1、 2004 NSF Mineral Oil 09/04 MINERAL OILS High Viscosity, Class I Medium and Low Viscosity, Class II Medium and Low Viscosity, and Class III Medium and Low Viscosity (per the World Health Organization classification) ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI September, 2004 Copyri
2、ght 2004 NSF International 2004 NSF Mineral Oil 09/04 iTABLE OF CONTENTS 1.0 INTRODUCTION.1 1.1 NSF Risk Assessment Procedures1 1.2 Evaluation of USP and Food Grade Mineral Oils by the World Health Organization 3 2.0 PHYSICAL AND CHEMICAL PROPERTIES.4 2.1 Organoleptic Properties5 3.0 PRODUCTION AND
3、USE .5 3.1 Production5 3.2 Use.5 4.0 ANALYTICAL METHODS.6 4.1 Analysis in Water 6 4.2 Analysis in Biological Matrices 6 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .6 5.1 Sources of Human Exposure 6 5.2 Sources of Environmental Exposure .7 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LA
4、BORATORY ANIMALS7 6.1 Absorption7 6.2 Distribution 7 6.3 Metabolism.8 6.4 Elimination/Excretion .8 7.0 EFFECTS ON HUMANS .8 7.1 Irritation and Sensitization.8 7.2 Eye Irritation .8 7.3 Single-Exposure Studies9 7.4 Repeated Dose Exposure.9 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS9
5、8.1 Limited-Exposure Effects .10 8.1.1 Irritation and Sensitization Studies.10 8.1.2 Ocular Exposure Studies.10 8.2 Single-Exposure Studies10 8.3 Short-Term Exposure Studies10 8.4 Long-Term and Chronic Exposure Studies 10 2004 NSF Mineral Oil 09/04 ii8.4.1 Subchronic Studies by BIBRA in F344 Rats 11
6、 8.4.2 Subchronic Feeding Studies in F-344 and Sprague-Dawley CRL:CD Rats .20 8.4.3 Subchronic Feeding Studies in Long-Evans Rats and Beagle Dogs .22 8.4.4 Chronic Studies23 8.5 Studies of Genotoxicity and Related End-Points23 8.6 Reproduction and Developmental Toxicity Studies .24 8.7 Studies of Im
7、munological and Neurological Effects.24 9.0 RISK CHARACTERIZATION .24 9.1 Hazard Assessment24 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .24 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization26 9.1.3 Selection of Key Study and Critical Effect27 9.1.4 Identification
8、of Susceptible Populations .28 9.2 Dose-Response Assessment.28 9.2.1 Uncertainty Factor Selection.28 9.2.2 Oral RfD Calculations.30 9.3 Exposure Assessment 31 9.4 TAC Derivation .32 9.4.1 TAC Derivation for High Viscosity Mineral Oils Based on P100 (H) .32 9.4.2 TAC Derivation for Class I Medium and
9、 Low Viscosity Mineral Oils 32 9.4.3 TAC Derivation for Class II Medium and Low Viscosity Mineral Oils.33 9.4.4 TAC Derivation for Class III Medium and Low Viscosity Mineral Oils .33 9.5 STEL Derivation33 9.5.1 STEL Derivation for High Viscosity Mineral Oils Based on P100 (H) .34 9.5.2 STEL Derivati
10、on for Class I Medium and Low Viscosity Mineral Oils 34 9.5.3 STEL Derivation for Class II Medium and Low Viscosity Mineral Oils.34 9.5.4 STEL Derivation for Class III Medium and Low Viscosity Mineral Oils .34 10.0 RISK MANAGEMENT 35 10.1 SPAC Derivation.35 10.1.1 SPAC Derivation for High Viscosity
11、Mineral Oils Based on P100 (H).35 10.1.2 SPAC Derivation for Class I Medium and Low Viscosity Mineral Oils 35 10.1.3 SPAC Derivation for Class II Medium and Low Viscosity Mineral Oils.35 10.1.4 SPAC Derivation for Class III Medium and Low Viscosity Mineral Oils .35 11.0 RISK COMPARISONS AND CONCLUSI
12、ONS 35 12.0 REFERENCES 38 13.0 APPENDICES .44 2004 NSF Mineral Oil 09/04 iii13.1 Other CAS Registry Numbers for USP Mineral oil (ChemIDplus, 2003) 44 13.2 Other CAS Registry Numbers for Mineral oil (ChemIDplus, 2003).44 14.0 PEER REVIEW HISTORY .44 2004 NSF Mineral Oil 09/04 ivAUTHORS, PEER REVIEWER
13、S, 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 the author noted above should be contacted with comments or for cla
14、rification. 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: Clif McLellan, M.S. External Peer Reviewers: NSF gratefully acknowl
15、edges 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 opinions of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chair, NSF H
16、ealth 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 Chair, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D
17、.Phil. Director, Environmental Health Science Safe Environments Programme Health Canada Steven Bursian, Ph.D. Professor of Animal Science Michigan State University Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries Inc. 2004 NSF Mineral Oil 09/04 vRober
18、t Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2004 NSF Mineral Oil 09/04 viEXECUTIVE SUMMARY Mineral Oil
19、, USP or Food Grade Oral Risk Assessment (oil classification per the World Health Organization) Mineral Oil Class NOAEL mg/kg-day Uncertainty Factor Oral RfD, mg/kg-day TAC1,4mg/L SPAC2,4mg/L STEL3,4mg/L High viscosity, 11 centistokes 2,000 100 20 700 70 700 Medium and low viscosity, Class I 8.5-11
20、centistokes 2,000 100 20 700 70 700 Medium and low viscosity, Class II 7.0-8.5 centistokes 200 100 2 40 4 40 Medium and low viscosity, Class III 3.0-7.0 centistokes 20 20 20 100 0.2 1 0.1 2 1Group TAC 2Group SPAC 3Group STEL 4 The solubility of a mineral oil in actual use as a direct or indirect dri
21、nking water additive should not be exceeded. KEY STUDY and KEY REVIEWS BIBRA Toxicology International. 1992a. A 90-day feeding study in the rat with six different white mineral oils N15(H), N70(H), N70(A), P15(H), N10(A), and P100(H), three different mineral waxes (a low melting point wax, a high me
22、lting point wax and a high sulphur wax) and coconut oil. Sponsored by CONCAWE, Brussels, Belgium. Project no. 3.1010. Report no. 1010/3/92. BIBRA Toxicology International. 1992b. Ninety-day feeding study in Fischer 344 rats of highly refined petroleum-derived food-grade white oils and waxes. Present
