SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL Allyl Alcohol (CAS No. 107-18-6) [9th CI Name: 2-Propen-l-ol] August 2007 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 1,400 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 Allyl Alcohol (CAS No. 107-18-6) Introduction The sponsor, Lyondell Chemical Company, submitted a Test Plan and Robust Summaries to EPA for Allyl Alcohol (CAS No. 107-18-6; 9th CI name: 2-propen-l-ol) dated December 18, 2003. EPA posted the submission on the ChemRTK HPV Challenge Website on January 23, 2004 (http://www.epa.gov/chemrtk/pubs/summaries/alYlalhl/cl4921tc.htm'). EPA comments were posted on June 29, 2004. Public comments were also received and posted to the website. The sponsor responded by submitting revised documents dated October 11, 2004 and June 16, 2005, which were subsequently posted to the ChemRTK HPV Challenge Website. 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 toxicity is based largely on SIDS endpoints and is described according to established EPA or OECD effect level definitions and hazard assessment practices. Sum m an-Conclusion The log k of alls I alcohol indicates that lis potential lo hioacciiniiilate is expected lo he low \ 11\ I alcohol is readils biodegradable, indicating llial il does noi ha\e lhe poieniial lo persist in ihe en\ iroiinieiit The es ahialion of as ailahlc Iomciis dala lor fish. aquatic 11in crtchrales and aqnalic plants indicates that the potential acute ha/ard of alls I alcohol to aquatic organisms is high \11\ I alcohol is nioderalels Iomc lo rats \ ia oral and inhalation routes follow nig an acute exposure Repeated oral exposure lo alls I alcohol caused reduced water and lood consumption, urine concentration ahilits. decreased hods weight, and increased absolute and relatis e kidnes and stomach weight Repeated inhalation exposure resulted in gasping, sesere depression, nasal discharge, ese irritation and corneal opaeits Similar signs were noted at low doses hut were less intense (hod> weight gams were statistical^ sigmlieantls decreased and relatis e weights ol' liser. Inngs. and kidnes were increased) Microscopicalls. hemorrhagic liser. pale and spotted lungs and congestion of lis er and Inngs s\ ere seen \lls alcohol affected estrns cs ele in female rats in the reprodnetis e loxicils studs and increased post-implantation losses in the deselopniental loxicils studs In viini niiiiagemeils studies indicate alls I alcohol has mutagenic potential, although the results of/'// viva niiitageiiieits studies were negatise The potential health ha/ard of alls I alcohol is moderate hased on repeated-dose and reprodnetis e deselopniental tO.XICIt.S \o data gaps were identified under the I IPX" ( hallenge I'rograni I losses er. hased on conflicting results of the in viini and in viva niiiiagemeils testing, the negatise in viva dala are not sufficient to alles late a concern of seseral positis e in viini studies Speeiliealls. niieertaiiits in the dominant lethal test is associated s\ nh the loss doses and the route of administration Therefore, the gciioio\ic potential of alls I alcohol remains ineoiieliisis e 1. Physical-Chemical Properties and Environmental Fate A summary of physical-chemical properties 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 was limited to the 3 ------- octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence, respectively. Octanol-Water Partition Coefficient LogKow: 0.17 (measured) Biodegradation In an aerobic biodegradation study using activated sludge was used as inoculum, allyl alcohol degraded 82-86% in 14 days. Allyl alcohol is readily biodegradable. Conclusion: The log Kow of allyl alcohol indicates that its potential to bioaccumulate is expected to be low. Allyl alcohol is readily biodegradable, indicating that it does not have the potential to persist in the environment. 