SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2) [9th CI Name: Propanoic acid, 3,3'-thiobis-, dimethyl ester] SUPPORTING CHEMICAL Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4) [9th CI Name: Propanoic acid, 3,3'-thiobis-, didodecyl ester] 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 Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2) Introduction The sponsor, Crompton Corporation, submitted a Test Plan and Robust Summaries to EPA for dimethyl 3,3'- thiobispropionate (CAS No. 4131-74-2; 9th CI name: propanoic acid, 3,3'-thiobis-, dimethyl ester) on September 3, 2003. EPA posted the submission on the ChemRTK HPV Challenge Web site on September 30, 2003 (http://www.epa.gov/chemrtk/pubs/summaries/dimthiat/cl4711tc.htm'). EPA comments on the original submission were posted to the website on January 30, 2004. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on March 18, 2004, which were posted to the ChemRTK website on June 30, 2004. 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. Justification for Supporting Chemical Data for didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4) have been used to address health effects endpoints for dimethyl 3,3'-thiobispropionate. Both compounds are esters of thiodipropionic acid (TDPA). The submitted toxicokinetics data show that these esters are completely absorbed and hydrolyzed to a common metabolite, TDPA, which is further hydrolyzed and rapidly eliminated in the urine. The toxicity of both esters will essentially be the toxicity of TDPA. EPA agrees that the use of data for didodecyl 3,3 '-thiodipropionate is appropriate. Sum man-Conclusion The log k of dimollis I V ^'-ihiohispropioualc mdicales dial lis potential to hioaccuniulale is expected to he low. I lie potential of dinielhs I V ^'-ihiohispropioualc to persist mi the en\ irounieui eainiol he e\aliialed because llie biodegradalioii endpoiiii remains a data gap The potential lia/ard of dinielhs I V ^'-ihiohispropioualc to aquatic organisms cannot he e\ aluated because lo\icil> data for fish, aquatic iu\ ertehrales and aquatic plants were inadequate \ll three aquatic lo\icil> endpoints remain as data gaps I'orthe human health eiidpoiuts. oiils data on the supporting chemical ididodccsl V ^'-thiodipropioualei are a\ ailahle. I lie acute oral lo\icil> of didodecs I V ^'-ihiodipropiouale m rats and mice is low Repeated onil e\posure ofdidodecs I V ^'-thiodipropiouale to rats lor I ' weeks resulted in niicroseopic lesions at the high dose siiggestne of imocardilis (small loci of degeuei.iled or necrotic libers associated w illi minimal to moderate mononuclear cell infiltration) Changes mi cluneal chcmisirs and uriuaKsis parameters were also seen at the high- dose (increase iu serum cholesterol mi females, increased serum alanine and aspartate aminotransferase acli\ Hies and decreased miliars pi I mi hotli se\esi \ll changes were re\ersihle altera 4 week reco\er\ period \o data for reproduce e lo\icil> w ere submitted, how e\ er. no effects on the reproduce e organs w ere ohser\ ed m the repeated- dose loMcils studs I)e\ elopnieiital lo\icil> studies conducted iu rats. mice, rahhilsaud hamsters showed no ireainieui-relaled effects on the number of implantations, maternal and lelal sur\ i\ al and the number of \ i see nil or skeletal abnormalities I)idodcc> I v ^'-ihiodipropioualc did not induce gcuc mutations hi bacteria iu \ itro. chromosomal aberrations or dominant lethal effects mi \ i\ o I lie potential health lia/ard of dinielhs I V ^'-ihiobispropiouale is low Data gaps for the biodegradatiou. acute lo\icil> to fish, aquatic iii\ ertebrales and lo\icil> to aquatic plants endpoints were identified under the I IPX" Challenge I'rograni 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: 0.98 (estimated) Biodegradation Data gap. Conclusion: The log Kow of dimethyl 3,3'-thiobispropionate indicates that its potential to bioaccumulate is expected to be low. The potential of dimethyl 3,3'-thiobispropionate to persist in the environment cannot be evaluated because the biodegradation endpoint remains a data gap. 2. Environmental Effects - Aquatic Toxicity The submitted data were inadequate to address the aquatic toxicity endpoints because the sponsor only provided estimated data from ECOSAR. For the purposes of the HPV Challenge Program, the sponsor needs to provide measured data on the subject chemical or predicted SAR values plus measured data on the supporting chemical. These data were not provided as part of the revised submission. Acute Toxicity to Fish Data gap