1、 Furfural 01/04 FURFURAL CAS # 98-01-1 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI January 2004 Copyright 2004 NSF InternationalTABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties4 3.0 PRODUCTION AND USE .4 3.1 Production4 3.2 Use
2、.4 4.0 ANALYTICAL METHODS.4 4.1 Analysis in Water and Biological Matrices .4 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .4 5.1 Sources of Human Exposure 4 5.2 Sources of Environmental Exposure .5 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS5 6.1 Humans 6 6.2 Laborato
3、ry Animals7 6.2.1 Absorption8 6.2.2 Distribution 8 6.2.3 Metabolism.8 6.2.4 Excretion9 6.2.5 Conclusions Regarding Comparative Kinetics and Metabolism 9 7.0 EFFECTS ON HUMANS .9 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS.9 8.1 Limited Exposure Effects .10 8.1.1 Irritation and Sensit
4、ization Studies.10 8.1.2 Ocular Exposure Studies.10 8.2 Single-Exposure Studies10 8.3 Short-term Exposure Studies .11 8.3.1 Oral 11 8.3.2 Inhalation.12 8.4 Long-Term and Chronic Exposure Studies 13 8.4.1 Subchronic Studies 13 8.4.2 Chronic Studies16 8.5 Studies of Genotoxicity and Related End-Points
5、19 8.5.1 Mutagenicity Assays 19 8.5.2 Assays of Chromosomal Damage23 8.5.3 Other Assays of Genetic Damage25 8.6 Reproductive and Developmental Toxicity Studies26 8.7 Studies of Immunological and Neurological Effects.26 9.0 RISK CHARACTERIZATION .26 9.1 Hazard Assessment26 9.1.1 Evaluation of Major N
6、on-Cancer Effects.28 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization29 9.1.3 Selection of Key Study and Critical Effect30 9.1.4 Identification of Susceptible Populations .31 9.2 Dose-Response Assessment.31 9.2.1 Benchmark Dose Modeling and Oral RfD Derivation .31 9.3 Exposure Assessm
7、ent 35 9.4 TAC Derivation .36 9.5 STEL DERIVATION36 10.0 RISK MANAGEMENT 38 10.1 SPAC Derivation.38 11.0 RISK COMPARISONS AND CONCLUSIONS 39 12.0 REFERENCES 41 13.0 APPENDICES .48 13.1 BMDL Analysis (Multistage Model)48 14.0 PEER REVIEW HISTORY .50 14.1 March 25, 1998 50 14.2 August 6, 1998 .51 14.3
8、 October 3, 200252 14.4 September 3, 2003 .53 AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: NSF Toxicology Services 1.800.NSF.MARK NSF International 789 Dixboro Road Ann Arbor, MI 48105 Disclaimer: The responsibility for the content of this document remains solely with NSF International, and
9、 the authors noted above should be contacted with comments or for clarification. Mention of trade names, proprietary products, or specific equipment does not constitute an endorsement by NSF International, nor does it imply that other products may not be equally suitable. Internal NSF Peer Reviewers
10、: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory Board in providing peer review. These peer reviewers serve on a voluntary basis, and their opinions do not necessarily represent the opinio
11、ns of the organizations with which they are affiliated. Current: Edward Ohanian, Ph.D. (Chairman, NSF Health Advisory Board) Director, Health and Ecological Criteria Division Office of Science and Technology/Office of Water U.S. Environmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chai
12、rman, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Director, Environmental Health Science Safe Environments Programme Health Canada Steven Bursian, Ph.D. Professor Michigan State University 2004 NSF Furfural 01/04 iiRandy Deskin, Ph.D., D
13、ABT Director, Toxicology and Product Regulatory Compliance Cytec Industries, Inc. Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Adi Pour, Ph.D. Director, Douglas County Health Depar
14、tment Omaha, Nebraska Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California Previous: Walter Decker, Ph.D. Toxicology Consultant Warren Foster, Ph.D. Health Canada Norbert Kaminski, Ph.D. Professor Michigan State University 2004 NSF Furfural 01/04 iiiEXECUTIVE SUMMARY Fur
15、fural Oral Risk Assessment CAS# 98-01-1 PARAMETER LEVEL UNITS DERIVED BMDL10(95% confidence limit at 10% response level) 3.3 mg/kg-day From a chronic rat study Oral RfD (oral reference dose) 0.03 mg/kg-day From the BMDL10with a 100x total uncertainty factor TAC (total allowable concentration) 0.2 mg
16、/L For a 70 kg adult drinking 2 L/day, with a 20% relative source contribution for drinking water SPAC (single product allowable concentration) 0.02 mg/L From the TAC, assuming 10 potential sources of furfural in drinking water STEL (short term exposure level) 3 mg/L From a subchronic rat study, for
17、 a 10 kg child drinking 1 L/day KEY STUDY National Toxicology Program. 1990. Toxicology and carcinogenesis studies of furfural (CAS No. 98-01-1) in F344/N rats and B6C3F1 mice (gavage studies). CRITICAL EFFECT Centrilobular hepatocellular necrosis in male rats at the BMDL10. Remaining critical respo
