SCREENING-LEVEL HAZARD CHARACTERIZATION FOR HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL 1,4-Cyclohexanedimethanol (CAS No. 105-08-8) [9th CI Name: 1,4-Cyclohexanedimethanol] 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 1,4-Cyclohexanedimethanol (CAS No. 105-08-8) Introduction The sponsor, Eastman Chemical Company, submitted a Test Plan and Robust Summaries to EPA for 1,4-cyclohexanedimethanol (CAS No. 105-08-8; 9th CI name: 1,4-cyclohexanedimethanol) on June 12, 2002. EPA posted the submission on the ChemRTK HPV Challenge website on July 3, 2002 (http://www.epa.gov/oppt/chemrtk/pubs/summaries/14cYclo/cl3816tc.htm). EPA comments on the original submission were posted to the website on November 14, 2002. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on November 26, 2002, which were posted to the ChemRTK website on December 10, 2002. 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 enviromnental 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 log Kow of 1,4-cyclohexanedimethanol indicates that its potential to bioaccumulate is expected to be low. Adequate biodegradation data were not submitted for 1,4-cyclohexanedimethanol. The evaluation of toxicity data for freshwater fish, aquatic invertebrates and aquatic plants indicate that the potential hazard of 1,4-cyclohexanedimethanol to aquatic organisms is low. The acute oral toxicity of 1,4-cyclohexanedimethanol is low. Repeated exposures of rats to 1,4- cyclohenanedimethanol via drinking water resulted in mortality, bloody or brown/red discolored urine, softened and/or reduced feces, reductions in body weights and weight gains, decreased food consumption and increased urinary protein levels at high doses. In the reproductive and developmental toxicity in rats, clinical abnormalities were only observed in parental animals at high doses. No effects were noted in reproductive organs upon histological examination or on epididymal and testicular sperm counts. A biologically significant decrease in sperm motility was noted in males at the highest dose; however, there were no reductions in any of the fertility parameters or indices examined. Fetotoxicity (i.e., decreased pup weight and postnatal survival) was noted only in levels that induced significant maternal toxicity. No reproductive or developmental effects were noted in the two lower dose groups. No genotoxic effects of 1,4-cyclohexanedimethanol were observed when tested in Salmonella typhimurium and Saccharomvces cerevisiae. No significant increases in cells with chromosomal aberrations or polyploidy were observed in rat bone marrow cells. The potential health hazard of 1,4-cyclohexanedimethanol is low based on repeated-dose and reproductive/developmental toxicity. Ready biodegradation data remain a data gap under the HPV Challenge Program. 1. Physical-Chemical Properties and Environmental Fate A summary of physical-chemical properties and enviromnental 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. 3 ------- Octanol-Water Partition Coefficient LogKow: 1.5 (estimated) Biodegradation No data were submitted on the ready biodegradability of 1,4-cyclohexanedimethanol. Conclusion: The log Kow of 1,4-cyclohexanedimethanol indicates that its potential to bioaccumulate is expected to be low. Adequate biodegradation data were not submitted for 1,4-cyclohexanedimethanol. 2. Environmental Effects-Aquatic Toxicity Acute Toxicity to Fish Fathead minnows (Pimephalespromelas\ 14 total) were exposed to 125.3 mg/L (measured) of 1,4- cyclohexanedimethanol for 96 hours. No mortality was observed. 96-h LCS0 > 125.3 mg/L Acute Toxicity to Aquatic Invertebrates Daphnia magna (10 total) were exposed to nominal concentration of 100 mg/L 1,4-cyclohexanedimethanol for 96 hours under static conditions. No mortality was observed. 96-h LC50 > 100 mg/L Toxicity to Aquatic Plants Green algae (Pseudokirchneriella subcapitata) were exposed to 122.9 mg/L (geometric mean measured concentration) of 1,4-cyclohexanedimethanol for 72 hours. No inhibition of biomass or growth rate was observed. 72-h EC50 (biomass) > 122.9 mg/L 72-h EC50 (growth) > 122.9 mg/L Conclusion: The evaluation of toxicity data for freshwater fish, aquatic invertebrates and aquatic plants indicate that the potential hazard of 1,4-cyclohexanedimethanol to aquatic organisms is low. 3. Human Health Effects Acute Oral Toxicity Rats (10 used, not specified if per dose or total) were administered 1,4-cyclohexanedimethanol via oral gavage at doses of 400 - 6400 mg/kg-bw and were observed for 14 days. Animals appeared normal to very weak with prostration and vasodilatation. LD50 > 3200-6400 mg/kg-bw 4 ------- Repeated-Dose Toxicity Male (12/dose) and female (10/dose) Sprague-Dawley rats administered 1,4-cyclohexanedimethanol in their drinking water at concentrations of 0, 4.0, 8.0 or 12.5 mg/L for 13 weeks. The approximate dose levels achieved were 0, 256, 479 or 861 mg/kg-bw/day in males and 0, 