SCREENING-LEVEL HAZARD CHARACTERIZATION FOR HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL 3-(Dodecylthio)propionic Acid, Neopentanetetrayl Ester (CAS No. 29598-76-3) CI Name: Propanoic Acid, 3-(dodecylthio)-, 2,2-bis[[3-(dodecylthio)-l- oxopropoxy]methyl]-l,3-propanediyl ester] 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 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 3-(Dodecylthio)propionic Acid, Neopentanetetrayl Ester (CAS No. 29598-76-3) Introduction The sponsor, Chemtura Corporation (formerly Crompton Corporation), submitted a Test Plan and Robust Summaries to EPA for 3-(dodecylthio)propionic acid, neopentanetetrayl ester (CAS No. 29598-76-3; 9th CI name: propanoic acid, 3-(dodecylthio)-, 2,2-bis[[3-(dodecylthio)-l-oxopropoxy]methyl]-l,3-propanediyl ester) on August 27, 2003. EPA posted the submission on the ChemRTK HPV Challenge Web site on October 2, 2003 (http://www.epa.gov/chemrtk/pubs/summaries/oxopropo/cl4713tc.htm). EPA comments were posted on the original submission on February 4, 2004. Public comments were also received and posted to the website. The sponsor submitted revised documents on March 18, 2004, which were posted to the ChemRTK website on June 30, 2004 and on November 10, 2006. 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. Summary-Conclusion The estimated log Kow value provided for 3-(dodccvlthio)propionic acid, neopentanetetrayl ester is inadequate, but does indicate the log Kow for this chemical is high (> 4). indicating that its potential to bioaccumulatc is expected to be high. 3-(Dodccyllhio)propionic acid, neopentanetetrayl ester is readily biodegradable, indicating that it does not have the potential to persist in the environment. The potential acute hazard of 3-(dodccvllhio)propionic acid, neopentanetetrayl ester to aquatic organisms is expected to be low. 3-(Dodccyllhio)propionic acid, neopentanetetrayl ester shows low acute oral toxicity to rats. Repeated exposure to this chemical via oral gavagc affected the heart (increased weight and histopathological changes), and enzyme levels (increased AST levels) in rats at all doses (ranging from 100 to 1000 mg/kg-bw/day). There was no reproductive or developmental toxicity observed in this study: specifically, no treatment-related effects on fertility, weight of pups, the number and survivability of pups or external abnormalities in live or dead pups. The submitted data indicate that this chemical docs not induce gene mutations and chromosome mutations. The potential health hazard of 3-(dodccylthio)propionic acid, neopentanetetrayl ester is moderate based on repeated- dose toxicity. No data gaps were identified under the HPV Challenge Program. 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 octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence, respectively. Octanol-Water Partition Coefficient Log Kow: 24.8 (estimated) 3 ------- The model used to estimate the Kow submitted (KOWWIN v. 1.66) has been demonstrated to be accurate in predicting log Kows between -4 and 10. The estimate for 3-(dodecylthio)propionic acid, neopentanetetrayl ester is outside this range, which indicates that the absolute value may not be accurate. Nonethless, it is reasonable to conclude that this prediction is indicative that the log Kow for this chemical is high (> 4). Biodegradation After 29 days, 72.43% of -(dodecylthio)propionic acid, neopentanetetrayl ester degraded in the ready biodegradation test using domestic sewage as inoculum. 3-(dodecylthio)propionic acid, neopentanetetrayl ester is readily biodegradable. Conclusion: The estimated log Kow value provided for 3-(dodecylthio)propionic acid, neopentanetetrayl ester is inadequate, but does indicate the log Kow for this chemical is high (> 4), indicating that its potential to bioaccumulate is expected to be high. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester is readily biodegradable, indicating that it does not have the potential to persist in the environment. 2. Environmental Effects - Aquatic Toxicity No measured data were submitted for aquatic toxicity. EPA did not recommend testing in its test plan comments because no aquatic toxicity is expected for this chemical at or below water saturation because of the very low estimated water solubility of the chemical (1.3 xlO"21 mg/L at 25°C; estimated by EPIWIN). Conclusion: The potential acute hazard of 3-(dodecylthio)propionic acid, neopentanetetrayl ester to aquatic organisms is expected to be low. 3. Human Health Effects Acute Toxicity Acute oral toxicity data show that 3-(dodecylthio)propionic acid, neopentanetetrayl ester has low toxicity to rats. Only limited details were provided for this study. LDS0 > 15,000 mg/kg-bw Repeated-Dose Toxicity In a combined repeated-dose/reproductive/developmental toxicity screening test, male and female rats were exposed to 3-(dodecylthio)propionic acid, neopentanetetrayl ester by oral gavage at 0, 100, 400 or 1000 mg/kg-bw/day (vehicle used is not mentioned in the robust summary). Males were dosed for a minimum of 4 weeks (2 weeks prior to mating, during mating and about 2 weeks following mating). Females were dosed for 2 weeks prior to mating, during mating, gestation and until postnatal day 4. Animals in a recovery group were observed for 14 days after treatment for reversibility, persistence or delayed occurrence of effects. Aspartate aminotransferase (AST) activity was increased in males at all dose groups and in females at 400 and 1000 mg/kg-bw/day. AST activity from the recovery group animals was comparable to the control group at the end of 14 day recovery period. Relative heart weights were increased in males at 400 and 1000 mg/kg-bw/day. Histopathological changes in the heart were observed in both males and females at all doses. Fibrosis in the hearts of the high-dose recovery group animals was observed after cessation of exposure; the severity of the fibrosis was less than that in the treatment groups. NOAEL = Not established LOAEL = 100 mg/kg-bw/day (based on histopathological changes in