### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

[OPTS-41023; FRL-3109-7]

Nineteenth Report of the Interagency Testing Committee tothe Administrator; Receipt and Request for Comments Regarding Priority List of Chemicals
AGENCY: Environmental Protection Agency (EPA). ACTION: Notice.
SUMMARY: The Interagency Testing Committee (ITC), established under section 4(e) ofthe Toxic Substances Control Act (TSCA),transmitted its Nineteenth Report to the Administrator ofEPA on October 31, 1986. This report, which revises and updates the Committee's priority list ofchemicals, adds four chemicals to the list for priority consideration by EPA in the promulgation oftest rules under section 4(a) ofthe Act. Thenew chemicals are isopropanol, C.I. Disperse Blue 79, methyl tert-butyl ether, and methyl ethyl ketoxime. These chemicals are not designated for response Within 12 months. One substance previously recommended with intent to designate, tributyl phosphate (51 FR 18368), is now designated for response within 12 months. The Nineteenth Report is included in this notice. The Agency invites interested persons to submit written comments on the Report, and to attend a Focus Meeting to help narrow and focus the issues raised by the ITC's recommendations. Members ofthe public are also invited to inform EPAif they wish to be notified ofsubsequent public meetings on these chemicals. ITC also notes the removal offive chemicals from the priority list because EPA has responded to the ITC'sprevious recommendations for testing ofthe chemicals. DATES: Written comments should be submitted by December 15, 1986. Focus Meetings willbe held on December 16 and 17, 1986. ADDRESSES: Sendwritten submissions
to: TSCA Public Information Office (TS793), Office ofPesticides and Toxic Substances, Environmental Protection Agency, Rm. NE G-404, 401 M St., SW., Washington, DC 20460. Submissions should bearthe document control number (OPTS-41023).

The public record supporting this action, including comments, is available for public inspection in Rm. NE G-004 at the address noted above from 8 a.m. to 4 p.m. Monday through Friday, except legal holidays. Focus Meetings will be held atEPA Headquarters, Rm. 103 NE Mall, 401 M St., SW., Washington, DC. Persons planning to attend the Focus Meetings and/or seeking to be informed ofsubsequent public meetings on these chemicals, should notify the TSCA Assistance Office at the address listed below. To ensure seating accommodations at the Focus Meetings,
persons interested in attending are asked to notify EPA at least one week ahead ofthe scheduled date.

FOR FURTHER INFORMATION CONTACT: Edward A. Klein,Director, TSCA Assistance Office (TS-799), Office of Toxic Substances, Environmental Protection Agency, 401 M St., SW., Washington, DC. 20460, (202-554-1404).

SUPPLEMENTARY INFORMATION: EPA has received the Report ofthe TSCA Interagency Testing Committee to the Administrator.

I. Background

TSCA (Pub.L. 94-469, 90 Stat. 2003 et seq;15 U.S.C. 2601 etseq.) authorizes the Administrator of EPA to promulgate regulations under section 4(a) requiring testing of chemical substances and mixtures in order to develop data relevant to determining the risks that such chemical substances and mixtures may present to health and the environment.

Section 4(e) ofTSCA established an Interagency Testing Committee to make recommendations to the Administrator ofEPA of chemical substances and mixtures tobe given priority consideration inproposing test rules under section 4(a). Section 4(e) directs the Committee to revise its list of recommendations at least every 6 months as necessary. The ITC may "designate" up to 50 substances and mixtures at any one time for priority consideration by the Agency. For such designations, the Agency must within 12 months either initiate rulemaking or issue in the Federal Register its reasons for not doing so.The ITC's Nineteenth Report was received by the Administrator on October 31, 1986, and follows this Notice. The Report adds four substances to the TSCA section4(e) priority list.

II. Written and Oral Comments and Public Meetings

EPA invites interested persons to submit detailed comments on the ITC's

new recommendations. The Agency is interested in receiving information concerning additional or ongoing health and safety studies on the subject chemicals as well as information relating to the human and environmental
exposure to these chemicals. A notice is published elsewhere in today's Federal Register adding the substances recommended in the ITC's Nineteenth Report to the TSCA section 8(d) Health and Safety Data Reporting Rule (40 CFR Part 716). The section 8(d) rule requires the reporting ofunpublished health and safety studies on the listed chemicals. These chemicals will also be added to the TSCA section 8(a) Preliminary Assessment Information Rule (40 CFR Part 712) published elsewhere in this issue.The section 8(a) rule requires the reporting ofproduction volume, use, exposure, and release information on the listed chemicals.

Focus Meetings willbe held to discuss relevant issues pertaining to these chemicals and to narrow the range of issues/effects which willbe the focus of the Agency's subsequent activities in responding to the ITC recommendations. The Focus Meetings willbe held on December 16 and 17, 1986 at EPA Headquarters, Rm. 103 NE Mall, 401 M St., SW., Washington, DC. This meeting is intended to supplement and expand upon written comments submitted in response to this notice. The schedule for theFocus Meetings is as follows: December 16, 10 a.m.-isopropanol; 1 p.m.-C.I. Disperse Blue 79. December 17, 10 a.m.-methyl tert-butyl ether; 1 p.m.-methyl ethyl ketoxime.

Persons wishing to attend this meeting

or subsequent meetings on these chemicals should call the TSCA Assistance Office at the toll free number listed above at least oneweek in advance.

All written submissions should bear the identifying docket number (OPTS41023).

III. Status ofList

In addition to adding the four recommendationsto thepriority list, the ITC's Nineteenth Report notes the removal offive chemicals from the list since the last ITCreport because EPA has responded to the Committee's prior recommendations for testing of the chemicals. Subsequent to the ITC's preparation ofits Eighteenth Report, EPA responded to the ITC's recommendations for six additional chemicals. The five chemicals removed and the dates ofpublication in the Federal Register ofEPA's responses to the ITC for these chemicals are: methylcyclopentane, May 15, 1986 (51 FR 17854); tetrabromobisphenol A, May 15, 1986 (51 FR 17872); triethylene glycol monomethyl ether,May 15, 1986 (51 FR 17883); triethylene glycol monobutyl ether, May 15, 1986 (51 FR 17883); triethylene glycol monobutyl ether, May 15, 1986 (51 FR 17883). Thereport also notes that tributyl phosphate, which was originally recommended with intent to designate (51 FR 18368, May 19, 1986), has now 

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### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

been designated for response within 12 months by the ITC.

The current list contains three designated substances. two chemicals recommended with intent-to-designate, and four recommended substances.

Authority: 15 U.S.C. 2603. Dated: November 6. 1986. J.Merenda, Director, ExistingChemical Assessment Division.

Nineteenth Report ofthe TSCA Interagency Testing Committee to the Administrator, Environmental Protection Agency Summary
Section 4 ofthe Toxic Substances Control Act of 1976 (TSCA, Public Law 94-469) provides for the testing of chemicals in commerce that may present

an unreasonable risk of injury to health

or the environment. It also provides for the establishment ofa Committee (ITC), composed ofrepresentatives from eight designated Federal agencies, to recommend chemical substances and mixtures (chemicals) to which the Administrator ofthe U.S. Environmental Protection Agency (EPA) should give priority consideration for the promulgation of testing rules.

Section 4(e](1)(A) ofTSCA directs the Committee to recommend to the EPA Administrator chemicals to which the Administrator should give priority consideration for the promulgation of testing rules pursuant to section 4(a). The Committee is required to designate those chemicals, from among its recommendations, to which the Administrator should respond within 12 months by either initiating a rulemaking proceeding under section 4(a) or publishing the Administrator's reason fornot initiating such a proceeding. At least every 6 months, the Committee makes those revisions in the TSCA section 4(e) Priority List that it determines to be necessary and transmits them to the EPA Administrator.

As a result of its deliberations, the Committee is revising theTSCA section 4(e) Priority Listby the addition offour chemicals, and is noting the removal of five as a result ofresponses by EPA. The Committee also is designating one chemical that had been recommended with intent-to-designate in the eighteenth report.

The Priority List is divided into three parts: PartA contains those recommended chemicals and groups designated for priority consideration and response by the EPA Administrator within 12 months. Part B contains chemicals and groups recommended with intent-to-designate. This category

was established by the Committee in its seventeenth report (50 FR 47603; November 19, 1985) to take advantage of rules promulgating automatic reporting requirements fornondesignated ITC recommendations under the section 8(a) Preliminary Assessment rule and the TSCA section 8(d) Health and Safety Data Reporting rule. Information received following recommendation with intent-to-designate may influence the Committee to either designate or not designate the chemical or group of chemicals in a subsequent report to the Administrator. Part C contains chemicals and groups of chemicals that have been recommended for priority consideration by EPWwithout being designated for response within 12 months. The changes to the Priority List

are presented, together with the types of testing recommended, in the following Table 1:

TABLE 1.-ADDITIONS TO THE SECTION 4(e) PRIORITY LIST, NOVEMBER 1986

Chemical/Group Recommended Studies

A. Designated for

Response Within 12 Months Tributyl phosphate'

(CAS No. 126- 73-8)

B. Recommended

With Intent-IoDesignate Isopropanol I(CAS

No. 67-63-0).

Methyl tert-butyl

ether3 (CAS No. 1634-04-4).

C. Recommended

Without Being Designated for Response Within 12 Months
C.I.Disperse Blue

79 4 (CAS No. 3956-55-6). Health Effects: Chronic Toxicity including oncogenic, neurotoxic, renal, reproductive and developmental effects. Cherical Fate: Persistence in anaerobic soils and sediments. Ecological Effects: Chronic effects on

aquatic and terrestrial plants; chron- ic effects on daphnids and/or other aquatic invertebrates; acute and chronic effects on benthic organisms and soil invertebrates, if found persistent under anaerobic conditions.

Health Effects: Genotoxicity. including

tests for mutagenicity in mammalian systems and clastogenicity;. chronic toxicity including oncogenicly. Health Effects: Chronic inhalation toxicity including neurotoxic, hematologic and ocogenic effects. Chemical Fate: Monitoring at representative gasoline terminals and service stations.

Health Effects: Subchronic toxicity adsorption and chemical disposition.

Chemical Fate: Solubility in water, bio.

degradation under aerobic and anaerobic conditions and the identification, of arty relatively persistent biodegradation intermediates. Ecological Effects: Acute toxicity to

fish, aquatic invertebrates, algae and benthic organisms (including filter leeders); bioconcentration in fish; chronic effects on aquatic and bent'ic biota, if the. acute studies show toxicity at low mg/L concentration or it the dye does bioconcenrater TABLE 1.-ADDITIONS TO THE SECTION 4(e)

PRIORITY LIST, NOVEMBER 1986-Continued

Chemical/Group Recommended Studies

Methyl ethyl Health Effects: Chronic toxicity with

ketoxime 5 (CAS special emphasis on hematopoietic No. 96-29-7). and oncogenic effects.

CA Index Names (9CI): ePhospnonc acid. tributyl ester (tributyl phosphate was recommended with intent-to-designate by the Committee in the eighteenth report (51 FR 18368)). r2-Propanol. 3 Propane. 2-methoxy-2-methyl- 4Acetamide, N-[5-[bis[2-(acetyloxytethyllaminol-2-[(2- bromo-4,6-dinitrophenyl)azo]-4-ethoxypnenyl]-

52-Butanone oxime.

TSCA Interagency Testing Committee
StatutoryMemberAgencies andTheir Representatives Council on Environmental Quality

Harvey Doerksen. Member Department ofCommerce

Patrick D.Cosslett.Member Environmental Protection Agency

John D.Walker,Member and Vice

Chairperson Laurence S.Rosenstein, Alternate National Cancer Institute

Richard Adamson, Member Elizabeth K.Weisburger. Alternate National Institute ofEnvironmental Health Sciences James K.Selkirk, Member National Institute for Occupational Safety and Health Rodger L.Tatken, Member and

Chairperson National Science Foundation

RodgerW.Baler, Member Jarvis L.Moyers, Alternate Occupational Safetyand Health Administration JosephJarvis, Member' StephenMallinger. Alternate

LiaisonAgencies andTheirRepresentatives Consumer Product SafetyCommission

Lakshmi C. Mishra Department ofAgriculture

Richard M.Parry, Jr. EliseA.B.Brown Department ofDefense

Edmund Cummings Department ofthe Interior

Ronald Eisler 2 Food and DrugAdministration

Arnold Borsetti National Library ofMedicine

Vera Hudson National Toxicology Program

Dorothy Canter

CommitteeStaff Robert H. Brink, Executive Secretary Norma Williams, ITC Coordinator
SupportStaff Alan Carpien-Office of the General Counsel, EPA
The Committee acknowledges and is grateful for theassistance and support

I Appointed on August 11, 1986.
2Appointed on July 11. 1986. 

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### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

given the ITC by the staffof Dynamac Corporation (technical support contractor) and personnel ofthe EPA Office ofToxic Substances. Chapter 1-Introduction

1.1 Background.The TSCA Interagency Testing Committee (Committee) was established under section4(e) ofthe Toxic Substances Control Act of 1976(TSCA, Public Law 94-469). The specific mandate ofthe Committee is to recommend to the Administrator ofthe U.S. Environmental Protection Agency (EPA) chemical substances and mixtures in commerce that should begiven priority consideration for the promulgation of testing rules to determine their potential hazard to human health and/or environment. TSCA specifies that the Committee's recommendations shall be in the form ofa Priority List, which is to be published in the Federal Register. The Committee is directed by section 4(e)(1)(A) ofTSCA to designate those chemicals on the Priority List to which the EPA Administrator should respond within 12 months by either initiating a rulemaking proceeding under section 4(a) or publishing the Administrator's

reason fornot initiating such a proceeding. There is no statutory time limit for EPAresponse regarding chemicals that ITC has recommended but not designated for response within 12 months.

At least every 6 months, the Committee makes thoserevisions in the section 4(e) Priority List that it determines to be necessary and transmits them to the EPA Administrator.

The Committee is composed of representatives from eight statutory member agencies and seven liaison agencies. The specific representatives andtheir affiliations are named in the front ofthis report. The Committee's chemical review procedures and priority recommendations are described in previous reports (Refs. 1through 3).

1.2 Committee's previousreports. Eighteen previous reports to the EPA Administrator have been issued by the Committee and published in the FEDERAL REGISTER (Refs. I through 3). Ninety-three entries (chemicals and groups of chemicals) were recommended for priority consideration by the EPA Administrator and designated for
response within 12 months. In addition, five chemicals and one group of chemicals were recommended without being so designated.

