NTP-CERHR EXPERT PANEL REPORT on the REPRODUCTIVE …

1 National Toxicology Program Department of Health and Human Services NTP-CERHR EXPERT PANEL REPORT on the REPRODUCTIVE and developmental toxicity of METHANOL APRIL 2002 NTP-CERHR -MeOH-02 2 II PREFACE The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of the Center is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction, including development, caused by agents to which humans may be exposed. Methanol was selected for evaluation by the CERHR based on high production volume, extent of human exposure, and published evidence of REPRODUCTIVE or developmental toxicity .

2 Methanol is used in chemical syntheses and as an industrial solvent. It is a natural component of the human diet and is found in consumer products such as paints, antifreeze, cleaning solutions, and adhesives. It is used in race car fuels and there is potential for expanded use as an automobile fuel. This evaluation is the result of a 10-month effort by a 12 member PANEL of government and non-government scientists that culminated in a public EXPERT PANEL meeting. This REPORT has been reviewed by CERHR staff scientists, and by members of the Methanol EXPERT PANEL . Copies have been provided to the CERHR Core Committee, which is made up of representatives of NTP-participating agencies. This REPORT is a product of the EXPERT PANEL and is intended to (1) interpret the strength of scientific evidence that a given exposure or exposure circumstance may pose a hazard to reproduction and the health and welfare of children; (2) provide objective and scientifically thorough assessments of the scientific evidence that adverse REPRODUCTIVE /development health effects are associated with exposure to specific chemicals or classes of chemicals, including descriptions of any uncertainties that would diminish confidence in assessment of risks; and (3) identify knowledge gaps to help establish research and testing priorities.

3 The EXPERT PANEL REPORT on methanol will be a central part of the subsequent NTP Center REPORT that will also include public comments on the Methanol EXPERT PANEL REPORT and any relevant information that has become available since completion of this EXPERT PANEL REPORT . The NTP Center REPORT will be made publicly available and transmitted to appropriate health and regulatory agencies. The NTP-CERHR is headquartered at NIEHS, Research Triangle Park, NC and is staffed and administered by scientists and support personnel at NIEHS and at Sciences International, Inc., Alexandria, Virginia. Reports can be obtained from the website ( ) or from: Michael D. Shelby, NIEHS EC-32 PO Box 12233 Research Triangle Park, NC 27709 919-541-3455 2 III A REPORT OF THE CERHR METHANOL EXPERT PANEL Name Affiliation Eula Bingham, , Chair University of Cincinnati, Cincinnati, OH *Stanley Barone, Neurotoxicology Division, USEPA, Research Triangle Park, NC Gary Burin, , DABT Technology Sciences Group, Washington, DC Robert Chapin, Bristol-Myers Squibb Co.

4 , Newark, DE *J. Michael Davis, National Center for Environmental Assessment RIP, USEPA, Research Triangle Park, NC David Dorman, DVM, CIIT Centers for Health Research, Research Triangle Park, NC John R. Glowa, LSU Medical Center, Shreveport, LA Deborah Hansen, Division of Genetic and REPRODUCTIVE Toxicology FDA/NCTR, Jefferson, AR (Skip) Matthews, Consultant, Durham, NC Mark Miller, , MPH Office of Environmental Health Hazard Assessment, Cal/EPA, Oakland, CA Kathleen M. Nauss, Consultant, Sudbury, MA John M. Rogers, REPRODUCTIVE Toxicology Division, MD-67, USEPA, Research Triangle Park, NC *These PANEL members did not fully concur with Section 5 of this REPORT , primarily because they felt (1) the Overall Conclusions did not adequately address uncertainties regarding susceptible subpopulations and total population exposures, and (2) the Critical Data Needs should include studies on female REPRODUCTIVE function.

5 With the Support of CERHR Staff: NTP/NIEHS Michael Shelby, Director, CERHR Christopher Portier, Director, Environmental Toxicology Program Lynn Goldman, Technical Advisor Sciences International, Inc. John Moore, DVM, DABT Principal Scientist Annette Iannucci, Toxicologist Gloria Jahnke, DVM Toxicologist Steve Donkin, Toxicologist Note to Reader: This REPORT is prepared according to the Guidelines for CERHR PANEL Members established by NTP/NIEHS. The guidelines are available from the CERHR web site ( ). The format for EXPERT PANEL Reports includes synopses of studies reviewed, followed by an evaluation of the 2 IV Strengths/Weaknesses and Utility (Adequacy) of the study for a CERHR evaluation.

6 Statements and conclusions made under Strengths/Weaknesses and Utility evaluations are those of the EXPERT PANEL and are prepared according to the NTP/NIEHS guidelines. In addition, the PANEL often makes comments or notes limitations in the synopses of the study. Bold, square brackets are used to enclose such statements. As discussed in the guidelines, square brackets are used to enclose key items of information not provided in a publication, limitations noted in the study, conclusions that differ from authors, and conversions or analyses of data conducted by the PANEL . 2 V ABBREVIATIONS ACGIH American Conference of Governmental Industrial Hygienists ADH alcohol dehydrogenase AF&PA American Forest & Paper Association AMI American Methanol Institute ANOVA analysis of variance apABGlu p-acetamidobenzoylglutamate Asp aspartame AUC area under curve BEI biological exposure index BMD05 benchmark dose.

7 5% effect level bw body weight C Celsius C1, 2, 5, 7 cervical vertebra 1, 2, 5, 7 cm2 centimeters squared Cmax peak concentration C-section Caesarian section CAS RN Chemical Abstracts Service Registry Number CERHR Center for the Evaluation of Risks to Human Reproduction CI confidence intervals CL P cleft lip and/or palate CNS central nervous system d day DCR decidual cell response DMDC

8 Dimethyl dicarbonate DNA deoxyribonucleic acid DOE Department of Energy EEG electroencephalogram EPA Environmental Protection Agency EX exencephaly F female FA folic acid FDA Food and Drug Administration FR fixed ratio FSH follicle stimulating hormone g gram GC gas chromatography gd gestation day h hour HEI Health Effects Institute HPLC high pressure liquid chromatography HSDB Hazardous Substances Data Bank IPCS International Programme on Chemical Safety IV intravenous

9 Kg kilogram Km Michaelis constant Kow octanol-water partition coefficient kPA kilopascal 2 VI L liter LD50 lethal dose, 50% mortality LH luteinizing hormone LOAEL lowest observed adverse effect level M male m3 meters cubed mg milligram min minute mM millimolar mL milliliter MLE maximum likelihood estimates mmol millimole 4-MP

10 4-methylpyrazole MRC Medical Research Council MRCA Market Research Corporation of America MTBE methyl tertiary butyl ether MV multivitamin n number NCAM neural cell adhesion molecule NE no effect NEDO New Energy Development Organization ng nanogram NHANES National Health and Nutrition Examination Survey NIEHS National Institute of Environmental Health Sciences NIOSH National Institute of Occupational Safety and Health nmol nanomol NOAEL no observed adverse effect level NS not specified NTD