18、nses confined to high-dose rats and mice. UNCERTAINTY FACTORS Furfural was evaluated by the benchmark dose approach, with a total uncertainty factor of 100x, considered adequately protective and including the following areas of uncertainty: 3x for interspecies extrapolation 10x for intraspecies extr
19、apolation 1x for study duration, since a chronic study was used 1x for extrapolation from a LOAEL to a NOAEL, since a BMDL10was used 3x for database deficiencies TOXICITY SUMMARY No treatment-related lesions were observed following short-term oral exposure in rats or mice at doses up to those dose l
20、evels responsible for significantly reducing survival. Significant increases in absolute and relative liver and kidney weights were identified following subchronic oral high-dose exposure in the rat, and centrilobular coagulative necrosis developed after subchronic oral high-dose exposure in the mou
21、se. Limited evidence for high-dose hepatic carcinogenicity in the rat (cholangiocarcinoma) and mouse (hepatocellular adenoma/carcinoma) was reported following chronic oral exposure. Non-neoplastic lesions observed in the chronic oral bioassays were limited to centrilobular hepatocellular necrosis in
22、 rats and chronic hepatic inflammation in mice. There was no indication of developmental toxicity when furfural was evaluated in the rat. There is a weak Salmonella reverse mutation response in TA104, a weak response in the mouse lymphoma assay, and a convincingly positive in vitro chromosomal aberr
23、ation response. Smaller responses were seen with metabolic activation, and were not seen in the in vivo chromosomal aberration assay, suggesting the intrinsic genetic toxicity is not expressed. The U.S. EPA includes furfural in the IRIS on-line database. Although the oral RfD indicates that the last
24、 revision was in 1996, revisions since the 1987 verification date were editorial or administrative, and the 1990 NTP study was not included in the U.S. EPA evaluation. CONCLUSIONS Based on the 1990 NTP study, it is proposed that a threshold exists below which no significant adverse responses to furf
25、ural are observed following chronic oral exposure. As carcinogenic lesions have been observed at doses above this threshold in chronic oral bioassays in two species, furfural exhibits suggestive evidence of carcinogenicity at high doses in rodents. There is, however, inadequate information to assess
26、 the carcinogenic potential of furfural in humans. Uncertainties in the data set have been addressed through use of appropriate factors for interspecies and intraspecies extrapolation and database deficiencies. Based on the available data, the drinking water action levels established in this documen
27、t are protective of public health. 2004 NSF Furfural 01/04 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant furfural in drinking water, as an extractant from one or more drinking water system components tested under NSF/ANSI 61 (2003e
28、), or as a contaminant in a drinking water treatment chemical under NSF/ANSI 60 (2003e). This chemical has also been evaluated as a drinking water treatment chemical for direct addition to water under NSF/ANSI 60 (2003e). Both non-cancer and cancer endpoints have been considered, and risk assessment
29、 methodology developed by the U.S. Environmental Protection Agency (U.S. EPA) has been used. Non-cancer endpoints are evaluated using the reference dose (RfD) approach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993; U.S. EPA, 2002a), which assumes that there is a threshold for these endpoi
30、nts that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996) are applied to the highest dose showing no significant effects. This highest dose is derived from human exposure data when available, but more often is derived from studies in laboratory animals. Either the no-ob
31、served-adverse-effect level (NOAEL) taken directly from the dose-response data, or the calculated lower 95% confidence limit on the dose resulting in an estimated 10% increase in response (the LED10or BMDL10from benchmark dose programs) can be used (U.S. EPA, 2001). The lowest-observed-adverse-effec
32、t level (LOAEL) can also be used, with an additional uncertainty factor, although the benchmark dose approach is preferred in this case. The RfD is expressed in mg/kg-day. It is defined by the U.S. EPA as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to t
33、he human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EPA, 1993; U.S. EPA, 1999a). NSF uses the RfD to derive three product evaluation criteria for non-cancer endpoints. The total