2. Environmental Effects - Aquatic Toxicity Acute Toxicity to Fish (1) Fathead minnows (Pimephales promelas; 10/concentration) were exposed to allyl alcohol at nominal concentrations of 0, 0.1, 1, 10 or 100 mg/L for 96 hours under static conditions. 96-h LCso=0.32 mg/L (2) Medaka (Oryzias latipes) were exposed to allyl alcohol under at nominal concentrations of 0, 0.32, 0.56, 0.68, 0.82 and 1.0 mg/L for 96 hours under semi-static conditions. 96-h LC50 = 0.589 mg/L Acute Toxicity to Aquatic Invertebrates (1) Daphnia magna (5/concentration) were exposed to allyl alcohol at nominal concentrations of 0, 0.33, 0.65, 1.3, 2.5, 5.0 and 10 mg/L for 96 hours under static conditions. Measured mean test concentrations were < 0.040, 0.373, 0.516, 1.06, 2.58, 4.85 and 10.5 mg/L. After 48 hours of exposure, immobility was 0, 0, 0, 0, 100, 100 and 100% in the 0, 0.33, 0.65, 1.3, 2.5, 5.0 and 10 mg/L treatments, respectively. Quiescence was observed in the 2.5 and 5.0 mg allyl alcohol/L treatments at 24 hours. No other sub lethal effects were observed during the exposure. 24-h ECS0 = 3.7 mg/L 48-h ECS0 = 1.8 mg/L (2) In two trials, Daphnia magna were exposed to allyl alcohol at measured concentrations of 0, 0.1, 1, 10 or 100 mg/L for 96 hours under static conditions. 96-h ECS0 = 0.25 - 0.40 mg/L (2) Polychaetes (Ophryotrocha diadema) were exposed to allyl alcohol at a half-logarithmic series of nominal concentrations for 48 hours exposed under static conditions. Actual concentrations tested were not provided in the robust summary. 48-h ECS0 = 0.33 - 1.0 mg/L Toxicity to Aquatic Plants (1) Green algae (Pseudokirchneriella subcapitata) were exposed to allyl alcohol at nominal concentrations of 0, 0.65, 1.3, 2.5, 5.0 and 10 mg/L for 72 hours. Measured mean test concentrations were 0.040, 0.343, 0.930, 2.41, 6.03 and 9.12 mg/L. 72-h EC50 (biomass) = 2.25 mg/L 72-h EC50 (growth) = 5.38 mg/L 4 ------- (2) Green algae (Pseudokirchneriella subcapitata) were exposed to allyl alcohol at measured concentrations of 0, 0.20, 0.46, 0.94, 2.1, 4.4 and 9.7 mg/L for 72 hours under static conditions. 48-h EC50 (growth) = 11 mg/L 48-h EC50 (biomass) = 11 mg/L (3) Green algae (Pseudokirchneriella subcapitata) were exposed to allyl alcohol at measured concentrations of 0, 1.4, 3.0, 5.8, 12.0, 22.2 and 42.2 mg/L for 72 hours. 72-h EC50 (growth) = 7.80 mg/L 72-h EC50 (biomass) = 2.58 mg/L Chronic Toxicity to Aquatic Invertebrates In a 21-day chronic study, Daphnia magna wee exposed to nominal concentrations of 0.046, 0.10, 0.22, 0.46, 1.0, and 2.2 mg/L under semi-static conditions. Measured concentrations were 0.031, 0.091, 0.210, 0.436, 0.919 and 2.02 mg/L. All of the organisms exposed to the highest concentration died. 21-d NOEC = 0.919 mg/L Conclusion: The evaluation of available toxicity data for allyl alcohol indicates that the acute hazard to fish is high and hazard to aquatic invertebrates and aquatic plants is moderate. 3. Human Health Effects Acute Oral Toxicity (1) Osborne-Mendel rats (5/sex/dose) were administered a 2% aqueous solution of allyl alcohol via oral gavage and observed for 14 days. Clinical signs included depression, colorless secretion from eyes, diarrhea and unkempt appearance. LDS0 = 70 mg/kg-bw (2) Male Long-Evans rats (5 total) were administered graded amounts of a 1% aqueous solution of allyl alcohol via oral gavage (doses reported as 75-130 and 79-140 mg/kg bw) and observed for 10 days. LDS0 = 99 - 105 mg/kg-bw (3) Male Swiss-Webster mice (6 total) were administered graded amounts of a 1% aqueous solution of allyl alcohol via oral gavage and observed for 10 days. LDS0 = 96 mg/kg-bw Acute Inhalation Toxicity Male Long-Evans rats (6/dose) were administered allyl alcohol vapor at 40 - 2300 ppm (equivalent to 95-5450 mg/m3) and observed for 10 days. Coma and diarrhea preceded death in moribund animals. Pathology revealed hepatic and renal lesions related to exposure to allyl alcohol. Lesions were also present in animals surviving the 10- day observation period. 