U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 SCREENING-LEVEL HAZARD CHARACTERIZATION Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester (CASRN 1115-20-4) The High Production Volume (HPV) Challenge Program 1 was conceived as 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 sponsored chemicals; sponsorship entailed the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data did 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 Setl1'2) 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 by developing hazard characterizations (HCs). These HCs consist of an evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. They are not intended to be definitive statements regarding the possibility of unreasonable risk of injury to health or the environment. The evaluation is performed according to established EPA guidance2'3 and is based primarily on hazard data provided by sponsors; however, 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. In order to determine whether any new hazard information was developed since the time of the HPV submission, a search of the following databases was made from one year prior to the date of the HPV Challenge submission to the present: (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.), Science Direct and ECHA4. OPPT's focus on these specific sources is based on their being of high quality, highly relevant to hazard characterization, and publicly available. OPPT does not develop HCs for those HPV chemicals which have already been assessed internationally through the HPV program of the Organization for Economic Cooperation and Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment 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. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 4 European Chemicals Agency, http://echa.europa.eu. ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are presented in an international forum that involves review and endorsement by governmental authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening-level hazard assessments. These hazard characterizations are technical documents intended to inform 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. 2 ------- Chemical Abstract Service Registry Number (CASRN) 1115-20-4 Chemical Abstract Index Name Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester Structural Formula o HO CH, O OH CH, CH, '3 '3 SMILES: Q=C(OCC(CO)(C)C)C(CO)(C)C Summary Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is a low melting solid with moderate vapor pressure and high water solubility. It is expected to have high mobility in soil. It has been shown to be readily biodegradable in one OECD guideline ready test and inherently biodegradable in a second OECD test. Volatilization is expected to be low. The rate of hydrolysis is considered negligible. The rate of atmospheric photooxidation is moderate. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is expected to have low persistence (PI) and low bioaccumulation potential (Bl). The acute oral toxicity of propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester in rats is low. The acute inhalation toxicity of propanoic acid, 3-hydroxy- 2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester in rats was not determined because the concentration tested was too low. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester did not induce gene mutation in bacteria in vitro. Propanoic acid, 3- hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is irritating to rabbit eyes. For propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester, the 96-h LCso for fish is 3160 mg/L, the 48-h ECso for aquatic invertebrates is > 500 mg/L and the 72-h ECso for toxicity to aquatic plants is 3170 mg/L and 1600 mg/L for growth rate and biomass, respectively. The repeated-dose, reproductive and developmental toxicity, and chromosomal aberrations endpoints were identified as data gaps under the HPV Challenge Program. ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 The sponsor, BASF Corporation, submitted a Test Plan and Robust Summaries to EPA for propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester (CASRN 1115- 20-4) dated November 28, 2006. EPA posted the submission on the ChemRTK HPV Challenge website on January 19, 2007 (http://www.epa.gov/chemrtk/pubs/summaries/prpacd3h/cl6470tc.htm). Revised robust summaries were submitted to EPA on December 28, 2006, and posted to the website on April 27, 2009. EPA comments on the original submission were posted to the website on June 4, 2009. Public comments were also received and posted to the website. Justification for Supporting Chemicals The sponsor proposed using data from two supporting chemicals: neopentyl glycol (CASRN 126-30-7), a metabolite of the sponsored substance, and isobutyl isobutyrate (CASRN 97-85-8), a structural analog of the sponsored substance. The use of data for neopentyl glycol is not supported because the test plan provides no data to show whether hydrolysis of the sponsored substance to neopentyl glycol occurs, and whether or not it occurs rapidly. The use of data for isobutyl isobutyrate is not supported because there are three major structural differences between isobutyl isobutyrate and the sponsored substance that are not adequately addressed in the test plan: (1) the presence of quaternary carbon atoms in the sponsored substance but not isobutyl isobutyrate; (2) a higher degree of steric crowding in the sponsored substance than in isobutyl isobutyrate; and (3) two hydroxy groups in the sponsored substance but none in isobutyl isobutyrate. Therefore, data submitted by the sponsor for neopentyl glycol and isobutyl isobutyrate are not used as supporting chemicals for this hazard characterization. 1. Chemical Identity 1.1 Identification and Purity Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is a low melting solid with moderate vapor pressure and high water solubility. It is used as an intermediate in the manufacture of binding agents and coatings. It is also used as a monomer in the manufacture of polymers. Purity is given in the test plan as generally greater or equal to 97.5%. 1.2 Physical-Chemical Properties The physical-chemical properties of CASRN 1115-20-4 are summarized in Table 1. Table 1. Physical-Chemical Properties of Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester 1 Property Value CASRN 1115-20-4 Molecular Weight 204.27 Physical State Solid Melting Point 48-54.9°C (measured) 4 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 1. Physical-Chemical Properties of Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester 1 Property Value Boiling Point 283.2°C (measured) Vapor Pressure 0.75 mm Hg at 115.17°C (measured); 0.0060 mm Hg at 25°C (estimated)2 Dissociation Constant Not applicable Henry's Law Constant 1.7xl0"9atm-m3/mol (estimated)3 Water Solubility 270,000 mg/L at 25°C (measured) Log Kow 0.858 (measured) 'BASF Corporation. 2009. Test Plan Revision updates for Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy- 2,2-dimethylpropyl ester. Available online at http://www.epa.gov/chemrtk/pubs/summaries/prpacd3h/cl6470tc.htm as of August 8, 2012. 2N0M05. 1987. PC-Nomograph- Programs to Enhance PC-Gems Estimates of Physical Properties for Organic Chemicals. Version 2.0. The Mitre Corp. 3U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of August 8, 2012. 2. General Information on Exposure 2.1 Production Volume and Use Pattern Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester had an aggregated production and/or import volume in the United States between 1 and 10 million pounds during calendar year 2005. Non-confidential information in the IUR indicated that the industrial processing and uses of the chemical include resin and synthetic rubber manufacturing as intermediates; and the information not readily obtainable (NRO). No commercial and consumer uses were reported for the chemical. 2.2 Environmental Exposure and Fate Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is expected to have high mobility in soil. It was readily biodegradable, degrading 99% after 21 days as measured by dissolved organic carbon (DOC) removal using activated sludge in a DOC Die Away test (OECD TG 301 A). It was also shown to be inherently biodegradable using mixed liquor suspended solids (MLSS) from a waste water treatment facility as inoculum in a Modified Zahn-Wellens test (OECD TG 302B). However, it only achieved 5% of its theoretical biochemical oxygen demand (BOD) after 28 days using an activated sludge inoculum in a MITI test (OECD TG 301C). The rate of volatilization is considered low based on the Henry's Law constant for this substance. The hydrolysis half-life of propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester was estimated as >10 years under environmental conditions. 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 The rate of atmospheric photooxidation is moderate. