1、p-Chloro-m-Cresol 12/02 p-CHLORO-m-CRESOL CAS # 59-50-7 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI December 2002 Copyright 2002 NSF International p-Chloro-m-Cresol 12/02 i TABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties3 3.0
2、PRODUCTION AND USE .4 3.1 Production4 3.2 Use.4 4.0 ANALYTICAL METHODS.5 4.1 Analysis in Water 5 4.2 Analysis in Biological Matrices 5 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .5 5.1 Sources of Human Exposure 5 5.2 Sources of Environmental Exposure .5 6.0 COMPARATIVE KINETICS AND METABOLISM I
3、N HUMANS AND LABORATORY ANIMALS6 7.0 EFFECTS ON HUMANS .6 7.1 Case Reports 7 7.2 Epidemiological Studies7 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS7 8.1 Limited-Exposure Effects .7 8.1.1 Irritation and Sensitization Studies.7 8.1.2 Ocular Exposure Studies.9 8.2 Single-Exposure Stud
4、ies10 8.3 Short-Term Exposure Studies11 8.4 Long-Term and Chronic Exposure Studies 11 8.4.1 Subchronic Studies 11 8.4.2 Chronic Studies13 8.5 Studies of Genotoxicity and Related End-Points20 8.5.1 Mutagenicity Assays 20 8.5.2 Assays of Chromosomal Damage22 8.5.3 Other Assays of Genetic Damage22 8.6
5、Reproductive and Developmental Toxicity Studies23 8.6.1 Developmental Toxicity .23 8.7 Studies of Immunological and Neurological Effects.24 p-Chloro-m-Cresol 12/02 ii 9.0 RISK CHARACTERIZATION .25 9.1 Hazard Assessment25 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .25 9.1.2 Weigh
6、t-of-Evidence Evaluation and Cancer Characterization28 9.1.3 Selection of Key Study and Critical Effect30 9.1.4 Identification of Susceptible Populations .30 9.2 Dose-Response Assessment.31 9.3 Exposure Characterization.32 9.4 TAC Derivation .32 9.5 STEL Derivation33 10.0 RISK MANAGEMENT 34 10.1 SPA
7、C Derivation.34 11.0 RISK COMPARISONS AND CONCLUSIONS 35 12.0 REFERENCES 37 13.0 PEER REVIEW HISTORY .41 p-Chloro-m-Cresol 12/02 iii AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: Toxicology Services Department 1.800.NSF.MARK NSF International 789 Dixboro Road Ann Arbor, MI 48105 Disclaimer:
8、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 equipment does not constitute an endorsement by NSF International, n
9、or does it imply that other products may not be equally suitable. Acknowledgement: NSF gratefully acknowledges the assistance of Bayer AG in providing unpublished studies and historical control records reviewed in this document. Internal NSF Peer Reviewers: Lori Bestervelt, Ph.D. Gwendolyn Ball, Ph.
10、D. Clif McLellan, M.S. Maryann Sanders, 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 opini
11、ons of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chairperson, NSF Health Advisory Board) Acting 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 Ch
12、airperson, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Acting Director, Environmental Health Science Save Environments Programme Health Canada p-Chloro-m-Cresol 12/02 Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory
13、Compliance Cytec Industries, Inc. Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, M.S. Associate Director for Science USEPA/NHEERL/WED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, Ph.D. Depa
14、rtment of Toxic Substance Control State of California 2002 NSF p-Chloro-m-Cresol 12/02 iv EXECUTIVE SUMMARY p-Chloro-m-Cresol Oral Risk Assessment CAS # 59-50-7 PARAMETER LEVEL UNITS CALCULATED: NOAEL (no-observed-adverse-effect level) 103 mg/kg-day From a 2-year rat feeding study Oral RfD (oral ref
15、erence dose) 0.1 mg/kg-day From a 2-year rat feeding study TAC (total allowable concentration) 0.7 mg/L For a 70 kg adult drinking 2 L/day with a 20% Relative Source Contribution from drinking water. SPAC (single product allowable concentration) 0.07 mg/L For a 70 kg adult drinking 2 L/day. STEL (sh
16、ort term exposure level) 1 mg/L For a 10 kg child drinking 1 L/day. KEY STUDY Leser, K.H. 1992. Chronic Toxicity and Carcinogenicity Study in Wistar Rats (Administration in Feed for 104 Weeks). Unpublished study prepared by Bayer AG Toxicological Institute. Wuppertal, Germany. Study Number T9030673.