1.3 Committee'sactivitiesduring thisreporting period. Between April 1, 1986, and September 30, 1986, the Committee continued to review 

### chemicals from its fourth and fifth scoring exercises, and from nominations by Member Agencies, Liaision Agencies and State Agencies.

The Committee contacted chemical manufacturers and trade associations to request information that would be of value in its deliberations. Most of those contacted provided unpublished information on current production,
exposure, uses, and effects ofchemicals under study by the Committee.

During this reporting period, the Committee reviewed available information on 26 chemicals and 7 large classes ofchemicals. Four chemicals

were selected for addition to the section 4(e) Priority List, and five were deferred indefinitely. The remaining chemicals

are still under study.

On August 7, 1986, the ITC published

an Intent-to-Designate notice (51 FR 28431) that listed hexamethylenediamine and described additional information needed by the ITC to reach a more informed decision on whether or not to designate hexamethylenediamine in a subsequent report to the EPA Administrator. The Committee requested information on biodegradation in aerobic ponds and under both aerobic and anaerobic conditions in disposal wells, in the
presence of other waste constituents typical ofhexamethylenediamine production. A deadline ofOctober 6, 1986 was provided for receipt of relevant information.

1.4 The TSCA section4(e)Priority List.Section 4(e)(1)(B) ofTSCA directs the Committee to: ".

. .make such revisions in the [priority] list as it determines to be necessary and. transmit them to the Administrator together with the Committee's reasons for therevisions." Under this authority, the Committee is revising the Priority List by adding fourchemicals: isopropanol, methyl tert-butyl ether, C.I. Disperse Blue 79, and methyl ethyl ketoxime. None ofthese chemicals is designated for response within 12 months but the Committee intends to designate isopropanol and methyl tertbutyl ether unless information received following recommendation influences the Committee to withhold designation. In addition, the Committee is designating forresponse within 12 months one chemical that wes recommended with intent-to-designate in the eighteenth report. The designated chemical is tributyl phosphate. The testingrecommended.for these chemicals and the rationales for the recommendations are presented in Chapter 2 ofthis report.

Five chemicals are being removed from the Priority List because the EPA Administrator has responded to the Committee's prior recommendations for testing them. They are listed in the following Table 2 with citations to EPA
responses:

TABLE 2-REMOVALS FROM THE TSCA SECTION 4(e) PRIORITY LIST APRIL 1, 1986
THROUGH SEPTEMBER 30, 1986

EPA Responses
Chemical/Group Federal Register Publication Date Citation

Methyl cyclopentane

. 51 FR 17854..... May 15, 1986. Tetrabromobisphenol A.. 51 FR 17872 May 15, 1986. Tnethylene glycol 51 FR 17883.May 15, 1986.

monomethyl ether. Triethylene glycol 51 FR 17883.May 15, 1986.

monoethyl ether. Triethylene glycol 51 FR 17883.May 15, 1986.

monobuyl ether.

Removal of87 entries was noted in previous reports (Ref.1through 3). To date, 92 chemicals and groups of chemicals have been removed from the Priority List.

With the fourrecommendations and five removals noted in this report, nine entries now appear on the section 4(e) Priority List. The Priority List is divided in the following Table 3 into three parts; namely, A. Chemicals and Groups of Chemicals Designated for Response Within 12 Months, B. Chemicals and Groups of Chemicals Recommended with Intent-to-Designate, and C. Chemicals and Groups of Chemicals Recommended Without Being Designated for Response Within 12 Months. Table 3follows:

TABLE 3.-THE TSCA-SECTION 4(e) PRIORITY LIST, NOVEMBER 1986

A. Chemicals and Groups of Chemicals

Recommended and Designated for Response Within 12 Months Entry and date of designation: 1.Cyclohexane

.. .......... ..................... 2. 2.6-Oiatert-butylphenol

............... 3. Tributyl phosphate

................... B. Chemicals and Groups of Chemicals Recommended with Intent-to-Designate
Entryand date of recommendation: 1.Isopropanol

........................ 2. MethyL fe/1-butyl ether

...................... C. Chemicals and Groups of Chemicals

Recommended Without Being Designated for Response Within 12 Months:

1.3,4.eichlorobenzotrifluonde

............... 2. Diisodecyl phenyl phosphite

............ 3. C.I. Disperse Blue 79

......................... 4. Methyl ethyl ketoxime

........................ May 1986. May 1986. Nov. 1986.

Nov. 1986. Nov. 1986.

May 1984, Nov. 1985. Nov. 1988. Nov. 1986.

References

(1)Sixteenth Report of theTSCA Interagency Testing Committee to the Administrator. Environmental Protection Agency. TSCA Interagency Testing Committee. May 21, 1985, 50 FR 20930-20939. 

### 41419Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

Includes references to Reports 1 through 15 and annotative list ofremovals.

(2)

Seventeenth Report of the TSCA Interagency Testing Committee to the Administrator, Environmental Protection Agency. TSCA Interagency Testing Committee, November 19,1985, 50 FR47603- 47612.

(3)Eighteenth Report of the TSCA Interagency Testing Committee to the Administrator, Environmental Protection Agency. TSCA Interagency Testing Committee, May 19, 1986, 51 FR 18368-18375.
Chapter 2-Recommendations of the Committee

2.1 Chemicalsrecommended for priority considerationby theEPA Administrator.As provided by section 4(e)(1)(B) ofTSCA, the Committee is adding the following chemical substances to the section 4(e) Priority List: isopropanol, methyl tert-butyl ether, C.I. Disperse Blue 79, and methyl ethyl ketoxime. The recommendation of these chemicals is being made after considering the factors identified in section 4(e](1)(A) and other relevant information, as well as the professional judgment ofCommittee members. In addition, the Committee is designating for response within 12 months one chemical substance that was recommended with intent-to-designate in the eighteenth report. The designated chemical is tributyl phosphate.

2.2 Chemicalsdesignated forresponse within 12 months-2.2.aTribulyl phosphate.In the eighteenth report to the Administrator ofEPA (51 FR 18368), tributyl phosphate was recommended with intent-to-designate. The rationale forthat recommendation appears in the eighteenth report. Information reviewed by the Committee in response to the eighteenth report included any public
comments on the Committee's recommendations; production volume,

use, exposure and release information reported by manufacturers of tributyl phosphate under the TSCA section 8(a) Preliminary Assessment rule; health and safety studies submitted under the TSCA section 8(d) Health and Safety Data Report rule; and any unpublished and published data available to the Committee. Health effects information included acute toxicity studies and skin and eye irritation studies (Ref. 1, Dow Chemical Co., 1986; Ref. 2, Eastman Kodak Co., 1986; Ref. 3, FMC Corp,, 1986; and RefL 6, Stauffer Chemical Co., 1986), mutagenicity (Ames test) data (Ref. 3, FMG Corp., 1986) and delayed neurotoxicity studies (Ref. 5, Monsanto Co., 1986). Chemical fate information included chemical and physical properties, biological oxygen demand, (BOD) data and-monitoringreports (Ref. 2, Eastman Kodak Co., 1986; Ref.3, FMC Corp., 1986; Ref. 4. Glyco, Inc., 1986; and Ref. 5 Monsanto Co., 1986). Ecological effects information included acute toxicity values with aquatic invertebrates and fish (Ref.5, Monsanto Co., 1986).

Afterreviewing the information, the Committee concluded that data are still lacking on chronic toxicity, chemical fate and ecological effects. For these

reasons and for the reasons previously presented (51 FR 18368) the Committee is now designating tributyl phosphate forresponse within 12 months and recommending that it be tested for the following:

1. Healtheffects. Chronic toxicity including oncogenic, neurotoxic, renal, reproductive and developmental effects.

2. ChemicalFate.Persistence in anaerobic soils and sediments.

3.Ecological Effects. Chronic effects

on aquatic and terrestrial plants; chronic effects on daphnids and/or other aquatic invertebrates; acute and chronic effects on benthic organisms and soil invertebrates, iffound persistent under anaerobic conditions.

References

(1)Dow Chemical Co., Midland, MI. Letter from R.L.Hagerman to Document Control Officer, U.S.EPA. August 15, 1986.

(2) Eastman Kodak Co.. Rochester, N.Y. Letter from R. HaysBell to U.S. EPA. August 11, 1986.

(3)FMC Corp., Philadelphia, PA. Letter from Ann S. Keller to U.S. EPA. August 8. 1986.

(4) Glyco, Inc.. Norwalk, CT. Letter from Michael J.Reale to U.S.EPA. August 8, 1986.

(5)Monsanto Co.. St.Louis, MO. Letter from J.R. Condray to Document Control Officer, Office ofPesticides and Toxic Substances, U.S. EPA. August 15, 1986.

(6) Stauffer Chemical Co., Westport, CT. Letter fromStauffer Chemical Co. to Document Control Office. Office ofToxicSubstances, U.S. EPA. August 12, 1986.

(7) Union Carbide Corp., Danbury, CT. Letter from D.L. Heywood to U.S. EPA. August 11, 1986.

2.3 Chemicalsrecommendedwith intent-to-designate-2.3.aIsopropanolSummaryofrecommended studies.It is recommended that isopropanol be tested for the following:

1. HealthEffects. Genotoxicity studies, including tests for mutagenicity in mammalian systems and for clastogenicity Chronic toxicity, including oncogenicity. PhysicalandChemicalInformation

CAS Number: 67-63-0 Synonyms: 2-propanol (9CI); dimethylcarbinol;' isopropyl alcohol Acronym: IPA Structural Formula: 

## OH 

# I
CH 3 

## --CH -CH 3

Empirical Formula: C31I0 Molecular Weight: 60.11 Melting Point: -87.8°C (Ref. 29, Mellan, 1977) Boiling Point: 82.3°C (Ref. 29, Mellan, 1977) Vapor Pressure: 33.0 mmHg at 20°C (Ref. 29, Mellan, 1977), 44.0 mmHg at 25°C (Ref. 7,Browning, 1965), 105.6 mmHg at 40°C (Ref. 18, Hatch, 1961) Solubility in Water: Miscible with water, insoluble in salt solutions (Ref. 56, Windholz, 1983) Solubilityin Organic Solvents: Miscible with ethanol, ether, and chloroform (Ref.56, Windholz, 1983) Specific Gravity: 0.79 at 20/20'C (Ref. 29 Mellan, 1977) Log Octanol/Water Partition Coefficient: (logP): 0.Z (estimated; Ref.27, Leo et al., 1971) Description of Chemical: colorless liquid

Rationale forRecommendations

I.Exposureinformation-A. Production/use/disposal/en vironmental release.The annual production capacities offour domestic producers of isopropanol -asofJanuary 1, 1985, totaled 2.5 billion pounds (Ref. 46, SRI, 1985). The 1985 U.S. production of isopropanol was reported to be 1.12 billion pounds, giving it the ranking of50
among the top 50 chemicals for that year (Ref.9, C&EN, 1986). The 1984 U.S. production ofisopropanol was reported

to be 1.39 billion pounds (Ref. 54, USITC, 1985), up from the 1983 production of 1.21 billion pounds (Ref. 53, USITC, 1984) but down from the 1980 production of 1.21 billion pounds (Ref. 52, US1TC, 1981).

Imports of isopropanol in 1985 totaled 136.2 million pounds (Ref.49, USDOC, 1986a). Exports in 1985 accounted for 178.4 million pounds.(Ref.50, USDOC, 1986b).

Most isopropanol produced in the United States is manufactured by the indirect hydration process. In this twostep process,,propylene reacts first with sulfuric acid; the products are then hydrolyzed to isopropanol and sulfuric acid (Ref. 45. SRI, 1980).

Isopropanol has a large number of

uses. The percentage breakdown of isopropanol demand for 1984 was estimated to be the following: production ofacetone (24 percent), coatings and related solvents (15 percent), other solvents (11 percentl. 

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### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

pharmaceuticals (11 percent), household and personal products (11 percent), chemical process solvents (9 percent), chemical intermediates (7 percent), and gasoline additives (4 percent). Exports
account for the other 8 percent (Ref. 12, CMR, 1984).

It has been estimated that 50 percent ofcommercial isopropanol is ultimately released to the environment. An additional 1.5 percent is estimated to be lost during production (Dorigan et al., 1976, cited in Ref.51, USEPA, 1979).

B.Evidenceforhumanand environmentalexposure.The National Occupational Hazard Survey (NOHS), conducted by the National Institute for Occupational Safety and Health (NIOSH) from 1972 to 1974, estimated that 5,483,862 workers in 357,173 plants

were potentially exposed to isopropanol in the workplace (Ref.32, NIOSH, 1976a). These estimates were derived

- from observations ofthe manufacture and use ofthe compound, oftrade name products knowri to contain the compound, and ofgeneric products suspected to contain the compound (19, 40, and 42 percent ofthe total estimate, respectively).

NIOSH conducted a second workplace survey, theNational Occupational Exposure Survey (NOES), from 1980 to 1983 (Ref. 34, NIOSH, 1984). Preliminary data from NOES indicated that 1,857,962 workers, including 1,186,141 women, in 43,616 plants were potentially exposed to the compound in the workplace in 1980. Unlike NOHS, the NOESestimates were based only on observations ofthe use and manufacture of the compound, per se.

The American Conference of Governmental Industrial Hygienists (ACGIH) has established a threshold limit value (TLV) of400parts per million (ppm) as an 8-hour time-weighted average with a 15-minute short-term exposure limit of 500ppm (Ref.2, ACGIH, 1986b). The TLVwas set on the basis of eye, nose, and throat irritation (Ref. 1,ACGIH, 1986a). The permissible
exposure limit (PEL)for the workplace adopted by the Occupational Safety and Health Administration is also 400 ppm (Ref.40, OSHA, 1983). General dilution/ventilation and the

use of personal protective equipment have been recommended as effective controls to reduce occupational exposure to isopropanol in a number of operations (Ref. 35, NIOSH/OSHA, 1978).

Isopropanol is a constituent of some commercial food flavors (Ref.47, Stanley, 1939; Ref.41, Pendleton, 1970). For this use and its use as an adjuvant, the Food and Drug Administration permits the use ofonly the minimum quantity ofisopropanol necessary to produce the desired effect. No residues of the chemical may remain in foods marked with isopropanol-derived color additives (Ref. 15, FDA, 1986).