4-h LCS0 = 125 - 140 ppm (0.295 - 0.33 mg/L) Acute Dermal Toxicity Male albino rabbits (3/treatment) were administered allyl alcohol to the surface of the skin at 25 - 200 mg/kg-bw and observed for 10 days. Clinical signs reported were apathy and flushing of the skin; however, ataxia and diarrhea preceded death in some animals. LDS0 = 89 mg/kg-bw 5 ------- Repeated-Dose Toxicity (1) Male and female rats were exposed to allyl alcohol via drinking water at 50, 100, 200 or 800 ppm (approximately 4.8, 8.3, 14.0 or 48.2 mg/kg-bw/day for male and 6.2, 6.9, 17.1 or 58.4 mg/kg-bw/day for female rats) for 15 weeks. Statistically significant decreases in water intake and urine concentrating ability were seen and were dose-dependent. Decreases in body weight and food consumption were also observed. Significant increases in absolute and relative kidney and relative stomach weights were seen at 100 ppm and above. LOAEL (male) = 8.3 mg/kg-bw/day (based on significant reduction in growth and reduced renal function) LOAEL (female) = 6.9 mg/kg-bw/day (based on significant increase in kidney weight) NOAEL (male) = 4.8 mg/kg-bw/day NOAEL (females) = 6.2 mg/kg-bw/day (2) Male rats were exposed via inhalation (whole body) to allyl alcohol at 1, 5, 20, 40, 60, 100 or 150 ppm (2.4, 4.7, 12, 47, 95, 142, 237 or 355 mg/m3), 7 hours/day, 5 days/week for 12 weeks. Mortality was seen in three high-dose groups. Clinical signs at the high dose included gasping, severe depression, nasal discharge, eye irritation and corneal opacity. Similar but less intense signs were observed at the 40-100 ppm doses. Statistically significant (p < 0.05) decreases in body weight gains were observed at 20 ppm and above. Relative weights of liver, lungs and kidney were increased at 40 ppm and above. At 150 ppm, hemorrhagic liver and pale and spotted lungs were seen macroscopically and congestion of liver and lungs was observed following microscopic examination. At 100, 60 and 40 ppm, similar, but less intense, lesions and microscopic findings were observed. LOAEL = 20 ppm (approximately 47 mg/m3 or 0.047 mg/L) (based on statistically significant reduction in growth) NOAEL = 5 ppm (approximately 12 mg/m3 or 0.012 mg/L) Reproductive/Developmental Toxicity In a combined reproductive/developmental toxicity screening test, Sprague-Dawley rats were administered allyl alcohol via gavage at dose levels were 2, 8 or 40 mg/kg-bw/day. Exposure durations were 42 days for males and 14 days prior to mating through 3 days of lactation for females. Reproductive effects, extension of mean estrous cycle length and increase in irregular estrous cycle, were seen in females at 40 mg/kg-bw/day. No adverse effects were seen on the other reproductive parameters. In offspring, a decrease in viability index on day 4 and eventually all pups in the litter died at 40 mg/kg-bw/day. No morphological abnormalities were seen. LOAEL = 40 mg/kg-bw/day (based on parental toxicity and reproductive/developmental toxicity) NOAEL = 8 mg/kg-bw/day Developmental Toxicity Pregnant female Sprague-Dawley rats were administered allyl alcohol via oral gavage at 0, 10, 35 or 50 mg/kg- bw/day on gestation days 9-19. Maternal toxicity occurred in dams that received > 10 mg/kg-bw/day, effects included hepatic toxicity in all treatment groups and mortality in rats receiving the highest doses. An