23、ed in part at The Toxicology Forum Special Meeting on Mineral Hydrocarbons, Green College, Oxford, United Kingdom, Sept. 21-23, 1992 and The Toxicology Forum 1993 Annual Winter Meeting, The Capital Hilton, Washington, D.C., February 15-17, 1993. WHO (World Health Organization). 1995a. Evaluation of
24、certain food additives and contaminants. Technical Report Series No. 859. Forty-fourth report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva. WHO (World Health Organization). 2002. Joint FAO/WHO Expert Committee on Food Additives. Fifty-ninth meeting. Geneva 4-13 June 2002. Summary
25、and Conclusions (full report in preparation). CRITICAL EFFECTS The critical effects depended to some extent on the physical properties of the mineral oils tested. The two highest viscosity oils did not show any effects considered adverse at the highest dose tested. Other oils produced liver and/or s
26、pleen weight effects with liver granulomas or other liver pathology. TOXICITY SUMMARY The available toxicology information on USP and food grade mineral oils has been summarized by the World Health Organization at a number of meetings of the Joint FAO/WHO Expert Committee on Food Additives, and was
27、not re-summarized in this document. The World Health Organization has taken the lead in the risk assessment of mineral oils, requesting or requiring additional studies as needed for clarification. It is clear from both human data and animal studies that mineral oil can accumulate to a small extent i
28、n organs and tissues. The liver is a target organ for the lower viscosity oils, based on liver weight effects, granulomas or micro-granulomas in the liver, and biochemical changes indicative of mild liver damage. Immune system effects of pigmented macrophages and lymph node histiocytosis have so far
29、 been observed in F-344 rats, but not in other rat strains or in Beagle dogs. Most genetic toxicity studies have shown that test results on mineral oils correlate directly with their polycyclic aromatic hydrocarbon content, suggesting the oil itself is not genotoxic. Oral exposure of humans to USP o
30、r food grade mineral oil in food and pharmaceuticals over many decades has not produced any evidence of carcinogenicity. Several older long-term oral studies in laboratory animals have shown no evidence of carcinogenicity, although these studies were not conducted according to current regulatory gui
31、delines. Since there are no human epidemiological studies and no adequate animal studies on mineral oil by the oral route, the “data are inadequate for an assessment of human carcinogenic potential”. CONCLUSIONS The drinking water action levels derived in this document are based on NOAEL values from
32、 well conducted subchronic studies of well characterized mineral oils. Based on these NOAEL values and appropriate uncertainty factors, the action levels are considered protective of the public health. 2004 NSF Mineral Oil 09/04 11.0 INTRODUCTION This document has been prepared to allow toxicologica
33、l evaluation of the unregulated contaminant mineral oil in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2003e), or as a drinking water treatment chemical evaluated under NSF/ANSI 60 (2003e). Both non-cancer and cancer endpoints have
34、been considered, and risk assessment methodology developed by the U.S. Environmental Protection Agency (U.S. EPA) has been used. USP grade, white, and commercial mineral oils will be evaluated using criteria developed in this document, with potential impurities in the lower grades evaluated separate
35、ly under the requirements of NSF/ANSI 60 (2003e) or 61 (2003e). 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, 2002a), which assumes that there is a threshold for these
36、endpoints that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996; U.S. EPA, 2002a) 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 an
37、imals. Either the no-observed-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, 2003a). The lowes
38、t-observed-adverse-effect 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)
39、of a daily exposure to the 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, 2003b). NSF uses the RfD to derive three product evaluation criteria for non-can
40、cer endpoints. The total 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 co
41、ntribution (RSC), to ensure 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 c
42、an be used (U.S. EPA, 1991a). The TAC calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other sources (mg/day) 2 L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2 L/day 2004 NSF Mineral Oil 09/04 2The single product allowable concentration (SPAC), u
43、sed for water treatment chemicals and for water contact 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 sourc
44、e factor of 10 is used. This 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 contamin
45、ants such as solvents expected 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 contamina
46、nt level must decay to a level at or below the TAC under static conditions, or to a level at or below the SPAC 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 t
47、o fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999; U.S. EPA, 2003c). 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
48、 document non-linearity, a linear model drawing a straight line from the LED10or BMDL10to 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
49、.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2003e) 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 counteract the additional risk. The RfD, TAC, SPAC, and STEL values deri
