1、 2005 NSF Titanium and Titanium Dioxide 05/05 TITANIUM (CAS # 7440-32-6) and TITANIUM DIOXIDE (CAS # 13463-67-7) ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI May 2005 Copyright 2005 NSF International This page is intentionally blank. 2005 NSF Titanium and Titanium Dioxide 05/05 TABL
2、E OF CONTENTS 1.0 INTRODUCTION.1 1.1 NSF Risk Assessment Procedures1 1.2 Scope of This Document3 2.0 PHYSICAL AND CHEMICAL PROPERTIES.4 2.1 Unique Properties5 2.2 Organoleptic Properties5 3.0 PRODUCTION AND USE .5 3.1 Production5 3.2 Use.5 4.0 ANALYTICAL METHODS.6 4.1 Analysis in Water 6 4.2 Analysi
3、s in Biological Matrices 7 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .7 5.1 Sources of Human Exposure 7 5.2 Sources of Environmental Exposure .8 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS8 6.1 Absorption8 6.2 Distribution 8 6.3 Metabolism.9 6.4 Elimination/Excreti
4、on .9 7.0 EFFECTS ON HUMANS .10 7.1 Irritation and Sensitization.10 7.2 Case Reports 10 7.3 Epidemiological Studies10 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS10 8.1 Limited-Exposure Effects .10 8.1.1 Irritation and Sensitization Studies.10 8.1.2 Ocular Exposure Studies.11 8.2 Sing
5、le-Exposure Studies11 8.3 Short-Term Exposure Studies11 8.4 Long-Term and Chronic Exposure Studies 12 2005 NSF Titanium and Titanium Dioxide 05/05 8.4.1 Subchronic Studies 12 8.4.2 Chronic Studies13 8.5 Studies of Genotoxicity and Related End-Points16 8.5.1 Mutagenicity Assays 16 8.5.2 Assays of Chr
6、omosomal Damage17 8.5.3 Other Assays of Genetic Damage20 8.6 Reproduction and Developmental Toxicity Studies .20 8.7 Studies of Immunological and Neurological Effects.21 9.0 RISK CHARACTERIZATION .21 9.1 Hazard Assessment21 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .21 9.1.2 We
7、ight-of-Evidence Evaluation and Cancer Characterization22 9.1.3 Selection of Key Study and Critical Effect23 9.1.4 Identification of Susceptible Populations .23 9.2 Dose-Response Assessment.24 9.3 Exposure Assessment 26 9.4 TAC Derivation .26 9.5 STEL Derivation27 10.0 RISK MANAGEMENT 29 10.1 SPAC D
8、erivation.29 11.0 RISK COMPARISONS AND CONCLUSIONS 29 12.0 REFERENCES 30 13.0 APPENDICES .35 13.1 WHO/IPCS Environmental Health Criteria 24 (1982)35 13.2 Dose Conversions 35 13.2.1 Subchronic Studies (NCI, 1978)35 13.2.2 Chronic Study (NCI, 1978)37 13.3 Toxicology Summaries for Other Than Titanium a
9、nd Titanium Dioxide.39 13.3.1 Titanocene Dichloride (C5H5)2TiCl2.39 13.3.2 Titanium Tetrachloride41 13.3.3 Other Titanium Compounds41 14.0 PEER REVIEW HISTORY .42 2005 NSF Titanium and Titanium Dioxide 05/05 iAUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: NSF Toxicology Services 1.800.NSF.MAR
10、K NSF International 789 Dixboro Road Ann Arbor, MI 48105 Disclaimer: The responsibility for the content of this document remains solely with NSF International, and the author noted above should be contacted with comments or for clarification. Mention of trade names, proprietary products, or specific
11、 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: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on t
12、he NSF Health Advisory Board in providing peer review. These peer reviewers serve on a voluntary basis, and their opinions do not necessarily represent the opinions of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chairman, NSF Health Advisory Board) Director, Health and E
13、cological Criteria Division Office of Science and Technology/Office of Water U.S. Environmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Director, Environmental Health Sci
14、ence Safe Environments Programme Health Canada Steven Bursian, Ph.D. Professor Michigan State University Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries Inc. 2005 NSF Titanium and Titanium Dioxide 05/05 iiRobert Hinderer, Ph.D. Director of Health, To
15、xicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, M.S. Associate Director for Science USEPA/NHEERL/WED Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2005 NSF Titanium and Titanium Dioxide 05/05 iiiEXECUTIVE SUMMARY Titanium (CAS # 7440-32-6) and Ti
16、tanium Dioxide (CAS # 13463-67-7) Oral Risk Assessment PARAMETER Ti LEVEL1UNITS DERIVED: NOAEL (no-observed-adverse-effect level) 2,680 mg/kg-day From a 2-year titanium dioxide feeding study in rats. Oral RfD (oral reference dose) 3 mg/kg-day From a 2-year titanium dioxide feeding study in rats. TAC
17、 (total allowable concentration) 90 mg/L From a 2-year titanium dioxide feeding study in rats, for a 70 kg adult consuming 2 L/day, with a 20% Relative Source Contribution for drinking water. SPAC (single product allowable concentration) 9 mg/L From the TAC, assuming the default 10 sources of titani
18、um in drinking water. STEL (short term exposure level) 90 mg/L Set equal to the TAC. 1 The solubility of titanium or titanium dioxide in actual use as a direct or indirect drinking water additive should not be exceeded. KEY STUDY NCI (National Cancer Institute). 1978. Bioassay of Titanium Dioxide fo
19、r Possible Carcinogenicity. NTIS PB288780. CRITICAL EFFECT No significant adverse responses at either of the tested doses UNCERTAINTY FACTORS Uncertainty factors applied in calculating the oral RfD are as follows: 10x for interspecies extrapolation 10x for intraspecies extrapolation 1x for study dur
20、ation, since a chronic study was used 1x for extrapolation from a LOAEL to a NOAEL, since a NOAEL was used 10x for database deficiencies The total uncertainty factor is, therefore, 1000x. TOXICITY SUMMARY While there are no experimental data by the oral route in humans, titanium is the ninth most ab
21、undant element and humans are routinely exposed to it as a natural, direct and indirect food additive. A statistically significant reduction in survival of female mice fed titanium dioxide for two years (NCI, 1978) was of questionable biological significance due to exceptionally high survival of con