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is expected to have low persistence (PI) and low bioaccumulation potential (Bl). The environmental fate properties of Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester are provided in Table 2. Table 2. Environmental Fate Properties of Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester 1 Property Value CASRN 1115-20-4 Photodegradation Half-life 11.8 hours (estimated)2 Hydrolysis Half-life 11.3 years at pH 8 (estimated)2 Biodegradation 99% after 21 days (readily biodegradable, OECD 301 A); 100% after 28 days (inherently biodegradable, OECD 302B); 5% after 28 days (not readily biodegradable, OECD 301C)3 Bioaccumulation Factor BAF =1.0 (estimated)2 Log Koc 1.0 (estimated)2 Fugacity (Level III Model)2 Air (%) Water (%) Soil (%) Sediment (%) <0.1 30.7 69.2 <0.1 Persistence4 PI (low) Bi oaccumul ati on4 Bl (low) 'BASF Corporation. 2009. Test Plan Revision updates for Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy- 2,2-dimethylpropyl ester. Available online at http://www.epa.gov/chemrtk/pubs/summaries/prpacd3h/cl6470tc.htm as of August 8, 2012. 2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of August 8, 2012. 3 National Institute of Technology and Evaluation. Chemical Risk Information Platform (CHRIP) database. Searchable by CASRN online at http://www.safe.nite.go.ip/english/db.html as of August 15, 2012. 4Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. Conclusion: Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is a low melting solid with moderate vapor pressure and high water solubility. It is expected to have high mobility in soil. It has been shown to be readily biodegradable in one OECD guideline ready test and inherently biodegradable in a second OECD test. Volatilization is expected to be low. The rate of hydrolysis is considered negligible. The rate of atmospheric photooxidation is moderate. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is expected to have low persistence (PI) and low bioaccumulation potential (Bl). 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 3. Human Health Hazard A summary of health effects data for SIDS and other endpoints is provided in Table 3. Acute Oral Toxicity Sprague-Dawley rats (5/sex/dose) were administered propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester (100% purity) via oral gavage at 4640 or 10,000 mg/kg and observed for 7 days following dosing. One of five female rats died at 4640 mg/kg and 4/5 females and 3/5 males died at 10,000 mg/kg. LDso = 8000 mg/kg Acute Inhalation Toxicity Twelve Sprague-Dawley rats (both sexes; number per sex not specified) were exposed via inhalation to a saturated atmosphere of propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester (100% purity) at an estimated concentration of 0.04 mg/L for 8 hours and were observed for 7 days following exposure. No mortalities were observed. 8-hour LC50 > 0.04 mg/L Repeated-Dose, Reproductive and Developmental Toxicity No adequate data were available. Genetic Toxicity — Gene Mutation In vitro Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester at concentrations of 4, 20, 100, 500 or 2500 |ig/plate with and without metabolic activation. Positive and negative controls were included, and responded appropriately. No cytotoxicity were noted at any dose including the highest concentration tested. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy- 2,2-dimethylpropyl ester did not induce gene mutation with or without activation. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester was not mutagenic in this assay. Genetic Toxicity — Chromosomal Aberrations No adequate data were available. 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Additional Information Eye Irritation Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester (0.05 mL, 100 % purity) was instilled into the conjunctival sac of one eye of each of two male rabbits (strain not specified) and eye reactions were examined for up to 8 days post-instillation. Moderate reddening, edema and corneal opacity developed > one hour, and persisted throughout the post- instillation observation period. The eye reactions were not expected to be reversible. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester was irritating to rabbit eyes in this study. Conclusion: The acute oral toxicity of propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester in rats is low. The acute inhalation toxicity of propanoic acid, 3-hydroxy- 2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester in rats was not determined because the concentration tested was too low. Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester did not induce gene mutation in bacteria in vitro. Propanoic acid, 3- hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester is irritating to rabbit eyes. Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Human Health Data Endpoints Propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester (1115-20-4) Acute Oral Toxicity LDso (mg/kg) 8000 Acute Inhalation Toxicity 8-h LC50 (mg/L) >0.04 Repeated-Dose Toxicity NOAEL/LOAEL (mg/kg-day) No Data Reproductive Toxicity NOAEL/LOAEL (mg/kg-day) No Data Developmental Toxicity NOAEL/LOAEL (mg/kg-day) No Data Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Chromosomal Aberrations In vivo No Data Additional Information Eye Irritation Positive Measured data in bold 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 4. Hazard to the Environment A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4. Acute Toxicity to Fish (1)Fathead minnow (Pimephalespromelas; ten fish per replicate, two replicates per test concentration) were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester for 96 hours under static conditions. Nominal concentrations were 0, 95.0, 171.5, 308.5, 555.5 and 1000.0 mg/L. Corresponding measured concentrations were 97.1, 176.3, 307.8, 586.4 and 1023.9 mg/L for the first series; 99.5, 179.1, 323.5, 546.0 and 1030.9 mg/L for the second series. Water quality parameters were the following: Hardness and total alkalinity (both as CaCCb) were 120 mg/L and 92 mg/L, respectively, pH = 7.3 - 8.2 and DO = 7.0 -9.0 mg/L. No mortalities or sub-lethal effects were observed during the study. 96-h LCso > 1024 mg/L (2) Golden orfe (Leuciscus idus) were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester for 96 hours under conditions according to the German Industrial Standard DIN 38412, Part 15 and OECD TG 203. Nominal concentrations were 0, 1,000, 2,150, 4,640, 10,000 and 10,000 (neutralized) mg/L. Sub-lethal effects observed were tumbling at the 2,150 mg/1 treatment group from 24 - 96 hours and narcosis at 1 hour in the 4,460 mg/L treatment group. pH = 5.7 - 7.9, DO = 7.5 - 8.5 mg/L and temp. = 20 °C throughout the study. 96-h LCso =3160 mg/L Acute Toxicity to Aquatic Invertebrates (1)Water fleas (Daphnia magna) were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3- hydroxy-2,2-dimethylpropyl ester (ten organism per treatment; purity at ~ 98.4 %) for 48 hours under static conditions to nominal concentrations of 0, 95.0, 171.5, 308.5, 555.5 and 1000.0 mg/L. Measured concentrations were 96.0, 175.8, 290.3, 568.5 and 1125.8 mg/L for the first series; 98.0, 173.3, 342.6, 559.6 and 1048.8 mg/L for the second series. In the first experiment, 1/10 daphnids exposed to 1125.8 mg/L were immobile at 24 hours. 1/10 exposed to 175.8 mg/L and 1/10 exposed to 1125.8 mg/L were immobile at 48 hours. In the second experiment, 1/10 daphnids exposed to 173.3 mg/L, 1/10 exposed to 342.6 mg/L and 2/10 exposed to 1048.8 mg/L were immobile at 48 hours. Water quality parameters were the following: hardness and total alkalinity (both as CaC03) during the study were 120 mg/L and 92 mg/L, respectively. The pH and dissolved O2 concentration ranged from 8.0 - 8.3 and 8.3 - 9.0 mg/L, respectively. Temperature remained at 20 ± 2°C throughout the test. 48-h ECso > 560 mg/L (2) Water fleas (Daphnia magna; 20 animals per concentration) were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester for 48 hours under static conditions to nominal concentrations of 0, 7.81, 15.6, 31.2, 62.5, 125, 250, and 500 mg/L. pH = 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 7.61-8.14, DO = 8.3 - 8.7 mg/L, temp. = 19 °C. Immobility was observed in the 15.6 mg/L treatment group at 24 and 48 hours (1/20), and in the 500 mg/L treatment group at 24 and 48 hours (2/20). 48-h ECso > 500 mg/L Toxicity to Aquatic Plants Green algae (Desmodesmus subspicatus; four replicates per test concentrations, 8 replicates per control) were exposed to propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2- dimethylpropyl ester for 72 hours under static conditions. Nominal concentrations were 0, 200, 400, 800, 1,600, 3,200, and 6,400 mg/L. Algae were exposed under constant illumination of 10,000 lux and pH = 7.9 - 9.6. 72-h EbCso = 1600 mg/L 72-h ErCso = 3170 mg/L Conclusion: For propanoic acid, 3-hydroxy-2,2-dimethyl-, 3-hydroxy-2,2-dimethylpropyl ester, the 96-h LC50 for fish is 3160 mg/L, the 48-h EC50 for aquatic invertebrates is > 500 mg/L and the 72-h EC50 for toxicity to aquatic plants is 3170 mg/L and 1600 mg/L for growth rate and biomass, respectively. Table 4. Summary of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Aquatic Toxicity Data Endpoint Propanoic Acid, 3-Hydroxy-2,2-Dimethyl-, 3-Hydroxy- 2,2-Dimethylpropyl Ester (1115-20-4) Fish 96-h LCso (mg/L) 3160 Aquatic Invertebrates 48-h ECso (mg/L) >560 Aquatic Plants 72-h ECso growth rate (mg/L) biomass (mg/L) 3170 1600 Bold = measured data (ie, derived from testing) 10 ------- |