SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL Methallyloxyphenol (CAS No. 4790-71-0) [9th CI Name: Phenol, 2-[(2-methyl-2-propenyl)oxy-] June 2008 INTERIM Prepared by High Production Volume Chemicals Branch Risk Assessment Division Office of Pollution Prevention and Toxics Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460-0001 ------- SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making publicly available screening-level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the environment. The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard- based screening process to prioritize review of the submissions. The hazard-based screening process consists of two tiers described below briefly and in more detail on the Hazard Characterization website3. Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as submitted by the sponsor. It does not include evaluation of the quality or completeness of the data. In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors. EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar chemical structures, properties and biological activities may be grouped together and their data shared across the resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all category members. As part of Tier 2, evaluation of chemical category rationale and composition and data extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance. The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing chemicals review process. These hazard characterizations are technical documents intended to support subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously not readily available to the public. The public, including sponsors, may offer comments on the hazard characterization documents. The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk- based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action. 1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm. 2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm. 3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html). 4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf. 6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm. 2 ------- SCREENING-LEVEL HAZARD CHARACTERIZATION Methallyloxyphenol (CAS No. 4790-71-0) Introduction The sponsor, FMC Corporation, submitted a Test Plan and Robust Summaries to EPA for methallyloxyphenol (CAS Number 4790-71-0, 9th CI Name: phenol, 2-[(2-methyl-2-propenyl)oxy) on December 28, 2001. EPA posted the submission on the ChemRTK HPV Challenge Web site on February 5, 2002 (http://www.epa.gov/chemrtk/pubs/summaries/methYall/cl3458tc.htm'). EPA comments on the original submission were posted to the website on were submitted on July 31, 2002. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on July 8, 2002, September 29, 2002, and December 30, 2004, which were posted to the ChemRTK website on July 24, 2002, October 17, 2002, and February 3, 2005, respectively. This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor's responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the structure(s) of the sponsored chemical(s) is included in the appendix. The screening-level hazard characterization for environmental and human health effects is based largely on SIDS endpoints and is described according to established EPA or OECD effect level definitions and hazard assessment practices. The sponsor claimed that methallyloxyphenol is a closed-system intermediate (CSI) and eligible for reduced testing under the HPV Challenge Program. EPA agreed that methallyloxyphenol met the criteria for a CSI and waived the requirement for repeated-dose and reproductive toxicity testing for the purposes of the HPV Challenge Program. Summary-Conclusion The log Kow of methallyloxyphenol indicates thai its potential to bioaccumulalc is expected to be low. Methallyloxyphenol is not readily biodegradable, indicating thai it has the potential to persist in the environment. The evaluation of available toxicity data indicates thai the potential acute hazard of methallyloxyphenol to fish and aquatic invertebrates is high and to aquatic plants is low. The acute oral toxicity of methallyloxyphenol in rats is low. Requirements for repealed dose and reproductive toxicity testing were waived under the HPV Challenge Program because methallyloxyphenol is a closed system intermediate. In a combined reproductive/developmental toxicity screening lest in rats, no treatment-related changes were seen on the developing fetuses. Mclhallyloxvphcnol induced gene mutations in bacteria and induced Ircalmenl-rclaled increases in the mutation frequency in mouse lymphoma 5178Y cells in vitro. Mclhallyloxvphcnol did not induce chromosomal aberrations in rat bone marrow cells in vivo or unscheduled DNA synthesis in ral. hcpalocylcs in vitro. The potential hazard of methallyloxyphenol is low: however, available data suggest thai mclhallyloxvphcnol has the potential to be gcnoloxic. No data gaps were identified under the HPV Challenge Program. 