440, 754 or 1754 mg/kg-bw/day in females. High-dose rats experienced decreased survival and had bloody or brown/red discolored urine, softened and/or reduced feces, reductions in body weights and weight gains, decreased feed consumption and increased urinary protein levels. No treatment-related effects were seen in animals receiving the mid- and low-dose levels. LOAEL (male) = 861 mg/kg-bw/day (based on decreased survival, abnormal urine and feces, reduced body weights and weight gains, decreased feed consumption and increased urinary protein levels) LOAEL (female) = 1754 mg/kg-bw/(based on decreased survival, abnormal urine and feces, reduced body weights and weight gains, decreased feed consumption and increased urinary protein levels) NOAEL (male) = 479 mg/kg-bw/day NOAEL (female) = 754 mg/kg-bw/day Reproductive/Developmental Toxicity Male and female Sprague-Dawley rats (12/sex/dose) were administered 1,4-cyclohexanedimethanol in their drinking water at concentrations of 0, 4.0, 8.0 or 12.5 mg/L during pre-mating (56 days), mating (up to 14 days), gestation (21-22 days), and early lactation (4 days). The approximate dose levels achieved were 0, 256, 479 and 861 mg/kg- bw/day in males and 0, 385, 854 and 1360 mg/kg-bw/day in females. One male and one female from the high dose group were euthanized in extremis during the pre-mating period. High-dose animals (gender not specified) exhibited bloody or discolored urine, reductions in body weights and weight gains and decreased feed consumption. These signs persisted through lactation in females. Decreased food consumption during lactation days 0-4 was observed in mid-dose females. No treatment-related effects were seen in organ weights harvested and histologically examined. There was no treatment-related effect on epididymal or testicular sperm counts. A decrease in sperm motility was noted in some males at the highest dose. This effect was not statistically significant, but was considered to be biologically significant. There were no reductions in any of the fertility parameters or indices examined. Biologically significant changes in litters were only noted in pups from high dose dams. These pups exhibited decreased body weights and weight gains as well as decreased postnatal survival between days 0 and 4. The incidence of pups with no or small amounts of milk in their stomachs, and pups that were either missing (presumably cannibalized) or found dead was also higher from dams exposed to higher doses. No treatment-related effects were noted in the two lower dose groups in the reproductive parameters assessed (reproductive performance, gestation length, pup survival rate, prenatal loss, number of implantation sites, number of live and dead pups, pup sex ration, body weights and weight gains). The fetotoxicity noted occurred at levels that induced significant maternal toxicity. LOAEL (systemic toxicity, male) = 861 mg/kg-bw/day (based on bloody or discolored urine, reductions in body weights and weight gains and decreased feed consumption) LOAEL (systemic toxicity, female) = 1360 mg/kg-bw/day (based on bloody or discolored urine, reductions in body weights and weight gains and decreased feed consumption) NOAEL (systemic toxicity, male) = 479 mg/kg-bw/day NOAEL (systemic toxicity, female) = 854 mg/kg-bw/day LOAEL (developmental toxicity) = 1360 mg/kg-bw/day (based on decreased fetal weight and postnatal survival) NOAEL (developmental toxicity) = 854 mg/kg-bw/day LOAEL (reproductive toxicity) > (highest dose tested) NOAEL (reproductive toxicity) = 1360 mg/kg-bw/day 5 ------- Genetic Toxicity - Gene Mutation In vitro In a mutagenicity test, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538, and Saccharomyces cerevisiae strain D4 were exposed, in the presence and absence of metabolic activation, to 1,4-cyclohexanedimethanol at 0.1, 1.0, 10, 100 or 500 (ig/plate (up to 1000 (ig/plate with activation). Positive and negative controls were used. Negative control was the test vehicle dimethylsulfoxide (DMSO). No positive responses were induced by the test material in any of the tester strains. The positive and negative control responses were not reported. 1,4-Cyclohexanedimethanol was not mutagenic in this assay. Genetic Toxicity - Chromosomal aberrations In vivo In a mammalian bone marrow chromosomal aberration test, male and female Sprague-Dawley rats (5/sex) were administered 1,4-cyclohexanedimethanol by oral gavage at doses of 0, 500, 1000 or 2000 mg/kg. Rats were exposed for 18 and 42 hours. Positive controls consisted of cyclophosphamide exposure. There were no mortalities and no clinical signs indicative of toxicity prior to sacrifice. No significant increases in cells with chromosomal aberrations or polyploidy were observed. Positive control findings were not reported. 