Isopropanol has been detected in
trace quantities in fish meal (Ref. 21, lida et al., 1978), white bread (Wideblatt and Kohn, 1960, cited in Ref. 16, Fenaroli, 1975), enzyme-inactivated beef (Wick, 1965, cited in Ref.16, Fenaroli, 1975), and pressure-cooked pork liver (Mussinan and Walradt, 1974, cited in Ref. 16, Fenaroli, 1975).

Isopropanol was identified in leachates from a Southington, CT, landfill site in 1982-83 at concentrations ranging from 3.9 to 8.8 mg/L (Ref.43, Sawhney and Kozloski, 1984). Levels of isopropanol ranging fromn 2.3 to 21.3 ug/L have been measured at a municipal effluent in a river in Oklahoma, and levels ranging from 10 to 2,000 ug/L have been found in a well in South Carolina

near an industrial impoundment area (Ref.48, STORET, 1986).

II.Chemical fate information. Although very large amounts of isopropanol are released to air and water, most ofthe releases are widely dispersed and isopropanol in the environment will be rapidly biodegraded or oxidized. Therefore, chemical fate testing isnot being recommended at this time.

1II. Biologicaleffects ofconcernto humanhealth-A.Metabolismand toxicokinetics.Isopropanol administered intravenously and orally
to normal, fasting dogs was rapidly absorbed from the gastrointestinal tract; distribution to the tissues occurred within a range of30 minutes to 1 or 2 hours (Ref.26, Lehman et al., 1945).

Isopropanol is metabolized to acetone in rats by alcohol dehydrogenase (ADH) (Ref. 37, Nordmann, 1980). Rats were intraperitoneally administered pyrazole,

an inhibitor ofADH and catalase, or amino-1,2,4-triazole, an inhibitor of catalase alone. Isopropanol was then administered either intraperitoneally or by gavage. Blood levels ofisopropanol and acetone were then monitored at regular intervals. Animals receiving amino-1,2,4-triazole showed no significant difference in blood isopropanol or acetone levels from those observed in rats receiving only isopropanol. In contrast, pretreatment with pyrazole decreased isopropanol clearance and delayed the rate of
acetone production (Ref.38, Nordmann
et al., 1973).

When isopropanol was perfused through rabbit liver in situ,a progressive rise in the acetone concentration in blood was observed (Ref. 14, Ellis, 1952).

An average of 10.2 percent ofthe dose ofisopropanol administered by gavage to rabbits was isolated as the glucuronide from the 24-hour urine sample. Acetone (about 0.5 percent of the dose) was also identified in expired airfrom treated rabbits (Ref. 22, Kamil
et al., 1953).

Blood levels ofisopropanol and
acetone in rats following inhalation
exposure to isopropanol for4 hours, in the test range of 500 to8,000 ppm, were directly related to atmospheric concentrations of the chemical. Increasing the exposure time to 8 hours magnified the amount ofacetone that could be detected even 20 hours following exposure. These results indicate a slow conversion ofthe alcohol to acetone (Ref.24, Laham et al., 1980).

In rats given single intraperitoneal doses ofisopropanol, the half-life of the chemical in plasma declined with decreasing dose level (Ref.42, Rietbrock and Abshagen, 1971).

B.Acute (short-term)effects. The
acute toxicity ofisopropanol is summarized in the following Table 4.

TABLE 4.-ACUTE TOXICITY OF ISOPROPANOL IN LABORATORY ANIMALS

Animal Route Effect Reference

Mouse

...................................................... Do

..................................................... Do

..................................................... Do

.................. .......................... Rat
...................................... ................ Do

................................................. Rat (14.day-old)

................................... Rat (young adult)

................................... Rat (older adult)

..................................... Rat

.................................. .................. Orl

........................... Ih

..................... Ipr

............................ Ivn

........................... Orn
........................... 01t

..................... .....
on .................... Orl

........................... Or

.................... . Orl

....................... LD

. 4.8 g/kg; CNS depression

................................................................................................ Levy and Zakhan (1976. Rel. 28). LD : 10.39 m g/L, 2-1wexposure.............................................................................................. o. LD.: 1.28 g/kg

............................................................................................................................. Do. LD.: 31.0 mmol/kg (about 1.9 g/kg)

................................................................................... ChVapil at al. (1962, Ret. 10). LD

,: 5.84 g/kg

............................................................................................................................. Smyth and Carpenter(1948, Ret. 44). LL : 6.73 cm!'/k9..................................................................................................................... Lehman and Chase (1944, Ref. 25). LD.: 5.6 mL/kg

.......................................................................................................................... Kim uraet al. (1971, Ret. 23). LD

.. :6.0 mL/kg

............................................................................................................................ Do

. LD .: 6.8 mL/kg

............................................................................................................................ Do.
LD : 4.7 g/kg

........................................................................................................................... Levy and Zakhari (1976, Re

. 28). 

### 41421

### 41422Feea eierIVl51No22 FrdyNoebr1,18INocs

TABLE 4.-AcuTE TOXICITY OF ISOPROPANOL INLABORATORY ANIMALS-Continued

Animal Route Effect Reference

Do

.................................. LD,.-. 19.000 ppm (females), 8-hr exposure. Severe irritation to mucous membranes. Laham et al. (1980, Ref. 24). Ataxia, prostration, narcosis. At levels between 20,000and 22,000 ppm, paralysis of hind legs was observed inboth sexesduring first 5daysof exposure. Rat

........................ Ih............. Congestion of liver, lungs, and spleen was observed in rats exposed at 4,000 and 8,000 ppm.

............... 500-16,000 ppm. 4-hr exposure: At 4,000 ppm slight hypothermia was observed. At Laham et al.(1980, Ref. 24). 8,000 and 16,000 ppm. severe hypothermia recorded. Do

........................................... p......... pr
............................ LD .: 1.87 g/kg

............................................................................................................................. Levy and Zakhari(1976, Ref. 28).
D

o

..................................................... Scu

.......................... LD

, 5.70 g kg

............................................................................................................................. Do

. Rabbit

...................................................... O64

........................... LD :6.41 cm-/kg

....................................................................................................................... Lehmanand Chase (1944, Ref. 25).
D

o

..................................................... O d

........................... LD o:6.15 cm3/kg

.................................................................. ................................................. D o.

When applied to rabbit eyes, a drop of isopropanol caused mild transitory injury (Ref.44, Smyth and Carpenter, 1948). Isopropanol did not produce any adverse effects when applied dermally
to guinea pigs, dogs, and white rats (Macht, 1922, cited in Ref.32, NOISH, 1976a; Steele and Wilhelm, 1966, cited in Ref. 32, NIOSH, 1976a). Similarly, the chemical did not produce tissue destruction when applied to intact and abraded skin ofrabbits and guinea pigs (Ref. 36, Nixon et al., 1975).

C. Genotoxicity.In the Salmonella microsomal assay using the spot test, isopropanol was nonmutagenic in strains TA98, TA100,TA1535, and TA1537 both with and without S-9 from Aroclor-induced rats (Ref. 17, Florin et al., 1980). The chemical was nonmutagenic in Salmonellastrains TA97, TA98,TA100, TA1535, and TA1537 both with and without metabolic activation, when tested using

a plate-incorporation modification of this microbial assay (Ref.39, NTP CHEMTRACK, 1986).

Isopropanol yielded negative results in mutagenicity tests in Neurospora

crassa(Ref.6, Brockman etal., 1984). Isopropanol did not enhance simian adenovirus (SA7) transformation using Syrian hamster embryo cells when tested over a concentration range of62
to 1,000 ug/mL (Ref. 19, Heidelberger et al., 1983).

D. Oncogenicity. In inhalation studies, C3H, ABC, and C57 mice were exposed
to isopropanol for 3to 7hours per day, 5 days per week for 5 to 8 months. There

was no significant increase in the number oftumors observed. Similarly,

no increases in pulmonary tumors were observed in the same strains ofmice received 20 to40 weekly subcutaneous injections of0.025 mL isopropanol (Ref. 55, Weil et al., 1952).

In skin painting studies, no tumors

were observed when isopropanol was painted on the clipped backs on 30 Rockland all-purpose mice 3 times per week for 1year (Weil, unpublished data, cited in Ref. 33, NIOSH, 1976b).

E. Chronic(long-term)effects. Isopropanol was administered as a 5 percent solution in tap water to male albino rats for 9 months. The average daily consumption ofisopropanol was 1.9 mL/kg. There was no significant differences in the death rates of the treated animals compared to controls given tap water. Treated animals experienced a marked decrease in fluid consumption compared to controls, as well as a significant weight depression. Both ofthese conditions were reversed in the month following withdrawal of the alcohol. Noisy breathing and sluggishness were also noted in the treated animals. In another test, 187 daily applications ofa 50percent solution ofisopropanol oftheheads of male rats failed to cause injury to the skin, hair, or eyes that would differentiate the treated from the control animals (Ref.5, Boughton, 1944).

White rats were administered 0.5, 1.0, 2.5, 5.0, and 10.0 percent solutions of isopropanol in water for 27 weeks. Rats given 10percent isopropanol refused to drink the fluid and died early in the experiment. Some deaths occurred in
two ofthe other exposure groups, but insufficient data were available to determine whether the deaths were treatment related.Food intake by the exposed rats was equal to or greater than that ofthe control rats. There was

a tendency for decreasing fluid intake with increasing alcohol concentration. Gross and histopathologic examination of selected organs showed no evidence of gross or microscopic changes (Ref.25, Lehman and Chase, 1944).

Three dogs were administered isopropanol in water daily for 7 months. The alcohol concentration was 4 percent from the end ofthe firstmonth until the conclusion ofthe experiment. Tolerance
to the alcohol developed, as manifested by an increased degree of neuromuscular coordination at similar blood levels in habituated versus control animals andby increased elimination of the alcohol.The only significant histopathologic changes were noted in the kidneys ofthe one dog that died (Ref. 26,Lehman et al., 1945).

F.Reproductiveanddevelopmental effects.In a three-generation reproductive study, male and female
rats receiving 2.5 percent isopropanol daily in drinking water exhibited no deleterious effects on their reproductive function and embryonic development. Some retardation ofgrowth was observed in the early life offirstgeneration rats (Ref.26, Lehman et al., 1945).

Isopropanol was administered by inhalation to groups of 15 pregnant Sprague-Dawley rats for 7 hours perday

on gestation days I to 19 at doses of 3,500, 7,000 and 10,000 ppm. Thehighest concentration produced maternal narcosis and reduced weight gain and feed intake.At 7,000 ppm isopropanol, the only observable maternal effect was decreased weight gain. No maternal effects were observed at 3,500 ppm. Following exposure to 10,000 ppm isopropanol, there was a statistically significant increase in resorptions and decrease in fetal weights. Fetal weights

were also decreased at the two lower dose levels.There was a significant increase in malformations in the litters ofdams exposed to 7,000 and 10,000
ppm isopropanol. No teratogenic effects

were observed atthe 3,5000 ppm dose level (Ref.31, Nelson et al., 1985; Ref.30, Nelson et al., 1986).

A single-generation reproduction study is being conducted in the Wistar
rat at dose levels of0.5, 1.0, and 2.0 percent isopropanol in drinking water. Males willbe exposed 70 days prior to mating andfemales 21 days prior to mating. Also underway is a teratology study in female Wistar rats at does levels of0.5, 1.5, and 2.5 percent isopropanol in drinking water. The high doeswas selected to produce maternal toxicity.Both studies are being conducted at the request of the government of theUnited Kingdom (Ref. 11, CMA, 1986).

G. Observationsinhumans. Occupational exposure to isopropanol

was assessed in 12 workers employed in

a printing works by testing environmental air,alveolar air,venous blood, and urine during their work shift. Isopropanol in environmental air ranged Federal Regzister / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices 

### 41422Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

between 7 and 645mg/m

. It was detected in alveolar air at levels ranging between 4 and 437mg/m

. The chemical

was not detected in blood orurine. Alveolar concentration ofalcohol was significantly corrected with its environmental concentration (Ref.8, Brugnone et al., 1983).

The blood half-lives ofisopropanol in
two patients suffering from acute overdoses ofthe alcohol were estimated
at 155 and 187minutes, respectively. In both patients, acetone levels were higher than the alcohol values at the beginning ofthe study andremained elevated throughout the study (Ref. 13, Daniel et al., 1981).

In five persons who died as a consequence of drinking isopropanol, deep and stubborn coma was observed

as well as varying degrees ofshock and hypothermia. Acetonuria without glycosuria was also observed (Ref.3, Adelson, 1962).

In a historical prospective study of 262

men who had worked at an isopropanol plant in Great Britain, the observed deaths were slightly higher than expected. There was a statistically nonsignificant increase in deaths from neoplasms. One person died from nasal
cancer; the authors stated that this finding wasunlikely to be due to chance

even though based on small numbers (Ref.4, Alderson and Rattan, 1980).

An increased incidence of cancer of the paranasal sinuses was observed in workers at factories manufacturing isopropanol bythe strong acid process. The risk oflaryngeal cancer may also have been elevated in these workers (Ref.20,IARC, 1977).

H.Rationale forhealtheffects recommendations. Annual domestic production ofisopropanol is greater than 1billion pounds.Well over 1 million persons are estimated to be exposed to the chemical in the workplace. Widespread consumer exposure results from its use in pharmaceuticals and household products. It-hasbeen detected in trace quantities in several foods. Ithas also been identified in leachates from a landfill site. Although several limited carcinogenicity studieshave been performed, insufficient data are available to assess its long-term effects. Therefore, the Committee recommends chronic toxicity studies, including tests to assess its oncogenic potential. Additional genotoxicity studies, including tests to assess its mutagenic potential in mammalian systems andits clastogenic effects, are also recommended. The Committee is concerned about possible reproductive and developmental effects of isopropanol given the teratogenic effects observed at high doses in inhalation studies in rats. However, the Committee recommends deferring the chemical from consideration for such testing pending the outcome ofrelevant studies presently being conducted at the request ofthe government ofthe United Kingdom.

IV.Ecologicaleffects ofconcern. There is sufficient information available
to show that isopropanol is unlikely to persist in the environment at concentrations that would cause adverse ecological effects. Therefore, ecological effects testing is not being recommended at this time.
References

(1)ACGIH. "Documentation ofthe Threshold Limit Values." 5th Ed. Cincinnati, OH: American Conference ofGovernmental Industrial Hygienists. p. 337 (1986a).