increase in post-implantation loss was reported in rats receiving 35 and 50 mg/kg-bw/day. No morphological abnormalities were seen in offspring. LOAEL (maternal toxicity) = 10 mg/kg-bw/day (based on liver effects) NOAEL (maternal toxicity) = Not established LOAEL (developmental toxicity) = 35 mg/kg-be/day (based on increase in post-implantation loss) NOAEL (developmental toxicity = 10 mg/kg-bw/day Genetic Toxicity - Gene Mutation In vitro In several in vitro studies provided in the submission (including both bacterial and mammalian cells), four out of six tests gave generally positive results. The weight-of-evidence indicates allyl alcohol produces positive results for this endpoint. Allyl alcohol was mutagenic in these assays. 6 ------- Genetic Toxicity - Chromosomal Aberrations In vitro and In vivo The in vitro study in human lymphocytes was positive with a significant increase in the number of aberrant cells in the exposed cells in comparison with the solvent control. However, in vivo tests for chromosome mutations (rat bone marrow and mouse erythrocyte micronuclei) were negative. An in vivo dominant lethal assay in male rats produced negative results. Allyl alcohol was mutagenic in some of these assays. Additional Information Metabolism In a metabolism study, male rats were pretreated with either saline or pyrazole (alcohol dehydrogenase inhibitor) prior to administration of 14C-ally alcohol (all intra-peritoneal exposure routes). Animals were sacrificed at 6, 8 or 24 hours post treatment and samples of liver, lung and kidney were harvested for microscopic examination. In the liver, periportal necrosis was present 24 hours post-treatment and no microscopic changes were visible in lungs or kidney tissue. Animals pretreated with pyrazole (alcohol dehydrogenase inhibitor) did not show signs of hepatic necrosis, approximately 80% decrease inbound radiolabel to the liver, autoradiograms confirmed 14C-ally alcohol was markedly reduced in periportal hepatocytes. Covalent binding in the lung was also reduced in pretreated animals and kidneys remained unaffected in both pretreated and saline-treated animals. Conclusion: Allyl alcohol is moderately toxic to rats via oral and inhalation routes following an acute exposure. Repeated oral exposure to allyl alcohol caused reduced water and food consumption, urine concentration ability, decreased body weight, and increased absolute and relative kidney and stomach weight. Repeated inhalation exposure resulted in gasping, severe depression, nasal discharge, eye irritation and corneal opacity. Similar signs were noted at low doses but were less intense (body weight gains were statistically significantly decreased and relative weights of liver, lungs, and kidney were increased). Microscopically, hemorrhagic liver, pale and spotted lungs and congestion of liver and lungs were seen. Ally alcohol affected estrus cycle in female rats in the reproductive toxicity study and increased post-implantation losses in the developmental toxicity study. In vitro mutagenicity studies indicate allyl alcohol has mutagenic potential, although the results of in vivo mutagenicity studies were negative. The potential health hazard of allyl alcohol is moderate based on repeated-dose and reproductive/developmental toxicity. 