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Multi-substance Rule: Neurotoxicity Test Results


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CAS Nos.   Attachment A

Proposed Test Rule (PRM)/10 Chemicals
56 FR 9105; March 4, 1991

Final Test Rule (FRM)/10 Chemicals
58 FR 40262; July 27, 1993

Decision Not to Test (DNT)/Revocation of FRM/10 Chemicals
60 FR 4514; January 23, 1995

Consent Order (CO)/7 Chemicals 1/
60 FR 4516; January 23, 1995

Notices/Modifications
56 FR 21115; May 7, 1991/Extension of Comment Period
58 FR 16669; March 30, 1993
59 FR 33184; June 27, 1994/Stay of Final Rule
59 FR 33187; June 27, 1994/Proposed Revocation of Final Rule
59 FR 33191; June 27, 1994/Notice of Opportunity to Participate in Consent Agreement
60 FR 16648; March 31, 1995/Conditional Exemption from Testing
61 FR 37685; July 19, 1996/Change in Test Guidelines for in vivo Hydrolysis

Project Manager: Catherine Roman

Branch Chief: Frank Kover

Status:  Closed. All required tests have been completed. Test results have been forwarded to the Risk Assessment Division for review and disposition. 

_________________________________
1/  Acetone -12 companies (AlliedSignal, Inc., Aristech Chemical Corp., BTL Specialty Resins Corp., The Dow Chemical Co., Eastman Chemical Co., Exxon Chemical Co., General Electric Co., Georgia Gulf Corp., Goodyear Tire & Rubber Co., Shell Oil Co., Texaco Refining & Marketing, Inc., and Union Carbide Corp.); n-amyl acetate - Union Carbide Corp.; butyl acetate - 9 companies (Aristech Chemical Corp., BP Chemical Corp., BASF Corp., Eastman Chemical Co., Hoechst Celanese Chemical Group., Rhone-Poulenc Inc., Shell Oil Co., Union Carbide Corp., and Vista Chemical Co.); ethyl acetate - 6 companies (BP Chemical Corp., Eastman Chemical Co., Hoechst Celanese Chemical Group., Monsanto Co., Rhone-Poulenc Inc., and Tolson USA, Inc.); isobutyl alcohol - 5 companies (BASF Corp., Eastman Chemical Co., Hoechst Celanese Chemical Group., Shell Oil Co., and Union Carbide Corp.); methyl isobutyl ketone - 6 companies (Eastman Chemical Co., Exxon Chemical Co., Hoechst Celanese Chemical Group., Rhone-Poulenc Inc., Shell Oil Co., and Union Carbide Corp.); tetrahydrofuran - 6 companies (Arco Chemical Co., BASF Corp., E.I. duPont de Nemours and Co., GE Plastics, ISP Management Company., Inc., and QO Chemical, Inc.)

Identification of Chemicals

Ten chemicals which are thought to be associated with neurological effects are being proposed for neurotoxicity testing. Selection was based on 5 criteria: (1) production level greater than 10 million pounds; (2) occupational exposure greater than 100,000 workers; (3) presence in consumer products; (4) vapor pressure greater than 5 mm Hg; and (5) environmental release of over 1 million pounds. As a result of the selection process, 14 chemicals were selected as candidates for the neurotoxicity test rule and available neurotoxicity data on the chemicals were reviewed. After the review, 4 candidates (ethanol, methyl ethyl ketone, toluene, and xylenes) were found to have sufficient neurotoxicity data to justify exclusion from the rule at this time. The chemicals for which neurotoxicity testing was proposed are listed in Attachment A. The same chemicals were included in the final rule. The only modification was that technical grade n-amyl acetate was specified.

As part of the settlement agreement with manufacturers, who have agreed to do testing under enforceable consent agreements for 7 of the 10 chemicals, EPA revoked the final rule. The 7 chemicals to be tested as part of the consent agreements appear in Attachment B.

Announced Receipt of Test Data

Test data for an acute inhalation neurotoxicity study of n-butyl acetate in the rat were submitted by the Chemical Manufacturers Association Oxo Process Panel pursuant to an ECA (59 FR 54193; October 28, 1994).

Test data for an acute neurotoxicity study of isobutanol in Sprague-Dawley rats were submitted by the Chemical Manufacturers Association Oxo Process Panel pursuant to an ECA (59 FR 60985; November 29, 1994).

Test data for an acute vapor inhalation study of ethyl acetate in the rat were submitted by the Chemical Manufacturers Association Oxo Process Panel pursuant to an ECA (60 FR 28409; May 31, 1995).