(2)ACGIH. TLV's. "Threshold LimitValues andBiological Exposure Indices for 1986- 1987." Cincinnati, OH: American Conference ofGovernmental Industrial Hygienists. p. 21 (1986b).

(3)Adelson, L. "Fatal intoxication with isopropyl alcohol (rubbing alcohol)," The AmericanJournal ofClinicalPathology. 38:144-151 (1962).

(4) Alderson, M. R., and Rattan, N.S. "Mortality ofworkers in an isopropyl alcohol plant and two MEK dewaxing plants,"British Journal of

Industrial Medicine.37:85-89 (1980).

(5)Boughton, L. I."Therelative toxicity of ethyl andisopropyl alcohols as determined by long-term ratfeeding andexternal application," Journal oftheAmerican Pharmaceutical Association.33:111-113 (1944).

(6)Brockman, H.E., de Serres, F. ., Ong,T., DeMarini, D. M., Katz,A.J., Griffiths, A.J.F., and Stafford, R. S. "Mutation tests in Meurosporacrasso.A report ofthe U.S. Environmental Protection Agency Gene-Tox Program," MutationResearch.133:87-134 (1984).

(7)Browning,E.ToxicityandMetabolism of

Industrial Solvents.pp.335-340 (New York: Elsevier Publishing Company, 1965).

(8)Brugnone, F.,Perbellini, L., Apostoli, P., Bellomi, M., and Caretta, D. "Isopropanol exposure: Environmental and biological monitoring in aprinting works," British Journal of

Industrial Medicine.40:160-168' (1983).

(9) C&EN. "Top 5chemicals production droppedmoderately in 1985," Chemicaland Engineering News. 64:34-37 (June9,1986). (10) Chvapil, M., Zahdradnik, R., and Cmuchalova,B. "Influence ofalcohols and potassium salts ofxanthogenic acids on various biological objects," Archives Internationales dePharmacodynamieetde Therapie.135(3-4):330-343 (1962).

(11) CMA. Chemical Manufacturers Association. Letter from C. R. Stack, Associate Director,Biomedical and Environmental SpecialPrograms, to R.Brink, Executive Secretary, Interagency Testing Committee, Washington, DC (March 31, 1986). (12) CMR. ChemicalMarketingReporter. "Chemical profile: Isopropanol." p.50 (September 3, 1984).

(13) Daniel, D. R., McAnalley, B.H., Garriott,J.C. "Isopropyl alcohol metabolism after acute intoxication inhumans," Journal of

AnalyticalToxicology.5:110-112 (1981). (14) Ellis, F.W. "The role ofthe liver in the metabolic disposition ofisopropyl alcohol," JournalofPharmacology andExperimental Therapeutics.105:427-436 (1952).

(15) FDA. Food and Drug Administration, U.S. Department ofHealth and Human Services. 21 CFR. Section 172.515, Synthetic flavoring substances and adjuvants. pp. 48, 52 (1986).

(16) Fenaroli, G.Fenaroli's Handbookof Flavor Ingredients.2nd Ed., Vol. It. (Cleveland, OH: CRC Press, 1975).

(17) Florin, I.,Rutberg, L., Curvall, M., and Enzell, C. R. "Screening oftobacco smoke constituents for mutagenicity using the Ames' test," Toxicology.18:219-232 (1980).

(18) Hatch, L.F. Isopropyl Alcohol pp. 1-5 (New York: McGraw-Hill Book Company, Inc., 1961).

(19) Heidelberger, C.,Freeman, A. E., Peinta, R. J., Sivak, A., Bertram, J.S., Casto, B. C., Dunkel, V. C., Francis, M. W., Kakunaga, T., Little, J.B., and Schechtman, L.M. "Cell transformation by chemical agents-a review and analysis ofthe literature. A report ofthe U.S. Environmental Protection Agency GeneTox Program," MutationResearch.114:283- 385 (1983).

(20) IARC. International Agency for Research on Cancer. "Isopropyl Alcohol and Isopropyl Oils," IARCMonographson the EvaluationofCarcinogenic Riskof ChemicalstoMan.Vol. 15, pp. 223-243 (Lyon, France: IARC, 1977).

(21) lida, H., Miwa, K.,Nakamura, K., and Tokunaga, T. "Amethod forthe trapping of volative components in food," Tukai-Ku SuisanKenkyujo Kenkyu Hokoku.93:87-94 [Abstract] (1978).

(22) Kamil, I. A., Smith J.N., and Williams, R. T. "The metabolism ofaliphatic alcohols. The glucuronic acid conjugation ofacyclic aliphatic alcohols," Biochemical Journal. 53:129-136 (1953).

(23) Kimura, E. T., Ebert, D. M., and Dodge, P. W. "Acute toxicity and limits of solvent residue ofsixteen organic solvents," Toxicology and AppliedPharmacology. 19:699-704 (1971).

(24) Laham, S., Potvin,M., Schrader, K., and Marino, I. "Studies on inhalation of toxicity of2-propanol," DrugandChemical Toxicology. 3(4):343-360 (1980).

(25) Lehman, A.I., and Chase, H. F. "The
acute and chronic toxicity ofisopropyl alcohol," TheJournal of

Laboratory and Clinical Medicine.29(6)561-567 (1944). (26) Lehman,A. J., Schwerma, H., and Rickards, E. "Isopropyl alcohol: Acquired tolerance in dogs, rate ofdisappearance from the blood stream in various species, and effects on successive generation ofrats." Journalof Pharmacology andExperimental Therapy.85:61-69 (1945).

(27) Leo, L, Hansch, C., and.Elkins, D. "Partition coefficients and their uses," ChemicalReviews. 71:525-616 (1971). 

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### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

(28) Levy, P., and Zakhari, S. "Acute inhalational, oral, intraperitoneal, and subcutaneous toxicity inmice and rats," Isopropanoland Ketones in theEnvironment: Isopropanol,Ch. 2. L. Goldberg, ed. (Cleveland, OH: CRC Press, 1976).

(29) Mellan, I., ed. "Isopropyl Alcohol," Industrial SolventsHandbook.2nd Ed. (Park Ridge, NJ: Noyes Data Corporation, 1977).

(30) Nelson. B. K., Brightwell, W. S., Mackenzie-Taylor, D.R., Khan, A., Burg, J.R., Weigel, W. N., and Goad, P.T. "Teratogenicity ofn-propanol and isopropanol administered at high inhalation concentrations to rats"; submitted for publication (May 1986).

(31) Nelson, B. K., Brightwell, W. S., Mackenzie, D. R., Khan, A., Burg,J.R., Weigel, W. W., and Goad, P.T. "Teratogenicity ofn- and iso-propanol at high inhalation levels in rats," The Toxicologist. 5:138 [Abstractl (1985).

(32) NIOSH. National Institute for Occupational Safety and Health. "National Occupational Hazard Survey (1972-19741" [data base]. Cincinnati, OH: U.S. Department ofHealth and Human Services (1976a).

(33) NIOSH National Institute for Occupational Safety and Health. "Criteria for

a Recommended Standard

... Occupational Exposure to Isopropyl Alcohol." Cincinnati, OH: U.S. Department of Health, Education and Welfare, Public Health Service. HEW Publication No. (NIOSH) 76-142 (1976b).

(34) NIOSH. National Institute for Occupational Safety and Health. "National Occupational Exposure Survey (1980-1983)" [data base]. Cincinnati, OH: U.S. Department ofHealth and Human Services (1984).

(35) NIOSH/OSHA. National Institute for Occupational Safety and Health/ Occupational Safety and Health Administration. "Occupational Health Guidelines for Isopropyl Alcohol" (1978).

(36) Nixon. G. A., Tyson, C. A., and Wertz, W. C. "Interspecies comparisons ofskin irritancy," Toxicology and Applied Pharmacology. 31:481-490 (1975). (37) Nordmann, R. "Metabolism ofsome higher alcohols," In: Coloquees de L'INSERM. AlcoholandtheGastrointestinalTract,Vol. 95, pp. 187-206 (1980).

(38) Nordmann, R., Ribiere, C., Rouach, H., Beauge, F.. Giudicelli, Y., andNordmann, J. "Metabolic pathways involved in the oxidation of isopropanol into acetone by the intact rat," Life Sciences.13:919-932 (1973).

(39) NTP CHEMTRACK [data base]. National Toxicology Program/National Institute ofEnvironmental Health Sciences. U.S Department of Health and Human Services, Research Triangle Park, NC (Results Report as of5-07-86).

(40) OSHA. "OSHA Safety and Health Standards for General Industry." 29 CFR 1910. Subpart Z. U.S.Department ofLabor, Occupational Safety and Health Administration. Washington. DC: U.S. Government Printing Office. p. 601 (1983).

(41) Pendleton, G. "Solvents used in the flavour industry," Flavour Industry.1(4): 220- 222 [Abstract] (1970).

(42) Rietbrock, N., and Abshagen, U. "Pharmacokinetics and metabolism of aliphatic alcohols," Arzneimittel-Forschung. 21:1309-1319 (1971). (43) Sawhney B. L., and Kozloski, R. P. "Organic pollutants in leachates from landfill sites,"Journal ofEnvironmentalQuality. 13(3):349-352 (1984).

(44) Smyth, H. F., Jr., and Carpenter, C. P. "Further experience with the range finding
test in the industrial toxicology laboratory," Journal ofIndustrial Hygiene and Toxicology.30:63-68 (1948).

(45) SRI. SRIInternational Chemical EconomicsHandbook.Section 300.5404 (Menlo Park, CA: SRI International, 1980).

(46) SRI. 1985DirectoryofChemical ProducersUnitedStates.p.658 (Menlo Park, CA: SRI International, 1985).

(47] Stanley, R. D. "Report on (the determination of) organic solvents in flavors," Journal oftheAssociationof OfficialAgriculturalChemists.22:594-596 [Abstract] (1939).

(48) STORET. Storage and Retrieval for Water Quality Data [data base]. Washington, DC:U.S. Environmental Protection Agency (1986).

(49] USDOC. U.S. Department of Commerce, Bureau ofthe Census. "Imports Statistics for TSUSA, No. 4280620." (1986a).

(50) USDOC. U.S. Department of Commerce, Bureau ofthe Census. "Export statistics for Schedule B, No. 4311060." (1986b).

(51) USEPA. Chemical Hazard Information Profile (CHIP). Revised draft report on isopropyl alcohol.Washington. DC: U.S. Environmental Protection Agency (November 20. 1979).

(52) USITC. United States International Trade Commission. "Synthetic Organic Chemicals. United States Production and Sales, 1980," USITC Publication No. 1183, p. 263 (1981).

(53) USITC. United States International Trade Commission. "Synthetic Organic Chemicals. United States Production and Sales, 1983." USITC Publication No. 1588, pp. 258. 282 (1984).

(54) USITC. United States International Trade Commission. "Synthetic Organic Chemicals. United States Production and Sales, 1984," USITC Publication No. 1745, p. 256 (1985).

(55) Weil, C. S., Smyth, H. F., Jr., and Nale, T. W. "Quest for a suspected industrial carcinogen," Archives of Industrial Hygiene andOccupational Medicine.5:535--547 (1952). (56) Windholz. M, ed. TheMerckIndex.An EncyclopediaofChemicals,Drugs,and Biologicals.9th Ed. (Rahway, NJ: Merck & Co., Inc., 1983).

2.3.b Methyl tert-butyletherSummary ofrecommended studies.It is recommended that methyl tert-butyl ether (MTBE) be tested for the following:

1. ChemicalFate. Monitoring studies
to determine typical concentrations of MTBE at representatives sites where MTBE-containing gasoline is transferred, including gasoline terminals and service stations.

2. HealthEffects. Chronic inhalation toxicity including neurotoxic, hematologic, and oncogenic effects.
PhysicalandChemical Information

CAS Number: 1634-04-4 Synonyms:

Propane, 2-methoxy-2-methyl-(9 CI);

Methyl 1,1-dimethylethyl ether; (2- Methyl-2-propyl) methyl ether; tertButyl methyl either Acronym:

MTBE Structural Formula:



## CH 3


## CHI-O-C-CH3


## CH 3

Empirical Formula:

C5H 1 20 Molecular Weight:

88.15 Melting Point: -110°C (Ref.16, Phillips Petroleum,

1984) Boiling Point:

55°C (Ref. 16, Phillips Petroleum, 1984) Vapor Pressure:

414 mmHg at 38°C (Ref. 16, Phillips

Petroleum, 1984) Solubility in Water:

40,000 mg/L (Ref. 11, Hawley, 1981)

43,000 mg/L (Ref.4, ARCO, 1986) Solubility in Organic Solvents:

Very soluble in alcohol and ether (Ref.

12, HSDB, 1986) Specific Gravity:

0.74 at 20/4°C (Ref. 16, Phillips

Petroleum, 1984) Log Octanol/Water Partition Coefficient: (log P): 1.30 (Ref. 13, Leo, 1982; cited in

ISHOW, 1984) Henry's Law Constant:

4.5X10-4atm-m3/mol (Ref. 20, USEPA,

1986) Description ofChemical:

Clear liquid, pleasant hydro-carbon

odor (Ref. 16, Phillips Petroleum, 1984)

Rationale forRecommendations
I.Exposureinformation-A. Production/use. The commercial production ofMTBE uses the reaction of isobutylene and methanol, in the
presence of a catalyst, at 30 to 100°C and 7 to 14 atmospheres. Production has increased dramatically since 1979 when MTBE was approved by the EPA for use

as a blending component ofunleaded gasoline. Current production is in the neighborhood of 2billion pounds per year in the United States. By 1989, production is predicted to reach 3 billion pounds per year (Ref.5, CEH, 1985).

Nearly all ofthe MTBE produced in the Uhited States is used as octaneI 

### 41424

### Federal Register / Vol. 51, No. 220 

## / Friday. November 14. 1986 / Notices

enhancing agent in some but not all unleaded gasolines. Although it has been approved as an additive at up to all percent, typical concentrations in gasoline range from 2 to 8 percent by weight (Ref. 4, ARCO, 1986).