Acute Toxicity to Aquatic Invertebrates Data gap Toxicity to Aquatic Plants Data gap Conclusion: The potential hazard of dimethyl 3,3'-thiobispropionate to aquatic organisms cannot be evaluated because toxicity data for fish, aquatic invertebrates and aquatic plants were inadequate. All three aquatic toxicity endpoints remain as data gaps. 3. Human Health Effects Acute Oral Toxicity Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) (1) Rats (5 or 10, sex and strain not specified) were administered didodecyl 3,3'-thiodipropionate in olive oil via gavage at 2000 or 2500 mg/kg-bw and observed for 7 days. No deaths were observed. LD 5o > 2500 mg/kg-bw 4 ------- (2) Rats (10 - 12 males/dose, strain not specified) were administered didodecyl 3,3'-thiodipropionate in saline via gavage at 50, 500 or 5000 mg/kg-bw and observed for 5 days. All animals survived until necropsy on day 6 and appeared normal. No gross morphological changes were observed. LD so > 5000 mg/kg-bw (3) Mice (19, 10, 20, 20, sex and strain not specified) were administered didodecyl 3,3'-thiodipropionate in olive oil via gavage at doses of 300, 500, 1000 or 2000 mg/kg-bw, respectively and observed for 1 week. There were 4, 0, 0 and 1 deaths at 300, 500, 1000 and 2000 mg/kg-bw, respectively. LD 5o > 2000 mg/kg-bw Repeated-Dose Toxicity Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) Sprague-Dawley rats (10/sex/dose) were administered didodecyl 3,3'-thiodipropionate in 1% carboxymethyl cellulose via gavage at 0, 125, 350 or 1000 mg/kg-bw/day for 13 weeks, followed by a 4-week recovery period. No mortality occurred and no clinical signs of toxicity were observed. No treatment-related effects on food consumption, body weight, ophthalmological examination, hematology parameters or organ weights were seen. Findings noted at 1000 mg/kg-bw/day included a minor increase in serum cholesterol concentrations in females and increased serum alanine and aspartate aminotransferase activities and decreased urinary pH in both sexes. Gross pathology findings were considered to be incidental or unrelated to treatment. Microscopic lesions in the heart suggestive of myocarditis were described as small foci of degenerated or necrotic fibers associated with minimal to moderate mononuclear cell infiltration. All changes were reversible after 4 weeks recovery period. No treatment- related findings were seen at 125 or 350 mg/kg-bw/day. LOAEL = 1000 mg/kg-bw/day (based on histopathological lesions of the heart) NOAEL = 350 mg/kg-bw/day Reproductive Toxicity No data for reproductive toxicity were submitted. Evaluation of effects on reproductive organs from the 13-week repeated-dose toxicity study, a dominant lethal assay and the developmental toxicity study adequately addresses the reproductive toxicity endpoint for the purposes of the HPV Challenge Program. Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) (1) In the repeated-dose toxicity study in rats described previously, reproductive organs that were examined histologically included the epididymides, mammary glands, ovaries, prostate, seminal vesicles, testes and uterus (horn + cervix). No macroscopic or microscopic changes in the reproductive organs were observed at any dose- level. (2)) Rats (10 males/dose) were administered didodecyl 3,3'-thiodipropionate via gavage at 50, 500 or 5000 mg/kg- bw/day for 5 days. Following treatment, each rat was sequentially mated with two females per week for 8 weeks. Females were sacrificed 14 days after separation from the male and the uterus was examined for early deaths, late fetal deaths and total implantations. There was no clear pattern of either increases or decreases between the control and treatment groups at any dose in any of the parameters studied. Positive and negative controls were tested concurrently; however, the results were not provided. Didodecyl 3,3'-thiodipropionate did not induce dominant lethal effects in this assay. Developmental Toxicity Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) (1) Pregnant Wistar rats (19 - 21/dose) were administered didodecyl 3,3'-thiodipropionate (in corn oil) via gavage at 16, 74, 350 or 1600 mg/kg-bw/day on days 6 - 15 of gestation. Caesarian sections were performed on day 20 of gestation. No adverse effects were found with respect to implantations, maternal and fetal survival and visceral or skeletal abnormalities. A positive control group was treated with 250 mg/kg-bw of aspirin; however, the results were not provided. NOAEL (maternal and developmental toxicity) = 1600 mg/kg-bw/day (based on no