17、 CRITICAL EFFECTS In males, increased incidence of unilateral papillary necroses, truncated papillae, and cortical dilations and fibrosis of the kidneys. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD: 10x for interspecies extrapolation 10x for intraspecies extrapolation 1x for subc
18、hronic to chronic 1x for LOAEL to NOAEL 10x for database deficiencies The total uncertainty factor is therefore 1,000x. TOXICITY SUMMARY The critical study was a two-year feeding study in which rats were administered p-chloro-m-cresol at 0, 21, 103.1, or 558.9 mg/kg-day in males and 0, 27.7, 134.3,
19、or 743.5 mg/kg-day in females. In mid-dose females and low-dose males, statistically significant pituitary adenomas were observed. In mid- and high-dose males, a statistically significant increasing trend of testicular interstitial cell adenomas was observed. All neoplastic effects were within histo
20、rical control ranges for the laboratory, thus were not considered biologically significant. The non-neoplastic effects observed in females included a dose-related trend of animals with “poor general condition,” a statistically significant reduction in mean body weight, a statistically significant, b
21、ut not dose related, decrease in mean absolute brain weight, and depression of the brain due to an enlarged pituitary at all doses. The brain effects were considered by the authors of this risk assessment to be related to the pituitary adenomas, which were not considered biologically significant, si
22、nce they were within the historical control range. In high-dose males, an increased incidence of unilateral papillary necroses, truncated papillae, and cortical dilations and fibrosis of the kidneys were observed. Also, an increase in unilateral reduced spermatozoa in the epididymides and unilateral
23、 seminiferous tubule degeneration were observed at the mid dose, and combined (unilateral and bilateral) reduced spermatozoa at the high dose. The reproductive effects were not considered by the authors of this risk assessment to be biologically significant based on the high background incidence of
24、these effects in this rat strain. The NOAEL for the study can be considered 103.1 mg/kg-day, based on the male rat kidney effects. In a developmental study, rats received p-chloro-m-cresol by gavage at 0, 30, 100 or 300 mg/kg-day from days 6-15 of gestation. For dams, the NOAEL can be considered 100
25、 mg/kg-day, based on clinical signs of toxicity and decreased mean body weight gain. In offspring, the NOAEL is also 100 mg/kg-day, based on the statistically significant decrease in mean fetal weight per litter. p-Chloro-m-cresol tested positive in one Salmonella reverse mutation assay in Strain TA
26、97 with metabolic activation, despite testing negative in all other tested strains in four other Salmonella studies, including Strain TA97 with rat and hamster S9 activation. p-Chloro-m-cresol tested positive for SOS DNA repair, although cytotoxicity was observed at all doses, but was negative in ch
27、romosomal aberration and unscheduled DNA synthesis assays. CONCLUSIONS Chronic oral exposure to p-chloro-m-cresol results in renal pathology in male rats. Due to the lack of human and second-species animal studies, the carcinogenic potential of p-chloro-m-cresol in humans cannot be determined. Howev
28、er, the weight of evidence suggests that p-chloro-m-cresol does not cause cancer in rats and is not genotoxic. Based on the uncertainty factors used to account for the database deficiencies, the drinking water action levels are considered adequately protective of human health. 2002 NSF p-Chloro-m-Cr
29、esol 12/02 1 1.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant p-chloro-m-cresol in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2002), or as a contaminant in a drinking
30、 water treatment chemical evaluated under NSF/ANSI 60 (2002). Both non-cancer and cancer endpoints have been considered, and risk assessment 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) a
31、pproach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993), which assumes that there is a threshold for these endpoints 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 deri
32、ved from human exposure data when available, but more often is derived from studies in laboratory animals. 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 i
33、n response (the LED10or BMDL from benchmark dose programs) can be used (U.S. EPA, 2001a). The lowest-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
34、 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 sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EP
35、A, 1993; U.S. EPA, 1999a). NSF uses the RfD to derive three product evaluation criteria for non-cancer 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
36、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 when food and other non-water sources of exposure to the chemical are considered, is also applied in calculating the TAC. The relative source cont
37、ribution 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 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.
38、2 (RSC) 2L/day The single product allowable concentration (SPAC), used 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 distribut
39、ion system. In the absence of source data, a default multiple source factor of 10 is used. 2002 NSF p-Chloro-m-Cresol 12/02 2 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. Final
40、ly, a short-term exposure level (STEL), at a higher level than the TAC, may be calculated for contaminants 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-
41、 to 90-days duration, with uncertainty factors appropriate to the duration of the study. The contaminant level must decay to the TAC 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 labora
42、tory extraction data. Endpoints related to cancer are evaluated using modeling to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999b). If there is sufficient evidence to use a non-linear model, the LED10or BMDL, divided by the anticipated exposure, is calculated to g
43、ive a margin of exposure. If there is insufficient evidence to document non-linearity, a linear model drawing a 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 10-6to 10-4is considered
44、by the U.S. EPA to be safe and protective of public health. (U.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2002) and 61 (2002), 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
45、 of a benefit to counteract the additional risk. The RfD, TAC, SPAC, and STEL values derived in this document are based on available health effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2002) and 61 (2002). Application of these valu
46、es to other exposure scenarios should be done with care, and with a full understanding of the derivation of the 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
47、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 from the National Research Council (1983) and from The Presidential/Congressi
48、onal Commission on Risk Assessment and Risk Management (1997a, 1997b). Other guidelines used in the development of 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 revise
49、d Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999b), 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 Risk Assessment (U.S. EPA, 1988a), and Health Effects Testing Guidelines (U.S. EPA 1996c, OPPTS series 870; U.S. EPA, 2002, 40 CFR