B.Evidenceforhumanexposure.The National Occupational Exposure Survey (NOES), conducted between 1980 and 1983, indicated that 2,571 workers, including 849 women, were potentially exposed to MTBE in the workplace (Ref. 14, NIOSH, 1984).

Occupational exposures at manufacturing sites are limited because manufacturing occurs in closed systems. However, two companies have reported measured 8-hour time weighted average (TWA) workplace exposures to MTBE of 1to 3ppm at manufacturing sites (Ref. 16, Phillips Petroleum, 1984; Ref.4, ARCO, 1986).

Workers involved in transportation and loading operations ofMTBEcontaining gasoline have been found to be exposed to less than 2 ppm MTBE (Ref. 4, ARCO, 1986). Halder et al. (Ref. 10 1986) monitored exposures oftruck drivers and terminal operators at five gasoline distribution terminals.A total of 183 samples were collected at the terminals over a 12-month period. Worker exposure to C4 and higher hydrocarbons in gasoline vapors, on a 8- hour TWA basis, varied from 0.4 to 80
ppm, with an overall 8-hourTWA geometric mean of 1.4 ppm. Some ofthe vapor samples were analyzed for individuas hydrocarbon constituents. No analyses were made forMTBE, but C4 and C 5 compounds constituted 61 to74 percent by weight ofthe total gasoline vapor samples. Similar hydrocarbon
exposures were reported in earlier studies at terminals (Ref. 15, Phillips and Jones, 1978; Ref.8 Diakun, 1983).

In a survey ofexposures to gasoline vapors at a service station plaza, Halder, et al.'(1986, Ref. 10) reported a geometric mean 8-hour TWA exposure of 1.0 ppm. Diakun (1983, Ref. 8), reporting on analyses of74 samples obtained during self-service consumer exposures, reported a cumulative mean concentration of59.9 ppm hydrocarbon vapor during pumping, which, projected
to an 8-hourTWA exposure, is 0.28 ppm.

Tests performed in 1983 indicated that MTBE accounts for approximately 3.3 percent ofthe organic vapors in the head space above gasoline containing 10 percent MTBE (Ref. 4, ARCO, 1986). It is
not known how that study was conducted or whether the results are useful in estimating MTBE concentrations in the hydrocarbon vapors in the "breathing zone" locations
at gasoline terminals and service station plazas. However, reports that C4 and C5 compounds make up 61 to 74 percent by weight of the total gasoline vapors at such sites (Ref.10, Halder, 1986) demonstrate, as might be expected, that gasoline constituents with lower molecular weights volatilize more readily than the heavier fractions. The available data are not sufficient to permit a reliable estimate ofthe MTBE concentration in gasoline vapors at terminals and service stations or of worker and consumer exposures at those sites.

C.Environmentalrelease.North Carolina authorities have found MTBE in ground water in test wells along the Cape Fear River (Ref. 18,Taylor, 1986)
at concentrations of0.18 to 3.0parts per million.This ground water contamination is probably due to spills during transfer ofgasoline from seagoing tankers to onshore storage facilities. The largest environmental release sources appear to be through fugitive emissions at gasoline terminals and service stations where distribution
to and dilution in the atmosphere will be strongly dependent on local conditions. Controls that recover gasoline vapors emitted at filling stations are used at less than 10 percent ofthe service stations in the nation (Ref. 19, USEPA, 1984).

II. Chemical fate information-A. Transport, Despite its relatively high
water solubility, MTBE is expected to partition largely to air.The Henry's law
constant of4.5X10- 4atmm 3/mol indicates that any MTBE present in surface water willhave a half-life of about 9 hours before volatilizing. Furthermore, most ofthe MTBEreleased
to the environment will be released directly to air during transfer operations. The low octanol/water partition coefficient and relatively high water solubility of MTBE indicate little tendency forsignificant partitioning to soils, sediments, or biota.

B. Persistence. Nearly all ofthe MTBE released to the environment will partition to the atmosphere where it will be degraded by hydroxy radicals, with

an atmospheric half-life of about 3.5 days. The products ofthis oxidation are likely to include t-butyl formate (major product). acetone, and methyl radical (Ref.7, Cox and Goldstone, 1981). Persistence inground water following spills is unknown, but it may persist for long periods ifvolatilization is prevented, since MTBE is not likely to be readily biodegraded or otherwise transformed in ground water.

C.

Rationale forchemical fate recommendations. MTBE released to the environment will partition to the atmosphere (except at spill and leak sites) where it will be degraded by reaction with hydroxy radicals.Other fate pathways are expected to be less significant.The major concern for MTBE involves exposures in the "breathing zone" of workers and consumers handling MTBE-containing gasoline during transfer operations. In view of this and the lack ofdata on exposure concentrations, it is recommended that appropriate monitoring studies be conducted to evaluate the concentration ofMTBE at representative sites Where MTBE-containing gasoline is transferred from shipping units (e.g., tankers, barges) into storage facilities, from storage facilities into shipping units, and from service station plaza pumps into
motor vehicles.

III.Biological effects ofconcernto humanhealth-A.Metabolismand toxicokinetics.Over 90percent ofan intraperitoneal dose ofMTBE (232 mg/ kg) was excreted untransformed in rat breath (Ref. 3,API, 1985). A fraction of the dose was also excreted as CO 2 in the breath and as formic acid in the feces and urine.

B.Acute andsubchroniceffects. In rats, the oral LD5o (short-term) was reported as 3,865.9 mg/kg. Acute oral
exposure resulted in central nervous system depression, ataxia, tremors, labored breathing, and loss ofrighting reflex. In rats exposed by inhalation, eye irritation, irregular respiration, incoordination and prostration were noted The inhalation LD5oin rats was found to be approximately 120 mg/L (Ref. 3,Atlantic Richfield Co., cited in API, 1985).

In tests with rabbits, MTBE was not found to be a primary skin irritant. It

was irritating to the rabbit eye {Ref. 3, Atlantic Richfield Co., cited in API, 1985).

A 9-day inhalation toxicity study was conducted on fasted and unfasted rats. Rats (20 per sex per group) were exposed for 6 hours per day, 5 days per week for 9 days at concentrations of0, 100, 300, 1,000, or 3,000 ppm. No doserelated mortality was noted. Phosphorus levels were significantly increased in the fasted females in the 1,000 and 3,000
ppm groups. An increase in relative liver weight in both sexes of fasted rats at 3,000 ppmwas noted. The same trend

was seen in the unfasted high-does male
rats. Microscopic pathology revealed chronic inflammation in the nasal

mucosa and trachea in the 1,000 and 3,000 ppmgroups. (Ref. 3, API 1985)

In a 90-day inhalation study in rats, MTBE was administered at 250, 500, and 1,000 ppm does levels for6 hours per day, 5 days per week for 3months. The. principal pharmacotoxic signwas increased anesthesia with increased 

### 41425

### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

concentration. A slight decrease in body weight was seen at 1,000 ppm. An increase in hemoglobin levels in male rats was noted at 1,000 ppm at the end ofthe study,but this wasnot considered toxicologically significant (Ref.3, API, 1985).

C. Genotoxicity.MTBE was tested in several invitrosystems (Atlantic Richfield Co., cited in API, 1985). Negative results were reported in the SalmonellaandSaccharomycestests with and without metabolic activation. In the mouse lymphoma forward mutation assay both with and without metabolic activation, a dose-related mutagenic effect was noted with S9 activation.

Sister chromatid exchange (SCE) and chromosomal aberration assays produced negative results. An increase in SCE was observed at 0.2 and 1.0uL/ mL in one activated sample. In an in vitrocytrogenetic study in rats, negative results were noted.

D. Oncogenicity.No information was found.

E.Reproductiveanddevelopment effects. Tests to determine the reproductive and developmental effects ofMTBE were conducted in female rats. The animals were exposed to 0, 250, 1,000, and 2,500 ppm for6 hours per day during gestation days 6 to 15. Dams

were sacrificed at day 20. No treatmentrelated effects were noted. In another study,female mice were exposed to the

same concentrations but were sacrificed
at day 18 ofgestation.No adverse effects Were noted in the dams. Minor fetal skeletal malformations were noted, but in the absence of vertebral rib defects these malformations were not considered to be teratogenic (Ref.6, Conaway et al., 1985).

An inhalation study was conducted on theeffects ofMTBE on the reproduction ofrats through one generation. The animals were exposed to 0. 250, 1,000 or 2,500 ppm MTBE for6hours per day,5 days per week for 12 weeks, including both premating andpostmating periods. Males were exposed for6 hours during themating period. Female rats were exposed for6 hours perday, 5 days per week for3 weeks during premating and daily for 6 hours during mating. After mating, females were exposed 6hours daily during gestation days 0 to 20 and lactation days 5 to 21. The study involved two litterintervals, and females were exposed for5 days per week, 6hours per day during a 2-week period between litterrest intervals. No dose-related adverse effects were noted (Ref.3,API, 1985).

F. Chronic(long-term)effects. No information was found. G. Observations inhumans.In viva dissolution ofgallstones by MTBE in fourpatients was reported (Ref. 2, Allen
et al., 1985b). Dissolution occurred within 4 to 7 hours after direct instillation. Hematology and blood chemistry profiles showed no abnormalities. Results ofboth urinalysis and 24-hour urine collection for
measurement oftotal protein were normal.

The Food andDrug Administration has classified MTBE as an Investigational New Drug. It is currently being used by one team of investigators
to dissolve gallstones (Ref.22, Wyngaarden, 1986).

H.Rationale forhealtheffects recommendations. Almost all MTBE produced in the United States is used as
a gasoline enhancer incertain unleaded blends, and the annual production is on the rise,with a projected volume of3 billion pounds in 1989, Consequently, humanexposure to MTBE low-level fugitive emissions at gasoline pumps is expected to occur.The major routes of expose would be via the skin and inhalation. In view ofthis potential exposure and the lack of chronic health effects information,the Committee recommends chronic health effects testing. Special emphasis should be given to neurotoxic, hematologic, and oncogenic effects.

IV.Ecologicaleffects ofconcern-A. Acuteandsubchronic(short-term) effects.Using a flow-through system, Veith et al. (1983, Ref.21) reported a 96- hour LC 0 with the fathead minnow of 760 mg/LMTBE. Using static systems, Tarkpea and Svanberg (1982, Ref. 17) found a 24-hour LCso of1,700 to 1,800 mg/L with the bleak Alburnusalburnus, and a 96-hour LCOogreater than 10,000 mg/L with the copepod Nitocraspinipes.

B. Chronic(long-term)effects. No information was found.

C. Otherecological effects (biological, behavioral, orecosystemprocesses).No information was found.

D. Bioconcontration and food-chain transport. Usingcarp in a flow-through system,Fujiwara et al. (1984, Ref.9) reported a bioconcentration factor of 1.5. MTBE was rapidly eliminated from the fish when they were transferred to fresh water. No other information was found.

E.Rationale forecological effects recommendations. Itdoes not appear that MTBE will be toxic to biota at concentrations likely to be found in the environment except at spill and leaking storage tank sites.Therefore, ecological effects testing is notbeing recommended
at this time. References (1)Allen,M. J., Borody,T. J., Bugliosi, T. F., May, G. R., LaRusso, N. F., and Thistle, J.L. "Cholelitholysis using methyl tertiary butyl ether," Gastroenterology.88:122-125 (1985a).

(2) Allen, M. J., Borody, T.J., Bugliosi, T.F., May, G. R., LaRusso, N. F., and Thistle, J.L. "Rapid dissolution ofgallstones by methyl tertbutyl ether," TheNew EnglandJournal of Medicine.312:217-220 (1985b).

(3) API. Unpublished information on the production, use, occupational exposure, release, and toxicity ofMTBE. Submitted by W. F. O'Keefe, American Petroleum Institute (March 15, 1985).

(4) ARCO. Letter fromE.C. Capaldi, ARCO Chemical Co., Newton Square. PA, to R. Brink, Executive Secretary, TSCA Interagency Testing Committee (July 21, 1986).

(5) CEH. ChemicalEconomicsHandbook. Stanford Research Institute. Menlo Park, CA: SRI International. Section 675.1000A675.1001F (1985).

(6) Conaway, C. C., Schroeder, R. E., and Snyder, N. K. "Teratology evaluation of methyl tertiary butyl ether in rats and mice." Journal ofToxicologyandEnvironmental Health.16:797-809 (1985).

(7) Cox, R. A., and Goldstone, A. "Atmospheric reactivity ofoxygenated motor fuel additives," inPhysico-Chemical Behaviorof AtmosphericPollutants, B. Versino and H. Ott. eds. (Dordrecht,Holland: D. Reidel Publishing Co., 1981].

(8) Diakun. R. "Characterization of workplace exposures." Documentation of presentation to EPAby API. Submitted by N. K. Weaver,American Petroleum Institute. FYI-AX-0783-0148, Supp. Sequence H (July 15, 1983].

(9] Fujiwara, Y., Kinoshita, T., Sato, H., and Kojima, I. "Biodegradation and bioconcentration ofalkyl ethers" Yukagahu. 33(2).,111-114[Abstract](1984).

(10) Halder, C.A., Van Grop. C. S., Hatoum, N. S., and Warne, T. M. "Gasoline
vaporexposures. PartI. Characterization of workplace exposures,"AmericanIndustrial HygieneAssociationJournal. 47:164-172 (1986).

(11) Hawley, G. G. The Condensed ChemicalDictionary,10th ED.. pp. 671-672. (New York: Van Nostrand Reinhold Co., 1981).

(12) HSDB. "Hazardous Substances Data Bank" [data base]. Bethesda, MD: Department ofHealth and Human Services, National Library ofMedicine (1986).

(13) ISHOW. (1985). Information System for Hazardous Organics in Water. [date base]. Baltimore, MD: Chemical Information Systems,Inc. Supported by the National Institutes ofHealth/U.S. Environmental Protection Agency.

(14) NIOSH. "National Occupational Exposure Survey (1980-1983)" [data base]. Cincinnati, OH: Department ofHealth and Human Services, National Institute for Occupational Safety and Health. (1984].

(15) Phillips,C. F., andJones, R. K. "Gasoline vaporexposure during bulk handling operations," AmericanIndustrial HygieneAssociationJournal. 39:118-128 (1978]. 

### 41426Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

(16) Phillips Petroleum. Material Safety Data Sheet and unpublished information on the production, use,and occupational exposure of MTBE. Submitted by J.J.Moon, Phillips Petroleum Company (January 12, 1984).