22、trol females, and represented the only significant toxicological effect seen in rats or mice in the 2-year studies. Neoplastic responses to long-term titanium exposure in laboratory animals were observed after high-dose titanium dust inhalation in rats. Those lesions, in addition to the non-neoplast
23、ic responses to titanium inhalation exposure in laboratory animals and humans, were attributed to excessive dust accumulation in the lung. Statistically increased neonatal deaths and runts were seen in the second generation of a three-generation reproduction study (Schroeder and Mitchener, 1971), in
24、 which rats were exposed to titanium in their drinking water. This study, however, was not conducted according to guidelines and had insufficient experimental detail for use in risk assessment. Titanium compounds did not induce gene mutations in microbial assays or in the mouse lymphoma assay. Titan
25、ium dioxide did not induce structural chromosomal aberrations in vitro or in vivo, but did induce micronuclei both in vitro and in vivo, suggesting that it induces micronuclei through chromosome loss (aneuploidy). CONCLUSIONS Based on positive clastogenicity data and negative cancer bioassays in rat
26、s and mice, there is inadequate information to assess the carcinogenic potential of titanium and titanium dioxide to humans by the oral route. The concern associated with positive clastogenicity (micronucleus) data is reduced because dietary titanium failed to induce neoplastic lesions following chr
27、onic oral exposure in rats or mice. Any significance to the positive micronucleus data or to results of the three-generation reproduction study have been addressed by incorporating appropriate uncertainty factors in the oral risk value calculations. There is limited evidence of carcinogenicity in la
28、boratory animals following inhalation and intramuscular exposure to high levels of titanium dioxide or titanium, but the adverse effects are not considered relevant to drinking water (oral) exposure. It is not appropriate to use the derived oral risk values for titanium tetraiodide, titanium tetrabr
29、omide, titanium tetrachloride, titanium tetrafluoride or organotitanium compounds as their chemical, physical, and biological properties differ from those of titanium and titanium dioxide evaluated in this document. Inorganic titanium compounds not specifically excluded are either not manufactured i
30、n the United States or have limited available data. Those compounds shall be evaluated on a case-by-case basis to determine whether use of the derived oral risk values is appropriate. The derived TAC, SPAC, and STEL values for titanium and titanium dioxide are protective of public health. 2005 NSF T
31、itanium and Titanium Dioxide 05/05 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminants titanium (leached from mined or natural products, or from titanium alloys) and titanium dioxide in drinking water, as extractants from one or more dr
32、inking water system components tested under NSF/ANSI 61 (2004), or as contaminants in drinking water treatment chemicals evaluated under NSF/ANSI 60 (2004). Both non-cancer and cancer endpoints have been considered, and risk assessment methodology developed by the U.S. Environmental Protection Agenc
33、y (U.S. EPA) has been used. 1.1 NSF Risk Assessment Procedures Non-cancer endpoints are evaluated using the reference dose (RfD) approach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993; U.S. EPA, 2002), which assumes that there is a threshold for these endpoints that will not be exceeded i
34、f 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-observed-adverse-effect level (NO
35、AEL) 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 BMDL from benchmark dose programs) can be used (U.S. EPA, 2003a). The lowest-observed-adverse-effect level (LOAEL) can also be use
36、d, 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 the human population (including
37、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, 2003b). NSF uses the RfD to derive three product evaluation criteria for non-cancer endpoints. The total allowable concentration (TAC),
38、 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 2 liters of water per day. A relative source contribution (RSC), to ensure that the RfD is not exceeded
39、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, 1991a). The TAC calculation is then
40、 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 contact materials normalized to flowing
41、 at-the-tap conditions, is the TAC divided by the 2005 NSF Titanium and Titanium Dioxide 05/05 2estimated 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. This accounts for
42、 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 expected to extract
43、 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 TAC or below u
44、nder 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 (U.S. EPA,
45、1996a; U.S. EPA, 1999; U.S. EPA, 2003c; U.S. EPA, 2005). If there is sufficient evidence to use a non-linear model, the LED10or BMDL, 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
46、 straight 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 10-4to 10-6is 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 (
47、2004) and 61 (2004), 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 counteract the additional risk. The RfD, TAC, SPAC, and STEL values derived in this document ar
48、e based on available health effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2004) and 61 (2004). Application of these values to other exposure scenarios should be done with care, and with a full understanding of the derivation of the
49、values 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 uncertainty factors to protect public health. The general guidelines for this risk assessment include those