3 ------- 1. Physical-Chemical Properties and Environmental Fate A summary of physical-chemical and environmental fate data submitted is provided in the Appendix. For the purpose of the screening-level hazard characterization, the review and summary of these data were limited to the octanol-water partition coefficient and biodegradation endpoints as indicators of bioaccumulation and persistence, respectively. Octanol-Water Partition Coefficient Log KoW: 2.47 (measured) Biodegradation (1) In a Closed-Bottle test using secondary clarifier supernatant inoculum, 0% of methallyloxyphenol had degraded after 28 days. Methallyloxyphenol is not readily biodegradable. Conclusion: The log Kow of methallyloxyphenol indicates that its potential to bioaccumulate is expected to be low. Methallyloxyphenol is not readily biodegradable, indicating that it has the potential to persist in the environment. 2. Environmental Effects - Aquatic Toxicity Acute Toxicity to Fish (1) Sheepshead minnow (Cyprinodon variegates, 10/replicate) were exposed to methallyloxyphenol at measured concentrations of 0, 2.3, 4.4, 8.8, 18 or 38 mg/L under flow-through conditions for 96 hours. Mortality ranged from 5% at 4.4 mg/L to 100% at 18 and 38 mg/L. 96-h LCS0 = 9.8 mg/L (2) Atlantic silverside (Menidia menidia, 10/replicate) were exposed to methallyloxyphenol at measured concentrations of 0, 0.684, 1.42, 2.96, 6.16 or 11.6 mg/L under flow-through conditions for 96 hours. The mortality was 5% at 0.684 mg/L and 100% at 11.6 mg/L. 96-h LCS0 = 4.6 mg/L (3) Marine spot (Leiostomus xanthurus, 5/replicate) were exposed to methallyoxyphenol at nominal concentrations of 0, 0.065, 0.125, 0.25, 0.50 or 1.0 mg/L for 96 hours. Partial loss of equilibrium was noted in four out of ten fish at 1.0 mg/L at 24 hours. There was 100% mortality at 1.0 mg/L at 48 hours. 96-h LCS0 = 0.71 mg/L Acute Toxicity to Aquatic Invertebrates Mysidopsis bahia (10/replicate) were exposed to methallyloxyphenol at measured concentrations ranging from 255 to 2307 |ig/L under flow-through conditions for 96 hours. 96-h LCS0 = 1.13 - 1.33 mg/L (2) Mysidopsis bahia (10/replicate) were exposed to methallyloxyphenol at measured concentrations of 67, 138, 257, 495 or 1053 |ig/L under flow-through conditions for 96 hours. After 96 hours, mortality ranged from 10% at 67 |ig/L to 100% at 1053 |ig/L. Partial loss of equilibrium was observed at the 24 hour observation period at 138 Hg/L. 48-h LCS0= 0.520 mg/L 96-h LCS0= 0.201 mg/L 4 ------- (3) Mysidopsis bahia (10/replicate) were exposed to methallyloxyphenol at nominal concentrations of 0.23, 0.39, 0.65, 1.1, 1.8 or 3.0 mg/L under static conditions for 96 hours. After 96 hours, mortality ranged from 10% at and below 0.39 mg/L to 100% at and above 1.8 mg/L. 96-h LCS0= 0.81 mg/L Toxicity to Aquatic Plants Algae (Skeletonema costatum) were exposed to methallyloxyphenol (68% purity) at measured concentrations of 0, 3.45, 10.59, 19.43, 37.64 or 76.4 mg/L for 96 hours. Loss of color (chlorophyll) and general fading of cells (representing disintegration of the cell wall and cell death) was noted only at 37.64 mg/L. No viable cell material was found at 74.6 mg/L. 96-h EC50 (biomass) = 26.6 mg/L Conclusion: The evaluation of available toxicity data indicates that the potential acute hazard of methallyloxyphenol to fish and aquatic invertebrates is high and to aquatic plants is low. 3. Human Health Effects Acute Oral Toxicity Sprague-Dawley rats (10/sex/dose) were administered single doses of methallyloxyphenol via gavage at 2000, 2500, 3000, 4000, or 4500 mg/kg-bw (males) or 2500, 2700, 3000, or 4500 mg/kg-bw (females) and observed for 14 days. Predominant clinical signs included decreased locomotion, ataxia, recumbency, exophthalmos, hematuria, lacrimation, oral discharge, and abdominogenital staining. Most signs of toxicity subsided by the 5th day of the study. Gross necropsy findings among decedents included red fluid in the intestines and bladder of several rats. The necropsy of survivals did not reveal any