effects at the highest dose tested) 5 ------- (2) Pregnant female CD-I mice (20 - 22/dose) were administered didodecyl 3,3'-thiodipropionate in corn oil via gavage at 16, 74, 350 or 1600 mg/kg-bw/day on days 6 - 15 of gestation. Caesarian sections were performed on day 17 of gestation. No adverse effects were found with respect to implantations, maternal and fetal survival and visceral or skeletal abnormalities. A positive control group was treated with 150 mg/kg-bw of aspirin; however, the results were not provided. NOAEL (maternal and developmental toxicity) = 1600 mg/kg-bw/day (based on no effects at the highest dose tested) (3) Pregnant female Dutch rabbits (15 - 29/dose) were administered didodecyl 3,3'-thiodipropionate in corn oil via gavage at 2.5, 10, 45, 216 or 1000 mg/kg-bw/day on days 6 - 18 of gestation. The number of pregnant rabbits at the end of the study ranged from 8 - 13/dose, all of which survived to term. Caesarian sections were performed on day 29 of gestation. There were no clear treatment-related effects on the number of implantations, maternal and fetal survival and visceral or skeletal abnormalities. NOAEL (maternal and developmental toxicity) = 1000 mg/kg-bw/day (based on no effects at the highest dose tested) (4) Pregnant female Golden hamsters (20 - 23/dose) were administered didodecyl 3,3'-thiodipropionate in corn oil via gavage at 16, 74, 350 or 1600 mg/kg-bw/day on days 6 - 10 of gestation. Caesarian sections were performed on day 14 of gestation. The numbers of implantations and maternal and fetal survival were not adversely affected at any dose and visceral or skeletal tissue changes were comparable to the sham controls. NOAEL (maternal and developmental toxicity) = 1600 mg/kg-bw/day (based on no effects at the highest dose tested) Genetic Toxicity - Gene Mutation In vitro Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) Salmonella typhimurium strains TA1535, TA1537, TA1538 and TA98 and Escherichia coli strain WP2 were exposed to didodecyl 3,3'-thiodipropionate at 33.3, 100, 333, 2500, 3333, 5000, 6667 or 10,000 (ig/plate and ,V. typhimurium strain TA100 was exposed to 3.3 or 10 (ig/plate, all in the presence and absence of metabolic activation. Positive controls were tested concurrently; however, the results were not provided. A precipitate was observed at the two highest doses. No evidence of mutagenic activity was noted at any dose either in the presence or absence of metabolic activation. Didodecyl 3,3'-thiodipropionate was not mutagenic in this assay. Genetic Toxicity - Chromosomal Aberrations Didodecyl 3,3'-thiodipropionate (CAS No. 123-28-4, Supporting Chemical) In vivo (1) Albino rats (five males/dose) were administered didodecyl 3,3'-thiodipropionate via gavage at 50, 500 or 5000 mg/kg-bw and sacrificed 6, 24 or 48 hours after dosing. Positive and negative controls were tested concurrently; however, the results were not provided. No chromosomal aberrations were observed and mitotic indices were normal. Didodecyl 3,3'-thiodipropionate did not induce chromosomal aberrations in this assay. (2) Rats (10 males/dose) were administered didodecyl 3,3'-thiodipropionate via gavage at 50, 500 or 5000 mg/kg- bw/day for 5 days. Following treatment, each rat was sequentially mated with two females per week for 8 weeks. Females were sacrificed 14 days after separation from the male and the uterus was examined for early deaths, late fetal deaths and total implantations. There was no clear pattern of either increases or decreases between the control and treatment groups at any dose in any of the parameters studied. Positive and negative controls were tested concurrently; however, the results were not provided. Didodecyl 3,3'-thiodipropionate did not induce dominant lethal effects in this assay. 6 ------- Conclusion: For the human health endpoints, only data on the supporting chemical (didodecyl 3,3 '- thiodipropionate) are available. The acute oral toxicity of didodecyl 3,3'-thiodipropionate in rats and mice is low. Repeated oral exposure of didodecyl 3,3'-thiodipropionate to rats for 13 weeks resulted in microscopic lesions at the high dose suggestive of myocarditis (small foci of degenerated or necrotic fibers associated with minimal to moderate mononuclear cell infiltration). Changes in clinical chemistry and urinalysis parameters were also seen at the highest dose (increase in serum cholesterol in females, increased serum alanine and aspartate aminotransferase activities and decreased urinary pH in both sexes). All clinical chemistry changes were reversible