(17) Tarkpea, M., and Svanberg, 0. "The acute toxicity of motor fuels to brackish water organisms," MarinePollution Bulletin. 13(4):125-127. (1982).

(18) Taylor,T. Memorandum from T. Taylor,North Carolina Department of Human Resources, to R. Brink, Executive Secretary, TSCA Interagency Testing Committee (August 25, 1986).

(19) USEPA. "Estimation ofthe public health risk from exposure to gasoline vapor via the gasoline marketing system." Draft Report. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Officeof Air Quality Planning and Standards (June, 1984).

(20) USEPA. Memorandum from P. Harrigan, Office ofToxic Substances, to R.H. Brink, Interagency Testing Committee. (October 6, 1986).

(21) Veith, G. D., Call, D. J.and Brooke, L. T. "Structure-toxicity relationships for the fathead minnow, Pimephalespromelas: narcotic industrial chemicals." Canadian JournalofFisheriesandAquatic Sciences. 40:743-748 (1983).

(22) Wyngaarden, J. B., "From the National Institutes of Health: New nonsurgical treatment removes gallstones." Journalofthe American MedicalAssociation.256:1692 (1986).

2.4 Chemicals andgroups of chemicalsrecommended withoutbeing designatedforresponse within 12 months-2.4.a CI. Disperse Blue 79- Summaryofrecommended studies. It is recommended that C.I. Disperse Blue 79 be tested for the following:

1. ChemicalFate. Solubility in water at 25 ° C.biodegradation under aerobic and anaerobic conditions and the identification ofany relatively persistent biodegradation intermediates.

2.Health Effects. Absorption and chemical disposition via oral route'of administration. Subchronic toxicity (90- day study).

3. Ecological Effects. Acute toxicity to fish, aquatic invertebrates, algae, and benthic organisms, including filter feeders. bioconcentration in fish. Chronic effects on aquatic and benthic biota ifthe acute studies show toxicity at low mg/L concentrations or ifthe dye bioconcentrates. PhysicalandChemicalInformation

CAS Number:

3956-55--6 Synonym:

Acetamide, N-[5-[bis[2- (acetyloxy)ethyl]amino]-2-[(2- bromo-4,6-dinitrophenyl)azo]-4- ethoxyphenyl](9CI) Structural Formula: 

### Br

NO 2 -/ N

NO 2 OC 2 H 5

=N-HO N(CHCH 2 -O-COCH3 2



### NHCOCH 3

Description ofChemical:

Blue powder with characteristic odor (Ref.12, Mobay Chemical, 1985) Empirical Formula:

C

24

H2

7BrN6Olo Molecular Weight:

639.44 Melting Point:

143 °C (estimated; Ref. 19, USEPA,

1986a) Boiling Point:

476 °C (estimated; Ref. 19, USEPA,

1986a) Vapor Pressure:

3.4X10 - 9mmHg at 25 °C (estimated;

Ref. 19, USEPA, 1986a) Solubility in Water:

5.4 mg/L (estimated; Ref. 19, USEPA,

1986a) Solubility in Organic Solvents:

No information was found. Specific Gravity:

No information was found Log Octanol/Water Partition Coefficient: (log P): 4.1 (estimated; Ref. 19, USEPA, 1986a) Henry's Law Constant:
5.9X10- 1 0 atm-m3/mol (estimated; Ref. 19, USEPA, 1986a) Log Adsorption Coefficient (log K,,)

3.6 (estimated; Ref. 19, USEPA, 1986a) Bioconcentration Factor (fish)

757 (estimated; Ref. 19, USEPA, 1986a) According to the Ecological and Toxicological Association ofthe Dyestuffs Manufacturing Industry (Ref. 6, ETAD, 1986), thebromoethoxy compound described above, which has the Colour Index (C.I.) Constitution No. 11345, is the only derivative properly referred to as C.I. Disperse Blue 79. However, there appear to be three other closely related derivatives that have been and may still be called Disperse Blue 79. The concerns expressed in this report for the bromoethoxy derivative apply also to these other derivatives which are expected to have physical and chemical properties similar to the bromoethoxy derivative and which have the following structures:

where, for derivative 1,X=Br and R=C-h 3 ; forderivative 2, X=CI and R=CH 3 , and for derivative 3, X=CI and R=C2I-.
Rationale forRecommendations

I.Exposure information-A. Production/use/en vironmentalrelease. The U.S. International Trade Commission listed the annual production ofC.I. Disperse Blue 79 at 5
to 10 million pounds peryear in the United States from 1980 through 1984 (Refs. 23 through 27, USITC, 1981-1985). Heath (Ref. 21, USEPA, 1986c) has estimated the current annual production
at 0.9 to 1.4 million kilograms (2 to 3 million pounds), as active colorant, which is a large production for a dye. Disperse Blue 79 appears to be the major blue dye for textile use and a major component ofgreen, brown, and black dyes. About 40 percent ofproduction is sold to users in a paste or liquid formulation and about 60 percent as a solid, mainly as low dusting granules (Ref.6, ETAD, 1986). 

### 41427



## X OR

NO 2

### -/ 

# \ -N- 

# / N=\ N(CHZCH2-O-C0CH4)2



### NO2 

### NHCOCH 3Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

Heath (Ref. 21 USEPA, 1986c) estimated that during the manufacture of Disperse Blue 79, there would be releases of4,500 to 14,000 kilograms (10,000 to 30,000 pounds) per year at a total ofnine sites, with an estimated 3 to 20kilograms (7 to 45 pounds) per site per day. Heath estimated releases of2 to 18 kg (4.4 to 40 pounds) per site per day at 400 to 600 textile dyeing operations.

B. Evidence forhumanexposure. According to the National Occupational Exposure Survey (NOES) 1,450 workers
at 25 plants in the chemical and allied products industry were potentially exposed to C.I. Disperse Blue 79 in the workplace in 1980 (Ref. 13, NIOSH, 1984). Workplace exposure limtis have not been established for C.I. Disperse Blue 79 by American Conference of Governmental Industrial Hygienists (Ref. 1,ACGIH, 1986) orthe Occupational Safety and Health Administration (Ref. 15, OSHA, 1983). Farris (Ref.20, USEPA, 1986b) estimated significant worker exposure during manufacture and use. Occupational exposure to this dye is expected from inhalation ofdye-containing dust particles, swallowing inhaled particles trapped in saliva and mucous, and from dermal exposure during open batch manufacture (Ref.20, USEPA, 1986b; Ref.21, USEPA, 1986c). Consumer exposures should be very low since this is a fast dye which is relatively insoluble in water and not likely to leach from the fabrics.

C. Environmental exposure.No published information was found. However, an assessment (based on mathematical modeling) has been made for the ITCby the Office ofToxic Substances (Ref.22,USEPA, 1986d). The assessment used estimates ofreleases (Ref.21, USEPA, 1986c) and took into consideration plant locations, receiving stream characteristics, and the locations ofdownstream drinking water treatment plants. The assessment also assumed 50 percent removal ofthe dye during passage through biological treatment plants by adsorption to sludge solids. Mean surface waterconcentrations downstream from manufacturing plants and fabric dyeing operations were estimated to range from 0.02to 40 ug/L. A high receiving stream concentration of 306 ug/L was predicted forlow flow conditions at one site. Drinking water exposures resulting from releases during manufacture and dyeing were calculated and were estimated to range from 0.06 to 43ug/kg/year. Variations are due to site features,releases perday, and the number ofdays per year that releases

occur. These estimates assumed no loss of the dye through biodegradation on other transformation processes.

II. Chemicalfateinformation-A. Transport. The low estimated vapor pressure and Henry's law constant indicate that volatilization of Disperse Blue 79 will not be significant. The estimated log K., value of3.6 indicates that about 50 to 60 percent ofthe dye will adsorb to the organic matter of waste treatment sludges and that about 40to 50 percent will be released to

- receiving streams.

B.Persistence. Information supplied byETAD (Ref.6, 1986) indicates that in static tests, where the disappearance of total organic carbon (TOC) was followed, 29 to 68 percent ofthe TOC disappeared over a 2-week period in solutions containing Disperse Blue 79. No data were presented on the specific features ofthe tests or on whether the TOC disappearance might have been due to some factors other than biodegradation, such as adsorption onto suspended and settled particulates or the walls of test vessels.In standard 5- day biological oxygen demand (BOD) tests, the BOD5 was 6.8 pounds 02 per 100 pounds dye (Ref.7,ETAD, 19861, which is about 4 percent ofthe theoretical oxygen uptake for complete oxidation. None ofthis biodegradation information is sufficient to evaluate the biodegradability ofDisperse Blue 79. Studies currently underway orplanned at theEPA Water Engineering Research Laboratory in CincinnatL OH, and at the Georgia Institute ofTechnology (Ref. 6, ETAD, 1986) may provide useful information on both adsorption and biodegradation.

Azo dyes in general are relatively resistant to biodegradation and Disperse Blue 79 is likely to persist during biological treatment, with a portion adsorbing to the sludge solids and the rest being discharged in the effluent. Under anaerobic conditions, microbial processes may cleave the azo bond to form two aromatic amines. The 2-bromo4,6-dinitroaniline produced by this reaction may be ofconcern by itself.

In its Fourth Report to the EPA Administrator (44FR 31867), the ITC recommended and designated certain anilines, including 2-chloro-4,6- dinitroaniline (CAS No. 3531-19-9) and 2-bromo-4,6-dinitroaniline (CAS No. 1817-73-8). In an Advance Notice of Proposed Rulemaking (ANPR) on January 3, 1984 f49 FR 108), the EPA noted that there appeared to be no current production of 2-chloro-4,6- dinitroaniline, but that the 2-bromo compound was being produced and that itwas being considered for a battery of chemical fate, health effects and environmental effects testing.

The potential forDisperse Blue 79 to be cleaved to release 2-bromo-4,6- dinitroaniline, both in the environment and in vivo following ingestion,needs to be investigated Ifthis product is formed via microbial processes in sediments,
waste treatment facilities, and intestinal tracts, then added emphasis should be placed on testing ofthe sort described by the EPA inthe ANPR ofJanuary 3, 1984.

Other transformation processes (e.g., hydrolysis and photolysis) are not expected to be major factors in the transformation ofthis dye.

C. Rationale forchemical fate recommendations.The lack ofmeasured values on physical and chemical properties for C.I.Disperse Blue 79 increases the uncertainty with respect to chemical fate predictions. At a minimum, water solubility values at 25 °C should be obtained for any commercially important forms of Disperse Blue 79.

Disperse Blue 79 released to the environment is likely to partition to both
water and sediments. In sediments, it may degrade anaerobically and release 2-bromo-4,6-dinitroaniline. No data have been found to substantiate orrefute these predictions. Since the dye has widespread large use in theUnited States and is likely to be released to the environment during both manufacture and use, it is recommended that biodegradation studies be conducted to determine (1)the potential for aerobic and anaerobic biodegradation, and (2) the identify ofrelatively persistent intermediates, ifany,resulting from biodegradation.

III.Biological effects ofconcernto humanhealth-A.Metabolismand toxicokinetics.No information was found on the metabolism ofC.l. Disperse Blue 79. The dye is likely to split at the

azo bond into 2-bromo-4,6-dinitroaniline, and 2-diethanolamino-4-methoxy-5- amino-6-acetanilide by azoreductases present in the intestinal flora. Many azo dyes are split at the azo bondby the intestinal flora (Ref.4, Chung et al., 1978; Ref. 7, Grasso and Golberg, 1968; Ref. 9, Honohan et al., 1976; Ref. 15, Pritchard et al., 1976; Ref. 16,Radomski, 1961; Ref 17, Roxon et al., 1967) and liver enzymes (Ref. 5,Daniel, 1967). Studies on the metabolism and disposition of2-bromo4,6-dinitroaniline, (BDNA) in male F344 rats were reported by Chopade and Matthews (1986, Ref3). The gastrointestinal absorption of 14CBDNA was nearly complete, and approximately 80 percent ofthe 

### 41428

### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

radioactivity was cleared from most tissues within 6 hours.

B.Acute andsubchronic(short-term) effects. The acute oral LD5oofDisperse Blue 79 in rats was greater than 5,000 mg 

### perkg ofbody weight (Ref. 6, ETAD, 1986). It was found to be nonirritating in primary skin irritation and eye irritation
tests (Ref. 6, ETAD, 1986).

C. Genotoxicity.Disperse Blue 79 was found to be strongly mutagenic in the standard SalmonellaS-9 assay in four
tester strains TA1535, TA1537, TA98, and TA100 (Ref. 11, Mishra et al., 1981). It was also found to be negative in the V79 mammalian cell and mouse micronucleus assays (Ref.6, ETAD, 1986).

D. Oncogenicity.No data were found



### on oncogenicity testing ofC.I. Disperse Blue 79. 2,6-Dichloro-4-nitro-aniline, a structural analog of 2-bromo-4,6- 

### dinitroaniline (oneofthefragments ofazo bond cleavage ofthe dye), was found to be negative in cancer bioassays in mice (Ref. 16, Innes et al., 1969) and rats (Ref. 8, Hadidian et al., 1968).

2-Chloro-4,6-dinitroaniline and 2- bromo-4,6-dinitroaniline (CASNo. 3531- 19-9 and 1817-73-18, respectively) were recommended by the ITC in its Fourth 

### Report to the EPA Administrator for carcinogenicity, mutagenicity, teratogenicity, and other chronic effects studies (see Part 1iB, above).

E. Chronic(long-term)effects. No information was found.

F.Reproductiveanddevelopmental effects. No information was found.

G. Observationsinhumans.No information was found.

H.Rationale forhealtheffects recommendations. Because ofthe 

### potential bioavailability ofC.I. Disperse Blue 79 to workers from ingestion of inhaled dye-containing dust, it is recommended that the dye be tested for subchronic toxicity (90-day study) and for absorption and chemical dispositon following the oral route of administration. A chemical disposition study is recommended to determine the potential for liberation of2-bromo-4,6- dinitroaniline in the intestines due to

azo bond cleavage ofthe dye.