1,4-Cyclohexanedimethanol did not induce chromosomal aberrations in this assay. Conclusion: The acute oral toxicity of 1,4-cyclohexanedimethanol is low. Repeated exposures of rats to 1,4- cyclohenanedimethanol via drinking water resulted in mortality, bloody or brown/red discolored urine, softened and/or reduced feces, reductions in body weights and weight gains, decreased food consumption and increased urinary protein levels at high doses. In the reproductive and developmental toxicity in rats, clinical abnormalities were only observed in parental animals at high doses. No effects were noted in reproductive organs upon histological examination or on epididymal and testicular sperm counts. A biologically significant decrease in sperm motility was noted in males at the highest dose; however, there were no reductions in any of the fertility parameters or indices examined. Fetotoxicity (i.e., decreased pup weight and postnatal survival) was noted only in levels that induced significant maternal toxicity. No reproductive or developmental effects were noted in the two lower dose groups. No genotoxic effects of 1,4-cyclohexanedimethanol were observed when tested in Salmonella typhimurium and Saccharomyces cerevisiae. No significant increases in cells with chromosomal aberrations or polyploidy were observed in rat bone marrow cells. The potential health hazard of 1,4-cyclohexanedimethanol is low based on repeated-dose and reproductive/developmental toxicity. 6 ------- 4. Hazard Characterization The log Kow of 1,4-cyclohexanedimethanol indicates that its potential to bioaccumulate is expected to be low. Adequate biodegradation data were not submitted for 1,4-cyclohexanedimethanol. The evaluation of toxicity data for freshwater fish, aquatic invertebrates and aquatic plants indicate that the potential hazard of 1,4-cyclohexanedimethanol to aquatic organisms is low. The acute oral toxicity of 1,4-cyclohexanedimethanol is low. Repeated exposures of rats to 1,4- cyclohenanedimethanol via drinking water resulted in mortality, bloody or brown/red discolored urine, softened and/or reduced feces, reductions in body weights and weight gains, decreased food consumption and increased urinary protein levels at high doses. In the reproductive and developmental toxicity in rats, clinical abnormalities were only observed in parental animals at high doses. No effects were noted in reproductive organs upon histological examination or on epididymal and testicular sperm counts. A biologically significant decrease in sperm motility was noted in males at the highest dose; however, there were no reductions in any of the fertility parameters or indices examined. Fetotoxicity (i.e., decreased pup weight and postnatal survival) was noted only in levels that induced significant maternal toxicity. No reproductive or developmental effects were noted in the two lower dose groups. No genotoxic effects of 1,4-cyclohexanedimethanol were observed when tested in Salmonella typhimurium and Saccharomyces cerevisiae. No significant increases in cells with chromosomal aberrations or polyploidy were observed in rat bone marrow cells. The potential health hazard of 1,4-cyclohexanedimethanol is low based on repeated-dose and reproductive/developmental toxicity. 5. Data Gaps Ready biodegradation data remain a data gap under the HPV Challenge Program. 7 ------- APPENDIX Summary Table of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 1,4-Cyclohexanedimethanol (105-08-8) H-0 / V N ' O-H Summary of Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) 41-61 Boiling Point (°C) 286 (cis-isomer) 283 (trans-isomer) Vapor Pressure (hPa at 25°C) 0.03 (extrapolated) Log K„w 1.5 (estimated) Water Solubility (mg/Lat 25°C)" 9.2 x 105 (a). 20°C Direct Photodegradation - Indirect (OH ) Photodegradation Half-life (t1/2) 6.1 h Stability in Water (Hydrolysis) (ti/2) < 1% hydrolyzed after 5 days Fugacity (Level III Model) Water (%) Sediment (%) Soil (%) Air (%) 38.3 < 1 61.5 < 1 Biodegradation at 28 days (%) Data Gap Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LC50 (mg/L) > 125.3 Aquatic Invertebrates 48-h EC50 (mg/L) > 100 Aquatic Plants 72-h EC50 (mg/L) (biomass) (growth) > 122.9 > 122.9 8 ------- Summary Tabic of the Screening Information Data Set as submitted under the U.S. HPV Challenge Program End points SPONSORED CHEMICAL 1,4-Cyclohexanedimethanol (105-08-8) Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) 3200-6400 Acute Dermal Toxicity LDS0 (mg/kg-bw) - Acute Inhalation Toxicity LC50 (mg/L) - Repeated-Dose Toxicity NOAEL/LOAEL (mg/kg-bw/day) NOAEL (male) = 479 LOAEL (male) = 861 NOAEL (female) = 754 LOAEL (female) = 1754 Reproductive Toxicity NOAEL/LOAEL (mg/kg-bw/day) NOAEL = 1360 LOAEL > 1360 Developmental Toxicity NOAEL/LOAEL (mg/kg-bw/day) NOAEL = 854 LOAEL = 1360 Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Gene Mutation In vivo _ Genetic Toxicity - Chromosomal Aberrations In vitro _ Genetic Toxicity - Chromosomal Aberrations In vivo Negative Additional Information - - indicates endpoint was not addressed for this chemical. 9 ------- |