after a 4 week recovery period. No data for reproductive toxicity were submitted; however, no effects on the reproductive organs were observed in the repeated-dose toxicity study. Developmental toxicity studies conducted in rats, mice, rabbits and hamsters showed no treatment-related effects on the number of implantations, maternal and fetal survival and the number of visceral or skeletal abnormalities. Didodecyl 3,3'-thiodipropionate did not induce gene mutations in bacteria in vitro, chromosomal aberrations or dominant lethal effects in vivo. The potential health hazard of dimethyl 3,3'-thiobispropionate is low. 4. Hazard Characterization The log Kow of dimethyl 3,3'-thiobispropionate indicates that its potential to bioaccumulate is expected to be low. The potential of dimethyl 3,3 '-thiobispropionate to persist in the environment cannot be evaluated because the biodegradation endpoint remains a data gap. The potential hazard of dimethyl 3,3 '-thiobispropionate to aquatic organisms cannot be evaluated because toxicity data for fish, aquatic invertebrates and aquatic plants were inadequate. All three aquatic toxicity endpoints remain as data gaps. For the human health endpoints, only data on the supporting chemical (didodecyl 3,3 '-thiodipropionate) are available. The acute oral toxicity of didodecyl 3,3'-thiodipropionate in rats and mice is low. Repeated oral exposure of didodecyl 3,3'-thiodipropionate to rats for 13 weeks resulted in microscopic lesions at the high dose suggestive of myocarditis (small foci of degenerated or necrotic fibers associated with minimal to moderate mononuclear cell infiltration). Changes in clinical chemistry and urinalysis parameters were also seen at the high- dose (increase in serum cholesterol in females, increased serum alanine and aspartate aminotransferase activities and decreased urinary pH in both sexes). All changes were reversible after a 4 week recovery period. No data for reproductive toxicity were submitted; however, no effects on the reproductive organs were observed in the repeated- dose toxicity study. Developmental toxicity studies conducted in rats, mice, rabbits and hamsters showed no treatment-related effects on the number of implantations, maternal and fetal survival and the number of visceral or skeletal abnormalities. Didodecyl 3,3'-thiodipropionate did not induce gene mutations in bacteria in vitro, chromosomal aberrations or dominant lethal effects in vivo. The potential health hazard of dimethyl 3,3'-thiobispropionate is low. 5. Data Gaps Data gaps for the biodegradation, acute toxicity to fish, aquatic invertebrates and toxicity to aquatic plants endpoints were identified under the HPV Challenge Program. 7 ------- APPENDIX Summary Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL Dimethyl 3,3'-thiobispropionatc (4131-74-2) SUPPORTING CHEMICAL Didodccyl 3,3'-thiodipropionatc (123-28-4) Structure 0 0 Summary of Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) Liquid at room temperature. - Boiling Point (°C) 130 °C (2.67 hPa) - 148 °C (24 hPa) - Vapor Pressure (hPa at 25°C) Log K„w 0.98 (estimated) - Indirect (OH) Photodegradation Half-life (t1/2) 6.2 h (estimated) _ Stability in Water (Hydrolysis) (ti/2) 1.02 y (estimated atpH 7), 37.14 d (estimated at pH 8) - Fugacity (Level III Model) Air (%) Water (%) Soil (%) Sediment (%) 0.01 42 57.9 0.0757 - Biodegradation at 28 days (%) Data gap. - Summary of Environmental Effects-Aquatic Toxicity Data Fish 96-h LCS0 (mg/L) Data gap. _ Aquatic Invertebrates 48-h EC50 (mg/L) Data gap. _ Aquatic Plants 72-h ECS0 (mg/L) (growth) (biomass) Data gap. - 8 ------- Summarv Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL Dimethyl 3,3'-thiobispropionate (4131-74-2) SUPPORTING CHEMICAL Didodecyl 3,3'-thiodipropionatc (123-28-4) Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) >2000 Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) - NOAEL = 350 I.OAF.I. = 1000 Reproductive Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) - No effects were seen on reproductive organs in the repeated-dose toxicity study in rats. Developmental Toxicity NOAEL/LOAL Oral (mg/kg-bw/day) Maternal and Developmental Toxicity - (rat) NOAEL = 1600 (hdt) (mouse) NOAEL = 1600 (hdt) (rabbit) NOAEL = 1000 (hdt) (hamster) NOAEL = 1600 (hdt) Genetic Toxicity - Gene Mutation In vitro - Negative Genetic Toxicity - Chromosomal Aberrations In vitro Negative Genetic Toxicity - Chromosomal Aberrations In vivo - Negative - Indicates that endpoint was not addressed for this chemical, hdt = highest dose tested 9 ------- |