IV. Ecological effects ofconcern-A. Acute andsubchronic(short-term) effects. Acute toxicity studies using rainbow trout and Disperse Blue 79 formulations were reported as follows (Ref.6, ETAD, 1986):
Granule formulation, containing approximately

26%Disperse Blue 79, LQo=320 mg/L. Granule formulation, containing

approximately 52%Disperse Blue 79, LCo=400 mg/L. Liquid formulation, containing

approximately 13%Disperse Blue79, LCo=700 mg/L. Without additional details, it is not possible to evaluate the validity of these
test data. The Committee is concerned about the reported LCso concentrations, since the values cited are about 100 times the estimated water solubility of Disperse Blue 79 and the test data are only for a 48-hour exposure time, whereas 96 hours is the minimal
exposure period for acute toxicitiy tests in fish.

B. Chronic(long-term)effects. No information was found.

C. Otherecologicaleffects (biological, behavioral orecosystemprocesses).No effects on activated sludge respiration

were observed when Disperse Blue 79

was present at concentrations up to 100 mg/L (Ref.2, Brown et al., 1981).

D.Bioconcentration and food-chain transport. No data were found for Disperse Blue 79.

E.Rationale forecologicaleffects recommendations. Although the estimated concentration levels for C.I. Disperse Blue 79 in surface waters are relatively low, ranging from 0.02 to 306 ug/L, the lack of adequate data on ecological effects and the nature of this dye molecule raise concerns for potential effects. Acute toxicity tests should be run with fish, aquatic invertebrates, algae, and benthic organisms. Ifbiodegradation studies demonstrate the formation of 2-bromo4,6-dinitroaniline, then this transformation product should also be evaluated as noted in the EPA Advance Notice ofProposed Rulemaking of January 2, 1984 (49 FR 108). The estimated log P value of4.1 for Disperse Blue 79, and an estimated bioconcentration factor in fish of757, indicate a potential for some sorption and bioconcentration ofthe dye in biolipids. Bioconcentration studies with fish are recommended to confirm or refute the prediction of Disperse Blue 79 uptake. Chronic studies with aquatic and benthic organisms are recommended ifthe results ofthe studies show toxicity at lowmg/L concentrations orifthe dye bioconcentrates.
References

(1)ACGIH. American Conference of Governmental Industrial Hygienists. "TLV's. Threshold Limit Values and Biological Exposure Indices for 1986-1987" (Cincinnati, OH: ACGIH, 1986).

(2)Brown, D., Hitz,H.R., and Shcafer, L. "The assessment ofthe possible inhibitory effect ofdyestuffs on the aerobic waste water bacteria: Experience with a screening test," Chemosphere.10(3):245-261 (1981).

(3) Chopade, H. M., and Matthews, H. B. "Disposition and metabolism of2-bromo-4,6- dinitroaniline in the male F344 rat," Journal of Toxicologyand EnvironmentalHealth.17:37- 50 (1986). (4)Chung, K.-T., Fulk, G.E., and Andrews, A.W. "The mutagencitiy ofmethyl orange and metabolites produced by intestinal anaerobes," MutationResearch.58:375-379 [1978).

(5)Daniel. J.W. "Enzymatic reduction of

azo food colourings," FoodandCosmetics Toxicology.5:533-534 (1967).

(6)ETAD. Ecological and Toxiciological Association ofthe Dyestuffs Manufacturing Industry. Letter from E. A. Clarke, Executive Secretary, ETAD, to R.H.Brink, Executive Secretary, TSCA Interagency Testing Committee (August 11. 1986).

(7)Grasso, P., and Golberg,L."Problems confronted and lessons learned in the safety evaluation ofBrown FK," Foodand CosmeticsToxicology.6:737-747 (1968).

(8)Hadidian, Z., Fredrickson, T.N.. Weisburger, E.K.,Weisburger, J.H., Glass, R.M., and Mantel, N. "Testsfor chemical carcinogens. Report on the activity of derivatives ofaromatic amines, nitrosamines, quinolines, nitroalkanes, amides, epoxides, aziridines, andpurine antimetabolites," JournaloftheNationalCancer Institute. 41:985-1036 (1968).

(9) Honohan, T, Enderlin, F.E., and Ryerson, B. A. "Absorption, metabolism, and excretion of the azofood dyes amaranth,
sunset yellow and tartrazine after oral administration to rats," Federation Proceedings, Federation of

American Societies forExperimentalBiology.35(3):328 (1976).

(10) Innes, J.R.M., Ulland, B.M., Valerio, M.G.,Petrucelli, L., Fishbein, L., Hart,E.R., and Pallotta, A.). "Bioassay ofpesticides and industrial chemicals for tumorigenicity in mice: Apreliminary note,"Journalof the NationalCancer Institute.42:1101-1114 (1969).

(11) Mishra, N.K., Bell, S.J., Gomez, Y.P., and Prival,M.J. "Mutagenicity ofsynthetic hair implant components: Biocompatibility studies ofleachates using Salmonella, " Environmental Mutagenesis.3:351 (1981). (12)Mobay Chemical. "Material Safety Data Sheet forResolin Navy Blue 2GLS200 (C.I. Disperse Blue 79)." Mobay Chemical Corporation, Union, NJ (March 22,1985).

(13] NIOSH. National Institute for Occupational Safety and Health. "National Occupational Exposure Survey (1980-1983)" [data base]. Cincinnati, OH: U.S. Department ofHealth and HumanServices (1984).

(14) OSHA. Occupational Safety and Health Administration. "OSHA Safety and Health Standards for General Industry," 29 CFR 1910. Subpart Z.U.S. Department of Labor, Washington, DC (1983).

(15) PritchardA.B., Holmes,P.A., and Kirschman,J.C. "The fate ofFD&C Red No.2 and its metabolite, naphthionic acid, after different routes ofadministration in the rat," ToxicologyandAppliedPharmacology. 35:1- 10 [1976).

(16) Radomski, J.L. "The absorption,fate and excretion ofCitrus Red No. 2(2,5- dimethoxy-phenyl-azo-2-naphthol} and Ext. D&C RedNo. 14 (1-xylylazo-2-naphthol)," TheJournalofPharmacology and ExperimentalTherapeutics.134:100-109 (1961). 

### 41429

### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

(17) Roxon, I.J., Ryan, A.,J., and Wright, S.E. "Reduction ofwater soluble azo dyes by intestinal bacteria." FoodsandCosmetics Toxicology: 5:367-369 (1967).

(18) USCPSC. U.S. Consumer Product Safety Commission. "Status ofBenzidine Congener Dyes Exposure andToxicology Testing,"Memorandum from A.I. Gerber to P.W. Preuss, USCPSC (February 11, 1983).

(19) USEPA. "Chemical Property Estimates for C.I. Disperse Blue79." Memorandum from P. Harrigan to J.Walker, Test Rules Development Branch, EPA (June3, 1986a).

(20) USEPA. "C.I. Disperse Blue 79." Memorandum from R.E. Farris, Industrial Chemistry Branch, to J.D. Walker, Test Rules Development Branch, EPA (June 6, 1986b).

(21) USEPA. "Engineering Assessment for Disperse Blue 79." Memorandum from G. Heath, Chemical Engineering Branch, to J.D. Walker, Test Rules Development Branch, EPA (May 30,1986c).

(22) USEPA. "Predicted Surface Water Concentrations and Drinking Water Exposure ofC.I. Disperse Blue 79." Memorandum from
M.H. Thomas, Exposure Assessment Branch,
to J.D. Walker, Test Rules Development Branch, EPA, (June 24, 1986d).

(23) USITC. U.S. International Trade Commission. "Synthetic Organic Chemicals, United States Production and Sales, 1980." Publication No. 1183, p.68. Washington, DC: U.S. Government Printing Office (1981).

(24) USITC. U.S. International Trade Commission. "Synthetic Organic Chemicals, United States Production and Sales, 1981."
Publication No. 1292, p. 59. Washington, DC: U.S. Government Printing Office (1982).

(25] USITC. U.S. International Trade Commission. "Synthetic Organic Chemicals, United States Production and Sales, 1982." Publication No. 1422, p. 61.Washington, DC: U.S. Government Printing Office (1983).

(26) USITC. U.S. International Trade Commission. "Synthetic Organic Chemicals, United States Production and Sales, 1983." Publication No. 1548, p.61. Washington, DC: U.S. Government Printing Office (1984).

(27) USITC. U.S. International Trade Commission. "Synthetic Organic Chemicals, United States Production and Sales, 1984." Publication No. 1745, p. 55.Washington, DC: U.S. Government Printing Office (1985).

2.4.b MethylEthylKetoximeSummaryofrecommendedstudies.It is recommended that methyl ethyl ketoxime (MEKO) be tested for the following:

1. HealthEffects.Chronic toxicity, with special emphasis on hematopoietic and oncogenic effects.
Physical andChemicalInformation

CAS Number:

96-29-7
Synonyms:

2-Butanone oxime (9 CI); MEKOXIME; MEKO
Structural Formula: 

## CH3-C-

## -CH.-CH 3 

# II
NOH

Empirical Formula:

C4

HsNO Molecular Weight:

87.12 Melting Point: -29.5 °C (Ref.25, Verschueren, 1983) Boiling Point:

152 °C (Ref.25, Verschueren, 1983) Vapor Pressure:

1.06mmHg at 20 °C 7.6 mmHg at 50 'C

(Ref.7, Kurita, 1967) Solubility in Water:

100g/L at unspecified temperature

(Ref.25, Verschueren, 1983) Solubility in Organic Solvents:

Miscible with alcohol and ether (Ref.

26, Weast, 1984) Secific Gravity

0.923 at 20/4 °C (Ref.25, Verschueren,

1983) Log Octanol/Water Partition Coefficient (log P): 0.8 (Ref. 6, Leo, 1982, cited in ISHOW,



### 1985) Description of Chemical:

Clear, colorless to light-yellow liquid

at ambient conditions (Ref.7, Kurita, 1967; Ref. 2, Allied, 1984a)


### Rationale forRecommendations
I.Exposureinformation-A. Production/use/en vironmen tal release. The public portion ofthe TSCA Inventory listed on aggregate production volume of520,000 to 5,202,000 pounds of MEKO in 1977 Ref.23, USEPA, 1986a). In 1982, approximately 1.9 to 2.7 million 

### pounds ofMEKO were produced in the United States and in 1983, 2.0to 2.9 millionpounds were produced (Refs.27 and 28, Zacharias, 1985, 1986; Ref. 17, SRI,-1984). Imports ofMEKO totaled 2.6 million pounds in 1984 (Ref.21, USDOC, 1985) and 2.2 million pounds in 1985 (Ref.22, USDOC, 1986).

MEKO is usedalmost exclusively as the major antiskinning agent in alkyd and coatings. (Ref.4, CEH, 1981). Antiskinning agents are added at less than 1percent concentration to typical 

### solvent-thinned paint formulations (Ref. 15, Scofield et al., 1975), prevent 

### oxidation ofthepaint while in the can and volatilize while the coating is drying (Ref.10,NIOSH, 1984a). Alkyd paints containing MEKO are used in interior 

### semigloss and gloss paints and exterior enamels,in auto refinishing, and in product finishes for metal furniture, machinery, and appliances (Ref. 16, SRI, 1982). B. Evidence forhumanand enviornmentalexposure.The National Occupational Hazard Survey (NOHS), conducted by the Natioal Institute for Occupational Safety and Health (NIOSH) from 1972 to 1974, estimated that 12,114 workers in 1,540 plants were potentially exposed to MEKO in the workplace in 1970 (Ref10, NIOSH, 1976).

NIOSH conducted a second survey, the National Occupational Exposure Survey (NOES), from 1980 to 1983. Preliminary data fromNOES indicated that 2,145 workers (including 209 women) in the chemical and allied products industry were potentially exposed to MEKO in 1980 (Ref. 11, NIOSH. 1984b).

It has been conservatively estimated that more than 900,000 individuals were potentially exposed to MEKO as professional painters in end-use applications in 1984 (Ref. 19, Stoecklein, 1986). This estimate is exclusive of

consumers incidentally exposed during routine painting/decorating activities.

Workplace exposure limits have not been recommended for MEKO by the American Conference ofGovernmental Industrial Hygienists (Ref. 1,ACGIH, 1986) orestablished by the Occupational Safety and Health Administration (Ref. 13, OSHA, 1983).

In a montoring study (Ref.5, Himmelsbach, 1984), a MEKOcontaining paint was applied by nonpowered equipment in an interior hall in an office building by four painters. During a 4-hour sampling period, the airborne concentration of MEKO ranged from approximately 0.27
to 0.46 ppm.

There are 764 products listed in the U.S. Consumer Product Safety Commission's Chemicals in Products data base that contained MEKO at concentrations of0.1 to 0.8 percent (Ref. 20,USCPSC, 1985). Ofthese, all but 16

are in the paints and coatings category, which includes house and trimfinish products, floor paints, wood stains, enamel finishes, yacht bottom and marine paints, traffic paints, heavy-duty equipment enamels, varnishes, interior paints, and primers. Some of the products identified in the nonpaint category are bathroom bowl cleaners, aluminum cleaners, adhesives, and caulking compounds.

No information was found on general population exposure to MEKO. However, it appears that consumers as well as professional painters would potentially be exposed to MEKO via the dermal and inhalation routes, principally through contact with alkyd paints (e.g., interior semigloss and gloss paints, exterior enamels). 

### 41430Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

An exposure assessment (basedon mathematical modeling) has been made for the ITC by the Office ofToxic Substances (Ref. 24, USEPA, 1986b). Based on this analysis, the level to which consumers might be exposed to MEKO was estimated. In this analysis,
two coats ofa solvent-based alkyd paint containing 1percent MEKO were applied by roller to most ofthe interior of a house. The total exposure toMEKO resulting from such an activity was estimated to be 432 mg. While

consumers could be exposed to this level on a casual basis, the exposure to professional painters would be more frequent. Hence, the levels to which this group could be exposed to MEKO would be considerably higher.

II. Chemical fateinformation.If released tothe environment, it is likely that MEKO will be photooxidized in the atmosphere and photolyzed or biodegraded in the aquatic environment. Therefore, chemical fate testing is'not being recommended at this time.

IlI. Biologicaleffects ofconcernto humanhealth-A.Metabolismand toxicokinetics.It is expected that MEKO would metabolize to methyl ethyl ketone and hydroxylamine (Ref. 3,Allied, 1984b).