abnormalities. LDS0 = 2943 mg/kg-bw Repeated-Dose Toxicity The requirement for repeated-dose toxicity endpoint was waived for the purposes of the HPV Challenge Program because methallyloxyphenol is a closed system intermediate. Reproductive Toxicity The requirement for reproductive toxicity endpoint was waived for the purposes of the HPV Challenge Program because methallyloxyphenol is a closed system intermediate. Developmental Toxicity In a combined reproductive/developmental toxicity study, Sprague-Dawley rats (group size not indicated) were administered methallyloxyphenol via gavage at 0, 60, 240 or 720 mg/kg-bw/day. Males were exposed from 2 weeks before mating to end of mating (28 days) and females were exposed from 2 weeks before mating through gestation to day 3 post partum (54 days). There was a high incidence of salivation in both sexes at 240 and 720 mg/kg-bw doses. There were no treatment-related changes in body weight, food consumption, necropsy findings, and male reproductive organ weights or histopathological findings. There were no treatment-related changes in precoital time, mating index, fertility index, pregnancy index and reproductive and litter findings such as gestation length, number of live and dead pups at birth, sex ratio, and body weights of live pups. NOAEL for maternal/developmental toxicity = 720 mg/kg-bw/day (based on no effects at the highest dose tested) 5 ------- Genetic Toxicity - Gene Mutation In vitro (1) In two separate assays, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to methallyloxyphenol at concentrations from 20 - 5000 |ig/plate in the presence and absence of metabolic activation. The test material was not mutagenic in the presence of metabolic activation. Methallyloxyphenol caused an increase in revertants/plate in TA1535 in the absence of metabolic activation. An increase in mutation frequency in TA100 was observed in the absence of metabolic activation; however this increase did not meet the criterion for a positive response due to the high background incidence in this strain. The positive and negative (DMSO) controls were included in the assay and gave appropriate responses. Methallyloxyphenol was mutagenic in these assays. (2) Salmonella typhimurium strain TA1535 was exposed to methallyoxyphenol at concentrations of 2.5, 12.5, 62.5, 312.5, 625, 1250, 2500, 5000, or 10,000 |ig/platc in the absence of metabolic activation in a modified Ames assay. No positive controls were used. All concentrations induced an increase in the revertants per plate. Methallyloxyphenol was mutagenic in these assays. (3) Mouse lymphoma L5178Y cells were exposed to methallyloxyphenol (64% purity) in the presence and absence of metabolic activation. Concentrations were 0.0006 - 0.0084 |iL/mL in the presence of metabolic activation and 0.0013 - 0.0075 |iL/mL in the absence of metabolic activation. In the absence of metabolic activation, methallyloxyphenol induced an increase in mutation frequency. In the presence of metabolic activation, there was no increase in mutation frequency. Methallyloxyphenol was mutagenic in these assays. (4) Mouse lymphoma L5178Y cells were exposed to methallyloxyphenol (64% purity) in the presence and absence of metabolic activation. Concentrations tested were 0.2 - 3.3 ng/mL in the presence of metabolic activation and 20.0 - 330 iig/mL in the absence of metabolic activation. The test material induced treatment-related increases in the mutation frequency in both the presence and absence of metabolic activation in this assay at concentrations in which cell survival was greater than 10%. The positive and negative (DMSO) controls were included in the assay and gave appropriate responses. Methallyloxyphenol was mutagenic in these assays. Genetic Toxicity - Chromosomal aberrations In vivo Sprague-Dawley rats (5 males/dose) were administered methallyloxyphenol via gavage at 0, 100, 300 or 1000 mg/kg-bw and were sacrificed 6, 24, and 48 hours later for each dose and for a corn oil control group. A positive control group of 5 rats received 40 mg/kg-bw cyclophosphamide and were sacrificed after 24 hours. Two hours prior to sacrifice, animals were given a single intraperitoneal injection of 2.0 mg/kg colchicine to arrest cells in metaphase. Bone marrow was collected from both femurs, cells were prepared and analyzed. The test material did not induce an increase in chromosomal aberrations relative to the solvent control. Methallyloxyphenol was did not induce chromosomal aberrations in this assay. Genetic Toxicity - Other In vitro In an unscheduled DNA synthesis assay, rat primary hepatocytes were exposed to methallyloxyphenol at 0.1, 0.5, 1.0, 5.0, 10, 50, 100, or 500 (ig/mL for 24 hours. There was no net increase in the mean net nuclear grain count in cells treated with the test article compared to the solvent control (100 cells counted). The positive controls showed the expected increase in net nuclear grain counts (50 cells counted). Higher doses (not specified) were cytotoxic. Methallyloxyphenol was did not induce unscheduled DNA synthesis in this assay. Conclusion: The acute oral toxicity of methallyloxyphenol in rats is low. Requirements for repeated dose and reproductive toxicity testing were waived under the HPV Challenge Program because methallyloxyphenol is a closed system intermediate. In a combined reproductive/developmental toxicity screening test in rats, no treatment- related changes were seen on the developing fetuses. Methallyloxyphenol induced gene mutations in bacteria and 6 ------- induced treatment-related increases in the mutation frequency in mouse lymphoma 5178Y cells in vitro. Methallyloxyphenol did not induce chromosomal aberrations in rat bone marrow cells in vivo or unscheduled DNA synthesis in rat hepatocytes in vitro. The potential hazard of methallyloxyphenol is low; however, available data suggest that methallyloxyphenol has the potential to be genotoxic. 4. Hazard Characterization The log Kow of methallyloxyphenol indicates that its potential to bioaccumulate is expected to be low. Methallyloxyphenol is not readily biodegradable, indicating that it has the potential to persist in the environment. The evaluation of available toxicity data indicates that the potential acute hazard of methallyloxyphenol to fish and aquatic invertebrates is high and to aquatic plants is low. The acute oral toxicity of methallyloxyphenol in rats is low. Requirements for repeated dose and reproductive toxicity testing were waived under the HPV Challenge Program because methallyloxyphenol is a closed system intermediate. In a combined reproductive/developmental toxicity screening test in rats, no treatment-related changes were seen on the developing fetuses. Methallyloxyphenol induced gene mutations in bacteria and induced treatment-related increases in the mutation frequency in mouse lymphoma 5178Y cells in vitro. Methallyloxyphenol did not induce chromosomal aberrations in rat bone marrow cells in vivo or unscheduled DNA synthesis in rat hepatocytes in vitro. The potential hazard of methallyloxyphenol is low; however available data suggest that methallyloxyphenol has the potential to be genotoxic. 5. Data Gaps No data gaps were identified under the HPV Challenge Program. 7 ------- APPENDIX Summary Tabic of the Screening Information Data Set as Submitted underthe U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL Mcthallyloxyphcnol (4790-71-0) Structure 0H // dh° Summary of Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) Liquid at room temperature Boiling Point (°C) Undergoes a Claisen rearrangement before reaching the boiling point Vapor Pressure (hPa at 25°C) 0.03 Log K„w 2.47 Water Solubility (mg/L at 25°C) 1.83 xlO3 at 20 °C Indirect (OH) Photodegradation Half-life (t1/2) 1.5 hours Stability in Water (Hydrolysis) (ti/2) 184 days (pH 1.2 and 37 °C) 534 days (pH 9 and 20 °C) 100 days (pH 9 and 37 °C) Stable at pH 4 and 7 and 50 °C Fugacity (Level III Model) Air (%) Water (%) Soil (%) Sediment (%) 1.9 48.4 49.5 <1% Biodegradation at 28 days (%) 0 Not readily biodegradable Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LCS0 (mg/L) 0.71 mg/L (Marine spot) 4.6 (Atlantic silverslide) 9.8 (Sheepshead minnow) Aquatic Invertebrates 48-h ECS0 (mg/L) 0.201 - 1.3 mg/L (Mysidopsis bahia) Aquatic Plants 72-h ECS0 (mg/L) (biomass) 26.6 8 ------- Summary Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL Mcthallyloxyphcnol (4790-71-0) Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) 2943 Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Requirement waived for closed system intermediates Reproductive Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Systemic & Reproductive Toxicity Requirement waived for closed system intermediates Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Maternal and Developmental Toxicity NOAEL = 720 (highest dose tested) Genetic Toxicity - Gene Mutation In vitro Positive Genetic Toxicity - Chromosomal Aberrations In vitro Negative Genetic Toxicity - Other Unscheduled DNA Synthesis Negative 9 ------- |