAA) = Not Derived

ancer classification: Not classified

lope factor (SF): Not applicable

Source of cancer slope factor (SF): Not applicable

Tumor site(s): Not applicable

Volatile: Yes (high)

Summary of Guidance Value History:

A noncancer Chronic HRL of 100 ug/L was promulgated in 1993. Noncancer Subchronic and

Chronic RAAs of 1000 and 200 ug/L were derived in 2010. The 2010 Chronic RAA was lower

than the previous HRL as a result of: 1) a re-evaluation of the toxicity data; 2) updated MDH risk

assessment methodology; and 3) rounding to one significant digit. In 2016, MDH evaluated the

available toxicity data and recalculated the non-cancer RAAs using MDH’s most recent

assessment methodology, which resulted in no changes to any value.

Ethyl Ether - 3 of 5

Summary of toxicity testing for health effects identified in the Health Standards Statute (144.0751):

Even if testing for a specific health effect was not conducted for this chemical, information about that effect might be

available from studies conducted for other purposes. MDH has considered the following information in developing

health protective guidance.

Endocrine

Immunotoxicity

Development

Reproductive

Neurotoxicity

Tested for

specific effect?

Yes Yes Yes Yes

Yes

Effects

observed?

Yes

Comments on extent of testing or effects:

Endocrine effects were only evaluated in inhalation studies. Mice exposed to ethyl ether at

1000 to 30,000 ppm experienced increases in plasma corticosterone and plasma

adrenocorticotrophic hormone (ACTH) levels. The increases were only significant for

corticosterone at 10,000 ppm and the statistical significance of the ACTH increases were not

reported.

Immunological effects were only evaluated in inhalation studies exposed to multiple anesthetic

agents, which included ethyl ether. Effects included loss of complement activity, suppression of

peripheral blood lymphocyte blastogenic response, an effect in B-cell response, and inhibition of

the induction of splenic natural killer cell activity. However, it was unclear whether the effects

were due to the general state of anesthesia or the chemical agents themselves.

Developmental effects were only evaluated in inhalation studies. Decreased health growth and

increased frequency of skeletal variation were seen in offspring born to female mice exposed to

ethyl ether by inhalation on gestation days 9 through 12. There was a significant increase in the

number Purkinjie cells of the cerebellum in offspring of female rats exposed 2 times during

gestation days 17 through 21. Offspring exposed early in organogenesis (the period where

organs and organ systems are forming during embryonic development) experienced

hydronephrosis and increased resorptions occurred while mice exposed later in organogenesis

experienced increased skeletal abnormalities. Rats exposed to ethyl ether early and later in

organogenesis experienced decreased body weight and decreased long bone length.

Reproductive effects were only evaluated in inhalation studies. Male rats exposed as newborn

infants to ethyl ether at anesthetic levels experienced decreased fertility as adults. Among 110

female anesthesiologists, 18 out of 31 pregnancies resulted in spontaneous abortions and those

that had abnormal pregnancies were exposed for 25 hours/week or more and those with normal

pregnancies were exposed for less than 15 hours/week. The effects observed in this study were

not linked to ethyl ether exclusively because the anesthesiologists were exposed to unknown

quantities of several different anesthetic agents.

Humans experienced anesthetic effects from inhalation of ethyl ether at concentrations ranging

from ~20,000 ppm up to ~150,000 ppm. Workers exposed to ~1200 mg/m

(exposure levels not

directly measured) reported dizziness, headaches, mood instability, fatigue, sleep disturbances,

difficulty concentrating, sexual dysfunction, and peripheral neuropathy. Anesthetic effects were

seen in rats exposed to 3500 mg/kg-day by oral gavage and an increase in response rates were

Ethyl Ether - 4 of 5

observed in mice that inhaled ethyl ether at 1000 to 10,000 ppm with an extinguishment of

response at all doses in animals exposed for 30 minutes.

Resources Consulted During Review:

ATSDR (Agency for Toxic Substances and Disease Registry). Minimal Risk

Levels. http://www.atsdr.cdc.gov/mrls.html

and Toxicological Profiles -

http://www.atsdr.cdc.gov/toxpro2.html

California Environmental Protection Agency, OEHHA Toxicity Criteria Database.

http://www.oehha.ca.gov/risk/ChemicalDB/index.asp

and

http://www.oehha.ca.gov/risk/pdf/cancerpotalpha81005.pdf

California Water Resources Control Board

http://www.waterboards.ca.gov/water_issues/programs/water_quality_goals/

Environmental Protection Agency (EPA). 1986. Rat oral subchronic study with ethyl ether.

Prepared by American Biogenics Corporation for the Office of Solid Waste, Washington, DC.

(as cited by IRIS 1993 & NCEA 2009)

EPA Health Effects Assessment Summary Tables (HEAST). July 1997.

EPA Integrated Risk Information System (IRIS) 1993. Ethyl Ether (CASRN 60-29-7)

http://www.epa.gov/ncea/iris/subst/0423.htm

EPA National Center for Environmental Assessment (NCEA). 2009 Provisional peer reviewed

toxicity values for ethyl ether (diethyl ether) (CASRN 60-29-7). Superfund Health Risk Technical

Support Center, NCEA, U.S. EPA.

EPA Office of Drinking Water http://www.epa.gov/waterscience/criteria/drinking/dwstandards.pdf

EPA Office of Pesticide Programs http://www.epa.gov/pesticides/reregistration/status.htm

EPA Toxicity and Exposure Assessment for Children's Health (TEACH)

http://www.epa.gov/teach/

EPA Voluntary Children's Chemical Evaluation Program (VCCEP)

http://www.epa.gov/oppt/vccep/pubs/chemmain.htm

European Union Pesticides Database

http://ec.europa.eu/food/plant/protection/evaluation/database_act_subs_en.htm

Health Canada Existing Substances - Priority Substances Assessment Program and Screening

Assessment Reports: http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/index-eng.php#existsub

International Agency for Research on Cancer (IARC). Agents Reviewed by the IARC

http://monographs.iarc.fr/ENG/Classification/index.php

International Programme on Chemical Safety http://www.who.int/ipcs/assessment/en/

Ethyl Ether - 5 of 5

International Toxicity Estimates for Risk (ITER) http://iter.ctcnet.net/publicurl/pub_search_list.cfm

National Toxicology Program http://ntp-server.niehs.nih.gov/

NIOSH. 1993. NEG and NIOSH basis for an occupational health standard: Ethyl Ether. U.S.

Department of Health and Human Services, Public Health Service, CDC. Link to abstract:

http://md1.csa.com/partners/viewrecord.php?requester=gs&collection=TRD&recid=20070431102306C

E&q=&uid=1079016&setcookie=yes

Oak Ridge National Laboratory. Screening Levels for Chemical Contaminants. http://epa-

prgs.ornl.gov/chemicals/download.shtml

Syracuse Research PhysProp Database. http://www.syrres.com/esc/physdemo.htm

TOXNET search http://toxnet.nlm.nih.gov/

U.S. Geological Survey http://infotrek.er.usgs.gov/traverse/f?p=HBSL:HOME:0

Wisconsin Department of Health Services. 2009. Scientific support document for Cycle 9

revisions of NR 140.10, Groundwater enforcement standard and preventive action limit

recommendations (includes Ethyl Ether). Division of Public Health, Wisconsin Department of

Health Services.

WHO Recommended Classification of Pesticides by Hazard. 2004.

http://www.who.int/ipcs/publications/pesticides_hazard_rev_3.pdf

World Health Organization:

http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html

(search Chapter 8

Chemical Aspects and Chapter 12 Chemical Fact Sheets for chemical name)