Test data for a thirteen-week subchronic inhalation neurotoxicity study of n-butyl acetate in the rat were submitted by the Chemical Manufacturers Association Oxo Process Panel on behalf of Aristech Chemical Corporation, BASF Corporation, BP Chemicals, Inc., Eastman Chemical Company, Hoechst Celanese Chemical Group, Inc. Rhone-Poulenc, Inc., Shell Oil Company, Union Carbide Corporation, and Vista Chemical Co. pursuant to an ECA (61 FR 11414; March 20, 1996).

Test data for a two-week inhalation probe study of n-butyl acetate in the rat were submitted by the Chemical Manufacturers Association Oxo Process Panel on behalf of Aristech Chemical Corporation, BASF Corporation, BP Chemicals,Inc., Eastman Chemical Company, Hoechst Celanese Chemical Group, Inc. Rhone-Poulenc, Inc., Shell Oil Company, Union Carbide Corporation, and Vista Chemical Co. pursuant to an ECA (61 FR 13192; March 26, 1996).

Test data for isobutanol were submitted by the Chemical Manufacturers Association on behalf of test sponsors and was received by EPA on March 18, 1996. The submission included three final reports entitled: (1) “Three Month Neurotoxicity Study of Isobutanol Administered by Whole-Body Inhalation to CD Rats,” (2) “Three Month Schedule Controlled Operatant Behavior Study of Isobutanol by Whole-Body Inhalation to CD Rats,” and (3) “Exposure Concentration Range-finding Study for a Subchronic Inhalation Neurotoxicity Study of Isobutanol Administered by Whole-Body Inhalation to CD Rats” (61 FR 17701; April 22, 1996).

Test data for tetrahydrofuran were submitted by the Tetrahydrofuran Task Force pursuant to a consent order and received by EPA on June 7, 1996. The submission includes a final report entitled “Acute Inhalation Neurotoxicity Study of Tetrahydrofuran in Rats” (61 FR 36378; July 10, 1996).

Test data for methyl isobutyl ketone were submitted by the CMAs Ketones Panel on behalf of sponsors, Eastman Chemical Company, Exxon Chemical Company, Hoechst Celanese Chemical Group, Inc., Rhone Poulenc Inc., Shell Chemical Company, and Union Carbide Corporation, pursuant to a consent order and received by EPA on August 16, 1996. The submission includes a final report entitled “Methyl Isobutyl Ketone: A Thirteen-Week Schedule-Controlled Operant Behavior Study in the Rat” (61 FR 42611; August 16, 1996).

Test data for tetrahydrofuran were submitted by Tetrahydrofuran Task Force pursuant to a consent order and received by EPA on November 26, 1996. The submission includes a final report entitled “90-Day Inhalation Neurotoxicity Study with Tetrahydrofuran in Rats” (61 FR 67334; December 20, 1996).

Test data for the pharmacokinetics of n-butyl acetate were submitted by the Chemical Manufacturers Association Oxo Process Panel on behalf of the following sponsors: Aristech Chemical Corporation, BASF Corporation, BP Chemicals, Inc., Eastman Chemical Company, Hoechst Celanese Chemical Group, Inc. Rhone-Poulenc, Inc., Shell Oil Company, Union Carbide Corporation, and Vista Chemical Co. pursuant to a consent order and was received by EPA on January 24, 1997. The submission included a final report entitled “The In Vivo Pharmacokinetics of n-Butyl Acetate in Rats after Intravenous Administration” (62 FR 8955; February 27, 1997).

Test data for n-amyl acetate were submitted by Regnet Environmental Services, Inc. on behalf of Union Carbide Corporation pursuant to a consent order andreceived by EPA on February 6, 1997. The submission includes a final report entitled “An Acute Neurotoxicity Study of a Single Inhalation Whole-Body Exposure of n-Amyl Acetate Vapor (with a 2-week observation) in Albino Rat” (62 FR 11183; March 11, 1997).

Test data for acetone were submitted by the CMA pursuant to a consent order and received by EPA on June 20, 1997. The submission includes a final report entitled “Subchronic Operant Behavior Study of Acetone by Inhalation in Rats” and additionally a report entitled “Schedule-Controlled Operant Behavior Study of Amphetamine and Chlorpromazine” (62 FR 42123; August 5, 1997).

Test data for ethyl acetate were submitted by the CMA Oxo Process Panel pursuant to a consent order and received by EPA on July 7, 1997. The submission includes final reports entitled “Subchronic Operant Behavior Study of Ethyl Acetate by Inhalation in Rats” and “Subchronic Inhalation Neurotoxicity Study of Ethyl Acetate in Rats” and additionally a report entitled “Schedule-Controlled Operant Behavior: Positive Control Study of Amphetamine and Chlorpromazine” (62 FR 42123; August 5, 1997).

Results of Testing Table



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