4. Hazard Characterization The log Kow of allyl alcohol indicates that its potential to bioaccumulate is expected to be low. Allyl alcohol is readily biodegradable, indicating that it does not have the potential to persist in the environment. The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates that the potential acute hazard of allyl alcohol to aquatic organisms is high. Allyl alcohol is moderately toxic to rats via oral and inhalation routes following an acute exposure. Repeated oral exposure to allyl alcohol caused reduced water and food consumption, urine concentration ability, decreased body weight, and increased absolute and relative kidney and stomach weight. Repeated inhalation exposure resulted in gasping, severe depression, nasal discharge, eye irritation and corneal opacity. Similar signs were noted at low doses but were less intense (body weight gains were statistically significantly decreased and relative weights of liver, lungs, and kidney were increased). Microscopically, hemorrhagic liver, pale and spotted lungs and congestion of liver and lungs were seen. Ally alcohol affected estrus cycle in female rats in the reproductive toxicity study and increased post-implantation losses in the developmental toxicity study. In vitro mutagenicity studies indicate allyl alcohol has mutagenic potential, although the results of in vivo mutagenicity studies were negative. The potential health hazard of allyl alcohol is moderate based on repeated-dose and reproductive/developmental toxicity. 7 ------- 5. Data Gaps No data gaps were identified under the HPV Challenge Program. However, conflicting results were obtained in the in vitro and in vivo mutagenicity tests. The negative in vivo data are not sufficient to alleviate a concern of several positive in vitro studies; specifically, the low doses tested and the route of administration are limitations associated with the dominant lethal test are highly uncertain. Therefore, the genotoxic potential of allyl alcohol remains inconclusive. 8 ------- APPENDIX Summary Tabic of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program E ml points Sponsored Chemical Allvl alcohol (107-18-6) Structure /-\i I Summary (if Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) -129 Boiling Point (°C) 97 Vapor Pressure (hPa at 25°C) 31.3 Log Kow 0.17 Water Solubility (mg/L at 25°C) 1000 g/L Direct Photodegradation 39% in 2 hours Indirect (OH ) Photodegradation Half-life (t1/2) 2-22 hours Stability in Water (Hydrolysis) Half-life (t1/2) Stable in water, allyl alcohol lacks functional groups subject to hydrolysis Fugacity (Level III Model) Air (%) Water(%) Soil (%) Sediment (%) 0.977 47.7 51.2 0.0885 Biodegradation at 28 days (%) 82-86 Readily biodegradable Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LCS0 (mg/L) 0.32-0.589 Aquatic Invertebrates 48-h ECS0 (mg/L) 1.8 Aquatic Plants 72-h EC50 (mg/L) (biomass) (growth) 2.25-2.58 5.38-7.8 Chronic Toxicity to Invertebrates 21-day NOEC, (mg/L) 0.919 Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) 70 Acute Dermal Toxicity LDS0 (mg/kg-bw) 89 Acute Inhalation Toxicity LC50 (mg/L) 0.295 - 0.330 mg/L (4-h) 9 ------- Summary Tabic of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program End points Sponsored Chemical Allvl alcohol (107-18-6) Repeated-Dose Toxicity NOAEL/LOAEL (mg/kg-bw/day) Oral (drinking water) NOAEL = 4.8; LOAEL = 8.3 (male) NOAEL = 6.2; LOAEL = 6.9 (female) Inhalation: NOAEL = 5 ppm (approx. 0.012 mg/L) LOAEL = 20 ppm (approx. 0.047 mg/L) Reproductive Toxicity NOAEL/LOAEL (mg/kg-bw/day) LOAEL = 40 NOAEL = 8 Developmental Toxicity NOAEL/LOAEL (mg/kg-bw/day) (maternal toxicity) (developmental toxicity) LOAEL = 10 NOAEL= Not established LOAEL = 35 NOAEL = 10 Genetic Toxicity - Gene Mutation In vitro Positive Genetic Toxicity -Gene Mutation In vivo Negative Genetic Toxicity - Chromosomal Aberrations In vitro Positive Genetic Toxicity - Chromosomal Aberrations In vivo Negative Additional Information - Metabolism Available Other Information Allyl alcohol is a priority chemical on Acute Exposure Guideline Levels (AEGL) list. An AEGL 2 (severe health hazard) has been established at 4.2 ppm for 60 min exposure. 10 ------- |