A summary ofan unpublished study

on tissue distribution (REF. 3,allied, 1984b), reported that pregnant female mice were administered a single oral (unspecified) dose of ' 4C-MEKO on day 14 ofgestation, and onemale mouse was administered an unspecified dose ofthe compound by intratracheal instillation. The following data were reported:

Wholebody autoradiography revealed that MEKO was rapidly absorbed from the stomach and lungs. Widespread uptake and distribution ofthe label over the entire body ofthe animal were noted.The tissues with the highest concentration ofMEKO included bone, bone marrow, liver, gallbladder,nasal and bronchial epithelium, pancreas,
seromucous and salivary glands, spleen. intestinal wall, and thymus. Urine andbile contained significant activity throughout the study. Interstinal activity was minimal. This suggests that MEKO is primarily excreted via the kidneys

... high concentrations of MEKO were detected in the liverofthe fetuses at 24 hours. This concentration was greater than that seen in the livers ofthe mothers.

B.Acute and subchroniceffects.The
acute toxicity ofMEKO is summarized in Table 5 which follows:

TABLE 5.-ACUTE ToxIcITY OF METHYL ETHYL
KETOXIME IN LABORATORY ANIMALS

Animal Route Effects Reference

Mouse. Ol. LDo: 1.0 g/kg'

................ Allied (1984b. Ret. 3). TABLE 5.-ACUTE TOXICITY OF MET KETOXIME IN LABORATORY ANIP tinued

Animal Route Effects

Mouse. lpr

.......... Approx. LDso: 1 g/kg

Rat

........... Oil LC6:2.3 g/kg

..................

Rat Oil LD :3.7 g/kg

..................

Rat
........... IN
..........

Rat

........... I.

Rat

........... ISkn.

Rat

........... Scn. Saturated vapors for 35 min. Agitation by 2 min and then drowsiness by 35 min when exposed to vapors for 35 min. 0.19. 1.45, and 4.83

rng/L of MEKO vapors for 4 hr produced no mortality. The high dose group showed evidence of anesthesia after
exposure. Methemoglobin formation was noted for the mid- and high-dose levels. Minor changes were noted in hematology

or clinical chemistry for all groups. Doses of 0.02. 0.2, or

2.0 mL/kg for 24 hr produced 100 percent mortality at 2.0 mL/kg; no mortality at lower doses. Methemoglobin was noted at 0.2 and 2.0 mL/kg and a small increase in reticulocytes at 0.2 mL/kg. Nervous system depression

was the predominant sign for acute doses. There was no effect
at 0.02 mL/kg. LDO:2.7 g/kg. LDo:

2.8 9/kg.

"Oral" LD reported as cited in Allied (198

In a study in which MEKO in

was applied to rat skin (Ref. 7, 1967], transient dermatitis was Mild dermal irritation in the ra usually disappearing within 72
exposure, has alsobeen report Allied, 1984b). Data obtained u guinea pig maximization test in that MEKO has a strong sensit potential (Ref.3,Allied, 1984b) hyperemia ofthe eyelid and bu conjunctiva was observed in ra following instillation ofMEKO of the eyes ofeach of three rat observed effects disappeared hours (Ref. 7, Kurita, 1967).

The effects of MEKO on van hematologic parameters in rats been studied (Ref. 7, Kurita, 19 study, five male albino rats rec subcutaneous doses ofMEKO oil (1.5 mL per kg every other d weeks). Five control rats were treated with olive oil alone (1.5 kg). At the end ofthe treatmen the only statistically significanTHYL ETHYL <0.05) effect noted was inhibition of MALS-Con- erythrocyte and plasma cholinesterease activity.

In another study (Ref. 7, Kurita, 1967), Reference four groups of male albino rats each
Plzak and received MEKO in olive oil at dose

Doull (1969. levels of0.1, 0.5, or 1.0 mL per kg body
Ref. 14). Allied (1984b. weight, respectively. The control group

Raf. 3). received olive oil only. The test material
Allied (1984b,

Rel. 3). was injected subcutaneously once daily

Kurita (1967. for 4 weeks. Clinical examinations,

Ra. 7), including body weight and hematologic

measurements were performed throughout the experimental period.

Allied (1984b. After 4 weeks, the rats were sacrificed,

Rel. 3). with blood samples taken and gross and microscopic pathological examinations performed. Dose-related effects were observed at the two highest doses but
not at the lowest dose level (0.1 mL per kgper day). According to the author, the effects associated with exposure to MEKO included growth inhibition, increases in the absolute and/or relative weights ofthe spleen, liver, and kidneys, decreased erythrocyte count and

Allied (1984b. hemoglobin content, secondary

Ret. 3). leukocytoses, lymphopenia, splenic hypertrophy, impairment ofclotting function, atrophy oflymphatic tissue, pulmonary atelectasis, pulmonary emphysema, and bronchial pneumonia. A statistically significant (p <0.01) decrease in serum protein concentration also was noted.

A summary ofan unpublished study (Ref. 3,Allied, 1984b) reported that rats

were administered MEKO by gavage at doses of25, 75, and 225 mg perkg per Rla. 7). day for 13 weeks. The following data

were reported: 84b). No mortality, changes in appearance or

vaseline behavior, or abnormalities in urine values Kurita, were observed in the rats during the study. noted. Slight to moderately lowermean body bbit, weights and food consumption were noted at hours of the high dose level at eight and thirteen ed (Ref.3, weeks in the males. All ofthe treated groups Ising the from both sexes showed dose related
ndicated decreases in erythrocyte count, hematocrit and hemoglobin values and displayed a ization moderate tomarket reticulocytosis. Heinz

Marked bodies,occasional siderocytes, tlb polychromasia, basophilic stippling and
ats Howell-Jolly bodies were generally present in into one the mid and high dose groups.Blood

s. The chemistries revealed an elevation oftotal ifter 6 to 9 bilirubin and erythrocyte cholinesterase in mid dose males and high dose males and

ous females. Alkaline phosphatase levels ofhigh have dose males also increased. A slight 67). In one depression in blood urea nitrogen and plasma
eived cholinesterase levels were noted in the high

olive dose level female group. in oDose related increases in the absolute and/ lay for4 orrelative weight ofthe spleen, liver and similarly kidney were observed in all treatment groups. mL per The spleens and livers appeared large and/or
t period, darkened upon necropsy. Histopathological
t (p examination revealed extramedullary

### 41431

### Federal Register / Vol. 51, No. 220 / Friday, November 14, 1986 / Notices

hematopoiesis andincreased amounts of greenish-brown pigment located in macrophages ofthe spleen and liver.

Kidney sections revealed an accumulation ofgreenish-brown pigment in the epithelial cells lining the proximal convoluted tubules. These data suggest that MEKO induces a hemolytic anemia in the rat with compensatory erythropoiesis. ANOEL (no observable effect level) was not established but was predicted tobe less than 25 mgkg/ day.

C. Genotoxicity.This chemical has been selected by the National Toxicology Program for testing in the Ames assay and is currently ontest for in vitrocytogenetics (Ref. 12, NTP, 1986). In previously conducted assays, however, MEKO was nonmutagenic in both the Ames and sister chromatid exchange assays (Ref.3,Allied, 1984b). In another study, MEKO was nonmutagenic in Salmonellastrains TA98, TA100 TA1535, TA1537, and TA1538 (Ref.8, NCI, 1985a). MEKO has also been tested in the mouse lymphoma
assay (Ref. 9, NCI, 1985b). Under the conditions of the assay,MEKO produced a positive response without metabolic activation and a negative response with metabolic activation.

D. Oncogenicity.No information was found.

E. Chronic(long-term)effects. No information was found.

F.Reproductiveanddevelopmental effects. No information was found.

G. Observationsin humans.No information was found.

H. Rationale forhealtheffects recommendations. MEKO is the major antiskinning agent in alkyd coating resins for use in interior semigloss and gloss paints and exterior enamels, in
auto refinishing and in product finishes formetal furniture, machinery, and appliances. It volatilizes while the coating is drying and may be inhaled in indoor settings by professional painters and consumers. Apart from the workers exposed to MEKO in the chemical and allied products industry, more than 900,000 professional painters are conservatively estimated to be exposed to this chemical at low levels on a continuous basis in end-use applications. The number ofconsumers exposed to MEKO through casual painting and decorating activities is assumed to be high, though data do not exist to provide a precise estimate.

Although several short-term toxicity studies have been performed, limited data exist to evaluate its long-term toxicologic effects, particularly on the hematopoietic system. In addition, no data are available that address the oncogenic potential ofthis compound. Therefore, the Committee recommends the performance ofchronic toxicity studies with special emphasis on potential hematopoietic and oncogenic effects.

IV. Ecologicaleffects ofconcern. MEKO is unlikely to persist in the environment at concentrations likely to

cause adverse ecological effects. Therefore, ecological effects testing is not being recommended at this time.

References

(1)ACGIH. "TLVs. Threshold Limit Values and Biological Exposure Indices for 1986- 1987." Cincinnati, OH: American Conference ofGovernmental Industrial Hygienists (1986).

(2) Allied Corporation. Product Safety Data Sheet on methyl ethyl ketoxime (November 1984a).

(3) Allied. Allied Corporation. Letter from J.B. Charm, Director, Corporate Product Safety,Allied Corporation, Morristown, NJ,
to R. Jones, Document Control Assistant, EPA (March 5, 1984b).

(4)CEH. Chemical EconomicsHandbook. SRI International, Menlo Park, CA. Section 592.60011. (1981).

(5) Himmelsbach, B.F. Internal memorandum on area monitoring for MEKO and MEK during the use ofalkyd paints from B.F. Himmelsbach, Allied Corporation, Morristown, NJ, to staff (April 27, 1984).

(6) ISHOW. Information System for Hazardous Organics in Water [data base]. Baltimore, MD: Chemical Information Systems, Inc. (19851.

(7) Kurita, H. "Experimental studies on methyl-ethyl-ketoxime toxicity," Nagoya Journal of

AedicalScience.29:393-418 (1967). (8) NCI. National Cancer Institute. Letter from 1.Olbrich, NCI, Bethesda, MD to L. Borghi, Dynamac Corporation, Rockville, MD (Iuly25,1985a).

(9) NCI. National Cancer Institute. "Mouse Lymphoma Mutagenesis Assay with #83890 (ML-NCI #160)." Report prepared by Microbiological Associates, Bethesda, MD. under Contract No. No1-CP-41004 (December 11, 1985b).

(10) NIOSH. National Institute for Occupational Safety and Health. "National Occupational Hazard Survey (1972-1974)" [data base]. Cincinnati, OH: U.S. Department ofHealth and Human Services (1976).

(11) NIOSH. National Institute for Occupational Safety and Health. "National Occupational Exposure Survey (1980-1983)" [data base]. Cincinnati. OH: U.S. Department ofHealth and Human Services (1948b).

(12)NTP. "National Toxicology Program" [data base]. Research Triangle Park, NC: National Institute ofEnvironmental Health Sciences, U.S. Department ofHealth and Human Services (Results Report ofAugust 7, 1986).

(13) OSHA. "OSHA Safety and Health Standards for General Industry." 29 CFR 1910. Subpart Z. U.S.Department ofLabor, Occupational Safety and Health Administration. Washington, DC: U.S. Government Printing Office (1983).

(14) Plzak, V.,and Doull, 1."AFurther Survey ofCompounds forRadiation Protection." USAF School ofAerospace Medicine, Aerospace Medical Division (AFSC), Brooks AirForce Base, TX (1969).

(15) Scofield, F., Levin, J., Beeland, C., and Laird, T. "Assessment ofIndustrial Hazardous Waste Practices, Paint and Allied Products Industry, Contract Solvent Reclaiming Operations, and Factory Application on Coating." EPA Report No. EPA/530/SW-119C, U.S. Environmental Protection Agency, Office ofSolid Waste Management Programs, Washington, DC (1975).

(16) SRI. "NPCA Data Bank Program," Section IV. Prepared for the National Paint and Coatings Association, Inc., Washington, DC. p. 77 (Menlo Park, CA: SRI International. 1982).

(17) SRI. "The U.S. Paint Industry: Technology Trends, Markets, Raw Materials" (Formerly "NPCA Data Bank Program"). Prepared forThe National Paint and Coatings Association, Inc., Washington, DC. pp. 173- 174 (Menlo Park, CA: SRI International, 1984).

(18) SRI. 1985DirectoryofChemical Producers,UnitedStates.p. 717 (Menlo Park, CA: SRI International, 1985).

(19) Stoecklein, P. Letter from P. Stoecklein, American Painting Contractor, St. Louis, MO.
to L. Borghi, Dynamac Corporation, Rockville, MD (September 25,1986).

(20) USCPSC. U.S. Consumer Product Safety Commission. Memorandum from E.W. Leland, CPSC, to M. Wind, CPSC (October 11. 1985).

(21) USDOC. U.S. Department of Commerce, Bureauof the Census. "U.S. Imports for Consumption and General Imports," Report FT246/Annual 1983. Washington, DC: U.S. Government Printing Office. P.1-355 (1985).

(22) USDOC. U.S. Department of Commerce, Bureau ofthe Census. "Import statistics for TSUSA No. 4252600." 1986.

(23) USEPA. Consumer printout (CICIS): 1977 production statistics for chemicals in the nonconfidential TSCA Chemical Substance Inventory. U.S. Environmental Protection Agency, Office ofPesticides and Toxic Substances, Washington, DC (1986a).

(24) USEPA. "Consumer Exposure to Methyl Ethyl Ketoxime." Memorandum from M.H. Thomas, Exposure Assessment Branch, EPA, to L.Rosenstein, Existing Chemical Assessment Division (August 5, 1986(b).

(25) Verschueren, K. Handbookof Environmental Dataon OrganicChemicals. 2nd Ed. pp.303-304 (New York: Van Nostrand Reinhold Company, 1983).

(26) Weast. CRC Handbook ofChemistry and Physics. A Ready-Reference Book of Chemical and Physical Data, 14th Edition, p. C-193. West Palm Beach, FL: CRC Press Inc. (1984.

(27) Zacharias, K. Personal communication from K.Zacharias, National Paints and Coatings Association, to A. Prevesz, Existing Chemical Assessment Division, EPA (September 3, 1985).

(28) Zacharias, K. Personal communication from K. Zacharias, National Paints and Coatings Association, to A. Revesz, Existing Chemical Assessment Division, EPA (September 24, 1986).

[FR Doc.86-25584 Filed 11-13-86; 8:45 am]

BILUNG CODE 6560-50-M 

### 41432