34、 allowable concentration (TAC), generally used to evaluate the results of extraction testing normalized to static at-the-tap conditions, is defined as the RfD multiplied by the 70 kg weight of an average adult assumed to drink two liters of water per day. A relative source contribution (RSC), to ens
35、ure that the RfD is not exceeded when food and other non-water sources of exposure to the chemical are considered, is also applied in calculating the TAC. The relative source contribution should be data derived, if possible. Alternately, a 20% default contribution for water can be used (U.S. EPA, 19
36、91a). The TAC calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other sources (mg/day) 2L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2L/day The single product allowable concentration (SPAC), used for water treatment chemicals and for water contac
37、t materials normalized to flowing at-the-tap conditions, is the TAC divided by the estimated total number of sources of the substance in the drinking water treatment and distribution system. In the absence of source data, a default multiple source factor of 10 is used. 2004 NSF Furfural 01/04 2This
38、accounts for the possibility that more than one product in the water and/or its distribution system could contribute the contaminant in question to drinking water. Finally, a short-term-exposure level (STEL), at a higher level than the TAC, may be calculated for contaminants such as solvents expecte
39、d to extract at higher levels from new product, but also expected to decay rapidly over time. The STEL is calculated from the NOAEL or the LED10of an animal study of 14- to 90-days duration, with uncertainty factors appropriate to the duration of the study. The contaminant level must decay to the TA
40、C or below under static conditions or to the SPAC or below under flowing conditions within 90 days based on the contaminant decay curve generated from over-time laboratory extraction data. Endpoints related to cancer are evaluated using modeling to fit a curve to the appropriate dose-response data (
41、U.S. EPA, 1996a; U.S. EPA, 1999b; U.S. EPA, 2003). If there is sufficient evidence to use a non-linear model, the LED10or BMDL10, divided by the anticipated exposure, is calculated to give a margin of exposure. If there is insufficient evidence to document non-linearity, a linear model drawing a str
42、aight line from the LED10or BMDL to zero, is used as a default. If a linear model (generally reflecting a genotoxic carcinogen) is used, a target risk range of 10-6to 10-4is considered by the U.S. EPA to be safe and protective of public health (U.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2003
43、e) and 61 (2003e), the TAC is set at the 10-5risk level, and the SPAC is set at the 10-6risk level. Use of a higher risk level is not ruled out, but would generally require documentation of a benefit to balance the additional risk. The RfD, TAC, SPAC, and STEL values derived in this document are bas
44、ed on available health effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2003e) and 61 (2003e). Application of these values to other exposure scenarios should be done with care, and with a full understanding of the derivation of the val
45、ues and of the comparative magnitude and duration of the exposures. These values do not have the rigor of regulatory values, as data gaps are generally filled by industry or government studies prior to regulation. Data gaps introduce uncertainty into an evaluation, and require the use of additional
46、uncertainty factors to protect public health. The general guidelines for this risk assessment include those from the National Research Council (1983) and from The Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a, 1997b). Other guidelines used in the development of
47、this assessment may include the following: Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986), Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996a), draft revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999b), draft final Guidelines for Carcinogen Risk Assessmen
48、t (U.S. EPA, 2003), Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991b), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996b), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998), Recommendations for and Documentation of Biological Values for Use in Ri
49、sk Assessment (U.S. EPA, 1988), A Review of the Reference Dose and Reference Concentration Process (U.S. EPA, 2002a), and Health Effects Testing Guidelines (U.S. EPA 1996c; U.S. EPA, 2002b). 2004 NSF Furfural 01/04 3The literature search strategy employed for this compound was based on the Chemical Abstract Service Registry Number (CASRN) and at least one common name. As a minimum, the following data banks were searched: ChemID Plus Registry of Toxic Effects of Chemical Substances (RTECS) Hazardous Substances Data Bank