the heart in males and females and increased AST levels in males) 4 ------- Reproductive Toxicity In the combined repeated-dose/reproductive/developmental toxicity screening test in rats described previously, there were no treatment-related effects on gestation and lactation body weights and food consumption, number and weight of pups, survivability of pups or fertility indices. LOAEL > 1000 mg/kg-bw/day NOAEL = 1000 mg/kg-bw/day Developmental Toxicity In the combined repeated-dose/reproductive/developmental toxicity screening test in rats described previously , there were no treatment-related effects on pup mortality or observations of external abnormalities of live and dead pups at any of the treated doses. LOAEL > 1000 mg/kg-bw/day NOAEL = 1000 mg/kg-bw/day Genetic Toxicity - Gene Mutation In vitro A bacterial reverse mutation assay was conducted using Salmonella typhimurium strains TA 98, TA 100, TA 1535 and TA 1537 and Escherichia coli WP2 uvrA with and without metabolic activation and test substance concentrations from 50 to 5000 |ig/plate. The positive controls were included in the assay and gave an appropriate response. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester did not induce muatagenic activity in the presence or absence of metabolic activation. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester was not mutagenic in this assay. Genetic Toxicity - Chromosomal Aberration In vitro Cultured Chinese hamster ovary (CHO) cells were treated with 3-(Dodecylthio)propionic acid, neopentanetetrayl ester up to 5000 ng/mL in the presence and absence of metabolic activation. The positive controls were included in the test and gave an appropriate response. The test substance did not induce chromosomal aberrations. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester was not mutagenic in this assay. Conclusion: 3-(Dodecylthio)propionic acid, neopentanetetrayl ester shows low acute oral toxicity to rats. Repeated exposure to this chemical via oral gavage affected the heart (increased weight and histopathological changes), and enzyme levels (increased AST levels) in rats at all doses (ranging from 100 to 1000 mg/kg-bw/day). There was no reproductive or developmental toxicity observed in this study; specifically, no treatment-related effects on fertility, weight of pups, the number and survivability of pups or external abnormalities in live or dead pups. The submitted data indicate that this chemical does not induce gene mutations and chromosome mutations. The potential health hazard of 3-(dodecylthio)propionic acid, neopentanetetrayl ester is moderate based on observations of systemic effects in a repeated-dose toxicity test in experimental animals. 4. Hazard Characterization The estimated log Kow value provided for 3-(dodecylthio)propionic acid, neopentanetetrayl ester is inadequate, but does indicate the log Kow for this chemical is high (> 4), indicating that its potential to bioaccumulate is expected to be high. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester is readily biodegradable, indicating that it does not have the potential to persist in the environment. The potential acute hazard of 3-(dodecylthio)propionic acid, neopentanetetrayl ester to aquatic organisms is expected to be low. 3-(Dodecylthio)propionic acid, neopentanetetrayl ester shows low acute oral toxicity to rats. Repeated exposure to this chemical via oral gavage affected the heart (increased weight and histopathological changes), and enzyme levels 5 ------- (increased AST levels) in rats at all doses (ranging from 100 to 1000 mg/kg-bw/day). There was no reproductive or developmental toxicity observed in this study; specifically, no treatment-related effects on fertility, weight of pups, the number and survivability of pups or external abnormalities in live or dead pups. The submitted data indicate that this chemical does not induce gene mutations and chromosome mutations. The potential health hazard of 3-(dodecylthio)propionic acid, neopentanetetrayl ester is moderate based on repeated- dose toxicity. 5. Data Gaps No data gaps were identified under the HPV Challenge Program. 6 ------- APPENDIX Summary Tabic of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 3-(Dodccylthio)propionic acid, ncopcntanctctrayl ester (29598-76-3) Structure O 4 Summary of Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) 51.2 Boiling Point (°C) 352.2 Vapor Pressure (hPa at 25°C) 9><10"24 (estimated) Log K„w 24.8 (estimated) Water Solubility (mg/L at 25°C) 1.3 xlO"21 (estimated) Direct Photodegradation — Indirect (OH )Photodegradation Half-Life (ti/2) 0.9 h Stability in Water (Hydrolysis) Half-Life (tV2) > 1 year at pH 7 (estimated) 59.4 days at pH 8 (estimated) Biodegradation % Degradation in 28 days 72.43 (29-days) Readily biodegradable Fugacity (Level III Model) Air(%) Water(%) Soil (%) Sediment(%) 0.031 2.38 28.9 68.7 Summary of Environmental Effects - Aquatic Toxicity Data No measured data are available for aquatic toxicity and EPA did not recommend any testing in its test plan comments because no aquatic toxicity is expected for this chemical at or below its water solubility limit based on the submitted EPIWIN estimate (1.3 xlO"21 mg/L at 25°C). Fish 96-hr LCS0 (mg/L) N/A Aquatic Invertebrates 48-hr EC50 (mg/L) N/A Aquatic Plants 72-hr EC50 (mg/L) (growth) (biomass) N/A Chronic Toxicity Data N/A Summarv of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) > 15,000 Repeated-Dose Toxicity NOAEL/LOAEL (mg/L/day) LOAEL = 100 NOAEL = Not established Reproductive Toxicity NOAEL/LOAEL (mg/kg-bw/day) LOAEL > 1000 NOAEL = 1000 7 ------- Su mmary Tabic of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 3-(Dodccylthio)propionic acid, ncopcntanctctrayl ester (29598-76-3) Developmental Toxicity NOAEL/LOAEL (mg/kg-bw/day) LOAEL > 1000 NOAEL = 1000 Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Gene Mutation In vivo Genetic Toxicity - Chromosomal aberrations In vitro Negative Genetic Toxicity - Chromosomal aberrations In vivo Additional Information — 8 ------- |